INTRODUCTION:

Lymphatic Filariasis (LF)

Filariae is a microscopic roundworm parasite that causes a disease called lymphatic filariasis¹. These Mf dwell in tissues and blood of human and migrate to the lymphatic system to become adult worms¹ and blocks the body’s lymphatic nodes and vessels. This obstruction results in fluid accumulation in tissues, which can lead to extreme swelling in the limbs and breasts².The disease is significantly progressive as leading to disfiguring elephantiasis in both genders. Elephantiasis is a common name for LF, because of the variation of illnesses where body parts of a person swell to enormous proportions ^3,4. The condition is known as elephantiasis because the ensuing skin has an elephant-like texture⁵. The disease is mostly visible in the lower limbs and arms. It also affects breasts in females and scrotum in males. Hydrocele is the predominant manifestation in males and in females loss of respiratory function due to tropical pulmonary eosinophilia (TPE). Patients with filariasis have episodi adenio lymphangitis (ADL)which results in severe pain and immobility. Other health issues brought on by filariasis include endomyno -cardial fibrosis, arthritis and renal failure etc⁶. Generally, it has been seen that this disease affects poor people more. People affected by this disease are alienated from society and while getting treatment for this disease, the poor become poorer. Because of the low socioeconomic position of the community and the poor sanitary conditions that result, the majority of those who are at risk for filariasis live in rural areas. This facilitates the spread of the disease⁷.

Etiology

Brugia timori, Wuchereria bancrofti and Brugia malayi are the three filarial worms from the family of Filarioidea and are responsible of lymphatic filariasis. These worms are handed over by mosquitoes namely Culex, Aedes and Anopheles. More than 90% of LF across the world are caused by W. bancrofti, while the remaining 10% is spread by B. malayi and B. timori. Few Southeast Asian nations have a high prevalence of the parasite B. timori⁸.

Current status of the disease

A World Health Organization (WHO) report which was released on 29^th Oct 2020. According to this, in the year 2019, 38 countries adopted the Massive Drug Administration (MDA) and provided drugs to vulnerable populations as recommended by WHO. As a result, 538.1 million people could be saved from the LF. The effect of MDA was such that 17 countries have achieved the target of eliminating LF as a public health problem. Some countries have been recently approved by WHO, that they have now successfully eliminated this deadly LF disease from their countries. Like Yemen, Kiribati and Malawi⁹. In the year 2000, a program was launched by WHO, named the Global Programme to Eliminate Lymphatic Filariasis (GPELF). Its main goal was to eliminate LF from all over the world by 2020. Unfortunately, the WHO failed to achieve this goal. Despite obstacles caused by COVID-19, WHO will speed up efforts to accomplish this objective by 2030. Since the beginning of GPELE, new worldwide estimates show a 74% drop in cases⁹. New guidance was published by WHO in 2017, on MDA therapy alternatives for the elimination of LF. A combination therapy using Ivermectin, Diethylcarbamazine citrate and albendazole (IDA) to enhance the effect of mass drug administration on the transmission of the parasite. 4.52 crore cases in eleven countries were treated in 2019. In India, IDA has expanded from 4 to 16 districts and treated more than 41 million cases⁹. WHO October 2022 reports state that, in 2021 48,77,12,408 Indian population required MDA. Medicine used during MDA is DA and IDA. The number of implementation units required for MDA is 195 but unfortunately, a total of 134 units implemented, the proportion of implementation units achieving effective coverage is 98.5%, the total population of implementation units targeted by MDA in 2021 is 91,39,845, and the reported number of people treated in 2021 is 25,02,16213 The Geographical coverage is 68.7%, program coverage is 78.5% and National coverage is 70.8 % is reported⁹.

