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TRANS MUCOSAL (BUCCAL)

DRUG DELIVERY SYSTEMS

By :

Mr.Kailash Vilegave

Lecturer in Pharmacy

S.S.Jhondle college of pharmacy,

Asangaon

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Traditional Routes

Enteral Oral

First Pass Metabolism

Pre-systemicMetabolism

Rectal

Slow drug absorption

Patient complianceissues

Parenteral

Intravenous

Localized pain Not for sustained

release

Intramuscular

Painful

Unpredictable release

rates

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Alternative Routes

Transdermal (TD) Permeability issues

Potent drugs

Oral Transmucosal

(TM) Bioadhesion issues

Better permeability

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Advantages of TM Drug Delivery

Avoids first-pass effect Avoids chemically hostile GI environment

Avoids GI Distress

Allows use of drugs with short t1/2s

Controls plasma levels of potent drugs

Can interrupt drug input quickly if toxicity

Reduces multiple dosing

Improvement in patient compliance

Fast cellular recovery following stress (TM)

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Disadvantages

Expensive

Multi-layering--uncomfortable to wear (i.e. Oral)

Processing methods (for cast films)

Generally not applicable for drugs that require highblood levels or large Doses

Limited absorption of high MW drugs

Relatively low surface area (TM)

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Comparison of Routes of Delivery

TM vs. Intravenous route Oral vs. TD and TM Routes

Oral CR formulation (0.76 mg);

TDD patch (8.0 mg);

TMD patch (0.5 mg)

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Therapeutic Applications

AnginaOrganic and nitrate compounds

Acute seizures; asthma & allergy

Chronic severe pain

Migraine; hypertension

Smoking cessation; alcohol abuse

Hormonal treatments

DiabetesEmerging indication for TM delivery TM delivery of traditional drugs; proteins, peptides,

vaccines

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Basic Facts & Considerations

Structure of mucosa

Factors affecting TM delivery

Permeation Enhancement

Devices & Formulations

Models for TM absorption testing

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The Mucosa

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Mucosa Characteristics(Oral, Nasal, Rectal, Vaginal, Pulmonary)

High cellular turn-over rate

Very Robust

Avoids First Pass Effect

Routinely exposed to exogenous compounds

Areas of relatively immobile tissue

Bioadhesion Issues (OralBuccal or more appropriately Labial mucosa)

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Comparison of Routes for

Systemic Drug Delivery

Issues NasalOral

Mucosal

Vaginal/

Rectal

Gastro-

IntestinalDermal

Accessibility First-pass

Clearance

Acceptability Surface Area

Onset of Action Robustness Duration

Permeability Vascular

Drainage

Surface

Environment

= Not Favorable; = Intermediate; = Very Favorable

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Drug/Mucosa Considerations

Barriers are in the outer layer of the mucosa

No Stratum CorneumHowever is Lipophilic

Transport is Intercellular for both Polar and Non-

Polar Penetrants

Drugs exposed to Enzymatic Degradation

Barrier Areas composed of Membrane-Coating

GranulesDischarged into Intercellular Space Contain glycoproteins and glycolipids in an amorphous arrangement

Keratinized tissues MCGs contain glycolipids organized as stacks of

lamellar discs

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Regional Variation in the

Oral Mucosa

Masticatory Mucosa

Keratinized epithelium

25% of total surface area of oral cavity

Lining mucosa

Non-keratinized epithelium

60% of total surface area

Specialized mucosa

Both keratinized and nonkeratinized

15% of total surface area

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Oral Cavity Schematic

Hard

palate

Gingival

Sublingual

Soft palate

Buccal

Tongue

Keratinized

LayerEpithelium

Lamina

Propria

Basal Lamina

Mucus

Layer

Basal Lamina

Epithelium

Lamina

Propria

Mucus Layer

Stratum Basale

Repka et al. Matrix and Reservoir-Based Transmucosal Systems: Tailoring Delivery Solutions.

American Journal of Drug Delivery, 2004.

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Pathways of Drug Penetration

(TM)

Drugs follow route of least resistance

Intercellular: Hydrophilic compounds

Transcellular: Lipophilic compounds

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Mechanisms of Drug Transport

Intercellular

flux, J = DEC

Transcellular

flux, J = (1-E)DCK

h

h

D=Diffusion Coefficient of the Memb.

E=Fraction of Surface Area

C=Donor Drug Conc.

