Design and Evaluation of Bigels Containing Flurbiprofen

 

Narayana Charyulu R*, Arjun Muaralidharan, Sandeep DS

Department of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University) Paneer, Deralakatte, Mangalore, Karnataka, India.

 

ABSTRACT:

The present study was aimed of design and evaluation of bigel containing flurbiprofen. Bigels are interesting innovative two phase systems that have been recently proposed as structured system for delivery of active ingredients. They possess the advantages of both hydrogel and organogel. Organogel was prepared by pluronic lecithin and hydrogel was prepared using HPMC. Bigels were prepared by mixing of organogel and hydrogel in appropriate ratio. Organogel and hydrogel was evaluated for pH, viscosity, extrudability and spreadabilty. Formulation F3 from organogel and formulation H3 from hydrogel was selected as optimized formulations and was used for the preparation of bigel. The prepared bigel was evaluated for pH, viscosity, extrudability, spread ability, in vitro drug release studies, ex vivo permeation studies, stability studies and skin irritation test. All formulations of bigel showed extended release out of which formulation B3 was selected as the optimized formulation on the basis of evaluation parameters. In vitro permeation release was found to be 89.99% at the end of 8 hrs. The release kinetics of flurbiprofen bigel followed Higuchi model. The bigels were found to be stable and skin irritation studies on Wistar rats showed that the prepared bigels were compatible. Based on the encouraging results bigels containing flurbiprofen can be used as extended release system.

 

 

 

INTRODUCTION:

Topical drug delivery is one of the commonly used drug delivery due to high patient compliance. It has got good patient compliance when compared to other conventional method due to the following reason such as pain less application, easiness of application, does not required trained medical staff for administration, painless application, helps in avoiding first pass metabolism, can be applied to all types of patient regardless of age etc. Such merits made this particular route of administration one of the best in medical field. The formulation is applied over the skin. Skin is one of the largest organs in the body. Skin has several functions in the body which includes thermoregulation, protection from microbes, physical stress and even from harmful radiation such as UV rays from sunlight etc. The skin has different layers, broadly divided into epidermis and dermis region.

 

The epidermis is the outer most portion and it’s not vascularised and it is formed of simple epithelial tissues.

 

Here the cells undergo thickening process which causes the formation of hardened cells, this process is called as keratinisation.  These cells will get accumulated and thus an area is formed called as stratum corneum. The stratum corneum acts as the rate limiting factor for the transport of drug from the site of application to the systemic circulation. The various other factors that affect the topical drug delivery are physiological factors which are moisture, skin texture, pH, age, sex etc. The other various factors that affect topical drug delivery are formulation factors and the factors which affect absorption such are particle size, chemical nature of drug etc.

 

The second major layer in the skin is called as dermis. It is formed of collagen fibers and elastic fibers   are present after epidermis. This dermis portion contains high amount of blood supply providing nourishment for tissues.¹

All the recent developments in the pharmaceutical field are focused on topical drug delivery system. The different type of topical preparation commonly used topical preparation are gels, creams, paste, lotion, ointment, dusting powder etc. Gels are 3D networked systems which have more application in pharmaceutical field. The commonly used gels are hydrogel and organogel. Hydrogel are water based gels which are transparent and is made by using polymers such as HPMC, carbopol etc. They have good water content present in their structure providing hydration of stratum corneum. Organogels are formed using organic solvent and polymers such as pluronic.²

 

Emphasizing on bigel, bigels are the gel formed by the combination of organogel and hydrogel in different proportion and ratio. The hydrogel present in the bigel helps in proper hydration of stratum corneum, and the organogel present in the bigel helps in increased penetration. The drug used in the formulation is flurbiprofen, which is a classical NSAID. The administration of flurbiprofen orally for pain management caused several problems when used continuously, such as gastric irritation, ulceration, bleeding etc.⁴ so it was necessary for the drug to be given through different route of administration using appropriate vehicle, which was done by formulating the drug into bigel. As the bigel provides increased penetration and slow release which will help in effective pain management. The bigel also provides good contact period and area and easy washability, also the demerits of the individual gels such as hydrogel and organogel is masked by the bigel and the combined advantage of both the individual gel was provided.³

 

MATERIALS AND METHODS:

Flurbiprofen was received as a gift sample from FDC limited Mumbai. Pluronic F127 was from Sigma Aldrich chemicals Mumbai. HPMC, Soya lecithin, isopropyl palmitate, sorbic acid were from HiMedia laboratories, Mumbai. Potassium sorbate, Ethanol were from Loba chemie, Mumbai. All the materials were of analytical grades.