Biology of LF

Nematode is the main cause of LF. The lymph channel of an infected person contains a long and thin parasitic worm whose length ranges from 7 to 10 cm. The adult form is known as microfilaria, both adult male and female microfilaria mate and generate millions of microfilariae (mf) and then release them into the bloodstream¹⁰. Now when the mosquito bites the infected person and sucks blood, then along with the blood, microfilariae also go inside through the proboscis. Then these microfilariae migrate through the gut wall to the thoracic muscles. Where microfilariae become shorter and thicker and develop into the first-stage larvae(L1) within a few weeks larvae progressively mature (L3, infective stage larvae) and move to the mosquito's proboscis. Now mosquito is ready to infect another person. At this point in time, when the mosquito bites a healthy person to take a blood meal, the mosquito can transfer mf into the person’s bloodstream and infect the person. Microfilaria progressively grows in the infected person’s bloodstream and later immigrates into the lymphatic system, where it obstructs lymphatic fluid movement. The blockage makes the fluid drain toward the body’s extremities, mainly the legs and feet, where phenotypic alterations in skin are visible. These alterations depend directly on the activity of the worm and the consequential obstruction in the lymph nodes¹¹. Mosquitoes serve as transmitting agent for LF. Several mosquito genera can transmit LF, but the most common is Wuhereria bancrofti. Other genera include Culex quinquefasciatus, which breeds in dormant water in urban villages, and Brugia malayi which is somewhat confined because it requires fresh water plants found in rural areas for growth of larvae.

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Parasite life cycle

Growth and replication of parasites take place in two phases. One is in the vector mosquito and the second one is in the human. For the parasite life cycle, both stages are essential. It is required for the growth cycle and transmission of parasites that the mosquito acts as a biological vector and intermediate host.

Figure 1. The life cycle of filariae

Mosquito: The mosquito sucks human blood meal and transfers microfilariae (eggs). When microfilariae are ingested in human blood the extrinsic life cycle of parasites starts. To reach the mosquito’s thoracic muscles, the microfilariae pass through its midgut wall. There, they grow shorter and thicker before becoming first-stage larvae. The first-stage larvae (L1) grow and develop into the more active second stage (L2) after 5- 7 days, and after 10 to 11 days, they expand and develop into the infective stage larvae (L3). After reaching maturity the majority of the infectious larvae (L3) relocate to the mosquito’s proboscis, where they are ready to infect people ^7,11.

Human: When a host is bitten by a mosquito, L3 is released onto the skin’s surface, and when the mosquito pulls its proboscis, L3 enters into the bite wound and moves to the lymphatics. The L3 larvae molt after 9-10 days to become the fourth-stage larvae. Before the L4 stage matures and becomes an adult, it takes a few days to a few months. Adult worms (both male and female) live together in lymph vessels and lymph nodes. The female worm creates a large number of microfilariae after mating, and these microfilariae go into the lymphatic system and disseminate through the bloodstream. It has been found that wuhereria bancrofti mature males measure 23.8 – 30.6 mm in length and 90 – 120 μm in width. The female measures from 42.2 – 46.3 mm in length and 160 -188 μm in width ^7,11.

Symptoms

The majority of filariasis patients exhibit no symptoms and unless they are tested. Before testing they are unaware that they have LF. At least 50% LF patients are asymptomatic. This silent infection gradually damages the lymphatic system, kidneys and disturbs the body’s immune system. This is directly related to the effectiveness of the patient’s immune system and may result in acute inflammation of lymphatic vessels with high temp. chills, body aches and swollen lymph nodes. Fluid may build up excessively in the tissues that are impacted ¹². In chronic cases LF causes lymphoedema (tissue swelling) or elephantiasis (skin thickening), as well as swelling in the limbs, breasts or scrotum (Hydrocele)¹³.

Diagnosis

Filariasis diagnosis can be done by various methods:

Blood tests: Blood is drawn at night and stained with Giemsa or hematoxylin and eosin to detect microfilariae, in addition to doing blood count, particularly of eosinophils. Identification of the kind of microfilariae is done according to the characteristics of the stage larva (L3) in humans, such as the number and position of caudal nuclei, cephalic space and the absence or presence of sheath¹⁴.

Urine and fluid examination: This is accomplished by centrifuging the fluid sample and the deposits that result are then placed on a slide and examined under a microscope and identified the microfilariae¹⁵.

Identification of adult worms in lymphatics: Using ultrasonography, it is possible to identify the adult worms in the lymphatic of diseased tissue in the spermatic cord, breast, scrotum and thighs¹⁶.

