Polymeric Novel Vesicular Drug Delivery System: An Updated Overview of Microspheres
Katta. Manogna*, E. Nanda Krishna Reddy, T.N. Shilpa
S V U College of Pharmaceutical Sciences, S V University, Tirupati
*Corresponding Author E-mail: k.p.manogna@gmail.com
ABSTRACT:
Microspheres are categorized under the vesicular drug delivery system, encapsulated by proteins or synthetic polymers which are biodegradable in nature and ideally having a particle size less than 200 μm. The internal structure of the microspheres can vary as a function of the microencapsulation process employed. The encapsulation is carried out by various preparation methods. Microspheres are multiparticulate drug delivery systems which are prepared to obtain prolonged or controlled drug delivery to improve bioavailability, stability and to target the drug to specific site at a predetermined rate. Drugs can be targeted to specific sites in the body using microspheres. The rate of drug release from the microspheres dictates their therapeutic action. Release is governed by the molecular structure of the drug and the polymer, the resistance of the polymer to degradation, and the surface area along with the porosity of the microspheres. This article aims to provide a comprehensive review of advantages, methods of preparation, mechanism, routes of administration, different types of microspheres based on natural and synthetic biodegradable polymers and application of biodegradable polymeric microspheres.
KEYWORDS: Microspheres, microencapsulation, polymers, controlled drug delivery, biodegradable
INTRODUCTION:
Definition
Micro indicates particle size from 1μm to 1000μm, spheres means spherical particles. Microspheres are defined as small spherical particles, with diameter ranges from 1μm to 1000μm (1 mm). It is a monolithic spherical structure with drugs or active principle ingredient distributed throughout the matrix either as molecular dispersion or as dispersion of particles. Sometimes they are also called as micro particles, and micro beads and beads. (1)
Fig No. 1: microspheres
Microsphere is characteristically free flowing powders consisting of protein or synthetic polymer, which are biodegradable in nature. This is the important approach in delivering therapeutic substances to the target site in sustained and controlled release (2).
Microspheres can be manufactured from various natural and synthetic materials. Glass microspheres, polymer microspheres and ceramic microspheres are commercially available. Solid and hallow microspheres vary widely in density and, therefore, are used for different applications. Hallow microspheres are typically used as additives to lower the density of a material. Polyethylene and polystyrene microspheres are two most common types of polymer microspheres (3).
Types of microspheres:
1. Glass microspheres
2. Polymer microspheres
3. Ceramic microspheres
4. Solid and hollow microspheres
1. Glass microspheres:
· These are mostly used as fillers and volumizers for weight reduction.
· As retro-reflector for highway safety.
· As additives for cosmetics.
2. Polymer microspheres:
· Polyethylene microspheres are commonly used as permanent or temporary filler.
· These are creating porous structures in ceramics and other materials due to their lower melting temperature.
· These are highly desirable for flow visualization, fluid flow analysis, microscopy techniques; health sciences process trouble shooting etc. due to the sphericity of colored and fluorescent poly ethylene microspheres.
· Charged poly ethylene microspheres are used for electronic paper digital displays.
3. Ceramic microspheres:
· Typically used as grind medium.
4. Solid and hallow microspheres:
· These are potential approach for gastric retention. They worked on the principal mechanism of floating to achieve gastric retention (3)
ADVANTAGES:
1) Microspheres supply constant and lengthened therapeutic effect.
2) Reduces the dosing frequency and thereby improves the patient compliance.
3) Microspheres could be injected into the body due to spherical shape and smaller in size.
4) Better drug utilization will improve the bioavailability and it will reduce the incidence.
5) Microsphere morphology allows convenient variability in degradation and drug release (4).
