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Traditional Routes
Enteral
Oral First Pass Metabolism Pre-systemic Metabolism Rectal Slow drug absorption Patient compliance issues
Parenteral
Intravenous
Localized pain
Intramuscular
Painful
Unpredictable release rates
Alternative Routes
Transdermal (TD)
Permeability issues Potent drugs
Oral Transmucosal
(TM)
Bioadhesion issues Better permeability
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)
Oral CR formulation (0.76 mg); TDD patch (8.0 mg); TMD patch (0.5 mg)
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
The Mucosa
Mucosa Characteristics
(Oral, Nasal, Rectal, Vaginal, Pulmonary)
Nasal
Oral Mucosal
Vaginal/ Rectal
GastroIntestinal
Dermal
Surface Area
Onset of Action Robustness Duration
Permeability
Vascular Drainage Surface Environment
Drug/Mucosa Considerations
Barriers are in the outer layer of the mucosa
Lining mucosa
Non-keratinized epithelium 60% of total surface area
Specialized mucosa
Both keratinized and nonkeratinized 15% of total surface area
Soft palate Gingival Buccal Mucus Layer Epithelium Sublingual Stratum Basale Basal Lamina Lamina Propria
Tongue
Repka et al. Matrix and Reservoir-Based Transmucosal Systems: Tailoring Delivery Solutions. American Journal of Drug Delivery, 2004.
Transcellular
flux, J = (1-E)DCK
h
D=Diffusion Coefficient of the Memb. E=Fraction of Surface Area C=Donor Drug Conc. K=Partition Coefficient h=Path Length
Biological factors
Formulation factors
Physicochemical Factors
Partition coefficient
Solubility
Ionization / pKa Molecular size and weight Stability or Half life
Biological Factors
Salivation (TM) pH of environment Area Condition of the Mucosa
Hydration Metabolism
Salivation
Substances that reduce salivary secretion would be expected to increase drug concentrations in the oral cavity.
Michael J. Rathbone. Oral mucosal drug delivery. Marcel Dekker, Inc. 1996.
Formulation Factors
Daily dose
Adhesion
use of bioadhesives
Permeability
use of enhancers
*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.
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).
Penetration Enhancement
X X X
Penetration Enhancement
Chemical Methods (TM):
Chemical Penetration Enhancers (CPE) Pro-drugs
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).
Inert release liner: Remove prior to use so that drugcontaining area and adhesive is exposed to mucosa
Matrix Systems:
Reservoir Systems:
Animal Studies:
Toxicokinetic studies in small and large animals Assessment of local tolerance
Studies in Volunteers:
Kinetics of parent compound and metabolites
Production of TM Systems
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
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
Initial weight
100
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
PRESENT STATUS
In Market Clinical Trials Completed Clinical Trials Completed
In Market In Market
Ergo Pharm
Cytokine Pharma Sciences Inc. Britannia Pharmaceuticals Limited Pharmax Limited
In Market In Market
In Market
In Market
In Market
Cephalon, Inc.
