1. INTRODUCTION:

Curcumin (diferulomethane), a naturally occurring polyphenol found in the rhizome of the Curcuma longa L., or turmeric. Curcumin generally used in the food industry as flavouring, coloring, and preservative agents and several products like cheeses, curry, soups, mustard and ice cream^[1]. In addition of these curcumin shows such medicinal properties like antimicrobial anti-inflammatory, anti-oxidant, anti-cancer activities, all suggested to be related to its chemical structure, this structure includes hydroxyl groups linked to benzene rings, double bonds in the alkene portion, and a central β-di-ketone moiety^[2]. Inspite of these, direct immix of curcumin into aqueous-based food formulations is hindered due to its low solubility in water (11 ng.mL−1 at 25°C), high photosensitivity and instability in the presence of chemical oxidants^[3].

To control these disadvantages, the curcumin enclosed in lipid carriers as liposomes appears to be apparent to increase its aqueous solubility, in addition to increasing its oral bioavailability^[4,9,12]. Liposome’s are colloidal spherical vesicles with an internal aqueous core formed by the self-assembly of amphiphilic phospholipids in aqueous media. These systems have been applied to improve the bioavailability of hydrophobic bioactive compounds and to promote their controlled release in food formulations^[5]. Phosphatidylcholines are the most abundant phospholipids in nature and used frequently in liposome productions. In addition, other phospholipids, such as lysophosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine, can also be utilized to produce liposomes. These lecithins can provide nutritional value to liposomes due to their high polyunsaturated fatty acid composition^[6]. The pro-liposomes hydration is most cost-effective and upgradable techniques for liposome production methods to produce deliberate amounts of liposomes^[7]. Pro-liposomes also defined as dry, free-flowing phospholipid particulate systems, which contain the bioactive to be encapsulated in their lipid matrix. Liposome vesicles are obtained after the hydration of these powders under controlled conditions of temperature and agitation. Pro-liposomes approach was developed as a straight forward, reproducible and reliable manufacturing technique for large-scale production of liposomes dispersions. The technology is based upon the intrinsic property of hydrated membrane lipids to form vesicles with water. It is designed particularly for the molecular dispersion and delivery of water-insoluble materials where association efficiencies approaching 100% can be achieved.

Pro-liposomes have been employed as a basis for a number of site-specific drug delivery approaches and also pro-liposomes have been employed as basis for a number of site-specific drug delivery approaches and also pro-liposomal formulations suggest increases solubility and bioavailability of some poorly soluble drugs. Pro-liposomes are easy to distribute, measure, transfer and store they are available in dry form which makes it a versatile system. By using a suitable hydrating fluid, liposomes can be formed in vitro prior to administration and also can be formed in vivo under the influence of physiological fluids. The liposomes formed on reconstitution are similar to conventional liposomes and more uniform in size^[8]. The solid-state of the pro-liposomes confirms their higher stability and also convenient for transportation, storage, distribution and dosage, rendering them suitable for industrial processes. The basic advantages which are related to the production of pro-liposomes by using a coated micronized sucrose (CMS) are the use of milder temperatures, which do not compromise the integrity of the bioactive compound to be encapsulated, and the higher process yield obtained at the end of the process when compared to other processes, such as spray drying^{[9,12] .}

Advantages of pro-liposome:

1. High entrapment of hydrophilic material.

2. Therapeutic benefits of pro-liposomes include enhanced bioavailability.

3. The Protection of drug from degradation in the GIT

4. Reduced toxicity and taste masking.

5. Relatively cheap.

6. The pro-liposomes used for targeted drug delivery and controlled drug release.

7. Targeting of anti-cancer drugs to tumour sites.

In general successful formulation of stable pro- liposomal drug product requires the following precautions:

1. The process should be with fresh, purified lipids and solvents.

2. Avoidance of high temperature and excessive shear forces

3. Low oxygen potential maintenance (Nitrogen purging)

4. Use of antioxidant or metal chelators

5. Formulating at neutral pH.

6. Use of lyo-protectant when freeze drying

Table 1 Comparison between liposome’s and pro-liposome’s:^[10]

Liposome	Pro-liposome
Liposomes are Unilamellar or multilamellar spheroid structures.	PLs are used as alternatives for liposomes.
Composed of phospholipid and cholesterol.	Composed of water soluble porous powder as carrier phospholipids
On oxidation, solubility of liposomes is increased and have tendency to aggregate or fuse to hydrolysis.	Drug and phospholipid material is coated on carrier material to form free flowing granular material which shows better stability, greater solubility and shows controlled release.

