Home  |  About JAPTR |  Editorial board  |  Search |  Ahead of print  |  Current issue  |  Archives |  Submit article  |  Instructions  |  Subscribe  |  Advertise  |  Contacts  |Login 
Users Online: 449   Home Print this page Email this page Small font sizeDefault font sizeIncrease font size
     

 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 2  |  Page : 127-131  

The effect of variation of tetrahydropentagamavunon-0 concentration in lotion and emulgel formula toward acute dermal irritation study


1 Department of Pharmaceutial Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada; Curcumin Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
2 Curcumin Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
3 Department of Pharmaceutic, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia

Date of Submission02-Dec-2020
Date of Decision08-Feb-2021
Date of Acceptance04-Mar-2021
Date of Web Publication27-Apr-2021

Correspondence Address:
Dr. Ritmaleni
Department of Phamaceutial Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta 55281
Indonesia
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/japtr.JAPTR_270_20

Rights and Permissions
  Abstract 


Tetrahydropentagamavunon-0 (THPGV-0) is a curcumin metabolite analog which known has a higher antioxidant activity than Vitamin E. This compound has been formulated in lotion as antiaging cosmetics, but the irritation effect is unknown yet. This study aims to analyze the effect of variation of THPGV-0 concentration in lotion and emulgel formula toward acute dermal irritation. The concentrations of THPGV-0 varied to 0.1%, 0.2%, and 0.4% in lotion/emulgel and tested for their physical properties such as organoleptic, homogeneity, pH, spreadability, and adhesion. Acute dermal irritation test is done in accordance with the In vivo Nonclinical Toxicity Test Guidelines by the Indonesian Food and Drug Administration (BPOM). This study showed that Primary Irritation Index (PII) value concentrations of 0.1%, 0.2%, and 0.4% THPGV-0 in lotion formula are 0.014, 0.014, and 0.028 (close to 0) and in emulgel formula are 0.08 at concentration of 0.1%, 0.33 at concentration of 0.2%, and 0.25 at concentration of 0.4%. PII of 0.1%, 0.2%, and 0.4% THPGV-0 in lotion and emulgel is included in negligible irritation response. Hence, the both of THPGV-0 formula in lotion and emulgel are considered safe to use on skin according to this study.

Keywords: Emulgel, irritation, lotion, tetrahydropentagamavunon-0


How to cite this article:
Ritmaleni, Susilo Putri DS, Wulandari T, Zulkarnain AK, Murrukmihadi M. The effect of variation of tetrahydropentagamavunon-0 concentration in lotion and emulgel formula toward acute dermal irritation study. J Adv Pharm Technol Res 2021;12:127-31

How to cite this URL:
Ritmaleni, Susilo Putri DS, Wulandari T, Zulkarnain AK, Murrukmihadi M. The effect of variation of tetrahydropentagamavunon-0 concentration in lotion and emulgel formula toward acute dermal irritation study. J Adv Pharm Technol Res [serial online] 2021 [cited 2021 Jun 25];12:127-31. Available from: https://www.japtr.org/text.asp?2021/12/2/127/314678




  Introduction Top


Nowadays, various kinds of cosmetics have been made from herbal ingredients to overcome various skin problems like that caused by the sun. Even though the sun plays the most important role as life source energy, the sun is a source of ultraviolet light which can cause erythema, hyperpigmentation, and skin cancer.[1] Free radicals raised by sunlight exposure can damage skin collagen, matrix dermal, induce wrinkled, scaly, and premature aging.[2] Skin protection and care are considered necessary to avoid skin damage due to sunlight exposure, dust, and pollutant. There are several ways to protect human skin from UV exposure, either physical protection or chemical protection. Wearing a cap and cover body skin with long sleeve clothes are considered as physical protection, while chemical protection can be used in some kinds of sunscreens and antiaging cosmetics.

