Copy (2) of Gastroretentive Delivery Systems

Gastroretentive Drug Delivery Systems Gastroretentive Drug Delivery Systems (GRDDS)(GRDDS)

• 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

Overview...

I. Why Gastroretention?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 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 ChallengesII. Physiological Challenges Physiology: The house keeping

activities!• Gastric Muscle: Longitudinal,

Circular, and Oblique• 3D Contractions

Gastric Emptying Cycle

Physiological Challenges…Physiological Challenges…

Food Effects

Fasting Fed


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.


Dosage Form Effects: Solids vs. Liquids


Dosage Form Effects: : Density Differences


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.III. Delivery Approaches: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: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[Source: Journal of Controlled Release 98 (2004) 75–85

Float Erode DiffuseFloat Erode Diffuse (FED)Tablets: (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

1.Floating of tablets

2.Dissolution of Polymer

3.Release of Cipro

Cipro: 1000 mg OD Vs. 500 mg bidCipro: 1000 mg OD Vs. 500 mg bid

• Ranbaxy research laboratories Vs. Bayer

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

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B. Expandable Swelling SystemsB. Expandable Swelling Systems

Eg.Devices with EVA / levamisole showed longer protection from worms in

sheeps (Source: US Patent, 3844285)

Expandable Swelling Systems…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…Expandable Swelling Systems…

Superporous Hydrogels:Superporous Hydrogels:

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

• Transit of the Superporous Hydrogel

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

InIn humanshumans, in the fasted state, the average gastric residence, in the fasted state, the average gastric residence time for the same time for the same system was system was 33 minutes33 minutes!!!!

C.Bioadhesive Particulate Carriers (BPCs)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..Case Studies..

D. GRDDS: Summary of Literature

Delivery system Objective Results Reference

Microcrystalline chitosans for gastro-retentive drug delivery

In vivo absorption studies in human volunteers

The in vivo study produced no evidence that the chitosan formulations studied can be used as mucoadhesive GRDDS.The results of in vitro mucoadhesion studies did not predict the results of in vivo studies.

EJPS 19(5): p 345-353. 2003

Fluorescence-labelled PVM/MA nanoparticles

gastrointestinal transit and Bioadhesive properties of poly(methylvinylether-co-maleic anhydride) after oral admn. in rats

The bioadhesive potential of PVM/MA was much higher when formulated as nanoparticles (NP) than in the solubilised form in water

JCR 89(1): p 19-30. 2003

Bioadhesive pellets containing different carbomers

Effect of different pHs on the bioadhesive properties of the formulations

Preferentially adherence to regions having a pH ranging from 6.2 to 6.6 (duodenum) rather than those with a higher pH (the ileo-coecal region)

S.T.P. Pharma Sciences. 12(3): p 157-162. 2002

Mucoadhesive nanoparticles having hydrophilic polymeric chains

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).

Enhanced sCT permeation in the presence of nanoparticles. Gastrointestinal mucosa contributed to the absorption enhancement of sCT

JCR, 81(3): p 281-290. 2002

Bioadhesive microdevices with multiple reservoirs

Bioadhesion of lectin conjugated silicon microdevices

In vitro studies show enhanced bioadhesion JCR, 81(3): p 291-306. 2002

Intestinal patches for oral drug delivery

Sandwiching a film of cross-linked bovine serum albumin microspheres between a film of ethyl cellulose and Carbopol/pectin.

mucoadhesive patches that adhere tothe intestinal wall and increased the Trans-lumenal flux of model drugs by 100-fold compared to that from a solution

Pharmaceutical Research. 19(4): p 391-395. 2002.