Sources:

Just like spinach is rich in iron and lemons are full of vitamin C, turmeric is a great sources of curcumin. The turmeric root basically contains about 2 to 5% of curcumin. Curcumin belong to a family of chemicals that are known as curcuminoid and which have a bright yellow colour. These compounds that leads the distinctive colour to the spice. Curcumin was first identified mainly as a compound back in 1815. Since then, there have been several studies conducted to learn more about its abilities. It is believed that curcumin work on multiple functions and processes at the same time that is why it has been touted to cure everything from pain and inflammation to fighting tumours and promoting brain health.

Chemistry of curcumin:

Curcumin incorporates several functional groups whose structure was first identified in 1910^[11]. The aromatic ring systems, which are phenols, are attached by two α, β-unsaturated carbonyl groups. The diketones form shows stable enols and are easily deprotonated to form enolates; and the α,β-unsaturated carbonyl group is well Michael acceptor and go through nucleophilic addition. Curcumin basically used as complexometric indicator for boron (^"EPA Method 212.3: Boron (Colorimetric, Curcumin). For the formation of a red-coloured compound (rosocyanine) it reacts with boric acid.

Chemical properties of Curcumin:

Common name: turmeric IUPAC name of curcumin (Figure 1): 1, 7-Bis (4-hydroxy-3-methoxyphenyl) hepta-1,6-diene-3,5-dione. Other name: Diferuloymethane. formula: (C21H2006), is most important active ingredient responsible for the biological activity of turmeric. Curcumin is soluble in ethanol and acetone but insoluble in water. The naturally occurring ratios of curcuminiods in curcumin are about 5% bisdemethoxycurcumin, 15% demethoxycurcumin, and 80% curcumin. Curcumin, generally unstable in phosphate buffer at pH 7.4. Raw turmeric generally uses in South Asian countries, although the powder spice is more common in India. After the turmeric root is harvested it is cleaned, cured and then dried. Later, the dried root may be sold as it or ground in to a fine powder. In India, it is often referred to as Indian saffron, yellow ginger, yellow root or Kachi haldi (Table 1).

Figure 1 Structure of Curcumin

Table 2.Morphological characters of curcumin.

IUPAC name	1, 7-Bis (4-hydroxy-3-methoxyphenyl) hepta-1, 6-diene-3, 5-Dione
Molecular formula	C₂₁H₂₀O₆
Botanical origin	Curcuma longa
Common name	Turmeric
Family	Zingiberaceae
Melting point	The melting point is 183ºC
Molecular weight	368.37g/mol
Solubility	Insoluble in water and ether but Soluble in ethanol, dimethyl sulfoxide and acetone
Colour	Bright yellow orange powder

Metabolism and mechanism of action of Curcumin:

Curcumin is lipophilic molecules which is insoluble in water and the process of sulfation and glucuronidation (by intestine and liver) and furnish its efficient excretion via the kidneys. Curcumin major metabolites are glucuronides of tetrahydrocurcumin (THC) and hexahydrocurcumin (HHC) both of which are significantly less active than curcumin in free form. The free and unconjugated (unmetabolised) curcumin basically less water soluble and so present for longer period of time in the body. The administration of oral curcumin may not consiquently deliver curcumin to the tissue outside of the gastrointestinal tract. Inflammation and pro-inflammation processes are centrally linked to several chronic human diseases, including cancer, diabetes, obesity, arthritis, cardiovascular disease and neurodegenerative diseases. Curcumin has shown antioxidant, anti-cancer, anti-tumour, anti-arthritis and anti-inflammatory properties as well as other benefits by the In-vitro animal and human studies. Curcumin health benefits are primarily (but not exclusively) attributed to its direct targeting of transcription factor nuclear factor kappa B (NF-kB), also known as the inflammatory master switch. When NF-kB is stimulated, it is released from its inhibitory molecules IKB, thereby allowing its movement to the cell nucleus where it switches on genes responsible for the production of a number of pro-inflammatory products, initiating as inflammatory cascade of events. Curcumin prevents NF-kB by entering the nucleus and thereby blocking inflammation at an early stage.

