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VOLUME: 08, Issue 04, Paper id-IJIERM-VIII-IV, August 2021
121EXPLORING THE POTENTIAL OF LIPOSOMES AS A TRANSDERMAL DRUG DELIVERY SYSTEM: A COMPREHENSIVE REVIEW OF PROGRESS, LIMITATIONS, AND NOVEL
APPROACHES
Hariprasad Kadiyam
Assoc. Professor, Department of Pharmaceutical Chemistry, Princeton college of Pharmacy, Hyderabad, Telangana, india
Golla Lavanya
Asst. Professor, Department of Pharmaceutical Chemistry, Princeton college of Pharmacy, Hyderabad, Telangana, india
Abstract - Because it circumvents a number of issues that are associated with the oral route of drug administration, the transdermal route of drug delivery has piqued the interest of pharmaceutical research. This kind of drug carrier system is one of a kind because it can carry hydrophilic, lipophilic, and amphiphilic drugs. Before being delivered to the skin, these medications are placed in a variety of locations within the vesicle. Liposomes are microscopic, lipoidal vesicles that are the subject of extensive research as potential drug carriers with the goal of enhancing the delivery of therapeutic agents. Several liposome- based drug formulations are currently in clinical trials as a result of recent advancements in liposome technology. Some of these formulations have recently received approval for clinical use. The reformulation of drugs into liposomes has provided an opportunity to alter the bio distribution of various agents, primarily in order to improve their therapeutic indices. With examples of formulations that have been approved for clinical use, this review discusses the potential uses of liposomes in drug delivery as well as the drawbacks of expanding their use.
Keywords: Liposome, Amphotericin B, Drug delivery system, Doxorubicin, Pharmacokinetic.
1 INTRODUCTION
The design and synthesis of hundreds of new agents with the potential to act in vitro against a wide range of therapeutic targets has been made possible by recent advancements in biomedical science and combinatorial chemistry. However, in the clinic, the majority of these new drugs do not live up to their potential. For instance, despite the fact that many anticancer agents are highly cytotoxic to tumor cells in vitro, they cannot be used in the clinic due to their lack of a selective antitumor effect in vivo. The low therapeutic index (TI) of antineoplastic drugs is one of their major drawbacks; this refers to the fact that the dose required to have an effect against tumors is toxic to healthy tissues.
These drugs may have a low TI because:
(i) that they are unable to attain therapeutic concentrations at the target site (solid tumors); ii) nonspecific cytotoxicity to vital normal tissues like the
heart, intestines, kidneys, and bone marrow; and/or (iii) issues with the drug's manufacturing, such as its low solubility in pharmaceutically appropriate containers, necessitating the use of organic cosolvents or surfactants, both of which have their own undesirable side effects. As a result, efficient delivery systems are required that not only facilitate drug formulation but also alter drug biodistribution so that a greater proportion of the dose reaches the intended site. Liposomes are colloidal or microparticulate carriers that spontaneously form when certain lipids are hydrated in an aqueous medium8.
Their typical diameter ranges from 0.05 to 5.0 micrometers. Liposomes are made of a material that is relatively biocompatible and biodegradable. They are made up of an aqueous volume that is held in place
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122 by one or more bilayers of lipids, eithernatural or synthetic.
2 CLASSIFICATION OF LIPOSOMES 2.1 On the Basis of Composition
Liposomes are composed of natural and/or synthetic lipids (phospho- and sphingo-lipids), andmay also contain other bilayer constituents such as cholesterol and hydrophilic polymer conjugated lipids. The net physicochemical properties of the lipids composing the liposomes, such as membrane fluidity, charge density, steric hindrance, and permeability, determine liposomes' interactions with blood components and other tissues after systemic administration. The nature and extent of liposome-cell interaction in turn determines the mode of intracellular delivery of drugs. Thus, the predominant mechanism behind intracellular delivery of drugs by liposomes may mainly depend on their composition, as depicted.
Liposomes can be classified in terms of composition and mechanism of intracellular delivery into five types as: (i) conventional liposomes (CL); (ii) pH- sensitive liposomes; (iii) cationic liposomes; (iv) immunoliposomes; and (v) long-circulating liposomes (LCL). The typical composition and characteristics for these types of liposomes.
