Proliposomal Formulation: A safer and effective approach for drug delivery with special mention to NSAIDS

 

Borade T, Pandey S.P., Saini T. R.

Department of Pharmacy, Shri G.S Institute of Technology and Science, Indore

 

ABSTRACT:

Proliposomes formulations have shown their importance and significance for the efficient delivery of medicament, especially in those cases where liposomal preparations are required with more stability. These are freely flowable powder preparation where a drug entangled with lipid and cholesterol is deposited over water-soluble carrier material which get converted into liposomes after dispersion in suitable media in-vitro or in-vivo. In past decades, several studies have been published regarding the safer and more effective use of Proliposomes for the administration of drugs via different routes such as oral, transdermal, vaginal etc. It has also been noted that they show their more utility for oral administration of drugs like NSAIDs where gastric absorption, bioavailability, and GI toxicity is a major concerns. The current review includes the various methods used for the pro-liposome preparation, methods to be used for its evaluation along with the application of proliposomes preparation for different purposes and routes of administration. It also includes a summary of work related to the pro-liposomes formulation development of NSAIDs.

 

 

 

1. INTRODUCTION: 

The oral route remains the preferred method for administering drugs due to its convenience and high patient compliance. However, its effectiveness is sometimes compromised by challenges such as weak solubility of the drug, limited penetration, and significant first-pass effect.

 

Gastric irritation and related toxicity is another important aspect that needs to have due consideration, especially in the case of Non-steroidal inflammatory drugs (NSAIDS)¹ . As, in some cases, pain management involves continuous medication for a longer time such as osteoarthritis, rheumatoid arthritis etc., and in this situation, prolonged use of pain-relieving medications may have a deleterious impact.

 

NSAIDs are one of the most preferable categories of prescribed medication groups, generally being used to treat the signs and symptoms of inflammatory diseases such as osteoarthritis, rheumatoid arthritis, and others that cause pain and swelling. However, the use of NSAIDs is severely constrained by their tendency to cause erosions and ulcers in the gastrointestinal (GI) tract. Approximately 50% of people who use NSAIDs get gastric erosions, and 2 to 4% of these people experience clinically severe GI ulcers and bleeding, which can occasionally result in fatalities². A recent FDA analysis estimates that the number of deaths from NSAID-related gastrointestinal bleeding range from approximately 3500 to 16,500 per year in the US³.

 

The ability of NSAIDs to suppress PG production accounts for their efficiency in lowering pain and edema. The primary enzymes for producing PGs, which have hyperalgesic properties and may accelerate edema production, are COX-1 and COX-2. Additionally, PGs regulate several GI mucosal defense mechanisms, including mucus and bicarbonate production, mucosal blood flow, epithelial cell turnover, and the activity of mucosal immunocytes⁴. Most PGs generated in a healthy stomach are sourced from COX-1; nonetheless, PGs produced by COX-2 play a significant role in gastric mucosal defense and aid in the healing of pre-existing stomach ulcers^5-6.

 

Conventional drug delivery systems have drawbacks, including low solubility, poor permeability, limited bioavailability, instability due to GI enzymes, food interactions, high required doses, and related drug toxicity. To overcome these limitations, novel drug delivery systems (NDDS) have been developed, offering target-specific activity, reduced dosages, lower toxicity risks, enhanced solubility and permeability, and increased bioavailability.⁷

Due to the gastrointestinal tract's substantial barrier for larger therapeutic molecules like proteins and peptides, drug absorption is influenced by stomach and intestinal enzymes. In response to these challenges, various delivery techniques using particulate carriers such as liposomes, microspheres, micelles, nanoparticles, and solid lipid nanoparticles have been developed to overcome these obstacles^8-9. A summary of such formulation is enlisted in the table-1.

