Microencapsulation là gì

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M.N. Singh

Department of Pharmaceutics, JSS College of Pharmacy, SS Nagar, Mysore, Karnataka-570015, India

K.S.Y. Hemant

Department of Pharmaceutics, JSS College of Pharmacy, SS Nagar, Mysore, Karnataka-570015, India

M. Ram

Department of Pharmaceutics, JSS College of Pharmacy, SS Nagar, Mysore, Karnataka-570015, India

H.G. Shivakumar

Department of Pharmaceutics, JSS College of Pharmacy, SS Nagar, Mysore, Karnataka-570015, India

This is an open-access article distributed under the terms of the Creative sầu Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Microparticles offer various significant advantages as drug delivery systems, including: (i) an effective protection of the encapsulated active sầu agent against (e.g. enzymatic) degradation, (ii) the possibility lớn accurately control the release rate of the incorporated drug over periods of hours to lớn months, (iii) an easy administration (compared to alternative sầu parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects và recent advances in drug-loaded microparticles to lớn improve sầu the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning lớn the targeting of drug to lớn a specific organ or tissue, & controlling the rate of drug delivery khổng lồ the target site. The development of oral controlled release systems has been a challenge to lớn formulation scientist due lớn their inability lớn restrain & localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting & promising option when developing an oral controlled release system. The objective of this paper is to lớn take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release protệp tin and drug targeting. In order to lớn appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed.

Keywords: Drug delivery systems, Microcapsules, Controlled release, Microencapsulation


Controlled drug delivery công nghệ represents one of the frontier areas of science, which involves multidisciplinary scientific approach, contributing khổng lồ human health care. These delivery systems offer numerous advantages compared to lớn conventional dosage forms, which include improved efficacy, reduced toxiđô thị, & improved patient compliance và convenience. Such systems often use macromolecules as carriers for the drugs. By doing so, the treatments that would not otherwise be possible are now in conventional use. This field of pharmaceutical giải pháp công nghệ has grown and diversified rapidly in recent years. Understanding the derivation of the methods of controlled release and the range of new polymers can be a barrier lớn involvement of the non-speciamenu. Of the different dosage forms reported, nanoparticles and microparticles attained much importance, due khổng lồ a tendency to accumulate in inflamed areas of the body. Nano và microparticles for their attractive properties occupy chất lượng position in drug delivery technology. Some of the current trends in this area will be discussed(1–3).

The terminology used to describe micro-particulate formulations can sometimes be inconsistent và confusing khổng lồ readers unfamiliar with the field. Basically, the term “microparticle” refers khổng lồ a particle with a diameter of 1-1000 μm, irrespective of the precise interior or exterior structure. Within the broad category of microparticles, “microspheres” specifically refers to spherical microparticles & the subcategory of “micro-capsules” applies lớn microparticles which have sầu a core surrounded by a material which is distinctly different from that of the core. The core may be solid, liquid, or even gas(4–6)

Despite the specific and logical subcategories, many researchers use the terms interchangeably, which often leads to lớn the confusion of the reader. It is usually assumed that a formulation described as a microsphere is comprised of a fairly homogeneous mixture of polymer and active agent, whereas microcapsules have sầu at least one discrete tên miền of active agent & sometimes more. Some variations on microparticle structures are given in Fig. 1. As the domains and subdomains of active agent within micro-capsules become progressively smaller, the microcapsules become microparticles(7–9)


The term “microcapsule” is defined, as a spherical particle with the kích thước varying between 50 nm khổng lồ 2 mm containing a core substance. Microspheres are in strict sense, spherically empty particles. However, the terms microcapsules và microspheres are often used synonymously. In addition, some related terms are used as well. For example, “microbeads” and “beads” are used alternatively. Sphere and spherical particles are also employed for a large kích thước và rigid morphology. Due khổng lồ attractive sầu properties and wider applications of microcapsules & microspheres, a survey of the applications in controlled drug release formulations is appropriate(1,6,7).

Although the word capsule implies a core and shell structure, the term microcapsules admits not only membrane enclosed particles or droplets but also dispersion in solid matrix lacking a distinctive sầu external wall phase as well as intermediate types. The form size range (2 lớn 2000 μm approximately) distinguishes them from the smaller nanoparticles or nanocapsules.

