Review of Micrencapsulation: A Review A Novel Approach in Drug Delivery

 

Priya D. Khode*, Tina B. Katre

Maharashtra Institute of Pharmacy (B. Pharm) Betala, Bramhapuri

 

ABSTRACT:

Microencapsulation is the enveloping of liquid droplets or fine solid particles to form microcapsule, having an average diameter as small as 1 μm to several hundred micrometers. Microencapsulation technology is of interest to a wide range of industries, including pharmaceutical, food, agricultural, biotechnological, cosmetic and other industries with various significant advantages, including: (i) an effective protection of the encapsulated active ingredient against degradation, (ii) the possibility to control the release rate of the active ingredient. This review paper will address the historical background of microencapsulation technology, commonly used microencapsulation methods with its advantages and disadvantages and its applications in pharmaceutical, food, agricultural, biotechnological and cosmetic field. It also focuses on the influence of process parameters, residual solvent and cross linking agents as described in the scientific journal and patent literature. Microencapsulation methods are divided into two basic groups, namely chemical and physical. Each method has its own advantages as well as disadvantages. However most of the commonly used methods have several disadvantages such as unfavorable conditions for the core material, complexity in procedure and low encapsulation efficiency. The results indicate that the number of process variables that should be optimized during core material encapsulation. The dependence so many process variables may become a problem in terms of reproducibility and scale-up process. Based on the existing results and authors' reflection, this review gives rise to reasoning and suggested choices of process parameters and microencapsulation procedure.

 

 

 

INTRODUCTION:

Microencapsulation is a process by which very tiny droplets or particles of liquid or solid material are surrounded or coated with a continuous film of polymeric material. Microencapsulation includes Bioencapsulation which is more restricted to the entrapment of a biologically active substance (from DNA to entire cell or group of cells for example) generally to improve its performance &/or enhance its shelf life.

 

Microencapsulation provides the means of converting liquids to solids, of altering colloidal and surface properties, of providing environmental protection and of controlling the release characteristics or availability of coated materials. Several of these properties can be attained by macropackaging techniques, however, the uniqueness of microencapsulation is the smallness of the coated particles and their subsequent use and adaptation to a wide variety of dosage forms and not has been technically feasible.³ This term as a spherical partical with size varying from 50nm to 2nm containing a core substance.⁵

 

Microencapsulation of pharmaceuticals was first investigated in 1931 by preparing gelatin spheres using coacervation technique. Processes and materials used for coating have since been developed by the pharmaceutical industry to aid in formulation of various dosage forms such as tablets, capsules, injectables, powders and topicals (Deasy 1984). The resultant product of the microencapsulation process is known as “microcapsule”. In a relatively simpler form, a microcapsule is a small sphere with a uniform wall around it. The material inside the microcapsule is referred to as the core, internal phase, or fill, where as the wall is sometimes called a shell or coating. Most microcapsules have diameters between a few micrometers and a few millimeters.^8,9 Microcapsule ranges in size between 1 and 1000 μm. Capsules greater than 1000 μm (1 mm) can be called macrocapsules and those smaller than 1μm are termed as nanocapsules. The first truly successful commercial development of a product using microcapsules was carbonless copy paper by The National Cash Register (NCR) of America in 1953, and then microencapsulation technology was further explored through encapsulation of active ingredients in pharmaceutical industry.^1,6,7

 

Fig. no. 1 Microencapsulatin

 

HISTORY:

The pharmaceutical industry has long used microcapculation for the preparation of capsules containing active ingredient. Mr. Green made first gelatin microcapsules in 1940 the technique of microencapsulation is adopted from natural itself it took nine years of research to make available marketed product. The origins of the process of microencapsulation lie in the pharmaceutical and paper industries of the 1940’s however the textile industry started introducing encapsulated products in its articles between 1980 and 1990. During the past 10 years this approach has been explored widely by the agriculture, food, cosmetics and textile industry. In the early 1950, Barrett K, Green developed the microencapsulation that use the process of phase separation coacervation.

 

The first pharmaceutical product consisting of microencapsulation was controlled release asprin product. In recent years the microencapsulation process are used in many industries such as food, food additives, cosmetics, house-hold product and agriculture material as well as agro-space industry and many more.¹¹

 

REASONS FOR MICROENCAPSULATION:

·       The primary reason for microencapsulation is found to be either for sustained or prolonged drug release.

