ABOUT AUTHORS:
Mayur Pansuriya*, DR. Amit Gupta, Vihar Gadhvi, Kathiriya Hashesh, Patel Chirag
Department of Quality assurance,
Mahatma Gandhi College of Pharmaceutical Sciences,
ISI-15 (A) RIICO Institutional Area,
Sitapura, Tonk Road, Jaipur-302022 (Rajasthan).
*mayurpansuriya45@gmail.com
ABSTRACT
Lipid-based drug delivery systems have been investigated in various studies and shown their potential in controlled and targeted drug delivery. Pharmacosomes are amphiphilic phospholipid complexes of drugs bearing active hydrogen that bind to phospholipids. Pharmacosomes impart better biopharmaceutical properties to the drug, resulting in improved bioavailability. As the system is formed by combining drug (pharmakon) to carrier(soma), they are termed as pharmacosomes. Depending upon the chemical structure of the drug lipid complex they may exist in ultrafine vesicular, micellar and hexagonal aggregate. Any drug having an active hydrogen group(-COOH,-OH etc) can be esterified to lipids, resulting in amphiphillic compound. In general two methods have been employed to prepare pharmacosomes. These are hand shaking method and ether injection method. Developing the pharmacosomes of the drug has been found to improve the absorption and minimize the gastro-intestinal toxicity. Pharmacosomes have been prepared for various non-steroidal anti-inflammatory drugs, proteins, cardiovascular and antineoplastic drug. The drug is released from pharmacosome by hydrolysis (including enzymatic). This article reviews the potential of pharmacosomes as a controlled and targeted drug delivery system and highlights the methods of preparation and characterization.
REFERENCE ID: PHARMATUTOR-ART-1856
INTRODUCTION
The novel drug delivery system should ideally fulfill two prerequisites: Firstly, it should deliver the drug at a rate directed by the needs of the body, over the period of treatment, Secondly; it should channel the active entity to the site of action. Conventional dosage forms including prolonged release dosage forms are unable to meet none of these. Novel drug delivery attempts to either sustain drug action at a predetermined rate, or by maintaining a relatively constant, effective drug level in the body with concomitant minimization of undesirable side effects[13]. It can also localize drug action by spatial placement of controlled release systems adjacentto, or in the diseased tissue or organ; or target drug action by using carriers or chemicalderivatization to deliver drug to particular target cell type [10] [1]. Different types of pharmaceutical carriers such as particulate, polymeric, macromolecular and cellular are present. Particulate type carrier also known as colloidal carrier system, includes lipid particles (low and high density lipoprotein-LDL and HDL, respectively), microspheres, nanoparticles, polymericmicelles and vesicular like liposomes, sphingosome, niosomes, transferosomes, pharmacosomes, virosomes [2,3]. Pharmacosomes bearing unique advantages over liposomeand niosome vesicles have come up as potential alternative to conventional vesicles. Pharmacosomes are the colloidal dispersions of drugs covalently bound to lipids and may exist as ultrafinevesicular, micellar or hexagonal aggregates, depending on thechemical structure of the drug–lipid complex [4]. Pharmacosomes can pass through biomembranes efficiently and possess advantages over the use of other vesicular systems such astransferosome, liposomes, and niosomes. Any drug possessing a free carboxyl group or an active hydrogen atom (–OH, NH2) can beesterified (with or without a spacer group) to the hydroxyl group of a lipid molecule, thus generating an amphiphilic prodrug, which will facilitate membrane, tissue, or cell wall transfer, in the organism. Any drug with a certain cut- off molecular weight maybe formulated as pharmacosomes provided it has active functiona lgroups to integrate with the vesicle-forming amphiphilic molecule. An amphiphilicprodrug is converted to pharmacosomesupon dilution with water.[12] The conjugate of drug with carrier produces a compound, which is amphiphilic in nature. The aqueous solution of these amphiphiles typically exhibits concentration dependent aggregation, which differs from that of most polar orionic molecules. At low concentrations the amphiphile exists dispersed in the monomer state. As the monomer are added acritical micelle concentration is reached, leading to dramatic changes in the concentration dependence of many physical parameters, such as osmotic pressure, surface tension and electrical conductivity. The further increment in monomers may lead to variety of structures i.e. micelles of spherical or rod like or disc shaped or bilayered vesicles or cubic or hexagonal phasesdepending upon physiochemical interactions and thermodynamic variables of amphiphile. The prodrug conjoins hydrophilic and lipophilic properties thereby acquiring amphiphilic characteristics thus reduces interfacial tension, and, at higher concentrations, exhibit mesomorphic behavior. Because