2. MATERIALS AND METHODS:

2.1. Chemicals and reagents:

Proliposomes were produced using two types of food-grade soybean lecithins purchased from Lipoid GmbH (Ludwigshafen, Germany): purified hydrogenated soy phosphatidylcholine Phospholipon 90H (P90H), containing a minimum of 90% w/w phosphatidylcholine (PC), a maximum of 4% w/w lysophosphatidylcholine (LPC), and 2% w/w triglycerides (TG) and fat-free powder lecithin Lipoid S40 (LS40), containing a minimum of 40% w/w phosphatidylcholine, 15% w/w phosphatidylethanolamine (PE), 4% w/w lysophosphatidylcholine and 3% w/w phosphatidylinositol (PI). Crystalline and purified curcumin was obtained from Sigma-Aldrich (St. Louis, MO, USA). Xanthan gum (XG) (Grindsted Xanthan 80) was donated by DuPont (Cotia, SP, Brazil), and guar gum (GG) was obtained from Êxodo Científica (Hortolândia, SP, Brazil). Sucrose, dimethyl sulfoxide (DMSO) and sodium benzoate were purchased from Synth (Diadema, SP, Brazil). All of the chemicals used in this study were reagent grade. Deionized water (from a Direct Q3 system, Millipore, Billerica, MA, USA) was used throughout the experiments.

2.2. Production of the curcumin-containing pro-liposome’s:

Pro-liposomes were produced using the coating of micronized sucrose method^[9,12]. 100ml of ethanolic solutions containing 3.2g of total phospholipids and curcumin (when added) were produced using the formulations described in the ethanolic solution was added as drops at a flow rate of 4 ml min−1 using a peristaltic pump (Masterflex 7528-30, Cole-Parmer, Vernon Hills, IL, USA) onto 2 g of sucrose previously micronized in a ball mill (CE500, CIENLAB, Campinas, SP, Brazil). The solutions were maintained under sonication until the end of the dripping to maintain the dispersion of Lipoid S40 in ethanol. The injection process occurred in a rotary evaporator (MA120, Marconi, Piracicaba, SP, Brazil) in which the rotary flask was maintained at 55±2°C to vaporize the ethanol. The rotary flask was also covered to avoid early degradation of the curcumin. The proliposomes were stored in vacuum desiccators protected from light at room temperature (25°C) prior to their hydration.

3. METHODS OF PREPARATION:

Proliposomes (PLs) are prepared by various methods such as:

· Film-deposition carrier method.

· Spray drying method.

· Fluidized-bed method.

· Supercritical anti-solvent method.

3.1. Film deposition carrier method:

Film deposition carrier method is used for the formation of Pro-liposomes. In this process, coating of drugs and phospholipids is discharged on a pervious water soluble carrier substance. By viewing Figure 2, an evaporative solution containing a solution of drug and phospholipids is injected drop by drop by a feed tube onto a core of carrier substance which is kept in a vessel of a rotary flash evaporator under vacuum. At any state moment, the matrix’s over wetting is avoided and following aliquot of organic mixture is feeding simply when a free flowing powder matrix is procured^[13]. Selected carriers should exhibit great surface area and permeability in order to regulate the quantity of carrier which is needed to assist the lipids. For the pro-liposomes production it also allows great surfactant to carrier mass proportion. As they are water soluble, they are able to fast production of liposomal dispersion on hydration and by appropiate managing the size of pervious powder, comparatively limited variety of reconstituted liposomes can be acquired. Mostly used carriers are maltodextrin, sorbitol, microcrystalline cellulose, magnesium aluminum silicates, mannitol, etc^[14]. Stride of solvent inclusion and evaporation which is sluggish^[15]. To avoid this issue, modify the procedure by dispersing the carrier substance in organic mixture of drug and phospholipids in the vessel of rotary evaporator and then manage it to vacuum evaporation. By doing so, highly consistent and well-organized lipid distribution is achieved and a steady and less time taking procedure is gained in contrast to the actual procedure^[16]

