1. INTRODUCTION:

Herbal medicines as the major remedy in traditional system of medicine have been used in medical practices since antiquity¹. Now a days, traditional medicine is revealed by an extensive activity of research on different plant species², Moreover, only a limited number of medicinal plants have received detailed scientific scrutiny thereby prompting the World Health Organization to recommend that this area be comprehensively investigated³

Skin, the largest human organ is the first line of defense for external exposure⁴

Creams have been used as topical preparations since ancient times because of facility application and removal of the skin. And due to their multiple uses as: cosmetic or therapeutic purposes, protect the skin from bacteria and fungal infections, as well as treat burns and wounds that the skin is exposed to⁵, also Creams have the ability to contain plant extracts⁶. It contains many active compounds, and plant flavonoids are among the most important of these compounds because they are a great source of antioxidants, and they are effective for minimizing the effects of aging, as they destroy free phosphate oxide radicals, and reduce the harmful effects of oxidative processes on organic molecules such as carbohydrates, fats, DNA and proteins in biological systems through a wide range of substances found in flavonoids, such as flavon and catechins, which is important sources of antioxidants⁷.

Among natural phenolics, the flavonoid forms the largest group and more than 2,000 flavonoids have been reported among woody and non-woody plants. The occurrence of free aglycones, however, appears to be mostly correlated with the existence of secretory structures. The flavonoids have more importance in providing strength and resistance to the plant against various diseases but also exhibit various biological and pharmacological activities⁸.

The word flavonoid is a Latin derivative of flavus which means "yellow" due to the color of these compounds in nature. Flavonoids are phenolic compounds that are commonly found in almost all types of plants. Referred to as "phytonutrients", because it imparts color and flavor to many fruits and vegetables and protects their enzymes and essential vitamins, making them suitable for consumption. Recently, about 6,500 types of flavonoids have been investigated so far⁹.

As plants produce a lot of antioxidants to control the oxidative stress caused by sun beams and oxygen, they can represent a source of new compounds with antioxidant activity.¹⁰

Plant kingdom consists of number of medicinal plants¹¹ Eggplant is an important species of various plants that contain antioxidant flavonoids¹², and it belongs to the genus Solanum, the most widespread genus all over the world, and the family that contains this genus is Solanaceae.¹³

Eggplant has several varieties: black, dark purple, white, or yellow, including elongated and spherical shape, and aubergine is the most common name for the plant¹³, and in Syria there are multiple varieties, including: (Black Eggplant Rectangle (Baladi), Dabouli (Homs), Tadfi ( Hamwi), this study focused on assaying the flavonoids present in these three varieties of eggplant calyxes extracts, then measuring the ability of plant extracts antioxidant by measuring their ability to remove free radicals of the fixed root DPPH, and incorporating them into three soft pharmaceutical forms to study The main components that have been released from it in vitro using a Franz cell to determine the release pattern of each formulation prepared in this study.

2. Aim of study:

Preparation of various semi solid pharmaceutical forms containing extracts of eggplant calyxes (ethanolic extract 70%, aqueous extract, methanolic extract) after assaying flavonoids and antioxidants, (the calyxes were for three types of eggplant cultivated in Syria), then studying the kinetics of the active substances being released from them in vitro using Franz cell, and determining the release model for each of the three formulas, In order to compare the formulas, select the optimal form of the plant extract and apply it topically.

3. MATERIALS AND METHODS:

3-1- Materials: Eggplant calyxes collected from the local market. They have been dried and kept in sealed containers, away from light and moisture (humidity less than 30%).- Distilled water-Ethanol 99.5% from Eurolab, UK- Methanol 99.8% from Sigma, Aldrich, USA.-Aluminum chlorine from Panreac, Spain.- (Dpph) 2,2-diphenyl 1-1-picrylhydrazylSanta cruz Biotechnology, united state of America-White petroleum jelly, paraffin oil, Stearic acid, cetyl alcohol, tri-ethanolamine, glycerin, Carbopol 940.

3-2- METHODS OF STUDY:

3-2-1- Preparation of plant samples:

The calyxes were removed from different types of eggplant (black rectangle, dabouli, tadfi), dried, , at a temperature of 23-25°C for a month. after that the powder was kept in airtight bottles, away from light and at the temperature of the laboratory until use.

3.2.2- Extraction and preparation of eggplant calyxes extracts:

Three types of extracts were prepared for each of the three types of eggplant (ethanolic 70%, methanolic, and aqueous).

