Copy (2) Of Gastroretentive Delivery Systems

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: The house keeping activities! • •

Gastric Muscle: Longitudinal, Circular, and Oblique 3D Contractions

Gastric Emptying Cycle

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 diameterabout 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 (2030 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 bid

Mean Concentration (ng/mL)

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1 T i m

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1 5

2 0

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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: •

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 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..

D. GRDDS: Summary of Literature Delivery system Microcrystalline chitosans for gastro-retentive drug delivery

Objective In vivo absorption studies in human volunteers

Results

Reference

•The in vivo study produced no evidence that the chitosan formulations EJPS 19(5): p 345-353. 2003 studied can be used as mucoadhesive GRDDS. •The results of in vitro mucoadhesion studies did not predict the results of in vivo studies.

Fluorescence-labelled PVM/MA gastrointestinal transit and Bioadhesive •The bioadhesive potential of PVM/MA was much nanoparticles properties of poly(methylvinylether-co- higher when formulated as nanoparticles (NP) maleic anhydride) after oral admn. in rats 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 bioadhesivePreferentially adherence to regions having a pH ranging from 6.2 to 6.6 S.T.P. Pharma Sciences. properties of the formulations (duodenum) rather than those with a higher pH (the ileo-coecal region) 12(3): p 157-162. 2002

Mucoadhesive nanoparticles having hydrophilic polymeric chains

The behavior of nanoparticles having surface hydrophilic poly(Nisopropylacrylamide), poly(Nvinylacetamide), poly(vinylamine) or poly(methacrylic acid) chains in the intestine permeability of salmon calcitonin (sCT).

Enhanced sCT permeation in the presence of nanoparticles. JCR, 81(3): p 281-290. 2002 Gastrointestinal mucosa contributed to the absorption enhancement of sCT

Bioadhesive microdevices with Bioadhesion of lectin conjugated silicon In vitro studies show enhanced bioadhesion multiple reservoirs microdevices

JCR, 81(3): p 291-306. 2002

Intestinal patches for Sandwiching a film of cross-linked bovinemucoadhesive patches that adhere to Pharmaceutical Research. oral drug delivery serum albumin microspheres between a the intestinal wall and increased the Trans-lumenal flux of model drugs 19(4): p 391-395. 2002. film of ethyl cellulose and by 100-fold compared to that from a solution Carbopol/pectin.

Summary of Literature…

Mucoadhesive nanosuspensions nanosuspension was formulated with Physically stable suspension; No mucoadhesive testing of Buparvaquone hydrogels made from mucoadhesive polymers, e.g. Carbopol(R) and chitosan

IJP, 237(1-2): p 151-161. 2002

Lectin-PLA microsphere conjugates

Gastrointestinal transit and A significant fraction of the conjugates adhered to the gastric and mucoadhesion of colloidal suspensions in intestinal mucosae rats

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

Intestinal mucoadhesive films

Retention and transit of Eudragit GIT(R) •pH-dependent intestinal adhesion site IJP, 224(1-2): p 61-67. 2001 L100, S100 or HP-55(R) films in rat small specificity. intestine •Adhesion to the intestinal wall •Retention in the small intestinal adhesion site for at least 2 h.

Chitosan mucoadhesive nanosuspensions

Delivery of antibiotics to the Cryptosporidium-infected GIT in mice

Improved bupravaquone efficiency

Chitosan microspheres

mucosa of rat small intestine

following intraduodenal injection more than half remained in the upper DDIP, 27(6): p 567-576. or middle part of the small intestine for over 8 h. 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.

polystyrene nanoparticles surface Mucoadhesion in the GIT of rats hydrophilic polymeric chains HPMC K4M tablets (Model drug: Barium sulfate)

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

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

The mucoadhesion of poly(N-isopropylacrylamide) nanoparticles, 177(Jan 25): p 161-172. which most strongly enhanced sCT absorption, was stronger than that of 1999 ionic nanoparticles

Mucoadhesion, and x-ray photography of the tablet was mucoadhesive even after 8 h. in the rabbit GIT. Enteric DDIP, 25(5): p 685-690. the rabbit Gi tract coating did not show any effect on mucoadhesion 1999

Summary of Literature…

Polycarbophil (Noveon AA-1) Migration of adhesive and nonadhesive Interactions between the intestinal mucus layer and polycarbophil JPS, 87(Apr): p 453-456. and nonadhesive Eudragit RL- particles in the rat intestine under altered and EudraGIT RL-100 particles were similar. 1998 100 particles mucus secretions (Ach) Mucoadhesive microspheres containing furosemide or riboflavin

mucoadhesive microspheres in rats/10 In rats: higher percentage of drug remained in the stomach. Plasma healthy male subjects and compared withdrug levels were higher. nonadhesive microspheres 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

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

Bioadhesive controlled release capsule

formulation of ursodiol was longer residence and absorption time in gastric and duodenumprepared and studied in jejunum. superior bioavailability vitro and in 10 healthy volunteers.

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 Mean residence time of carbopol microspheres was higher compared small intestine and GI transit in rats. with that of PGEF-microspheres.

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

Carbomer 934, GI transit of in rats poly(styrenesulfonic acid), (poly(styrenesulphonic acid); and hyaluronic acid bioadhesion

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

•Significant differences in oro-cecal transit were obtained with certain JCR, 12(Mar): p 55-65. 1990 formulations. •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

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