Ufasomes: The Symphony of Drug Delivery

Paul Ehrlich developed the target drug delivery approach in 1909, which entails administering target drugs directly to damaged cells.¹ The vesicular drug delivery system is a novel approach to delivering drugs at precise sites. These show that treatments work where they are supposed to while avoiding negative side effects.² Vesicular drug delivery systems are especially useful for targeted drug delivery because they can localize the drug’s activity at the site of organ or action, reducing its concentration elsewhere in the body, delaying the removal of medications that metabolize quickly and functioning as sustained-release systems.

The vesicular drug delivery mechanism produces the liposome, transferosome, neosome, phytosome and ufasome.³ Liposomes are a kind of concentric, colloidal bilayer vesicles, totally enclosed in a bilayer membrane and mostly composed of lipids, either synthetic or natural, in their aqueous compartment. Liposomes are composed of phospholipids, while ufasomes are mostly composed of fatty acids.⁴ To improve the stratum corneum’s capacity to absorb medications into the skin, ufasomes were created. Ufasomes have a lipid carrier that sticks to the skin’s surface and makes it easier for lipids to move from the stratum corneum to the skin’s outermost layer.⁵

Suspensions of a closed lipid bilayer composed of ionized species of fatty acids are known as ufasomes. Their pH ranges from 7-9, making them unsaturated fatty acid vesicles.⁶ Ufasomes, which are long-chain unsaturated fatty acid vesicles, are created when an evaporated film is physically stirred in the presence of a buffer solution.⁷ Ufasomes represent a groundbreaking approach to vesicular drug delivery in the future. They are more stable than liposomes and have higher entrapment efficiency for both hydrophilic and hydrophobic drugs. They are less expensive than liposomes.⁸ One of the primary benefits of ufasomes over liposomes is their availability of fatty acids.⁹ Ufasomes lengthen a drug’s half-life in the blood and lessen its toxicity. The drug can be absorbed selectively since it is delivered directly to the source.^10,11 Improves bioavailability, especially for those having difficulty dissolving medications. Drugs that are lipophilic or hydrophilic can be incorporated into ufasomes.

As ufasomes may encapsulate both hydrophilic and hydrophobic medicines, they are used as a drug delivery mechanism. They are also biocompatible and biodegradable.¹² Fatty acid molecules’ carboxyl groups come into contact with water in ufasomes, but their hydrocarbon tails are directed into the interior of the membrane. They can function as medication transporters as a result of this.¹³

Fatty acid vesicles are created when ionized fatty acids are dispersed colloidally. When synthesizing ufasomes, unsaturated fatty acids like oleic and linoleic acids are used as natural permeability enhancers.¹⁴ One of the primary advantages of ufasomes over liposomes is the easy availability of fatty acids.¹⁵

In order to increase skin suppleness and enhance medicine dispersion across the skin membrane, fatty acids and surfactants are frequently used. Ufasomes have long improved skin cell membranes’ capacity to hold onto drugs. The ufasome is composed of fatty acid vesicles. The direction of the carboxyl groups in contact with water and the membrane fatty acid hydrocarbon tails toward the membrane’s interior produce the bilayer structure.¹⁶ Ufasomes are soapy suspensions of closed lipid bilayers, mostly made up of fatty acids. Their pH is typically maintained between 7 and 9.

Unlike liposomes, ufasomes are more stable.
For both hydrophilic and hydrophobic medicines, ufasomes show improved entrapment efficiency.¹⁷
Ufasomes are less expensive than liposomes.¹⁸
Ufasomes can be used as oral delivery systems for drugs that are less soluble.¹⁹
When applied topically, the medication readily permeates the skin.²⁰
A possible method of administering anti-inflammatory medications.²¹

Ufasomes easily oxidize, which causes issues with stability in fatty medication preparations.
Certain byproducts of oxidation may be harmful.²²
Ufasomes’ colloidal instability prevents them from being used as food additives or drug delivery systems.
Risk of atherosclerosis.

