Glycerosomes: A Novel Vesicular Drug Delivery System

 

Deepika Rani*, Vaishali Sharma, Pinki Singh, Ranjit Singh

Adarsh Vijendra Institute of Pharmaceutical Sciences, Shobhit University,

Gangoh, Saharanpur (U.P.) India – 247341.

*Corresponding Author E-mail: deepikapharma94@gmail.com

 

ABSTRACT:

Glycerosomes are novel vesicular drug delivery systems used both for topical as well as systemic drug delivery. These noninvasive carriers can penetrate into the deeper layer of skin to such extent a free drug would not penetrate. Glycerosomes are composed of phospholipids, water and high concentration of glycerol (from 20 to 40%), which are harmless and fully acceptable ingredients for topical preparations. High concentration of glycerol gives positive contributes to the penetration of drug by increasing flexibility of vesicles; italso enhances the stability of vesicles.They have capability to encapsulate both lipophilic and hydrophilicdrugs and protect them from degradation. Now a days glycerosomal carrier are the most interesting area of work for researchers. This review article summarizes the structure, advantages, composition, methods of preparations, characterization and applications of glycerosomes.

 

KEYWORDS: Glycerosomes, Novel formulaion, Glycerol, Penetration.

 

 


INTRODUCTION:

Topical drug delivery systems (TDDS) involve administration of a drug to the body either for local or systemic action. Skin patches are one of the examples of topical drug delivery systems1. TDDS offer a number of potential advantages over conventional drug delivery system such as injectables or oral delivery, like avoidance of first pass metabolism, prolongation of the action of drugs, reduction of adverse effects, utility of drugs having short half-lives, avoidance of drug level fluctuation, improvement in inter and intra patient variations, and the most importantly, the better patient compliance2.

 

Recently different strategies are being used to augment the percutaneous delivery of bioactives, which include electrophoresis, iontophoresis, sonophoresis, penetration enhancers, microneedles and vesicular drug delivery systems. Among these strategies vesicular drug delivery system appears most promising3,4.

 

 

 

 

 

The vesicular systems are highly ordered assemblies of one or several concentric lipid bilayersformed when certain amphiphilic building blocks are confronted with water5. Biologic origin of these vesicles was first reported in 1965 by Bangham, and was given the name Bangham bodies6,7. These systems have exceptional ability to enhance permeability of drugs. A number of novel vesicular drug delivery systems like ethosomes, liposomes, pharmacosomes, etc. have been emerged, to achieve targeted and controlled drug delivery8.

 

However in most cases, the use of vesiclesas carriers for topical and/or transdermal administration of active principles is of little or no value due to shortcomings like instability, low entrapement efficiency and limited drug delivery efficiency. To overcome these shortcomings, new modified formulations, such as transfersomes and ethosomes have been introduced. Ethosomes are novel modified liposomes containg high amount of alcohols, like ethanol, propylene glycol or a mixture of both. High concentration of alcohol in ethosomes improves the deformability, flexibility and encapsulation efficiency of vesicles so provide better penetration of drug in deeper layers of skin. But due to high concentration of alcohol, the use of ethosomes may have unfavourable resultslike skin irritation.

 

New approach to enhance the vesicular properties as transdermal and dermal drug delivery systems was described by Manca etal. by modifying liposomal bilayer fluidity. These reside were named as glycerosomes, which were composed of phospholipids, water and high amount of Glycerol (20-40%)9,10. Likeother vesicular systems these carriers do not contain any harmful chemical such as ethanol as structural component, so these are harmless and fully accepted formulation for topical applications and can be suitable for the hypersensitive skin11. These are versatile vesicular carriersthat can be prepared from any natural or synthetic phospholipids used in the construction of conventional liposomes and can be obtained by any of one of the techniques commonly used for the preparation of conventional liposomes. Furthermore, the drug delivery efficiency of glycerosomes can be improved by using essential oils as penetration enhancers due to their high penetration efficiency and negligible toxicity12. On the basis of composition and method of preparation, glycerosomes can results in unilamellar or multilamellar vesicles. Multilamellar vesicles of glycerosomes can be converted in to unilamellar by sonication or homogenization. The phospholipid components consisting of one or more phospholipids can be choosen from natural or synthetic sources, such as phosphotidylcholine (lecithin), phosphatidylethanolamine (cephalin), phosphatidylserine, mixtures of soybean derived hydrogenated and non-hydrogenated phospholipids such as Phospholipon 100 (p100) polyene phosphotidylcholine, Phospholipon® 90 (p90) lecithin or similar mixtures9. Cholesterol is another most important component of cell membrane that maintains a proper membrane permeability and fluidity. Other components such as stearylamine may be added to formulation to modify electric charge.