 

Method of preparation of Bigel:

The preparation of bigel involves three steps as they consist of two individual gels in making, the steps are

·        Preparation of organogel

·        Preparation of hydrogel

·        Mixing of hydrogel and organogel to form bigel.

 

Preparation of pluronic lecithin organogel:

The organogel involves two phase, one is the aqueous phase and the other is the oil phase.

 

Preparation of aqueous phase:

Required amount of pluronic F127 was added to cold water and was allowed to soak for 1 hr under cold temperature. Then the sample was taken and continuously stirred and this mixture was stored in refrigerator for 24 hrs to obtain clear solution. Potassium sorbate in required quantity was added as a preservative.⁴

 

Preparation of oil phase:

Required amount of soya lecithin was weighed and taken in a beaker and dissolved in required quantity of isopropyl palmitate with continuous stirring. Sorbic acid was added as a preservative and this solution was kept it for 24 hrs at room temperature.⁵

 

Preparation of organogel by mixing of oil phase with aqueous phase:

The oil phase was then added in little amount to the aqueous phase with continuous stirring until whole the volume was added. The formulae for preparation of pluronic lecithin organogel are given in the Table 1.

 

Table 1: Formulation of pluronic lecithin organogel

 

Preparation of hydrogel

HPMC was the polymer used for the preparation of hydrogel. Required quantity of HPMC was added with distilled water and allowed for soaking.

 

Table 2: Formulae for the preparation of hydrogel

Contents	H1	H2	H3	H4	H5
HPMC(gm)	1	1.5	2	2.5	3
Distilled water(ml)	25	25	25	25	25

 

After 1 hr the dispersion was mixed continuously in order to obtain a uniform gel. The formula for the preparation of hydrogel is given in the Table 2.

 

Characterization for organogel and hydrogel

Physical appearance

Physical appearance of the formulated gels was evaluated by visual inspection. Parameters such as consistency, colour and transparency was analysed.^{6, 7}

 

pH:

pH of all the formulations was determined by placing an electrode of the digital pH meter on surface of the prepared gel and then to equilibrate for 1 min and reading was taken.⁸

 

Viscosity

Viscosity of the formulated gels was determined by using Brookfield viscometer (Brookfield DV-II+ Pro). The samples to be analyzed were taken in a 25 ml beaker. The viscosity of the samples was measured by using spindle number 96. The test was repeated 6 times for each sample and the average value was calculated. The test was conducted at room temperature and angular velocity was kept at 10 rpm.⁹

 

Extrudability test:

Extrudability test of all the prepared formulations was done by using monsanto hardness tester. The weighed 15 gm of the gel was inserted in the collapsible aluminum tube and the end of the tube was crimped. Then this aluminum tube was placed in the monasanto tester and plunger of the tester was adjusted to hold the tube properly. 1 kg/cm² pressure was applied to it for 30 sec. The amount of formulation extruded out was weighed.¹⁰

 

Spreadability:

Spreadability of the formulated gels was measured by using two glass plates and a weight to be kept. A circle of 1 cm was premarked on the glass plate into which 0.5 gm of gel was placed. On the top of this glass plate a similar glass plate was placed. The 1000 g weight was kept on the upper glass plate for 5 min. The increased diameter caused by the spreading of the gel is measured.¹¹

 

Mixing of hydrogel and organogel to form bigel:

It is the most important step in the formation of bigel. The optimised formulation from organogel and hydrogel was taken for the preparation of bigel. Required amount of the optimised hydrogel and organogel were taken and then mixed according to the ratio required. The process was continued until a creamy white colour uniform gel was obtained. Then the required amount of the drug was dissolved in very less amount of ethanol, this mixture was then mixed thoroughly for uniform dispersion. The formulations for the preparation of bigel are given in the Table 3.

 

Table 3: Formulation of flurbiprofen bigel

Contents	B1	B2	B3	B4	B5
Drug(%)	5	5	5	5	5
Hydrogel(%)	25	35	45	55	65
Organogel(%)	70	60	50	40	30

Characterization of bigel Physical appearance:

 

 

Physical appearance of the formulated gels was evaluated by visual inspection. Parameters such as consistency colour and transparency was analyzed.

 

pH:

pH of all the formulations was determined by placing an electrode of the digital pH meter on surface of the prepared gel and then to equilibrate for 1 minute and reading was taken.

