Oral Controlled Release Drug

Delivery Systems (OCRDDS) :

recent trends & future challenges

RAJEEV S. RAGHUVANSHI
Ph.D.
5th Oct07, Mumbai
R&D

NDDS CURRENT GLOBL BUSINESS SCENARIO

TRANSDERMAL
12.3%

OCULAR & BUCCAL

0.59%
NASAL
7.1 %
ORAL
51.8%

TRANSMUCOSAL
26.3%

LIPOSOMES
1.5%

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INJECTABLES
8%

PULMONARY
18.5%

NDDS - INNOVATION THEME

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

FUTURE
4 ONCE-A-DAY + Value Addition
9 Safety profile improvement
9 Better therapeutic efficacy
9 Better tolerability
NDDS A tool for product life cycle management

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BLOOD PROFILES
Controlled Release vs. Immediate Release

30
3rd dose

2nd dose

25
Blood Conc.

Side Effects
4th dose

1st dose

20
15

Effective Therapy

10
Ineffective Level

5
IR
CR

0
0

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10 12 14 16 18Hrs.

Schematic of dissolution
from different types of delivery systems

100

%Drug Dissolved

80

60

40

IR
ER

20

DR

0
0

10

12

Time (h)

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14

16

18

20

22

24

Schematic of plasma profiles

from different types of delivery systems

Plasma Concentration (ng/mL)

50

IR
ER

40

DR
30

20

10

0
0

10

12

Time (h)

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14

16

18

20

22

24

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
(swelling)

Drug Diffusion

Soluble matrix
erosion
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Smooth &
continuous
release for
extended
time

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.

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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
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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.

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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 druglayered 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
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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.
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Recent Trends: Multiparticulate technology

CODOS ( Chrono Oral Drug Absorption System)
Products in market: Verelan
Drug core coated
with CR polymers
for timed release

Filled in the capsule

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

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Case studies 1

Human Clinical Study Goal:

Refn: Sandimmune
Test: LEDDS Cyclosporine

Study Design:
8 male volunteers
Cross-over

Mean Concentration (ng/ml)

Recent Trends : LEDDS Technology

700
600
500
400
300
200
100

Results:
Safe/Effective
Bioavailability
Rate of Uptake

Case study 2

12
Time

Sand immune

16

20

24

LEDDS Cyclosporine

400
350

Determine LEDDS dose to achieve reference

bioequivalence

Anticipated results:

300
250

130mg Vs. 200mg

Bioequivalence at 65% (35% Less Active)

200
150
100
50
0
0

Sandimmune (200mg)

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12
Time

16

20

LEDDS Cyclosporine (130mg)

24

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, paminobenzoic 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

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Recent Trends : Gastro-Retentive Drug Delivery

Size-increasing drug delivery system

Systems unfolding in the stomach:

Systems unfolding in the stomach:

e.g., Tetrahedron-shaped drug delivery system
formed by assembling two components: silastic
corners and erodible arms.

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Gastric retention of a highly swellable, gastroretentive drug delivery system

A) The device significantly swells on contact with gastric fluids (to a few hundred times of the original
volume); B D) the gastric contraction pushes the hydrogel to the pylorus; E) the gastric contraction
slips over the surface of the hydrogel; and F) the hydrogel is pushed back into the body of the stomach.

Recent Trends : Gastro-Retentive Drug Delivery

Density controlled drug delivery system

9Floating system
Inherent low density
Low density due to swelling
Low density due to gas formation and entrapment

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Recent Trends: OROS Technology (ALZA corporation)

ELEMENTARY OSMOTIC PUMP

Single layer tablet: Drug

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 waterinsoluble 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

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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

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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

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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

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OCRS Approvals Post - 2006

Product

Drug

Company

Approval date

Technology

CLARINEX-D 12
HOUR tablets

Desloratadine (2.5 mg) +

Pseudoephedrine sulfate
(120 mg)

Schering

February 01,
2006

Bilayer tablets
(Desloratidine as IR
and Pseudoephedrine
as ER)

OPANA ER
tablets

Oxymorphone HCl
(5/10/20/40 mg)

Endo

June 22, 2006

Matrix tablets

COREG CR
capsules

Carvedilol phosphate
(10/20/40/80 mg)

SB Pharmco

October 20,
2006

Multiparticulates

Paliperidone (3/6/9 mg)

Janssen

December 19,
2006

OROS

Cyclobenzaprine
hydrochloride (15/30 mg)

ECR

February 01,
2007

Multiparticulates

Quetiapine fumarate
(50/200/300/400 mg)

Astrazeneca

May 17, 2007

Matrix tablets

Zileuton 600 mg

Critical

May 30, 2007

Matrix tablets

Trospium chloride 60 mg

Indevus

August 03,
2007

INVEGA tablets
AMRIX ER
capsules
SEROQUEL XR
tablets
ZYFLO CR
tablets
SANCTURA XR
tablets

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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 +

metformin HCl)

GSK

Phase III

Gepirone ER

GSK

Phase III

Rosiglitazone XR

GSK

Phase III

Coreg CR + ACE inhibitor

GSK

Phase III

Depomed

Phase III

Gabapentin GR

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THANK YOU

R&D