Szerző szerinti böngészés "Pham, Le Khanh Ha"

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    Investigation of biocompatibility of polyethylene glycol derivatives and preparation of solid dispersion containing ketoprofen
    Pham, Le Khanh Ha; Bácskay, Ildikó; Gyógyszertudományok doktori iskola; Gyógyszerésztudományi Kar
    Polyethylene glycols (PEGs) are widely used polymer that have a variety of applications in many fields, including biomedical, chemical, and industrial processes. It has many applications in various industries, including pharmaceuticals, cosmetics, and food. These compounds are important group of excipients due to their widespread use in different pharmaceutical formulations, especially is a favorable choice to reach the optimal drug delivery system. Polyethylene glycols (PEGs) possess a range of physicochemical properties that make it an invaluable polymer in pharmaceutical sciences. Its solubility, viscosity, molecular weight, thermal behavior, and interactions with biological systems play pivotal roles in drug delivery system, formulation design, and therapeutic applications. PEGs have a favorable safety profile. They are ideal excipients due to their excellent features such as inert, non-immunogenicity, hydrophilicity, high biocompatibility making them ideal for pharmaceutical formulations. Its ability to increase solubility and stability of drugs makes it a valuable tool in pharmaceutical and biomedical research. For PEG to be used to theirs full potential in the creation of novel drug delivery systems, a thorough understanding of these properties is essential. In recent years, the quest for biocompatible materials has become paramount in biomedical research and applications. Every stage of the drug formulation process must take the drug safety profile into consideration. In order to ensure the safe and efficient interaction of biomedical materials with living systems, biocompatibility is a crucial component in their development. The aim of biocompatibility testing is to make sure that a substance or device will offer the patient the greatest benefit with the least amount of risk. The evaluation of a biomaterial's biocompatibility at the cellular and tissue levels is one of the primary requirements for its suitability for clinical use. Cytotoxicity testing, which illustrates how cultured cells are exposed directly to the test material or to its extract, is the fundamental and required component of biocompatibility evaluation at early stages of drug development. The cytotoxicity assays are a low-cost and quick in vitro techniques that assess the impact of drugs on cultured cells. This assay is applied to evaluate and characterize the potentially harmful/toxic of the tested compound to the cells. Based on the concept that living cells have quantifiable intrinsic metabolic activities, cytotoxicity assays are designed to measure the toxicity of a sample. The reduction in cell viability due to drug exposure can be measured through various endpoints, including cell proliferation, membrane integrity, enzymatic activity, and mitochondrial function. Ketoprofen, which has chemical name that is 2-(3-benzoylphenyl)-propionic acid, belongs to a propionic acid group of a non-steroidal anti-inflammatory drug (NSAID). By blocking the production of prostaglandins, ketoprofen helps to reduce pain, swelling, fever and inflammation. This medication is commonly used to relieve symptoms associated with various conditions, including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gout, menstrual cramps, and musculoskeletal injuries such as sprains and strains. It is available in various formulations, including oral tablets, capsules, extended-release capsules, and topical gels. The solubility of ketoprofen is an important characteristic that affects its dissolution rate, absorption, and bioavailability. The solubility of ketoprofen in water is 51 mg/L at 22oC which means that ketoprofen is practically insoluble in water. This solubility profile is critical for formulation development, as it affects the choice of appropriate solvents, co-solvents, and surfactants to enhance drug solubility and bioavailability. As solubility and permeability play a critical role in determining the bioavailability of the drug, The Biopharmaceutics Drug Classification System (BCS) is a system that categorizes a drug (API) based on aqueous solubility and permeability across intestinal membrane properties which is classified in to four classes which are class I: high solubility (S), high permeability (P), class II: low S, high P, Class II: high S, low P, class IV: low S, low P. More than 70% of medications are reported to be poorly soluble and belong to BCS classes II and IV. It is estimated that most compounds undergoing development at the present time are subjected to poor bioavailability of these compounds. The solubility is an important factor for drug release which is an essential and limiting step for oral drug bioavailability. The poor solubility and low dissolution rate of poorly water-soluble drugs in the gastro intestinal fluid often lead to an insufficient efficacy. The solubilization behavior of the drug is the key determinant for the oral bioavailability determination The low solubility of the drugs which leads to low dissolution rate is the biggest obstacle in the performance of poorly water-soluble (PWS) drugs. . The creation of efficient drug formulations presents many difficulties in the field of pharmaceutical sciences, especially when dealing with poorly soluble drugs. Poor solubility and limited permeability significantly hinder the successful delivery of therapeutic compounds. Therefore, improving the solubility and permeability of poorly soluble/permeable drugs is necessary to increase the drug bioavailability, thereby enhancing therapeutic efficacy, and optimizing the pharmacokinetic parameter of pharmaceutical products for better patient outcomes. To solve this problem, various strategies for solubilization enhancement have been developed such as nanoparticle, inclusion complex, lipid formulation, salt formation and solid dispersion. Among these strategies, solid dispersion (SD) is a well-known method for improvement in the solubility, dissolution rate and bioavailability of poorly water-soluble drugs. Solid dispersion is defined as dispersion of one or more active ingredients (hydrophobic) in an inert carrier matrix (hydrophilic) at in the solid state. The characteristics of the API, the carriers or the excipient should be evaluated carefully before selecting appropriate method to prepare the SD because each method have its own advantages and disadvantages. Solid dispersion shows many mechanisms to become one of the promising techniques for the low solubility drugs. The underlying mechanisms for improvement of the bioavailability of poorly water soluble (PWS) drug by SD technique are particle size reduction, particles with high porosity, wettability and dispersibility improvement, drug in amorphous state. Based on the points mentioned above, solid dispersion techniques have the potential to significantly increase the bioavailability and dissolution rate of drugs with poor water solubility, such as NSAID. General objective of my thesis was to investigate various PEGs derivatives and their characteristics and followed by the preparation of ketoprofen-containing solid dispersion using selected PEG derivatives.As most studies involved only a limited number of derivatives and I wished to better understand the cytotoxicity of these compounds, eleven substances of various molecular weights on a much wider scale: PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1500, PEG 4000, PEG 8000, PEG 10000, PEG 12000, PEG 20000 were examined. Also, I would like to check how the change of PEGs’ molecular weight affects on the properties of PEGs and their SDs. In the first part of my thesis is to examine the toxicity of various PEG derivatives based on cellular effects (cytotoxicity and autophagy) and in vivo toxicity which is a necessary step before investigating the solid dispersion containing PEG derivatives and poorly soluble API. Because PEGs are a common excipient used to increase the solubility of active pharmaceutical ingredients, I looked for an API that is not well soluble. The solubility of ketoprofen was improved by solid dispersion preparation using PEG derivatives that I had previously studied for the first section of my thesis. In the second part of the thesis, the aim is to formulate binary ketoprofen - PEG hot melt homogenization solid dispersions with low molecular weight polymers which were PEG 1000, 1500 and 2000. The physicochemical characteristics and the dissolution profiles of theses solid dispersions were examined. The relationship between low molecular weight PEG derivates and ketoprofen-SD characterization were also investigated regarding the effects of molecular weight of PEGs.