 

Viscosity:

Viscosity of the formulated gels was determined by using Brookfield viscometer (Brookfield DV-II+ Pro). The samples to be analyzed were taken in a 25 ml beaker. The viscosity of the samples was measured by using spindle number 96. The test was conducted at room temperature and angular velocity was kept at 10 rpm.¹²

 

Gel-sol transition temperature:

Gel-sol transition temperature of all gels was determined by incubating the formulated gels in a constant temperature bath ranging from 25 ⁰C – 60 ⁰C. Within a 5 min interval the temperature of the water bath was increased with and increment of 5 ⁰C. The temperature was noted at which the gel started to flow when the beaker was inverted.¹³

 

Spread ability:

Spread ability of the formulated gels was measured by introduction of 0.5gm formulated gel inside a circle of 1cm diameter premarked on a glass plat. On the top of this glass plate a similar glass plate was placed. The 1000 g weight was kept on the upper glass plate for 5 min. The increased diameter caused by the spreading of the gel was measured.

 

Extrudability test:

Extrudability test of all the prepared formulations was done by using Monsanto hardness tester. The weighed 15 gm of the gel was inserted in the collapsible aluminum tube and the end of the tube was crimped. Then this aluminum tube was placed in the monsanto tester and plunger of the tester was adjusted to hold the tube properly. 1 kg/cm² pressure was applied to it for 30 sec. The amount of formulation extruded out was weighed and the procedure was repeated.

 

In vitro drug release:

In vitro drug release studies were conducted in modified in vitro permeation apparatus using a cellophane membrane as shown in Fig. Phosphate buffer pH 7.4 is the dissolution medium used in the study. Cellophane membrane obtained for the study was soaked in phosphate buffer pH 7.4 over night. Bigel was accurately weighed and placed over the center portion of the cellophane membrane and this cellophane membrane was tied to one of the opening end of the specially designed hollow glass cylinder. The glass cylinder was then attached to the metallic shaft and then dipped in a way that the membrane just touches the surface of 50 ml phosphate buffer pH 7.4 kept in the beaker. The dissolution medium was kept at a temperature of 37+ 0.5 ^ºC and stirred throughout the studies using a magnetic stirrer at 50 rpm and this condition was maintained till the end of the experiment. In a specified time interval aliquots of 3 ml sample from the receptor medium was withdrawn and filtered. Each filtered sample was diluted and the absorbance was measured by UV spectrometer at 247 nm.^{14, 15}

 

Ex-vivo permeation studies:

Modified ex-vivo permeation apparatus was used for the ex-vivo drug release study using pig ear skin membrane. The dissolution medium used in this procedure is phosphate buffer. Pig ear skin which was collected from the local slaughter house and was cleaned properly. The collected skin was cut in suitable size was stored at -20 ºC. Before the permeation study was started the pig ear skin which was stored in a freezer was taken out and allowed to come into room temperature. 1 gm of the bigel was weighed accurately and placed over the center portion of the excised pig ear skin and tied to the specially designed hollow glass cylinder. The glass cylinder was then attached to the metallic shaft and then dipped in a way that the membrane just touches the surface of 50 ml phosphate buffer pH 7.4 kept in the beaker. Temperature of dissolution medium was kept at 37+ 0.5 ºC throughout the experiment and was stirred at 50 RPM using a magnetic stirrer. In a specified interval 3 ml sample was taken from the receptor medium and filtered. Samples again diluted and analyzed by UV spectrometer at 247 nm.^{16, 17}

 

Skin irritation test:

The approval from CPCSEA was obtained for skin irritation test and the test was conducted following as per the guidelines provided. Skin irritation test was carried out for optimized formulation in Wistar rats. The rats were housed in cages, with free access to laboratory diet and water. The rats were anesthetized using anesthetic ether and 3 cm² was shaved on one side of the rats. The rats were used after 24hrs of hair depilation. The Wistar rats were categorized into 3 group. The group contains 2 study animals in which one was used as control and other was used as test. On the control the optimized gel without drug was applied and on the test the optimized gel with 5% drug was applied. The rats were observed for 48 hrs for any sign of itching, redness and swelling.¹⁸ then the study was graded according to the standards given in the Table 4.