TYPES OF MICROSPHERES:
Bioadhesive microspheres (5-7)
Adhesion can be defined as sticking of drug to the membrane by using the sticking property of the water soluble polymers. Adhesion of drug delivery device to the mucosal membrane such as buccal, ocular, rectal, nasal etc can be termed as bio adhesion. These sort of microspheres present a extend residence time at the site of application and causes intimate contact with the absorption site and construct a better therapeutic action.
Magnetic microspheres:
This type of delivery system is very much important which limit the drug to the disease site. In this larger quantity of freely circulating drug can be replaced by smaller amount of magnetically targeted drug. Magnetic transporter receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are Chitosan, dextran etc. The different types are Therapeutic magnetic microspheres be used to deliver chemotherapeutic agent to liver tumour. Drugs like proteins and peptides can also be selected from side to side this system.
Diagnostic microspheres:
These Can be used for imaging liver metastases and also can be used distinguish bowel loops from other abdominal structure by forming nano size particles supra magnetic iron oxides.
Floating microspheres:
In floating types the bulk density is less than the gastric fluid and so remains buoyant in stomach without moving gastric emptying rate. The drug is released slowly at the desired rate, but the system is floating on gastric content and increases gastric residence and increases changes in plasma concentration. Moreover it also decreases chances of striking and dose dumping. One another way it produces prolonged therapeutic effect and therefore minimize dosing frequencies.
Radioactive microspheres:
Radio embolisation therapy microspheres sized 10-30 nm are of larger than capillaries and gets tapped in first capillary bed when they come across. They are injected to the arteries that lead to tumour of interest so all these conditions radioactive microspheres deliver high radiation dose to the targeted areas without damaging the normal local tissues. It differs from drug delivery system, as radio activity is not released from microspheres but acts from within a radioisotope typical distance and the different kinds of radioactive microspheres are α emitters, β emitters, γ emitters.
Polymeric microspheres:
The different types of polymeric microspheres can be classified as follows and they are
Ø Biodegradable polymeric microspheres and
Ø Synthetic polymeric microspheres.
Biodegradable polymeric microspheres:
Natural polymers such as starch are used with the concept that they are biodegradable, biocompatible, and also bio adhesive in nature. Biodegradable polymers lengthen the residence time when contact with mucous membrane due to its high degree of swelling property with aqueous medium, results gel formation. The rate and extent of drug release is controlled by concentration of polymer and the release pattern in a sustained manner. The main drawback is, in clinical use drug loading efficiency of biodegradable microspheres is complex and is difficult to control the drug release. However they provide wide range of application in microsphere based treatment.
Synthetic polymeric microspheres:
The absorption of synthetic polymeric microspheres are widely used in clinical application, moreover that also used as bulking agent, fillers, embolic particles, drug delivery vehicles etc. and proved to be safe and biocompatible but the main disadvantage of these kind of microspheres, are tend to migrate away from injection site and lead to possible risk, embolism and further organ damage. (8)
METHODS OF MICROSPHERES:
Preparation of microspheres should satisfy certain criteria:
1. The capability to incorporate practically high concentrations of the drug.
2. Stability of the preparation after synthesis with a clinically acceptable shelf life.
3. Controlled particle size and dispersability in aqueous vehicles for injection.
4. Release of active reagent with a good control over a wide time scale.
Several methods are available for the preparation of microspheres those are,
Ø Single emulsion technique
Ø Double emulsion technique
Ø Polymerization technique
Ø Normal polymerization
Ø Interfacial polymerization
Ø Phase separation coacervation method
Ø Spray drying and spray congealing
Ø Solvent evaporation
Ø Quassi emulsion solvent diffusion
Ø Wax coating and hot melt
1. Single emulsion technique:
Proteins and carbohydrates are single emulsion technique. The natural polymers are dispersed in aqueous medium followed by dispersion in non-aqueous medium like oil. The cross linking can be achieved either by means of heat or by using the chemical cross linkers. The chemical cross linking agents used are glutaraldehyde, formaldehyde, acid chloride etc. chemical cross linking suffers from the excessive exposure of active ingredient to chemicals if added at the time of preparation.(9)
Figure: Processing scheme for microspheres-preparation by single emulsion technique
2. Double emulsion technique
The preparation of microspheres by double emulsion method involves the formation of multiple emulsions or the double emulsion of type W/O/W and is best suited to water soluble drugs, peptides, proteins and vaccines. This method can be used with both the natural and synthetic polymer. The aqueous protein solution is dispersed in a lipophilic organic continuous phase. This protein solution may contain the active ingredients. The continuous phase is generally containing polymer solution that eventually encapsulates the protein contained in dispersed aqueous phase. The primary solution subjected to the homogenization or sonication before addition to the aqueous solution of poly vinyl alcohol. This results in the formation of double emulsion. The emulsion is then subjected to solvent removal either by solvent evaporation or by solvent extraction. Hydrophilic drug like luteinizing hormone releasing hormone (LH-RH) agonist, vaccines, proteins/peptides and conventional molecule are successfully incorporated into the microspheres using the method of double emulsion.
Figure: Processing scheme for microspheres-preparation by double emulsion technique
3. Polymerization technique
The polymerization technique mainly used for the preparation of microspheres is classified as:
I. Normal polymerization
II. Interfacial polymerization. Both are carried out in liquid phase.
Figure: Polymerization method
4. Normal polymerization
This method is carried out using different techniques as bulk, suspension, preparation emulsion and micelle polymerization processes. In bulk, a monomer or a mixture of monomers along with the initiator or catalyst is usually heated to initiate polymerization. Drug loading may be done during the process of polymerization. Suspension polymerization also referred as bead or pearl polymer. It is carried out by heating the monomer or mixture of monomers as droplets dispersion in a continuous aqueous phase. The droplets also contain and initiator and other additives. Emulsion polymerization as due to the presence of initiator in the aqueous phase, which later on diffuses to the surface of micelles.
Advantage - Formation of the pure polymer,
Disadvantage – It is Very difficult to dissipate the heat of reaction, which can adversely affect the thermo labile active ingredients.
5. Interfacial polymerization
This method involves the various monomers at the interface between the two immiscible liquid phases to form a film of polymer that essentially envelops the dispersed phase.
6. Phase separation coacervation technique
This technique is based on the principle of decreasing the solubility of the polymer in organic phase to affect the formation of coacervatates. Particles are dispersed in a solution of the polymer and an incompatible polymer is added to the system which makes first polymer to phase separate and engulf the drug particles. Addition of non-solvent results in the solidification of polymer. The process variables are very important since the rate of achieving the coacervates determine the distribution of the polymer film, the particle size and agglomeration of the formed particles. The process of microspheres formation begins the formed polymerize globules start to stick and form the agglomerates. Therefore the process variables are critical as they control the kinetic of the formed particles since there is no defined state of equilibrium attainment. (10)
Figure: The formation of a Coacervation around a core material
7. Spray drying and spray congealing
Concept of spray drying technique depending upon the removal of solvent or the cooling of solution the two processes are spray drying & spray congealing. Evaporation is the basic mechanism in spray drying, whereas in spray congealing it is that of a phase inversion from a liquid to a solid. Both processes are similar, except for energy flow1. Spray drying is the most widely used industrial process involving particle formation and drying. Therefore, spray drying is an ideal process where the end product must comply with precise quality standards regarding particle size distribution, residual moisture content, bulk density, and particle shape.
Principle: Three steps involved in spray drying
a) Atomization: of a liquid feed change into fine droplets.
b) Mixing: it involves the passing of hot gas stream through spray droplets which result in evaporation of liquids and leaving behind dried particles.
c) Dry: Dried powder is separated from the gas stream and collected.
