Development and in vitro Characterization of Intranasal Microemulsions of Sumatriptan Succinate for brain Targeting

 

R. Nagaraju¹, U. Rajeswari¹, G. Ravi², P. Subhash Chandra Bose²*, Damineni Saritha³

¹Department of Pharmaceutics, Sri Padmavati Mahila Visvavidyalayam, Tirupati - 517502,

Andhra Pradesh, India.

²Department of Pharmaceutics, MNR College of Pharmacy, Sangareddy - 502294, Telangana State, India.

³Department of Pharmaceutics, Sultan-ul-Uloom College of Pharmacy, Hyderabad - 500034, TS, India.

 

ABSTRACT:

Microemulsions, by virtue of their lipophilic nature and low globule size, are widely explored as a delivery system to enhance uptake across mucosa. The main aim of the present investigation is to develop and in vitro characterization of intra nasal microemulsion of sumatriptan succinate for brain targeting for treating acute attack of migraine. The liquid microemulsion was prepared by dissolving drug (sumatriptan succinate) and mucoadhesive polymer sodium alginate in double distilled water. The prepared microemulsion was evaluated for particle size measurement, zeta potential measurement, viscosity measurement, centrifugation, drug content, optical clarity and in vitro drug release studies. The prepared formulations were showed particle size in the range of 106.2±2.03 to 282.8±2.51. The zeta potential value of the formulation ME2 showed −32.0mv indicating negative surface charge. The drug content showed in the range of 89.3±0.242 to 94.3±0.128. the optimized formulation showed in vitro drug release 74.2±0.95% at 12 h. and 86.23±0.41% at 24 hrs. From the results it was concluded that the prepared optimized microemulsion formulation as drug delivery system to improve bioavailability of the drugs like sumatriptan succinate.

 

 

 

INTRODUCTION:

Microemulsions, by virtue of their lipophilic nature and low globule size, are widely explored as a delivery system to enhance uptake across mucosa. Evidences of intranasal drug delivery systems formulated using mucoadhesive agents and their benefits in enhancing nose-to-brain drug transport have been reported by various scientists in literature. It was hypothesized that microemulsion based alternative drug delivery systems will results in rapid nose-to-brain transport of drug and distribution into and within the brain. This can help to maximize the therapeutic index of the drug, reduce side effects, decreases the dose frequency of dosing, and perhaps even the cost of the therapy^1,2.

 

 

Sumatriptan succinate, triptan derivatives are serotonin agonist (5HTD1) used in the treatment of migraine. It is administered orally, in the doses of 25, 50 or 100mg as a single dose, nasally in doses of 10 or 20mg and also subcutaneously, as 2, 6mg doses within 24 hours³. Migraine patients not only suffer from gastric stasis but also have severe nausea and vomiting, which results in erratic absorption of SS from GIT. Low oral bioavailability (15%) due to high first pass metabolism justifies a need of nasal drug delivery⁴.

 

Nasal delivery is an alternative route of drug delivery that can selectively target drug directly into the various regions of the brain, including vasculature which is needed for the treatment of acute attack of migraine. Nasal route is not only used recently but it has been used since long time, Ayurveda has references for the “Nasya karma” for administration of the drugs. In Recent years, growing interest has focused on the use of nasal route for systemic delivery and brain targeting, as well as for compounds, which impact local pharmacological effects. In this respect, an understanding of the human nasal cavity is important in order to optimally exploit the nasal route for delivery of drugs. Nasal drug administration for systemic effects has been practiced since ancient times⁵. In the last decade, there has been much interest in the nasal route for delivery of drug to the brain via the olfactory region in order to circumvent the blood brain barrier (BBB). Targeting the brain via the nasal administration of drugs offers potential for drug development since the olfactory receptor cells are in direct contact with both the environment and the central nervous system (CNS). The absence of a strict nose-brain barrier could, then, allow air-borne substances viruses, metals or drugs to be delivered directly in to the CNS^6,7.