 

 

Table 1: Summary of novel formulations prepared with NSAIDS

S. No.	Formulation/ Therapeutic moiety	Description	Purpose	Ref.
1.	Nanospheres Aspirin and Naproxen	Amphiphilic polymers were employed to create nanospheres. These nanospheres ranged from 100-200 nm in diameter and exhibited both biodegradable and non-biodegradable properties, with some designed as immune or magnetic nanospheres.	To increase the efficacy and reduce the side effects associated with the oral route	10
2.	Lipid nanocapsules Ibuprofen	Prepared by the phase inversion method using triglycerides as an oily phase and mixing with PEG-660 hydroxy stearate. These are considered as a cross between liposomes and nanoemulsion particles and have a size range from 25-100nm.	Large-scale production of lipid nanocapsules for the delivery of drugs through the oral route.	11
3.	Polymeric micelles Naproxen	Prepared by solvent evaporation technique by taking m-PEG-PCL as a copolymer, chloroform as an organic phase, and 0.5% w/v PVA as an aqueous phase. These are nanoscopic core/shell structures formed by amphiphilic block copolymers having a size range between 10-100 nm.	Prolonged circulation of drugs in the blood for the delivery of drugs to the brain	12
4.	Nanocrystals Ibuprofen	Prepared by the melt-emulsification method by taking Tween-80, Span-80, and PVP-K30 as surfactants. It is a carrier-free colloidal delivery.	Sustained drug delivery	13
5.	Nanoemulsion Ibuprofen	Prepared by using the D-phase emulsification method by taking olive oil as the oil phase, sucrose ester, and laurate as cosurfactants, and glycerol as a surfactant having their size varying from 10 to 1000 nm.	To increase the oral bioavailability of the poorly soluble drug.	14
6.	Dendrimers Naproxen	It is a highly branched polymers with a well-defined structure that allows precise control of size, shape, and functionality.	Enhanced permeability and safety of the drug.	15
7.	Liposomes Meloxicam	Prepared by thin-film hydration method using phosphatidylcholine as a phospholipid followed by sonication. These are small vesicles, spherical having at least one lipid bilayer with a size range of 0.025 µm to 2.5 µm.	For topical and transdermal delivery to reduce GI side effects and enhanced local and systemic impact	16
8.	Solid-lipid nanoparticles Ibuprofen	Solid lipid nanoparticles were prepared by the RESS process by taking ibuprofen as a model drug and stearic acid as a phospholipid. Solid-lipid nanoparticles ranging from 50-1000 nm	To enhance oral bioavailability and drug solubility.	17
9.	Nanostructured lipid carriers (NLCs) Ibuprofen,	Prepared by melted-ultrasonic method by taking sterylamine and CA-loaded NLCs were prepared by the melt-emulsification method by taking Tween-80 as an emulsifier.	Controlled release and increased AUC	18
10.	Carbon nanotubes Naproxen	Drug loaded Carbon nano-tubes in chitosan hydrogel	Sustained drug delivery	19
11.	Nanoshells Ibuprofen	Prepared by stirring method.	Controlled delivery of ibuprofen	20

 

Among all the formulations, proliposomes may be a better choice for the oral delivery of NSAIDS due to their specific behavior like their freely flowable powder form which leads to the formation of drug-loaded vesicles(liposomes) after dispersing it in the water. They almost have similar characteristics as liposomes after the reconstitution but as such proliposomes show better stability in comparison to liposomes. With the formulation of proliposomal systems, an improvement in the solubility of the poorly water-soluble drug, increment in the permeability, improved gastric uptake along with the decrease in first-pass hepatic metabolism and GI toxicity may be achieved easily.

 

1.1 Proliposomes:

Proliposomes are dry, free-flowing solid particles that can instantly transform into a multilamellar liposomal solution when they come into contact with water.²¹ As mentioned in figure 1, when a free-flowing proliposomal formulation is reconstituted, it started to form liposomal structures loaded with drugs.

 

 

Fig.1: Diagram showing the formation of concentric lipid bilayers by amphiphilic phospholipid (liposome) after reconstitution of pro liposomes

 

A typical proliposomal system includes the active substance placed onto a suitable water-soluble carrier together with phospholipids. After hydration, the water-soluble carrier utilized to wrap the phospholipids is essential for the creation of liposomes.

 

1.2    Formulation of proliposomes:

1.2.1 Phospholipid:

Proliposomes can be prepared using several phospholipids including phosphatidylcholine (lecithin) which is one of the most commonly employed lipids derived from natural or artificial sources. These are preferred due to their chemical inertness, lack of charge, and cost-effectiveness as key components of pro-liposomes The primary natural sources include egg yolk, soybean, and occasionally bovine heart and spinal cord.

 

Recently, chemically produced highly purified lipids consisting of saturated fatty acid species with the same carbon number have emerged. The length and saturation of the fatty acid chain exert significant influence on several physical properties of liposomes, including stability, permeability, phase behaviour, and membrane order.²²

 

1.2.2 Carriers for deposition of the lipid layer:

Carriers for the preparation of proliposomes are selected based on the availability of high surface area and porosity which is required to provide the support the lipids ²³. The water solubility of the carrier is another important characteristic needed for the preparation of pro-liposomes after subjecting them to hydration. The porosity of the carrier is also important for controlling the size of the final formulation.