·       This technique has been widely used for masking taste and odor of many drugs to improve patient compliance.

·       This technique can be used for converting liquid drugs in a free flowing powder.

·       The drugs, which are sensitive to oxygen, moisture or light, can be stabilized by microencapsulation.

·       Incompatibility among the drugs can be prevented by microencapsulation.

·       Vaporization of many volatile drugs e.g. methyl salicylate and peppermint oil can be prevented by microencapsulation.

·       Many drugs have been microencapsulated to reduce toxicity and GI irritation including ferrous sulphate and KCl.

·       Alteration in site of absorption can also be achieved by microencapsulation.

·       Toxic chemicals such as insecticides may be microencapsulated to reduce the possibility of sensitization of factorial person.

Ÿ  ·Bakan and Anderson reported that microencapsulated vitamin Apalmitate had enhanced stability.³

 

CORE MATERIALS:

The core material, defined as the specific material to be coated, can be liquid or solid in nature. The composition of the core material can be varied, as the liquid core can include dispersed and/or dissolved materials. The solid core be active constituents, stabilizers, diluents, excipients, and release-rate retardants or accelerators. The ability to vary the core material composition provides definite flexibility and utilization of this characteristics often allows effectual design and development of the desired microcapsule properties.²

 

COATING MATERIALS:

The coating material should be capable of forming a film that is cohesive with the core material; be chemically compatible and nonreactive with the core material; and provide the desired coating properties, such as strength, flexibility, impermeability, optical properties, and stability. The coating materials used in microencapsulation methods are amenable, to some extent, to in situ modification.²

 

The selection of a given coating often can be aided by the review of existing literature and by the study of free or cast films, although practical use of free-film information often is impeded for the following reasons:

1.     Cast or free films prepared by the usual casting techniques yield films that are considerably thicker than those produced by the microencapsulation of small particles; hence, the results obtained from the cast films may not be extrapolate to the thin microcapsule coatings.

2.     The particular microencapsulation method employed for the deposition of a given coating produces specific and inherent properties that are difficult to simulate with existing film-casting methods.

3.     The coating substrate of core material may have a decisive effect on coating properties. Hence, the selection of a particular coating material involves consideration of both classic free-film data and applied results.^2,5

 

TECHNIQUES ON MANUFACTURE MICROENCAPSULES:

Physical method

1    Air suspension coating

2    Coacervation process

3    Centrifugal extrusion

4    Pan coating

5    Spray coating

 

Chemical method

1    Solvent evaporation

2    Polymerization

a.     Interfacial polymer

b.     In-situ polymer

3    Matrix polymer

 

Physical methods:

1 Air-suspension:

Air-suspension coating of particles by solutions or melts gives better control and flexibility. The particles are coated while suspended in an upward-moving air stream. They are supported by a perforated plate having different patterns of holes inside and outside a cylindrical insert. Just sufficient air is permitted to rise through the outer annular space to fluidize the settling particles. Most of the rising air (usually heated) flows inside the cylinder, causing the particles to rise rapidly.

 

 

Fig 2. Air suspension coating

 

At the top, as the air stream diverges and slows, they settle back onto the outer bed and move downward to repeat the cycle. The particles pass through the inner cylinder many times in a few minutes methods. The air suspension process offers a wide variety of coating materials candidates for microencapsulation. The process has the capability of applying coatings in the form of solvent solutions, aqueous solution, emulsions, dispersions or hot melts in equipment ranging in capacities from one pound to 990 pounds. Core materials comprised of micron or submicron particles can be effectively encapsulated by air suspension techniques, but agglomeration of the particles to some larger size is normally achieved.²

 

2. Coacervation Process:

The core material will be added to the solution. The core material should not react or dissolve in water (maximumsolubility 2%). The core material is dispersed in the solution. The particle size will be defined by dispersion parameter, as stirring speed, stirrer shape, surface tension and viscosity. Size range 2µm - 1200µm. Coacervation starts with a change of the pH value of the dispersion, e.g. by adding H2SO4, HCl or organic acids. The result is a reduction of the solubility of the dispersed phases (shell material).

·       The shell material (coacervate) starts to precipitate from the solution.