 

Currently, several drugs for systemic administration have registered nasal dosage forms in Sweden. Desmopressin (a vasopression analogue and potent antidiuretic), nafarelin (used as pre-treatment in invitro fertilisation) and oxytocin (for secretion of milk in response to suckling during breast feeding or contraction of the uterine muscle to hasten childbirth) are all small polypeptides consisting of 9 amino acids that are available as a nasal are available as a nasal dosage form. Nicotine is also available in a nasal dosage form for use in assisting smoking cessation⁸.

 

The aim of the present investigation is to develop and in vitro characterization of intra nasal microemulsion of sumatriptan succinate for brain targetting for treating acute attack of migraine.

 

MATERIALS AND METHODS:

Sumatriptan succinate was gifted from Smilax laboratories Ltd., India. Tween 80, Span 80, PEG-400, Iso propyl myristate and Sodium alginate were procured from Merck specialties Pvt. Ltd., India. Potassium Dihydrogen phosphate, Sodium Hydroxide, Acetonitrile and Sodium chloride were procured from SD fine chemicals Ltd., India. Dialysis membrane was procured from Hi-Media, India.

 

Experimental method:

Method of preparation of Microemulsion:

Construction of pseudo ternary phase diagrams⁹:

Pseudo ternary phase diagrams were constructed by water titration method. Iso propyl myristate used as oil phase, Tween80 and span80 as surfactants, PEG-400 was used as co-surfactants were selected from solubility studies. Pseudoternary phase diagram were constructed by titrating the blend of oil and Smix by incremental amount of water. Mixture of surfactant and co-surfactant were prepared different weight ratios (1:1, 2:1 and 3:1). The Smix ratios were selected by increasing concentration of surfactant with respect to co-surfactant. In which tween80 and span80 are used in 7:3 propotions respectively. Each Smix was mixed with oil in different weight ratios (oil: Smix) 1:9, 1:8, 1:7, 1:6, 1:5, 1:4 and 1:3.

 

Each mixture of oil and Smix was subjected to form homogenous mixture before titration with water.  During titration the aqueous phase was added in increments of 5% to 95% with   proper mixing. The tubes were kept aside for 10 mins after each incremental addition of water to identify the phase behaviour and to avoid metastable compositions. Amount of water to be added at each incremental addition was calculated by maintaining total percentage of oil, Smix and water as 100%. The change in composition upon incremental addition of water with different oil to Smix ratios are shown in Table 1.

 

Table 1: Change in compositions upon incremental addition of water with oil to Smix ratio 1:3

Oil(mg)	Smix(mg)	Water (mg)	Water added	Total (mg)	Oil (%)	Smix (%)	Water (%)
50	150	0	0	200	25.00	75.00	0.00
50	150	10	10	210	23.81	71.43	4.76
50	150	22	12	222	22.52	67.57	9.91
50	150	35	13	235	21.28	63.83	14.89
50	150	50	15	250	20.00	60.00	20.00
50	150	67	17	267	18.73	56.18	25.09
50	150	86	19	286	17.48	52.45	30.07
50	150	108	22	308	16.23	48.70	35.06
50	150	135	27	335	14.93	44.78	40.30
50	150	165	30	365	13.70	41.10	45.21
50	150	200	35	400	12.50	37.50	50.00
50	150	245	45	445	11.24	33.71	55.06
50	150	300	55	500	10.00	30.00	60.00
50	150	370	70	570	8.77	26.32	64.91
50	150	470	100	670	7.46	22.39	70.15
50	150	600	130	800	6.25	18.75	75.00
50	150	800	200	1000	5.00	15.00	80.00
50	150	1150	350	1350	3.70	11.11	85.19
50	150	1850	700	2050	2.44	7.32	90.24
50	150	4000	2150	4200	1.19	3.57	95.24

 

The Smix ratios were selected in increasing concentration of surfactant with respect to cosurfactant. Each Smix was mixed with oil in different weight ratios (Oil: Smix) 1:3. A series of the mixtures of oil and Smix were prepared without drug and their self emulsifying properties were observed visually by adding incremental amount of water. The phase diagrams were constructed at surfactant/co-surfactant ratios of 1:1, 2:1, 3:1.