Immunological tests: Such as antigen tests, antibody assays, and polymerase chain reaction (e.g. TropBio Og4C3 test from TropBio in Australia) ^17,18.

Filariasis is generally diagnosed by figuring out microfilariae on Giemsa staind, skinny and thick blood film smear, utilizing the “gold standard” referred to as the finger prick test¹⁹.

The recent trails in the diagnosis of LF are:-

v Membrane filtration technique

v Ultrasonography

v Lympho Scintigraphy

v Immuno Chromatographic test (ICT)

Strategies for treatment or control of Lymphatic filariasis disease

In order to eradicate lymphatic filariasis, the National Filaria Control Programme (NFCP) was launched in the nation in 1955 with the intention of defining the issue and implementing control measures in endemic regions. The massive increase in filariasis over the past four decades is evidence that efforts to control the disease have failed¹⁹. The WHO began the worldwide project to eradicate lymphatic filariasis in 2000, and a disability control strategy is also being implemented in 27 countries. In the year 2000 and 2009 more than 695 million people received almost 2.7 billion treatments. The need to treat filariasis is growing with the present development of diagnostic and management techniques. In fact, the government and WHO have started number of programmes with the aim of halting the parasite that causes lymphatic filariasis transmission by using MDA to give an annual remedy to people living in endemic regions who are at risk of disease, and dealing with morbidity and stopping the disability amongst people who have already been afflicted with the ailment.

Lymphatic filariasis can be cured and controlled by a combination of three factors.

i. Control of vectors

ii. Transmission Blocking (WHO strategy)

iii. Reduce symptoms and killing of adult worms by chemotherapy.

Major important approaches to control or eliminate LF

i. Allopathic approach: Chemotherapy

ii. Ayurvedic approach

iii. Natural plants /Active constitute and their filaricidal activity

Table 1. List of conventional drugs and dosage regimens used in the treatment of Lymphatic filariasis disease

Drug	Dosage regimen	Advantages	Disadvantages	Drug-susceptibility	Reference
Diethyl Carbamazine (DEC)	6 mg/kg body weight in single or divided doses for 12 days.	mainstay drug to treatment of Filariasis hydrophilic, oral dosage form, low toxic	Only prophylactic used, contraindicated onchocerciasis	Microfilaricidal	21
Ivermectin (IVM)	Single doses of 150-200 mg/kg	broad-spectrum antiparasitic agent	First choice in onchocerciasis, less effective against filariasis	Microfilaricidal	22
Albendazole (ALB)	Single 400 mg progressively for 6-12 months.	broad spectrum anti- anthementic effect, oral dosage form, low toxicity	Individual not effective, effective in case of combination with other drug.	Microfilaricidal, anti-anthementic	23
Doxycycline	200 mg single dose on day one and then 100mg once a day	Broad spectrum antibiotic,	Contraindicating in children less than 9 years of age and pregnant women.	Wolbachia bacteria, Micro and Macrofilaricidal	24

Nano technological strategies for intestinal lymphatic drug transport

In recent years nanotechnology has gained more popularity in the range of drug delivery systems. Nanocarriers may fulfill the all-needed criteria in the field of advanced drug delivery systems. The major advantages of using nanocarriers are to promote drugs or vaccines by providing protection against unfavorable conditions or extracellular degradation, to improve selectivity in the targeted delivery and to reduce the drug administration frequency i.e. require less amount of drug in the duration of the treatment and to beneficial change the ADME profile of the drug²⁵.

Lymph node targeting by lipid-based nanocarrier DDS

Numerous lipid-based nanocarriers, including lipid emulsion, lipid nanoparticles and liposomes, phytosomse, neosomes have been used to study lymph node targeting for a long time²⁶. Effective targeting of lipid based nanocarriers to LNs depends on a number of parameters including particle size, surface charge, polyethylene glycol (PEG) modification, and an antigen-presenting cell (APC)²⁷.