Ufasomes are composed of the following components and their specific function, description was given in Table 1 and the structure of ufasomes is described in Figure 1.^23–35

Materials that are not oxidized are used to create ufasomes. Oleic and linoleic acid stock solutions are made and kept at 20°C. Chloroform has 10% of each acid. For standard preparations, 0.02 mL of the stock solution is evaporated in a test tube using a water pump. The solution is then sprayed with nitrogen to dry it off. The solvent most commonly employed to make ufasomes is trichlorohydroxymethyl aminomethane; however, buffers like borate, glycine-hydroxide and bicarbonate solutions can also be effective. The fatty acid composition, cholesterol level, pH range, buffer and lipoxygenase quantity are the main factors that affect the formation of stable ufasomes.³⁶ Ufasomes are lipid-based vesicular systems that may be used to encapsulate and distribute a wide range of materials, including vitamins, medications and chemicals for cosmetics. They are made by combining lipids and surfactants to create vesicles that self-assemble.

The acidic stomach environment makes ufasomes less stable, which can cause them to break down too soon. Using pH-sensitive formulations or enteric coatings are two methods to increase stability.

Bypassing the digestive tract, Intravenous (IV) injection of ufasomes results in improved bioavailability and a speedier therapeutic impact.³⁷

The Reticuloendothelial System (RES), which has the ability to remove ufasomes from circulation and the ufasomes’ interactions with plasma proteins determine their distribution within the body.³⁸

Surface alterations can improve targeting to particular cells or tissues. By lessening immune system detection and clearance, PEGylation-the addition of polyethylene glycol-can lengthen the period of circulation.³⁹

Ufasomes’ capacity to enter tissues and absorb cellular contents is influenced by their size, charge and surface characteristics.

The body’s natural lipid metabolic pathways break down ufasomes made of fatty acids.

Fatty acids can be further broken down into smaller components by enzymes such as lipases, allowing the body to use or metabolize them further.⁴⁰

The kidneys can filter small breakdown products of ufasomes, like free fatty acids and excrete them in urine.

If certain lipid constituents are converted into bile acids or other lipid-soluble metabolites, they may be eliminated through the bile.

Larger vesicles may circulate longer and be removed more quickly than smaller ones. The stability and metabolism of ufasomes might be affected by the fatty acids included in the formulation.

By modifying circulation time and targeting capabilities, PEGylation and targeting ligands can change the pharmacokinetic profile.

Pharmacokinetics is greatly impacted by the route of administration. When opposed to oral approaches, IV treatment offers a more direct and controlled delivery.⁴¹

Gel matrices and ultra flexible liposomes (ufasomes) are combined in ufasomal gels, a novel drug delivery technology that improves drug stability and penetration. Because of their flexibility, ufasomes can penetrate the skin more effectively and the gel matrix allows for regulated release. These gels work well for transdermal and topical applications, enhancing the prolonged release and bioavailability of medications. Benefits of pharmacokinetics include improved absorption, systemic and localized distribution, decreased metabolism at the location and extended duration of action. In the realms of cosmetics and pharmaceuticals, they provide noteworthy therapeutic benefits.^42,43

Prepare the lipid and surfactant mixture in an organic solvent,⁴⁴ evaporate with a rotary evaporator or nitrogen stream to cover the flask walls. To eliminate remaining solvent, lower the pressure overnight.⁴⁵ Rehydrate the lipid film with an aqueous solution of the appropriate component to ensure vesicle fusion. Optionally, further treat ufasomes to ensure uniform size distribution.

Figure 1:
Structure of ufasomes.

To generate an oil phase, dissolve lipids and surfactants in organic solvent; then, prepare an aqueous phase containing the desired component. Combine all phases to produce an emulsion, then evaporate the solvent under low pressure to generate a water-oil emulsion.⁴⁶ To create a thick gel-like consistency, add water solution, homogenize and vortex.^47,48 Allow the system to acclimate for vesicle production before performing additional processing processes such as sonication or extrusion to ensure size and homogeneity.⁴⁹

By using this method, a stock of 10% oleic and linoleic acid in chloroform at 200°C is produced and kept fresh. The 0.2 mL of this stock solution in a test tube is dried with a nitrogen stream to produce a film after being allowed to evaporate on a water pump. When 0.2 mL of 0.1 M Tris-hydroxymethyl aminomethane buffer with a pH of 8-9 is added, the resulting fatty acid coating is totally eliminated, yielding a ufasome solution.

