Article

The Formulation of Transdermal Patch Ethanol Extract of Java Chili (Piper

retrofractum Vahl.) Based and Its Analgesic Activity

Annisa Luthfiyyah¹, Elisma¹*, Uce Lestari¹, Naufal Nabillah Putra¹, Istiazah Putri Sisva¹

Johan Hasyim Nugroho¹, Aulia Tria Yustika¹

¹Department of Pharmacy, Universitas Jambi, Jambi 36361, Indonesia

Abstract

Pain is an unpleasant sensory and emotional experience caused by actual or potential tissue damage.

Java chili (Piper retrofractum Vahl.) is an Indonesian plant known for its secondary metabolites, including

piperine, pipernonalin, guineensine, and essential oils. Among these, piperine is the primary compound

with potential analgesic properties. This study evaluates the analgesic effects of transdermal patches

containing ethanol extract of Java chili using the writhing test and macrophage count in acetic acid-

induced mice. The patches were formulated with different concentrations of the active ingredient: F1 (1g

extract), F2 (2g extract), and F3 (3g extract). The results show that increasing the ethanol extract

concentration significantly alters the physical characteristics of the patches, including shape, thickness,

color, and durability. In the analgesic test, the macrophage count in the negative control group was 29.33

± 0.57. In contrast, the treatment groups showed a concentration-dependent reduction: F1 (20.00 ± 1.73),

F2 (13.00 ± 3.00), and F3 (7.33 ± 1.15). The positive control group exhibited the lowest macrophage count

(3.66 ± 1.15). These findings indicate that transdermal patches containing Java chili ethanol extract

possess significant analgesic potential, with higher concentrations yielding stronger effects.

Keywords: Analgesic; java chili; pain; transdermal patch

Graphical Abstract

*

Corresponding author

Email addresses: elisma@unja.ac.id

DOI: https://doi.org/10.22437/chp.v9i1.38136

Received October 30^th2024; Accepted February 13^rd2025; Available online June 01^st2025

(https://creativecommons.org/licenses/by/4.0 )

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Chempublish Journal, 9(1) 2025, 36- 46

Introduction

gastrointestinal

disorders,

hypersensitivity

reactions, kidney damage and too much

consumption can also damage the liver. Although

it can be cured with medication, cases of people

suffering from drug poisoning are still common

[5].

Pain is an unpleasant sensory and emotional

experience that results from actual or potential

forms of tissue damage. Although pain is a

sensation, it has cognitive and emotional

components, which are described in terms of

suffering. Pain stimuli are initially received by

nociceptors, which are sensory neurons that

function as pain receptors on the skin [1]. Pain

can occur at high or low intensity when stretched

or when the temperature increases due to tissue

damage. Necrotic cells will release intracellular

K+ and proteins. Increased extracellular K+ levels

can cause depolarization of pain receptors or

nociceptors allowing proteins to penetrate the

microorganisms and cause inflammation. This

One of the Indonesian plants with high utilitarian

value is Java chili (Piper retrofractum Vahl.) [6].

Javanese chili plant parts have several secondary

metabolite compounds and the most are found

in the fruit. Javanese chili fruit contains active

compounds in the form of alkaloids, terpenoids

and saponins. Meanwhile, Javanese chili leaves

contain active compounds in the form of

flavonoids, terpenoids saponins [7]. The main

secondary metabolite compounds in chili plants

are piperine, pipernonaline, guineensine and

essential oils. Piperine has pharmacological

activity as an antipyretic analgesic [8].

results

in

the

release

of

pain-inducing

substances, such as leukotrienes, prostaglandin

E2, and histamine, which stimulate pain

receptors and cause pain (hyperalgesia or

allodynia) in response to painful or innocuous

stimuli [2].

According to research conducted by Sari, et al.

[10],

piperine

shows

analgesic

activity

comparable to the analgesic standard drug

indomethacin. Piperine at doses of 20 mg and 30

mg/kg body weight provides effects close to

those of indomethacin. In another study,

piperine was reported to act as a penetration

enhancer in the transdermal delivery of

curcumin. In addition to increasing curcumin flux,

piperine flux in vitro permeation also increased

with increasing piperine concentration as a

penetration enhancer [11].