 

Table 4: Standards for skin irritation study

Erythema and eschar formation
No erythema	0
Very slightly erythema	1
Well-defined erythema	2
Moderate to severe erythema	3
Severe erythema to slight eschar formation	4
Oedema
No oedema	0
Very slightly oedema	1
Well- defined oedema	2
Moderate to severe oedema	3
Severe oedema	4
Total possible score formation	8

 

Stability studies:

The stability studies were carried out as per ICH guidelines for 3 months. The purpose of the stability studies is to provide data on how the active pharmaceutical ingredient varies with time under the influence of various environmental conditions such as humidity, temperature and light. The study was carried out at 25ºC±2ºC (60%RH) and 45ºC±2ºC (75%RH). All the prepared formulation was filled in aluminum collapsible tube and crimped. Then the packed gels are kept under the above given various temperature and climatic condition. After the study was finished the gels were examined for % drug content, % drug release, viscosity and pH.¹⁹

 

RESULTS AND DISCUSSION:

Drug excipient compatibility studies using FTIR:

FTIR spectrum of flurbiprofen given characteristic sharp peak at 1219.05 cm^-1 representing the presence of carbonyl group, peak at 3466 cm^-1 representing characteristic peak of flurbiprofen due to aromatic stretch. In the drug peaks, principle peaks were approximately matched with the referral peaks of the formulation. Hence it showed no possible interaction.

 

 

Fig 1. FTIR of HPMC

 

 

Fig 2. FTIR of Pluronic F127

 

 

Fig 3. FTIR of Flurbiprofen

 

 

Fig 4. FTIR of Formulation

Formulation of organogel:

Organogel was formulated by mixing aqueous phase which contains pluronic F127 and distilled water with oil phase containing soya lecithin and isopropyl palmitate. After optimization based on the characterization the optimized organogel was selected. Polymers were used in different concentration for the preparation of the gel. Other ingredients such as emulsifying agent, preservative, polar solvent used was kept constant during the formulation of organogel. In all the formulations prepared, constant amount of drug was added. All the prepared formulation had good consistency.

 

Characterization:

Physical appearance:

Visual appearance of the formulation is an important parameter for topical delivery as it affects the patient compliance. All formulations were subjected to visual appearance on the basis of transparency, colour and consistency. All formulation was found to be non-transparent, off white in colour and creamy in consistency.

 

pH:

The pH obtained was within topically accepted range and hence it would not cause any irritation on skin. The pH of formulated gels are enlisted in the Table 5.

 

Table 5. Results of pH, visual appearence of organogel

Formulation code	Appearance	pH*
F1	Non Transparent, off white, creamy	6.9+0.1
F2	Non Transparent, off white, creamy	7.0+0.3
F3	Non Transparent, off white,creamy	7.4+0.1
F4	Non Transparent, off white, creamy	5.8+0.2
F5	Non Transparent, off white, creamy	5.5+0.1

 

Viscosity:

The viscosity of the formulated organogel was measured using Brooksfield viscometer and the results obtained are reported in the Table 6. The viscosity of the pluronic lecithin organogel gradually increased from formulation F1 to F5. The increment was based on the concentration of pluronic added to the formulation. Concentration of pluronic in the formulation was directly proportional to the viscosity of the formulation.

 

Table 6. Viscosity of formulated organogel

Formulation code	Viscosity* (cps)
F1	4100±0.01
F2	4200±0.02
F3	4500±0.01
F4	4500±0.03
F5	4600±0.02

 

Spreadability:

The spreadability of the formulated organogel was measured. The values of spreadability are given in Table 7. From the results, it was found that the formulation F1 has the highest spreadability and formulation F5 has the least spreadability. The amount of the polymer added to the formulation determines the integrity and viscosity of the formulation. The formulation F5 with highest viscosity showed least spreadability and the formulation F1 with least viscosity showed high spreadability.

 

Extrudability:

The extrudability of the formulated organogels was determined. The values are enlisted in the Table 7. From the results, it was found that F1 has got the highest extrudability and F5 has got the least extrudability. The amount of polymer incorporated to the formulation determines the integrity and viscosity of the formulation. The formulation F5 with highest viscosity showed least extrudability and the formulation F1 with least viscosity showed highest extrudability.

 

Table 7.  Spreadability and extrudability of organogel

Formulation code	Spreadabilty (mm)*	Extrudability (gm/sec)
F1	17.29+0.02	1.46±0.01
F2	16.26+0.01	1.38±0.02
F3	15.23+0.20	1.30±0.01
F4	13.96+0.11	1.28±0.01
F5	10.25+0.01	1.19±0.02

 

Formulation of hydrogel:

After optimization the best hydrogel was selected. Polymers were used in different concentration for the preparation of the gel. Other ingredients such as preservative, solvent used was kept constant during the formulation of hydrogel. In all the formulations prepared, constant amount of drug was added. All the prepared formulation had good consistency.

