transmucosal drug delivery by kailash Vilegave

1. TRANS MUCOSAL (BUCCAL)
DRUG DELIVERY SYSTEMS
By :
Mr.Kailash Vilegave
Lecturer in Pharmacy
S.S.Jhondle college of pharmacy,
Asangaon

2. Traditional Routes
 Enteral
 Oral
 First Pass Metabolism
 Pre-systemic
Metabolism
 Rectal
 Slow drug absorption
 Patient compliance
issues
• Parenteral
– Intravenous
• Localized pain
• Not for sustained
release
– Intramuscular
• Painful
• Unpredictable release
rates

3. Alternative Routes
 Transdermal (TD)
 Permeability issues
 Potent drugs
 OralTransmucosal
(TM)
 Bioadhesion issues
 Better permeability

4. 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)

5. Disadvantages
• Expensive
• Multi-layering--uncomfortable to wear (i.e. Oral)
• Processing methods (for cast films)
• Generally not applicable for drugs that require high
blood levels or large Doses
• Limited absorption of high MW drugs
• Relatively low surface area (TM)

6. 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)

7. Therapeutic Applications
• Angina – Organic and nitrate compounds
• Acute seizures; asthma & allergy
• Chronic severe pain
• Migraine; hypertension
• Smoking cessation; alcohol abuse
• Hormonal treatments
• Diabetes – Emerging indication for TM delivery
• TM delivery of traditional drugs; proteins, peptides,
vaccines

8. Basic Facts & Considerations
• Structure of mucosa
• Factors affecting TM delivery
• Permeation Enhancement
• Devices & Formulations
• Models for TM absorption testing

9. The Mucosa

10. 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
• (Oral—Buccal or more appropriately “Labial” mucosa)

11. Comparison of Routes for
Systemic Drug Delivery
Issues Nasal
Oral
Mucosal
Vaginal/
Rectal
Gastro-
Intestinal
Dermal
Accessibility     
First-pass
Clearance
    
Acceptability     
Surface Area     
Onset of Action     
Robustness     
Duration     
Permeability     
Vascular
Drainage
    
Surface
Environment
    
 = Not Favorable;  = Intermediate;  = Very Favorable

12. Drug/Mucosa Considerations
• Barriers are in the outer layer of the mucosa
• No Stratum Corneum—However is Lipophilic
• Transport is Intercellular for both Polar and Non-
Polar Penetrants
• Drugs exposed to Enzymatic Degradation
• Barrier Areas composed of “Membrane-Coating
Granules”—Discharged into Intercellular Space
– Contain glycoproteins and glycolipids in an amorphous arrangement
– Keratinized tissue’s MCGs contain glycolipids organized as stacks of
lamellar discs

13. 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

14. 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.

15. Pathways of Drug Penetration
(TM)
• Drugs follow route of least resistance
– Intercellular: Hydrophilic compounds
– Transcellular: Lipophilic compounds

16. 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

17. Factors Affecting
Drug Delivery

18. Factors Affecting Drug Delivery
• Physicochemical factors
• Biological factors
• Formulation factors

19. Physicochemical Factors
• Partition coefficient
• Solubility
• Ionization / pKa
• Molecular size and weight
• Stability or Half – life

20. Biological Factors
• Salivation (TM)
• pH of environment
• Area
• Condition of the Mucosa
• Hydration
• Metabolism

21. 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.

22. Formulation Factors
• Daily dose
• Adhesion
– use of bioadhesives
• Permeability
– use of enhancers

23. Daily Dose Delivery
• The total amount of drug that could be
systematically delivered across the buccal
mucosa from 2-cm2 system in one day has
been 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.

24. 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 buccal
tablets. Int. J. Pharm. 188: 1-10 (1999).
Bioadhesive used – Hakea
 40 mg CPM and 22 mg Hakea
 25 mg CPM and 22 mg Hakea
 40 mg CPM and 32 mg Hakea

25. Penetration Enhancement

26. 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)

27. Penetration Enhancement
• Chemical Methods (TM):
– Chemical Penetration Enhancers (CPE)
– Pro-drugs

28. 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

29. “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 or
solvent into the membrane
• Modify Drug Solubility Parameters (Ethanol,Lactose)
J = D•Kp•Cv/h

30. 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 with
Glycodeoxycholate as an absorption enhancer in pigs. J. Pharm. Sci. 85: 457-460 (1996).

31. TM Delivery System Requirements
• Local drug delivery to superficial tissues or systemic
delivery
• Systems must make drug available for permeation
through the substrate at a specific rate
• Must adhere to mucosa
• Must easily be removed & Non-irritating
• For systemic use, must permeate series of barriers to
reach systemic circulation
• The drug must partition from the vehicle into the
epithelial barrier and the drug must diffuse through
the epithelial barrier (rate-limiting step)

32. 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 to
the mucosa. E.g. Polypropylene, polyethylene
• Inert release liner: Remove prior to use so that drug-
containing area and adhesive is exposed to mucosa

33. Basic Types of TM Patches
• Drug-in-Adhesive Systems:
• Incorporates the active ingredient
directly into the adhesive
• Works best if the drug is highly potent
(adhesive performance may deteriorate
as conc. of drug )
• Matrix Systems:
• Semi-solid drug containing mixture
encapsulated into a self-contained core;
adhesive incorporated into the release
liner
• Reservoir Systems:
• Drug delivery mixture and adhesive
separate
• Easy to design; incorporate much
higher volumes of drug and additives
• Allow semi-solid suspensions and
alcoholic solutions