One of the cosmetics ingredients that popular is curcumin compound which has been known to have antioxidant, anti-inflammatory, and anticancer activities.[3] A new analog of curcumin active metabolite which has a higher antioxidant activity than Vitamin E, called tetrahydropentagamavunon-0 (THPGV-0) [Figure 1], also has been found.[4] ES50 value of THPGV-0 is 29.19, PGV-0 is 64.56, and Vitamin E is 47.87 which show that THPGV-0 antioxidant activity is better than PGV-0 and Vitamin E.[5] Due to its potential activity as a strong antioxidant, some research starts to formulate THPGV-0 into lotion and emulgel dosage form. It can be used more easily and may become a great antiaging cosmetic. A previous study has been performed to prove the effectiveness of both formulas, but the irritation effect is unknown yet. Hence, this study aimed to determine the acute dermal irritation effect (Primary Irritation Index [PII]) of THPGV-0 (varied concentrations) in lotion or emulgel formula of THPGV-0 compound in an in vitro study. In long term, we would like to establish this new antiaging can be formulated in many different formulas of antiaging cosmetics.
Figure 1: Structure of tetrahydropentagamavunon-0 (THPGV-0)

Click here to view



  Materials and Methods Top


Materials

The active compound in this research is THPGV-0 which is synthesized by the Faculty of Pharmacy Universitas Gadjah Mada with purity 99%, cetyl alcohol (pharmaceutical grade), glycerin (pharmaceutical grade), liquid paraffin (pharmaceutical grade), triethanolamine (pharmaceutical grade), tween 80 (pharmaceutical grade), stearic acid (pharmaceutical grade), citric acid (pharmaceutical grade), DMDM hydantoin (1,3-Dihydroxymethyl-5,5-dimethylhydantoin) (pharmaceutical grade), span 80 (pharmaceutical grade), propylene glycol (pharmaceutical grade), methylparaben (pharmaceutical grade), propylparaben (pharmaceutical grade), Carbopol 940 (pharmaceutical grade), triethanolamine (pharmaceutical grade), aquadest, perfume, and Ethanol.

Preparation of THPGV-0 Lotion

The formula of THPGV-0 lotion in this study was referred to published method.[6] The Oil phase which consisted of liquid paraffin and cetyl alcohol were put in the first cup. The second cup contains an aqueous phase such as glycerin, triethanolamine, stearic acid, and distilled water. Then, the two cups were heated at 65°C–75°C. The active substance THPGV-0 is dissolved in tween 80 solution, sonicated, and then mixed in the oil phase. The water phase is transferred into the beaker glass and mixed using a stirrer in warm conditions. The oil phase is added little by little in the aqueous phase while still being mixed using a constant-speed stirrer. When mixture becomes homogeneously and the temperature decresed, the citric acid in water is added. Then DMDM hydantoin and perfume are also added. Stirring is continued (for 15–20 min) and put the finished lotion into the primary packaging [Table 1].
Table 1: THPGV-0 lotion formula

Click here to view


Preparation of THPGV-0 Emulgel

Emulgel formula of THPGV-0 was formulated according to a published method.[7] Emulgel was prepared in three concentrations of THPGV-0: 0.1% as Formula 1, 0.2 as Formula 2, and 0.4% Sebagai Formula 3. THPGV-0 in ethanol was mixed with the oil phase (span 80 in liquid paraffin). The water phase was prepared by dissolving tween 80 in water. Methylparaben and propylparaben as preservatives were dissolved in propylene glycol and then added into water phase. Each phase was heated up to 70°C, mixed in water phase, stirred, and then allowed to reach room temperature until emulsion was formed. Then, gelling agent 1% of Carbopol 940 was dissolved in water phase and stirred, and then, triethanolamine was added. Emulsion formula of HPGV-0, paraffin (liquid), span 80, and tween 80 was mixed into Carbopol 940 water phase [Table 2].
Table 2: THPGV-0 emulgel formula