The scanning electron microscopy (SEM) has revealed the structural features of microcapsules as khổng lồ be varying và complex. The walled prototype may be mononuclear as shown in Fig. 2a, or may have sầu multiple core structure. Also double or multiple concentric coating may be present. Aggregated microcapsules greatly vary in kích thước & shape (Fig. 2b), and may also posses additional external wall. The perfect microcapsules are obtainable by using the liquid cores or forming the microcapsules as a liquid dispersed phase prior to lớn the solidification. Although micro-structure of both membrane and interior can be detected by SEM of surfaces or sections (Fig. 2c), their physical unique, involving porosity, tortuousity and crystallinity, is difficult to be characterized quantitatively in microcapsules. However, some progress has been made, và efforts are continuing khổng lồ calculate permeability và porosity from release data, dimensions, densities, và core/wall rattiện ích ios. The effect of form size and shape distribution has only been studied recently(8–10)


Microcapsules are finally dispersed in various dosage forms, such as hard gelatin capsules, which may be enteric coated, soft gelatin capsules, or suspensions in liquids, all of which allow dispersion of individual microcapsules on release.

Microcapsules continue to be of much interest in controlled release because of relative sầu ease in design và formulation and partly on the advantages of microparticulate delivery systems. The latter include sustained release from each individual microcapsule and offer greater uniformity & reproducibility. Additional advantage over monolithic systems containing multiple doses is the greater safety factor in case of a burst or defective individual in subdivided dosage forms. Finally, it has been argued that multiple particle systems are distributed over a great length of gastro-intestinal tract, which should result in, (a) lowered local concentrations & hence reduced toxithành phố or irritancy, & (b) reduced variability in transit time & absorption rate(12–14)

Composition of microcapsules

Coating materials

A wide variety of coating materials are available for microencapsulation. Some patent innovative sầu coating polymers have also been developed for some special applications particularly aao ước the bioadhesives & mucoadhesives. However, many traditional coating materials are satisfactory for the use in the gastrointestinal tract. They include inert polymers & pH sensitive ones as carboxylate and amino derivatives, which swell or dissolve sầu according khổng lồ the degree of cross-linking(15–19)

The selection of appropriate coating material from a long list of candidate materials needs consideration of the following general criteria by the retìm kiếm pharmacist:

What are the specific dosage forms or sản phẩm requirements, such as stabilization, reduced volatility, release characteristics, và environmental conditions?

What coating material will satisfy the sản phẩm objective and requirements?

What microencapsulation method is best suited khổng lồ accomplish the coated sản phẩm objectives?

The selection of appropriate coating material decides the physical & chemical properties of the resultant microcapsules/ microspheres. While selecting a polymer the hàng hóa requirements i.e. stabilization, reduced volatility, release characteristics, environmen-tal conditions, etc. should be taken into consideration. The polymer should be capable of forming a film that is cohesive sầu with the core material. It should be chemically compatible, non-reactive sầu with the core material and provide the desired coating properties such as strength, flexibility, impermeability, optical properties and stability(1,5,20–22)

Generally hydrophilic polymers, hydrophobic polymers or a combination of both are used for the microencapsulation process. A number of coating materials have been used successfully; examples of these include gelatin, polyvinyl alcohol, ethyl celluchiến bại, celluchiến bại acetate phthalate and styrene maleic anhydride. The film thickness can be varied considerably depending on the surface area of the material khổng lồ be coated và other physical characteristics of the system. The micro-capsules may consist of a single particle or clusters of particles. After isolation from the liquid manufacturing vehicle và drying, the material appears as a không tính tiền flowing powder. The powder is suitable for formulation as compressed tablets, hard gelatin capsules, suspensions, và other dosage forms(23,26)

Core materials

The core material is the material over which coating has lớn be applied to serve the specific purpose. bộ vi xử lý Core material may be in size of solids or droplets of liquids & dispersions. The composition of core material can vary và thus furnish definite flexibility and allow effectual thiết kế and development of the desired microcapsule properties. A substance may be microencapsulated for a number of reasons. Examples may include protection of reactive sầu material from their environment, safe & convenient handling of the materials which are otherwise toxic or noxious, taste masking, means for controlled or modified release properties means of handling liquids as solids, preparation of không lấy phí flow powders & in modification of physical properties of the drug(5,27–32)

