Presentation_ Oral Controlled Release Drug

8/9/2019 Presentation_ Oral Controlled Release Drug

1/38

R&DR&D

Oral Controlled Release Drug

Delivery Systems (OCRDDS) :recent trends & future challenges

RAJEEV S. RAGHUVANSHIPh.D.5 th Oct07, Mumbai


2/38

R&DR&D

NDDS CURRENT GLOBL BUSINESS SCENARIO

TRANSMUCOSAL26.3%

LIPOSOMES1.5%

INJECTABLES8%

TRANSDERMAL12.3%

ORAL51.8%

NASAL7.1 %

OCULAR & BUCCAL0.59%

PULMONARY18.5%


3/38

R&DR&D

NDDS - INNOVATION THEME

PRESENT

ONCE-A-DAY : A WAY OF LIFE

Greater consumer awarenessDemand for a Quality life

FUTURE4 ONCE-A-DAY + Value Addition

Safety profile improvement

Better therapeutic efficacyBetter tolerability

NDDS A tool for product life cycle management


4/38

R&DR&D

0

5

10

15

20

25

30

0 2 4 6 8 10 12 14 16 18

B l o o

d C o n c .

IRCR

BLOOD PROFILESControlled Release vs. Immediate Release

1st dose

2nd dose 3rd dose

4th dose

Hrs.

Side Effects

Effective Therapy

Ineffective Level


5/38

R&DR&D

0

20

40

60

80

100

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

Time (h)

% D r u g

D i s s o

l v e

IR

ER

DR

Schematic of dissolutionfrom different types of delivery systems


6/38

R&DR&D

0

10

20

30

40

50

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

Time (h)

P l a s m a

C o n c e n t r a

t i o n

( n g

/ m L )

IR

ER

DR

Schematic of plasma profilesfrom different types of delivery systems


7/38

R&DR&D

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


8/38


9/38

R&DR&D

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.


10/38

R&DR&D

Recent Trends : Extended release form ulation 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.


11/38

R&DR&D

Recent Trends : Extended release form ulation of Bupropion


12/38

R&DR&D

-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, ensuring100% release

Products in market:

Cordicant -uno

Madopar DR

SULAR ER

Recent trends: Geomatrix (SKY Parma)


13/38

R&DR&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.


14/38

R&DR&D

Recent Trends : Multiparticulate drug delivery system

Polymeric membrane layer

Drug Layer

Inert core

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


15/38

R&DR&D

Carvedilol ER Innovator Coreg CR TM (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 forthe oral administration of small molecule drugs.

COREG CR hard gelatin capsules are filled with carvedilol phosphateimmediate-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


16/38

R&DR&D

Carvedilol ER

- Technology consist of 5000- 10000 microparticles per capsule.

- 200-500 micron particles released in stomach, and pass into smallintestine, where each microparticle release drug by osmotic pressureat adjustable rate over an extended period.


17/38

R&DR&D

Recent Trends: Multiparticulate technology

CODOS ( Chrono Oral Drug Absorption System)

Drug core coatedwith CR polymersfor 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

Products in market: Verelan


18/38

R&DR&D

METOPROLOL PORT SYSTEM


19/38

R&DR&D

Recent Trends : LEDDS Technology

Liquid and Emulsion Drug Delivery System (LEDDS)

Enabling Oral Controlled Release Liquids/Emulsions/Suspensions

Customise drug release profile

ControlledSustainedPulsatile

Format flexibility


20/38

R&DR&D

0

100

200

300

400

500

600

700

0 4 8 12 16 20 24Time

Sand immune LEDDS Cyclosporine

M e a n

C o n c e n

t r a

t i o n

( n g

/ m l )Case studies 1

Human Clinical Study Goal: Refn: Sandimmune Test: LEDDS Cyclosporine

Study Design:

8 male volunteers Cross-over

Results: Safe/Effective Bioavailability Rate of Uptake

Case study 2

Determine LEDDS dose to achieve referencebioequivalence

Anticipated results:

130mg Vs. 200mg

Bioequivalence at 65% (35% Less Active)

0

50

100

150

200

250

300

350

400

0 4 8 12 16 20 24Time

Sandimmune (200mg) LEDDS Cyclosporine (130mg)



21/38

R&DR&D

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



22/38

R&DR&D

Need for gastro-retentive drug deliveryA 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

Recent Trends : Gastro-Retentive Drug Delivery


23/38

R&DR&D

Size-increasing drug delivery systemSystems unfolding in the stomach: 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 originalvolume); B D) the gastric contraction pushes the hydrogel to the pylorus; E) the gastric contractionslips over the surface of the hydrogel; and F) the hydrogel is pushed back into the body of the stomach.

