Curr. Pharm. Res. 2019, 9(3), 3174-3191

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Current Pharma Research ISSN-2230-7842

CODEN-CPRUE6

www.jcpronline.in/

Research Article

Polycaprolactone based Injectable Microspheres of Erlotinib Hydrochloride for Sustained

Release: Optimization using Factorial Design.

Tejeswini V. Deshmukh1*, Rajendra C. Doijad

2, Adhikrao V. Yadav

3

1*Department of Pharmaceutics, Gourishankar Institute of Pharmaceutical Education and

Research, Limb, Satara 415015, Maharshtra, India.

2Department of Pharmaceutics, Krishna Institute of Pharmacy, Malkapur, Karad 415539,

Maharshtra, India.

3Department of Pharmaceutics,Gourishankar Institute of Pharmaceutical Education and

Research, Limb, Satara 415015, Maharshtra, India.

Received 02 April 2019; received in revised form 26 May 2019; accepted 31 May 2019

*Corresponding author E-mail address: tejeswini.deshmukhsvpm@gmail.com

ABSTRACT

The aim of this research was to formulate and evaluate Injectable microspheres of Erlotinib

Hydrochloride. Erlotinib HCL Injectable microspheres were prepared by O/W emulsion

solvent evaporation technique using polycaprolactone polymer. Erlotinib HCL microspheres

were evaluated for particle size, in-vitro release, in-vivo study, FTIR, DSC, X-ray diffraction

study. All formulations showed good encapsulation efficiency i.e. 51.2 % to 86.8%.Amount of

polycaprolactone influenced the properties of encapsulation efficiency of different formulations.

The optimised formulation containing drug and polycaprolactone polymer showed the best

results with 86.8 % drug entrapment efficiency and 95.23% sustained drug release at the end of

48 hrs. Polyvinyl alcohol acts as good emulsifying agent. Polycaprolactone based injectable

microspheres of Erlotinib Hcl can be effectively used for target specificity and sustained drug

release for extended period of time in treatment of different types of organ specific cancers like

non small cell lung cancer, pancreatic cancer, neck cancer etc.

KEYWORDS

Emulsion solvent extraction, Injectable microsphere, Target specific delivery, Erlotinib,

Polycaprolactone, polyvinyl alcohol.

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1. INTRODUCTION

Microspheres are drug delivery system which consists of a drug uniformly dispersed in a

polymeric matrix.[1] Contrasts to microparticles which can assume multiple shapes,

microspheres are spherical in nature. Being spherical has other advantages including flow

properties, uniformity in drug distribution in matrix, drug release. [2,3] Microspheres are

generally small spherical particles, with diameters in the size range in 1–1000µm. Biodegradable

microspheres have been used widely for administration of many types of active compounds for

controlled drug release. [4]

The polymer polycaprolactone (PCL) is appropriate for the formulation development of

sustained and controlled release formulations as it not only as good permeability properties for

the entrapped drug but also slower degradation compared to other degradable polymers like

polylactide and polyglycolide. [5, 6] Being a US-Food and Drug Administration-approved

polymer PCL has advantages of being both biocompatible and biodegradable. The other lucrative

pharmaceutical properties PCL has included its non-immunogenic profile and the semi-

crystalline nature which is due to its hydrophobicity. All these benefits makes this polymer a

very promising candidate for pharmaceutical applications.[7] PCL based microspheres have been

developed for encapsulation and controlled delivery of hydrophilic and hydrophobic drugs.[8]

PCL based degradable microspheres can be administered by injection (or even ingested) to

provide sustained drug release or provide targeted release to a particular organ.[9] The desired

release profile of the entrapped drug is possible because PCL can be easily tailored with other

co-polymers in formulation of microspheres. Injectable microspheres have huge potential in

cancer therapy as they are suitable for localized delivery of the anticancer drug in solid tumors.

These microspheres can be formulated as injectable depots which not only provide a site-specific

drug release but also avoid the drug toxicity at non-targeted tissues.