34. 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

35. Production of TM Systems

36. Formulation of Compressed
Disks
Drug (20 mg Omeprazole) + Polymer (200 mg)
Ratio: 1: 10
Polymers used: HPC, PVP, HPMC, Carbopol, Na. CMC
Formulation with various polymer combinations
Drug content fixed – Polymer ratio changed
HPC + HPMC – 2:1, 3:1, 4:1
PVP +HPMC – 2:1, 3:1, 4:1

37. 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, 4.6
gm, 4.8 gm, 5.0 gm)
Drug: Diltiazem hydrochloride (1 gm)
Solvent mixture: Alcohol + Dichloromethane (50:50)
Plasticizer: 20% v/w propylene glycol

38. Quality control tests
Assay
Weight variation
Thickness variation
In vitro Release studies
Moisture absorption studies
% Moisture absorbed = Final weight – Initial weight
__________________________________________________________
Initial weight
× 100

39. 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 equipment
demands
– Shorter and more efficient
processing times
– Favorable cost
– Potential “Continuous
Process”
– Can Produce “Solid
Solutions or Dispersions”

40. ORGANIZATION PRODUCT PRESENT STATUS
Generex Biotechnology
Corporation
Insulin Buccal Spray
ORALGEN (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 Limited
Glyceryl 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

41. Wyeth Pharma
Ceuticals
Lorazepam Buccal Tablets (Temesta
Expidet)
Oxazepam Buccal Tablets (Seresta
Expidet)
In Market
In Market
GW Pharmaceuticals
Mucosal 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 Corporation
Estrogen 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 Rorer
Prochlorperazine Bioadhesive
Buccal Tablet (Tementil) In Market
Ciba-Geigy
Methyltestosterone Buccal Tablets
(Metandren) In Market

42. Some buccal –adhesive matrix tablet formulations
Formulation components Active ingredient References
Hydroxypropyl cellulose, Cetostearyl alcohol
and Hydroxyethyl cellulose
Several suggested
e.g., Morphine
Jenkins et al., (1986)
Chitosan and Sodium hyaluronate Brilliant blue used as
model drug
Takayama et al., (1991)
Modified maize starch with either
Poly(acrylic acid) or poly(ethylene
Oxide)
Fluoride
Bottenberg at al.,
(1991)
Hydroxypropyl cellulose and
Carboxyvinyl polymer
Triamcinolone
acetonide
Kubo et al., (1989)
Sodium carboxymethylcellulose and
Hydroxypropyl methylcellulose Codeine Phosphate Ranga rao et al., (1989)
Hydroxypropyl methylcellulose and
Poly(acrylic acid) Fluoride
Bottenberg et
al.¸(1989)

43. Bioadhesive Polymer(s)
Studied
Investigation objectives Reference
HPC and CP
Preferred mucoadhesive strength on CP,
HPC, and HPC-CP combination
Ishida et al., 1981
HPC and CP
Measured Bioadhesive property using
mouse peritoneal membrane
Satoh et al., 1989
CP, HPC, PVP, CMC
Studied inter polymer complexation and its
effects on bioadhesive strength
Gupta et al., 1994
CP and HPMC
Formulation and evaluation of
buccoadhesive controlled release delivery
systems
Anlar et 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 CP
Used 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 PIB
Used a two roll milling method to prepare a
new bioadhesive patch formulation
Guo,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

44. Chitosan, HPC, CMC, Pectin,
Xanthum gum, and
Polycarbophil
Evaluate mucoadhesive properties by
routinely measuring the detachment force
from pig intestinal mucosa
Lehr et al., 1992
Hyaluronic acid benzyl esters,
Polycarbophil, and HPMC
Evaluate mucoadhesive properties Sanzgiri et al., 1994
Hydroxyethyl cellulose
Design and synthesis of a bilayer patch
(polytef-disk) for thyroid gland diagnosis
Anders et al., 1983
Polycarbophil
Design of a unidirectional buccal patch
for oral mucosal delivery of peptide drugs
Veillard et al., 1987
Poly(acrylic acid) and
Poly(methacrylic acid)
Synthesized and evaluated cross-linked
polymers differing in charge densities and
hydrophobicity
Ch’ng 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

45. 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 and
adhesion 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 mucoadhesive
drug delivery
Benes et al., 1997
DeGrande, 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

46. 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 of
PAA for buccal mucoadhesive drug delivery
Shojaei, A. H and Li, X., 1995
Shojaei, 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 delivery
Voorspoels et al., 1997
Natural oligosaccharide gum,
hakea
Evaluation of mucoadhesive buccal tablets
for sustained release of salmon calcitonin
(SCT)
Alur et 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

47. Classification Examples Mechanism
Surfactants
Anionic
Cationic
Non-ionic
Bile salts
Sodium lauryl sulfate, Sodium laurate
Cetylpyridinium chloride
Polaxamer, Brij, Span, Myrj, Polysorbate
Sodium glycodeoxycholate,
Sodium glycocholate,
Sodium taurodeoxycholate,
Sodium taurocholate.
Perturbation of intercellular
lipids, protein domain integrity
Fatty acids Oleic acid,
Caprylic acid.
Increase fluidity of phospholipid
domains.
Cyclodextrins -,-, γ- cyclodextrins,
Methylated -cyclodextrins
Inclusion of membrane
compounds
Chelators EDTA, Sodium citrate, Polyacrylates Interfere with Ca+2
Positively
charged
polymers
Chitosan, Trimethyl chitosan Ionic interaction with negative
charge on the mucosal surface
Cationic
compounds
Poly-L-arginine, L-lysine
Miscellaneous Azone
Mucosal penetration enhancers and mechanisms of action

48. 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)

49. 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)

50. Oral Controlled Drug Delivery System
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