Click here to view


Acute dermal irritation test

Animal and sample preparation

This test used healthy New Zealand albino rabbits (white hair skin, red eyes) weighed ±2 kg to identify the toxic effects that may arise after sample exposure. Rabbits were collected from animal farm, Trimulyo, Jetis, Bantul. This evaluation has done by shaving the hair of the rabbits and then applying sample on the rabbits' back that has been shaved, so the sample comes in direct contact with the skin of the test animal (rabbits). The irritation response is measured using erythema and edema response parameters which can be observed on the skin for 1, 24, 48, and 72 h after application. Erythema and edema responses are assessed by score, based on severity.[8]

Ethics

The certified number of ethical clearance for this research is 00060/04/LPPT/XII/2019.

Animal handling protocol for rabbit

Rabbit is very susceptible to lumbar spinal luxation which can cause paralysis. Picking and lifting a rabbit is by grasping the loose skin over the shoulder with one hand and the other hand gasping the loose skin along the back or supporting its abdomen. Rabbit should never be lifted by the ears.

Determination of acute dermal irritation responses to THPGV-0 lotion formula

The responses were recorded in 1, 24, 48, and 72 h after exposure.

PII can be determined based on the Indonesian Food and Drug Administration acute dermal irritation toxicity test[9] by applying this formula shown below:



Annotation:

  • A is total erythema and edema score of all sample observation at 1, 24, 48, and 72 h divided by the number of observations
  • B is total erythema and edema score of all control observation at 1, 24, 48, and 72 h divided by number of observations
  • C is number of animals.


Annotation:

  1. Head
  2. Exposure area of lotion 0.1% THPGV-0
  3. Exposure area of lotion 0.2% THPGV-0
  4. Exposure area of lotion 0.4% THPGV-0
  5. Without exposure (control)
  6. Exposure area for base
  7. Tail.


PII value is then categorized according to [Table 3].
Table 3: Primary Irritation Index category

Click here to view


The erythema and edema's responses were observed and summarized then determined according to [Table 4].
Table 4: Reaction assessment guideline

Click here to view



  Results Top


Formulation and physical properties of tetrahydropentagamavunon-0 lotion and emulgel

This preparation was conducted based on Amalia's optimized formula.[6] The optimized formula modified its THPGV-0 concentration to 0.1%, 0.2%, and 0.4% and added with citric acid to adjust pH value, which shows in [Table 5].
Table 5: Physical Properties

Click here to view


Assessment of acute dermal irritation response of tetrahydropentagamavunon-0 lotion and emulgel

Rabbits were prepared by shaving its back and applied a 0.5 g sample for 4 h in each marked area. Exposure is conducted for 4 h because the sample is suspected not to be irritating/corrosive.[9] The sample sites are applied bases, lotion/emulgel THPGV-0 0.1%, lotion/emulgel THPGV-0 0.2%, and lotion/emulgel THPGV-0 0.4%, and the area without treatment was also prepared as a control for irritating effects. The application area is shown in [Figure 2]. Observations were made at 1, 24, 48, and 72 h after exposure, as well as monitoring the reversibility effects for 2 weeks.
Figure 2: Application area

Click here to view


Body weight record of rabbit

Based on paired t-test, analysis shows a significant value >0.05 which means that rabbit weight before and after are not significantly different.


  Discussion Top


Lotion and emulgel of THPGV-0 in this study were formed in white color, semi-solid, homogeneous, and with an Aloe vera odor (from its perfume). Physical property tests to both formulas were then conducted. The pH value measurements are made using universal pH paper and produce a value of 6 for all preparations. This shows the degree of acidity of THPGV-0 lotion corresponding with facial skin pH, which is between 4.5–6.5.[10] Preparations which have a very low pH value can irritate, while too high pH value may cause dry skin.[11]

