Formulation and Evaluation of Rectal Delivery System for ...€¦ · Formulation and Evaluation of...

Pharmaceutical Resonance 2018 Vol.1 - Issue 1

© Published by DYPIPSR, Pimpri, Pune - 411 018 ( MH ) INDIA 42

RESEARCH ARTICLE

Formulation and Evaluation of Rectal Delivery System for the

Treatment of Hemorrhoids

Suchita Dhamane1*, Aditi Kulkarni 2. Potnis Vaishali1, Manoj Modase2

1Department of Pharmaceutics, JSPM’s Jayawantrao Sawant college of Pharmacy and Research, Hadapsar, Pune.

2Department of Pharmacognosy, JSPM’s Jayawantrao Sawant college of Pharmacy and Research, Hadapsar, Pune.

1. Introduction

A conventional suppository is a semi solid dosage form

which melts in the rectum at body temperature [1]. The

patient compliance for conventional suppository is less as

it causes discomfort and sometimes refusal. Conventional

suppository may undergoes first pass metabolism as it

reaches to the end of rectum [2,3] Therefore, an attempt

was made to develop a liquid rectal dosage form which

forms a gel at body temperature, with suitable gel strength

that does not leak out of the anus after administration and

has suitable bio adhesive force so as not reach at the end

of the colon. Liquid suppositories aimed either to improve

the local effect or to enhance the drug absorption.[3,4]

Poloxamer are the base of the liquid suppositories.

Poloxamer solutions are known to exhibit phenomenon of

reverse thermal gelation remaining as solution at low

temperature (40oC) and gelling upon increasing the

temperature to 25-35oC.[5,6]

Lidocaine belongs to class of local anaesthetic.

Lidocaine increases permeability to sodium ions in

neuronal membranes, resulting in inhibition of

depolarization, blocking transmission of nerve impulses.

This helps in reducing the pain while passing bowels. It

also shows anti-inflammatory properties. Pure aloe vera is

used to treat pain and inflammation. Hence, combination

of lidocaine and aloe Vera was used for preparation of

liquid suppository.

2. Experimental

2.1 Materials

Lidocaine was obtained from Titan Laboratory, India,

Poloxamer 407 and poloxamer 188 were from BASF,

Germany; HPMC K4M from Emcure Pharmaceutical Ltd,

Pune and Carbopol 940 from New Modern Chemical

corporation, Mumbai and aloe vera juice from Patanjali

Ayurveda.

2.2 Methods

2.2.1 Pre-formulation Studies [6,7]

2.2.1.1. UV-spectrophotometric study of lidocaine

Stock solutions of Lidocaine (100 μg/ml) was prepared by

dissolving accurately weighed 10mg quantity using 100

ml distilled water. From stock solution 1 ml was diluted

with distilled water to give solutions of 10 μg/ml

concentration. The solutions were scanned in the range of

400 to 200 nm and respective λ max values were reported

in triplicate. Calibration curve of lidocaine in distilled

* Dahmane Suchita

Department of Pharmaceutics

JSPM’s Jayawantrao Sawant college of Pharmacy and

Research, Hadapsar, Pune

Email : [email protected]

ABSTRACT:The aim of this research was to introduce rapid onset of action of lidocaine in relief of pain and inflammation

in treatment of haemorrhoids. Haemorrhoids are swollen and inflamed veins in the rectum and anus that cause discomfort

and bleeding. Rectal delivery of drugs promotes rapid absorption and high bioavailability, with a subsequent immediate

onset of pharmacological effect. Conventional suppositories are solid forms which often cause discomfort during insertion.

The leakage of suppositories from the rectum also gives uncomfortable feelings to the patients. In addition, when the solid

suppositories without mucoadhesivity reach the end of the colon, the drugs can undergo the first-pass effect. To solve these

problems, we developed a novel in situ-gelling and mucoadhesive lidocaine liquid suppository with gelation temperature at

30–36°C and suitable gel strength and bioadhesive force. The mixtures of P407 (25%) and P188 (5%) existed as a liquid at

room temperature, but gelled at 30–36°C. To modulate gel strength and mucoadhesive force, mucoadhesive polymers such

as HPMC K4M and carbopol 940 was used. Optimized formulation was tested in haemorrhoids induced rats for 5 days.