Technologies used for the preparation of microcapsules

The method of preparation and the techniques employed for microencapsulation overlap considerably (Fig. 3). The various microencapsulation processes can be divided into lớn chemical, physiochemical, and electrostatic and mechanical processes. Chemical processes include the interfacial and in situ polymerization methods. Physiochemical processes include coacervationphase separation, complex emulsion, meltable dispersion and powder bed methods. Mechanical processes include the air-suspension method, pan coating, & spray drying, spray congealing, micro-orifice system & rotary fluidization bed granulator method. Also the spheronization is some times included under the mechanical process of microencapsulation. Sustained release polymers microcapsules containing drug with various solubility characteristics were prepared with colloidal polymer dispersion in a completely aqueous environment as an alternative khổng lồ the conventional microencapsulation technique(5,33,40)


The microencapsulation by coacervation-phase separation generally consists of three steps carried out under continuous agitation: (a) formation of three immiscible chemical phases, (b) deposition of coating, and (c) rigidization of the coating. The coacervation-phase separation has been classified inkhổng lồ two categories, simple coacervation và complex coacervation. The former implies addition of a strongly hydrophilic substance lớn a solution of colloid. This added substance causes two phases lớn be formed. The complex coacer-vation is principally a pH dependant process. The acidic or basic nature of the system is manipulated khổng lồ produce microcapsules. Above sầu a certain critical pH value, the system depending upon its acidic or basic nature may produce microcapsules. Below that pH value they will not be formed. Usually complex coacervation giao dịch with the system containing more than one colloid(42–44)

In interfacial polymerization, a monomer is made lớn be polymerized at the interface of two immiscible substances. If the internal phase is a liquid, it is possible to disperse or solublize the monomer in this phase & emulsify the mixture in the external phase until the desired particle kích cỡ is reached. At this point a cross-linking agent may be added to lớn the external phase. Since there is usually some migration of the monomer from the internal khổng lồ external phase, và since it is preferred that the cross-linking agent does not transfer to the internal phase, the bulk of any polymerization will take place at the interface(45–47).

The electrostatic methods of microencapsulation involve trigging together the wall material and the material to be encapsulated when both are aerosolized. The wall material must be liquid during encapsulation stage và must be capable of surrounding the core material. The aerosols produced must be oppositely charged. Three chambers are used for the process, two for atomization of the wall and core material & the third for mixing. Oppositely charged ions are generated & deposited on the liquid drops while they are atomized(1,6,21,48)

Mechanical methods used for microencapsulation utilize the special equipments for their own. The microcapsules produced result from mechanical procedures rather than from a well-defined physical or chemical phenomenon. The most commonly employed mechanical methods for the preparation of micro-capsules and microspheres are(1,5,48,49):

(a) Multiorifice-centrifugal process, developed by the Southwest Retìm kiếm Institute as a mechanical process for producing micro-capsules that utilizes centrifugal forces to lớn hurl a core material particle trough an enveloping microencapsulation membrane thereby affecting mechanical microencapsulation. The multiorifice-centrifugal process is capable for microencapsulating liquids and solids of varied size ranges, with diverse coating materials.

(b) Air suspension coating (wurster) consist of the dispersing of solid, particulate core materials in a supporting air stream và the spray coating on the air suspended particles.

(c) Spray drying và Spray congealing, both methods have sầu been used for many years as microencapsulation techniques. Because of certain similarities of the two processes, they are discussed together. Spray drying and spray congealing processes are similar in that both involve sầu dispersing the core material in a liquefied coating substance & spraying or introducing the core coating mixture into lớn some environmental condition, whereby relatively rapid solidification of the coating is affected. The principal difference between the two methods is coating solidification. Coating solidification in the case of spray drying is affected by rapid evaporation of a solvent in which the coating material is dissolved whereas in spray congealing it is accomplished by thermally congealing a molten coating material or by solidifying a dissolved coating by introducing the coating core material mixture into lớn a nonsolvent.