 

Characterization:

Physical appearance:

Visual appearance of the formulation is an important parameter for topical delivery as it affects the patient compliance. All formulations were subjected to visual appearance on the basis of transparency, colour and consistency. All formulation were found to be transparent, colourless and smooth in consistency.

 

pH:

The pH obtained was within topically accepted range and hence it would not cause any irritation on skin. The pH of formulated gels reported in the Table 8.

 

Table 8. Results of pH, visual appearance of Hydrogel

Formulation code	Appearance	pH*
H1	Transparent, colourless, homogenous	6.9+0.1
H2	Transparent, colourless, homogenous	7.0+0.3
H3	Transparent, colourless, homogenous	7.4+0.1
H4	Transparent, colourless, homogenous	5.8+0.2
H5	Transparent, colourless, homogenous	5.5+0.1

 

Viscosity:

The viscosity of the formulated organogel was measured using Brooksfield viscometer and the results obtained are given in the Table 9. The viscosity of hydrogel gradually increased from formulation H1 to H5. The increment was based on the concentration of HPMC added to the formulation. The concentration of HPMC in the formulation was directly proportional to the viscosity of the formulation. The formulation H1 shows showed least viscosity and the formulation H5 showed the highest viscosity.

 

Table 9: Viscosity of formulated hydrogel

Formulation code	Viscosity*(cps)
H1	3000+0.001
H2	3300+0.002
H3	3500+0.01
H4	3600+0.03
H5	3800+0.01

 

Spreadability:

The spreadability of the formulated hydrogel was measured. The values of spreadability are reported in Table 10. From the results, it was found that the formulation H1 has the highest spreadability and formulation H5 has the least spreadability. The amount of the polymer added to the formulation determines the integrity and viscosity of the formulation. The formulation H5 with highest viscosity showed least spreadability and the formulation H1 with least viscosity showed higher spreadability.

 

Extrudability:

The extrudability of the formulated organogels was determined. The values are given in the Table 10. From the results, it was found that H1 has the highest extrudability and H5 has got the least extrudability. The amount of polymer incorporated to the formulation determines the integrity and viscosity of the formulation. The formulation H5 with highest viscosity showed least extrudability and the formulation H1 with least viscosity showed highest extrudability.

 

Table 10: Spreadability and extrudability of hydrogel

Formulation code	Spreadabilty (mm)*	Extrudability (gm/sec)
H1	19.29+0.02	1.72
H2	17.26+0.01	1.56
H3	16.23+0.20	1.41
H4	14.96+0.11	1.26
H5	11.25+0.01	1.19

 

Formulation of Flurbiprofen bigel:

The optimized formulation of hydrogel (H3) and the optimized formulation of organogel (F3) were selected for preparing bigel. Hydrogel and organogel were mixed in different concentration to obtain different formulations of bigel. The drug was dissolved in 1 ml of ethanol and mixed with the gel. Other ingredient such as preservative was kept constant during the formulation of bigel. In all the formulations prepared, constant amount of drug was added. All the prepared formulation had good consistence.

 

 

Fig 5. Bigel

 

Characterization:

Physical appearance:

Visual appearance of the formulation is an important parameter for topical delivery as it affects the patient compliance. All formulations were subjected to visual appearance on the basis of transparency, colour and consistency. All formulation was found to be non-transparent, off white in colour and smooth in consistency.

 

pH:

The pH obtained was within topically accepted range and hence it would not cause any irritation. The pH of formulated gels is reported in the Table 11.

 

Gel Sol transition temperature:

It was found that the formulation B5 has the highest gel sol transition temperature and the formulation B1 has the least gel sol transition temperature. The formulation B1 contains 70 % organogel and the formulation B5 contains 30 % organogel. Which implies that the gel sol transition temperature directly depends on the amount of organogel added to the formulation.  As the formulation with 70 % organogel showed the highest gel sol transition temperature and the formulation with 30 % organogel showed least gel sol transition temperature.

 

Viscosity:

The viscosity of the formulated bigel was measured using Brooksfield viscometer and the results obtained are given in the Table 12. The viscosity of flurbiprofen bigel gradually increased from formulation B1 to B5. The increment was based on the concentration of organogel added to the formulation; the concentration of organogel present in the formulation was directly proportional to the viscosity of the formulation. As the formulation B1 containing 70 % organogel showed the highest viscosity and the formulation B5 containing 30% organogel showed the least viscosity.