In this technique polymer is first dissolved in a suitable volatile organic solvent such as dichloromethane, acetone, etc. The drug in the solid form is then dispersed in the polymer solution under high-speed homogenization. This dispersion is then atomized in a stream of hot air, this form small droplets or the fine mist, from which the solvent evaporates instantaneously leading the formation of the microspheres. The size range is 1-100 μm. By using hot air separate of Micro particles by means of the cyclone separator while the traces of Solvent are removed by vacuum drying. Advantages of the process are probability of operation.
The sprays are produces by either rotary (wheel) or nozzle atomizers. Evaporation of moisture from the droplets and formation of dry particles proceed under controlled temperature and airflow conditions. (11)
The microsphere size is controlled by the rate of spraying, nozzle size, temperature (in drying and collecting chambers.) and the feed rate of polymer drug solution. The quality of product is improved by addition plasticizer spray flow rate should kept constant around 6ml/min. Spray drying technique is also useful for preparing chitosan microsphere are Used formaldehyde as a cross linking and also reported a novel method in which cimetidine and Famotidine were entrapped in microspheres prepared by spray drying of multiple emulsion (o/w/o or w/o/w). They found that the release of the drugs from microspheres by this novel method was significantly sustained as compared to those prepared by conventional spray drying or o/w emulsion method. It was used spray drying used for the preparation of PCL microspheres of ketoprofen. Solid microspheres were collected into final bottom vessel spray-drier.
Figure: Diagram of the equipment and process of conventional spray-drying
Advantages and disadvantages
Spray drying is very useful for pulmonary drug delivery as well as for oral dosages form and it is remarkable versatility of the technology, and a wide range of product can be obtained by this technique.
Ø It is very flexible and reproducible method that, why number of industries use this technique for drying operation.
Ø It can be considered to practically any capability required easily.
Ø Can be used with both heat-resistant and heat responsive products.
Ø Powder quality remainder constant throughout the dryer.
Ø Particles which twisted uniform in size and commonly hollow thus decrease the bulk density of the manufactured goods.
But there are some drawbacks in technique;
Ø The equipment is especially bulky and exclusive.
Ø The overall thermal good organization is low, as the large volumes of intense air pass from side to side the chamber without contact a particle.
8. Solvent Evaporation
The processes are carried out in a liquid manufacturing vehicle. The microcapsule coating is dispersed in a volatile solvent which is immiscible with the liquid manufacturing vehicle phase. A core material to be Micro encapsulated is dissolved or dispersed in the coating polymer solution. With agitation the core material mixture is dispersed in the liquid manufacturing vehicle phase to obtain the appropriate size microcapsule. The mixture is then heated if necessary to evaporate the solvent for the polymer of the core material is disperse in the polymer solution, polymer shrinks around the core. If the core material is dissolved in the coating polymer solution, matrix – type microcapsules are formed. The core materials may be either water soluble or water in soluble materials. Solvent evaporation involves the formation of an emulsion between polymer solution and an immiscible continuous phase whether aqueous (o/w) or non-aqueous. (12)
Figure: Solvent evaporation method for preparation of microspheres
APPLICATIONS OF MICROSPHERES
Medical applications:
Ø Release of proteins, hormones and peptides over extended period of time.
Ø Gene treatment with DNA plasmids and also release of insulin.
Ø Vaccine release for treatment of disease like hepatitis, influenza, pertussis, ricin, toxiod, diphtheria, birth control.
Ø Passive targeting of leaky tumour vessels, active targeting of tumour cells, antigens, by intra-arterial/intravenous application.
Ø Tumour targeting with doxorubicin and also treatment of laishmaniasis.
Ø Magnetic microspheres can be used for stem cell withdrawal and bone marrow purging.
Ø Used in separation of antibodies, cell division and toxin withdrawal and bone marrow by attraction chromatography.
Ø Used for various diagnostic tests for communicable diseases like bacterial, viral, and fungal.
Ø Radioactive microsphere’s application.
Ø It can be used for radio embolisation of liver and spleen tumours.
