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ABSTRACT
Novel drug delivery systems have several advantages over conventional multi dose therapy.
Much research effort in developing novel drug delivery system has been focused on controlled
release and sustained release dosage forms. Now considerable efforts are being made to deliver
the drug in such a manner so as to get optimum benefits. There are various approaches in
delivering a therapeutic substance to the target site in a sustained controlled release fashion.
One such approach is using microspheres as carriers for drugs. Microspheres received much
attention not only for prolonged release, but also for targeting of anticancer drugs to the tumor.
Microencapsulation is used to modify and delayed drug release form pharmaceutical dosage
forms. Microspheres efficiently utilized in controlled delivery of many drugs but wastage of drug
due to low drug entrapment efficiency is the major drawback of such microparticulate system.
Well designed microspheres can overcome such problems by enhancing the loading efficiency of
a particular drug and minimizing the wastage of drug. It is the reliable means to increase the
loading efficiency, if optimize the formulation as well as process variables. This will only
possible by understanding the effect of various variables which affect the drug entrapment
efficiency of these microspheres. The intent of the paper is to highlight the various variables
which influence the drug entrapment efficiency along with method of preparation and
characterization of microspheres.
Key Words: Novel drug delivery system, Controlled release, Microspheres, Drug entrapment,
formulation variables, process variables.
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Carrier technology offers an intelligent approach for drug delivery by coupling the drug to a
carrier particle such as Microspheres[1], nanoparticles, liposomes, etc. which modulates the
release and absorption characteristics of the drug. Dosage forms that can precisely control the
release rates and target drugs to a specific body site have created enormous impact on the
formulation and development of novel drug delivery systems [2]. Controlled drug delivery
occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or
other active agent in such a way that the active agent is released from the material in a
predesigned manner [3, 4].
Microspheres constitute an important part of these particulate DDS by virtue of their small size
and efficient carrier characteristics. Microspheres have many applications in medicine, with the
main uses being for the encapsulation of drugs and proteins. The drug loaded microspheres are
delivered to the target area by passive means (trapping by size) or active means (magnetic
targeting)[5] and slowly release the encapsulated drug over a desired time period, the length of
which is determined by the drug’s biological half-life and release kinetics of the microsphere
matrix. The bio-distribution of the drug from microspheres is highly dependent on the size and
% drug entrapment of the microspheres. Release kinetics of the microsphere matrix is depend on
the various factors i.e. type of polymer used [1], concentration of polymer [1, 6-10], drug to
polymer ratio, solubility of drug, dispersed phase to continuous phase ratio etc. These variables
directly affect the loading efficiency of the microspheres. Polymeric microspheres and
microcapsules have received much attention for the delivery of therapeutically useful proteins in
a controlled way[11] Microparticulate systems can be made by various techniques involving
physicochemical processes (solvent evaporation method, phase separation method) and
mechanical processes (e.g., spray drying)[12].
A protein delivery system with high loading capacity is very advantageous, because it can
prevent the loss of antigen and also limit the need of administering high level of carrier [13].
In solvent evaporation method entrapment efficiency of water-soluble drugs is low due to drug
loss from the organic emulsified polymeric phase before solidification of polymer in the
microspheres [14, 15]. Therefore, process optimization may be advantageous for the efficient
entrapment of water-soluble labile drugs like therapeutic enzymes.
However, the success of microspheres is limited due low drug entrapment efficiency. Therefore
process optimization by understanding of variables which affect the drug entrapment is very
important for improving the loading efficiency of microspheres. Purpose of writing this review
was to compile the recent literature which focus on the various variables influencing the drug
loading efficiency and approaches to improve the loafing efficiency of microspheres.
Additionally this also summarized the method of preparation and characterization of
microspheres.
Preparation of microspheres:
The most commonly investigated techniques to prepare microspheres are emulsion solvent
evaporation techniques, Spray drying, emulsion cross-linking method Solvent evaporation, Hot
melt microencapsulation, Solvent removal, Hydrogel microspheres and Phase inversion
Microencapsulation.
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Characterization of microspheres:
A. Particle size, shape and surface morphology analysis [23-25]:
All the microspheres were evaluated with respect to their size and shape using optical
microscope fitted with an ocular micrometer and a stage micrometer. The particle diameters
of more than 100 microspheres were measured randomly by optical microscope. The average
particle size was determined by using the Edmondson's equation D mean = εnd/εn, where n=
number of microspheres observed and d= mean size range. The shape and surface
morphology of the microspheres was studied by using a scanning electron microscope.
B. Entrapment efficiency[16,26] :
To determine the incorporation efficiency, 25 mg of propranolol loaded microspheres were
washed with 10 ml of suitable solvent to remove the surface associated drug. The
microspheres were then digested in 10 ml of suitable solvent for 12 h at room temperature
(25±2 0) to release the entrapped drug. Drug content was determined spectrophotometrically.
