Benefits of Liposomal Nonsteroid-Anti-Inflammatory Drugs

Liposomal


INTRODUCTION
Liposomes were discovered by Alec D Bangham in 1961 at the Babraham Institute, University of Cambridge, and consist of single or multiple concentric lipid bilayers encapsulating an aqueous compartment.It took an unexpectedly long period and varying levels of applications and popularity to establish liposomes as a drug delivery platform.With their biocompatibility and well-understood chemistry of encapsulation of a wide variety of active pharmaceutical ingredients (APIs) liposomes make it through the screening process for many potential products [1].
Liposomes are small artificial vesicles of spherical shape that can be created from cholesterol and natural non-toxic phospholipids.Due to their size, hydrophobic and hydrophilic character (besides biocompatibility), liposomes are promising systems for drug delivery [2].Liposomes are robust drug delivery systems that have been developed into FDAapproved drug products for several pharmaceutical indications.Direct control in producing liposomes of specific dimensions for their distribution is extremely important since their size may impact cellular uptake and biodistribution [3].

TOPIC
Depending on the substance they are intended to carry, the size of these nearly spherical lipid vesicles can range from a few nanometers to several micrometers [3].However, liposomes applied for specific medical purposes range between 50 and 450 nm [4].
Generally, liposomes could be used for local (topical) and system applications (ampules and pills).The development of liposomal formulations began by studying their topical application as cosmetics and topical medication carriers (gels, creams, and ointments).Given the relatively new technology in pharmacy and clinical pharmacology, trends of their usage encompass topical application for the most frequent indications of rheumatic degenerative diseases: rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, tendonitis, ankylosing spondylitis, gout pain, bursitis, as well as other diseases and conditions accompanied by mild to moderate pain and inflammation as backaches, muscle aches, sports injuries/sprains, headaches, fever, dental pain, menstrual cramps.Liposomal formulations of non-steroidal anti-inflammatory drugs (NSAIDs) can be used in all population groups (children, adults, and the elderly) which gives them a wide range of applications [5].NSAIDs oral administration is associated with severe adverse effects in the gastrointestinal tract such as epigastric pain, heartburn, nausea, diarrhea, vomiting, peptic ulcer, and hepatic impairment [6].It has been observed in clinical trials, that liposomal formulations enhanced the drug permeability and the percentage of accumulated dose in the skin compared to control conventional gel formulations [7,8].Liposomal gel controls ibuprofen release and drug permeability in vitro and has shown a permeability pattern conducive to maintaining constant drug levels [9].
The possibility of developing a good formulation of liposomal NSAIDs is being investigated in several research sites worldwide.Due to its clinical significance and financial effect, the development of liposomal drugs is greatest in the field of cytostatics [10].Until the publication of this paper, no drugs have been registered in the NSAID group [11,12,13].