Ø Use for radiosynvectomy of arthritis joint, local radiotherapy, interactivity treatment. (13)
Other potential applications include
Ø Change of oil and other liquid to solids for ease of treatment
Ø Taste and odor masking
Ø To interruption the volatilization
Ø Safe treatment of toxic substance
CHARACTERIZATION/ EVALUATION OF MICROSPHERES
Particle size analyzer
Microsphere was suspended in distilled water (5mL) containing 2%w/v of Tween 80. To prevent microsphere aggregation, the above suspension is sonicated in water bath and the particle size was expressed as volume mean diameter in micrometer.
Optical microscopy
This method was used to determine particle size by using optical microscope (Meizer OPTIK) The measurement was done under 450x (10x eye piece and 45x objective) and100 particles were calculated.
Scanning electron microscopy (SEM)
Surface morphology was determined by the method of SEM. In this microcapsule were mounted directly on the SEM sample slub with the help of double sided sticking tape and coated with gold film under reduced pressure.
Swelling index
This technique was used for Characterization of sodium alginate microspheres were performed with swelling index technique Different solution (100mL) were taken such as (distilled water, buffer solution of pH(1.2, 4.5, 7.4) were taken and alginate microspheres (100mg) were placed in a wire basket and kept on the above solution and swelling was allowed at 37oC and changes in weight variation between initial weight of microspheres and weight due to swelling was measured by taking weight periodically and soaking with filter paper.
Entrapment efficiency
Microspheres containing of drug were crushed and then dissolved in distilled water with the help of stirrer stir for 3 hr, and was filtered then assayed by UV, visible spectroscopy. Entrapment efficiency is equal to ratio of actual drug content to theoretical drug content. (14)
X-ray diffraction
Crystalline nature of drug can be determined by this technique. Microparticles and its individual components were analyzed by the help of X ray Diffraction. (Bruker, Germany).
Ø Scanning range angle between 8 0C - 70 0C
Ø Scan speed - 4o/min
Ø Scintillation detector Primary silt=1mm Secondary silt=0.6 mm.1
Thermal analysis
Thermal analysis of microcapsule and its component can be done by using-
Ø Differential scanning calorimetry (DSC)
Ø Thermo gravimetric analysis (TGA)
Ø Differential thermometric analysis (DTA)
Accurately the sample was weighed and heated on alumina pan at constant rate of 10oc/min under nitrogen flow of 40 ml/min.
UV-FTTR (Fourier transform infrared)
In the process of drug and polymer interaction, may be degradation of drug will occurs while processing for microencapsulation can be determined by FTIR.
Stability studies
By placing the microspheres in screw capped glass container and stored them at following conditions:
Ø Ambient humid condition
Ø Room temperature (27+/-2 0C)
Ø Oven temperature (40+/-2 0C)
Ø Refrigerator (5 0C -80C).
It was carried out of a 60 days and the drug content of the microsphere was analyzed.
Zeta potential
The polyelectrolyte shell was prepared by incorporating suitable polymer of different molecular weight into the W2 phase and the resulting particles were determined by zeta potential measurement.
CONCLUSION:
The concept of encapsulating the drug as microsphere is for a better targeting of the drug at appropriate tissue destination is widely accepted by researches and academicians and polymers are used here to encapsulate and also help to design the delivery system of drug. Microspheres are spherical & free flowing particles are in average particle which consist of proteins or synthetic polymers. In future by combining various other strategies, microspheres will find the central place in novel drug delivery.
ACKNOWLEDGEMENT:
The authors thankful to the Prof. K. Thyagaraju Garu, Principal, SVU College of sciences, SV University Tirupati for providing required facilities to carry out this research work
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Received on 10.11.2017 Accepted on 26.12.2017
©A&V Publications all right reserved
Research J. Topical and Cosmetic Sci. 8(2): July-Dec. 2017 page 64-72
DOI: 10.5958/2321-5844.2017.00008.5