Figure 2 Apparatus for preparing PLs film deposition carrier

3.2. Spray drying method:

The characteristic feature of this process is reclined in its tendency to include particle composition and drying together in a consistent stride, permitting more desirable production of particles. This method is generally used for any of the aqueous or non-aqueous systems for particles production. Primarily, this process is utilized when shaped particles and invariable sized are needed and can be simply scaled up. Its price is effectual and acceptable for massive preparation of PLs^[17]. As shown in the Figure 3, Spray drying procedure consists of four phases: atomization of the product into a spray nozzle, drying of the spray droplets, Spray-air association and collection of the solid product^[18]. Firstly, the preparation of liquid dispersions carrying lipid or pure lipids and carriers in organic mixture is done and then it is poured into the dry cell. Dispersion is atomized into dry cells by utilizing a spray nozzle and desiccated to the simultaneous air flow which is then gathered in a tank. Primary factors which affect this methods are high temperatures, absorption episodes, shearing stresses and these can provide results into the thermal and mechanical degradation of active molecules. Further it can be upgraded by making the better working variables. Examples of working variables are liquid spraying rate and drying air temperatures. For shielding the association of active molecules, stabilizing adjuvants e.g. disaccharides, cyclic oligosaccharides and polyols can be utilized and by augmenting the surface area of lipids, the effectiveness of hydration can be intensifying^[19].

Figure 3 Apparatus for preparing PLs Spray drying method

3.3 Supercritical anti-solvent method:

In Super critical anti-solvent method for the production of PLs we use Supercritical Carbon dioxide (ScCO2) which actually is carbon dioxide’s fluid state when it is held at on some level above its critical temp and pressure.

Because of three main factors involved here are

· Lower residual solvents,

· Simple steps,

· Mild operation temperatures.

For the preparation of PLs we generally use anti-solvent technology. An apparatus consisting of three parts (e.g. sample delivery unit, precipitation unit and separation unit) are basically used in those simple steps. Two pumps, one for the delivery of CO2 which is supplied through CO2 cylinder (72 cm3) after being cooled down by refrigerator and a high pressure pump is used to introduce to the buffer tank (-7°C) for preheating, thus conditions of temperature and pressure of the reaction vessel or CO2 cylinder should be 45°C and 10 MP and one for the drug solutions which is introduced via HPLC pump combines up to make the sample delivery unit [20]. Solvent which are completely miscible with CO2 should be used for dissolving the drugs. For both preparations, the phospholipid, cholesterol and drug dissolve in organic solvents followed by sonication until a clear and homogeneous solution is obtained. For the entrance of CO2 into the vessel through nozzle valves A and B will be opened. CO2 is sprayed through the outer tubule whereas the solution is sprayed though inner tubule of the nozzle. The second part of the apparatus consists of heat by air bath vessel, and the last part comprises wet gas meter and a separator. ScCO2 is separated from organic solvent in the last part’s separator because of its low pressure and on the other hand wet gas meter is used to measure the CO2 ^{[18, 20, 21]}. After reaching the regulate value of temp and pressure, valve A is opened for the entrance of CO2 right after that, valve B allows drug solution to enter the nozzle. Solution is mixed with ScCO2 and diffused into each other rapidly like it is sprayed through coxial nozzle. Thus the solute will dissolve in organic solvent to reach super saturation in a very short period of time about 30 minutes and this all because of the solubility of solute in the organic solvent decreases slightly and thus the PLs are precipitated in the vessel. After complete utilization of solutions, A and B valves are closed while valve C is opened to depressurize the vessel at the opening temp and in the end we collect these samples at the bottom of vessel on the filter. The pressure, temperature and the flow rate of the drug solution should be optimized to obtain the high drug loading PLs.

