Drug Delivery to the Oral Cavity Molecules to Market 1st edition by Tapash Ghosh,William Pfister 9780849398513 0849398517

 

Intraoral Delivery Systems: An Overview, Current Status, and Future Trends

I. Introduction

II. Intraoral Drug Delivery

A. Product Market

B. Anatomy of Oral Cavity

C. Intraoral Drug Delivery

D. Intraoral Drug Absorption

III. Overview: Intraoral Delivery Systems

A. Routes of Administration

B. Classification of Intraoral Dosage Forms

1. Quick-Dissolving Delivery Systems

2. Slow-Dissolving Delivery Systems

3. Nondissolving Delivery Systems

IV. Current Status: Intraoral Drug Delivery

A. Quick-Dissolving Delivery Systems

1. Lyophilized Wafers

2. Orally Disintegrating Tablets

3. Thin Films and Strips

4. Quick-Dissolve Products

5. Intraoral Liquid Delivery Technology

B. Slow-Dissolving Delivery Systems

1. Buccal Tablets

2. Slow-Dissolve Products

C. Nondissolving Delivery Systems

1. Medicated Chewing Gums

2. Buccal Patches

V. Intraoral Drug Delivery Excipients

VI. Intraoral Dosage Form Barrier Packaging

VII. Future Trends: Intraoral Drug Delivery

A. Patent Domain

B. Products in Development

VII. Summary

Acknowledgments

References

2

Preclinical Assessment of Oral Mucosal Drug Delivery Systems

I. Introduction

II. Anatomical and Physiological Details of the Oral Mucosa

A. Tissue Types and Characteristics

B. Generalized Structure of Oral Mucosa and Its Barrier Function

1. Epithelium

2. Basement Membrane and Connective Tissue

3. Salivary Flow

III. Evaluation of Mucosal Permeation

A. In Vitro Mucosal Permeation Techniques

B. In Vivo Methods

C. Animal Models for Permeability Measurement

IV. Evaluation of Mucoadhesion

A. In Vitro Assessment of Mucoadhesion

1. Methods Based on Measurement of Adhesion Strength

2. Methods Based on Measurement of Shear Strength

3. Bioadhesion Test Using Nonbiological Substances

4. Fluorescent Probe Method

5. In Situ Method

6. Organ Culture Technique

7. Ligand Receptor Binding Method

8. Flow Channel Methods

9. Falling Liquid Film Method

10. Colloidal Gold Staining Method

11. Thumb Test

12. Viscometric Method

B. In Vivo Assessment of Mucoadhesion

V. Oral Mucosal Drug Delivery Systems

A. Bioadhesive Tablets

B. Bioadhesive Patches

C. Phase Change Polymers

VI. Product Safety

VII. Summary

References

3

Modulation of Oral Transmucosal Permeability: Permeation Enhancers

I. Introduction

II. Oral Mucosal Drug Delivery

III. Anatomy of the Oral Cavity

A. Buccal Epithelium

B. Lamina Propria

C. Submucosa

D. Biochemical Structure

IV. Physiology and Environment of the Oral cavity

V. Modes of Transport across Buccal Mucosa

A. Transcellular Pathway

B. Paracellular Pathway

C. Active (Carrier-Mediated) Transport System

VI. Kinetics of Transport Mechanisms

A. Paracellular Pathway

B. Transcellular Pathway

C. Intraoral Drug Absorption and Transport Pathways

VII. Permeability of Buccal Mucosa

VIII. Methods of Transport Enhancement

A. Chemical Methods

B. Bile Salts

1. Acyclovir

2. ISIS Oligonucleotide

3. Buserelin

4. Surfactants

5. Fatty Acids and Derivatives

6. Vehicles and Adjuvants

7. Chelators

8. Cyclodextrins

9. Chitosan

10. Enzyme Inhibitors

IX. Delivery System Design

X. Impact of Enhancers on Dosage Form

References

4

Oral Transmucosal Delivery of Protein and Peptide Therapeutics

I. Introduction

II. Barrier to Peptide Delivery

A. Passive Barrier

B. Pathways for Peptide Transport

C. Enzymatic Barrier

III. Bioadhesive Systems

IV. Peptide and Protein Delivery

A. Insulin

B. Somatostatin Analogue

C. Thyrotropin Releasing Hormone (TRH)

D. LHRH

E. Other Polypeptides

V. Summary

References

5

Sublingual Transmucosal Delivery of Organic Nitrates: Treatment of Angina Pectoris