Effect of size

Numerous research have concentrated on the efficient delivery of lipid-based carriers to LNs either directly or by cell-mediated delivery. The impact of particle size in targeting LNs has received much study attention. Lymphatic delivery was accomplished using engineered liposomes and solid lipid nanoparticles. Particle size has been revealed to be a key component in the intestinal fluid absorption of SLNs, which are delivered subcutaneously ^28,29. A 100 nm-diameter aqueous channel makes up the interstitial, a tiny structure. Thus SLNs of 10 to 100 nm in size are easily transported from administration through aqueous channels to target areas, i.e. lymphatics. Particles more than 100 nm in diameter will be maintained at the injection site, whereas particles less than 10 nm in size are reabsorbable into blood capillaries. Using the extrusion technique Oussoren et al., prepared several non-sized lipid vesicles that ranged in size 400 nm, 170 nm, 70 nm, and 40 nm (29). Smaller lipid vesicles (40nm) are taken up by the lymphatic system following subcutaneous delivery at a greater rate than more massive and unsized lipid vesicles. Lipid vesicles with a size of 400 nm were observed to be less uptaken by lymphatic system(<20%). In contrast to bigger small lipid vesicles, those in the 40 nm size range were not retain inside the LN (29). A more affinity for LN was found in large-size vesicles compared to small lipid vesicles, concluded that small sized vesicles (40 nm) improve LN transport ²⁹. Kato et al., have prepared 111 in-loaded lipid emulsions of various diameters (67 nm and 25 nm ) and analysed their uptake into the lymph and Lymph node from the intramuscular administration site³⁰. A comparison of lymphatic uptake revealed that particles of emulsion containing 67 nm size particles were more strongly retained in LNs than particles with a size of 25 nm, indicating that larger particles were more likely to be withstand in LNs. was observed. Additionally, it was noted that after being administered directly to lymphatic vessels, bigger size particle like 520 nm had been delivered to the subcapsular sinus³¹. Particle size of less than 100 nm in lipid vesicle formulation shows remarkable permeability both In vitro and Ex vivo. Bioavailability has been also improved by oral administration of the drug³². Less than 100 nm sized nanoemulsion have improved the oral absorption and solubility of lipophilic drugs³³.

Effect of surface charge

Drugs delivered intravenously, subcutaneously or orally are subject to certain limitations while entering the lymphatic system. The lymphoid stroma acquires a negative surface charge due to the presence of glycosaminoglycans³⁴. Nanocarriers bearing a neutral or negative charge are made permeable to the lymphatic system by the local negative charge³⁴. The most of cationic nanocarriers, on the other hand, are kept at their target locations by electrostatic interaction³⁵. The charges play a crucial role and also has different effects on the distribution and transit processes to LN³⁶ The anionic liposomes’ phosphatidylserine component promoted APC absorption by cells. In comparison to neutral and cationic particles, LNPs with a size of 30 nm and an anionic charge exhibited considerable particle aggregation within the LN. Positive charges on the surface of liposomes, nanoparticles and NLCs like novel drug systems can lead to improved retention at the injection site through interaction with negatively charged interstitial molecules³⁷.

Effect of PEGylation in lipid-based nanocarriers

The biomimicking membrane coating, Zwitterion coating, alteration in physicochemical properties, and blockade of the reticuloendothelial system pre-administration are few approaches used to bypass accelerated blood clearance^38-42But, conjugation using PEG (i.e., PEGlyation) is one of the most commonly used approaches to develop the nanocarriers with an enhanced half-life (plasma), pharmacokinetics, and biodistribution⁴³ PEGylated liposomes currently serve as a promising approach to LN targeting agonists for the stimulator interferon genes (STING)⁴⁴. The STING route is the primary mode for starting antitumor immunity versus the immunogenic tumor ⁽⁴⁵⁾ and it results in the stimulation of the STING route, which activates APC ripening and Type I Interferon generation^46,47. Although there are advantages offered by the PEGylation process, the cellular uptake due to the increase in the size of lipid-based nanocarriers may remain a challenge.

