Gastroretentive Drug Delivery Systems

(GRDDS)
Overview...
• I. Need for Gastroretention

• II. Physiological Challenges

• III. Delivery Approaches

– Altered density products
– Expandable swelling systems
– Bioadhesive particulate carriers

• IV. Bioadhesive GRDDS

• V. Future Trends
I. Why Gastroretention?
– Oral Route: ‘the safest’

– More than 50% of pharmaceutical products are orally

administered.

Limitations:

– Variability in solubility/permeability characteristics →

incomplete absorption.

– Variability in site of absorption → incomplete absorption.

– Limited GI residence → poor bioavailability.

Gastro retention… a viable, but challenging alternative!

Drugs incorporated into GRDDS:

Drugs with narrow absorption window:

• Acyclovir, Alendronate, Atenolol, Captopril,

Cinnarizine, Ciprofloxacin, Cisapride, Furosemide,
Ganciclovir, Glipizide, Ketoprofen, Levodopa,
Melatonin, Metformin, Minocyclin, Misoprostol,
Nicardipine, Riboflavin, Tetracycline, Verapamil,
Vitamin E
II. Physiological Challenges
Physiology: Gastric Emptying Cycle
The house keeping
activities!
• Gastric Muscle: Longitudinal,
Circular, and Oblique
• 3D Contractions
Physiological Challenges…

Food Effects
Fasting Fed
Physiological Challenges…

Mucus turnover

 Gastric emptying, small intestinal, colonic and total transit of dosage

forms.

 Age, posture, time of dosing, exercise, bed rest, psychologic status.

 Pathophysiology on gastrointestinal transit, e.g. irritable bowel

syndrome, inflammatory bowel disease.
Physiological Challenges…

Dosage Form Effects: Solids vs. Liquids

Physiological Challenges…

Dosage Form Effects: : Density Differences

Physiological Challenges…

Dosage Form Effects: Size

• Non-disintegrating tablets with about 13 mm diameter-

about 3 h.

• Non-disintegrating tablets with about 7 mm diameter-about

2 h.

• Microparticles– rapid clearance from stomach.

An ideal GRDDS should address all these issues!!

III. Delivery Approaches:
– Altered density systems

– Expandable swelling systems

– Bioadhesive systems

Ideal Qualities:

– should not intervene with gastric motility

– should not damage GI.mucosa.

– Time for ‘collapse’ should be reproducible

– should leave/disintegrate before the second dose!

A. Altered Density Products:
• Low density (less than 1) or high density (more than 1.4) products.
• Extensive literature on low density products (Hollow microspheres)

Floating Microspheres Vs. nonfloating microspheres:

• Riboflavin / EudragitR S100 and HPMC
• human subjects under fasted and fed conditions.

[Source: Journal of Controlled Release 98 (2004) 75–85

Float Erode Diffuse (FED)Tablets:

1. Absorption window of Cipro:

stomach and duodenum (20-
30 cms long).

2. OD products.. a big challenge.

3. FED approach improved gastric

residence
2.Dissolution of Polymer

1.Floating of tablets 3.Release of Cipro

 Cipro: 1000 mg OD Vs. 500 mg bid

• Ranbaxy research laboratories Vs. Bayer

10000
Mean Concentration (ng/mL)

A
T
1000

100
0 5 10 15 20 25
T im e ( h o u r s )

• OD is expected to provide similar efficacy as the conventional tablet 500

mg
B. Expandable Swelling Systems

Eg.
Devices with EVA / levamisole showed longer protection from worms in
sheeps (Source: US Patent, 3844285)
Expandable Swelling Systems…

• Haloperidol ESS: Prolonged pharmacodynamics (Source: US Patent,

4207890)

• [A-Drug reservoir; B-Swellable resin; C-Elastic outer polymeric

envelope]
Expandable Swelling Systems…

Superporous Hydrogels:

• Transit of the Superporous Hydrogel

• A Superporous Hydrogel in its Dry
and Water-swollen State

Alza’s gastroretentive OROS® system, showed prolonged gastric residence time in a dogs (12-
24 h).

In humans, in the fasted state, the average gastric residence time for the same system was 33
minutes!!
C.Bioadhesive Particulate Carriers (BPCs)
Safe and superior to single unit dosage forms.

Types:

1.Non specific Bioadhesive particulates:

– Non specific interaction with mucins

– Eg: coated liposomes, microspheres, nanospheres

2.Specific Bioadhesive particulates:

– Adhesion directly to the surface cells through specific interactions.

– very effective

– limited by their capacity to reach cell surface/toxicity issues.