After 5 days of treatment with optimized formulation histopathological studies reveals that there was significant reduction

in inflammation as compared to positive group.

Keywords: Haemorrhoids, liquid suppository, mucoadhesive, lidocaine



water was prepared in distilled water and phosphate buffer

pH 6.8.

2.2.1.2. IR spectrometry

The IR absorption spectrum of Lidocaine was recorded by

potassium dispersion method. The drug was previously

dried in desiccator and then spectrum was recorded by

blending with potassium bromide. For this, sample of drug

and potassium bromide was mixed in a 1:3 ratio and kept

in sample cell. The cell was then fitted on sample holder

and an IR spectrum was recorded 4000-400 cm-1 after

baseline correction was made.

2.2.2 Drug-excipient compatibility studies

The compatibility of mixture of Lidocaine with or without

polymeric addition was ascertained by exposing to the

environmental conditions over the 15 days. The detection

of changes in any of the physical or physicochemical

characteristics of blends if any was carried out by visual

and FT-IR spectrophotometry (Jasco 4600, USA).

2.2.3 Preparation of liquid suppository

Formulation and evaluation of placebo liquid

Suppository

Placebo liquid suppositories were prepared to determine

optimum concentration of polymer. Prepared suppositories

were evaluated for gelling temperature, gel strength and

gelling time and gelling ability. All excipients except

poloxamer as given in table no.1 were completely

dispersed in distilled water with continuous agitation at

room temperature and cooled to 4°C. Poloxamer was then

slowly added to the solution with continuous agitation.

Temperature of liquid suppository was maintained to 4°C

until a clear solution was obtained.

Placebo liquid suppositories were evaluated for general

characteristics, pH, gelation temperature, gel strength.

2.2.4 Formulation and evaluation of medicated liquid

suppositories by using 32 factorial design [8]

Medicated liquid suppository was prepared by using

poloxamer 407 (5-25%) and poloxamer 188 (1-5%).

Concentration of polymers was selected based on

evaluation of preliminary placebo suppository batches.

Design expert version 10.0.3.1 was used for factorial

design of formulation of liquid suppository. Poloxamer

Name of ingredient

(% w/w) F1 F2 F3 F4 F5

Poloxamer 407 5 10 15 20 25

Poloxamer 188 1 2 3 4 5

Aloe vera juice Q.S. Q.S. Q.S. Q.S. Q.S.

Table 1. Formulation composition of placebo

(preliminary) batches of in situ gel.

407 and poloxamer 188 were two factors with three

different concentrations. Concentration of polymers was

selected based on evaluation of preliminary placebo

suppository batches. Formulations were optimized by

application of 32 full factorial designs, to study effect of

concentration and type of polymer on gelation temperature

and drug release at the end of 5 hrs.

All nine formulations of medicated liquid suppositories

were evaluated for colour, clarity, pH, gelation

temperature, gel strength, drug content and drug release

through dialyzing membrane.

2.3 Formulation of mucoadhesive medicated liquid

suppositories

The medicated liquid suppository formulation was

optimized using Design expert, in whichMF9 was

optimized for preparation of mucoadhesive liquid

suppository. From among the nine medicated formulation,

the MF9 demonstrating good gelling ability (+++),

physiologically acceptable pH range in rectal delivery (pH

-6.9), gellation temperature (36oC), gel strength (5mm)

and prolong diffusion (In-vitro) over 5 hrs. To reinforce

the gel strength and bioadhesive force of the liquid

suppositories, the poloxamer solutions was added with

bioadhesive polymers. Medicated Gel was found to have

weak mechanical strength. HPMC K4M, Carbopol 940

were selected as the bioadhesive polymer.

All six formulations of medicated mucoadhesive liquid

suppositories were evaluated for colour, clarity, pH,

gelation temperature, gel strength, drug content and drug

release through dialyzing membrane. Selected formulation

was evaluated for anti-haemorrhoidal activity.

Formulation

code

X1: Poloxamer

407

X2: Poloxamer

188

MF1 5 1

MF2 15 1

MF3 25 1

MF4 5 3

MF5 15 3

MF6 25 3

MF7 5 5

MF8 15 5

MF9 25 5

Table 2. Different batches with their respective

compositions as per (32) factorial design



2.4 Evaluation of liquid suppository

2.4.1 Physical Examination

Appearance of formulation, for this 5 ml of placebo

formulation was taken into clean and dry glass test tube

and was observed carefully for clarity and presence of

suspended particle if any against black and white

background.