Effect of ligand alteration in lipid-based nanocarriers

One of the key elements for LN targeting in lipid-based nanocarriers, aside from PEGylation, is ligand modification. Oral absorption and transport can be changed by using ligands to modify the surface of LNPs. The oral bioavailability and lymphatic absorption of SLNs coated with N-carboxymethyl chitosan have been shown to significantly enhance in studies^48,
49. The class II anti-major histocompatibility complex (MHC) Fab' is used to modify liposomes in order to target APCs and increase the aggregation of nanocarriers in LNs after subcutaneous injection⁵⁰. The modified liposomes made with the MHC class Fab' fragment have a reduced size (about 85 nm) and are more easily transported via the lymphatic system. Targeting to LNs is further increased by converting the PEG moiety to a liposome (size 134 nm) and including a ligand (immunoglobulin, or IgG)⁵¹. The ligand-assisted modification of nanocarriers also enhances the uptake of cells at the injection site by dendritic cells (DCs). The 90 nm-sized liposomes containing gold nanocages were modified utilising the ligand (CD11c antibody) to target DCs, aid in DC cellularization, and transport to LNs⁵². To target the DCs, however, the modification in mannose (multivalent) is also helpful. A lipid-polymer combination containing trimannosylates has been proposed by Le Moignic et al. as a viable and potential approach for a cancer messenger RNA (mRNA) vaccination that targets LN⁵³.

In another study, it was reported that the increase in length of the lipid chain improves lymphatic transport, and the lipids with long chains were found to be highly efficient carriers⁵⁴.

Lipid-Mediated Lymphatic System Targeting

Dietary lipids are mostly transported from the gut to the systemic circulation via the lymphatic system. Normally, receptor-mediated endocytosis or micropinocytosis allows lipids to enter the gastrointestinal tract's enterocytes.

Chylomicrons are bundled into chylomicrons in the gastrointestinal epithelium and are exocytosed into the lamina propria from the basolateral aspect of enterocyte cells, where they essentially enter the first lymphatic channel. Eventually, chylomicrons drain into the subclavian vein and reach the systemic circulation via the thoracic duct. The chylomicron processing pathway facilitates systemic administration of oral medicines while preserving initial bypass, in addition to offering a channel to lymph nodes to augment immunotherapy. As a result, it presents numerous special chances for the creation of medication delivery systems. Triglycerides and other fatty acid-like lipid formulations have been shown in several studies to enhance the transportation of different medications to intestinal lymph nodes and lymphatics following oral administration^55-58.

Indeed, the advancement of lymph cannula technology has made it possible for scientists to directly observe how lymph is transported from the small intestine to the lymphatic veins and lymph nodes that merge in the superior mesenteric lymphatics⁵⁹. The chylomicron route has been used recently by a number of organisations to deliver particle cargo to intestinal lymphatics. Mao et al. initiated the chylomicron treatment and developed 100–120 nm mesoporous silica lipid support systems covered with diglycerides. It was demonstrated that lipids on the surface of lipid carriers are broken down by lipases found in the gastrointestinal lumen, which results in chylomicron absorption, processing, and lymphatic transport.They examined intracellular pathways using a variety of transport inhibitors to ascertain the degree to which chylomicron processing was necessary for the transcellular transfer of carriers, in order to verify that the lipid carrier system was processed as chylomicrons. They also verified that lymphatic transport was used to deliver these lipid carriers, which resembled chylomicrons, to the lymph nodes⁶⁰. Baek, J. S et al., also administered curcumin to lymphatics using a method akin to this. Curcumin was added to solid lipid-supporting carrier systems with a size of 150–250 nm, which were then swallowed orally. They coated the nano lipid carrier with chitosan to increase the absorption of the produced product into enterocytes and stop the release of the encapsulated medication caused by low stomach pH. They discovered that chitosan-coated lipid nanocarriers had oral bioavailability and lymphatic absorption that were, respectively, 9.5 and 6.3 times higher than curcumin solutions⁶¹. Recently Kochappan et al., formulated mycophenolic acid (MPA) that binds to triglycerides. They postulated that the chylomicron processing route would enable the immunomodulatory medication to enter lymphatic arteries and lymph nodes with the assistance of the bound fatty acids. Compared to MPA and co-administered MPA (unconjugated), intraduodenal injection of MPA-fatty acid conjugate increased lymphatic drug concentrations. When the MPA-fatty acid conjugate was compared to MPA alone, the levels of MPA in lymph nodes were found to be 20 times higher ⁶².