1. Ethanolic extract:

The ethanolic extract was prepared using a Soxhlet device, where 30g of eggplant cones were extracted with 300 ml of ethanol 90% for four hours, after which the resulting extracts were collected and dried using a rotary evaporator¹⁴.

2. Methanol extract:

The methanolic extract was prepared by a Soxhlet device, where 30g of the plant sample was extracted with 250ml of methanol 99% for four hours, after which the resulting extract was collected and dried using a rotary evaporator¹⁴.

3. Aqueous extract:

30g of calyxes powder is placed in an extraction flask with 200ml of distilled water, and heated under an upward cooler for an hour and a half, then the resulting extract is filtered, and evaporated using a rotary evaporator until dry¹⁵.

3-2-3- Determination of the antioxidant capacity - the (DPPH) test of eggplant calyxes extracts: (2,2-diphenyl-1-picryl hydrazyl)

Principle: The antioxidant ability of plant extracts was measured by measuring their ability to remove free radicals of the DPPH fixed root according to the method reported by Molyneux¹⁶

The ability to inhibit oxidative stress is assessed by standard IC50: the concentration of the extract that achieves an inhibition of free radicals of 50% and is calculated graphically from the concentration series graph of the extract. Low values of IC50 indicate the extract's high ability to inhibit the free radicals of DPPH ¹⁷

Preparation of extract:¹⁸

A series of concentrations were prepared for each of the extracts: ethanol, aqueous, and methanol at concentrations of 200-400-800-1600 mcg/ml. Then 100 μl of extracts were placed in each tube with 2.5 ml of DPPH solution (0.0024g in 50ml of ethanol) after Therefore, the tubes are placed in the dark at room temperature for 30 minutes. Then the decrease in the violet color intensity of the free radicals of DPPH is measured at a wavelength of 517nm using a spectrophotometer. The measurement is repeated three times and the average is taken

% DPPH = (A_blank – A_sample / A_blank) x 100

A_blank: is the clear absorption that contains all the reagents except for the tested extract.

A _sample: is the absorption of the tube containing the tested extract in addition to the reagent.

The graph of each concentration series is drawn and the concentration of the extract that leads to the inhibition of free radicals of DPPH is calculated by 50% (IC50).- The measurement is repeated three times and the average is taken.

3.2.4 Assaying the flavonoids content of eggplant calyxes extracts:

Determination of total flavonoid content is performed according to the procedure described in References^19,20 Mix 1 ml of the plant extract with 3 ml of ethanol in a test tube, then add 200 μl of 10% (3% AlCl), and 200 μl of Potassium acetate solution Then 5.6 mL distilled water is added to the solution and mixed. Leave the mixture at room temperature for 40 minutes, The absorbance is measured against the control solution at 440 nm. A titration curve for solutions of quercetin in ethanol (70%) was prepared where the equation was: Y = 0.008X + 0.0096 , R² = 0.9986 (samples were analyzed three times), and the results are expressed as mg of quercetin equivalents per gram of dry calyxes.

3-2-5- Preparation of pharmaceutical forms:

Table 1: Formulas of prepared topical pharmaceutical forms.

No.	Substance	Gel formula(1)	Aqoueos formula(2)	Cream o/w formula(3)
1	Carbopol	0.3%	%0	0%
2	Cetyl alcohol	%0	%0	10%
3	Paraffin oil	%0	%0	5%
4	Glycerin	10.5%	%0	10%
5	Tween 60%	%0	%0	2%
6	Preservative substance	0.15%	0.15%	0.15%
7	Sweet almond oil	%0	%0	15%
8	Vaseline	%0	%0	5%
9	Aqueous abstract	88%	40%	40%
10	Acid wax	%0	%0	10.5%
11	Polyethylene glycol 200	%0	43%	%0
12	Polyethylene glycol 4000	%0	17%	%0
13	Tri ethanol Amine	%1	%0	2.5%
14	EDTA	0.025	0%	0%

Preparation methods:

1. preparation of the gel(formula 1): The gel was prepared by mixing Carbopol 940 with glycerin, then adding distilled water to which the plant extract and Triethanolamine were added, and the pH was adjusted to 6.

2. Preparation of hydrophilic polyethylene glycol cream (formula 2):Polyethylene glycol 4000 was dissolved on a water bath, then added polyethylene glycol 200, plant extracts that is dissolved in distilled water, and sodium benzoate with constant stirring to obtain the required ointment.