Measurement of adhesion test showed that the average adhesion time of THPGV-0 lotion base is 1.47 s, lotion with 0.1% THPGV-0 is 1.123 s, with 0.2% THPGV-0 is 0.953 s, and lotion with 0.4% THPGV-0 is 1.123 s. The longest adhesion is the base formula, while the lowest is a lotion with 0.2% THPGV-0 form. A good lotion's adhesion should be more than 4 s, so adhesion of all lotions which has been made in this research felt to be less long to stick on the skin surface.[12] The average adhesion time of THPGV-0 emulgel base is 3 s, lotion with 0.1% THPGV-0 is 1.9 s, with 0.2% THPGV-0 is 3.7 s, and lotion with 0.4% THPGV-0 is 2.1 s.

The average spreadability of lotion base is 52.80 cm2, while lotions which contain THPGV-0 0.1%, 0.2%, and 0.4% THPGV-0, respectively, 66.23 cm2, 60.32 cm2, and 56.30 cm2. These results indicate that the spreadability decreased while its concentration increased. This is related to the increased amount of active substances, so it becomes thicker and also the distribution becomes narrower. Low spreadability value requires more pressure to apply, so the spreadability of lotion obtained is quite good because the average is above 25 cm2.[13] The average spreadability of emulgel base is 17.0 cm2, while emulgel contains THPGV-0 0.1%, 0.2%, and 0.4% respectively are 20.6 cm2, 19.5 cm2, and 17.7 cm2 [Table 5].

The irritation effect is determined based on the erythema and edema score [Table 4] caused by assessing the PII and then categorized according to the level of irritation based on ISO 10993-10,2002.[13] The negative control has 0 value because it did not experience any changes or treatment. The irritation value of lotions which contain THPGV 0 0.1% and 0.2% produce the same irritation response due to appearance of erythema in rabbits 1, at hour 1 after exposure. But, the irritation value of lotions which contain THPGV 0 0.1% and 0.2% are lower than the irritation response value of lotion contained THPGV 0 0.4% which shows erythema in rabbit 1 at hour-1 and hour-24 after exposure. Besides that, the lotion base actually has the highest PII value among all samples. This may possible because of the presence of DMDM preservatives with sufficient concentration (0.4%), without the antioxidant content in the base [Table 5].

PII values occurred due to erythema, and not because of edema. In addition, the skin condition of the rabbits themselves can also affect the results because most erythema occurred in rabbit 1 and rarely occurred in the other rabbits. The results obtained indicate a very small IIP value (even close to 0), so the result is included in the negligible category [Table 6]. All erythema that occurs in rabbit skin has been reversed to its normal condition in <72 h after exposure. Also the literature study conducted by Basketter et al.[14] states that testing the irritating effect on rabbits can be overpredicted. This research result can be said that lotion and emulgel with 0.1%, 0.2%, and 0.4% THPGV-0 are safe to use, although still must be careful to use, especially on sensitive skin. Before and after exposure, the test animals are weighed and their weights are recorded. The increased weight in rabbit 1 which is 0.2 kg is the highest compared to rabbit 2 (0.15 kg) and rabbit 3 (0.1 kg). Rabbit 1 also has the most erythema animals had edema, so the weight increase happens because of rabbits eat and drink a lot during treatment, not due to an edema appearance [Table 7].
Table 6: Primary Irritation Index result

Click here to view
Table 7: Rabbit weight

Click here to view



  Conclusion Top


The study showed that lotion and emulgel formula of THPGV-0 are safe to use in cosmetics application. There is no irritation effect considered hazardous to skin during the study.

Acknowledgment

We would like to thank RTA Gadjah Mada University 2020 for funding.