Colour of formulation was visually observed.

2.4.2 pH of liquid suppository

The pH of suppository formulations was determined by

using digital pH meter. The pH meter was calibrated

before each use with standard phosphate buffer ( pH 7 and

4).

2.4.3 Gelation temperature [9]

Tube tilting method was used to determine gelation

temperature of placebo, medicated and mucoadhesive

liquid suppository. For this, 2 ml aliquot of liquid was

transferred to a test tube which was sealed with aluminium

foil, and test tube was placed in a water bath at 4°C. The

temperature of water bath was increased in increments of

1°C and left to equilibrate for 5 min at each new setting.

Gelation temperature was noted when the meniscus would

no longer move upon tilting of test tube through 90°.

2.4.4 Gel strength [10,11]

For this, 100ml glass measuring cylinder containing 50gm

of liquid suppository was placed in thermostat at 36.5°C

for gelation. For measuring gel strength apparatus

weighing 35gm was placed onto gelled suppository and

time required for the apparatus to move 5cm into the bulk

of gel was noted.

2.4.5 Mucoadhesive strength [12,13]

The mucoadhesive force of in situ gels liquid suppository

was determined on tissue specimen (A section of tissue cut

from the fundus of sheep rectum). The pieces of tissue

were stored in simulated fluid having pH 6.8. For

determination of mucoadhesive force, a section of tissue

was secured (keeping the mucosal side out) to the upper

Sr.

No

Formulation

code

Drug

(%)

P 407

(%)

P 188

(%)

HPMC

K4M

(%)

Carbopol

940 (%)

Aloevera

Juice

1 MF9HP1 2 25 5 0.5 - QS

2 MF9HP2 2 25 5 0.75 - QS

3 MF9HP3 2 25 5 1.0 - QS

4 MF9CP1 2 25 5 - 0.5 QS

5 MF9CP2 2 25 5 - 1.0 QS

6 MF9CP3 2 25 5 - 1.5 QS

Table 3. Composition medicated mucoadhesive Liquid suppository

side of a glass vial using a using double sided adhesive

tape. The diameter of each exposed mucosal membrane

was 1.5 cm. The vials were equilibrated and maintained at

37° for 10 min. One vial with a section of tissue was

connected to the balance and the other vial was fixed on a

height adjustable pan. To the exposed surface of the tissue

attached on the vial, a constant amount of 0.1 g gel was

applied. The distance between two vials was adjusted in

such a way that the gel sample remained adhered to

mucosal membrane. Sufficient pressure was applied on

both of the vials for 10 seconds to allow proper adhesion

of gel to mucosa. A constant weight was added to the pan

(B) to the vial (C). The weight required for detaching the

two vials and hence, film of the sample between them was

noted down. The mucoadhesive force expressed as the

detachment stress in dyne/cm2, was determined from the

minimal weights needed to detach the tissues from the

surface of each formulation, using the following equation.

Where,

m : weight added to the balance (gm)

g : acceleration of gravity

A : area of the tissue exposed (πr2)

2.4.6 Dissolution studies (In vitro) pH 6.8Phosphate

buffer for lidocaine [13,14]

The in vitro drug release studies from medicated liquid

suppository and mucoadhesive liquid suppository was

monitored by using USP II dissolution apparatus. A 2g of

the formulation was placed in semi permeable bag and

secured with the aid of non absorbing thread. The bag was

immersed in a vessel containing dissolution medium, 500

ml phosphate buffer, pH 6.8 at 370C. The speed of rotation

was 100rpm. At predetermined time intervals 4 ml of

aliquots were withdrawn and analyzed spectro-

photometrically at 263 nm. The experiments were

conducted in triplicates.



2.4.7 In vivo animal study (Anti haemorrhoidal

activity) [15]

To test the anti haemorrhoidal activity of optimized in situ

gel liquid suppositories,male wistar rats weighing (200-

250gm) that were housed in standard conditions of

temperature (22±3°C), relative humidity (55±5%), and

(12h light-dark cycle) before and during the study. Rats

were fed with standard pellet diet and water ad libitum.