·       The shell material forms a continuous coating around the core droplets.

·       The shell material is cooled down to harden and forms the final capsule.³

 

 

Fig 3. Coacervation Process

Coacervation-Phase Separation:

The general outline of the processes consists of three steps carried out under continuous agitation: A liquid manufacturing vehicle phase, a core material phase, and a coating material phase. To form the three phases, the core material dispersed in a solution of the coating polymer, the solvent for the polymer being the liquid manufacturing vehicle phase. Deposition if the liquid polymer coating around the core material occurs if the polymer is adsorbed at the interface formed between the core material and the liquid vehicle phase, and this adsorption phenomenon is a prerequisite to effective coatings, rigidizing the coating, usually by thermal, crosslinking, or desolvation techniques, to form a selfsustaining microcapsules.³

 

 

Fig 4. Coacervation Phase sepration

 

3. Centrifugal extrusion:

Liquids are encapsulated using a rotating extrusion head containing concentric nozzles. In this process, a jet of core liquid is surrounded by a sheath of wall solution or melt. As the jet moves through the air it breaks, owing to Rayleigh instability, into droplets of core, each coated with the wall solution. While the droplets are in flight, a molten wall may be hardened or a solvent may be evaporated from the wall solution. Since most of the droplets are within ± 10% of the mean diameter, they land in a narrow ring around the spray nozzle. Hence, if needed, the capsules can be hardened after formation by catching them in a ring-shaped hardening bath. This process is excellent for forming particles 400–2,000 µm (16–79 mils) in diameter. Since the drops are formed by the breakup of a liquid jet, the process is only suitable for liquid or slurry. A high production rate can be achieved, i.e., up to 22.5 kg (50 lb) of microcapsules can be produced per nozzle per hour per head. Heads containing 16 nozzles are available.²

 

4. Pan coating:

The pan coating process, widely used in the pharma-ceutical industry, is among the oldest industrial procedures for forming small, coated particles or tablets. The particles are tumbled in a pan or other device while the coating material is applied slowly. The pan coating process, widely used in the pharmaceutical industry, is among the oldest industrial procedures for forming small, coated particles or tablets.

 

 

Fig 5. Pan coating

 

The particles are tumbled in a pan or other device while the coating material is applied slowly with respect to microencapsulation, solid particles greater than 600 microns in size are generally considered essential for effective coating, and the process has been extensively employed for the preparation of controlled - release beads. Medicaments are usually coated onto various spherical substrates such as nonpareil sugar seeds, and then coated with protective layers of various polymers.²

 

5. Spray–drying:

Spray drying serves as a microencapsulation technique when an active material is dissolved or suspended in a melt or polymer solution and becomes trapped in the dried particle. The main advantages is the ability to handle labile materials because of the short contact time in the dryer, in addition, the operation is economical. In modern spray dryers the viscosity of the solutions to be sprayed can be as high as 300mPa.s Spray drying and spray congealing processes are similar in that both involve dispersing the core material in a Liquified coating substance and spraying or introducing the core - coating mixture into some environmental condition, whereby, relatively rapid solidification (and formation) of the coating is affected.²

 

 

Fig. 6. Spray drying

The principal difference between the two method is the means by which coating solidification is accomplished. Coating solidification in the case of spray drying is effected by rapid evaporation of a solvent in which the coating material is dissolved. Coating solidification in spray congealing methods, however, is accomplished by thermally congealing a molten coating material or by solidifying a dissolved coating by introducing the coating - core material mixture into anon solvent. Removal of the non-solvent or solvent from the coated product is then accomplished by sorption, extraction, or evaporation techniques.^2,10,12

 

Chemical method:

1. Solvent Evaporation/Solvent Extraction:

Microcapsule formation by solvent evaporation /solvent extractio is very similar to suspension crosslinking, but in this case the polymer is usually hydrophobic polyester The polymer is dissolved in a water immiscible volatile organic solvent like dichloromethane or chloroform, into which the core material is also dissolved or dispersed. The resulting solution is added dropwise to a stirring aqueous solution having a suitable stabilizer like poly (vinyl alcohol)or polyvinylpyrrolidone, etc. to form small polymer droplets containing encapsulated material. With time, the droplets are hardened to produce the corresponding polymer microcapsules

 

