Transferosomes : An Overview

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Swarnlata Saraf

Swarnlata Saraf

The skin acts as a major target as well as a principle barrier for topical/transdermal drug delivery. The stratum corneum plays a crucial role in barrier function for transdermal drug delivery8.

Despite major research and development efforts in transdermal systems and the advantages of these routes, low stratum corneum permeability limits the usefulness of topical drug delivery. To overcome this, methods have been assessed to increase permeation1. Transferosomes is a supramolecular entity that can pass through a permeability barrier and there by transport material from the application to the destination site. These are more elastic than standard liposomes. Transferosomes have been widely used as a novel carrier for effective transdermal drug delivery. Transferosomes enhances the penetration of most of the low as well as high molecular weight drugs,while in case of lipophilic drugs the entrapment efficiency can reach upto 90%. it is now widely used as a novel carrier for both systemic as well as topical delivery of drugs. Transferosomes have easily deformable properties so that it can easily squezz out from the stratum corneum, and the mechanism for penetration is the generation of “osmotic gradient” due to evaporation of water while applying the lipid suspension (transferosomes) on the skin surface.Flexibility of transferosomes membrane is achieved by mixing suitable surface active components in the proper ratios. Transferosome penetrate the stratum corneum by either intracellular route or the transcellular route. With the excellent distribution property of transferosomes, it has been widely used as a carrier for various proteins , steroids ,NSAIDS,and anti cancer agents etc3.

Introduction:

liposomes and niosomes are the vesicular carrier systems which have received a lot of attention over the last decade as a means of transdermal drug delivery, in most cases transdermal drug penetration has not been achieved9. To overcome these problems a new type of carrier system called “transferosomes” was introduced for the effective transdermal delivery of number of low and high molecular weight drugs.It consist of both hydrophilic and hydrophobic properties,high deformablity gives better penetration of intact vescicles. A transferosomes, i n functional terms, may be described as lipid droplets of such deformability that permits its easy penetration through the pores much smaller than the droplets size. They protect the encapsulated drug from metabolic degradation. In thermodynamics terms this typically corresponds to an aggregate in the quasi-metastable state, which facilitates the formation of highly curved bilayers. From the composition point of view, a transferosomes is a self adaptable and optimized mixed lipid aggregate. They act as depot,releasing their content slowly and gradually3.

Transferosomes have been developed in order to take adventage of phospholipids vescicles as transdermal drug carrier. These self optimized aggregates,with ultraflexible membrane, are able to deliver the drug reproducibily either into or through the skin, depending on the choice of administration or application, with high efficiency. These vescicular transferosomes are several orders of magnitude more elastic than the standard liposomes and thus well suited for the skin penetration. Transferosomes overcome the skin penetration difficulty by squeezing themselves along the intracellular sealing lipids of stratum corneum. There is provision for this, because of the high vescicle deformability, which permits the entry due to mechanical stress of surrounding, in a self adapting manner. Flexibility of transferosomes membrane is achieved by mixing suitable surface active agents in the proper ratios. The resulting flexibility of transferosome membrane minimize the risk of complete vescicle rupture in the skin and allow transferosomes to follow the natural water gradient across the epidermis ,when applied under non occlusive condition. Transferosomes can penetrate the intact stratum corneum spontaneously either through intracellular route or transcellular route6.

The high and self-optimizing deformability of typical composite transferosomes membrane, which are adaptable to ambient stress allow the ultra deformable transferosomes to c hange its membrane composition locally and reversibily, when it is pressed against and attracted into narrow pore.

Some of the limitations which have been encountered is that transferosomes are chemically unstable because of their predisposition to oxidative degradation as well as Purity of natural phospholipid is another criteria militating against adoption of transferosomes as drug delivery vehicles.

Materials And Methods:

Materials which are widely used in the formulation of transferosomes are various phospholipids, surfactants, alcohol, dye, buffering agent etc (n.k jain).different additives used in the formulation of transferosomes are summarized in table no. 1

Table No.1

Method of preparation of transferosomes

CLASS

                       EXAMPLE

USES

Phospholipids

Soya phosphatidyl choline,egg phosphatidyl choline,dipalmitoyl phosphatidyl choline

Vesicles forming            component

Surfactant

Sod.cholate,Sod.deoxycholate,Tween-80,Span-80

For providing flexibility

Alcohol

Ethanol,methanol

As a solvent

Buffering agent

Saline phosphate buffer   (pH 6.4)

As a hydrating medium

First of all phospholipids and surfactants are dissolved in organic solvent. Any lipophilic drug could also be encorporated in these organic solvent. Then prepare thin film using rotary evaporator then keep under vacuum for 12 hrs, after that hydrate it with buffer (pH 6.5) at 60 rpm, any hydrophilic drug can be encorporated in these buffer. Then sonicate for 30 min using probe sonicator at 380 W, and then homogenize it using polycarbonate membranes (extrusion 10 times through a sandwich of 200 and 100 nm). Then finally we got the transferosomes.