Erlotinib hydrochloride [N-(3-ethynylphenyl)-6, 7-bis (2-methoxyethoxy) quinazoline-4-amine]

acts on the epidermal growth factor receptor (EGFR) for treatment of non-small cell lung cancer

and pancreatic cancers. ERB is also stated to be used effectively in ovarian cancer and for head

and neck cancer. Erlotinib HCl (ERB) is currently available as oral tablets to be taken once a day

with a dose of 25 mg to 150 mg. [10] While the oral route has benefits of easy administering

there are a number of adverse effects or toxicities reported which necessitates for an alternative

delivery system. First major limitation is its poor water solubility as it falls under the BCS- class

II drug which limits its bioavailability.[11] Secondly administration of oral ERB tablets is not

convenient to cancer patients who have gastrointestinal disorders. The abnormalities in the GIT

are common with cancer patients who show the development of mucositis and other structural

and functional changes. Thirdly, there are reported dose- limiting toxicities from the

conventional oral delivery of ERB. Presently there is no injectable formulation of ERB in the

market, although such a form would be useful for patients with gastrointestinal abnormalities.

This hypothesis is also supported by the fact that some of the recent findings have suggested that

the intravenous administration of Erlotinib was well-tolerated with minor adverse events as

compared to oral tablet.[12] Another major concern with ERB therapy is the development of

drug resistance by the NSCLC tumors. ERB has been used as the first line therapy in patients

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with EGFR mutations. However, most advanced NSCLC tumors develop resistance after 6-12

months of drug therapy.

Anticancer drugs can be efficiently loaded into polymeric microparticles to deliver the entrapped

drug in a sustained manner for a longer duration.[13] In this context, the present study was

undertaken to develop an injectable formulation of Erlotinib to provide sustained release using

PCL. A factorial design was chosen to optimize the entrapment efficiency of the drug in the

polymer matrix so as to get the optimum drug release kinetics from the formulation. Hence the

objective of the present study was investigating the feasibility of exploiting a solvent

evaporation-extraction method to entrap ERB in PCL microspheres and study the effect of

polymer concentration and method on size of microspheres, entrapment efficiencies and drug

release rates.

2. MATERIALS AND METHODS

2.1. Materials

Erlotinib HCl was kindly supplied as a gift sample from Shilpa Medicare Limited, India.

Polycaprolactone (Average Mn 45,000) was purchased from Sigma Aldrich, USA. Polyvinyl

alcohol (AR grade), dichloromethane and methanol were procured from S. D. Fine chemicals

limited, Mumbai, India. All the other chemicals used were of the AR-analytical grade. Distilled

or purified water used in the study throughout was taken from the Millipore set-up.

2.2. ATR-FTIR measurements

ATR-FTIR measurements were done for ERB, PCL and ERB_PCL_MS by Perkin Elmer

Frontier, (Perkin Elmer Instruments, USA) in the spectral wavelength ranging from 4000 cm−1

to 400 cm−1 at the resolution of 4 cm−1. The baseline corrections were done using the software

Spectrum.

2.3. Differential scanning calorimetry (DSC) measurements

The thermal behavior of erlotinib (ERB) pure drug, PCL polymer and erlotinib loaded PCL

microsphere (ERB_PCL_MS) were studied by carrying out the DSC measurements using a

DSC1 instrument (Mettler Toledo, Switzerland). About 3 mg of the sample was weighed and

crimped into the aluminum crucibles. The temperature range was kept as 30-400˚C and heating

rate was maintained at 10˚C/min

2.4. Preparation of ERB loaded in PCL Microspheres

Microspheres were prepared by emulsion and solvent extraction evaporation technique reported

by Sathyamoorthy et al. (2017) with minor modifications. [14] Poly caprolactone (100 mg) was

kept in a beaker to which5 ml of dichloromethane, was added to dissolve the polymer and get a

transparent solution. To this ERB was added in drug: polymer ratio of 1:1, 1:2 or 1:3. This

dispersion was then added drop wise into 1% w/v, 2%w/v, or 4%w/v PVA solution in water (20

mL) and sonicated. The resulting O/W emulsion was homogenized by UltraTurrax T-25 (Ika,

Germany) at 9000 rpm for 5 min. The organic solvent comprising of DCM was evaporated

overnight with the help of a magnetic stirrer. The dispersion was then subjected to centrifugation

(Remi) to get the microspheres settle down at the bottom.

2.5. Evaluation of Microspheres

2.5.1. Production yield (%) of microspheres

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The production yield of microspheres obtained after every batch were calculated by weighing the

final product obtained in terms of the dried microspheres in relation to the initial mass of drug,

polymer and surfactants taken to prepare microspheres.