K=Partition Coefficient

h=Path Length

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Factors Affecting

Drug Delivery

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Factors Affecting Drug Delivery

Physicochemical factors

Biological factors

Formulation factors

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Physicochemical Factors

Partition coefficient

Solubility

Ionization / pKa

Molecular size and weight

Stability or Halflife

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Biological Factors

Salivation (TM)

pH of environment

Area

Condition of the Mucosa

Hydration

Metabolism

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Salivation

Michael J. Rathbone. Oral mucosal drug delivery. Marcel Dekker, Inc. 1996.

Substances that reduce salivary secretion would be

expected to increase drug concentrations in the oral cavity.

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Formulation Factors

Daily dose

Adhesion

use of bioadhesives

Permeability

use of enhancers

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Daily Dose Delivery

The total amount of drug that could be

systematically delivered across the buccal

mucosa from 2-cm2

system in one day hasbeen estimated to be 10-20 mg.*

*J. R. Robinson, M. A. Longer, and M. Veillard. Bioadhesive polymers for controlled drug

delivery. Biological Approaches to the Controlled Delivery of Drugs (R. L. Juliano, ed.). Annals

of the New York Academy of Sciences 507: p.307 (1987).

*Michael J. Rathbone. Oral mucosal drug delivery. Marcel Dekker, Inc. 1996.

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Adhesion and Use of

Bioadhesives

Hemant H. Alur, S. Indiran Pather, Ashim K. Mitra, Thomas P. Johnston. Transmucosal sustained-delivery of

chlorpheniramine maleate in rabbits using a novel, natural mucoadhesive gum as an excipient in buccaltablets. Int. J. Pharm. 188: 1-10 (1999).

Bioadhesive used

Hakea40 mg CPM and 22 mg Hakea

25 mg CPM and 22 mg Hakea

40 mg CPM and 32 mg Hakea

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Penetration Enhancement

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Permeability Barrier: Lipid Nature

LIPID SKIN KERATINIZED NONKERATINIZED

ORAL EPITHELIUM ORAL EPITHELIUM

Ceramides X X

Cholesterol X X X

Fatty acids X X

Phospholipids X X

Glycosylceramides X X (high)

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Penetration Enhancement

Chemical Methods (TM):

Chemical Penetration Enhancers (CPE)

Pro-drugs

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Chemical Penetration

Enhancers (CPEs)

A substance that will increase the permeability

of the epithelial barrier by modifying its

structure

Ideal Penetration Enhancer:

Non-toxic, non-irritating, non-allergenic

Immediate onset of increased permeability

Immediate recovery of normal barrier properties upon

removal

Physically and Chemically compatible with a wide range of

drugs

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Trans Absorption Enhancing

Mechanism of Action of CPEs

Drug Flux can be Enhanced by:

Disruption of the highly ordered structure of permeability

barrier lipids (modifying D)

Fluidizing Intercellular Lipids (DMSO, Azone)

Interaction with intracellular protein

Alter Protein Conformation

Improved partitioning of a drug, co-enhancer orsolvent into the membrane

Modify Drug Solubility Parameters (Ethanol,Lactose)

J = DKpCv/h

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Use of Permeation Enhancers

Buccal delivery of FD4 without GDC.

Buccal delivery of FD4 with 10 mM GDC.

A. J. Hoogstraate et al. In-vivo buccal delivery of Fluorescein Isothiocyanate-Dextran 4400 withGlycodeoxycholate as an absorption enhancer in pigs. J. Pharm. Sci. 85: 457-460 (1996).

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TM Delivery System Requirements

Local drug delivery to superficial tissues or systemicdelivery

Systems must make drug available for permeationthrough the substrate at a specific rate

Must adhere to mucosa Must easily be removed & Non-irritating

For systemic use, must permeate series of barriers toreach systemic circulation

The drug must partition from the vehicle into theepithelial barrier and the drug must diffuse throughthe epithelial barrier (rate-limiting step)

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Devices & Formulations

Passive transdermal systems: Driven by concentration

gradient

Typical Design: Rectangular or round therapeutic

system (TS) or patch

Core: Drug, polymeric carrier (HPC, Eudragits) and

adhesive (Polybutylacrylate, polyisobutylene, karaya gum)

Inert backing (transparent or pigmented): Attach the TS tothe mucosa. E.g. Polypropylene, polyethylene

Inert release liner: Remove prior to use so that drug-

containing area and adhesive is exposed to mucosa

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Basic Types of TM Patches

Drug-in-Adhesive Systems: Incorporates the active ingredientdirectly into the adhesive

Works best if the drug is highly potent(adhesive performance may deteriorateas conc. of drug )

Matrix Systems: Semi-solid drug containing mixtureencapsulated into a self-contained core;adhesive incorporated into the releaseliner