– Eg: lectin conjugates

In Vivo (poor?) Performance of BPCs.
i. Bioadhesive Polymer Coated Liposomes:
• liposomes improve the enteral absorption of drugs (eg. insulin)

• Coating of liposomes with bioadhesive polymers-may also improve

gastroretention

– Eg: Amylopectin, poloxamers, carboxy methyl chitosan, dextran derivatives

coated liposomes

• Effect of chitosan coating on the mucoadhesion of liposomes in rat

intestine (Source: Handbook of Pharm controlled release, Donald L.Wise (edi), Marcel Dekker)
Pharmacodynamics of chitosan coated insulin liposomes

1.control; 2.insulin solution; 3.non coated liposomes; 4.CS-coated liposomes

(Source: Pharm.Res.13,896-901,1996)
ii. Bioadhesive Microspheres:
Albumin microspheres with 30% polycarbopol particles

• Absorption window of Chlorothiazide: limited to proximal parts of G.I.T.

• Albumin microspheres containing 30% carbopol adhered to stomach

mucosa & ↑BA by 2 folds.

Triangle-Carbopol-Albumin beads; Circles-Albumin beads

(Source:JPS,76,433-436,1987)
Polymer incorporation:

Carbopol coating Vs.carbopol dispersion:

a-Plain microspheres; b-Carbopol coated microspheres; c-carbopol

dispersed microspheres (Source: Pharm. Dev. Technol, 1998)
iii. Bioadhesive Nanospheres:

• PLGA nanospheres coated with chitosan / PAA / sod.alginate.

• Chitosan coated NS-showed better mucoadhesion

• Regional variation in mucoadhesion

iv. Lectin Conjugated Particulate Carriers:

• Lectins: Diverse class of proteins with sugar binding properties

• Source: plants /Animals / Microbes.

• lectin conjugated microparticles/liposomes/latex established their sugar

specificity
Lectin conjugated Particulate Carriers:
(Source: ADDR, 34, 191-219, 1998)
• Potential limitations:

– Toxicity issues (exception:Tomato lectins)

– complexity of design and preparation of drug loaded

conjugates.

– Food/beverage interactions not documented.

– limited availability.
Case Studies..