Drugs that selectively relieve pain without

significantly altering consciousness are called

analgesics. Analgesic drugs are commonly used

to relieve or reduce pain. Analgesics commonly

used by the general public include non-opioid

analgesic drugs such as aspirin, mefenamic acid,

and paracetamol [3,4]. Unlike opioid analgesic

drugs, these drugs are not addictive. Non-opioid

analgesic drugs can cause side effects, especially

(c)

(a)

(c)

Figure 1. Structure of main secondary metabolite compounds of java chili: (a) piperine; (b) pipernonaline;

(c) guineensine [9]

The piperine content in Java chili that is active as

an analgesic can be innovatively formulated into

a practical and effective transdermal patch with

minimal side effects, which can be used for

pass effect, and rapid metabolism, resulting in

significantly reduced systemic circulation of the

drug. Additionally, transdermal formulations can

provide prolonged therapeutic effects with a

single application, increasing patient comfort

compared to other forms that require frequent

dosing to achieve therapeutic doses [12]. Given

alleviating

mild

to

moderate

pain.

The

advantages of drug formulations in the form of

transdermal patches include ease of use,

reduced frequency of drug administration,

maintained bioavailability, avoidance of the first-

these

advantages,

transdermal

patches

represent a good and effective form of herbal

37

A.Luthfiyyah et al.

Chempublish Journal, 9(1) 2025, 36- 46

drug delivery pharmacologically; therefore,

chili powder was dissolved in 2L of 70% ethanol,

ensuring that all the powder was submerged, and

maceration was performed for 24 hr with 2

repetitions, stirring during the first 6 hr. The

solvent mixed with the Java chili powder was

filtered through a funnel lined with filter paper to

obtain the filtrate (macerate) of Java chili extract.

The macerate was then evaporated using a

vacuum rotary evaporator at a temperature of

60°C to obtain a liquid extract. The yield of the

extract was then calculated using formula 1[13]

research

on

innovative

formulations

of

transdermal patches from Java chili extract to

address pain is necessary.

Materials and Methods

Time and Place of Implementation

This research was conducted in the Laboratory of

Technology

and

Formulation

of

Solid

Preparations at the Faculty of Medicine and

Health Sciences, Jambi University. The research

lasted for 4 months from May to August 2024.

Yield (%) = ^{Weight of Extract Obtained (푔)}x 100%

(1)

Initial Sample Weight(푔)

Formulation

Materials and Instrumentations

The formulation of the ethanol extract was

prepared in the form of a patch consisting of an

active substance, namely the ethanol extract of

Java chili (Piper retrofractum Vahl.) at various

concentration levels, as well as positive control

(K+), negative control (K-), and other additives.

The formula for the transdermal patch of ethanol

extract of Java chili (Piper retrofractum Vahl.) is

shown in Table 1. Preparing of the Transdermal

Patch of Ethanol Extract of Java Chili (Piper

retrofractum Vahl.) according to Hendriati and

Hamid (2021) [14].

The sample consisted of 400 mg of the powdered

simplicia of Java chili (Piper retrofractum Vahl.)

obtained

Department Laboratory, Faculty of Pharmacy,

Gadjah Mada University, hydroxhypropyl

from

the

Pharmacy

Biology

metilylmetlulose (HPMC) (PT. Indo Sukses

Pratama), polyvinylpyrrolidone (PVP) (PT. Chori

Indonesia), sodium lauryl sulfate (SLS) (PT.

Anugrah Putra Kencana), propylene glycol (PT

Iniko Karya Persada), Giemsa (Merck) and water

for injection (PT. Otsuka Indonesia). The

Instrumentation used in this research are vacum

rotary evaporator (Scilogex), measuring cup,

beaker glass and test tube (Pyrex), petri dish

(OneMed), filter paper and laboratory funnel

(Pyrex), waterbath and oven (Memmert), animal

scales and analytical scales (Ohaus), oral sonde

and 1cc syringe (OneMed), microscope (Euromex),

stopwatch and animal cages.