APPLICATION
Liposomal technology is most commonly applied in cosmetology [14].Liposomes have a significant perspective in cancer therapy because by targeting the active site, they do not damage the surrounding healthy tissue and thus give fewer side effects.To some extent, there are also yet unexplored application possibilities for liposomes, such as therapy for Alzheimer's disease [15,16].
So far, liposomes containing sodium diclofenac, indomethacin, aceclofenac, and related NSAIDs have been produced in laboratory conditions.Although varying in size and structure, they all possess certain common advantages -increased dermal availability of lipophilic drugs and their targeted delivery onto the required location [17].Liposomes have been proven highly effective in terms of retaining the NSAIDs in the synovial cavity, most of all because of their size and chemical composition.Undesirable therapy effects, fast clearance, and exposure to nontargeted sites could be minimized by administering NSAIDs using liposomes as carriers.Side effects and complications associated with the long-term oral and intramuscular applications of NSAIDs could especially be avoided using their liposomal formulations [18].In animal models, liposomes containing NSAIDs have been detected even one week upon injection into the organism, explaining the prolonged action of drugs over this period of time [19].Liposomes offer the capacity of delivering lower doses of drugs with reduced toxicity, thus improving the risk/ benefit ratio of NSAIDs.However, routine clinical applications of liposomal NSAIDs are yet to be developed to their full potential, with improvements required in regards to the stability and efficacy of the specific liposome formulations.
Chronic inflammation is defined as a chronic, low-level inflammation process that can last for months, years, or a lifetime.Constant tiredness, soreness in the mouth, discomfort in the joints, chest or abdomen, rash, and fever are often symptoms or indications of inflammation [18].To achieve the intended therapeutic effects on inflammatory cells, high doses of drugs are often given, which can have side effects on healthy tissue.Non-steroidal anti-inflammatory drugs (NSAIDs) weaken pain by reversing the action of the enzyme cyclooxygenase (COX).NSAIDs prevent pros-taglandin synthesis and reduce or eliminate pain.Some of the drugs in this group in widespread use are aspirin, ibuprofen, diclofenac, etc.Since they are among the most commonly used drugs, the study has been conducted to investigate the method to improve their clinical effects by means of using liposomes as NSAID drug delivery systems.Such kind of delivery has a number of advantages related to commonly used methods since liposomes could be specifically designed to gradually release the API, which is especially important for topical applications.Furthermore, liposomes are biocompatible, have the capacity to self-assemble, are able to carry large drug loads, can be functionalized enabling targeted drug delivery, and could be modified in a wide range of physicochemical and biophysical properties controlling their biological characteristics.The advantages of using liposomal NSAIDs are better penetration into the tissue and thus greater efficiency and longer duration of action, the lower dose required to achieve greater therapeutic effects (reduction of pain, swelling, and redness), and the possibility of combining two or more drugs [18,20,21].Recent studies show that dipalmitoylphosphatidylcholine (DPPC)/ Cholesterol spin-labeled liposomes containing NSAIDs penetrate deeply into the skin remaining stable for several hours, making them promising chronic inflammation therapeutics carriers [22].Global's Burden of Diseases 2000 incidence data on Rheumatoid arthritis (RA) illustrate the significance of a proper therapeutic choice in the treatment of this degenerative painful syndrome.The incidence of RA ranges between 20-300 per 100,000 adults per year.The global average case fatality rate is around 1 per 1,000 prevalent cases in both male and female populations [23].Treatment of painful conditions with topical preparations is mostly performed as a patient self-treatment, so the drug formulations have to be fast-acting and comfortable for application, especially in the case of sports injuries [24].
The usage of liposomes to assist NSAIDs delivery has a major impact on many biomedical areas (rheumatology, immunology, sport, recreation, physical treatment, etc.).They are biocompatible, biodegradable, and enable the trapping of both hydrophobic and hydrophilic compounds.They increase drug delivery to the tumor site while lowering systemic toxicity [25].
A few clinical trials of transdermal www.hophonline.orgapplications showed the superiority of nanoliposome formulations over non-vesicular ones, and that lipid composition containing a 7/3/1 molar ratio of phosphatidylcholine, cholesterol, and dicetyl phosphate is optimum for nanoliposome preparations, in the cases where controlled delivery of a drug is needed for a sufficient period of time [26].
Liposomes can be seen as ideal carriers for anti-inflammatory drugs as their ability to (passively) target sites of inflammation and release their content to inflammatory target cells enables them to increase local efficacy with only limited systemic exposure and adverse effects [27].
Consequently, for poorly watersoluble drugs, the cationic liposome system was a potential approach to improve ocular bioavailability and patient compliance [26].A few NSAIDs are experimentally formulated in liposomes having improved pharmacokinetic characteristics.Further clinical investigations will show their pharmaco-dynamic effects.The in vitro release and ex vivo permeation (permeability) study showed a prolonged diclofenac release with high permeation flux [29].
Improving modern pharmacotherapy is demanding and is done through the optimal choice of drugs, optimal dosing, control of interactions between drugs, as well as minimizing the occurrence and consequences of drug side effects.In accordance with that, the development of new forms of liposomes as delivery systems could be one of the best solutions.Achieving desired therapeutic effects is a challenging task and a motive for adhering to the highest ethical standards of Good Clinical Practice [30].
The selection of registered NSAIDs is mostly the same worldwide, with some minimal differences [31].Typical non-selective NSAIDs include Diclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Oxaprozin, Piroxicam, Sulindac, Tolmetin.COX-2 Selective NSAIDs: Celecoxib, Rofecoxib, Valdecoxib.NSAIDs are able to prevent prostaglandin synthesis and reduce or eliminate pain.NSAIDs typically relieve pain by reversing the action of the enzyme cyclooxygenase (COX).Some of the drugs in this group that are mostly used are aspirin, ibuprofen, diclofenac, etc.Therefore, investi-gations should be conducted in way to study the method of improving their clinical effects using liposomes as NSAID drug delivery systems.Such kind of delivery has a number of advantages related to commonly used methods since liposomes could be specifically designed to gradually release the active pharmaceutical ingredients, which is especially important for topical applications [22].Furthermore, liposomes are biocompatible, have the self-assembling ability, can carry large drug loads and be functionalized enabling targeted drug delivery, and could be modified in a wide range of physicochemical and biophysical properties controlling their biological characteristics.The usage of liposomes to assist NSAIDs delivery has a major impact on many biomedical areas (rheumatology, immunology, sport, recreation, physical treatment, etc.) [22,30].
Liposomes present attractive delivery systems due to their flexible physicochemical and biophysical properties, which allow easy manipulation to address different delivery considerations.The advantage of liposomalbased products is the ability of liposomes to deliver active pharmaceutical ingredients in a targeted manner [1].The targeting precision of the exterior of the phospholipid/liposome can be readily designed for a wide level of applications.The topical application of liposomes and the final registration of products through all four phases are feasible according to regulations without the special complexity in terms of the research equipment.Without entering into the pharmacoeconomic analysis of consumption and financial share of NSAIDs in the Republic of Serbia, researchers are studying the advantages and specifics of drug-loaded liposome production in laboratory conditions, because they are affordable and convenient to develop, improve and adapt [22,30].However, in some cases, liposomes' production complexity, deterioration, particle size variability, and distribution make them rather challenging for production, which often turns out to be more of an art than a science.Therefore, the development of liposomes as carriers of the active substances highlights new directions that are being considered for the next generation of therapies [1,32].More should be discussed related to the advances in liposome-assisted NSAID drug delivery, especially liposome composition, size, control of their degradability, biological challenges, and current clinical and experimental use for biowww.hophonline.orgmedical applications [22,33].

CONCLUSION
The use of liposomes as drug carriers becomes a notable positive step in the treatment of inflammatory, pain-causing, and rheumatic diseases.Liposomes present an attractive delivery system due to their flexible physicochemical and biophysical properties, which allow easy manipulation to address the different delivery considerations.
The main objectives for the development of NSAIDs in liposomal carriers are deeper penetration of the active substance, fewer side effects, better and longer effect, the ability to change the characteristics of both the drug and the carrier, and adequate dose adjustment.Despite several challenges that accordingly still need to be addressed, liposomal drug formulations have significant health-promoting potential.
Despite the encouragement of NSAID development and research studies, it still takes a long time for liposomal NSAID formulations to become available for everyday use.