Reservoir Systems: Drug delivery mixture and adhesive

separate Easy to design; incorporate much

higher volumes of drug and additives

Allow semi-solid suspensions andalcoholic solutions

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Models for TM absorption testing

In vitro methodology: Access to human membranes

Comparative studies using patches, ointments and creams

Distribution of drug in various membrane layers

Determination of membrane biotransformation Prediction of local tolerance and enhancing techniques

Animal Studies:

Toxicokinetic studies in small and large animals

Assessment of local tolerance

Studies in Volunteers:

Kinetics of parent compound and metabolites

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Production of TM Systems

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Formulation of Compressed

DisksDrug (20 mg Omeprazole) + Polymer (200 mg)

Ratio: 1: 10

Polymers used: HPC, PVP, HPMC, Carbopol, Na. CMC

Formulation with various polymer combinations

Drug content fixedPolymer ratio changed

HPC + HPMC2:1, 3:1, 4:1

PVP +HPMC2:1, 3:1, 4:1

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OPTIMIZATION OF PATCHES

Optimizing the polymer content

Uniformity and Flexibility of film,Drug release

Optimizing the plasticizer content - Flexibility

Optimizing the solvent volume Swelling, air entrapment etc

Formulation of patches

Polymer: HPMC E 5 cps(3.8 gm, 4.0 gm, 4.2 gm, 4.4 gm, 4.6gm, 4.8 gm, 5.0 gm)

Drug: Diltiazem hydrochloride (1 gm)

Solvent mixture: Alcohol + Dichloromethane (50:50)

Plasticizer: 20% v/w propylene glycol

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Quality control testsAssay

Weight variation

Thickness variation

In vitro Release studies

Moisture absorption studies

% Moisture absorbed = Final weightInitial weight__________________________________________________________

Initial weight 100

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Cast Films vs. HME Films

Cast Films

Processing Methods

Environmental Concerns

Organic Solvents

Aqueous Solvents P-M

Stability

Reproducibility

Time Consuming Process

Labor Intensive

Multi-step Process

HME Films Environmental

No organic solvents or water

Recycling of material

Less labor and equipmentdemands

Shorter and more efficient

processing times

Favorable cost

Potential Continuous

Process

Can Produce Solid

Solutions or Dispersions

List of marketed buccal preparations under various

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ORGANIZATION PRODUCT PRESENT STATUS

Generex Biotechnology

Corporation

Insulin Buccal SprayORALGEN (US)

ORALIN (Canada)

Heparin Buccal Delivery System

Fentanyl Buccal Delivery Systems

In Market

Clinical Trials Completed

Clinical Trials Completed

Columbia Laboratories Inc.Testosterone Buccal Tablet (Straint)

Desmopressin Buccal Tablet

In Market

In Market

Ergo Pharm

Androdiol Buccal Tablets (Cyclo-Diol

SR)

Norandrodiol Buccal Tablets (Cyclo-

Nordiol SR)

In Market

In Market

Cytokine Pharma Sciences

Inc.

Pilocarpine Buccal Tablet

(PIOLOBUC)In Market

Britannia Pharmaceuticals

Limited

Prochlorperazine Buccal Tablet

(Buccastem)In Market

Pharmax LimitedGlyceryl Trinitrate (Suscard Buccal

Tablet)In Market

Cephalon, Inc.Oral Transmucosal Fentanyl Citrate

Solid Dosage Form (ACTIQ) In Market

List of marketed buccal preparations under various

stages of development

Lorazepam Buccal Tablets (Temesta

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Wyeth Pharma

Ceuticals

p (

Expidet)

Oxazepam Buccal Tablets (Seresta

Expidet)

In Market

In Market

GW PharmaceuticalsMucosal Spray and Buccal Tablets

(Cannabis-Based Medicines) Under Development

NovaDel Pharma Inc.

Buccal Aerosol Spray for

Clemastine,Nicotine,

Testosterone,Estradiol,

Progestorone,Fluoxetine,

Piroxicam

Under Development

IVAX CorporationEstrogen Buccal Tablet Under Phase III clinical

trials

Regency Medical research Vitamins Trans Buccal Spray In Market

Leo Pharmaceuticals

Nicotine Mucoadhesive Tablet

(Nicorette)

Nicotine Chewing Gum (Nicotinell)

In Market

In Market

Teijin Ltd. Triamcinolone acetonmide(Aftach) In Market

Rhone-Poulenc RorerProchlorperazine Bioadhesive

Buccal Tablet (Tementil) In Market

Ciba-Geigy

Methyltestosterone Buccal Tablets

(Metandren) In Market

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Some buccaladhesive matrix tablet formulations