3. Preparation of the cream O / W (formula 3):Prepared by heating Stearic acid and the rest of the ingredients on water bath to 60-70 C° until the Stearic acid is completely melted, then add the aqueous phase to which the plant extract is added and mixed with glycerin and tween (heating to 75 ° C), and gradually add tri ethanolamine after being heated to 50 degrees and stirring until cold.

3-2-6-Study of the patterns of release of the medicinal substance from the cream in the glass ^21,22

The study of drug release in vitro is considered one of the most important procedures for drug development, and the cumulative quantity curves released from drug are the most commonly used to describe drug release and dissolution.

Several models are used to study the kinetics pattern of drug release from dosage forms, namely:

1- Zero order release model 2- First order release model 3- The pattern of liberation according to Hixson-crowell, 4- Higuchi release pattern 5- Korsmeyer-peppas liberation pattern

The pattern that has a high correlation coefficient value compared to the rest of the patterns is considered the best pattern.

3-2-7-Statistical studies:

Statistical studies were performed on the experimental data using the Prism program and the application of one way ANOVA test of variance followed by Tukey's test to compare the binary cases with each other. The correlation coefficient between the flavonoid content and the antioxidant capacity was also calculated, and the P-value <0.05 was taken to indicate the statistically significant difference.

RESULTS AND DISSECTION:

1. Results of the assay for flavonoids in plant extracts:

Table 2: Flavonoids assay results for the cone extracts of the three eggplant species .

The equivalent gram of quercetin mg/100 g	Extract type	Eggplant type
2.85±35.27^a	aqueous	black, oblong eggplant
1.43±40.81^c	Ethanolic 70%	black, oblong eggplant
2.83±30.09^a	methanolic	Dabolian eggplant
1.6±20.37^b	aqueous
1.22±37.8^a	Ethanolic 70%
1.83±28.8^b	methanolic
2.44±12.20^d	aqueous	eggplant tadpole
1.4±28.94^b	Ethanolic 70%
2.83±22.06^b	methanolic

Similar letters indicate that the statistical differences are not significant, while the different letters indicate that the statistical differences are significant, and the consideration of the value of P <0.05 was relied upon to indicate the statistically significant difference.

By comparing the cones of the three varieties of eggplant cultivated in Syria and after assaying the content of flavonoids: it was found that the ethanolic extract 70% in general had a higher and greater content than the aqueous extract and the methanolic extract, and the ethanolic extract of the rectangular black eggplant showed the highest content among the nine extracts (Three extracts for each type), and as a result, the rectangular black eggplant with its three extracts contained the largest amount of flavonoids, followed by Dabolian eggplant and finally Tadfi eggplant.

Table 3: Average readings of the standard series of quercetin

100

Concentration of quercetin mg /l

0.8

0.42

0.2

0.14

0.1

0.04

Average absorption

Figure 1: Titration curve for the flavonoids assay

2. Results to determine the antioxidant capacity of the eggplant cones extract (DPPH) test:

Table 4: The antioxidant capacity values of extracts prepared from eggplant cones

SD ± IC50 mcg/ml	Extract type	Eggplant type
6.7±278	aqueous	Black, oblong eggplant
8.4±265	Ethanolic 70%
4.9±405	methanolic
4.6±380	aqueous	Dabolian eggplant
2.4±360	Ethanolic 70%
8.2±645	methanolic
6.2±379	aqueous	Eggplant tadpole
6.6±358	Ethanolic 70%
8.8±638	methanolic

DPPH, a relatively stable organic radical has been widely used in the determination of antioxidant activity of single compounds, as well as of different plant extracts²³. Through a comparison between the cones for the three varieties of eggplant cultivated in Syria and after determining the antioxidant capacity - the (DPPH) test for extracts of eggplant cones: it was found that the ethanol extract 70% in general had a higher and greater antioxidant capacity than the aqueous extract and methanolic extract, as well as The ethanolic extract of the rectangular black eggplant showed the best antioxidant capacity out of the nine extracts, while the antioxidant capacity of the Dabolic eggplant was the lowest.

Figure 2: Histogram representing averages of the antioxidant capacity of eggplant cones extracts

Figure 3: Graphical curve of the antioxidant capacity of vitamin C

Vitamin C is used as a standard to calculate the antioxidant capacity of prepared plant extracts.