Preparation of Transdermal Patch from Ethanol

Extract of Java Chili

HPMC and PVP were dissolved in pre-heated

water, then propylene glycol, Java chili extract,

enhancer, and 96% ethanol were added

sequentially until reaching 15 mL. The solution

was poured into a petri dish and allowed to stand

for 24 hr until all air bubbles were eliminated. The

patch was then oven-dried at 40°C for 48 hr. The

patch sheets were cut into 1 x 1 cm pieces for

application on the abdomen of the mice.

Preparation of Ethanol Extract of Java Chili

The preparation of Java chili extract was

conducted using the maceration method with

70% ethanol as a solvent. A total of 400 g of Java

Table 1. Composition transdermal patch of formula

Formulas

Function

Materials

K (-)

F1

1g

2%

5%

F2

2g

F3

3g

Extract ethanol of java chili

HPMC

PVP

Na lauryl sulfate

Propylen glycol

-

Active substance

Polymer

Surfactant

Preservative

2%

-

2%

5%

2%

5%

2mL

2Ml

2mL

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A.Luthfiyyah et al.

Chempublish Journal, 9(1) 2025, 36- 46

96% Ethanol

15mL

Solvent

Evaluation of Physical Quality of the Patch

Preparation

The

determination

of

the

number

of

macrophages was carried out by making a smear

of the peritoneal fluid, staining the preparation

with giemsa solution, and observing it under a

microscope at 400x magnification, followed by

counting the macrophages [14].

The evaluation of the physical quality of the

preparation included clarity, shape, color, odor,

pH, thickness, and folding endurance [15].

Adaptation of Test Animals

Data Analysis of Research

A total of 25 male mice that have passed the

ethical code test and obtained research ethics

approval from Jambi University with certificate

The analysis of the physical quality test data of

the patch was performed descriptively, while the

data obtained from the observation of the

number of writhes and macrophages were tested

using parametric statistical methods. Data

analysis was conducted using analysis of variance

(ANOVA) followed by Fisher’s test. If significant

differences were found (p≤0.05), further testing

was conducted using Duncan’s multiple range

test. Data analysis was carried out using SPSS

version 20.0.

number

2006/UN21.8/PT.01.04/2024.

These

male mices have never been used at all in

research and were randomly selected, healthy,

and have normal activity.. Before being used in

the study, the mice were adapted for 2 weeks

under the same conditions as treatment. Mice

were declared healthy and suitable for research

if they showed no signs of illness and did not lose

more than 10% of their initial body weight [16].

The mice were fasted for 12 hr while still being

given drinking water before the experiment.

Results and Discussion

Ethanol Extract of Java Chili

Analgesic Activity

The powdered simplicia of Java chili (Piper

retrofractum Vahl.) weighing 400 g was extracted

using the maceration method for 24 hr, followed

by two remaceration. The resulting ethanol

extract of Java chili weighed 67 g. The ethanol

extract of Java chili appeared as a thick brown

liquid with a characteristic aroma of Java chili, the

result obtained in the following Figure 2. The

yield percentage of the ethanol extract of Java

chili was calculated to be 16.75%, according to

the Indonesian Herbal Pharmacopoeia, a good

extract should have a yield percentage above

7.5%, it meets the required standard [17].

Mice were induced with 0.1 mL of acetic acid

intraperitoneally, leading to a motor response in

the form of writhing. The patches according to

the formula (F1-F3 and negative control) were

applied to the shaved abdomen of the mice [14].

In the positive control group, mice received

paracetamol orally. Mice were observed for 6 hr,

and the number of writhes was counted every 15

min.

Collection of Peritoneal Fluid and Macrophage

Samples The euthanized mice were placed in a

supine position, the abdominal skin was opened

and cleaned with 70% alcohol, then 1 mL of

aquadest was injected into the peritoneal cavity.

The abdomen was massaged, then the peritoneal

cavity was opened, and the peritoneal fluid was

collected. The obtained peritoneal fluid was used

for macrophage smears for observation [14].

(a)

(b)

Figure 2. (a) Powdered simplicia of Java chili; (b)

ethanol extract of Java chili

Determination of the Number of Macrophages

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Chempublish Journal, 9(1) 2025, 36- 46

Physical Properties of the Transdermal Patch

F2, and F3 exhibiting its characteristic aroma,

while the control remained odorless.