Charecterization Of Transferosomes3, 6

Entrapment efficiency

Entrapment efficiency was determined by first separation of unentraped drug by the use of mini-column centrifugation method (Fry et al, 1978; New, 1990). After centrifugation, the vesicle was disrupted using 0.1%Triton X-100 or 50% n-propanol and then followed by suitable analytical technique to determine the entrapped drugs.

Vesicle diameter

Vesicle diameter can be determined using photon correlation spectroscopy or dynamic light scattering (DLS) method. Samples were prepared in distilled water, filtered through a 0.2 mm membrane filter and diluted with filterd saline and then size measurement done by using photon correlation spectroscopy or dynamic light scaterring measurements (Gamal et al, 1999)

Confocal scanning laser microscopy (CSLM) study

In this technique lipophilic flouresence markers are in corporated into the transferosomes and the light emited by these markers are used for the investigation of mechanism of penetration of transferosomes across the skin, for determining histological organization of the skin and for comparision and differentiation of the mechanism of penetration of transferosomes with liposomes, niosomes and micelles.

Degree of deformability or permeability measurement

The deformability study is done against the pure water as standard. Transfrosomes preparation is passed through a large number of pores of known size through a sandwhich of different micropores filters with pore diameter between 50 nm and 400 nm, depending on the starting transferosomes suspension. Particle size and size distribution are noted after each pass by dynamic light scattering (DLS) measurements (Cevc et al, 1998)

In vitro drug release

The information from in-vitro studies are used to optimize the formulation before more expensive in vivo studies is performed. For determining in vitro drug release ,beaker method is used in which transferosomes suspension is incubated at 32oc using cellophane membrane and the samples are taken at different times and then detected by various analytical techniques (U.V., HPLC,HPTLC) and the free drug is separated by minicolumn centrifugation (Fry et al,1978), then the amount of drug release is calculated.

Vesicle shape and type

Transferopsomes vesicles can be visualized by TEM, with an accelerating voltage of 100 kv. Transferosomes vesicles can be visualized without sonication by phase contrast microscopy by using an optical microscope.

Number of vesicle per cubic mm

This is an important parameter for optimizing the composition and other process variables. Transferosome formulations (without sonication) can be diluted five times with 0.9% of sodium chloride solution and studied with optical microscopy by using haemocytometer.

Penetration ability

Penetration ability of transferosomes can be evaluated using fluorescence microscopy

Turbidity measurement

Turbidity of drug in aqueous solution can be measured using nephelometer

Surface charge and charge density

Surface charge and charge density of transferosomes can be determined using zetasizer

Application Of Transferosomes:

Transferosomes have been widely used as a carrier for the transport of proteins and peptides. Proteins and peptide are large biogenic molecules which are very difficult to transport into the body, when given orally they are completely degraded in the GI tract. These are the reasons why these peptides and proteins are still have to be introduced into the body through injections. Various approaches have been developed to improve these situations. The bioavaibility obtained from transferosomes is some what similar to that resulting from subcutaneous injection of the same protein suspension. The transferosomal preparations of this protein also induced strong immune response after the repeted epicutaneous appilication, for example the adjuvant immunogenic bovine serum albumin in transferosomes, after several dermal challenges is as active immunologically as is the corresponding injected proteo-transferosomes preparations.

Delivery of insulin by transferosomes is the successful means of non invasive therapeutic use of such large molecular weight drugs on the skin (Cevc et al, 1990). Insulin is generally administered by subcutaneous route that is inconvenient. Encapsulation of insulin into transferosomes (transfersulin) overcomes these entire problems. After transfersulin application on the intact skin, the first sign of systemic hypoglycemia are observed after 90 to 180 min, depending on the specific carrier composition3.

Transferosomes have also been used as a carrier for interferons, for example leukocytic derived interferone-α (INF-α) is a naturally occurring protein having antiviral, antiproliferive and some immunomodulatory effects. Transferosomes as drug delivery systems have the potential for providing controlled release of the administred drug and increasing the stability of labile drugs. Hafer et al studied the formulation of interleukin-2 and interferone-α containing transferosmes for potential transdermal application .they reported delivery of IL-2 and INF- α trapped by transferosomes in sufficient concentration for immunotherapy (Hafer et al,1999)

Another most important application of transferosomes is transdermal immunization using trnsferosomes loded with soluble protein like integral membrane protein, human serum albumin, gap junction protein. These approach offers at least two advantages, first they are applicable without injection and second, they give rise to rather high titer and possibly, to relatively high IgA levels.

Transferosomes have also used for the delivery of corticosteroids. Transferosomes improves the site specificity and overall drug safety of corticosteroid delivery into skin by optimizing the epicutaneously administered drug dose (Cevc et al, 1997). Transferosomes beased cortiosteroids are biologically active at dose several times lower than the currently usd formulation for the treatment of skin diseases (Cevc et al, 1997).

Application of anesthetics in the suspension of highly deformable vesicles, transferosomes, induces a topical anesthesia, under appropriate conditions, with less than 10 min. Maximum resulting pain insensitivity is nearly as strong (80%) as that of a comparable subcutaneous bolus injection, but the effect of transferosomal anesthetics last longer. Transferosmes has also been used for the topical analgesics, anaesthetics agents, NSAIDS and anti-cancer agents. 