I. Introduction

II. Medical Rationale for Sublingual Nitroglycerin

A. Pharmacological Rationale

B. Pharmacokinetic Rationale

III. Oral Transmucosal Products for Angina Therapy

A. Organic Nitrate Products

1. Nitroglycerin

2. Other Organic Nitrates

B. Organic Nitrate Tolerance

C. Non-Nitrate Vasodilators for Oral Transmucosal Delivery

IV. Regulatory Aspects

VI. Summary

ACKNOWLEDGMENTS

REFERENCES

6

Oral Transmucosal Delivery of Melatonin

I. INTRODUCTION

A. Biosynthesis and Chronokinetics of Secretion

B. Metabolic and Pharmacokinetic Considerations

C. Potential Therapeutic Indications and Safety Considerations

II. TMD Device Design Considerations and In Vitro Testing

A. Materials and Geometry

B. Manufacturing Processes

C. In Vitro Testing: Adhesion and Delivery

III. Animal Testing

A. Choice of Models

B. Correlation between Buccal Absorption in Dogs and in Humans

C. Effect of Formulation Factors on Bioadhesion and Delivery

D. Safety Assessment in Dogs

IV. Human Testing

A. Initial Pharmacokinetics and Dose Selection

B. Chronokinetics

C. Comparison of TMD Melatonin versus Oral Controlled Release and TDD

D. Patient Wear and Comfort

V. CONCLUSIONS

Acknowledgments

REFERENCES

7

Oral Transmucosal Delivery of Nicotine: Smoking Cessation Therapy

I. Introduction

II. Nicotine Smoking Cessation

A. Nicotine Physicochemical Properties

B. Nicotine Pharmacology

C. Nicotine Toxicity

D. Nicotine Intraoral Absorption

E. Nicotine Addiction and Smoking Cessation

F. Medical Rationale: Nicotine Replacement Therapy

G. Nicotine Dosage Form Considerations

H. Nicotine Pharmacokinetics

III. Commercial Nicotine Replacement Products

A. Nicotine Transdermal Systems

B. Nicotine Oral Transmucosal Products

1. Chewing Gums

2. Lozenges

3. Sublingual Tablets

4. Oral Inhalers

5. Artificial Cigarettes

6. Lollipops

7. Smokeless Tobacco Products

C. Nicotine Nasal Sprays

IV. Nicotine PRODUCTS IN THE R&D PIPELINE

A. Intraoral Products in Development

1. Nicotine Lozenge

2. OT-Nicotine

3. Nicotine Chewing Gums

4. Nicotine Transmucosal Patches

B. Patent Domain: Nicotine Intraoral Products

C. Future Products

V. Summary

Acknowledgments

References

8

Oral Transmucosal Powder Injection

I. Introduction

A. Medical Rationale for Transmucosal Drug Delivery

B. Oral Mucosal Membranes

C. Oral Mucosal Vascularization

II. Powder Injection System

A. The Oral PowderJect® System

1. Gas Cylinder

2. Expansion Chamber

3. Shock Tube

4. Inverting Dome

B. Oral PowderJect® Dynamics

C. Design Considerations

1. Powder Formulation

2. Payload

3. Dome Design

4. Target Area

5. Use Pattern

D. In Vitro Test Methods

1. Pressure Characterization

2. High-Speed Imaging

3. Penetration Energy Measurement

4. In Vitro Permeability Measurement

III. Preclinical Studies: Delivery Of Testosterone

A. Experimental Methods

B. Results

C. Discussion and Conclusions

IV. Clinical Results: Delivery of Lidocaine Hydrochloride

A. Oral PowderJect‚ Clinical Study Objectives

B. Experimental Methods

1. Methods: Pain on Administration and Mucosal Damage

2. Methods: Local Anesthesia Effectiveness

3. Methods: Statistical Analysis

C. Results

1. Pain on Administration

2. Tissue Response

3. Surface Deposit and Residue in the Oral PowderJect‚ System

4. Quality of Local Anesthesia

D. Discussion and Conclusions

V. Future Applications

References

9

Drug Delivery Systems for the Treatment of Periodontal and Dental Diseases

I. Introduction

II. Periodontal and Dental Diseases

A. Periodontal Disease

1. Gingivitis

2. Periodontitis

3. Scaling and Curettage

4. Periodontal Surgery

B. Dental Diseases

1. Operative Dentistry

2. Endodontics

3. Orthodontics

4. Biofilm and Dental Diseases

III. Periodontal and Dental Products

A. Classification of Drug Delivery Products

1. Chemotherapy for Pulpotomy

2. Local Delivery of NSAIDs in Root Canals

3. Formulations Used in Orthodontia

4. Chemotherapeutic Agents for Periodontitis

5. Fluoride and Antimicrobial Products

B. In Vitro Mechanisms and Functionality

1. Periodontal Products

2. Products for Pulpotomy and Root Canals

3. Products for Fluoride and Antimicrobial Therapies

C. In Vivo Pharmacokinetics and Pharmacodynamics

1. Periodontal Products

2. Products for Pulpotomy and Root Canals

3. Products for Fluoride and Antimicrobial Therapies

D. Regulatory and Clinical Aspects

IV. Summary

Acknowledgments

REFERENCES

10

Oral Transmucosal Systems for Local Anesthetics: Dental and Oral Surgical Premedication