 

Some common examples of such carriers include Pearlitol, Mannitol, Sorbitol, Maltodextrin, Microcrystalline cellulose (MCC), Magnesium Aluminium Silicates, etc.

 

1.2.3 Solvents:

Solvents are employed to supply and ensure the suppleness of the vesicle membrane. Ethanol, Methanol, Ether, and chloroform are the volatile organic solvents or solvent mixes that are employed the most frequently.

 

1.3 Digestion of proliposomes in the gastrointestinal tract:

Pro-liposomes, after ingestion start to form liposomes without any major change in the size of vesicles over time due to the presence of a specific osmotic environment.²⁴

 

After hydration of proliposomes either in-vitro or in-vivo convert into liposomes and go for gastric digestion. Under fasting conditions, the stomach's pH is around 1-3. Once oral-digested food enters the stomach by the esophagus, the pH can rise to 5-7 and gradually drop to around 2 within an hour. The pH range during stomach digestion may somewhat vary due to the varying buffering capacities of different foods^25-26. Moreover, the mechanical agitation produced by the stomach due to peristaltic movement can fragment larger food matrixes into smaller pieces²⁷.

 

However, the structure of liposomes is little affected by this action. It means that the structure of liposomes hardly alters in the gastrointestinal environment. In stomach conditions, liposomal structural integrity essentially does not change²⁸.

 

1.4 Method of preparation:

Several methods can be utilized for the preparation of Proliposomes:

 

1.4.1 Deposition of Lipid on carrier method:

The deposition of a drug containing lipid film on the carrier material as illustrated in figure 2A, is one of the most common methods utilized for the preparation of pro-liposomes at the laboratory scale. This procedure consists of the coat of the drug and phospholipids discharged onto the carrier material that was previously placed in a round bottom flask (RBF). The drug and phospholipids solution in an organic solvent is poured into the round bottom flask (RBF), where the carrier material is already present. This can be achieved using either the slurry method or the aliquots method.

 

The slurry method involves pouring the whole organic solution containing phospholipids, cholesterol, and drug onto a water-soluble carrier bed in the RBF, while in aliquots methods which involves the step of drop-by-drop solvent incorporation and a slow evaporation process²⁹.

 

1.4.2 Spray-drying method:

This approach to preparing proliposomes involves the spraying of drug, carrier, and lipid feed in the chamber of the spray dryer simultaneously followed by the drying of the particles.³⁰ Typically, this procedure is used when there is an invariable size and form of the particles that are required.

 

The significant advantage of this method lies in its easy scalability and cost-effectiveness for preparing large quantities of phospholipids (PLs). As depicted in Figure-2B, the procedure comprises atomization of the solution containing the mixture of organic solvent, phospholipid, drug, and carrier in a chamber followed by drying the spray droplets and concurrently evaporating the organic solvent.³¹

 

1.4.2 Fluidized bed method:

Fluidized bed coater with top spray or bottom spray as shown in figure 2C is another method that can be used for the large-scale production of proliposomes. In this methodology, efficient coating of the carrier material (powder or non-pareil beads) with the drug-containing lipid solution can easily be obtained. In the case of non-pareil beads, a seal coat is necessary to achieve a smooth surface, facilitating the application of phospholipids and drug solutions for uniform distribution around the core.²³

 

But at the same time, critical control of the parameters like inlet temperature, outlet temperature, bed temperature, the pressure of fluidizing air, pressure of atomization, solution application rate, etc., are of utmost importance as any uncontrolled parameter may either lead to over-wetting of bed or premature drying of the solution system.

 

1.4.3 Super-critical anti-solvent method:

Super-critical fluid technique is one of the fascinating techniques nowadays which utilizes carbon dioxide for preparing pro-liposomes. It involves supercritical anti-solvent technique(SAS), depressurization of an expanded liquid organic solution-suspension method (DELOS), Supercritical assisted atomization, Supercritical reverse phase evaporation(SCRPE), etc.^32-33. A diagrammatic representation of the Super critical anti-solvent method for the preparation of pro-liposomes is mentioned in figure 2D. 