3.4. Fluidized bed method:

The large production of PLs whose principle convey on particle coating technology, in this technology carrier material can vary from crystalline powder to non pareil beads. While non pareil beads used as carrier material, first smooth surface pareil beads should be coated with seal coating which can further help in the coating of phospholipids, which also assure thin uniform throghout the phospholipids around the core and small sized liposomes on hydration. The materials of carrier are then sprayed with organic solvent solutions and solution of drugs through nozzle, and then apply vacuum and simultaneously remove the fluid bed organic solvent. The elementary amount of further remaining solvent is removed by the finished lipid-coated powder/beads when dried under vacuum overnight (Figure 4).

Figure 4. Fluidized bed method

4. EVALUATION OF PRO-LIPOSOME:

4.1. Scanning electron microscopy (SEM):

It is used basically to observe surface structure of the PL powder. It is also used for the comparison of the image of liposome and pure carrier material. Carrier material in the formulation approves the disposition of phospholipids on the carrier and then pro-liposomes formulation confirms^[22].

4.2. Transmission electron microscopy (TEM):

This method is generally used to check the structure of liposomes after PL powder hydration. In this process hydrate the pro-liposome’s powder with distilled water and then view lamellarity and the shapes under microscope^[22].

4.3. Hydration study:

Hydration study is carried out on the fact that liposomes are formed on contact with aqueous environment. In this method we place small quantity of dry powder of pro-liposomes and place it on a glass slide and then gradual addition of water in it and is observed by using microscope to view vesicle formation. During hydration dissolution and disintegration occur rapidly as soon as hydration. Liposomes are formed when the water come in contact with the lipid surface of pro-liposomes. This process continuous tills the complete hydration lipid layer and carrier dissolution^[23].

4.4. Zeta potential:

Zeta potential can be determined by surface charge of particle. It is the potential difference between electro neutral region of the solution and surface of tightly bound layer (shear place)^[24].

4.5. Flow property:

Contented uniformity and handling processing operation can be explained by the flow property of a powder formulation. For a formulation based on solid powder it is required to analyse the pro-liposome’s property. It can be assessed by measuring following parameters; Angle of repose, Carr’s Index and Hausner’s ratio^[23] .

5. APPLICATIONS:

Pro-liposomes can be formulated by mentioned routes of administration.

5.1 Parenteral delivery:

For parenteral application, most important is their sterilization. Sterilization techniques commonly used are steam sterilization, γ-irradiation, aseptic manufacturing and filtration sterilization. Terminal sterilization is not proper for liposomal formulations because requires steam at 121°C. At high temperature liposome structure is destroyed because of lipid hydrolysis and boosts the per oxidation of unsaturated lipids^[25]. Pro-liposomes are adequate for parenteral delivery of liposomes. The benefit linked with Pro-liposomes is that it permits sterilization without affecting the intrinsic characteristics^[26,13,20]. After sterilization pro-liposomes can be stored in dry form and can be hydrated before administration to form multi-lamellar liposomal suspension^[27]. In the past few decades, Pro-liposomes played a vigorous role in the area of injectable drug delivery system. Allurement of drug into multi-vesicular liposomes leads to novel approach in sustained release drug delivery. Liposomal entrapment of drugs result in sustained release eternal over several days to weeks^[28].

5.2. Oral delivery:

Pro-liposomes help to enhance the dissolution efficiency of poorly soluble drugs and it produces multi-lamellar vesicles on contact with fluid which guarantees higher entrapment of insoluble drugs due to widened hydrophobic volume within the liposomal lamellae. It also allows conversion of drug from crystalline to amorphous form^[2]. Development in bioavailability of drugs, having extensive first pass metabolism and increased lymphatic uptake is due to larger particle size of multi-lamellar liposomes formed on hydration^[29]. Pro-liposomes are formulated to increase stability of liposomes. Formulations improve solubility and bioavailability of some poorly soluble drugs. Domperidone is a specific 5HT3 receptor antagonist used as anti-emetic. Domperidone is poorly water soluble and after oral administration it undergoes extensive gastric and hepatic first pass metabolism which leads to very low oral bioavailability that will not produce its required therapeutic effect. Pro-liposomes of Domperidone are formulated in order to increase bioavailability by enhancing intestinal permeability that results in improved lymphatic uptake and circumventing first pass metabolism^[30]. Pro-liposomal formulations are now extensively used for drugs having low aqueous solubility like Exemestane^[13,26,31], Salamon Calcitonin^[29], Glyburide^[32],Halofantrine^[33]and Progesterone^[5,34].