Yields were calculated as per the equation 1:

%Yield= (weight of dried microspheres)/ (weight of drug taken + total excipients weight) x100

---Equation 1

2.5.2. Particle Size and Surface charge of Microspheres

The dried microspheres were dispersed in distilled water for analysing their particle size using

Malvern Zetasizer 3000 (Malvern Instruments, UK). This particle analysis is based on photon

correlation spectroscopy. The same instrument Malvern Zetasizer 3000 was used to study the

surface charge on the microspheres by analysing the zeta potential using the electrophoretic light

scattering in the instrument. The dried microspheres for zeta analysis were also suspended in

distilled water for determination of zeta potential. All the measurements were carried out in

triplicate.

2.6. Entrapment Efficiency

Predetermined amount of ERB loaded microspheres (25 mg) were dissolved in methanol (25

mL) by sonication. The solution was passed through Whatman filter paper (0.45 μm). From this

1.0 mL of the solution was kept in a 10 mL volumetric flask and methanol was used to make-up

the volume. A UV-visible spectrophotometer (Shimadzu-1800) was used for checking the

absorbance of the sample by taking the wavelength of 247nm.

The percentage entrapment efficiency (%EE) was calculated by as per the equation 2.

%EE= (calculated drug concentration/theoretical drug content) ×100. ---Equation 2

2.7. Optimization of Entrapment Efficiency using Experimental design

Factorial design is type of design of experiments carried out to determine the effect of

investigated factors on the expected outcome in terms of responses. The factorial designs allow

minimum number of experiments to carry out the understanding of the responses as a function of

the parameters investigated. [14] In a typical 32 factorial design there are 2 factors studied at 3

levels. The factorial design makes it possible to study the all combinations of the levels possible

of the factors that are investigated. To optimize the entrapment efficiency (Y1) and thereafter the

drug releases a 32 factorial design was utilized to study the effect of ratio of drug: polymer (X1)

and concentration of PVA (X2). The selection of the two-independent variable X1 and X2 with

the dependent variable (Y1) was done by performing initial experimental studies. The 32

factorial design is a type of experimental design where three levels (coded as -1, 0 and +1)

reflecting the minimum, medium and maximum level is studied to bring the output in the form

of a polynomial equation. [15] The polynomial equation so generated was with the help of

Design expert software (version 10, USA) is shown in equation 3.

Y = b0+b1X1+ b2X2+ b3X12 + b4X2

2 + b5X1X2 ---Equation 3

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In the above equation „Y‟ is the response which is the quantitative effect of the two independent

variables X1, X2; b is the coefficient of the term X. The F-statistics was used with ANOVA to

analyze the response using the interactive multiple regression statistics.[16] Using this factorial

design nine experimental runs were carried out as per the factor combinations shown in Table 1.

The Table 1 also shows the coded values obtained for individual terms of X1, X2, X1X1, X2X2

and X1X2for the nine formulation batches.

The actual values of X1 taken were 100 mg (1:1), 200mg (1:2) and 300 mg (1:3) where the drug

was kept constant at 100 mg in the drug: polymer ratio (d:p ratio). The actual value of X2 (PVA)

was taken as 100 mg, 200 mg and 400 mg depicting the 1, 2 and 4% PVA solution in distilled

water.

Table1. Formulation of ERB loaded PCL MS by 32

factorial designs: Factors and the levels.

Formulation

Code

X1

PCL

Conc.

X2

PVA

Conc. (%)

X1 X2 X1X1 X2X2 X1X2

ERB-PCL1 1 1 -1 -1 1 1 1

ERB-PCL2 1 2 -1 0 1 0 0

ERB-PCL3 1 4 -1 1 1 1 -1

ERB-PCL4 2 1 0 -1 0 1 0

ERB-PCL5 2 2 0 0 0 0 0

ERB-PCL6 2 4 0 1 0 1 0

ERB-PCL7 3 1 1 -1 1 1 -1

ERB-PCL8 3 2 1 0 1 0 0

ERB-PCL9 3 4 1 1 1 1 1

2.8. Drug release study

A quantity equivalent to 10 mg of ERB was taken from the microspheres batch and kept in the

dialysis bag (MWCO 12000) tied at two ends with a thread to separate the microspheres from the

dissolution medium and suspended in a 50 mL beaker filled with phosphate buffer saline pH 7.4.

The study was carried out at 37 °C using magnetic stirring for 48 hours at gentle stirring. An

aliquot of 1mL was withdrawn at time intervals of 0.5, 1, 2, 4, 6, 24, 36 and 48 hours to

understand the drug release.