Protocol for animal study was approved by the

Institutional Animal Ethics Committee (IAEC) of Prado

preclinical research and development organization.

2.4.8 Procedure for induction of haemorrhoids

Four groups of male wistar rats (200-250gm) were

formed, each group having 8 rats. Croton oil preparation

containing deionized water, pyridine, diethylether, and 6%

croton oil in diethylether(1:4:5:10)was used for induction

of haemorrhoids. After overnight fast, hemorrhoids were

induced by inserting sterile cotton swabs (4 mm diameter)

soaked in 100 μL of croton oil preparation into the anus

(rectoanal portion, 20 mm from anal opening) of all group

animals except normal control group. After 10 seconds

cotton swab was removed and animals were observed for

development of edema and blood in faces up to 8 hours

after induction of croton oil. Twenty-four hours after

induction of haemorrhoids, animals of respective groups

were treated for five days.G1-Distilled water, G2-positive

control, G3-test aloe vera suppository (once daily for 5

days), G4-test mixture suppository (once daily for 5 days).

On the fifth day, 1 hour after the treatment, all the animals

were sacrificed by deep isoflurane anesthesia and

rectoanal tissues (20mm in length) were isolated.

Rectoanal tissues were fixed in 10% neutral buffered

formalin solution for histological examination. The

inflammatory cells, congestion, haemorrhage,

vasodilatation, and medium to high degrees of necrosis

were the histological observations for rectoanal tissue.

Results of the animal study were expressed as mean ±

SEM and analyzed by one-way ANOVA followed by

Dunnett’s post test using GraphPad Prism version 4.01.

3. Result and Discussion

3.1 Spectrophotometric characteristics of lidocaine

The UV spectrum (λ max) of lidocaine in water and pH

6.8 phosphate buffer indicated λmax at 263 nm. The

standard calibration curve of Lidocaine in distilled water

and phosphate buffer pH 6.8 was found to be linear over

the range of 2 -10 µg/ml as shown in Fig.1.

3.2 Drug-excipient compatibility study

FT-IR spectrum (Fig 2) of lidocaine showed major peaks

at 3030cm-1, 3248 cm-1, 1667 cm-1, 2860 cm-1, 2931 cm-1,

3447 cm-1. FTIR spectrum of mixture of lidocaine and

excipients revealed that there was no interaction between

drug and excipients, as there was no major change in the

position of peaks of lidocaine.

3.3 Characteristics of placebo liquid suppositories

All placebo liquid suppositories were clear, colorless

solution. There was no gelation and colour change of any

suppository during processing. pH of all the

suppositories was found to be in range of 6.7-6.9

respectively. The pH of placebo liquid suppository

solution was near to pH of rectum (6.7-6.9). Thus

therefore formulation will not produce irritation on

instillation into the rectum.

The liquid suppository should remain liquid at room

temperature and should instantly form gel in rectum, so

the gelation temperature should be 30-36o C. Formulation

F1, F3, F5 showed gelation temperature in range of 30-36°

C.Hence, this formulation concentration used for 32

factorial design of medicated liquid suppository. The

temperature-dependent gelation of poloxamer solutions

could be explained by configuration change. Poloxamer

molecules exhibit a well-arranged zigzag configuration.

With increasing temperature, the zigzag configuration of

poloxamer may be transformed into a close-packed

meander configuration, forming a more close-packed and

more viscous gel.

3.4 Characteristics of medicated liquid suppositories

All 9 formulations were prepared by following 32 full

factorial designs. The formulations were evaluated for

Fig. 1 Calibration curve of lidocaine in distilled water

and pH 6.8 phosphate buffer

ab

so

rpti

on

ab

so

rpti

on

conc µg/ml

conc µg/ml



physicochemical characterization and drug release study.

All formulations were clear, colourless solution. The pH

of medicated liquid suppository solution was nearing to

pH of rectum (6.7-6.9). Gelation temperature range for

liquid suppository should be 30-36o C. So that it will be a

liquid at room temperature and forms a gel instantly in the

rectum. Formulation MF2, MF5 and MF9 shown gelation

temperature between 30 to 36oC. Gel strength of all

formulation was found in the range of 6 to 45 sec. The gel

strength is an indication for viscosity of the gel at

physiological temperature. The data obtained indicates, as

the polymer grade variation increases gel strength.

