` MINSITRY OF HEALTH HANOI UNIVERSITY OF PHARMACY PHAM HUE NHI RESEARCH ON FORMULATION OF DICLOFENAC EPOLAMINE TRANSDERMAL PATCH GRADUATION THESIS HANOI - 2025 MINISTRY OF HEALTH HANOI UNIVERISTY OF PHARMACY PHAM HUE NHI STUDENT ID: 2001458 RESEARCH ON FORMULATION OF DICLOFENAC EPOLAMINE TRANSDERMAL PATCH GRADUATION THESIS Supervisors: 1. Nguyen Thi Thanh Duyen 2. Pham Van Hung Affiliation: Department of Industrial Pharmaceutics Faculty of Pharmaceutics and Pharmaceutical Technology HANOI - 2025 INDEX ACKNOWLEDGEMENTS .i LIST OF SYMBOLS AND ABBREVIATIONS. ii LIST OF TABLES.
iii LIST OF FIGURES AND GRAPHICS. Skin anatomical characteristics and transdermal drug delivery. Some information on transdermal patches. Advantages and disadvantages of patches.
General structure of the patch. Components of drug-in-adhesive patch. Preparation techniques and equipment. Overview of diclofenac epolamine .Physical and chemical properties.
Pharmacological effects and toxicity. Overview of studies. Research on preparation of topical medicine containing diclofenac epolamine. Research on the preparation of transdermal patches containing other pain-relieving drugs .16 CHAPTER 2: MATERIALS, EQUIPMENT, RESEARCH CONTENT AND METHODS.
Experimental materials and equipment. Data processing and result presentation methods.25 CHAPTER 3: EXPERIMENT, RESULTS AND DISCUSSION. Evaluation of some properties of raw material diclofenac epolamine. Solubility of DCE in some solvents.
Validation of assay of diclofenac epolamine. Establisment of linearity range in phosphate buffer 6. Allotropy of the pharmaceutical starting material diclofenac epolamine. Results of formula development for preparing diclofenac epolamine patch by solvent evaporation method.
Effect of matrix-forming polymer types. Effect of polymeric adhesive content. Effect of plasticizer content. Effect of drug content.
Effect of type of permeation enhancer .36 CONCLUSION AND RECOMMENDATIONS .42 ACKNOWLEDGEMENTS First of all, I would like to express my respect and gratitude to Assoc. Nguyen Thi Thanh Duyen - the lecturer who has wholeheartedly instructed, cared for and encouraged me during the process of doing this thesis. I would like to sincerely thank M. Pham Van Hung - the teacher who always cares, helps and guides me to have more correct directions during the time of scientific research as well as implementing the topic.
I would like to send my thankfulness to the staff members of the Department of Pharmaceutical Industry - Hanoi University of Pharmacy for helping and creating favorable conditions for me to complete this thesis. I would like to thank Ms. Hoang Thi Anh Nhat and Ms. Tran Tra Ly for always wholeheartedly guiding, supporting and encouraging me during my study and research.
My undergraduate experience would not be fulfilled without my friends and partners at the Industrial Pharmaceutics Laboratory - Nguyen Thi Kim Ngan, Tran The Ninh, Hoang Viet Khoa. Thank you for always accompanying, supporting and encouraging me a lot during the difficult time. I would like to thank my friends at the Pharmaceutical Chemistry Technology and Extraction Laboratory and the National Institute of Pharmaceutical Technology, and the class of 2026’s underclassmen gave me a lot of support and assistance throughout my scientific research and project implementation. And especially, I would like to thank my family, who have always been a strong advocacy, a spiritual motivation, and who have always supported and encouraged me on this path.