Systems unfolding in the stomach:e.g., Tetrahedron-shaped drug delivery systemformed by assembling two components: silasticcorners and erodible arms.



24/38

R&DR&D

Density controlled drug delivery systemFloating system

Inherent low density

Low density due to swelling Low density due to gas formation and entrapment



25/38

R&DR&D

Single layer tablet: Drugcore (water soluble drugwith or without excipients)

Semipermeable membranewith a drilled orifice

Water imbibition by the corebecause of osmotic actionresults in drug dissolution,

which is released at acontrolled rate through theorifice

Not suitable for water-insoluble drugs

Examples: Sudafed 24hours (Pseudoephedrine);Volmax (Salbutamol)

ELEMENTARY OSMOTIC PUMP

Recent Trends: OROS Technology (ALZA corporation)


26/38

R&DR&D

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)


27/38

R&DR&D

Extended release formulation of M ethylphenidate

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.


28/38

R&DR&D

Extended release formulation of M ethylphenidate


29/38

R&DR&D

Challenges in Oral Drug Delivery

(A) Oral: easily administered formulations

(B) Stomach: gastric retention platforms

(C) Intestine: formulations for improvedabsorption of poorly soluble drugs andhigh molecular weight drugs

(D) Colon: colon targeted drug deliverysystems


30/38

R&DR&D

(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



31/38

R&DR&D

(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 platformsLow density microspheres with bioadhesive coatsModerately swelling matrix systems

BioadhesivesSuperswelling hydrogel systems



32/38

R&DR&D

(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 solubilitySolid dispersions

Nanocrystals and nanoparticles

Polymeric micelles

Self emulsifying systems



33/38

R&DR&D

(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 coatingBiodegradable swellable polymers

pH-controlled systems

Time delayed systems



34/38

R&DR&D

GI PHYSIOLOGY

WINDOW OF ABSORPTION SPATIAL DELIVERY

ORAL DELIVERY OF MACROMOLECULES

COST LOW PERMEABILITY DRUGS (BCS III / IV)



35/38

R&DR&D

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


36/38

R&DR&D

OCRS Approvals Post - 2006

MultiparticulatesOctober 20,2006

SB PharmcoCarvedilol phosphate(10/20/40/80 mg)

COREG CRcapsules

MultiparticulatesFebruary 01,2007

ECRCyclobenzaprinehydrochloride (15/30 mg)

AMRIX ERcapsules

August 03,2007

IndevusTrospium chloride 60 mgSANCTURA XRtablets

Matrix tabletsMay 30, 2007CriticalZileuton 600 mgZYFLO CRtablets

Matrix tabletsMay 17, 2007AstrazenecaQuetiapine fumarate

(50/200/300/400 mg)

SEROQUEL XR

tablets

OROSDecember 19,2006JanssenPaliperidone (3/6/9 mg)INVEGA tablets

Matrix tabletsJune 22, 2006EndoOxymorphone HCl(5/10/20/40 mg)

OPANA ERtablets

Bilayer tablets(Desloratidine as IR

and Pseudoephedrineas ER)

February 01,2006

ScheringDesloratadine (2.5 mg) +Pseudoephedrine sulfate

(120 mg)

CLARINEX-D 12HOUR tablets

TechnologyApproval dateCompanyDrugProduct


37/38

R&DR&D

OCRS under development/filed post 2006

NDA FiledGSKRequip ER (Ropinirole)

NDA filedAstellasTacrolimus MR

Approved in EU/Out licensedin US

J&JJurnista tablets (OROS Hydromorphone)

ApprovableGSKLamictal XR tablets (Lamotrigine)

ApprovableWyethPristiq (Desvenlafaxine succinate ER)

Phase IIIGSKGepirone ER

Phase IIIGSKCoreg CR + ACE inhibitor

Phase IIIDepomedGabapentin GR

Phase IIIGSKRosiglitazone XR

Phase IIIGSKAvandamet XR (Rosiglitazone maleate +metformin HCl)

Development stageCompanyProduct


38/38

R&DR&D

THANK YOU

Documents

Presentation_ Oral Controlled Release Drug