3. Results of tests on prepared pharmaceutical forms:

3-1- Results of checking the viscosity of the prepared pharmaceutical forms:

This examination was performed to ensure the ease of stretching the prepared pharmaceutical forms at 24 ° C and using a viscometer, Table 5.

Table 5: Viscosity of the prepared pharmaceutical forms.

Viscosity ± SD (Sante Boise)	Type of pharmaceutical form prepared
22.09±2234^a	Gel (formula 1)
23.62±2833^a	aqueous cream (formula 2)
17.962±3244^b	Cream O/ W(formula 3)

Similar letters indicate that the statistical differences are not significant, while the different letters indicate that the statistical differences are significant, and the consideration of the value of P <0.05 was relied on to indicate the statistically significant difference.

The viscosity of the prepared pharmaceutical forms was good and suitable according to the form in which they were prepared, as the viscosity of the gel was less than other pharmaceutical forms, and the highest viscosity value was for the cream O/ W, and this corresponds to the nature of the prepared form.

3.2- Results of pH measurement of prepared pharmaceutical forms:

Table 6 shows the pH measurement results for the prepared pharmaceutical forms.

Table 6: The pH value of the prepared pharmaceutical forms.

pH	Type of pharmaceutical form prepared
6.1 ± 0.40^b	Gel (formula 1)
6.3 ± 0.33^b	aqueous cream (formula 2)
5.8 ± 0.22^b	Cream g / m (formula 3)

In formulated pharmaceutical forms, pH values are acceptable and close to the pH of skin.

3-3- Results of a kinetics study of the release of active substances in vitro for the prepared pharmaceutical forms:

After studying the spread of the extract components from the three prepared formulas, we studied the patterns of propagation kinetics according to the decay data by Microsoft Excel 2010, and the values of (R2) were calculated for the correlation coefficient for the following patterns:Zero order, First order, Higuchi order, Hixon order, Korsmeyer - Peppas and the results are illustrated in Table (7) and Table (8).

Table 8: The kinetic data of the prevalence of etanolate black eggplant extract from formulations prepared according to the Kurs Meyer Bebas pattern *

Formula	Korsmeyer –Peppas
Formula	K_p(Q%.min^-1)	n	R²
Gel	99.82	0.29	0.95
Aqueous cream	54.43	0.92	0.96
Cream	104.6	0.21	0.97

* Note: The symbols K0, K1, KH, KHC, Kp are the release constants for the Zero ordar, First order, Higuchi, Hixon-crrowell patterns.

Kors meyer –Peppas, respectively. n: the exponent of the diffusion, R2 the correlation coefficient.

The gel formula released about 70% of the extract after four hours, while the aqueous ointment released 60% of the extract compounds at a slower release rate than the gel, and for the cream O/ W the amount of extract released was 92% after two hours.Figure (4) shows the percentage released from the eggplant cones extract with time from the three prepared formulas.

Figure 4: The percentage released from the extract of cones over time for the three prepared formulas

The results of the study that released the extract of cones from the previous three formulas showed that the release of the gel corresponds to the Kurs Meyer-pepas pattern (As the correlation coefficient: Kors meyer –Peppas) , Note that the value of the exponential coefficient of the equation expressing the Kors Meyer - peppas kinetics in gel = 0.29 i.e. less than 0.45 R2 = 0.95

This indicates that liberation follows Fick's first law, that is, the diffusion mechanism is the process that controls the release of the extract from the gel, while the release from the aqueous cream and cream o/w corresponds to the pattern of rank 0 because it achieved the highest value of the correlation coefficient R ^ 2 =, 0.980.99 The arrangement, which makes the diffusion of the extract from these formulas almost linear and this is in agreement that the diffusion across the membrane often corresponds to the liberation of the class zero, and this pattern corresponds to the long-acting skin forms where the drug release is constant during the unit of time, but the liberation from the cream remains better because Free up the amount of active ingredients in a greater proportion and in a relatively shorter time.

DISCUSSION AND CONCLUSIONS:

The viscosity of the prepared pharmaceutical forms was good and appropriate according to the form in which they were prepared. Also, the pH values are acceptable in the prepared pharmaceutical forms and are close to the pH value of the skin,.the diffusion study of the active substances showed that the release from the gel corresponds to the KorsMeyer-peppas pattern.The liberation followed Fick's first law, meaning that the diffusion mechanism is the process that controls the release of the extract from the gel, and this formula is good in the case of prolonged application, except that the amount released after six hours was not high at 70% and began to decrease after this period, and this is consistent with some properties of Carbopol in terms of its incompatibility with bacteriostatic agents, strong acids and phenols²⁴.