Hanoi, June 18, 2025 Student Pham Hue Nhi i LIST OF SYMBOLS AND ABBREVIATIONS Abbreviation Full text BCS Biopharmaceutics classification system BP British Pharmacopoeia BDM Volumetric flask CT Recipe DDVN Vietnamese Pharmacopoeia DCE Diclofenac epolamine EtOH Ethanol weight/weight Mass/mass NaCMC Sodium Carboxymethylcellulose HPLC High-performance Liquid Chromatography NSAIDs Nonsteroidal anti-inflammatory drugs PBS Phosphate buffered saline PEG Polyethylene glycol PVP Polyvinyl pyrrolidone RH Relative humidity RSD Relative standard deviation SD Standard deviation STT Numerical order TB Medium TCCS Manufacturer’s standards TLTK References tt/tt Volume/volume USP United States Pharmacopeia ii LIST OF TABLES Table 1. Some examples of adhesive excipients. Some examples of permeability enhancers. Solubility of some diclofenac compounds.
Some examples of permeability parameters of Diclofenac salts. List of materials used in the study. List of equipment and tools used in the research. Patch formulation composition in the study.
Assessment of patch adhesive properties. Solubility of diclofenac epolamine in some solvents. System suitability results. Linear validation results.
UV absorption of the standard diclofenac epolamine solutions in phosphate buffer 6. Formulas of patches examining matrix-forming polymers and patch adhesion assessment results. Drug release rate of the patches examining matrix-forming polymers. Formula of patches examining adhesive polymer content and patch adhesion assessment results.
Drug release rate of patches examining adhesive polymer content. Formulas of pacthes examining plasticizer content and patch adhesion assessment results. Drug release rate of patches examining plasticizer content. Formulas of patches examining drug content and patch adhesion assessment results.
Drug release rate of patches examining drug content. Formulas of patches examining permeation enhancers and patch adhesion assessment results. Drug release rate of the patches examining permeation enhancers. Amount of diclofenac epolamine permeating from patches examining permeation enhancers across cellulose acetate membrane.38 iii LIST OF FIGURES AND GRAPHICS iii Figure 1.
a) Longitudinal section of the skin, b) Structure of the epidermis. Routes of drug absorption through the skin. Structural formula of diclofenac epolamine. XRD spectrum of DCE-A: diclofenac epolamine anhydrous; DCE- MH: diclofenac epolamine monohydrate; DCE-DH: diclofenac epolamine dihydrate.
DSC spectra of DCE-A; DCE-MH; DCE-DH. Chromatograms of blank sample (a), standard sample (b), test sample (c) and placebo sample (d). Correlation between UV absorption and diclofenac epolamine concentration. XRD spectrum of diclofenac epolamine.
Release curve of the patch examining the matrix-forming polymer adhesion in pH 6. Release curve of the patches examining the adhesive polymer content in pH 6. Release curve of the patch examining the plasticizer content in pH 6. Release curve of the patch examining the drug content in pH 6.
Release curve of the patches examining permeation enhancers in pH 6. Amount of diclofenac epolamine permeating from the patches examining enhancer through cellulose acetate membrane .39 iv Introduction Diclofenac is a typical NSAID drug commonly prescribed for acute or chronic inflammation and pain in musculoskeletal diseases [3]. Current preparations on the market use diclofenac in the form of acid or sodium, potassium, diethylamine, epolamine salts, formulated according to a variety of routes of administration including enteric-coated tablets, rectal suppositories, aerosol solutions, topical gels, deep intramuscular injection solutions, etc. Oral diclofenac-containing drugs are well tolerated and have low accumulation due to their short half-life, but can cause undesired effects such as gastric ulcers, gastrointestinal bleeding, allergies or cardiovascular complications [11].
The skin is the largest organ composed of many layers and is the first immune barrier of the body, with the function of protecting the body from external agents [2]. The anatomical characteristics as well as the role of protecting the skin from the effects of chemicals limit the diffusion of drugs through the stratum corneum of the epidermis, making it difficult for drugs applied to the skin to achieve their treatment goals. On the other hand, topical preparations containing diclofenac have been studied to overcome the disadvantages of oral diclofenac. In particular, transdermal patches with the ability to release controlled drugs at the contact site or neighboring tissues have many advantages such as concentrating drugs at the target tissue, precise dose distribution, and limiting the impact of factors from the digestive tract.