For the drug release kinetics, the data obtained from the drug release was fitted to various

kinetics models including zero-order (Qt = K0t), first-order [ln (1 – Q) = –K1t], Higuchi (Q =

K2t 1/2), and Korsmeyer– Peppas model (Mt/M∞=Ktn). In which Mt and M∞ are the amount of

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drug released at time t and at infinity. The kinetic constant is represented by „K‟ and the

diffusional coefficient is represented by the term „n‟. [17]

2.9. Injectability test for microspheres

The injection ability of the microspheres is termed as injectability and it is needed to check the

possibility of the microsphere dispersion to be injected appropriately at the time of injection in

vivo.[18]The present test was done in-vitro using an insulin syringe and needle. The injectability

of the microsphers was evaluated using an injection device (Insulin Syringe and needle,

Hindustan Medical Devices). The plastic syringe (20 mm internal diameter), and a needle

(26guage size).

3. RESULTS AND DISCUSSION

3.1. ATR-FTIR measurements

FTIR analysis showed absorption bands at 3278 cm− 1

, 1632 cm− 1

, 1164 cm− 1

, 1024 cm− 1

,

940 cm− 1

and 742 cm− 1

corresponding to O H bond stretch of alcohols, N H bending

of amines, C O bond stretch, C H bending and C Cl stretch [19] as shown in Fig.1A.

For PCL the C O vibration bond stretch at 1728 cm− 1

and C O bond stretch at 1240 cm− 1

confirmed the characteristic vibrations of the polymer PCL (Fig. 1B).

The absorption bands of the pure drug did not shift in presence of PCL MS indicating

compatibility of drug with excipients used in ERB_PCL_MSas shown in Fig. 1C.

Fig. 1A. FTIR spectrum of ERB.

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Fig. 1B. FTIR Spectrum of PCL.

Fig. 1C. FTIR Spectrum of ERB_PCL_MS.

3.2. Differential scanning calorimetry (DSC) measurements

The DSC thermograms of erlotinib pure drug, PCL polymer and erlotinib loaded PCL

microsphere (ERB_PCL_MS) is shown in Fig. 2. The DSC thermograms explain the physical

state of the polymer and the drug in the formulation and also analysis of any possibility of

interaction between the drug and the polymer is predictable.

The DSC thermograms of Erlotinib and polycaprolactone showed endothermic peak at 219°C

and 59°C respectively which were identical to their melting points. The drug loaded

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microspheres did not show any drug peak showing that the drug was molecularly homogenized

in the matrix and only the peak of PCL was visible at 56°C.

Fig. 2. DSC thermograms of Erlotinib pure drug, PCL polymer and Erlotinib loaded PCL

microsphere (ERB_PCL_MS).

3.3. Preparation and Evaluation of Microspheres

The choice of solvent evaporation extraction method was based on the solubility profile of drug

and the polymer used and hence DCM as the solvent was selected.

In preparation of microspheres, use of degradable and biocompatible polymers definitely has an

edge over the traditional non-biodegradable polymers. Some of the note-worthy biodegradable

polymers include the poly (ε-caprolactone) (PCL) which is both biocompatible and

biodegradable. As compared to the otherwise widely used copolymers of PLA and PGA the PCL

do not have issues of producing extreme acid environments during their degradation.

Poly (vinyl alcohol) (PVA) was used as the emulsifier in this procedure to stabilize the emulsion

formed between polymer and drug solution.

3.3.1. Production yield (%) of microspheres

The nine batches shown in Table 2 had the practical yield ranging from 76.3 to 87.37% showing

that the method used for preparation of microspheres was good with minimum production losses.

The total amount of PCL MS was estimated by weighing the obtained microspheres powder on a

weighing machine and found to be 82 ± 5.37% as per the equation 1.

3.3.2. Particle Size and Surface charge of Microspheres

Microspheres obtained were of size in the range from 26.3 ±2.5 to 45.8±2.2 microns as shown in

Table 2. The zeta potential values obtained were in the range of −16.3±1.6 to −25.5±0.9 mV as

shown in Table 2. The higher side of negative surface charge shows that the dispersed

microspheres would be stable and non-aggregating in the dispersion.

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Table 2. Mean particle size and Zeta potential values of different formulations of ERB loaded

PCL MS.