(d) Pan coating, for the microencapsulation of relatively large particles, has become wide spread in the pharmaceutical industry. With respect to microencapsulation, solid particles greater than 600 microns in kích cỡ are generally considered essential for effective sầu coating & the process has been extensively employed for the preparation of controlled release beads. In practice, the coating is applied as a solution or as an atomized spray to lớn the desired solid core material in the coating pan. Usually, to remove sầu the coating solvent, warm air is passed over the coated materials as the coatings are being applied in the coating pans.

Mechanism and kinetics of drug release

Major mechanisms of drug release from microcapsules include diffusion, dissolution, osmosis và erosion.


Diffusion is the most commonly involved mechanism wherein the dissolution fluid penetrates the shell, dissolves the core & leak out through the interstitial channels or pores. Thus, the overall release depends on, (a) the rate at which dissolution fluid penetrates the wall of microcapsules, (b) the rate at which drug dissolves in the dissolution fluid, and (c) the rate at which the dissolved drug leak out and disperse from the surface(3,4,16). The kinetics of such drug release obeys Higuchi’s equation as below(4,5,8,50,51):

Where, Q is the amount of drug released per unit area of exposed surface in time t; D is the diffusion coefficient of the solute in the solution; A is the total amount of drug per unit volume; CS is the solubility of drug in permeating dissolution fluid; ε is the porosity of the wall of microcapsule; J is the tortuosity of the capillary system in the wall. The above equation can be simplified khổng lồ Q = vt where, v is the apparent release rate.


Dissolution rate of polymer coat determines the release rate of drug from the microcapsule when the coat is soluble in the dissolution fluid. Thickness of coat & its solubility in the dissolution fluid influence the release rate(5,6,52)


The polymer coat of microcapsule acts as sengươi permeable membrane và allows the creation of an osmotic pressure difference between the inside and the outside of the microcapsule và drives drug solution out of the microcapsule through small pores in the coat(7,53)


Erosion of coat due khổng lồ pH and/or enzymatic hydrolysis causes drug release with certain coat materials lượt thích glyceryl monostearate, bee’s wax và stearyl alcohol(13,54)

Attempts khổng lồ mã sản phẩm drug release from microcapsules have become complicated due lớn great diversity in physical forms of microcapsules with regard to size, shape và arrangement of the core and coat materials(1,4,6,55). The physiochemical properties of core materials such as solubility, diffusibility và partition coefficient, và of coating materials such as variable thickness, porosity, và inertness also makes modeling of drug release difficult. However, based on various studies concerning the release characteristics, the following generalizations can be made:

Drug release rate from microcapsules conforming to lớn reservoir type is of zero order.

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Microcapsules of monolithic type & containing dissolved drug have sầu release rates that are t50% dependant for the first half of the total drug release và thereafter decline exponentially.

However, if a monolithic microcapsule containing large excess of dissolved drug, the release rate is essentially tmột nửa dependant throughout almost the entire drug release.

In monolithic capsules the path traveled by drug is not constant; the drug at the center travels a large distance than the drug at the surface. Therefore, the release rate generally decreases with time.

Applications of microcapsules and microspheres

Some of the applications of microencapsulation can be described in detail as given below:

Recent advances in microencapsulation

Several methods and techniques are potentially useful for the preparation of polymeric microparticles in the broad field of microencapsulation. The preparation method determines the type và the size of microparticle và influence the ability of the interaction ahy vọng the components used in microparticle formulations. The term microparticle designates systems larger than one micrometer in diameter and is used usually to lớn describe both microcapsules và microspheres. Microparticles-containing drugs are employed for various purposes including -but not restricted to- controlled drug delivery, masking the taste và odor of drugs, protection of the drugs from degradation, và protection of the body toàn thân from the toxic effects of the drugs. Polymeric carriers being essentially multi-disciplinary are commonly utilized in microparticle fabrication và they can be of an erodible or a non-erodible type(63)