The release from aqueous cream (polyethylene glycol) and cream O/ W was consistent with the pattern of rank zero because it achieved the highest value of the correlation coefficient R ^ 2 = 0.980.99, respectively, which makes the release of active substances from these formulas almost linearly and this The pattern corresponds to long-acting skin forms where the drug release is constant during the unit of time, but the release from the cream in O/W remains better because it released a quantity of the active substances after two hours 92%, and the released percentage remained in an acceptable percentage after six hours, and this is what we did not notice in the release From the aqueous cream, the rate of release was very slow, and after six hours it gave its highest value of 65%, then it began to decrease, and this indicates that a part of the active substances was not released or destroyed, meaning that there was a dissonance between the excipients of the formula and the active substances in Formula, and this dissonance is due to the possibility of the influence of some properties of polyethylene glycol ²⁵, which is the decrease in the antimicrobial activity of some active medicinal substances, meaning that the result is compatible with these properties. There is a part of the concentration of the active substances that was lost in this formula either because of the incompatibilities on one hand or due to the oxidation of the active substances in it, especially as they are present in a aqueous medium.

Also, the current research results indicate that the eggplant cones contain flavonoids, but in different proportions according to the type of eggplant and according to the solvent used in the extraction, and these ratios are very important and useful through their presence in the prepared pharmaceutical forms because they have effective anti-fungal, anti-viral and anti-bacterial effects in addition to their Important role in repairing skin cells and reducing the signs of aging ²⁶.Through the comparison between the flavonoids content assay of cones extracts: it was found that the ethanolic extract 70% in general had a higher and greater content than the aqueous extract and the methanolic extract for each of the three varieties.

As for the comparison between the varieties, the rectangular black eggplant extracts showed a greater Flavonoids content, followed by Dabolian eggplant and finally Tadfi eggplant, with the distinction of the ethanolic extract 70% having the highest flavonoids percentage.That is, the rectangular black eggplant cones are the best in terms of use for medicinal benefits because they contain the highest flavonoids percentage, especially the ethanol extract 70%, After determining the antioxidant capacity by (DPPH) test of eggplant cones extracts: it was found that the ethanolic extract had a higher and greater antioxidant capacity than the aqueous extract and the methanolic extract of the three varieties of eggplant, and the ethanolic extract of the black eggplant showed the best antioxidant capacity among the nine extracts, As for the lowest antioxidant capacity, it was for the methanolic extract of Daboli eggplant, and this is consistent with the results of the flavonoids assay for the three cultivar cones where the correlation coefficient R2 was compared to the total flavonoids content for the three aqueous extracts, ethanolic, 70% and methanolic, with its antioxidant ability by DPPH Results (correlation coefficient -0.86 when O.OO3 is significant) and this value is significant because it is within the limits (-1, +1).

This indicates a strong to very strong negative association between the flavonoid content and the value of antioxidant capacity, indicating that the antioxidant capacity is mainly due to its flavonoids content.

CONCLUSION:

The cream O / W gave the best flavonoids release (the active substances contained in the ethanolic extract of the rectangular black eggplant cones), and the release was from class zero as it achieved the highest feature of the correlation coefficient R ^ 2 = 0.99, which makes the spread of the extract from this formula almost linear and this pattern corresponds to long-acting skin forms where the drug release is constant over time, and therefore the use of this formula will be better than using the gel formula or the polyethylene glycol cream formula In terms of better effect and effectiveness.

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Received on 24.12.2020 Modified on 08.01.2021

Research J. Pharm. and Tech 2021; 14(10):5411-5417.

DOI: 10.52711/0974-360X.2021.00943

formula	Zero order		First order		Higuchi		Hixon-crrowell
formula	K_0(Q%.min^-1)	R²	K_1(Q%.min^-1)	R²	K_H(Q%.min^-1)	R²	K_HC(Q%.min^-1)	R²
gel	2.2	0.76	0.012	0.60	11.3	0.94	5.8	0.88
Aqueous cream	0.34	0.98	0.08	0.69	3.6	0.92	5.1	0.95
cream	1.52	0.99	0.7	0.98	14.2	0.98	0.81	0.82