I. Introduction

II. Local Anesthetic Agent Selection

A. Onset of Local Anesthesia

B. Duration

C. Toxicity/Degradation

1. Esters

2. Amides

3. Ketones

D. Relative Potency

III. Bioadhesive Polymers

A. Natural Bioadhesive Products

B. Modified Natural Bioadhesives

C. Synthetic Bioadhesives

D. Biocompatability

E. Matrix Compatibility

IV. VEHICLE SELECTION

V. Dentipatch‚ Development

VI. Clinical Studies

A. Overview

B. Background Information

C. Evaluation of DentiPatch® in Reducing Needle-Insertion Pain

1. Study Design

2. Statistical Analyses

3. Results

D. DentiPatch® Anesthetic Effects during Scaling and Root Planing

1. Study Design

2. Results

VII. Summary

REFERENCES

11

Quick-Dispersing Oral Drug Delivery Systems

I. Introduction

II. WOWTAB® Tablets

A. Technology

B. Processing and Packaging

Process 1

Process 2

Process 3

Process 4

Process 5

C. Formulations

Example 1

Example 2

Example 3

Example 4

D. Performance and Clinical Testing

1. Hardness Test

2. In Vitro Disintegration Test

3. In Vivo Disintegration Test

E. Commercial and Future Products

III. ZYDIS® TABLETS

A. Technology

B. Processing and Packaging

C. Formulations

Example 1

Example 2

Example 3

Example 4

D. Performance and Clinical Testing

1. Uniformity Test

2. In Vitro Disintegration Test

3. Bioavailability Study

E. Commercial and Future Products

IV. Orasolv® Tablets

A. Technology

B. Processing and Packaging

C. Formulations

Example 1

Example 2

Example 3

Example 4

D. Performance and Clinical Testing

1. Disintegration Effervescent Test

2. Acid Neutralization Capacity (ANC) Test

3. Clinical Testing

E. Commercial and Future Products

V. ShearformTM Tablets

A. Technology

B. Processing and Packaging

C. Formulations

Example 1

Example 2

Example 3

Example 4

D. Performance and Clinical Testing

1. Microparticulate Size Analysis

2. Bulk Density Test

3. Calcium Release Test

4. In Vivo Disintegration Test

5. Clinical Evaluation

E. Commercial and Future Products

VI. Summary

References

12

Quick-Dissolving Intraoral Tablets

I. Introduction

II. Rationale for Formulating Quick-Dissolving Tablets

III. Formulation and Manufacturing Technology

A. OraSolv®

B. DuraSolv®

IV. Shipping Tests

V. Organoleptic Tests

A. OraSolv® versus Standard Tablet

B. OraSolv® versus Zydis®

VI. Pharmacokinetic Tests on OraSolv®

VII. The OraVescent™ Oral Cavity Drug Delivery Systems

REFERENCES

13

Process Development and Scale-Up of Oral Fast-Dissolving Tablets

I. Introduction to ODTs

II. Technology Overview

A. Commercial ODT Technologies

B. ODT Concepts, Formulation, and Mechanisms

1. Conventional Tablet Process

2. Freeze-Drying Process

3. Floss Technology

III. Product Quality and Design Approaches in Developing ODT

A. PQD Overview

1. Philosophy behind PQD

2. Benefits of PQD

B. Quality of Design

1. Input-Output Relationships

2. Design of Experiments

C. Quality of Conformance

1. Overview of Statistical Process Capability Analysis

2. Definitions, Terminologies, and Computational Approaches

3. Interpretation of Cpk

4. Assumptions for Process Capability

5. Applications of Process Capability in Pharmaceutical Development

D. Case Studies for PQD: Developing WOWTAB® ODT

1. General Formulation Considerations in WOWTAB® ODT

2. Case Study for Applying QOD via DOE

3. DOE Application at Pilot Scale

IV. Commercial Scale-Up

A. Case Study for QOC via Process Capability

B. Stability Testing of Scale-Up Product

V. Regulatory Considerations and Guidance in ODT Product Development

VI. Conclusions

Acknowledgments

References

14

Quick Dissolving Oral Dosage Forms: Scientific and Regulatory Considerations from a Clinical Pharmac

I. Introduction

II. Quick-Dissolving Oral Dosage Forms

III. Advantages and Limitations of Orally Disintegrating Tablets

IV. Clinical Pharmacology Considerations

A. In Vivo Assessment

1. Bioequivalence

2. Water Effect

3. Food Effect

V. Biopharmaceutics Considerations

A. In Vitro Assessment

B. In Vitro Dissolution Methodology, Requirements, and Challenges

VI. General Regulatory Issues and Considerations

VII. Summary