Recently, numbers of publications và patents have been published. Hughes(64) provided a method of sustained delivery of an active sầu drug lớn a posterior part of an eye of a mammal to treat or prevent a disease or condition affecting mammals. The method is comprised of administering an effective amount of an ester prodrug of the active sầu drug such as tazarotene (prodrug of tazarotenic acid) subconjunctivally or periocularly since a systemic administration requires high systemic concentration of the prodrug. The ester prodrug is contained in biodegradable polymeric microparticle system prepared using the o/w emulsion solvent evaporation methods. Lee et al.(65,66) prepared a composition in the size of thin film or strip composed of microspheres containing antibiotic such as minocycline HCl. It was made using a biodegradable polymer, prepared by a modified o/w emulsification technique followed by solvent evaporation. Water-soluble polysaccharide polymers such as pectin was used for making thin film or strip containing microspheres intended for local sustained release administration into the periodontal pocket. The thin film or strip is coated by spray-coating with cation salt aqueous solution of calcium or barium chlorides. In one embodiment, Traynor et al. used the o/w emulsion khổng lồ produce sol-gel microcapsules (containing sunscreens) that are highly positively charged using non-ionizing cationic additives which can include cationic polymers(67)

An injectable slow-release partial opioid agonist or opioid antagonist in a poly (D, L-lactide) microspheres with a small amount of residual ethyl acetate was provided by Tice et al.(68) and Marklvà et al.(69) where an o/w emulsion is first prepared from an organic phase made of ethyl acetate & an aqueous phase comprised an aqueous ethyl acetate containing solution of polyvinyl alcohol. Microspheres are recovered by extraction with water. Wen và Anderson(70) prepared single wall biodegradable microspheres by extracting an o/w emulsion containing steroidal and non-steroidal anti-inflammatory agents. Otherwise, double wall microspheres were prepared. Microspheres containing the active ingredient were then immobilized on a substrate surface in a polymeric matrix that is an implantable medical article or an in situ formed matrix. Solidification method of the hydrophilic capsule materials such as gelatin can be through rapidly lowering the temperature và subsequent dehydration. While such method achieved some significant commercial success, difficulties have sometimes been encountered in rapidly inducing solidification of the microencapsulating material.

The use of various gel forming proteins (collagene and gelatin) & polysaccharides (agar, calcium alginate, and carrageenan) introduced a milder, biocompatable immobilization or isolation system. Obeidat và Price(71) employed a one step method for the preparation of microspheres having enteric & controlled release characteristics in one embodiment and swelling và controlled properties in an other using the nonaqueous solvent evaporation method. Microspheres were especially useful for delivery of moderately non-polar active ingredients but can be formulated khổng lồ deliver very soluble polar compounds.

Delgado(72) developed a method for preparing enteric polymeric microparticles containing a proteinaceous antiren in a single or double emulsification process in which the enteric polymer acts as a stabilizer for the microparticles which are formed in the process.

Single o/w or double w/o/w emulsion solvent evaporation method was utilized by Yamamokhổng lồ et al.(73–75)khổng lồ prepare microspheres with improved dispersibility by dispersing a w/o type emulsion in an outer aqueous phase that contains an osmotic pressure regulating agent(73) or khổng lồ prepare sustained release microsphere containing a LHRH derivative or its salternative text in a large amount without containing gelatin by using a lactic acid-glycolic acid polymer or salts. When the low molecular weight of lactic acid-glycolic acid polymer fraction (8,000 to lớn about 15,000) is contained in a large amount, LHRH derivative sầu readily interacts with these polymers of high reactivity(74) or otherwise to produce a sustained-release composition which comprises emulsifying an aqueous solution containing LHRH derivative and an acid or a base with a solution of a biodegradable polymer(75)

Rickey et al.(76) provided a novel method for the preparation of biodegradable and biocompatible microparticles containing a biologically active sầu agent such as risperidone, or testosterone dissolved in a blend of at least two substantially non-toxic solvents, miễn phí of halogenated hydrocarbons such as benzyl alcohol & ethyl acetate. The blkết thúc was dispersed in an aqueous solution to lớn form droplets. The resulting emulsion was then added to an aqueous extraction medium. One of the solvents in the solvent blkết thúc would be extracted in the quench step (aqueous solution) more quickly than the other solvent. Owing to lớn the high boiling point of the left solvent (benzyl alcohol) which is not easily removed by evaporation in air or other conventional evaporative sầu means, some of the more rapidly extracted solvent can be added khổng lồ the quench extraction medium prior khổng lồ addition of the emulsion. Thus, when the emulsion is added to lớn the quench liquid, extraction of the more rapidly extracted solvent is retarded và more of the second, more slowly extracted solvent is removed. A method for encapsulating vitamins, food supplements, oil soluble substances at high loading (70 wt%) by the solvent o/w emulsion extraction technique is provided by Kvitnitsky et al.(78,79). Since evaporating the solvent from the dispersion is not applicable for delicate & sensitive sầu compounds and it is not effective, because diffusion of solvent through a hard polymer wall is very slow, water at 10-30 times higher than the whole quantity of the organic solvent is added lớn the emulsion for extracting the solvent.