Formulation components Active ingredient References

Hydroxypropyl cellulose, Cetostearyl alcohol

and Hydroxyethyl celluloseSeveral suggested

e.g., MorphineJenkins et al., (1986)

Chitosan and Sodium hyaluronate Brilliant blue used as

model drugTakayama et al., (1991)

Modified maize starch with either

Poly(acrylic acid) or poly(ethylene

Oxide)Fluoride

Bottenberg at al.,

(1991)

Hydroxypropyl cellulose and

Carboxyvinyl polymerTriamcinolone

acetonide

Kubo et al.,(1989)

Sodium carboxymethylcellulose and

Hydroxypropyl methylcellulose Codeine Phosphate Ranga rao et al., (1989)

Hydroxypropyl methylcellulose and

Poly(acrylic acid) FluorideBottenberg et

al.(1989)

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Bioadhesive Polymer(s)

StudiedInvestigation objectives Reference

HPC and CP Preferred mucoadhesive strength on CP,HPC, and HPC-CP combination

Ishida et al., 1981

HPC and CPMeasured Bioadhesive property using

mouse peritoneal membraneSatoh et al., 1989

CP, HPC, PVP, CMCStudied inter polymer complexation and its

effects on bioadhesive strengthGupta et al., 1994

CP and HPMCFormulation and evaluation of

buccoadhesive controlled release delivery

systems

Anlaret al., 1994

HPC, HEC, PVP, and PVA

Tested mucosal adhesion on patches with

two-ply laminates with an impermeable

backing layer and hydrocolloid polymer

layer

Anders, R. and Merkle, H., 1989

HPC and CPUsed HPC-CP powder mixture as peripheral

base for strong adhesion and HPC-CP freeze

dried mixture as core base

Ishida et al., 1982

CP, PIP, and PIBUsed a two roll milling method to prepare a

new bioadhesive patch formulationGuo,J.-H., 1994

Xanthum gum and Locust bean

gum

Hydrogel formation by combination of

natural gums Watanabe et al., 1991

Related research on mucoadhesive polymers and delivery systems

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Chitosan, HPC, CMC, Pectin,

Xanthum gum, and

Polycarbophil

Evaluate mucoadhesive properties by

routinely measuring the detachment force

from pig intestinal mucosa

Lehret al., 1992

Hyaluronic acid benzyl esters,

Polycarbophil, and HPMCEvaluate mucoadhesive properties Sanzgiri et al., 1994

Hydroxyethyl celluloseDesign and synthesis of a bilayer patch

(polytef-disk) for thyroid gland diagnosisAnders et al., 1983

PolycarbophilDesign of a unidirectional buccal patch

for oral mucosal delivery of peptide drugsVeillard et al., 1987

Poly(acrylic acid) and

Poly(methacrylic acid)

Synthesized and evaluated cross-linked

polymers differing in charge densities and

hydrophobicity

Chng et al., 1985

Number of Polymers including

HPC, HPMC, CP, CMC.

Measurement of bioadhesive potential

and to derive meaningful information on

the structural requirement for bioadhesion

Park, k. and Robinson, J.R., 1984

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Poly(acrylic acid-co-

acrylamide)

Adhesion strength to the gastric mucus

layer as a function of crosslinking agent,

degree of swelling, and carboxyl group

density

Park, H. and Robinson, J.R., 1987

Poly(acrylic acid)Effects of PAA molecular weight and

crosslinking concentration on swelling and

drug release characteristics

Garcia- Gonzalez et al., 1993

Poly(acrylic acid-co-methyl

methacrylate)

Effects of polymer structural features on

mucoadhesion

Leung, S and Robinson, J.R., 1988

Leung, S and Robinson, J.R., 1990

Poly(acrylic acid-co-butylacrylate)

Relationships between structure andadhesion for mucoadhesive polymers

Bodde et al., 1990

HEMA copolymerized with

Polymeg (polytetramethylene

glycol)

Bioadhesive buccal hydrogel for

controlled release delivery of

buprenorphine

Cassidy et al., 1993

Cydot by 3M (bioadhesive

polymeric blend of CP and

PIB)

Patch system for buccal mucoadhesivedrug delivery

Benes et al., 1997DeGrande, et al., 1996

Formulation consisting of PVP,

CP, and cetylpyridinium

chloride (as stabilizer)

Device for oral mucosal delivery of LHRH

- device containing a fast release and a

slow release layer

Nakane et al., 1996

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CMC, Carbopol 974P, Carbopol