 

Preparation of Microemulsion:

After the identification of microemulsion existing region in the phase diagram, the microemulsion formulations were selected at desired component ratio. Formulation was further optimized with surfactant/co-surfactant ratio. The liquid microemulsion was prepared by dissolving drug (sumatriptan succinate) and mucoadhesive polymer sodium alginate in double distilled water. The resultant solution was added drop wise in to the mixture of tween80, span80, PEG-400, and iso propyl myristate, with continuous stirring on magnetic stirrer.  No heat is required during formulation. In all the formulations the level of sumatriptan succinate was kept constant.  The resulting microemulsion were tightly sealed and stored at ambient temperature and their physical stability was measured by observing periodically for the occurance of phase separation¹⁰. Drug loaded formulations are subjected to various evaluation parameters as described below. Formulation chart for microemulsion was depicted in Table 2.

 

Table 2: Formulation chart for microemulsion

Sl. No.	Ingredients	Composition %w/v
		ME1	ME2	ME3	ME4
1.	Sumatriptan Succinate (gm)	1	1	1	1
2.	Iso propyl myristate (ml)	7.5	10	7.5	10
3.	Tween 80 (ml)	15.75	14.75	15.75	14.75
4.	Span 80 (ml)	6.75	6.23	6.75	6.23
5.	PEG-400 (ml)	7.5	6.52	7.5	6.52
6.	Double distilled water (ml)	12.5	12.5	12.5	12.5
7.	Sodium alginate(mg)	50	50	50	50

 

 

Evaluation of Sumatriptan Succinate Microemulsion ^11-14:

Clarity test:                                        

The prepared microemulsion was observed visually to find out their clarity and transparency.

 

Dilutability test:

The microemulsions prepared were diluted in 1:10, and 1:100, ratios with double distilled water to find out any signs of separation

 

pH Measurement:

pH of all microemulsion for nasal delivery should be 4.5 to 6.5, in acidic pH, lysozyme found in nasal secretion which is responsible for destroying certain bacteria. Under alkaline condition lysozyme is inactivated and the nasal tissue susceptible to microbial infection therefore advisable to keep pH 4.5 to 6.5. The pH measurement was carried out using pH meter. The 25ml of prepared microemulsion were taken and immersed in glass electrode and allowed to stabilize. After stabilization the pH of the formulation was recorded.

 

Particle size measurement:

0.1ml of microemulsion was added to 10ml of double distilled water in a beaker and gently mixed using a glass rod. The resultant emulsion was then subjected to particle size analysis using Malvern zetasizer. Particle size was calculated from the volume size distribution.

 

Zeta potential measurement:

Zeta potential is determined by using Zetasizer. Zeta potential was essentially useful for assessing flocculation since electrical charges on particles influence the rate of flocculation.

 

Viscosity measurement:

Viscosity is an expression of the resistance of a fluid to flow, the higher the viscosity, the greater is the resistance. Viscosity is measure by using Brookfield viscometer (DV-E) equipped with Spindle number 34. The viscosities of prepared microemulsions were measured at 50rpm. The measurement was done at ambient temperature.

 

Centrifugation¹⁶:

The microemulsion system was centrifuged at 3000rpm for 15 minutes to find out the whether the system shows signs of creaming or phase separation.

 

Microemusification time and precipitation assessment:

The emulsification time is the time for a pre concentrate to form a homogeneous mixture upon dilution; It was monitored by visually observing the disappearance of MEDDS and the final appearance of the microemulsion in triplicate. In this method, a predetermined volume of formulation 1ml was introduced into 300ml of water in a glass beaker that was maintained at 37⁰C, and the contents were mixed gently, by using a magnetic stirrer. The time to emulsify spontaneously and progress of emulsion droplets were observed. Precipitation was evaluated by visual inspection of the resultant emulsion after 24 hrs. The formulations were then categorized as clear (transparent or transparent with bluish tinge) non clear (turbid), stable (no precipitation at the end of 24 hrs), or unstable (showing precipitation within 24 hrs).