Summary of Literature…

Mucoadhesive nanosuspensions of Buparvaquone

nanosuspension was formulated with hydrogels made from mucoadhesive polymers, e.g. Carbopol(R) and chitosan

Physically stable suspension; No mucoadhesive testing IJP, 237(1-2): p 151-161. 2002

Lectin-PLA microsphere conjugates

Gastrointestinal transit and mucoadhesion of colloidal suspensions in rats

A significant fraction of the conjugates adhered to the gastric and intestinal mucosae

Pharmaceutical Research. 18(6): p 829-837. 2001

Intestinal mucoadhesive films

Retention and transit of Eudragit GIT(R) L100, S100 or HP-55(R) films in rat small intestine

pH-dependent intestinal adhesion site specificity. Adhesion to the intestinal wall Retention in the small intestinal adhesion site for at least 2 h.

IJP, 224(1-2): p 61-67. 2001

Chitosan mucoadhesive nanosuspensions

Delivery of antibiotics to the Cryptosporidium-infected GIT in mice

Improved bupravaquone efficiency 214(Feb 19): p 83-85. 2001

Chitosan microspheres mucosa of rat small intestine following intraduodenal injection more than half remained in the upper or middle part of the small intestine for over 8 h.

DDIP, 27(6): p 567-576. 2001

Cholesyramine resin gastric mucoadhesion and residence in 12 fasted normal subjects

Cholestyramine exhibited prolonged gastric residence via mucoadhesion. This effect was reduced by polymer coating the cholestyramine.

IJP, 205(Sep 15): p 173-181. 2000

polystyrene nanoparticles surface hydrophilic polymeric chains

Mucoadhesion in the GIT of rats The mucoadhesion of poly(N-isopropylacrylamide) nanoparticles, which most strongly enhanced sCT absorption, was stronger than that of ionic nanoparticles

177(Jan 25): p 161-172. 1999

HPMC K4M tablets (Model drug: Barium sulfate)

Mucoadhesion, and x-ray photography of the rabbit Gi tract

the tablet was mucoadhesive even after 8 h. in the rabbit GIT. Enteric coating did not show any effect on mucoadhesion

DDIP, 25(5): p 685-690. 1999

Summary of Literature…

Polycarbophil (Noveon AA-1) and nonadhesive Eudragit RL-100 particles

Migration of adhesive and nonadhesive particles in the rat intestine under altered mucus secretions (Ach)

Interactions between the intestinal mucus layer and polycarbophil and EudraGIT RL-100 particles were similar.

JPS, 87(Apr): p 453-456. 1998

Mucoadhesive microspheres containing furosemide or riboflavin

mucoadhesive microspheres in rats/10 healthy male subjects and compared with nonadhesive microspheres

In rats: higher percentage of drug remained in the stomach. Plasma drug levels were higher.In human: plasma AUC was 1.8 times higher for furosemide and urinary recovery was 2.4 times higher for riboflavin

JPP, 50(Feb): p 159-166. 1998

Calcium alginate and poly(fumaric-co-sebacic anhydride) 20:80 microspheres

In vivo transit and dicumarol bioavailability in rats

Poly(FSA)microspheres significantly prolonged retention in the gut when compared to alginate microspheres and increase in the plasma AUC

JCR 48(Sep 22): p 35-46. 1997.

Bioadhesive controlled release capsule

formulation of ursodiol was prepared and studied in vitro and in 10 healthy volunteers.

longer residence and absorption time in gastric and duodenum-jejunum. superior bioavailability

Bollettino Chimico Farmaceutico. 135(Jan): p 12-14. 1996.

Microspheres of polyglycerol esters of fatty (PGEF)- acids and carbopol 934P

In vitro adhesion testing rat stomach and small intestine and GI transit in rats.

Mean residence time of carbopol microspheres was higher compared with that of PGEF-microspheres.

Pharmaceutical Pharm.Research. 12(Mar): p 397-405. 1995

Carbomer 934, poly(styrenesulfonic acid), (poly(styrenesulphonic acid); and hyaluronic acid bioadhesion

GI transit of in rats Significant differences in oro-cecal transit were obtained with certain formulations.4% and 5% solutions of Carbopol showed delays of 25% in transit to the ileo-cecal junction

JCR, 12(Mar): p 55-65. 1990

IV. Future Trends: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.

ThanksThanks

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Copy (2) of Gastroretentive Delivery Systems