Table 11. pH and gel-sol transition temperature of bigel

Formulation code	Appearance	pH*	Gel-sol transition temperature (ºC)
B1Y	Non transparent, creamy	6.8+0.1	45+0.01
B2	Non transparent, creamy	7.1+0.3	47+0.02
B3	Non transparent, creamy	7.4+0.1	49+0.01
B4	Non transparent, creamy	7.2+0.2	51+0.02
B5	Non transparent, creamy	7.0+0.1	52+0.01

 

Table 12: Results of viscosity of formulated bigels

Formulation code	Viscosity (cps)*
B1	6100 ±0.01
B2	6200 ±0.02
B3	6500 ±0.03
B4	6500 ±0.03
B5	6600 ±0.01

 

Spreadability:

The spread ability of the formulated bigel was measured. The values of spreadability are enlisted in Table 13. From the results, it was found that the formulation B5 has the highest spreadability and formulation B1 has the least spreadability. The amount of the organogel added to the formulation determines the integrity and viscosity of the formulation. As the formulation B5 containing 30 % organogel showed highest spreadability and the formulation containing 70% organogel showed least spreadability. Also the formulation B1 with highest viscosity showed least spreadability and the formulation B5 with least viscosity showed high spreadability.

 

Extrudability

The extrudability of the formulated bigels was determined. The values are reported in the Table 13.  From the results, it was found that B5 has the highest extrudability and B1 has got the least extrudability. The amount of organogel incorporated to the formulation provides integrity and viscosity. As the formulation B5 containing 30 % organogel showed highest extrudability and the formulation with 70 % organogel showed the least extrudability. The formulation B1 with highest viscosity showed least extrudability and the formulation B5 with least viscosity showed highest extrudability.

 

Drug content

The drug content of the formulated flurbiprofen bigel was determined. The values are reported in the Table 13. The values of the drug content estimation ranges from 94.01±0.02 % - 97.10±0.02 %. From the results it was found that formulation B5 has the highest drug content and the formulation B1 has the least drug content.

Table 13: Extrudability, spreadability and drug content of formulated bigel

Formulation code	Spreadabilty (mm)*	Extrudability (gm/sec)	Drug content (%)
B1	20.29+0.02	1.72±0.01	94.01±0.02
B2	18.26+0.01	1.66±0.02	95.24±0.01
B3	17.23+0.08	1.59±0.01	96.55±0.03
B4	14.96+0.11	1.31±0.03	95.46±0.01
B5	12.25+0.01	1.12±0.01	97.10±0.02

 

In vitro drug release study:

The data in vitro drug release profile of all the formulated flurbiprofen bigel is given in Table 14. The study was carried out for 8 hrs using modified in vitro permeation apparatus through cellophane membrane. Formulations B1, B2 and B3 showed release up to 8hrs, formulation B1 showed 75.03% release, formulation B2 showed 86.6% release and formulation B3 showed 98.99% release. The formulation B4 showed release 99.9% upto 7 hrs, formulation B5 showed 99.9% release upto 6 hr. The percentage of organogel added to the formulation B4 and B5 was comparatively high when compared to B1, B2 and B3. A significant decrease in the rate and extent of drug release was observed with increasing concentration of organogel in the formulation.

 

Table 14. Cumulative percentage drug release of bigel

Time (min)	Cumulative % Drug Release of Formulation from B1 –B5
	B1	B2	B3	B4	B5
15	17.35	16.66	16.3	18.9	25
30	22.41	24.85	25.07	29.8	32.5
60	34.15	36.05	34.06	37.3	44.7
120	42.58	44.62	44.04	44.6	56.36
180	48.79	54.49	55.44	55.7	67.2
240	55.78	67.15	67.69	67.8	74.8
300	68	70.76	75.6	76.9	86.8
360	69.81	76.4	83.6	87.8	99.9
420	72.04	83.75	90.93	99.9	-
480	75.03	86.6	98.99	-	-

 

 

Fig 6. Cumulative % drug release of formulations from B1-B6 Kinetic studies

 

The in vitro drug release kinetics based on mechanism of release was evaluated. The regression coefficient R² of the drug for different model is shown in the Table 15.