Conclusion:

Transferosomes are specially optimized particles or vesicles, they are highly deformable particles and thus can be used to penetrate the skin. When tested in artificial systems transferosomes can pass through even tiny pores (100 nm) nearly as efficient as water, which is 1500 times smaller. Transferosomes are complex lipid molecules that can increase the transdermal flux, prolonging the release and improving the site specificity of bioactive molecules. Hence enhanced delivery of bioactive molecules through the skin by means of an ultradeformable vesicular carrier open new challenges and opportunities for the development of novel improved therapies.

References:

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  3. Arun Nanda., Sanju Nanda., Manish Dhall.,, and Rekha Rao., transferosomes: A Novel Ultradeformable Vesicular Carrier for Transdermal Drug Delivery, Vol. 5 No. 9 · October 2005, article=395.
  4. Payne R., factors influencing quality of life in cancer patients: the role of transdermal fentanyl in the management of pain. Semin on col. 1998:25(7):47-53.
  5. Barry B.W., Novel mechanism and device to enable successful transdermal drug delivery, Enr J pharm Sci, 2001:14:101-114.
  6. Jain S., Sapee R., Jain N.K., Proultraflexible lipid vesicles for effective transdermal delivery of norgesterol, proceedings of 25th conference of C.R.S., U.S.A., 1998: 32-35.
  7. Vara B., Khapade A.J., Jain N.K., Proniosome based transdermal delivery of levonorgesterol for effective contraception, J control Rev. 1998:54:149-165.
  8. Cevc G., Drug delivery across the skin. Exp. Opin invest Drugs 1997:1887-1973.
  9. Cevc G., lipid vesicles and other colloids as drug carriers on the skin , Adv. Drug delivery Rev 2004: 56(5):675-711.
  10. Bhatia A.,Kumar R., Tamoxifen in topical liposomes., development and characterization and invitro evaluation, j Pharm sci.; 2004; 7(2); 252-259.
  11. New RRC., preparation of liposomes in liposomes : a practical approach, New RRC, ods; Oxford university press: oxford,U.K.; 1990; 33-35.
  12. Dayan N., Touilun E., Carrier for skin delivery of tri hexiphenidyl HCL: ethosomes Vs liposomes , material, 2000; 21; 1879-1885.
  13. Kim M.K., Chuny S.J., Lee M.H., Cho A.R., Shim C.K., targeted and sustained delivery of hydro cortisone and stratum corneum removing skin without enhanced skin absorbtion using liposome gel, J Control .,Ref . 1997; 46;243-251.
  14. Fry D.W., Whit j.C., Goldman I.D., rapid separation of low molecular weight solutes from liposomes without dilution J Anal Biochem. 1978; 90; 809-815.
  15. Guo J.,Ping Q.,Sung.,Jiao C., Lecithin vesiculsr carrier for transdermal delivery of cyclosporine. Int. J. pharm 2000; 194: 201-207.

About Authors:

Swarnlata Saraf

Dr.(Mrs.)Swarnlata Saraf has nearly 14 years of research and teaching experience. She is a leading scientist and well-known in the field of herbal cosmetics. Mrs. Saraf did her doctoral research at the Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. She has over 40 publications to her credit published in international and national journals. She is an active member of IPA, APTI and ISTE. Her research interest extends from Herbal Cosmetics to transdermal drug delivery (especially Iontophoresis), New Drug Delivery Systems for biological and therapeutic agents. She has Co-authored 1 book on cosmeceuticals. Presently, She is working as a Reader at Institute of Pharmacy Pt. Ravishankar Shukla University, Raipur, (C.G.) INDIA.

* For correspondence

Dr. (Mrs.)Swarnlata Saraf , Reader, Institute of Pharmacy , Pt. Ravishankar Shukla University, Raipur (C. G.) - 492010

e-mail- swarnlata_saraf@rediffmail. com

Shailendra Saraf

Prof.S.Saraf has nearly 17 years of research and teaching experience at both U.G. and P.G. levels. He is a leading scientist and well-known academician . Prof. Saraf did his doctoral research at the Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. under the supervision of Prof. V. K. Dixit, a renowned Pharmacognosist. He has over 50 research publications to his credit published in international and national journals. He has delivered invited lectures and chaired many sessions in several National Conferences and Symposia in India. His research interest extends from Herbal Cosmetics to Herbal drug standardization Modern analytical techniques, New Drug Delivery Systems with biotechnology bias. He has authored 1 books. Presently, he is Professor and Director Institute of pharmacy and Dean, Faculty of Technology, Pt. Ravishankar Shukla University, Raipur , (C.G.).

Rakesh singh

Rakesh singh

M. Pharm II sem (pharmaceutics), Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chattisgarh. Rakesh singh has done his B.Pharm from B.R.Nahata college of Pharmacy, Mandsaur, Madhya Pradesh.

Rajendra jangade, Nilesh k gorde

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