of a decrease in interfacial tension, the contact area increases, therefore increasing bioavailability. Pharmacosomes impart better biopharmaceutical properties to the drug, resulting in improved bioavailability. Pharmacosomes have been prepared for various non-steroidal antiinflammatory drugs, proteins, cardiovascular and antineoplastic drugs. Developing the pharmacosomes of the drugs has been found to improve the absorption and minimize the gastrointestinal toxicity. The idea for the development of the vesicular pharmacosome is based on surface and bulk interactions of lipids with drug. The different membranes in body contain phosphatidylcholine, phosphatidyl-ethanolamine, ceramides and sphingomyeline. These resemble lipid prodrugs in physicochemical structure. Therefore, it can be expected that pharmacosomes can interact with biomembranes enabling a better transfer of active ingredient. This interaction can also change the phase transition temperature of biomembranes, thereby improving the membrane fluidity leading to enhanced permeation. Pharmacosomes are designed to avoid the usual problems associated with the liposomal entrapment of polar drug molecules like low drug incorporation, leakage and poor stability.[5]
ADVANTAGES OF PHARMACOSOMES [1]
1) Pharmacosomes provide an efficientmethod for delivery of drug directly to the site of infection, leadingto reduction of drug toxicity with no adverse effects and also reduces the cost of therapy by improved bioavailability of medication, especially in case of poorly soluble drugs.
2) Pharmacosomes are suitable for incorporating bothhydrophilic and lipophilic drugs. The aqueous solution of these amphiphiles exhibits concentration dependent aggregation.
3) Entrapment efficiency is not only high but also predetermined, because drug itself in conjugation with lipids forms vesicles and covalently linked together.
4) Unlike liposomes, there is no need of following thetedious, time-consuming step for removing the free, unentrapped drug from the formulation.
5) Since the drug is covalently linked, loss due to leakage ofdrug, does not take place. However, loss may occur by hydrolysis.
6) No problem of drug incorporation.
7) Encaptured volume and drug-bilayer interactions do notinfluence entrapment efficiency, in case of pharmacosome. These factors on the other hand have great influence on entrapment efficiency in case of liposomes
8) The lipid composition in liposomes decides its membranefluidity, which in turn influences the rate of drug release, and physical stability of the system. However, in pharmacosomes, membrane fluidity depends upon the phase transition temperature of the drug lipid complex, but it does not affect release rate since the drug is covalently bound. The drug is released from pharmacosome by hydrolysis(including enzymatic).
LIMITATION OF PHARMACOSOMES [6]
1) Amphiphilic nature is responsible for synthesis of compound.
2) Covalent bonding is required to protect the leakage of drugs.
3) Surface and bulk interaction of lipid with drug is the basic principle of pharmacosomes.
4) On storage, pharmacosome undergoes fusion, aggregation, as well as chemical hydrolysis.
METHOD OF PREPARATION [4]
There are two methods which have been employed to prepare vesicles:
Hand-shaking method
In the hand-shaking method, a mixture of drug and lipid are dissolved in a volatile organic solvent such as dichloromethane in a round bottom flask. The organic solvent is removed at room temperature using a rotary evaporator, which leaves a thin films of solid mixture deposited on the walls of flask. The dried film can then be hydrated with aqueous medium and readily gives a vesicular suspension.
Ether-injection method
In the ether-injection method, an organic solution of the drug–lipid complex is injected slowly into the hot aqueous medium, wherein the vesicles are readily formed.
FORMULATION OF PHARMACOSOMES [1]
Drug salt was converted into the acid form to provide an active an hydrogen site for complexion drug acid was prepared by acidification of an aqueous solution of drug salt, extraction Into chloroform, and subsequent recrystallization. drug-PC complex was prepared by associating drug acid with and equimolar concentration Of PC. the equimolar concentration of PC and drug acid were placed in a 100 ml round bottom flask And dissolved in dichloromethane. the solvent was evaporated under vacuum at 40 c in a rotary vacuum evaporator. the pharmacosomes were collected as the dried residue and placed in a vacuum dessicator Overnight and then subjected to characterization.
EVALUATION OF PHARMACOSOMES
Drug content
To determine the drug content in pharmacosomes of drug (e.g.: diclofenac-PC complex), a complex equivalent to 50 mg diclofenac was weighed and added into a volumetric flask with 100 mL of pH 6.8 phosphate buffer. Then the volumetric flask was stirred continuously for 24 h on a magnetic stirrer. At the end of 24 h, suitable dilutions were made and measured for the drug content at 276 nm UV spectrophotometrically.