This hardening process is accomplished by the removal of the solvent from the polymer droplet either by solvent evaporation (by heat or reduced pressure), or by solvent extraction (with a third liquid which is a precipitant for the polymer and miscible with both water and solvent). Solvent extraction produces microcapsules with higher porosities than those obtained by solvent evaporation. Figure 2 shows a schematic representation of microencapsulation by solvent evaporation technique. Solvent evaporation/extraction processes is suitable for the preparation of drug loaded microcapsules based on the biodegradable polyesters such as polylactide, poly (lactide-co-glycolide) and polyhydroxybutyrate.^4,10,14

 

 

2 Polymerization:

a. Interfacial Polymer:

Interfacial polymerization, the two reactants in a polycondensation meet at an interface and react rapidly. The basis of this method is the classical SchottenBaumann reaction between an acid chloride and a compound containing an active hydrogen atom, such as an amine or alcohol, polyesters, polyurea, polyurethane. Under the right conditions, thin flexible walls form rapidly at the interface. A solution of the pesticide and a diacid chloride are emulsified in water and an aqueous solution containing an amine and a polyfunctionalisocyanate is added. Base is present to neutralize the acid formed during the reaction. Condensed polymer walls form instantaneously at the interface of the emulsion droplets.²

 

b. In –situ polymerization:

In a few microencapsulation processes, the direct polymerization of a single monomer is carried out on the particle surface. In one process, e.g. Cellulose fibers are encapsulated in polyethylene while immersed in dry toluene. Usual deposition rates are about 0.5µm/min. Coating thickness ranges 0.2-75µm. The coating is uniform, even over sharp projections.²

 

3 Matrix polymer:

In a number of processes, a core material is imbedded in a polymeric matrix during formation of the particles. A simple method of this type is spray-drying, in which the particle is formed by evaporation of the solvent from the matrix material. However, the solidification of the matrix also can be caused by a chemical change.²

 

MECHANISM OF ACTION:

 

Fig 8 Mechanism

 

Release Mechanism:

·       Even when the aim of a microencapsulatio application is the isolaiton of the core from its surrounding ,the wall must be ruptured at the time of use

·        A varity of release mechanism have been proposed for microencapsulation:

1.     By pressure or shear.

2.     By melting the wall.

3.     By dissolving it under particular condition ,as in the case of an enteric drug caoting.

4.     By solvent action

5.     By enzyme attack

6.     By chemical reaction

7.     By hydrolysis or slow disintegration ¹³

 

 

Release Mechanism:

Degradation Controlled Monolithic System	Diffusion Controlled Monolithic System	Diffusion Controlled Reservoir System	Erosion
1.The drug is strongly attached to the matrix and is released on degradation of the matrix. 2. Diffusion of the drug is slow as compared with degradation of matrix.	Rate of release also depend upon polymer degrades by homogeneous or heterogeneous mechanisms.	1.The active agent is encapsulated by a rate controlling member through which the active agent diffusion and the member erodes only after its delivery is completed. 2.Drug release is unaffected by the degradation of matrix.	Erosion of the coat due to pH and enzymatic hydrolysis causes drug release. Ex. Glyceryl mono stearate, bees wax, steryl alcohol. Etc.

 

APPLICATION:

Applications in pharmaceutical industry:

A major application of microencapsulation technique in pharmaceutical field is controlled or sustained drug delivery. A wide number of pharmaceutical microencapsulated products are currently on the market, such as aspirin ® controlled release tablets (ZORprin CR) are used to treat pain and fever, to relieve pain and inflammation associated with arthritis and other inflammatory conditions, Cephalexin (Ceff-ER) and Cefadroxil (Odoxil OD) antibiotic for bacterial infections.