 

 

Figure 1: Structure of glycerosomes

 

Potential features of glycerosomes:

a)     They are fully biocompatible and biodegradable.

b)    They have strong ability to scavenge free radicals and to protect human keratinocytes in vitro against hydrogen peroxide damage13.

c)     They consist of hydrophobic and hydrophilic moieties together and can able to entrap drug molecules with wide range of solubility.

d)    They protect the encapsulated drug from metabolic degradation.

e)     They contain glycerol, which act as edge activator for phospholipid bilayer when used in concentration above than 10 percent.

f)     They are safe and fully accepted complexes for topical administration.

g)    They can penetrate into deeper layers of skin, so most suitable for topical drug delivery

h)    They are compatible with most of the drugs.

 

Advantages of glycerosomes over liposomes:

a)     They show significantly higher incorporation efficiency than liposomes.

b)    They contain high glycerol concentration, which improves the rheological properties and consequently, give a positive contribution to the stability of the glycerosomes.

c)     They are more flexible than liposomes, having higher flux rate across the skin.

d)    They have higher penetration efficiency than liposomes.

 

METHODS OF PREPARATION OF GLYCEROSOME AND DRUG LOADING:

The glycerosomes can be prepared by different approaches used for the preparation of liposomes.

 

General methods of preparation14

All the methods used for preparation of glycerosomes involve four basic stages:

a)     Drying the organic solution of lipids.

b)    Hydrating the lipid layer in glycerol solution of various concentrations.

c)     Purifying the resultant glcerosomes.

d)    Analysing the final product.

 

The preparation of glycerosomes are based on following three strategies:

a)     Mechanical methods

b)    Organic solvent replacement methods

c)     Size transformation methods

 

a) MECHANICAL METHODS:

i. Lipid thin film hydration:

It is the simplestproceduregiven by Bangham et al., for formulation of glycerosomes but having the some limitationof its poor encapsulation efficiency. This method involves drying a solution of lipid and cholesterol in an organic solvent so that a thin film of lipid is formed at the bottom of round bottom flask and then hydrating the film by adding aqueous solution of glycerol15. The hydration step should be done at a temperature at or above the gel-liquid crystalline transition temperature (Tc) of the lipid. The compounds to be encapsulated are added either to the hydrating medium or to the organic solvent containing lipid materials depending upon their solubilities16,17, .

 

ii. Ultrasonic method18

This method is used for the preparation of tiny unilamellar vesicles with diameterin the range of 15-25 nm. Ultrasonication of glycerol dispersionof lipid is done by two types of sonication processes.

 

      Probe sonication:

The tip of a sonicator is directly engaged into the glycerosomal dispersion. The input of energy into lipid dispersion is very high in this method. The coupling of energy at the tip of probe results in local hotness; therefore, the vessel which contains formulation must be engrossed into a water/ice bath. Sonicator tip also tend to slough off titanium, which may pollute the solution and must be removed by centrifugation.

 

      Bath sonication:

In bath sonicator, a test tube containing glycerosomal dispersion is placed inside the sonicator and sonicating the suspension for 5-10 minutes above the critical solution temperature (Tc) of the lipid. Temperature can be easily controlled in this method as compared to probe sonicator.

 

b) Organic solvent replacement methods:

In this method lipid materials are co-solvated in organic solution, which is then dispersed into glycerol solution containing material to be entrapped within the vesicles. Following ways can be used to achieve this.

 

i. Reverse Phase Evaporation:

In this method water in oil emulsion is first formed by sonication of a two phase system containing phospholipids and cholesterol in organic solvent like ethanol or isopropylether or mixture of isopropyl ether and chloroform and aqueous glycerol solution. Organic solvent is removed under reduced pressure, leads to the formation of a viscous gel19. The glycerosomes are preparaed when residual solvent is removed by the continuous rotary evaporation under reduced pressure. This method is used for the preparation of large uni and multi-lamellar vesicles and it has the capability to encapsulate large macromolecules with high encapsulation efficiency. The main drawback of this method is the exposure of the materials to organic solvents and to brief periods of sonication.