Gel strength play important role in the development of

liquid suppository. Determination of gel strength allows

the easy insertion of the suppository and no leakage from

the anus. The contents of lidocaine in the medicated liquid

suppository range between 99-101% which is acceptable.

Formulation indicated comparable release profile over 5

hrs. Release of lidocaine is higher in first hrs, because it is

entered in sol form (Fig 3). Because thermo sensitivity

nature, formulation require few minutes to convert to gel

form. In the gel form retardation of release rate is less. The

probable mechanism in retardation of release may be

reduction in number and dimension of the channels in the

gel structure.

3.5 Full factorial design

Effect of formulation variables on gelation

temperature

On applying the factorial design, the quadratic model was

found to be significant with model F value of 33.00, p

value < 0.008 which implied that model was significant.

Following quadratic equation describes the effect of

concentration of polymers on gelation temperature.

Y1= 32.55 - 5.83X1 + 1.66X2 + 1.25 X1X2 + 4.16X12 +

1.66X22

Fig.2: FTIR spectrum of lidocaine & physical mixture

of lidocaine and excipient

There was significant (p<0.008) effect of individual

variable on gelation temperature. The gelation temperature

decreases with increase in concentration of Poloxamer 407

(X1). At low level of factor X1 gelation temperature is

high and at medium level gelation temperature is about

36oC. The gelation temperature increases with

concentration of factor poloxamer 188(X2), but as not

rapid as X1. The combined effect of factor X1 (poloxamer

407) and X2(Poloxamer 188) can be further elucidated

with help of response surface plot (figure). At high level

of X1 and X2 the gelation temperature was 36oC.

3.6 Contour plot and three dimensional response

surface plot of Gelation temperature

Two-dimensional contour plot and three dimensional

response surface plot is shown in Fig 4A and 4B

respectively. The contour plot does not show straight line,

it indicates that there is no linear relationship between the

factor X1 and X2. The gelation temperature decreases

with increase in concentration of Poloxamer 407 (X1). At

low level of factor X1 gelation temperature is high and at

medium level gelation temperature is about 36o C. The

gelation temperature increases with concentration of factor

X2, but as not rapid as X1. The combined effect of factor

X1 (poloxamer 407) and X2(Poloxamer 188) can be

further elucidated with help of response surface plot

(figure). At high level of X1 and X2 the gelation

temperature was 36oC.

Fig 3: Dissolution plots of cumulative drug release of

lidocaine liquid suppository of above formulation

Source Sum of

Squares

Degree

of

freedom

Mean

Square

F

value

p-value

Prob>F

Model 267.3 5 53.47 33.00 0.008

(S)

Residual 4.86 3 1.62 - -

Total 272.22 8 36.44 - -

Table 4. Summary of ANOVA for gelation

temperature parameters



Effect of formulation variables on drug release

On applying the factorial design, the quadratic model was

found to be significant with model F value of 5.63, p

value < 0.0465 which implied that model was significant.

Following quadratic equation describes the drug release.

Y2= 86.39- 2.34X1 +0.74X2 +6.90 X1X2

The quadratic model was found to be significant with F

value 5.63 (p<0.046) that indicates that the model is

significant. Positive sign in the above equation indicates

that response increases with the factor. Negative sign

indicates negative effect on drug release, response does

not increase with factor.

Fig 5A and 5B indicate two-dimensional contour plot and

three dimensional response surface plot respectively. The

contour plot does not show straight line, it indicates that

there is no linear relationship between the factor X1 and

X2. The percentage release increases with increase in

concentration of Poloxamer 407 (X1). At low and medium

level of factor X1 drug release is less and high level

Design-Expert® SoftwareFactor Coding: ActualGelat temp

Design Points45

30

X1 = A: AX2 = B: B

-1 -0.5 0 0.5 1

-1

-0.5

0

0.5

1Gelat temp

A: conc. of Poloxamer 407

B: C

onc.

of p

olox

amer

188

30

35

40

Design-Expert® SoftwareFactor Coding: ActualGelat temp

Design points above predicted valueDesign points below predicted value45

30

X1 = A: AX2 = B: B

-1

-0.5

0

0.5

1

-1

-0.5

0

0.5

1

25

30

35

40

45

Gela

t te

mp

A: conc. of Poloxamer 407

B: Conc. of poloxamer 188

Fig. 4 b

Fig. 4 a

Fig 4 a: Contour plot showing combined effect of

Poloxamer 407 and Poloxamer 188 on Gelling

temperature.