Table 15: Kinetic models of formulations B1 to B5

Formulation code	Kinetic models
	Zero order		First order		Higuchi		Korsmeyer-peppas
	R2	K	R2	K	R2	k	R2	k	n
B1	0.934	-0.122	0.746	-0.0034	0.990	4.47	0.990	0.0497	0.633
B2	0.950	-0.144	0.992	-0.0017	0.994	3.87	0.995	0.4675	0.693
B3	0.980	-0.170	0.811	-0.0031	0.995	4.49	0.994	0.5056	0.625
B4	0.990	-0.185	0.613	-0.0048	0.976	4.52	0.991	0.6950	0.231
B5	0.980	-0.201	0.637	-0.0059	0.989	4.66	0.993	0.4190	0.896

 

Ex vivo drug release study:

The ex vivo drug release study of the optimized formulation B3 was carried out. The study was carried out for 8 hrs using modified in vitro permeation apparatus through pig ear skin membrane. The study was carried out for 8 hrs, in which formulation B3 showed release up to 8 hrs. The amount of organogel added to the formulation B3 was 50% and hydrogel added was 45%. The formulation B3 showed 84.9±0.02 % drug release at the end of 8 hrs.

 

Table 16: Ex vivo permeation studies of bigel (B3)

Time(min)	Cumulative % drug release of B3
15	14.2±0.02
30	22.07±0.01
60	30.36±0.01
120	39.04±0.01
180	49.24±0.02
240	55.69±0.01
300	68.63±0.04
360	74.61±0.01
420	80.93±0.03
480	84.99±0.02

 

 

Fig 7. Ex vivo Cumulative % drug release of B3

 

Skin irritation test:

Skin irritation studies of the optimized gel showed that the prepared gel are compatible with rat skin, it showed no skin irritation and can be used for further studies. Scoring of the study was done as per the standards; the results are given in Table 17. The rats were observed for any oedema and erythema formation. No rat showed erythema formation for an entire period of 48 hrs. The wistar rats were categorized into 3 sets and each group contained two study animals, in which one was used as control and other was used as test.  In case of erythema, rat used as test in group 1 showed very little erythema for formulation B3. Other all study rats showed no indication for any oedema or erythema. Primary irritation index was calculated for each rat, the rat used in set 1 showed primary irritation index of 0.5. The average primary irritation index was calculated and was found to be 0.08.

 

Table 17. Skin irritation test using optimized formulation B3

Study sample	Type	Parameters		Primary irritation index
		Erythema	Oedema
GROUP1	Test	1	0	0
	Control	0	0	0
GROUP2	Test	0	0	0
	Control	0	0	0.5
GROUP3	Test	0	0	0
	Control	0	0	0

 

 

Fig 8. Skin irritation test for flurbiprofen bigel

 

Stability studies:

The stability studies of the formulations were carried out and the formulation were kept at different temperature and humidity. The formulation were sealed in a glass vial and placed in stability chamber at 25±2⁰C and at 40±2⁰C for a period of 3 months. The sample was analyzed for percentage drug content, percentage drug release, viscosity and pH. The results obtained upon the evaluation of the formulation are shown in Table 18. The prepared flurbiprofen bigel was found to be physically and chemically stable and showed no significant change in pH, percentage drug content, percentage drug release and viscosity from the initial values. It is evident that all the gels are stable under normal shelf-condition.

Table 18: Stability studies of formulation from B1 to B5

Formulation code	Parameters evaluated	Storage temperature+ SD
		25±2ºC±SD	40±2ºC±SD
B1	% Drug content	94.01±0.01	98.01±0.02
	% Drug release	75.03±0.02	75.21±0.01
	Viscosity(cps)	6000±0.001	6000±0.012
	pH	6.8+0.1	6.82+0.2
B2	% Drug content	95.24±0.01	95.85±0.02
	% Drug release	86.6±0.01	89.2±0.03
	Viscosity(cps)	6100±±	6100±0.004
	pH	7.1+0.3	7.2+0.2
B3	% Drug content	96.55±	98.45±0.02
	% Drug release	98.99±	99.99±0.01
	Viscosity(cps)	6300±0.001	6300±0.002
	pH	7.4+0.1	7.4+0.2
B4	% Drug content	95.6±0.01	98.6±0.01
	% Drug release	99.9±0.01	99.9±0.02
	Viscosity(cps)	6500±0.001	6500±0.004
	pH	7.2+0.2	7.3+0.2
B5	% Drug content	97.10±0.02	97.98±0.01
	% Drug release	99.9±0.01	99.9±0.03
	Viscosity(cps)	6400±0.001	6400±0.004
	pH	7.0+0.1	7.0+0.3

 

CONCLUSION:

The formulation B3 had good consistency which provides good visual appearance; also B3 has got required viscosity. The pH of the formulation B3 was found to be neutral which is best suited for topical formulations. Hence on the basis of these conclusions, B3 is selected as the best formulation.