Dawson và Koppenhagen(80)employed a relatively high nonionic emulsifier concentration (5-15 wt%) in an emulsion-extraction method particularly applicable khổng lồ those active agents that are susceptible to lớn thermal degradation at temperatures above sầu room temperature (i.e. trăng tròn °C) such as enzymes, hormones & antigens. Eyles et al.(81) used the w/o/w & o/w/o emulsions lớn produce biodegradable microparticles that stimulate production of cytokines in a host cell, và contain single-stranded ribonucleic acid material, a stabilizing agent and a biologically active sầu macromolecule where the outer surface of the microparticle is miễn phí from adsorbed molecules. Polysaccharides such as starch have been used as a matrix for encapsulation many active ingredients including proteins.

Wen & Anderson(82) prepared double wall microspheres using two biodegradable polymers by the o/w emulsification solvent extraction process. Fulớn et al.(83)used a relatively large molecular weight (11,000 to about 27,000) lactic acid polymer or its salternative text to lớn produce microspheres with prolonged release over a long period of time with a suppressed initial excessive sầu release of a watersoluble LHRH derivative via single or double emulsion.

Ducrey et al.(84)incorporated LHRH in the khung of a water insoluble peptide salternative text (The LHRH agonist triptorelin pamoate) to provides slow release microparticles made of a copolymer of the PLGA type (at least 75 % of lactic acid) by the emulsion method.

A method of encapsulating DNA retaining its ability to lớn induce expression of its coding sequence in a microparticle for oral administration prepared using the w/o/w emulsion & using biodegradable polymers under reduced shear is produced by Jones et al.(86–90). In addition, Little et al.(91)provided a high throughput method of preparing multiple (at least 10) different microparticle formulations (containing plasmid DNA) in parallel based on the double emulsion/solvent evaporation technique. The encapsulation of hormones such as calcitonin for the sustained release delivery has been achieved by Woo et al.(92). Biodegradable microspheres prepared using o/w emulsion technique and incorporating release-modifying agents & pH-stabilizing agents that resist changes in pH upon the addition of small amounts of acid or alkali such as basic amino acids, such as L-arginine were prepared(93). According lớn the disclosure of the invention, sustained release is affected by the chất lượng interplay of the components of the novel microsphere delivery system.

Reslow et al.(94)utilized starch to lớn encapsulate vaccines using emulsification method. In process, an immunologically active substance (vaccine) is suspended in an aqueous starch solution with an amylopectin content exceeding 85% by weight before being mixed with an aqueous solution of a polymer having the ability of forming a two phase aqueous system. The starch droplets containing the vaccine are allowed khổng lồ gel as the starch has capađô thị to lớn gel naturally.

Encapsulation of nucleotides và growth hooc môn using simple or double emulsification methods was achieved by Johnson et al.(95)respectively. Similar to lớn synthetic polymers, such as poly (lactic acid) or polyorthoesters, proteins have sầu also been used to lớn form microparticles or microspheres for drug delivery. Most are cross-linked in solution using glutaraldehyde, or hardened at elevated temperatures(96). Unfortunately, there are problems with significant loss of biological activity of incorporated materials và laông xã of controlled kích cỡ & in vivo degradation rates.

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Susliông xã et al.(97) produced surface modified microparticles that possess a novel protein shell, & a surface coating. The protein shell might consist of cross-linked albumin or other proteins with functional moieties for cross-linking, while the surface coating comprises polyethylene glycol, a second protein or an antibody toàn thân. Microparticles are prepared via emulsification followed by protein agglomeration and cross-linking(98). The surface coating may be covalently-bonded khổng lồ the cross-linked protein shell or it may be electrostatically adsorbed to the cross-linked protein shell. The surface of the microparticles can be altered lớn vary the in vivo pharma-cokinetics và biodistribution.

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