Financial support and sponsorship

This research was supported by RISTEKBRIN-DIKTI, Indonesia.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Elmarzugi NA, Keleb EI, Mohamed AT, Issa YS, Hamza AM, Layla AA, et al. The relation between sunscreen and skin pathochanges mini review. Int J Pharm Sci Invent 2013;2:43-52.  Back to cited text no. 1
    
2.
Dominica D, Handayani D. Formulation and Evaluation of Logan Leaf Extract (Dimocarpus Longan) Lotion as an Antioxidant. Jurnal Farmasi dan Ilmu Kefarmasian Indonesia 2019;6:1-7.  Back to cited text no. 2
    
3.
Beevers CS, Huang S. Pharmacological and clinical properties of curcumin. Botanics 2011;11:5-18.  Back to cited text no. 3
    
4.
Ritmaleni, Simbara A. Synthesis of tetrahydro pentagamavunon-0. Majalah Farm Indonesia 2010;21:100-5.  Back to cited text no. 4
    
5.
Simbara A. Synthesis and Antioxidant Antivity Test of Senyawa Tetrahydroxypentagamavunon-0 (THPGV-0). Thesis. Yogyakarta: Postgradueate Program Faculty of Pharmacy, Universitas Gadjah Mada; 2009.  Back to cited text no. 5
    
6.
Amalia R. Formula Optimation of THPGV-0 Lotion by Combination of Steric acid and Trietanolamine through Simplex Lattice Design Method. Final Project. Yogyakarta: Fakultas Farmasi, Universitas Gadjah Mada; 2019.  Back to cited text no. 6
    
7.
Kumar V, Mahant S, Rao R, Nanda S. Emulgel based topical delivery system for loratadine. ADMET DPMK 2014;2:254-71.  Back to cited text no. 7
    
8.
Fitriana AY, Wahyuningrum R, Sudarso. Repelan Power and Irritation Test of Lotion Formula of Ethanolic Extract of Sirih Leaf (Piper betle Linn) with Variation of Lanolin Base to Aedes Aegypti Mosquito. Pharmacy 2012;9:39-57.  Back to cited text no. 8
    
9.
BPOM RI. The Regulation of Indonesian Food and Drug Administration, No. 7 year 2014, Guidelines for Non-clinic In Vivo Toxicity Testing. Jakarta: BPOM RI; 2014. p. 65-70.  Back to cited text no. 9
    
10.
Yulianti E, Adelsa A, Putri A. The determination of SPF (Sun Protection Factor) Value of 70% ethanol extract Curcuma mangga and 70% ethanol extract Curcuma mangga Cream In vitro using Spektrophotometry method. Majalah Kesehatan FKUB 2015;2:41-50.  Back to cited text no. 10
    
11.
Mappa T, Edi JH, Kojong M. Sasaladahan Leaf Extract Gel Formulation (Peperomia pellucida L.) and its Effectiveness Test on Skin Burn in Rabbit. J Pharm Sci 2013;2:49-56.  Back to cited text no. 11
    
12.
Kusumorini N. Formula Optimation and In vitro Activity Test of Lotion W/O Ethanolic Extract of Temu Mangga (Curcuma Mangga Val.) as Sun Protector by combining Cetyl Alcohol, Glycerin, and Cera Alba. Final Project. Yogyakarta: Faculty of Pharmacy, Universitas Gadjah Mada; 2016.  Back to cited text no. 12
    
13.
International Standard ISO 10993-10. In: Biological Evaluation of Medical Devices. 2nd ed., Part 10 – Tests for Irritation and Delayed-Type Hypersensitivity. Switzerland: Genève 20: International Organization for Standardization; 2002.  Back to cited text no. 13
    
14.
Basketter D, Jirova D, Kandavora H. Review of skin irritation/ corrotion hazards on the basis of human data: A regulatory perspective. Interdiscip Toxicol 2012;5:98-104.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
   Abstract
  Introduction
   Materials and Me...
  Results
  Discussion
  Conclusion
   References
   Article Figures
   Article Tables

 Article Access Statistics
    Viewed462    
    Printed6    
    Emailed0    
    PDF Downloaded92    
    Comments [Add]    

Recommend this journal