 

 

2A

 

2B

 

2C

 

2D

Fig.2: Different Techniques for the preparation of Proliposomes A) Film formation on carrier B) Spray drying C) Fluidized bed coating D) Supercritical fluid technique

 

1.5 Evaluation of Proliposome:

There are several parameters that will be required for the evaluation of proliposomes like the angle of repose, rate of hydration, drug loading entrapment efficiency vesicular size after hydration, and invitro release etc.

 

1.5.1 Yield of pro-liposomes:

To assess the product quantity change, we measure this parameter. Once the drug-loaded proliposomes or carrier powder is fully dried, we collect the solid product and perform accurate weighing. The yield of pro-liposomes can be determined by the following formula:

 

Total wt. of proliposomes

Percentage yield ------------------------------------------------------ = × 100

Total wt. of drug + Total wt. of added materials

 

1.5.2 Hydration study:

A hydration study is conducted to study liposome formation when they interact with water or an aqueous system. For this evaluation, a small amount of proliposomal powder is placed directly on a glass slide, petri dish, or watch glass. The gradual addition of water or a suitable buffer system is performed, and then a drop is covered with a cover slip after placing it on the slide and observed under a microscope to visualize vesicle formation.³⁴

 

1.5.3 Flow property:

In a powder formulation, it is essential to assess the flow property and content distribution, particularly when it needs to be delivered in sachet-type packaging. Flow property of such formulations can be evaluated by calculating the Angle of repose, Carr’s index, and Hausner’s ratio.

 

1.5.4 Entrapment efficiency:

The final product of pro-liposomes i.e liposomes includes both encapsulated and drug portions that are not entrapped. The term "free" drug is also used to describe the unencapsulated drug fraction. Entrapment efficiency is carried out to get the entrapped drug after the formation of liposome dispersion. For checking the percent entrapment efficiency, separation of unentrapped drugs and calculating the amount of drug which is entrapped is required. Several methods are reported that can be used to separate unentrapped or free drugs like size exclusion chromatography, solid phase extraction, mini-column centrifugation, centrifugation ultra-filtration etc.^35-36.

 

1.5.5 Transmission electron microscopy (TEM):

It is used to evaluate the structure of vesicular structures like liposomes that are produced after the hydration of pro-liposomes. A drop of the mixture containing resultant liposomes after hydration of pro-liposomes is placed onto a copper grid which is carbon coated, forming a thin liquid film. Then the film is stained and after air drying, the stained film is observed under the transmission electron microscope and determines the lamellarity and shape of liposomes.³⁴

 

1.5.6 Scanning electron microscope (SEM):

Surface morphology of proliposomal formulation may be studied with Scanning electron microscopy after coating with gold³⁷ or platinum³⁸. It can also be compared with SEM images of carrier moiety for confirming the distribution of phospholipids over the carrier ensuring the formation of proliposomes³⁹.

 

1.5.7 Zeta potential:

Zeta potential serves as a measure of a particle's surface charge. It represents the potential difference between the electro-neutral region of the solution and the solid charged layer present on the surface of particle/vesicle. This value serves as an indicator of particle stability. A proliposomal formulation relying on electrostatic repulsion for physical stability will exhibit a minimum zeta potential of ±30mV, ensuring stability and preventing aggregation.²³

 

1.5.8 Powder x-ray diffractometry and Differential scanning calorimetry:

The molecular state of the drug in proliposomes will evaluate by differential scanning calorimetry of pure drug and drug-containing proliposome powders. The crystalline characteristics of proliposomes will be checked to find out the distribution of a drug in proliposomes by X-ray diffractometer.⁴⁰

 

1.5.9 In-vitro drug release:

In-vitro drug release study can be performed by suitable methods for proliposomes like USP-dissolution apparatus type-1, Franz-diffusion cell, dialysis tubing method, reverse dialysis, cellophane dialyzing membrane, K-C diffusion cell and spectrapormolecular porous membrane tubing.^41-42

 

1.6 Applications of proliposomes:

1.6.1 Proliposomes for the prevention of gastric problems from NSAIDs:

Currently to prevent gastric irritation problems induced by NSAIDs, proton-pump inhibitors are used as the co-medication. PPIs works on mechanism involved decrease in gastric acid secretion. Studies have shown that co-administration of a PPI with NSAID reduces the symptoms of dyspepsia and guards against gastroduodenal ulcers⁴³. NSAIDs administration by proliposomes decrease the ulcerogenic or gastric side-effect of indomethacin (NSAIDs), prepared by using soyabean lecithin as phospholipid⁴⁴. Several other reports are there which mention the utility of proliposome formulation for delivery of NSADIS. A list of such drugs is mentioned in the table No. 2