Delivery system
Microcrystalline chitosans for
gastro-retentive drug
delivery
Fluorescence-labelled
PVM/MA nanoparticles
Bioadhesive pellets
containing different
carbomers
Mucoadhesive nanoparticles
having hydrophilic polymeric
chains
Bioadhesive microdevices
with multiple reservoirs
Intestinal patches
for oral drug
delivery
D. GRDDS: Summary of Literature
Objective
In vivo absorption studies in human
volunteers
gastrointestinal transit and
Bioadhesive properties of
poly(methylvinylether-co-maleic
anhydride) after oral admn. in rats
Effect of different pHs on the
bioadhesive properties of the
formulations
The behavior of nanoparticles having
surface hydrophilic poly(N-
isopropylacrylamide), poly(N-
vinylacetamide), poly(vinylamine) or
poly(methacrylic acid) chains in the
intestine permeability of salmon
calcitonin (sCT).
Bioadhesion of lectin conjugated
silicon microdevices
Sandwiching a film of cross-linked
bovine serum albumin microspheres
between a film of ethyl cellulose and
Carbopol/pectin.
Results Reference
The in vivo study produced no evidence that the chitosan EJPS 19(5): p 345-353.
formulations studied can be used as mucoadhesive GRDDS. 2003
The results of in vitro mucoadhesion studies did not predict the
results of in vivo studies.
The bioadhesive potential of PVM/MA was much JCR 89(1): p 19-30. 2003
higher when formulated as nanoparticles (NP)
than in the solubilised form in water
Preferentially adherence to regions having a pH ranging from 6.2 to S.T.P. Pharma Sciences.
6.6 (duodenum) rather than those with a higher pH (the ileo-coecal 12(3): p 157-162. 2002
region)
Enhanced sCT permeation in the presence of nanoparticles. JCR, 81(3): p 281-290.
Gastrointestinal mucosa contributed to the absorption enhancement 2002
of sCT
In vitro studies show enhanced bioadhesion JCR, 81(3): p 291-306.
2002
mucoadhesive patches that adhere to Pharmaceutical Research.
the intestinal wall and increased the Trans-lumenal flux of model 19(4): p 391-395. 2002.
drugs by 100-fold compared to that from a solution
 Summary of Literature…
Mucoadhesive
nanosuspensions of
Buparvaquone
Lectin-PLA microsphere
conjugates
Intestinal mucoadhesive
films
Chitosan mucoadhesive
nanosuspensions
Chitosan microspheres
Cholesyramine resin
polystyrene nanoparticles
surface hydrophilic polymeric
chains
HPMC K4M tablets (Model
drug: Barium sulfate)
nanosuspension was formulated with
hydrogels made from mucoadhesive
polymers, e.g. Carbopol(R) and
chitosan
Gastrointestinal transit and
mucoadhesion of colloidal
suspensions in rats
Retention and transit of Eudragit
GIT(R) L100, S100 or HP-55(R) films
in rat small intestine
Delivery of antibiotics to the
Cryptosporidium-infected GIT in mice
mucosa of rat small intestine
gastric mucoadhesion and residence
in 12 fasted normal subjects
Mucoadhesion in the GIT of rats
Mucoadhesion, and x-ray photography
of the rabbit Gi tract
Physically stable suspension; No mucoadhesive testing IJP, 237(1-2): p 151-161.
2002
A significant fraction of the conjugates adhered to the gastric and Pharmaceutical Research.
intestinal mucosae 18(6): p 829-837. 2001
pH-dependent intestinal adhesion site IJP, 224(1-2): p 61-67.
specificity. 2001
Adhesion to the intestinal wall
Retention in the small intestinal adhesion
site for at least 2 h.
Improved bupravaquone efficiency 214(Feb 19): p 83-85.
2001
following intraduodenal injection more than half remained in the DDIP, 27(6): p 567-576.
upper or middle part of the small intestine for over 8 h. 2001
Cholestyramine exhibited prolonged gastric residence via IJP, 205(Sep 15): p 173-
mucoadhesion. This effect was reduced by polymer coating the 181. 2000
cholestyramine.
The mucoadhesion of poly(N-isopropylacrylamide) nanoparticles, 177(Jan 25): p 161-172.
which most strongly enhanced sCT absorption, was stronger than 1999
that of ionic nanoparticles
the tablet was mucoadhesive even after 8 h. in the rabbit GIT. DDIP, 25(5): p 685-690.
Enteric coating did not show any effect on mucoadhesion 1999
 Summary of Literature…
Polycarbophil (Noveon AA-
1) and nonadhesive Eudragit
RL-100 particles
Mucoadhesive microspheres
containing furosemide or
riboflavin
Calcium alginate and
poly(fumaric-co-sebacic
anhydride) 20:80
microspheres
Bioadhesive controlled
release capsule
Microspheres of polyglycerol
esters of fatty (PGEF)- acids
and carbopol 934P
Carbomer 934,
poly(styrenesulfonic acid),
(poly(styrenesulphonic acid);
and hyaluronic acid
bioadhesion
Migration of adhesive and
nonadhesive particles in the rat
intestine under altered mucus
secretions (Ach)
mucoadhesive microspheres in rats/10
healthy male subjects and compared
with nonadhesive microspheres
In vivo transit and dicumarol
bioavailability in rats
formulation of ursodiol
was prepared and studied
in vitro and in 10 healthy
volunteers.
In vitro adhesion testing rat stomach
and small intestine and GI transit in
rats.
GI transit of in rats
Interactions between the intestinal mucus layer and JPS, 87(Apr): p 453-456.
polycarbophil and EudraGIT RL-100 particles were similar. 1998
In rats: higher percentage of drug remained in the stomach. Plasma JPP, 50(Feb): p 159-166.
drug levels were higher. 1998
In human: plasma AUC was 1.8 times higher for furosemide and
urinary recovery was 2.4 times higher for riboflavin
Poly(FSA)microspheres significantly prolonged retention in the gut JCR 48(Sep 22): p
when compared to alginate microspheres and increase in the plasma 35-46. 1997.
AUC
longer residence and absorption time in gastric and duodenum- Bollettino Chimico
jejunum. superior bioavailability Farmaceutico. 135(Jan): p
12-14. 1996.
Mean residence time of carbopol microspheres was higher Pharmaceutical
compared with that of PGEF-microspheres. Pharm.Research.
12(Mar): p 397-405. 1995
Significant differences in oro-cecal transit were obtained with JCR, 12(Mar): p 55-65.
certain formulations. 1990
4% and 5% solutions of Carbopol showed delays of 25% in transit
to the ileo-cecal junction
IV. Future Trends:

• Until Date:
– Particulate carriers based on non swellable polymers adhere
(to some extent) at the intestinal mucosa / enhance BA
(variable) of some drugs.

• The key to success:

– Molecular level understanding of adhesion, to a degree
suitable to attach devices to specific GI locations!!
– Intelligent devices, based on [mucoadhesive]-[mucolytic]-
[biofriendly & intelligent bioadhesive]… a break-through in
gastroretentive drug delivery.
 Thanks

ravichandranooty@yahoo.com