Batch No. Mean Particle Size (µm) Zeta Potential (mV)

ERB-PCL1 29.6 ±3.4 −16.3±1.6

ERB-PCL2 27.1±2.9 −18.3±2.1

ERB-PCL3 26.3 ±2.5 −20.9±1.5

ERB-PCL4 36.8 ±4.8 −19.3±3.1

ERB-PCL5 32.2 ±5.2 −23.5±0.7

ERB-PCL6 28.1±3.8 −20.5±0.9

ERB-PCL7 45.8±2.2 −18.1±2.3

ERB-PCL8 38.1±1.4 −22.0±1.1

ERB-PCL9 32.3±1.8 −25.5±0.9

3.4. Response- EE

Table 3 shows %Encapsulation Efficiency of different formulations of ERB loaded PCL MS.

Table 4 gives the regression statistics of the factorial design output data. From the data depicted

in Table. 3, it was seen that the EE varied from 51.2 to 86.8% showing a wide-ranging output.

This wide range data obtained shows that the EE as a response is strongly dependent on the two

factor variables chosen in the design. As there is an increase in the X1 factor (PCL

concentration) there is linear increase in the EE which is supported by the + sign of the X1 model

term in the equation 2. However, such linearity is not seen for the X2 term (PVA concentration).

The F-value obtained was 595.10 of the factorial design model which suggested that the model

was significant. Statistically speaking there could be just a 0.01% probability that an F-value so

high could be due to noise. It is reported that the „F value' implies or inspects the overall

significance of the regression model. This fact was supported by the low p-value (0.0001) which

was much lesser than 0.05 to show significance in the F-statistics terminology.

In the same context, a high R-squared value of 0.9990 indicates that the model could have only

0.10 % chances of variability around the mean. The "Pred R-Squared" value of 0.9916 was in

reasonable agreement with the "Adj R-Squared" value of 0.9973 as the difference between the

two was less than 0.2. This again emphasized on the fact that the model used was significant. An

adequate precision ratio above 4 is desirable and indicative of adequate model discrimination. In

our case the ratio obtained was 77.221 indicating an adequate signal. Hence, the model was

known for strong navigation in the entire design space.

All the five individual model terms (X1, X2, X12, X2

2, and X1X2) had p-values less than 0.05

indicating the significance of each term in the final equation (Table 5). It means that each term

contributed to the response value obtained. The full model regression equation for Y (EE) in

terms of coded factors is represented in equation 4.

Y (EE) =72.677+10.766X1+2.150X2+2.933X12-8.516X2

2-2.80X1X2 (Eq. 4)

The responses (Y) results data obtained from the experiments can be linear or quadratic fitting

model obtained by the multiple regression analysis. The equation 4 is a quadratic equation

depicting the response surface methodology of the design of experiments utilizing the quadratic

effects (X12 and X2

2). [20]

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The contour plots (Figure 3) of the response EE and response surface plots (Figure 4) show that

the region of interest as marked in red colour (86.8%). The said region could be obtained with an

X1 value set at highest +1.0 and X2 value set in the range from -0.5 to +0.

Table 3. % Encapsulation Efficiency of different formulations of ERB loaded PCL MS.

Formulation Code X1

PCL

Conc.

X2

PVA Conc.

(%)

Y

EE

(%)

ERB-PCL1 1 1 51.2

ERB-PCL2 1 2 65.0

ERB-PCL3 1 4 61.3

ERB-PCL4 2 1 62.5

ERB-PCL5 2 2 72.1

ERB-PCL6 2 4 66.4

ERB-PCL7 3 1 78.2

ERB-PCL8 3 2 86.8

ERB-PCL9 3 4 77.1

Table 4. Regression Statistics of the Factorial Design.

Observations 9

Multiple R 0.999496

R Square 0.998993

Adjusted R Square 0.997314

Standard Error 0.555111

F Value 595.1019

Significance F 0.000108

Table 6 gives the information on residual output of the model which shows that there was no

significant difference between the obtained values of the production batches and predicted

valued from the factorial design.

Table 5. ANOVA output from the Regression analysis of the Factorial design.

Model Term Coefficients Standard Error t Stat P-value

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Intercept 72.67778 0.413755 175.654 4.07E-07

X1 10.76667 0.226623 47.50913 2.05E-05

X2 2.15 0.226623 9.487118 0.002483

X1X1 2.933333 0.392523 7.473028 0.004962

X2X2 -8.51667 0.392523 -21.6973 0.000214

X1X2 -2.8 0.277555 -10.0881 0.002074

Table 6. Residual Output of the Model.