Fourier Transform Infrared Spectroscopy [7]
The formation of the complex can be confirmed by IR spectroscopy comparing the spectrum Of the complex with the spectrum of the complex with the spectrum of individual And components and their mechanical mixture. Fourier transform infrared spectroscopy Is an important analytical tool for the evaluation of stability of pharmacosomes. stability can be evaluated by comparing the spectrum of the complex in solid form with the spectrum of its Microdispersion in water after lyophilization, at different time intervals.
Solubility [8]
To determine the change in solubility due to complexation, solubility of drug and drug-PC complex was determined in pH 6.8 phosphate buffer and n-octanolby the shake-flask method. Drug (50 mg) (and 50 mg equivalent in caseof complex) was placed in a 100-mL conical flask. Phosphate buffer pH 6.8 (50 mL) wasadded and then stirred for 15 minutes. The suspension was then transferred to a 250 mL separating funnel with 50 mL n-octanol and was shaken well for 30 minutes. Then the separating funnel was kept still for about 30 minutes. Concentration of the drug was determinedfrom the aqueous layer spectro photometrically at suitable wavelength.
Surface Morphology
surface morphology of the pharmacosomes can be observed with scanning electron microscopy (SEM) or transmission electron microscopy (TEM). The shape and size of the pharmacosomesmay be affected by the purity grade of phospholipid and the process variables such as speed rotation, vacuum applied or the method used. Pharmacosomes prepared by low purity grades of lipids yields a greasy product, which in tern results in the formation of sticky large aggregates. Pharmacosomes prepared by very high purity grades (>90%) lipids are prone to oxidative degradation, which intern adversely affect the stability of complexes. Most commonly phospholipids of 80% purity have been used.
Differential scanning calorimetry (DSC)
Thermograms of diclofenac acid, phosphatidylcholine (80 %) and the diclofenac- The thermal behavior was studied by heating 2.0 ± 0.2 mg of each individual sample in a covered sample pan under nitrogen gas flow. The investigationswere carried out over the temperature range 25–250 °C at a heating rateof 10 °C min–1. This thermoanalytical technique is performed to determined drug-excipient compatibility and to demonstrate the possible interactions. Here, an interaction is concluded by elimination of endothermic peak, appearance of new peak, and change in peak shape and its onset, peak temperature/melting point and relative peak area or enthalpy. X-ray powder diffraction (XRPD)The crystalline state of drug in the different samples was evaluated using X-ray powder diffraction. The X-ray generator was operated at 40kV tube voltages and 40 mA tube current, using the K a lines of copper as the radiation source. The scanning angle ranged from 1 to 60° of 2q in the step scan mode (step width0.4° min–1). Drug, phosphatidylcholine 80 % (Lipoid S-80) and the prepared complex were analyzed. 337A. Semaltyet al.: Development and physicochemical evaluation of pharmacosomes of diclofenac, Acta Pharm. 59 (2009) 335–344.
Dissolution study [9]
In vitro dissolution studies of drug –PC complex as well as plain diclofenac acid were performed in triplicate in a USP (8) six station dissolution test apparatus, type II (Veego Model No. 6 DR, India) at 100 rpm and at 37 °C. An accurately weighed amount of the complex equivalent to 100 mg of drug acid was put into 900 mL of pH 6.8 phosphate buffer. Samples (3 mL each) of dissolution fluid were withdrawn at different intervals and replaced with an equal volume of fresh medium to maintain sink conditions. Withdrawn samples were filtered (through a 0.45-mm membrane filter), diluted suitably and then analyzed spectrophotometrically at 276 nm.
APPLICATIONS:
The approach has successfully improved the therapeutic performance of various drugs i.e. pindolol maleate, bupranolol hydrochloride, taxol, acyclovir, etc. The phase transition temperature of pharmacosomes in the vesicular and Micellar state could have significant influence on their interaction with membranes. Pharmacosomes can interact with bimembranes enabling a better transfer of active ingredient. This interaction leads to change in phase transition temperature of bimembranes thereby improving the membrane fluidity leading to enhance permeations.[11,4]
CONCLUSION:
Vesicular systems have been realized as extremely useful carrier systems in various scientific domains. Over the years, vesicular systems have been investigated as a major drug delivery system, due to their flexibility to be tailored for varied desirable purposes. In spite of certain drawbacks, the vesicular delivery systems still play an important role in the selective targeting, and the controlled delivery of various drugs. Researchers all over the world continue to put in their efforts in improving the vesicular system by making them steady in nature, in order to prevent leaching of contents, oxidation, and their uptake by natural defense mechanisms.
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