 

The method of preparation was found to be simple, effective and requires minimum excipients, thus making the product cost effective. Further, these findings may help the industry to scale up for commercial products.

 

REFERENCES:

1.       Tortora GJ, Derrickson B. Anatomy and physiology.1^st ed. India edition, 2015, Wiley Publishers, pp. 125-137.

2.       Enas Ahmed. Hydrogel: Preparation, characterization and applications: A review. J Adv Res. 6(1); 2015: 105–121.

3.       Mahmoud Mokhtar I, Salma Hafez A, Mahmoud Mahdy M. Organogels, hydrogels and bigels as transdermal delivery systems for diltiazem hydrochloride. Asian J Pharma Sci. 8; 2013:48-57.

4.       Lupi FR, Ahmed S, Greco V, Rossi CO, Baldino N. A rheological and micro structural characterization of bigels for cosmetic and pharmaceutical uses. Material Sci and Eng. 69; 2016:358-365.

5.       Lupi FR, Gentle L, Baldino N. Olive oil and hyper thermal water bigels for cosmetic use. J Colloid and Interface Sci. 4(5); 2015:70-78.

6.       Akhtar MF, Hafez SA, Mahdy MM. Organogels, hydrogels and bigels as transdermal delivery of diltiazem hydrochloride. Asian J Pharm Sci. 8; 2013:48-57.

7.       Banks SR, Bajwa GS, Timmins P. The influence of substituted phenols on the sol: gel transition of hydroxypropyl methylcellulose (HPMC) aqueous solutions. Carbohydrate Polymers.101; 2014:1198-1204.

8.       Makwana SB, Patel VA, Parmer SJ. Development and characterization of in situ gel for ophthalmic formulation containing ciprofloxacin hydrochloride. Res Pharm Sci. 6(1); 2016:1-6.

9.       Chandira RM and Pradeep PA. Design, development and formulation of Antiacne Dermatological Gel. J Chem Pharm Res. 2(1); 2010:401-404.

10.     Vikrant J, Sonali N. Formulation and evaluation of topical flurbiprofen gel using different gellying agents. World J Pharma Sci. 3(9); 2013:654-663.

11.     Khan AW, Kotta S, Ansari SH, Sharma RK, Kumar A. Formulation, development, optimization and evaluation of aloe vera gel for wound healing. Pharmacogn Mag. 9(1); 2013: 6-10.

12.     Singh VK, Anis A, Banarjee I. Preparation and characterization of novel carbopol based bigels for topical delivery of metronidazole for the treatment of bacterial vaginosis. Materials Sci and Eng. 44; 2014:151-158.

13.     Shaikh IM. et al. Aceclofenac Organogels: In vitro and in vivo Characterization. Curr Drug Deliv. 6(1);2009: 1-7.

14.     Sakarkar DM, Shrikande VN, Vyas JV, Mahajan N. Studies on formulation development, characterization and transdermal permeation of nimesulide from emulgel. Int J Pharm Excip. 16(5); 2004: 381-387.

15.     Guleri KT, Preet KL. Formulation and evaluation of topical gel of aceclofenac. J Drug Deliv Therapeutics. 3(6); 2013: 51-53.

16.     Tazrart A, Bolzinger MA, Moureau A, Molina T, Coudert S. Penetration and decontamination of americium-241 ex vivo using fresh and frozen pig skin. Chem Bio Inter. 267; 2017:40-47.

17.     Nava G, Pinon E, Mendosa L, Mendosa N. Formulation and in vitro, ex vivo and in vivo evaluation of elastic liposomes for transdermal delivery of ketorolac tromethamine. Int J Pharm. 3; 2011:954-970.

18.     Jain S, Goswami M, Bhandari A. Skin irritation study in transdermal patch of chitosan containing trazodane HCl on rat skin. Int J Res Pharm Bio Sci.2011;2(3)1082-1084.

19.     WHO-GMP and ICH stability testing guidelines for drug products. The pharm Sci Pharm Pathway.2.72-2.79.

 

 

 

 

 

 

 

 

 

 

 

Received on 22.07.2017         Modified on 18.08.2017

Accepted on 12.09.2017      © RJPT All right reserved