5.3. Pulmonary delivery:

Liposomal preparations are also formulated for localized drug action in the respiratory tract. As liposomes are composed of phospholipids that are also a part of lung surfactant thus, drug entrapment within the liposomes result in improved absorption. Drugs encapsulated in Liposome are present in blood for extended period of time and with decreased adverse effects^[35]. Pulmonary drug delivery is attained by following three types of devices:

5.3.1. Pressurized metered dose inhalers (pMDI):

Drugs solution or suspensions are added to liquify the propellants. Hydro-fluroalkanes are oftenly used inplace of Chlorofluorocarbons because of they are non-ozone depleting propellants but they are poorly soluble in phospholipids. Pro-liposome can be suspended in these propellants that act as as carrier of liposomes for pulmonary route^[36].

5.3.2. Dry powder inhalers (DPIs):

This involves the inhalation of drug as fine powder which causes dispersion of drug directly into the airstream of patient. Dry powder inhalers have some benefits such as enhanced potency, decreased toxicity controlled delivery, displacement of drugs locally, increased patient compliance, large amount of drug entrapment and improved stability. Pro-liposome formulations are generally in dry powder form so they are used preferably for liposomes delivery by dry powder inhaler^[36]. Spray dried liposomes trapped Dapsone dry powder inhaler have extended drug action in lungs to impede Pneumocystis carinii pneumonia. In vitro studies predict 16 hours prolonged drug release^[37].

5.3.3. Nebulizers:

It is the simplest method for providing liposomes to the respiratory system but it can be upset by liposome leakage and drug instability. Dry powder formulations are used to get rid of this problem. So, pro-liposomes are strong carriers of liposomes through nebulization^[35].

5.4. Mucosal delivery:

Pro-liposomes on contact with aqueous mucosal surfaces transfer into liposomes. Phospholipids are the basic component of pro-liposomes which are non-irritant, non-toxic and compatible with biological membranes. The molecular dispersion of drug into bilayer results in increased therapeutic action^[27]. The vaginal proliposomal formulation of Clotrimazole has prolonged release of drug and may improve the drug retention time within the mucosa that leads to better antifungal effect^[38].

5.5. Transdermal delivery:

Pro-liposomes are composed of phospholipids that have natural affinity for skin lipids and thus enhance the drug permeation within the skin. Pro-liposomes on hydration are converted to liposomes that lead to sustained action of entrapped drug and these liposomes developed on contact with aqueous environment regulate diffusion across the skin. Hence the permeation of skin is increased by avoiding the stratum corneum hindrance^[38]. Aceclofenac and Nicotine pro-liposomal formulations have been formulated for sustained transdermal action^[39].

5.6. Ocular drug delivery:

Conventional ocular drugs have generally poor bioavailability because of pre-corneal loss effects. Pro-liposomes are basically used to enhance the drug bioavailability and their therapeutic action. Drug entrapped within the lipid bilayer of liposomes which have high solubility and can traverse cornea. Liposomal formulations can easily be used for ocular drug delivery. Liposomal hydrogels of Ciprofloxacin are used in order to prevent catheters from bacteria^[39].

6. CONCLUSION:

Pro-liposomes have played a major role in solving the problems related to stability and bioavailability and solubility of poorly soluble drugs. Although the significant progress has been made towards the development of pro-liposomes as useful oral dosage forms conversely there are no marketable products.

7. ACKNOWLEDGEMENT:

Authors are thankful to the Faculty of Pharmacy, Integral University, Lucknow for providing suitable facilities and support for the successful completion of this review (IU/R&D/2020-MCN000803).

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Received on 13.02.2020 Modified on 03.04.2020

Research J. Pharm. and Tech. 2020; 13(12):6276-6283.

DOI: 10.5958/0974-360X.2020.01092.6