2.2 On the Basis of Size
The liposome size can range from very small (0.025 /~m) to large (2.5/~m) vesicles. Furthermore, liposomes may have single or multiple bilayer membranes. The vesicle size is a critical parameter in determining circulation half- life of liposomes, and both size and number of bilayers influence the extent of drug encapsulation in the liposomes. On the basis of their size and number of bilayers, liposomes can also be classified into one of three categories: (i) multilamellar vesicles (MLV); (ii) large unilamellar vesicles (LUV); and (iii) small unilamellar vesicles (SUV). The size and
characteristics of these types of liposomes.
2.3 Applications of Liposomes in Drug Delivery
When an existing formulation is unsatisfactory and a reformulation offers superior therapeutic efficacy and safety over the existing formulation, new drug delivery systems like liposomes are developed. For sure, liposome plans of certain medications have shown a critical expansion in remedial viability or potentially helpful records in preclinical models and in people, contrasted with their non-liposomal details. There are a few general categories that liposomes can be used for in medicine, which are briefly described below.
Definition Help: For human systemic administration, hydrophobic medications like cyclosporin and paclitaxel typically consist of surfactants and organic co- solvents. At the dosages required to deliver the drug, these solubilizers may cause toxicity. Liposomes, on the other hand, can contain a wide variety of drugs that are water-insoluble (lipophilic) and are made up of lipids, which are relatively non-toxic, non-immunogenic, biocompatible, and biodegradable molecules. Preclinical studies have evaluated liposomes as a vehicle for the delivery of paclitaxel and its analogs as an alternative to the cremophor/ethanol vehicle. At the moment, liposomes or phospholipid mixtures are being used as excipients for the preparation of better- tolerated preclinical and clinical formulations of several lipophilic, poorly water soluble drugs, such as amphotericin B. These formulations are being prepared using liposomes Paclitaxel liposomes had the option to convey the medication foundationally and increment the restorative file of paclitaxel in human ovarian growth models.
Intracellular Medication Conveyance:
For a drug to have pharmacological activity, it must cross the plasma
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123 membrane and have targets or receptorswithin the cell. Liposomes can be used to improve the cytosolic delivery of some drugs, like N-(phosphonacetyl)-L- aspartate (PALA), which are typically not well absorbed by cells16,17. Through fluid-phase endocytosis (pinocytosis), PALA enters the tumor cells and diffuses into the cytoplasm as the endosome pH drops12. However, pinocytosis only works in a very limited way.
Drug Administration with Sustained Release: Drugs like cytosine arabinoside (Ara-C), which are rapidly cleared in vivo and require plasma concentrations at therapeutic levels for an extended period of time for optimal pharmacological effects4,9, necessitate sustained release systems. Now, formulations of sustained release liposomes with a longer half-life in circulation and an improved drug release rate in vivo can be designed. For instance, Ara-C embodied in LCL is viable as a drawn out discharge framework in the treatment of murine L1210/C2 leukemia3,5. By slowly leaking drugs from RES into the general circulation, conventional liposomes that localize by phagocytosis in the cells of RES may also serve as a sustained release depot.
Site-Evasion Conveyance: Drugs used to treat cancer typically have a low therapeutic index (TI) and can be extremely toxic to healthy tissues. By reducing their delivery to essential normal organs, these drugs may be less toxic. By encapsulating the drug in liposomes, it has been demonstrated that even a modest reduction in the amount of drug that reaches critical organs can significantly reduce its toxicity.
Site-Explicit Focusing on: The idea of site-specific delivery, which was first put forth by Paul Ehrlich15, entails delivering a larger portion of the drug to the target location, thereby minimizing exposure to normal tissues. Both passive and active drug targeting have been achieved with liposomes.
3 LIMITATIONS OF LIPOSOME TECHNOLOGY
As described above, liposomes have a great potential in the area of drug delivery. However Liposome-based drug formulations have not entered the market in great numbers so far. Some of the problems limiting the manufacture and development of liposomes have been stability issues, batch to batch reproducibility, sterilization method, low drug entrapment, particle size control, and production of large batch sizes and short circulation half-life of vesicles. Some of these issues such as short half-life have been resolved resulting in increased numbers of clinical trials and new approvals. Some of the remaining problems are discussed in detail below.