 

Microencapsulation of proteins and peptides has recently become a relevant alternative to develop novel drug delivery system The number of commercially available microsphere does not reflect the amount of research that has been carried out in this field, nor did the benefits that can achieve using this technology.^1,4

 

Applications in food industry:

Currently food industry uses more and more purified natural synthetic fragile substances and there is an increased need to protect them. Consumers are more aware regarding what they eat and what benefits certain ingredients has maintaining good health. Functional food ingredients (for e.g. flavors, vitamins or antioxidants etc.) are sensitive to environmental stress during manufacturing, storage and consumption of the food product. Sometimes these food ingredients slowly degrade and lose their bioactivity during digestion in the stomach and intestine. Spray drying techniques is generally used in food industry to decrease water content and thereby ensure a microbiological stability of products. Microencapsulation technology is used to encapsulate liquid flavor compounds in a carrier matrix to provide dry free-flowing materials protected against degradative reaction and the loss of flavors during food processing.^1,13

 

Applications in agricultural industry:

One of the most important applications of microencapsulated products in pesticide industry is to improve handling safety of the pesticides by hazard and exposure reduction. Microencapsulation technology satisfies many of the drivers towards the safer use of pesticides. The heavy use of herbicides has given rise to serious environmental and public health problems. It is therefore important to develop new herbicide formulations that are highly effective, safer for the worker and for the environment. Controlled release formulations of herbicides have become necessary in recent years, since they often increase herbicide efficacy at reduced doses. Pesticide is widely used throughout the world in the area of crop protection. Aldicarb is a carbamate pesticide, highly toxic to mammals. In order to overcome these problems, microspheres of aldicarb by using carboxymethyl cellulose (CMC) as the biodegradable support material cross-linked with aluminium chloride Endosulfan, a known pesticide has been identified as an important environmental pollutant. Controlled release formulation of endosulfan microspheres prepared by Roy et al. by cross linking sodium alginate with calcium ions in the presence of gelatin serve for reducing environmental impact of pesticides.^1,4

 

Applications in cosmetic industry:

In the field of Cosmetics microencapsulation technology has been used for making products like deodorants, shampoos, sprays, to improve their stability or bioavailability. The particulate delivery systems used in cosmetics include microparticulates, porous polymeric systems, nanoparticulates, cyclodextrincompl exe s. Generally microparticles are used in cosmetics to avoid incompatibility of substance, reduce odor of actives and for protection of substances prone to oxidation or action by atmospheric moisture.

 

Nylon microspheres are being used in cosmetic make-up and skin care products because of the feel and skin adhesion they impart. Chemical inertia of nylon microspheres allows them to hold hydrophilic and lipophilic ingredients including vitamins, sun filters, moisturizers, fragrances and many other actives (Patravale and Mandawgade 2008). The use of vitamin E, a natural antioxidant, in skin care products protects tissue from the effects of UV radiation, delays the photoaging process and exhibits moisturizing propertie.¹

 

 

ADVANTAGES AND DISADVANTAGES:

 

Fig. 9 Advantages and Disadvantages

 

MARKED FORMULATION:

Brand Name	Composition	anufacture	Use
Micronac plus 100mg	Aceclofenac + Paracetamol/ Acetaminophen 500mg	Micro Lab.	Pain relief
Nyde P tablet	Nimesulide + Paracetamol	Paston Laboratoires Pvt.Ltd	pain relief
Betaloc 50mg	Metoprolol tartrate	Astrazeneca	Chest pain
Clobitab	Clopidogel+Aspirin	Lupinpinnacale	Chest pain
Clopigrel	Clopidogrel + Aspirin	Lupin pinnacle	Heart attack & heart disease
Aciloc RD	Domperidon +Omeprazole	Cadila pharmaceutical	Acidity &geart burn
Niftas SR	Nitrofurantoin	Intas pharmaceutical	Bacterial infection, Urinary infection
Osteofos 70	Alendronic acid	Cipla Ltd.	Osteoporosis
Telma H	Telmisartan+Hydrochlrothiazide	Glenmark pharmaceutical	High blood pressure
Flavendon MR 35mg	Trimetazidine	Serdia pharmaceutical	Chest pain
Pantocoid tablet	Pantoprazol	Sun Pharmaceutical	Gastroesophageal reflux disease

 

CONCLUSION:

Since the concept of controlled drug delivery was introduced in 1970s, great progresses have been made in microencapsulation areas as microencapsulation offers a variety of opportunities such as protection and masking, reduced dissolution rate, facilitation of handling, and spatial targeting of the core material. A single microencapsulation method cannot be universally applied for a variety of drug materials.