 

Determination of drug content:

Sumatriptan succinate from micro emulsion formulation was dissolved in pH 6.8 phosphate buffer. The solution was filtered, using Whatman filter paper. The solution was analyzed for the drug content spectrophotometrically (UV- Systronics 117, India) at 226nm, and drug concentration was calculated. Using standard curve.

 

Optical clarity¹⁷:

Each formulation (1ml) was diluted with 100ml of water in glass beaker. Absorbance of each dispersion was measured at 400nm using a UV spectrophotometer immediately after microemulsions formulation, and after 0hrs, 6hrs, and 24hrs respectively.

 

In vitro drug release studies:

The release of sumatriptan succinate from microemulsions was determined using membrane diffusion technique. The microemulsion formulation equivalent to 10mg of sumatriptan succinate was placed in a glass tube of diameter 2.5cm with an effective length of 8cm that was previously covered with soaked osmosis cellulose membrane, which acts as a donor compartment. The glass tube was placed in a beaker containing 100ml phosphate buffer pH 6.8, which acts as receptor compartment. The whole assembly was fixed in such a way that the lower end of the tube containing suspension was just touching (1-2mm deep) the surface of diffusion medium. The temperature of receptor medium was maintained at 37⁰C±1⁰C and agitated at 100rpm speed using magnetic stirrer. Aliquots of 1ml sample were withdrawn at different time intervals (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24hr) and replaced with same volume of medium. The collected samples were analyzed by UV-VIS spectrophotometer at 228nm using phosphate buffer pH6.8 as blank. Three trails were conducted and the average ±SD is reported¹⁸.

 

Drug-Excipient compatibility study:

Fourier transforms infrared spectroscopy (FTIR) studies:

FTIR studies were conducted on pure drug and polymer by making a KBr disc. Spectral measurements were performed using thermo electron FTIR spectrometer at wavelengths 4000cm^-1 to 400cm^-1 show that there are some interactions between drug (Sumatriptan succinate) and polymer¹⁹.

 

RESULTS AND DISCUSSION:

The sumatriptan succinate microemulsions that were prepared with different composition of surfactant (tween 80, span 80) and co-surfactant (PEG-400), oil (isopropyl myristate). Were evaluated for clarity test, dilutability test, pH measurement, viscosity measurement, centrifugation, Emulsification time and precipitation assessment, particle size measurement, zetapotential measurement, Optical clarity, determination of drug content, and in vitro drug diffusion study.

 

Clarity test:

The formulation was observed visually, and found that  clear and transparent.

 

Dilutability test:

The formulation was diluted in 1:100 ratio with double distilled water The formulation was observed visually and found that no phase separation.

 

The results of pH measurement, viscosity measurement and centrifugation.

 

OBSERVATION:

pH Measurement:

The pH of the prepared all formulations was in the range of 5.47 to 6.01. The pH of microemulsion for nasal delivery should be 4.5 to 6.5. Lysozyme found in nasal secretion which is responsible for destroying certain bacteria, results showed in Table 3.

 

Viscosity measurement:

The viscosity of the prepared formulations were found to be increased i,e., 286.6±0.15 to 349.2±0.16. The order of increase in viscosity was found to be as follows: ME1 ≤ ME2≤ ME3≤ ME4, results showed in Table 3.

 

Centrifugation:

The centrifugation of sumatriptan succinate microemulsions prepared with different composition of surfactant, co-surfactant, and oil were found to be no phase separation and creaming and was stable. Similar results are reported by Ashwini Rasal, et al., Among all the formulations ME4 was found to have higher viscosity, thus is expected to provide prolonged residence time in the nasal cavity, results showed in Table 3.

 

Table 3: pH measurement, viscosity measurement and centrifugation for formulation ME1 – ME4:

Formulation code	pH Measurement	Viscosity (Cp)	Centrifugation
ME1	5.47	286.6±0.15	Stable
ME2	5.58	305.4±0.11	Stable
ME3	5.96	335.6±0.58	Stable
ME4	6.01	349.2±0.16	Stable

 

Emulsification time and precipitation assessment:

Emulsification time and precipitation assessment of prepared sumatriptan succinate microemulsions which is an important index for the assessment of the efficiency of emulsification, that is the sumatriptan succinate microemulsion should disperse completely and quickly when subjected to aqueous dilution under mild agitation.