Stability: The physical and chemical stability of liposomes is one of the main barriers to their widespread use. The chemical and physical instability of the final liposome formulations may result in short shelf lives, depending on their composition. Ester bond hydrolysis and/or lipid unsaturated acyl chain oxidation can both lead to chemical instability. Drug leakage from the vesicles and/or vesicle aggregation or fusion to form larger particles can both result in physical instability.
Efficiency of Encapsulation: Because lipids in high doses may be toxic and also cause non-linear (saturable) pharmacokinetics of liposomal drug formulation, liposome formulation of a drug cannot be developed unless the encapsulation efficiency is such that therapeutic doses can be delivered in a reasonable amount of lipid. For hydrophilic drugs, some novel strategies with high encapsulation efficiencies have been developed. For example, dynamic stacking of the amphipathic frail acidic or fundamental medications in void liposomes can be utilized to build the embodiment productivity. Paclitaxel, a hydrophobic drug with an encapsulation efficiency of less than 3 mole percent, is not a good candidate for active loading
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124 because of its low affinity for lipidbilayers.
Aiming at the Future: Due to RES's non- specific uptake by cells, active targeting with ligand-directed immunoliposomes has been limited by their rapid clearance.
Since LCL are not as quickly cleared by RES, the creation of LCL that are conjugated with ligands has rekindled interest in this area. However, there are still numerous issues to be resolved. For instance, immunoliposome-conjugated foreign immunoglobulin ligands may increase clearance upon subsequent exposure and induce immunogenicity.
Degradation of Lysosomes: The efficacy of the liposome is determined not only by the quantity of drug associated with the cell but also by the quantity of drug reaching the "target molecule" within the cells once it reaches the target cell.
Although immunooliposomes can selectively deliver the drug to cells, the drug's pharmacological activity is contingent on the drug's intact ability to diffuse sufficiently into the cytoplasm from the endosomes.
Liposome Formulations in Market Several nations have granted clinical approval to liposome and lipid-complex formulations of doxorubicin, daunorubicin, and amphotericin B (AmB).
Doxorubicin and daunorubicin, two examples of highly effective antineoplastic drugs, However, in humans, they can cause severe cardiac toxicity. The major dose-limiting factor for free doxorubicin is the potential for irreversible cardiomyopathy, which limits the human lifetime cumulative drug dose to 550 mg/m2. It has been demonstrated that long-circulating liposome formulations of anthracyclines improve the TI of the drugs against a variety of solid tumors by increasing drug accumulation in tumors and reducing cardiac toxicit. Doxorubicin is an excellent candidate for encapsulation in liposomes because it can be encapsulated into liposomes using an active loading technique with high efficiency. DoxilTM, a doxorubicin LCL
formulation, was the first liposome product approved for use in the United States. Due to avoiding high peak concentrations of the free drug, Doxil TM had a circulation half-life that was up to 8 times longer than that of the free drug19.
Additionally, the incidence of side effects was lower. Epitome of doxorubicin in liposomes has expanded the TI and made conceivable portion acceleration mostly by diminishing the portion restricting heart poisonousness. Amphotericin B (AmB) is an antifungal medication used to treat severe fungal infections of the body.
However, serious side effects of AmB therapy include nephrotoxicity, thrombophlebitis, hypokalemia, and anemia. The primary reason for therapy failure or discontinuation is these side effects, which limit the dose levels that can be achieved (0.7-1.5 mg/kg of Fungizone TM). Due to a decrease in the dose-limiting nephrotoxicity, lipid- and liposome-based formulations of AraB have been shown to have superior TI to the deoxycholate-based formulation (FungizoneTM). Other adverse effects are also less common; in certain examinations these (basically hypokalemia) went from 10 to 20%. It's possible that the selective transfer of AmB from lipid bilayers or complexes to the fungus (the target site) has reduced toxicity by reducing the drug's interaction with human cell membranes. AmB doses have been increased because side effects like nephrotoxicity have decreased in severity and frequency. In conclusion, this article briefly discussed some formulation and development issues as well as a review of the potential uses for liposomes.
The rising number of clinical trials involving liposome and lipid-based products is a positive sign. Several businesses are actively expanding and evaluating liposome products for use in anticancer and antifungal therapy as well as prophylaxis (vaccinations) against diseases in light of recent advancements in the field. The full development of
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