Phytovesicles

To create lipid-conformable molecular complexes known as phytosomes, plant extracts or water soluble phyto-constituents are added to phospholipids. In some research reported a hydrogen bonding between a flavonoid molecule and a phospholipid molecule⁶³. In the past, there was controversy about the formation of phyto-phospholipid complexes⁶⁴. A study on the interaction of the 20(S)-protopanaxadiol phospholipid complexes at the molecular level using molecular docking showed that a hydrogen bond formed between one of the –OH group in 20(S)-protopanaxadiol and the —P=O group in the phospholipids⁶⁵. Phyto-phospholipid complexes, which are employed by the reaction of a stoichiometric amount of phospholipids and the phytoconstituents complex, are revealed by the spectroscopic data that the phopspholipid – active ingredient interaction is due to theformation of hydrogen bond between the polar head and the polar functionalities of the active ingredient.

Lipid-based nano-structured novel drug delivery systems^55-63

The 1HNMR and 13CNMR data show that, the signal of the fatty chain has not changed both in free phospholipids and in the complex, which suggested that long aliphatic chains are wrapped around the active principle, producing lipophilic envelope⁶⁶. The same conclusion can also be drawn from the thermal analysis in other studies that, the interaction between the two molecules had been attributed to the formation of hydrogen bonds or hydrophobic interaction⁶⁷.

In phytovesicles composition, the phospholipids are the chief component of this drug delivery system due to its higher phosphatidylcholine (PC) contents, i.e., 76%, cylindrical shape with higher entropy, amphiphilicity, and biocompatibility nature with the mammalian cell membrane^72,73 and thus, assists in improving the oral bioavailability of drugs and bioactive via crossing lipid-rich bio-membrane⁷⁴. Phytosomes are obtained from a stoichiometric chemical reaction (e.g., solvent evaporation, salting out, and lyophilization method) between the active constituents and phospholipids non-polar solvents such as dichloromethane, 1,4–dioxane, tetrahydrofuran, and ethanol, etc^75-77.Phytosomes were first developed by Indena in 1989 and marketed under the name PHYTOSOMES®⁷⁸ Phyto vesicles contain the phytoconstituents of herbs that are bioactive and form a strong complex with a polar head of phospholipids through intermolecular forces of interactions viz., hydrogen bonds and van der Waals forces. Phytosomes in drug delivery have certain advantages such as enhancement of complexation rate, drug loading capacity, drug stability, encapsulation efficiency, and most importantly, inhibition of drug expulsion^68-71. Telange D.R. et al., have developed the phytosomal nanoparticle loaded mangiferin– phospholipids complex (MPLC SNPs) to improve the biopharmaceutical properties of mangiferin. The CCD produced optimal values of mangiferin: phospholipids ratio (X1, 1:1.76 w:w), reaction temperature (X2, 50.55 ◦C), and reaction time (X3, 2.02 h) revealed lower particle size ~ 507 nm, polydispersity index (PDI) ~ 0.43 and zeta potential ~ − 12.53 mV, however, after nanoprecipitation and lyophilization (~2% w/w sucrose) enhanced the particle size to ~ 907 nm, PDI of 0.50 but maintained the same zeta potential value (− 12 mV). Telange reported that obtained phospholipids complex and MPLC SNPs resulted in improved aqueous solubility, dissolution rate, ex vivo permeation rate, and in vivo antioxidant activity compared to plain mangiferin. powder x-ray diffractometry (PXRD), FT-IR, Differential scanning calorimetry (DSC), and 1H NMR studies confirmed the complex formation and reported that there is the involvement of weak intermolecular forces between mangiferin and phospholipids. Pharmacokinetics studies at 60 mg/kg in albino rats reported that MPLC SNPs compared to phospholipids complex showed significantly improved oral bioavailability ~53.29% by enhancing the C_max, T_max, and AUC of mangiferin. The stability study concludes with no significant particle size changes, PDI, drug loading, and entrapment efficiency after 6 months⁷⁹. Li et al., formulated, evaluated, and pharmacologically characterized the mangoflorin-phospholipid complex in an animal model of chronic unpredictable mild stress. Blood-brain distribution and in vivo antidepressant activity studies were performed by dividing male her ICR mice into his 8 and 4 groups. At the end of the study, 30 minutes after intravenous injection, the study showed that the complex (17 mg/kg) improved blood-brain barrier permeability compared to pure mangoflorin. Similarly, ICR mice (7 mg/kg) treated with the conjugate clearly showed an antidepressant-like response⁸⁰. Biswas et al., To enhance the absorption and oral bioavailability of ursolic acid, they prepared phospholipid complexes by a reactive surface method. Animal studies were performed using a carbon tetrachloride (CCl4)-induced rat model. Optimal values for formulation and process variables, i.e. ratio of ursolic acid to hydrogenated soy phosphatidylcholine (HSPC), reaction time and reaction temperature for ursol-phospholipid complexes were 1:1, respectively, by applying the Box-Behnken design. 1.96, 1.7 hours and 55.2 °C were observed. The optimized conjugate improved water solubility (1.3-fold) over 12 hours, oil-water partition coefficient, and in vitro dissolution performance in both gastric and intestinal fluids. The in vivo study concluded that the ursolic acid-HSPC complex at a dose of 20 mg/kg provided hepatoprotection to CCl4-treated animals by restoring in vivo antioxidant marker enzyme levels⁸¹. Jain et al., prepared a raloxifene-phospholipid conjugate (RLX-C) and studied its effects on raloxifene compatibility, in vitro release, cytotoxicity and pharmacokinetics. Phase solubility studies showed that his RLX-C in stoichiometric ratio (7:3) has a higher Gibbs free energy value, as higher values indicate higher solubility in water. rice field. Release studies conclude that RLX follows non-Fickic release when complexed with phospholipids. Cell viability studies performed on MCF-7 cells showed that RLX-C reduced cell viability (4-fold) compared to pure RLX, suggesting that the cytotoxicity of RLX-C formulations was suggested. Flow cytometric studies showed that RLX-C treated His MCF-7 cells at a concentration of 12.50 μg/mL reduced early-stage apoptosis (78.26 %) was induced. However, the late apoptosis of reference controls RLX or RLX-C was found to increase from 2.92% to 11.26%. A pharmacokinetic study (60 mg/kg) showed that RLX-C improved Cmax and Tmax. In contrast, other parameters such as half-life (t1/2) and circulation time were also shortened, suggesting an overall improvement in the biopharmaceutical profile of RLX⁸².