Batch No. Obtained Y Predicted Y Residuals

ERB-PCL1 51.2 51.37 -0.177

ERB-PCL2 65.0 64.84 0.155

ERB-PCL3 61.3 61.27 0.022

ERB-PCL4 62.5 62.01 0.488

ERB-PCL5 72.1 72.67 -0.577

ERB-PCL6 66.4 66.31 0.088

ERB-PCL7 78.2 78.51 -0.311

ERB-PCL8 86.8 86.37 0.422

ERB-PCL9 77.1 77.21 -0.111

Fig. 3. Contour Plot of the response EE.

Design-Expert® SoftwareFactor Coding: ActualEE

Design Points86.8

51.2

X1 = A: X1X2 = B: X2

-1 -0.5 0 0.5 1

-1

-0.5

0

0.5

1

EE

A: X1

B: X

2

60

70 80

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Fig. 4. Surface response plots of the response EE.

Effect of Polymer concentration

The results so obtained are in line with similar reported works before too. It has been reported

that when the polymer concentration was increased from 20 to 32% there was a linear increase in

the encapsulation efficiency increased from 53 to as high as 70% respectively.[21] Entrapment

efficiency generally increases with increasing polymer concentration in microspheres as the loss

of drug lost during washing step is reduced.[22] As the viscosity of the polymer in dispersion

increases the porosity in the prepared microspheres reduces.[23]

The mechanism of increase in the entrapment efficiency due to increase in polymer

concentration is understood by the following points.

More is the concentration of the polymer, faster it precipitates on the surface of the formed

microsphere. This phenomenon is also useful in preventing the dispersed/ matrixed drug from

diffusing across the boundary which eventually makes it a suitable delivery system to sustain the

release of the entrapped drug.

The size of microspheres also increases with an increase in polymer concentration.[24]

Effect of D: P ratio (DPR)

Another interesting fact seconded is that the results obtained from the study showed that as there

was a decrease in the DPR there is an increase in the encapsulation efficiency.

3.5 Drug release rates

The two optimized batches based on factorial design were chosen for carrying out the drug

release rates in PBS pH 7.4. The Figure 5 shows the drug release profile of ERB_PCL8 and

Design-Expert® SoftwareFactor Coding: ActualEE

Design points above predicted valueDesign points below predicted value86.8

51.2

X1 = A: X1X2 = B: X2

-1

-0.5

0

0.5

1

-1

-0.5

0

0.5

1

50

60

70

80

90

EE

A: X1B: X2

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ERB_PCL9 microspheres batch. The batch ERB_PCL8 was able to sustain the release of the

drug up to 48 hours whereas the batches ERB_PCL9 completely release the drug in 24 hours.

Novel drug delivery systems have proven to be useful in medicine as these would bring drastic

improvement in the treatment of cancer. Secondly the easy tailoring properties of the polymers

allow not only good encapsulation efficiency of the entrapped drug but also allow pre-planned

release rates and mechanism of the anticancer drug.[25]

Fig. 5. Drug release study of ERB_PCL_MS batch No. 8 and 9.

Anticancer drugs when taken daily have a major limitation of compliance with disadvantage of

drug accumulation in non-targeted sites which results in many side effects. Injectable

microspheres as a depot formulation would allow the drug to be in the blood circulation in a

controlled fashion in the required therapeutic concentrations.

As the degradation of PCL takes a longer time they serve as excellent materials for prolonged

drug release and developing controlled delivery system. In addition, PCL degrades into non-toxic

products that are easily metabolized and excreted in the body.

0

20

40

60

80

100

120

0 0.5 1 2 4 6 12 24 36 48

% C

u D

rug

rele

ased

Time (Hours)

ERB MS Drug release Study in PBS

ERB-PCL8

ERB-PCL9

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Fig. 6. Higuchi Plot for ERB_PCL8 and ERB_PCL9 Microspheres.

The Higuchi plot shown in Figure 6 for ERB_PCL8 and ERB_PCL9 Microspheres show that the

ERB_PCL8 had better diffusion characteristics.

Fig. 7. Korsemeyer-Peppas Plot for ERB_PCL8 and ERB_PCL9 Microspheres.