EX-55, Pectin (low viscosity),

Chitosan chloride,

Mucoadhesive gels for intraoral delivery Nguyen-Xuan et al., 1996

HPMC and Polycarbophil (PC)Buccal mucoadhesive tablets with optimum

blend ratio of 80:20 PC to HPMC yielding

the highest force of adhesion

Taylan et al., 1996

PVP, Poly(acrylic acid)Transmucosal controlled delivery of

isosorbide dinitrate

Yukimatsu et al., 1994

Nozaki et al., 1997

Poly(acrylic acid-co-poly

ethyleneglycol) copolymer of

acrylic acid and polyethylene

glycol monomethylether

monomethacrylate

To enhance the mucoadhesive properties ofPAA for buccal mucoadhesive drug delivery

Shojaei, A. H and Li, X., 1995Shojaei, A. H and Li, X., 1997

Poly acrylic acid and

polyethylene glycol

To enhance mucoadhesive properties of

PAA by interpolymer complexation through

template polymerization

Choi et al., 1997

Drum dried waxy maize starch(DDWM), Carbopol 974P, and

sodium stearylfumarate

Bioadhesive erodible buccal tablet for

progesterone deliveryVoorspoels et al., 1997

Natural oligosaccharide gum,

hakea

Evaluation of mucoadhesive buccal tablets

for sustained release of salmon calcitonin

(SCT)

Aluret al., 1999

Poly(acrylic acid-co-ethylhexyl

acrylate), P(AA-co-EHA)

Evaluation of P (AA-co-EHA) films for

buccal mucoadhesive drug delivery. Shojeai et al., 2000

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Classification Examples Mechanism

SurfactantsAnionic

Cationic

Non-ionic

Bile salts

Sodium lauryl sulfate, Sodium laurateCetylpyridinium chloride

Polaxamer, Brij, Span, Myrj, Polysorbate

Sodium glycodeoxycholate,

Sodium glycocholate,

Sodiumtaurodeoxycholate,

Sodium taurocholate.

Perturbation of intercellularlipids, protein domain integrity

Fatty acids Oleic acid,

Caprylic acid.

Increase fluidity of phospholipid

domains.

Cyclodextrins -,-, - cyclodextrins,

Methylated -cyclodextrins

Inclusion of membrane

compounds

Chelators EDTA, Sodium citrate, Polyacrylates Interfere with Ca+2

Positivelycharged

polymers

Chitosan, Trimethyl chitosan Ionic interaction with negativecharge on the mucosal surface

Cationic

compounds

Poly-L-arginine, L-lysine

Miscellaneous Azone

Mucosal penetration enhancers and mechanisms of action

List of macromolecular drugs delivered through buccal route

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List of macromolecular drugs delivered through buccal route

Drug Enhancer Results Method (Ref)

Insulin 5% Sodium glycocholate F sublingual from

0.3% to 12%, F

buccal from 0.7% to

26%

Rat in vivo ( Aungust et

al., 1988)

Insulin Sodium glycocholate Absorption only in

presence of enhancer

(F=0.5%)

Dog in vivo (Ishida et al.,

1981)

Insulin 5% laureth-9,

5% Sodium salicylate,

5% Sodium EDTA,

Aprotinin

F from 0.7-3.6% to

27% with laureth-9.

Others had no effect

Rat in vivo (Aungst et al.,

1988)

Calcitonin Various saponins,

Bile salts,

Fatty acids,

Sucrose esters,

Sodium lauryl sulfate

pharmacologic effect Rat in vivo (Nakada et al.,

1988)

Calcitonin Various bile salts pharmacologic

effect, stability in

mucosal homogenate

Rat in vivo (Nakada et al.,

1989)

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Insulin Sodium lauryl sulfate,

Sodium taurocholate, EDTA,

POE 23 lauryl ether,

Methoxysalicylate,

Dextran sulfate

Maximum F~12% Rabbit in vivo (Oh et al.,

1990)

Octreotide 3% Azone,

4% Sodium glycocholate,

Sodium taurocholate, Sodium

taurocholate + EDTA

Azone F from 1.5%

to 6%, sodium

glycocholate F from

~ 0.4% -4.2%

Dog in vivo (Wolany et

al., 1990)

Interferon 1-4% sodiumtaurocholate, 5%

polysorbate 80,

1% sodium lauryl sulphate,

5% cyclodextrins

F from 0.014% to

0.25% with sodium

taurocholate. Others

less effective

Rat in vivo (Steward et

al., 1994)

Insulin Various alkyl glycosides (0.1-

0.2M)

F from 0.8% to ~

30% maximum

Rat in vivo (Aungst et al.,

1994)

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Thank you !!!