In this novel manner, alcohol, which has the same chain length as fatty acids, is added to promote the formation of vesicles. Over a wide pH range, this technique produces very stable unsaturated fatty acid vesicles. This is a laborious process. This laborious procedure is prevented in part by the matrix effect, which offers helpful support all throughout the production process. This technique entails increasing the rate of vesicle synthesis using pre-added fatty acid vesicles in the system.

When an aqueous solution containing fatty acids is introduced to a solution that has been water-bubbled, fatty acid vesicles are produced. This pH change happens on its own. The formation of vesicles is often observed when half of the fatty and carboxylic acids ionize. Unlike the aqueous compartment, the hydrocarbon chain is wrapped in a bilayer structure that decreases the chain’s interaction with the water.

It’s crucial to keep in mind that the specific ratios, manufacturing processes and composition could vary depending on the desired applications and characteristics of the ufasomes.

The average diameter and size distributions of ufasome suspensions at a fixed angle of 90 degrees and a temperature of 25°C are evaluated using photon correlation spectroscopy in a particle size analyser. The suspensions were diluted with phosphate buffer and then passed over a polycarbonate membrane (pH 7.4). As a result, particulate matter interference is lessened at the size level.

Transmission Electron Microscopy (TEM) is one method to examine the sphericity and accumulation of drug-loaded ufasomal dispersion. One drop of the chosen ufasomal dispersion can be examined and negatively stained with 1% phosphotungstic acid on a copper grid covered in carbon film. Prior to TEM inspection, the sample must dry for 10 min at room temperature.

The percentage of medication that is delivered that is trapped by ufasomes is known as entrapment efficiency, or EE%. It is possible to remove unencapsulated, free medicine from the solution by using ultracentrifugation or dialysis. One may observe the supernatant using UV spectroscopy.^50,51

To determine the proportion of medication that is entrapped, apply the following equation:

To investigate the effects of pH on stability and drug release activity, buffers with pH values of 8.5, 7.4, 6.5 and 5.5 were incubated with optimum vesicular dispersion.¹⁴ Samples are obtained at predetermined intervals and centrifuged at 14,000 rpm for 30 min. The supernatant can be used to test the free medication. To determine how much medicine has leached, use the method described below.

This study aims to assess the ufasome release kinetics and rate of the medication. Franz diffusion cells might be used to do this. Two compartments make up the Franz diffusion cell: a donor compartment and a receptor compartment. There is a porous polycarbonate membrane, 50 nm in size, separating these two compartments. 1 mL of ufasomal dispersion was present in the donor compartment, while PBS with a pH of 7.4 was kept in the receptor compartment and constantly agitated at 37°C using a magnetic stirrer. Aliquots of the samples are taken on a regular basis and swapped out by comparable volumes of brand-new PBS (pH 7.4).

The degree of charge, electrostatic repulsion, or attraction between particles is measured by the zeta potential. The zeta potential is affected by the properties of the liquid as well as the particles.⁵² It is crucial for figuring out the aggregative stability of the solution or emulsion. With larger zeta potentials, the system is more stable and the repulsion is stronger.

For the purpose of vesicle organization and morphology, vesicle scattering was seen using photographic microscopy. An optical magnifying lens and a camera with an amplification range of 40 to 100 x 11 were used to investigate ufasomal suspensions.

Cis-4, 7, 10, 13, 16 and 19-Docosahexaenoic Acid (DHA) spontaneously forms vesicles at pH values between 8.5 and 9. This offers another fatty acid substitute for ufasome production, expanding the scope of possible uses.

The need for carboxylic acid ionization frequently restricts the pH range across which vesicles made from fatty acids may be produced. Recent developments have extended this pH range in a number of ways:

In atypical pH settings, vesicle production is stimulated by adding linear alcohols or surfactants with sulfate or sulfonate head groups to fatty acids. For example, these compounds can be combined with decanoic acid to reduce the required pH for vesicle production to 4.3.

Lower pH levels improve vesicle stability when an oligo (ethylene oxide) unit is inserted between the fatty acids carboxylate head group and hydrocarbon chain. This alteration impacts the phase transition temperature as well as the pH range where vesicles form.

Ufasomes are typically associated with divalent cations such as Mg2+ and Ca2+, which can precipitate vesicles even in trace amounts. Recent advances have employed fatty acid glycerol esters to stabilize ufasomes in the presence of these cations, enhancing their stability and applicability for a variety of uses.

