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
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
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 18Hrs.

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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.

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 Recent Trends : Extended release formulation of Bupropion

¾ Bupropion is used in the treatment of major depressive disorder.

¾ Conventional formulation has to be administered 3 times daily

¾ Initially 150 mg ER formulation was introduced for bid regimen

¾ Later on 300 mg ER formulation was introduced for once daily regimen

¾ 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 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
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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

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
¾ Controlled
¾ Sustained
¾ Pulsatile
• Format flexibility

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 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)

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 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

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 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.

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 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)

• 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

¾ Indicated for the treatment of attention Deficit Hyperactivity Disorder (ADHD)

¾ Immediate-release overcoat provides a rapid onset of action (1-2 hours).
¾ Controlled release of methylphenidate in the morning hours helps avoid the
troughs seen with immediate-release products.
¾ 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

¾ Low density microspheres with bioadhesive coats
¾ Moderately swelling matrix systems
¾ Bioadhesives
¾ 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

¾ Solid dispersions
¾ Nanocrystals and nanoparticles
¾ Polymeric micelles
¾ 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

¾ Modified enteric coating
¾ Biodegradable swellable polymers
¾ pH-controlled systems
¾ 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 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
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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 + 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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