Abstract
Controlled drug release first emerged as an idea in the early 20th century and has been a topic of interest to the scientific community since then. It involves discreetly combining a polymer, natural or synthetic, with a drug or active agent in such a way that the active agent is released from the material in a predetermined manner. In addition to the polymeric materials used in this field, important factors include the pharmaceutical form (such as tablets, creams, patches, injectable solutions, nanoparticles and microspheres) and the mode of administration (such as oral, parenteral, pulmonary, transdermal, intranasal, cardiovascular, etc.). Compared to conventional drug delivery methods, the benefits of controlled drug release are numerous. Non-water soluble drugs can be transported more effectively in larger doses, and multiple types of drugs and diagnostic agents can be used for combined treatments. Targeted drug delivery to a specific cell or tissue increases the effectiveness of t ...
Controlled drug release first emerged as an idea in the early 20th century and has been a topic of interest to the scientific community since then. It involves discreetly combining a polymer, natural or synthetic, with a drug or active agent in such a way that the active agent is released from the material in a predetermined manner. In addition to the polymeric materials used in this field, important factors include the pharmaceutical form (such as tablets, creams, patches, injectable solutions, nanoparticles and microspheres) and the mode of administration (such as oral, parenteral, pulmonary, transdermal, intranasal, cardiovascular, etc.). Compared to conventional drug delivery methods, the benefits of controlled drug release are numerous. Non-water soluble drugs can be transported more effectively in larger doses, and multiple types of drugs and diagnostic agents can be used for combined treatments. Targeted drug delivery to a specific cell or tissue increases the effectiveness of treatment and minimizes serious side effects, while it can be administered in specific doses and at specific times. However, scientists must solve certain problems in order to effectively synthesize a controlled system. These include eliminating the potential for toxicity and incompatibility of in polymeric systems, controlling the likelihood of different in vivo behavior of formulas compared to in vitro behavior observed in the laboratory. Finally, the correct adjustment of the required dosage, the elimination of unwanted by-products and even the reduction of costs are important evaluation factors.Schizophrenia is a neuropsychiatric disorder that primarily affects adolescents and young adults. Its symptoms affect about 0.4% - 0.6% of the population at a young age. Risperidone, a first generation antipsychotic drug, is an effective treatment for patients with schizophrenia. Currently, the main commercially available form of risperidone are tablets or pills, which must be taken daily. However, it has been observed that patients may discontinue their treatment after a period of time, believing they have been cured, leading to regression of their symptoms. To address this issue, Long Acting Injectables (LAIs) have been developed as an alternative formulation, which is easier to administer and can give patients a sense of non-illness.LAIs are drug delivery systems that are administered topically, by intramuscular administration, creating a "depot" of drug that is released at a controlled rate and leads to the creation of a specific concentration of the drug in the human body. The advantages of LAIs over other formulations include the lack of unnecessary drug concentration in the liver and the constant "available" amount of drug in the body. The disadvantage of the currently commercial form of risperidone (Rispedral consta) is that there is a period of 7-8 days before its release begins. This is due to the hydrolysis of PLGA which is used as a polymeric matrix in these microspheres. Therefore, during the first week of administration, co-administration of risperidone tablets is required to achieve the desired concentration of the drug.The scientific community aims to prepare risperidone microspheres that release the drug from the first day of administration by replacing the PLGA copolymer with a faster-degrading polymer. PLA and its copolymers have been used as carriers for the delivery of various substances and drugs, including risperidone, due to their biodegradability, bioabsorption, and biocompatibility with the human body. While PLA has been proposed as a biocompatible material for medical use, its properties can be improved by modifying its structure or adding other polymers. PLA and its copolymers are considered safe by the US Food and Drug Administration (FDA) and are widely used in the medical field.The present dissertation examines the synthesis of new poly (lactic acid) (PLA) copolymers and their application in the preparation of risperidone microspheres for transport and gradual release into the human body. The aim of this PhD thesis is to prepare microspheres of a size similar to the commercial formulation, to control the release of risperidone and to eliminate the initial 7-day gap during release. PLA is biocompatible, bioabsorbable, non-toxic and has good physicochemical properties. However, its degradation rate is relatively slow, necessitating its modification. The addition of poly(hexylene succinate) (PHSu) is expected to improve the hydrolysis rate of PLA. PHSu has been chosen because, according to studies on succinic acid and its derivatives, it is non-toxic, has good thermal and mechanical properties, can be easily modified and is biodegradable.The first objective of this thesis was to synthesize PHSu and PLA-b-PHSu block copolymers in various concentrations. PHSu was synthesized through the 2-step polycondensation of succinic acid and hexanediol, while PLA-b-PHSu copolymers, in 95/05 90/10 and 80/20 mass ratios, were synthesized by ring opening polymerization (ROP) of L-lactide. The structural, chemical, mechanical and thermal properties of the prepared materials were studied using Nuclear Magnetic Resonance Spectroscopy (NMR), Fourier Transform Infrared Spectroscopy (FTIR), X-Ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Pyrolysis-Gas Chromatography-Mass Spectroscopy (Py-GC/MS), Broadband Dielectric Spectroscopy (BDS), Polarized Light Microscopy (PLM), Size exclusion chromatography (SEC), Scanning Electron Microscopy (SEM) and tensile tests. Cytotoxicity tests were also conducted to confirm the biocompatibility of the samples. The multiple experimental techniques were used not only to confirm the block copolymer structure of the prepared materials but also to verify and evaluate the set of properties that characterize the materials. The thermal degradation of the samples, as well as the non-isothermal crystallization during heating/cooling were further investigated through kinetic analysis by the application of multiple mathematical models. After fulfilling the initial requirements for further investigation, enzymatic hydrolysis, and its effect on the properties of the samples were studied. As part of the aim of this research is to enhance the degradation rate of the prepared materials, it is important to study the weight loss during enzymatic hydrolysis. The surface of the hydrolyzed samples was studied in relation to the primary materials (SEM) as well as their thermal properties through TGA, DSC and Py-GC/MS. The chemical and structural properties of the materials were also examined (XRD, FTIR) and compared with those before enzymatic hydrolysis.In the final part of this research, risperidone-loaded microparticles were prepared from PLA-b-PHSu copolymers and subjected to in vitro study. The spray drying procedure was used to synthesize the microparticles, and their morphology was examined through the SEM microphotographs. The properties of the samples were again examined to verify whether spray drying, and the encapsulation of the drug affect the properties of the microparticles compared to the primary materials. Finally, the drug loading and entrapment efficiency of risperidone were also investigated, as well as the in vitro release by the HPLC method. The release of risperidone was further studied using different theoretical models.
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