Cristiano MC, et al, developed ufasomes can supply oleuropein while enhancing antioxidant activity and cell-nano system interaction. Oleuropein and unsaturated fatty acids can be combined to achieve these goals.⁵³

Hashem SM, et al, study indicate that ITZ-loaded ufasomes have the potential to cure Candida albicans infections by downregulating immunomodulatory markers and inhibiting important enzymes.⁵⁴

Bhattacharya S. et al, examined entrapment efficacy, drug-to- lipid ratio and size. Glyceryl oleate ufasomes improved skin penetration and showed strong antifungal action against cutaneous candidiasis in rats. To increase the stability of cationic ufasomes, more study is required.⁵⁵

5-Fluorouracil (5-FU) is used topically to treat basal cell carcinoma; however typical formulations can cause eczema and redness. Ufasomes, or fatty acid vesicles, encapsulate 5-FU, allowing it to penetrate the epidermal layer while decreasing side effects and boosting therapeutic efficacy.⁵⁶

Ufasomes, which carry anti-inflammatory medications like dexamethasone, have shown potential in lowering inflammation, notably in rheumatoid arthritis. They provide better drug delivery than traditional formulations, possibly altering treatment approaches for inflammatory illnesses such as psoriasis through increased skin penetration and targeted administration.

Ufasomes loaded with antifungal drugs like terbinafine hydrochloride and oxiconazole demonstrate enhanced skin penetration and systemic absorption compared to traditional creams and gels, vital for treating deep fungal infections including those caused by Candida albicans. Adjusted ufasomal formulations exhibit increased effectiveness, as indicated by a larger zone of inhibition, highlighting their potential for more efficient antifungal therapy.⁵⁷

Because of their excellent entrapment effectiveness, glucosamine-sulfate-loaded ufasomes offer a viable treatment for osteoarthritis by quickly encapsulating and delivering medication. With established continuous drug release in vitro, these vesicles are a viable option for topical delivery, potentially allowing for long-term symptom relief and management of osteoarthritis.

Ufasomes are used in a variety of medical and cosmetic applications, including the treatment of hair loss with minoxidil and the enhancement of antioxidant capabilities in products such as Oleuropein. Their diversity demonstrates their efficacy in treating a variety of medical and aesthetic conditions.

Ufasomes provide an effective delivery mechanism for transdermal hormone replacement treatment, delivering hormones such as Estrogen and progesterone to postmenopausal women. This approach ensures regulated hormone distribution through the skin, eliminating the need for oral medication and lowering systemic side effects.⁵⁸

Ufasomes, containing analgesic pharmaceuticals like lidocaine and diclofenac, revolutionize pain management. Lidocaine-loaded ufasomes target regional pain effectively,⁵⁹ while diclofenac-loaded ones offer localized anti-inflammatory relief, minimizing systemic side effects.⁶⁰

Ufasomes enriched with Vitamins C and E improve skincare formulations by offering powerful antioxidants and UV protection. Vitamin C ufasomes stimulate collagen formation, reduce oxidative stress and brighten skin, whereas vitamin E ufasomes protect the skin from damaging UV rays and improve general skin health.⁶¹

Ufasomes containing antiviral medicines, such as acyclovir, show potential in treating viral skin diseases like herpes. Targeted administration improves efficacy while reducing systemic exposure, allowing for effective control of herpes outbreaks via skin penetration.^62,63

Ufasomes deliver antibiotics such as clindamycin for localized skin infections, reducing systemic exposure and the possibility of resistance while providing tailored treatment.

Ufasomes containing peptides and retinoids provide targeted anti-aging advantages in cosmetics, with retinoid-loaded ones specifically targeting fine lines and wrinkles. Encapsulation ensures regulated release, boosting efficacy in revitalizing aged skin.⁶⁴

Ufasomes enable the transdermal administration of salicylic acid-based acne medicines, improving their efficacy in acne treatment. Ufasomes, which contain salicylic acid, promote penetration to effectively treat acne while minimizing skin irritation.⁶⁵

Ufasomes are the future of drug administration. They have the potential to improve the way drugs work. However, there are several obstacles to overcome. Still, the prospect of ufasomes making drugs more effective, safer and tailored is very appealing.

Scientists are working hard to discover all of the great things that ufasomes can perform.

The authors are thankful to the Raghavendra Institute of Pharmaceutical Education and Research for provided support.