 

ii. Solvent dispersion method:

It may be divided into two categories depending on the type of solvent used.

 

 

      Ether injection method:

In ether injection method a solution of lipids dissolved in diethyl ether or ether-methanol mixture is gradually injected to an aqueous or buffered glycerol solution of the materials to be encapsulated at a temperature of 55°C to 65°C or under reduced pressure. The main drawback of the method is that the population of glycerosomes is heterogenous (70-190nm) and the exposure of entrapped material to organic solvent and high temperature20.

 

      Ethanol injection method:

In ethanol injection method the lipid is injected rapidly through afine needle into an excess of glycerol solution. The major drawback of this method is that glycerosomes are very dilute; it is difficult to remove all ethanol because it forms azeotrope with water21.

 

c) Size transformation methods:

i. Freeze thaw extrusion method:

It is an extension of the classical Dehydration- Rehydration method. This method involves the extrusion of multilamellar vesicles using 20,000psi pressure at 4°C through a small orifice. An important feature of the freeze thaw method is that the proteins do not seem to be significantly affected as in sonication process so it is widely used for encapsulation of proteins. The method provides several advantages over sonication method like simplicity, reproducibility and involves gentle handling of unstable materials. The size of glycerosomes produced by this method is larger than sonicated Small unilamellar vesicles22. In this method, the major drawback is that the working volumes are relatively small (about 50ml as the maximum).

 

ii. The Dehydration- Rehydration Method:

In this method the empty buffer containing small unilamellar vesicles are rehydrated with the aqueous fluid containing the material to be entrapped after that they are dried. This leads to the formation of lipid dispersionin finely subdivided form. Glycerosomes obtained by this method are usually oligo-lamellar vesicles23.

 

1.     Characterization of glycerosomes:

The glycerosomal formulation is characterized in terms of following parameters.

 

a)    Vesicles size and size distribution:

The size distribution is of primary consideration, when glycerosomes are intended for parenteral administration. Various techniques are used for the determination of particle sizeof the vesicles. These include Light Microscopy24, Electron Microscopy (Transmission Electron Microscope and Scanning Electron Microscope), Laser Light Scattering, Photon Correlation Spectroscopy, Gel Permeation and Gel Exclusion25 Among all of these, the most precise method to determine size of glycerosomes is Transmission Electron Microscopy since it permits one to view each individual glycerosome and give exact information on its size profile.

 

b)    Vesicle shape and lamellarity:

Vesicle shape and lamellaritycan be assessed by using electron microscopic techniques26,27,28. Lamellarity can be determined by using freeze fracture electron microscopy and 31P-Nuclear magnetic resonance analysis. Apart from the shape and lamellarity, the surface morphology of glycerosomes can be studied using freeze-fracture and freeze-etch electron microscopy29.

 

c)     Encapsulation efficiency:

Itdefines the percent of the drug which is ultimately entrapped inthe glycerosomes and usually is expressed as percentage entrapment/mg lipid30. Encapsulation efficiency can be determined by two techniques namely minicolumn centrifugation method31 and Protamine aggregation method32. Minicolumn centrifugation is also used as a mean of purification and separation of glycerosomes on small scale.

 

d)    Drug release:

The drug release mechanism from glycerosmes can be studied by using well calibrated Franz diffusion cell33,34. The glycerosomal based formulation can be subjected to in vitro assay to assess pharmacokinetic parameters and bioavailability of the drugs before initiating in vivo studies35.

 

e)     Stability studies:

The stability of glycerosomes can be determined by dimensional analysis using Photon Correlation Spectroscopy technique, Zeta potential determination, Dynamic Laser Light Scattering and measuring the polidispersity index at various time intervals9.

 

Therapeutic Applications of Glycerosomes:

When a conventional dosage form fails to provide a desired therapeutic effect, then new drug delivery systems are developed. Glycersomes are among such systems which provide a superior therapeutic efficacy and safety in comparison to presently available formulations. Some of the major clinical/therapeutic applications of glycerosomes in drug delivery are as follows.