Fig 4 b: Response surface plot showing combined effect

of Poloxamer 407 and Poloxamer 188 on Gelling

temperature.

Poloxamer 407 (X1) drug release is high. The drug release

increases with concentration of factor X2 , but as not rapid

as X1. The combined effect of factor X1 (poloxamer 407)

and X2(Poloxamer 188) can be further elucidated with

help of response surface plot (figure). At high level of X1

and X2 the drug release was maximum.

Source Sum of

Squares

Degree

of

freedom

Mean

Square

F

value

p-value

Prob>F

Model 227.6 3 75.75 5.63 0.0465

(S)

Residual 67.30 5 13.46 - -

Total 294.56 8 86.39 - -

Table 5. Summary of ANOVA for Drug release

parameters

Design-Expert® SoftwareFactor Coding: ActualInvitro

Design points above predicted valueDesign points below predicted value94.28

76.75

X1 = A: AX2 = B: B

-1

-0.5

0

0.5

1

-1

-0.5

0

0.5

1

75

80

85

90

95

Invi

tro

A: conc. of poloxamer 407

B: conc. of poloxamer 188

Fig. 5 b

Design-Expert® SoftwareFactor Coding: ActualInvitro

Design Points94.28

76.75

X1 = A: AX2 = B: B

-1 -0.5 0 0.5 1

-1

-0.5

0

0.5

1Invitro

A: conc. of poloxamer 407

B: c

onc.

of p

olox

amer

188

80

85

85

90

90

Fig. 5 a

Fig 5 a: Contour plot showing combined effect of

Poloxamer 407 and Poloxamer 188 on drug release

Fig 5 b: Response surface plot showing combined effect

of Poloxamer 407 and Poloxamer 188 on drug release



3.7 Characteristics of medicated mucoadhesive

liquid suppositories:

The medicated liquid suppository formulation was

optimized using Design expert, in which MF9 containing

25% poloxamer 407 and 5% poloxamer 188 was

optimized for preparation of mucoadhesive liquid

suppository. To increase the gel strength and bioadhesive

force of the liquid suppositories, bioadhesive polymers

were added in optimized medicated liquid suppository.

Medicated liquid suppository gel was found to have weak

mechanical strength. HPMCK4M, Carbopol 940 were

selected as the bioadhesive polymer. These bioadhesive

polymers are water-soluble or swellable, but different in

their nature and charges. HPMC a cellulose derivative is

neutral and swelling in water. Carbopol940, a polyacrylic

acid derivative polymerized without cross-linking agent, is

anionic and water-swellable. Gelation temperature range

for liquid suppository should be 30-36°C. This allows it to

remain liquid at room temperature and gel formation in the

rectum instantly. Increase in concentration of

mucoadhesive polymer decreases gelation temperature.

HPMC K4M has less effect on gelation temperature as

compared to Carbopol 940. Mucoadhesive polymer

decreases gelation temperature of thermosensitive in situ

gel containing poloxamers, due to their ability to bind to

the polyoxyethylene chain present in the poloxamer

molecule. This promotes dehydration causing increasing

inter molecular bonding which leads to gelation at lower

temperature. As concentration of bioadhesive polymer

increases gel strength also increases.

Formulations containing carbopol 940 shows more gel

strength as compare to formulations containing HPMC

K4M. There was increase in bio-adhesive strength with

increase in concentration. Mucoadhesive force means the

force with which liquid suppository binds to mucosal

membrane. Poloxamer gels without addition of

mucoadhesive agent had less mucoadhesive force. HPMC

K4M and Carbopol 940 mucoadhesive strength increases

with concentration. But carbopol 940 have effect on

gelation temperature with increase in concentration.