C. Swelling index [27,28]:
Swelling index was determined by measuring the extent of swelling of microspheres in a
particular solvent. To ensure the complete equilibrium, exactly weighed 100 mg of
microspheres were allowed to swell in solvent for 34 h. The excess surface adhered liquid
drops were removed by blotting and the swollen microspheres were weighed by using
microbalance. The Hydrogel microspheres then dried in an oven at 60° for 5 h until there
was no change in the dried mass of sample. The swelling index of the microsphere was
calculated by using the formula swelling index= (mass of swollen microspheres-mass of dry
microspheres/mass of dried microspheres) ×100.
D. In vitro bioadhesion [29]:
Bio-adhesive properties of IN microspheres were evaluated using everted sac technique.
E. In vitro drug release [16,29] :
To carry out the in vitro drug release, accurately weighed drug-loaded microspheres were
dispersed in dissolution medium in a beaker and maintained at 37±2° under continuous
stirring at 100 rpm. At selected time intervals 5 ml samples were withdrawn through a
hypodermic syringe fitted with a 0.4 mm Millipore filter and replaced with the same volume
105
X. Fu et al., studied the effect of molecular weight of the polymer on encapsulation efficiency,
developed a long-acting injectable huperzine A-PLGA microsphere for the chronic therapy of
Alzheimer's disease, the microsphere was prepared by using o/w emulsion solvent extraction
evaporation method. The encapsulation efficiency of the microspheres improved as the polymer
concentration increase in oil phase and PVA concentration decreased in aqueous phase.
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In order to explain the low encapsulation efficiency obtained with benzene, the authors mention
that the benzene required a larger amount of water (non-solvent) than methylene chloride for
precipitation of the polymer, and the drug was lost due to the delayed solidification. However,
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Park et al., 1998, lysozyme-loaded PLGA microparticles were prepared using the oil in water
(o/w) single emulsion technique. Here, the authors used a co-solvent system, varying the ratio of
the component solvents. DMSO was used for solubilization of lysozyme and PLGA, and
methylene chloride was used for generation of emulsion drops as well as solubilization of
PLGA. Encapsulation efficiency increased, and initial burst decreased as the volume fraction of
DMSO in the co-solvent system increased. Particle size increased, and density of the
microparticle matrix decreased with increasing DMSO. Overall, these results indicate that the
presence of DMSO increased the hydrophilicity of the solvent system and allowed fast
extraction of the solvent into the continuous phase, which led to higher encapsulation efficiency
and larger particle size [41].
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Bozena et al was determined drug (Pipemidic acid) content for all selected size fractions of
microspheres prepared at different stirring rates. Results are shown in Fig. 3.
The drug content (9—21%) increases with increasing particle size for each sample of
microspheres prepared at different stirring rates. Furthermore, drug content determined for the
biggest size fractions was higher than theoretical drug content in both series, although this effect
was more expressed in the system without chitosan. Significance of the influence of particle size
on drug content was also statistically confirmed (analysis of variance (ANOVA), p_0.001)[52].
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There was a significant decrease in the entrapment efficiency with an increase in the
concentration of span-85 from 2% wt/wt to 5% wt/wt. The decrease in the entrapment efficiency
with an increase in the emulsifier concentration is because of dissolution of Celecoxib in the
external phase of the emulsion at higher concentration of span-85. This decrease in the
entrapment efficiency was more pronounced at a lower concentration of albumin [33].
Figure 4: 3D surface curve for the effect of emulsifier (Tween 80) on the drug content of
Microspheres [52]
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Figure 5: 3D surface curve for the desirable output in terms of maximum drug content and
low level of DCM [52]
Effect Microcapsulation time:
Prajapati et al has investigated the effect of microcapsule formation time on loading efficiency of
Gliclazide microspheres. Gliclazide microcapsules were prepared using sodium alginate and
mucoadhesive polymer such as sodium carboxymethyl cellulose (sodium CMC), carbopol 934P
or hydroxy propylmethyl cellulose (HPMC) by orifice-ionic gelation method.
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The higher amount of glutaraldehyde appears to favor the cross-linking reaction, and hence
spherical free-flowing microspheres were obtained with an increase in loading efficiency[54].
CONCLUSION
The purpose of this work was to understanding effect of various process as well as formulation
variables on the encapsulation efficiency of the microspheres. This review will focus on how the
formulation variables of microspheres formulation affect the drug entrapment efficiency the
microspheres. This paper also explains that how drug entrapment efficiency depend upon
particle size, Polymer concentration, type of polymer, drug: polymer ratio, DP: CP ratio, drug:
polymer interaction, solubility of polymer as well as drug, method of preparation etc. The
stirring rate of emulsion system, concentration of polymer, drug: polymer interactions,
concentration of cross linkers are directly proportional to drug entrapment efficiency. Whereas
higher drug to polymer ration, high concentration of emulsifier decrease the drug loading
efficiency of microspheres. It is the reliable means to increase the loading efficiency, if optimize
the formulation as well as process variables. This will only possible by understanding the effect
of various variables which affect the drug entrapment efficiency of these microspheres. Among
all the variables stirring speed, polymer concentration, solubility of drug and polymer and drug:
polymer interactions are the variables which have significant effect on the drug entrapment
efficiency.
REFERENCES
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