The physical properties of the transdermal patch

formulated with the ethanol extract of Java chili

(Piper retrofractum Vahl.) were assessed to

determine its suitability for application. The

evaluation covered clarity, form, color, odor, pH,

thickness, and fold resistance [18]. The results of

the transdermal patch formulation of Java chili

ethanol extract can be seen in the Figure 3.

The pH of all patches was within a skin-

compatible range, with the control at 5 and the

formulations ranging from 5.5 to 6. According to

standard for a qualified pH value is 4.5-6.5 which

aims to prevent the patch from irritating the skin

[19].

Thickness increased slightly with the

addition of the extract, from 0.12 mm in the

control to 0.15 mm in F1 and 0.16 mm in F2 and

F3. The thickness results for each formula have

met the thickness requirements which should

not exceed 1 mm, because if the patch is too thick

it will be difficult to release the active substance

from the patch [20]. Lastly, fold resistance, which

reflects the durability of the patches, was

excellent (>300 folds) for the control, F1, and F2

but decreased (<300 folds) in F3, likely due to

reduced elasticity or increased stiffness at higher

extract concentrations. For patch fold resistance,

it has not fully met the requirements because the

requirement for patch fold resistance is more

than 300 folds [21]. For K(-), F1, and F2, the

folding resistance can be said to be good, while

F3 does not meet the folding resistance

requirements. For transdermal patches of

Javanese chili ethanol extract, it can be said that

it meets the applicable requirements, it's just that

the folding resistance test on F3 does not meet

the requirements. The results of the evaluation

of the physical properties of the transdermal

patch of ethanol extract of Java chili can be seen

in the Table 2.

Figure

3.

Result

of

transdermal

patch

formulation: (K-) Transdermal Patch (0g extract);

(F1) Transdermal Patch (1g extract); (F2)

Transdermal Patch (2g extract); (F3) Transdermal

Patch (3g extract)

The evaluation of the physical properties of the

transdermal patches prepared with ethanol

extract of Java chili (Piper retrofractum Vahl.)

revealed notable variations across the tested

parameters. The clarity of the patches decreased

with increasing extract concentration, as the

Analgesic Test in Mice

The analgesic test was conducted to determine

the analgesic effects caused by the use of Java

chili ethanol extract on the abdomen of mice. The

writhing test was chosen because it is the most

widely used test to measure the response of

analgesic activity on peripheral nerves using a

chemical stimulus in the form of intraperitoneal

acetic acid injection [22]. Mice induced with 0.1

mL of acetic acid intraperitoneally were then

observed for writhing over a period of 6 hr, with

the number of writhing counted every 15 min.

control was clear, Formula

1

(F1) was

transparent, and both Formula 2 (F2) and

Formula 3 (F3) were translucent. The form of the

patches showed that the control, F1, and F2 were

elastic, whereas F3 was slightly elastic, indicating

reduced flexibility likely due to the higher

concentration of the extract. The color of the

patches also changed with increasing extract

concentration, ranging from colorless in the

control to light brown in F1, brown in F2, and dark

brown in F3. Additionally, the odor of the patches

was influenced by the Java chili extract, with F1,

The results of the analgesic test of the ethanol

extract patch of Java chili can be seen in the table

3. At the 15th minute, which is the initial point of

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Chempublish Journal, 9(1) 2025, 36- 46

writhing in the mice after being induced with

acetic acid, the positive control mice had received

oral paracetamol, while F1, F2, and F3 contained

the ethanol extract of Java chili. The greatest

decrease in activity occurred in the positive

control treatment group (oral administration of

paracetamol). Paracetamol, as the positive

control, is capable of reducing pain and

inflammation. The analgesic and antipyretic

compounds decrease pain and inflammation by

inhibiting the cyclooxygenase enzyme, which

plays a role in the synthesis of prostaglandins.

The decrease in activity began to be noticeable at

minute 35. This is because peak serum levels of

paracetamol are reached within 30-60 min [23].

Formulas 1, 2, and 3 also exhibited analgesic

effects, with a decrease in activity observed from

minute 30 to minute 120. From the table 3, it can

be seen that the effectiveness of the ethanol

extract of Java chili with increased concentration

can provide more effective effects than the

negative control.