In Market
Lorazepam Buccal Tablets (Temesta Expidet) Oxazepam Buccal Tablets (Seresta Expidet) Mucosal Spray and Buccal Tablets (Cannabis-Based Medicines) Buccal Aerosol Spray for Clemastine,Nicotine, Testosterone,Estradiol, Progestorone,Fluoxetine, Piroxicam Estrogen Buccal Tablet Vitamins Trans Buccal Spray Nicotine Mucoadhesive Tablet (Nicorette) Nicotine Chewing Gum (Nicotinell) Triamcinolone acetonmide(Aftach) Prochlorperazine Bioadhesive Buccal Tablet (Tementil) Methyltestosterone Buccal Tablets (Metandren)
In Market In Market
GW Pharmaceuticals
Under Development
Under Development
In Market In Market
In Market
Active ingredient
Several suggested e.g., Morphine
References
Jenkins et al., (1986)
Fluoride
Sodium carboxymethylcellulose and Hydroxypropyl methylcellulose Hydroxypropyl methylcellulose and Poly(acrylic acid)
Fluoride
Investigation objectives
Preferred mucoadhesive strength on CP, HPC, and HPC-CP combination Measured Bioadhesive property using mouse peritoneal membrane Studied inter polymer complexation and its effects on bioadhesive strength Formulation and evaluation of buccoadhesive controlled release delivery systems Tested mucosal adhesion on patches with two-ply laminates with an impermeable backing layer and hydrocolloid polymer layer Used HPC-CP powder mixture as peripheral base for strong adhesion and HPC-CP freeze dried mixture as core base Used a two roll milling method to prepare a new bioadhesive patch formulation Hydrogel formation by combination of natural gums
Reference
Ishida et al., 1981
HPC and CP
CP, PIP, and PIB Xanthum gum and Locust bean gum
Guo,J.-H., 1994
Chitosan, HPC, CMC, Pectin, Xanthum gum, and Polycarbophil Hyaluronic acid benzyl esters, Polycarbophil, and HPMC Hydroxyethyl cellulose
Evaluate mucoadhesive properties by routinely measuring the detachment force from pig intestinal mucosa
Design and synthesis of a bilayer patch (polytef-disk) for thyroid gland diagnosis
Polycarbophil
Design of a unidirectional buccal patch for oral mucosal delivery of peptide drugs
Synthesized and evaluated cross-linked polymers differing in charge densities and hydrophobicity
Measurement of bioadhesive potential and to derive meaningful information on the structural requirement for bioadhesion
Poly(acrylic acid-coacrylamide)
Adhesion strength to the gastric mucus layer as a function of crosslinking agent, degree of swelling, and carboxyl group density
Poly(acrylic acid) Poly(acrylic acid-co-methyl methacrylate) Poly(acrylic acid-cobutylacrylate) HEMA copolymerized with Polymeg (polytetramethylene glycol) Cydot by 3M (bioadhesive polymeric blend of CP and PIB) Formulation consisting of PVP, CP, and cetylpyridinium chloride (as stabilizer)
Effects of PAA molecular weight and crosslinking concentration on swelling and drug release characteristics Effects of polymer structural features on mucoadhesion Relationships between structure and adhesion for mucoadhesive polymers Bioadhesive buccal hydrogel for controlled release delivery of buprenorphine
Leung, S and Robinson, J.R., 1988 Leung, S and Robinson, J.R., 1990
Device for oral mucosal delivery of LHRH - device containing a fast release and a slow release layer
CMC, Carbopol 974P, Carbopol EX-55, Pectin (low viscosity), Chitosan chloride, HPMC and Polycarbophil (PC)
Buccal mucoadhesive tablets with optimum blend ratio of 80:20 PC to HPMC yielding the highest force of adhesion Transmucosal controlled delivery of isosorbide dinitrate
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
To enhance mucoadhesive properties of PAA by interpolymer complexation through template polymerization Bioadhesive erodible buccal tablet for progesterone delivery Evaluation of mucoadhesive buccal tablets for sustained release of salmon calcitonin (SCT) Evaluation of P (AA-co-EHA) films for buccal mucoadhesive drug delivery.
Examples
Sodium lauryl sulfate, Sodium laurate Cetylpyridinium chloride Polaxamer, Brij, Span, Myrj, Polysorbate Sodium glycodeoxycholate, Sodium glycocholate, Sodium taurodeoxycholate, Sodium taurocholate. Oleic acid, Caprylic acid. -,-, - cyclodextrins, Methylated -cyclodextrins EDTA, Sodium citrate, Polyacrylates Chitosan, Trimethyl chitosan
Mechanism
Perturbation of intercellular lipids, protein domain integrity
Increase fluidity of phospholipid domains. Inclusion of membrane compounds Interfere with Ca+2 Ionic interaction with negative charge on the mucosal surface
Cationic compounds
Miscellaneous
Poly-L-arginine, L-lysine
Azone
Enhancer
5% Sodium glycocholate
Results
F sublingual from 0.3% to 12%, F buccal from 0.7% to 26% Absorption only in presence of enhancer (F=0.5%)
Method (Ref)
Rat in vivo ( Aungust et al., 1988)
Insulin
Sodium glycocholate
Insulin
Calcitonin
Calcitonin
Insulin
Sodium lauryl sulfate, Sodium taurocholate, EDTA, POE 23 lauryl ether, Methoxysalicylate, Dextran sulfate
Maximum F~12%
Octreotide
Interferon
Insulin
NKV
50