Pain is a feeling of discomfort associated with tissues, and painful sensations include acute and chronic pain. Acute pain is intense pain that lasts for a short time, usually caused by trauma, an internal disease, usually less than four weeks of pain and will go away once the wound heals. Chronic pain is pain that lasts longer than acute pain, usually up to 3-6 months, and can be mild, dull, or intense, the pain of any cause. Pain is regarded as a disease and needs to be treated in a timely manner, avoiding the consequences that affect not only affect one individual but also affect the family and society, not only in terms of emotional but also economic and social influences in general. The American Society of Anesthesiologists (ASA) published this burden status with at least 10 percent of the world's population, about 60 million people, having chronic pain. The estimation rates are close to 20-25 percent in some countries and regions. It is a fact that there is still a lack of optimal medicine, high pain relief, safety, low degradable, to avoid waste and save budget. Therefore, we want to more deeply investigate the role of ‘chronic pain relief’ with the greatest efficiency and safety.
The most commonly used clinical analgesics can be broadly classified into strong opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). Developing new pharmacological treatments with long-term efficacy and few side effects remain one of the key challenges in the study of chronic inflammatory pain base on the development of a single-step method of water-in-oil-in-water (W/O/W) synthesis poly (lactic-co-glycolic acid) (PLGA) nanoparticles. This nanoparticle has the ability to achieve dual encapsulation of hydrophilic drug Ketorolac Tromethamine (KT) and hydrophobic drug Prednisolone (Pred), which nanocarriers ensure compatibility, benefit in long-term efficacy treatment, and reduce side effects such as some serious complications of treatment with KT, such as GI ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions, and liver failure. Besides that, implementation of single-step synthesis of PLGA with a steroid (proposed as hydrophobic Pred) in order to prolong the absorption time for chronic inflammatory pain.
We demonstrated the characterization of the dual encapsulation PLGA nanoparticles (PLGA@KT@Pred NPs), including particle size, encapsulation efficiency, drug loading efficiency, drug release, and biocompatibility by using the zeta potential at a dielectric constant 78.3, DLS and TEM. In vitro release of bioactive agents can be carried out in simulated body fluids (SBF) such as HG-DMEM (Dulbecco's Modified Eagle Medium with High Glucose) at 37 °C, and the released drug can be quantified by using a UV-VIS spectrophotometry at 325 nm for KT and 248nm for Pred. The drug release was calculated for 120 hours with KT; Pred was showed faster delivery just only for 24 hours. Vero cell viability and cytotoxicity have been measured and demonstrated under different drug concentrations.
Animal model by measuring pain-induced changes in thresholds of hind paw withdrawal from mechanical pressure in a pain ICR mouse model. The pain killer and inflammation reduction effectiveness were conducted while two main therapeutic approaches were compared between pure drugs and drugs entrapped in PLGA nanoparticles. Whereas tissue samples of liver, stomach, and kidney were also harvested and tested for toxicology in animal models after 48hrs of drug application.
In our study, we developed a dual-emulsion drug encapsulation in PLGA NPs that includes two layers of hydrophilic and hydrophobic drugs successfully. We demonstrated that the nanomedicines with KT and Pred can reduce chronic pain and these dual entrapped drugs have also been clearly proven to be non-toxicity and have no side effects in both in vitro and in vivo studies. The aim of our study is to explore and develop the potential of a highly effective dose of pain relief with minimal side effects, possibly improving the quality of life for chronic pain patients and reducing the cost of treatment.

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