Table 2. Evaluation of the physical properties of the transdermal patch of ethanol extract of Java chili

(Piper retrofractum Vahl.)

Parameter Test

Formulas

Control (-)

F1

F2

F3

Clarity

Form

Color

Clear

Elastic

Transparant

Elastic

Translucent

Elastic

Brown

Translucent

Slightly Elastic

Dark Brown

Colorless

Light Brown

Odor

Odorless

Java Chili Aroma

pH

5

5.5

6

Thickness (mm)

Fold Resistance

0.12

>300

0.15

>300

0.16

>300

0.16

<300

Table 3. Writhing count of mice

Mice Writhing (mean ± SD)

Time (Min)

K (+)

K (-)

F1

F2

F3

26.8 ± 3.77

72.2 ± 3.96

70.20 ± 2.39

66.40 ± 2.07

62 ± 2.55

56.8 ± 4.20

48.4 ± 3.85

42.2± 2.95

25.20 ± 3.49

22.00 ± 3.74

11.80 ± 1.64

6.60 ± 1.52

1.8 ± 0.84

40.00 ± 3.16

35.80 ± 2.28

19.00 ± 1.58

10.80 ± 3.11

6.80 ± 2.49

4.4 ± 1.14

35.6 ± 2.97

11.60 ± 2.41

6.20 ± 1.30

3.00 ± 1.00

1.8 ± 0.84

0.40± 0.55

00.00 ± 00.00

15

30

18.00 ± 3.54

11.40 ± 1.14

5.60 ± 1.14

45

60

00.00 ± 00.00

59.60 ± 3.05

41.80 ± 2.77

36.60 ± 1.52

30.8 ± 0.84

75

90

2.20 ± 0.45

0.40 ± 0.55

105

120

Based on Figure 2, increasing the concentration

of the ethanol extract patch formulation of Java

chili significantly enhanced the analgesic effect in

male mice. In the F3 treatment group, which

contained 3 g of Java chili ethanol extract, the

analgesic response was comparable to that of the

positive control group treated with oral

paracetamol. In contrast, the negative control

group (untreated) exhibited no nociceptive

response after the 60th minute. Meanwhile, in

the F3 treatment group, the absence of

nociceptive activity was observed between the

90th and 120th min.

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Chempublish Journal, 9(1) 2025, 36- 46

90

80

70

60

50

40

30

20

10

0

15

30

45

60

75

90

F2

105

F3

120

Time (min)

K (+)

K (-)

F1

Figure 2. Graph of mice writhing versus time

Macrophage test and calculation of peritoneal

macrophages in mice

induced with 1% acetic acid and given treatments

can be seen in the figure 3. Based on the

observations of the number of macrophages

after 120 min, the highest number was found in

the peritoneal fluid sample from the negative

control group, followed by the transdermal

patches F1, F2, F3 and positive control. Compared

to the negative control, the administration of the

ethanol extract of Java chili can reduce the

number of macrophages in mice induced with

acetic acid.

Macrophage testing is conducted to see how

infection affects the immune response through

changes in the number of macrophages. The

number of macrophages was observed using a

microscope with a magnification of 400x [14]. The

characteristics

of

macrophages

from

the

peritoneal fluid of mice can be seen in figure 3.

The average number of macrophages in mice

a

c

b

e

d

Figure 3. Characteristic of Macrophages from peritoneal fluid (a) negative control; (b) positive control; (c)

Formula 1; (d) Formula 2; (e) Formula 3

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Chempublish Journal, 9(1) 2025, 36- 46

Average number of macrophages

35

30

25

20

15

10

5

0

K(+)

K(-)

F1

F2

F3

Figure 4. Average number of macrophages

The macrophage test results demonstrated that

transdermal patches containing Java chili ethanol

extract significantly decreased the quantity of

macrophages in the inflammatory area when

administered to mice. According to figure 4, in

comparison to the negative control group (K-),

this decline was noted in the treatment groups

F1, F2, and F3. The average number of

macrophages in the negative control group was

29.33, but the treatment groups—F1 had 20.00,

F2 had 13.00, and F3 had 7.33—showed a

fewer the number of macrophage cells in the rat

mandibular socket tissue. Which is in accordance

with the results obtained, namely the increase in

the concentration of ethanol extract of Java chili

can reduce the number of macrophages in mice.