Diclofenac epolamine is a salt form improving lipophilicity and water solubility compared to sodium and potassium salts, increasing the permeability of diclofenac through the stratum corneum and epidermis, suitable for use in transdermal dosage forms [13]. Drug-in-adhesive transdermal patches have a simple structure, are usually very thin and convenient to use. The drug and other ingredients are dispersed directly into the adhesive matrix-forming polymer, forming an adhesive layer capable of sustained release of the drug with appropriate adjustments in the formula [2][6]. Domestic and foreign studies have developed diclofenac epolamine drug-in-adhesive patches that show the effectiveness of maintaining stable drug concentrations in tissues, ensuring better compliance with the treatment regimen, and easily discontinuing the dose by removing the patch from the skin when the patient experiences adverse reactions.
On the foundations mentioned, the thesis "Research on the preparation of diclofenac epolamine transdermal patch containing" was conducted with the following objective: “Initial research on formulation of diclofenac epolamine 180 mg drug-in-adhesive patch using solvent evaporation method on laboratory scale. Skin anatomical characteristics and transdermal drug delivery The structural characteristics of the skin are a very important factor when using transdermal patches, as the skin is the first and primary barrier that determines the effectiveness of active ingredient absorption through the patch. a) Longitudinal section of the skin, b) Structure of the epidermis [10] The skin is the largest organ of the body consisting of water, proteins, fats and minerals, acting as body's first line of defense, protecting the body from external biological, physical and chemical agents. The skin is made up of three main layers (Figure 1.1a): the epidermis, the dermis, and the hypodermis.
[2][10] The epidermis (cuticle) is the outermost layer of the skin, which can be observed and touched (Figure 1. On the surface of the epidermis, there is a layer of fat, mainly fatty acids, triglycerides, cholesterol, and sebum, which helps the skin not to be too moist or dry and resists sudden changes in temperature. Because of the nature of fat containing cholesterol, it is both soluble in oil-based excipients and emulsifiable in polar liquids, so the fat layer almost does not affect the penetration of drugs into the skin. Below the fat layer is the stratum corneum, which is made up of 10-30 layers of tightly packed, durable horny cells that are bonded together in extracellular lipid fluid.
The stratum corneum contains 70% protein, 15% fat, and 15% water. When absorbed, it will swell and soften. The average thickness of the stratum corneum is about 20 - 40 , varying according to different skin areas and age, so the level of absorption of drugs from topical drugs depends on the location of the drug and the individual patient. The stratum corneum is considered the main agent in creating a protective barrier that prevents the penetration of substances through the skin, including drugs.
Effects on the stratum corneum such as removing or increasing the hydration of the stratum corneum significantly increase the level and rate of penetration/absorption of drugs through the skin [10]. Below the epidermis is the dermis, about 0.5-3 mm thick, with the functions of structure, support, elasticity, temperature regulation, providing oxygen and nutrients to 2 nourish the epidermis. The epidermis is made up of a network of collagen and elastin in a polysaccharide gel that creates a hydrophilic environment with many tissues including sweat and sebum glands, muscles and hair follicles, nerve endings, and a capillary system. The hypodermis (subcutaneous tissue layer) located below the dermis has the function of insulating body temperature, storing energy in the form of fat, containing sensory organs as well as protecting organs, bones, and internal organs.
It is a fatty tissue that connects under the skin and connects with the sebaceous glands in the dermis, containing large blood vessels. Therefore, the drug substance from the external drug form can enter the general circulation from the capillary system (dermis) (arteries and veins in the dermis) without being metabolized first through the liver; In addition, lipophilic drugs can pass through hair follicles directly into the dermis, however, drug absorption via this route is insignificant because hair follicles only account for 1-2% of the skin surface area. Routes of drug absorption through the skin [10] When applying topical drugs to the skin surface, the drug is released from the excipient matrix and then penetrates the epidermis to the skin tissues mainly by passive diffusion mechanism through three pathways (Figure 1.2) [10]: (i) Through the intercellular route: The most common route, the drug passes through the intercellular space between the horny cells, is mainly hydrophilic, and has a fairly large molecular size.