 

Table 2: List of NSAIDs loaded proliposomes

S. No.	Nsaids loaded proliposomes	Description	Reference
1.	Ibuprofen proliposomes	Effervescent granules-based proliposomes of ibuprofen were prepared and enhanced the anti-inflammatory activity of ibuprofen has shown as compared to plain ibuprofen.	45
2.	Indomethacin proliposomes	Indomethacin proliposomes were prepared from effervescent granules. The in-vivo characteristics were characterized in the rats with inflamed paws which have shown enhanced anti-inflammatory activity as compared to plain proliposomes.	46
3.	Diclofenac sodium proliposomes	Diclofenac sodium-loaded proliposomes were prepared using film deposition on carrier method.  In-vivo gastric damage study has shown enhanced bioavailability of diclofenac sodium-loaded proliposomes and was safer as compared to plain diclofenac sodium.	47
4.	Aceclofenac proliposomes	Aceclofenac proliposomes were prepared for topical formulation to overcome the problem associated with the oral route. Characterization studies have shown sustained release and better stability.	37
5.	Ketoprofen proliposomes	To enhance the dissolution rate, gastric absorption, and tolerance of ketoprofen, proliposomes were prepared.	48
6.	Mefenamic acid proliposomes	Mefenamic acid proliposomes were prepared to enhance the bioavailability and reduce its gastric and systemic side effects.	49

 

1.6.2 Proliposomes for encapsulation of peptide drugs to enhance oral bioavailability and stability:

Along with benefits like high selectivity, efficiency and stability, peptides also serves certain limitations such as shorter half-life, poor permeability, poor oral bioavailability etc.⁵⁰. etc. As it is evident that liposomes suffer with stability issue, proliposomes may be a better alternate specifically for oral delivery of medicaments as well as proteins and peptides⁵⁰.

 

1.6.3 Proliposomes for vitamins delivery:

Vitamins are to be comparatively less stable against environmental stress. The stability of such vitamins like Vitamin C and Vitamin E may be increased by formulating proliposomes of such vitamins. In such work, Parhizkar et.al reported the high ex-vivo antioxidant activity of vitamin C in brain and liver cells after the oral delivery⁵¹.

 

1.6.4 Proliposomes for the treatment of vaginal infections:

Studies reveal that the local application of antibacterial agents is shown to be more effective in case of bacterial vaginosis, a most common cause of vaginal infection due to avoidance of side effects of such drugs in case of systemic administration⁵². Generally, anti-infectives used to treat such conditions suffers with their limitation like insufficient residence time, and at the same time, prolonged contact with such medication at the affected site will also be required⁵³.

1.6.5 Proliposomes in the treatment of hepatitis:

Silymarin loaded liquid proliposomes has been reported for their enhanced hepatoprotective activity.⁵⁴ In another work, Adefovir dipivoxil loaded proliposomes for the management of hepatitis B virus with improved bioavailability of drug⁵⁵.

 

1.6.6 Proliposomes in the treatment of cancer:

Exemestane is a steroidal aromatase inhibitor that is used to treat metastatic breast cancer because of its weak solubility, has a restricted bioavailability (42%) and substantial first-pass metabolism and absorption are influenced by the kind of food and formulation. Drug delivery using proliposomes were designed for exemestane's transdermal administration.⁵⁶

 

2. CONCLUSION:

Proliposomes of different medicament has been proven to be better alternative for enhancing the stability in their liposomal form. With the optimized selection of different ingredient, a good stable formulation can be preprepared which may have all the required attributes of good novel formulation like high entrapment, better permeation, good release on controlled, improved safety etc. Proliposomes formulation may alienate the toxicity associated with drugs specially in case of oral administration. Several literatures have revealed that the toxicity like GI bleeding, irritation, ulcer etc. associated with NSAIDs may successfully controlled. At the same time, this formulation may also be utilized for the effective and safe delivery of bioactive, proteins and peptides etc may also be ensured with more stability. Several proliposomes formulation have been reported till date but for still for use of these formulation more effectively in clinical set up need to be established.

 

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Accepted on 29.03.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(11):5536-5543.