Figure 7 shows the Korsemeyer-Peppas Plot for ERB_PCL8 and ERB_PCL9 microspheres

showing log of fraction of drug release (Mt/M∞) Vs Log time. Table 7 shows the drug release

kinetics linear equation and R2

values for the batches ERB-PCL9 and ERB-PCL8 using different

models. It was seen that the release profile followed by ERB-PCL8 is nearly zero-order.

It has been reported that as per the geometry of the delivery system different values of „n‟ will

predict different release kinetics. In the case of microspheres, if the „n‟ value is less than 0.43 it

follows Fickian release kinetics. Further if the „n‟ values are between 0.43 and 0.85 it is said to

be non-Fickian, and a case II transport or a zero-order profile is prevailing if the „n‟ value is

more than 0.8. [17] In our case the ERB-PCL8 has n value falling in the non-Fickian profile.

0

20

40

60

80

100

120

0 2 4 6 8

Cu

. % d

rug

rele

ased

Sq. root Time (h)

Higuchi Plot

ERB-PCL8 ERB-PCL9

y = 0.360x - 0.580R² = 0.981

y = 0.308x - 0.390R² = 0.952

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0 0.5 1 1.5 2

Log

Mt/

M∞

Log Time

Korsemeyer-Peppas Plot

ERB-PCL8

ERB-PCL9

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Which is also supported with a lower R2 value in Higuchi profile. A Non-Fickian diffusion

would mean that there is a presence of boundary separating the swollen and the dry region. In

this case the amount of fluid absorbed increases linearly with time.

Table 7. Drug release Kinetics of Batch ERB-PCL9 and ERB-PCL8 using different models.

Kinetic Plot Batch No. Linearity Equation R² value

Zero-order

ERB-PCL9 Y=13.664X-6.7425 0.9858

ERB-PCL8 Y= 10.747X-10.684 0.9952

Higuchi Plot

ERB-PCL9 y = 20.083x +

14.831

0.8982

ERB-PCL8 y = 13.512x + 9.481 0.9563

Korsemeyer-Peppas

Plot

ERB-PCL9 y = 0.3084x - 0.3901 0.9528

ERB-PCL8 y = 0.3607x - 0.5802 0.9812

3.7. Injectability test for microspheres

It was observed that a gentle pressure on the syringe allowed the passing of the microsphere

dispersion. Hence the said microspheres could be termed as “injectable”. Injecting the

microspheres allows minimum invasion at the site of injection and show many clinical relevance

in terms of ease of use and application. [26, 27]

4. CONCLUSION

Erlotinib HCl (ERB) is currently available as oral tablets. While the oral route has benefits of

easy administering there are a number of adverse effects or toxicities reported which necessitates

for an alternative delivery system. First major limitation is its poor water solubility as it falls

under the BCS- class II drug which limits its bioavailability. Secondly administration of oral

ERB tablets is not convenient to cancer patients who have gastrointestinal disorders. The

abnormalities in the GIT are common with cancer patients who show the development of

mucositis and other structural and functional changes. Thirdly, there are reported dose- limiting

toxicities from the conventional oral delivery of ERB. Presently there is no injectable

formulation of ERB in the market, although such a form would be useful for patients with

gastrointestinal abnormalities.

Hence injectable microspheres of Erlotinib were prepared to achieve the target specificity and

sustain release action. Microsphere formulations prepared by using polycaprolactone polymer

and were prepared by using emulsion solvent evaporation/extraction method. The significant

factors selected were concentration of drug and polymers. The dependent variables selected such

as %entrapment efficiency, and % drug release. It was found that on increasing the polymer

concentration from 1 to 3% there was a linear increase in the encapsulation efficiency increased

from 51.2 to as high as 86.8%. Entrapment efficiency generally increases with increasing

Curr. Pharm. Res. 2019, 9(3), 3174-3191

3189

polymer concentration in microspheres as the loss of drug lost during washing step is reduced.

Another interesting fact seconded is that the results obtained from the study showed that as there

was a decrease in the DPR there is an increase in the encapsulation efficiency.

5. ACKNOWLEDGEMENTS

The authors are thankful to Gourishankar Institute of Pharmaceutical Education and Research,

Limb, Satara 415015, Maharshtra, India, for their valuable support and permission to carry out

the work.

6. ETHICAL ISSUES Not applicable

7. CONFLICT OF INTEREST

None Declared.

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