 

a)    Site specific drug delivery:

Delivery of maximum amount of drug to the desired (diseased) site, by reducing the exposure to normal tissues can be done by site specific targeting. Encapsulating the drug in glycerosomes can be used both for active and passive targeting of drugs in order to provide a safe and efficacious therapy. On systemic administration, glycerosomes are able to recognize and bind to target cells with greater specificity36,37,38.

 

b)    Intrasynovial drug delivery:

Numbers of treatments are available to cure rheumatoid arthritis including non-steroidal anti-inflammatory drugs, corticosteroids, and diseases modifying anti-rheumatic drugs. However, none of them is able to achieve ultimate goal of treatment, due to their inability to deliver the drug in to synovial cavity in proper dose. This problem can be solved using glycerosomal drug delivery system. Paeoniflorin, an anti-inflammatory and immune–regulating agent mostly used for the management of rheumatoid arthritis is of limited clinical use due to poor penetration. This drug when encapsulated within glycerosomes, showed greater accumulation in synovial cavity12.

 

c)     Sustained release drug delivery:

Glycerosomes can be used to provide a sustained release of drugs, to maintain a constant drug level for specified time with negligible side effects. Drugs like rifampicin, betamethasone have been encapsulated in glycerosomes for sustained release and optimized drug release rate in vivo11.

 

d)    Intra-follicular administration:

Intra-follicular administration of drugs may represent a feasible therapeutic approach to skin disease such as hair loss. Novel glycerosomal formulation enables the topical delivery of difficult to absorb agents such as minoxidil for localized action, specifically to the hair follicles and sebaceous gland35.

 

e)     Glycerosomes in dermatology:

The application of glycerosomess on the skin surface has been proven to be effective, because they help in reducing skin irritation by sustaining the release of drugs and by hydration of the epidermis. Glycerosomes are nonaggressive and fully biocompatible and are suitable for even most sensitive skin. Promising results have been obtained with glycerosomal encapsulated drugs in acne, psoriasis, psoriasis arthritis and in rosacea39. Prigen, a pharmaceutical industry has successfully developed an anti-aging formulation (GEN-HYAL) based on glycerosomal technology.

 

f)     Glycerosomes for pulmonary targeting of drugs:

Glycerosomes have potential to be used in different respiratory disorders as it provides several advantages over ordinary aerosol such as sustained release, prevention of local irritation and high stability in the large hydrophillic core. Recently glycerosomes have been successfully used for the delivery of rifampicin40 and curcumin41 via intra-tracheal route to the lungs. This resulted an improved accumulation of drugs in lungs.

 

g)    Glycerosomes for the delivery of anti-inflammatory agents:

 Anti-inflammatory drugs have great variety of side effects. One possible way to increase the therapeutic efficacy of these drugs could be glycerosomal encapsulation. Nonsteroidal anti-inflammatory drugs such as diclofenac42, celecoxib and cupferron43 have been successfully incorporated in glycerosomes. Finally results have been showed that glycerosomes provide high biocompatibility towards human keratinocytes.

 

h)    Enhanced antimicrobial efficacy/ safety:

Antimicrobial agents encapsulated in glycerosomes for two reasons. First, they protect the encapsulated drug against enzymatic degradation.Secondly, the lipid nature of the vesicles promotescellular uptake of the antimicrobials into the microorganisms, thus reducing the dose andthe incidence of toxicity. Different antimicrobial agents like resveratrol, gallic acid44, Tolnafate45 and citrus lemon extract45 were successfully loaded in glycerosomes, which exhibited better antimicrobial efficacy against cultured plankton of different species of Streptococcus and Lactobacillus.

 

CONCLUSION:

Glycerosomes have been realized as extremely useful carrier system for controlled and targeted drug delivery. Due to high flexibility and deformability of vesicles, they can be exploited for the drug delivery through any route of administration and for any drug irrespective of its solubility status. Glycerosomes can be prepared by various methods in which the most common method applied for therapeutic is lipid thin film hydration method. It has also been proved that this technology increases the action of medicament up to three folds. The uses of glycerosomes in the delivery of bioactive are promising and are sure to undergo further developments in future.

 

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Received on 27.06.2020            Modified on 13.11.2020

Accepted on 09.02.2021           © RJPT All right reserved

Research J. Pharm.and Tech 2022; 15(2):921-926.

DOI: 10.52711/0974-360X.2022.00154