The decrease in the number of macrophages in

the treatment group compared to the negative

control (K-) is strongly related to the analgesic

and anti-inflammatory activity of the ethanol

extract of Java chili, which contains piperine.

Piperine, as the main active compound in Java

chili, is known to have mechanisms that inhibit

progressive

decline.

The

reduction

in

macrophages suggests that the immunological

response involved in the analgesic process can

be suppressed by the transdermal patch of Java

chili ethanol extract.

inflammatory

mediators,

including

pro-

inflammatory cytokines such as TNF-α and IL-6,

as well as the enzyme cyclooxygenase-2 (COX-2).

Additionally, piperine is also capable of inhibiting

the activation of the transcription factor NF-κB,

which plays an important role in regulating the

genes that trigger the inflammatory response.

Based on research conducted by Malik [24], the

negative control does not have the same effect as

that given to the positive control. This is because

mice in the negative control are induced without

treatment in the form of active substances that

can increase the immune system in test animals.

According to previous research [25], it shows that

macrophage cells in the treatment group are less

than in the control group. While it can also be

seen that the higher the concentration of noni

leaf extract given, the number of macrophage

cells will decrease. Consequently, it can be seen

that the higher the amount of extract given, the

The decrease in macrophages following the

administration of the transdermal patch also

indicates that the extract effectively reduces

inflammation in mice. This anti-inflammatory

activity can be attributed to piperine, a bioactive

component in Java chili. Previous research has

demonstrated that piperine possesses analgesic

and anti-inflammatory properties by inhibiting

cyclooxygenase

(COX)

and

5-lipoxygenase

activity, reducing prostaglandin production. The

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A.Luthfiyyah et al.

Chempublish Journal, 9(1) 2025, 36- 46

observed reductions in COX-2 expression and

PGE2 levels further support the conclusion that

the ethanol extract of Java chili can modulate

inflammatory pathways, providing a potential

therapeutic approach for inflammatory pain

management [26].

responsibility for the content and any remaining

errors, omissions, and inaccuracies is our own

Author Contributions

Conceptualization, A.L., E., U.L; Methodology,

U.L., N.N,P., Software, A.I., N.NP; Validation, A.L.,

U.L., J.H.N; Formal Analysis, E, U.L., A.T.Y;

Investigation, A.L., I.P.S.; Resources, A.L., E., U.L;

Data Curation, A.L.; Writing – Original Draft

Preparation, U.L, N.N.P.; Writing – Review &

Editing, A.L, E., A.T.Y; Visualization, N.N.P., I.P.S.;

Supervision, J.H.N; Project Administration, A.L.;

Funding Acquisition, A.L”.

Transdermal

delivery

allows

the

active

compounds in Java chili to be absorbed slowly

through the skin, resulting in stable levels of the

compounds in the blood and providing sustained

therapeutic effects. This method also reduces the

risk of fluctuations in drug concentration that

commonly occur with oral or injection routes [27]

Conflict of Interest

Conclusion

The authors declare no conflict of interest

References

Based on the research results obtained, it was

found that the ethanol extract of Java chili with

increased

concentrations

provides

more

effective effects compared to the negative

control (-). The decrease in the number of

macrophages following the administration of the

transdermal patch of ethanol extract of Java chili

also indicates that the extract can reduce

inflammation and pain in mice. In the patch

evaluation for organoleptic tests, the best results

were observed in formula 2. The folding

endurance evaluation was best in formulas 1 and

2, which was >300 folds. For the pH evaluation, all

three formulas had a good pH of 5

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This research is funded by the Directorate

General of Learning and Student Affairs of the

Ministry of Research, Technology and Higher

Education of the Republic of Indonesia in 2024.

However, this research would not have been

successfully conducted without the contributions

of various parties. Therefore, we thank all the

volunteers who participated in this study, as well

as staff at Jambi University for administrative

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Elisma, S. Farm., M. Farm., Apt., as our

supervising lecturer who has assisted and guided

our team in conducting this research. We also

express our gratitude to the Faculty of Medicine

and Health Sciences, Jambi University, which

A. V. Wardoyo and R. Zakiah Oktarlina.

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