Ravi et al., developed a nano-lipid complex of rutin at a molar ratio of (1:1, 1:2, and 1:3) using solvent evaporation, salting out, and lyophilization method. Effect on hepatoprotective, antioxidant, and oral bioavailability in rats have been studied by the Authors. The results showed that the lyophilization method at a molar ratio of (1:2) using a combination of dimethyl sulfoxide (DMSO) and t-butyl alcohol as an optimal solvent system improved the particle size, zeta potential, and release behavior of rutin. In vivo study was performed in CCl4-induced intoxicated rats for seven days. After seven days, the results revealed that rutin-lipid complex at ratio (1:2) at a dose of (100 mg/kg and 200 mg/kg) significantly restored enzyme levels compared to pure rutin. The oral bioavailability of prepared phytosome complex was found to be 86.23% compared to pure rutin. It was concluded that the dry freezing method can be a suitable strategy for preparing nano-lipid complex and enhancing the absorption and permeation profile of rutin⁸³.

CONCLUSION:

Phytovesicles made from phytoconstituents and phospholipid complex can be used to treat lymphatic filariasis. Because these phytovesicle protects the drug from acidic degradation in the stomach and allow it to absorb directly into the small intestine. This approach can able to increase the bioavailability of drugs. Therapeutic compounds can be designed as prodrugs with cleavable lipid moieties that activate this natural transport mechanism in order to best use the chylomicron processing pathway for lymphatic delivery and kill lymphatic filariasis-causing worms.

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Received on 20.10.2023 Accepted on 04.12.2023

Int. J. Tech. 2023; 13(2):90-100.

DOI: 10.52711/2231-3915.2023.00012