Sr. No. Formulation code Gelation

temperature (oC) Gel strength

Cumulative

drug release

Mucoadhesive strength

(dyne/cm2)

1 MF9HP1 36.75±0.375 15.66±0.57 90.73±0.27 5748

2 MF9HP2 34.45±0.102 14.36±0.471 91.37±0.38 5992

3 MF9HP3 30.98±0.896 14.57±0.467 83.75±0.48 6998

4 MF9CP1 33.02±0.368 16.33±0.57 82.64±0.47 5717

5 MF9CP2 29.67±0.896 17.0±1.0 81.59±0.34 6338

6 MF9CP3 28.09±0.367 17.6±0.57 78.89±0.62 6660

Table 7. Character istics of mucoadhesive medicated liquid suppository

Fig 6: Dissolution plots of cumulative drug release of lidocaine mucoadhesive liquid suppository

Batch X1 conc. of poloxamer

407

X2 conc. of poloxamer

188

Response (Y1)

Gelation temperature

Response (Y1)

Gelation temperature

MF9 25% 5% Actual value - 36oC

Predicted value - 35.47oC

Actual value - 92.41 %

Predicted value - 91.61%

% error - - 1.47% 1.08%

Table 6. Result of exper iments for confirming optimization capability



3.7.1 In vitro drug release study of mucoadhesive

liquid suppository

Drug release was retarded by the addition of

mucoadhesive polymers. Formulations containing HPMC

K4M showed more than 82% drug release in 5 hrs while

formulations containing carbopol 940 showed less than

80.40% drug release in 5 hrs. The retarding effect of the

carbopol 940 could be attributed to high viscosity.

Formulation MF9HP2 was selected for further study as

drug release was found to be 91.37% at the end of 5hrs

(Fig 6).

3.7.2 In vivo animal study

A. Normal rectoanal region : Fig A shows normal

architecture of recto anal region. In normal rectoanal

region mucosal layer, submucosal layer and blood

vessels are intact.

B. Haemorrhoids induced rectoanal region (Possitive

control) : The sections of rectoanal region showing

severe infiltration of inflammatory cells in mucosa as

well as submucosa of colon (Arrow). Marked to

severe inflammation, congestion, haemorrhage,

dilatation of blood vessels, degeneration, and necrosis

can be observed in the section of untreated positive

control group

C. Haemorrhoids induced recto anal region treated

with aloe vera juice in situ gel suppository: The

sections of recto anal region showing minimal

infiltration of inflammatory cells of recto anal region.

Mild inflammation, marked congestion, degeneration,

and necrosis.

D. Haemorrhoids induced recto anal region treated

with aloe vera juice+ lidocaine in situ gel

suppository: Minimal infiltration of inflammatory

cells (arrow) and degeneration of lining mucosa.

From the above findings of the study (Fig 7), it can be

concluded that after five days of treatment of prepared in

situ gel liquid suppositories containing (Lidocaine) and

aloe vera juice as a vehicle liquid suppositories (Fig.7d)

has shown near normal architecture. In situ gel liquid

suppository containing aloe vera juice has shown mild

inflammation, marked congestion, degeneration, and

necrosis. Though aloe vera juice liquid suppository has not

shown normal architecture, it is indicating positive sign

towards cure of hemorrhoids. After treatment with Aloe

vera juice-liquid suppository and combination of lidocaine

+ aloe vera juice liquid suppository shows significant

reduction in the inflammation of croton oil-induced

hemorrhoids in rats compared to positive control. This

may be due to the potent anti-inflammatory activity of the

herbs present in the tested formulation.

4. Conclusion

Liquid suppository of lidocaine MF9HP2 containing

poloxamer 407, poloxamer 188 and HPMC K4M found to

be most effective in imparting stability of formulation by

maintaining gelation temperature 30-36oC. The selected

formulation exhibited relevant drug release (in vitro). This

formulation exhibited the optimal Gelation temperature,

gelling ability, gelling time, pH, gel strength, viscosity, %

drug content, mucoadhesive strength, reduce

inflammation in croton oil-induced rats to qualify as

rectal drug delivery system for treatment of hemorrhoids.

The (MF9HP2) formulation has been successfully

formulated to offer stable, cost effective and safe delivery

system for treatment of hemorrhoids.

A

B

C

D

Fig 7: Histopathology of mucosal layerof recto anal

region treated with final formulation in hemorrhoids

induced rats



Acknowledgments

The authors are grateful to JSPM’s Jayawantrao

Sawant College of pharmacy and research, Hadapsar,

Pune for supplying of all the basic requirements of this

research.

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https://www.hindawi.com/32721413/

https://www.hindawi.com/80262487/

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