 

In developing a new microparticle system for a given drug, it is important to understand the physicochemical properties of the drug and polymers that best match the properties and find an encapsulation method. However most of the commonly used methods have several disadvantages such as unfavorable conditions for the core material, complexity in procedure and low Encapsulation efficiency. Organic solvents, such as dichloromethane, chloroform, ethyl acetate or acetone are used to dissolve the biodegradable polymers but the toxicity of the solvent is a great matter of concern. Trace amounts of these solvents may remain in the final product as residual solvents. Therefore it is preferable to minimize the exposure to toxic organic solvents. Additional drying procedures, such as vacuum drying at elevated temperatures or lyophilization, may produce microspheres with low content of residual solvent. Cross-linking agents such as formaldehyde or glutaraldehyde are toxic, therefore cannot be used as the product may be applied to or ingested within a mammalian body. Naturally-occurring enzymes with good cross-linking property may solve this problem. Most of the work is in lab-scale setups; therefore the manufacturing process requires enough knowledge to scale up to the commercial scale.¹

 

FEATURE ASPECT:

·       Microorganism and enzyme immobilization

·       Protection against UV, heat (eg. Colorants and vitamins)

·       Improved the shelf life due to preventing degredative reaction

·       lmproved processing, texting and less wastage of ingredient

1)    control of hygroscopy

2)    due free powder

·       Enhance visual aspect and marketing concept

·       Carbonless copy paper was the first marketable product to employ microcapsules

·       Controlled and targeted release of active ingredients

·       Microencapsulation allows mixing of incompatible compounds

·       Pesticides

 

REFERENCE:

1.      Sanjay Kumar Das, Shaheba Rani Nakka David, TriptHalder, Mohanrajpalanisamy, JasminaKhanam, Microencapsulation techniques and its practice; Department of pharmaceuticals technology, Jadhavpur University Kolkata, Volume 6, Issue-2 July December-2011; ISSN 0972-0525; Page No. 1-17.

2.      S.S. Bansode, S.K. Banarjee, D.D. Gaikwad, S.L. Jadhav, R. M. Thorat, Microencapsulation: A Review; Vishal Institute of pharmaceuticalsEducation and Research, Ale, Pune, Volume 1, issue 2, March – April 2010; ISSN 0976 – 044X; Page no. 38-42

3.      K. Shekhar, M. Naga Madhu, B. Pradeep, David Banji, A Review on Microencapsulation; Department of pharmaceuticals, Nalgonda College of Pharmacy, Nalgonda; Volume 5, issue 2, November- December 2011 ISSN 0976-044X page no.58-62

4.      Rama Dubey, T. C. Shami and K.U. BhaskerRao, Microencapsulation Technology and Application, Defence material and stores Research and Development Establishment, Kanpur, volume 59, No.1, January 2009

5.      K. Malleswari, R.B Desi Reddy and M. Swathi, Microincapsulation: A review a novel Approach in Drug Delivery; Department of pharmaceutics, Nalanda institute of pharmaceutical science, Kantepudi, Guntur 2016, ISSN 2394-3221, page no. 186-194

6.      Lachman Leon, Herbert. A. Liberman, Joseptie, L. Kanig, The theory and practice of Industrial pharmacy; Third edition, Varghese publishing tiouse, Hind Rajsthan Biulding Dadar Bombay Page no. 412-429

7.      Aulton E. Michael, Pharmaceutics, The design and -manufacturing of Medicine; Third Edition Page no. 81-83

8.      Indian Pharmacopoeia 1996, Government of India Ministry of Health and Family Welfare, Published by the Controller of Publication Delhi, volume 1,2

9.      British Pharmacopoeia 2007, Introduction General Notice Monograph Medicinal and Pharmaceutical Substances, Volume 1,2,3,4

10.   http://www.niroinc.com

11.      Re MI, Microencapsulation by spray drying, Drying Technology, 16, 1998,

12.      James S, Encylopediaof Pharmaceutical Technology, 3rd edition, Vol.1325-1333.

13.      Dziezak JD, (Microencapsulation and Incapsulated Ingredeints), Food Technology, 1988; 42(4): 136-51.

14.      Green BK and Schleicher L, The National Cash Register Company, Dayton, Ohio, Oil containing microscopic capsule and method of making them US Patent 2, 800, 457.23 July 1957;11

 

 

 

 

Received on 26.04.2019         Modified on 28.05.2019

Accepted on 21.06.2019       ©A&V Publications All right reserved