 

The emulsification time of ME1, ME2, ME3 and ME4 were found 49.6±0.43, 46.5±0.25, 87.6±0.41 and 109±0.21 respectively. The dispersed formulations were assessed visually and no sign of drug precipitation was observed even upon incremental dilution of formulation ME1 and ME2, both of these formulations were clear and the dispersed formulations were assessed visually and sign of ME3 and ME4 has shown precipitation and were nonclear, results depicted in Table 4.

 

Table 4: Evaluation of sumatriptan succinate microemulsion

RUN	Emulsification time (sec)	Particle size in water(nm)	Zeta potential(mv)	% Drug content	Precipitation	Clarity
ME1	49.6±0.43	239.1±2.42	- 33.8	92.6±0.236	Stable	Clear
ME2	46.5±0.25	282.8±2.51	- 32.0	94.3±0.128	Stable	Clear
ME3	87.6±0.41	15.3±2.08	- 7.2	90.5±0.123	Unstable	Nonclear
ME4	109±0.21	106.2±2.03	- 4.5	89.3±0242	Unstable	Nonclear

 

 

Particle size analysis by zeta sizer:

The Mean particle size of the microemulsion made with different composition of oil, surfactant and cosurfactant was determined by zeta sizer. The mean particle size of optimum formulation of sumatriptan succinate loaded microemulsion i.e., ME1, ME2, ME3 and ME4 were found to be 239.1±2.42nm, 280.8±2.51nm, 115.3±2.08 and 106.2±2.03 respectively.

 

The following figure shows the particle size of sumatriptan succinate loaded microemulsions.

 

The particle size of the prepared sumatriptan succinate microemulsions were found to be range of 106.2±2.03 to 280.8±2.51 nm indicating all the particles were in the nanometer range. ME2 formulation having larger particle size of 280.8nm and also it determines the rate and extent of drug release as well as absorption. The results showed that the higher Smix formulation showed larger particle size. The results were depicted in Table 4 and Optimized formulation (ME2) particle size was showed in Figure 1.

 

Figure 1: Particle size of ME2 formulation.

 

Zeta potential:

The zeta potential of prepared microemulsions was investigated to known the possibility of stability and aggregation. The following figure shows the zeta potential of optimum formulation ME2 of sumatriptan succinate loaded microemulsion was found to be -32.0mv. The results were depicted in Table 4 and Optimized formulation (ME2) zeta potential was showed in Figure 2.

 

 

Figure 2: Zeta potential of sumatriptan succinate microemulsion (ME2)

 

% Drug content:

The drug content of different composition of sumatriptan succinate microemulsion formulations ME1 to ME4 was found to be range of 89.3±0.242 to 94.3±0.128. ME2 formulation having higher drug content of 94.3%. The results were depicted in Table 4.

 

Optical clarity:

Table 5: variation in optical clarity with time in water

Formulation code	Absorbance at 400 nm
	0 hrs	6 hrs	12 hrs
ME1	0.058±0.002	0.051±0.005	0.0068±0.003
ME2	0.052±0.004	0.056±0.006	0.057±0.002
ME3	0.089±0.003	0.091±0.006	0.22±0.004
ME4	0.310±0.003	0.34±0.007	0.46±0.005

 

Optical clarity is measured by measuring the absorbance of the diluted microemulsions. It is a measure of droplet stability. The results indicated that formulation ME2 was stable till 24 hrs as its absorbance values did not change at the end of 24 hrs. Moderate changes in absorbance values were observed for formulations ME1 and of droplets with time. The ME2 was selected as the optimized formulation as it has shown good emulsification time, visually clear without precipitation and was stable.

 

Optical clarity is measured by direct taking the absorbance of the diluted microemulsions. It is a measure of droplet stability. The results indicated that Moderate changes in absorbance values was observed for formulation ME3 at the end of 24 hrs. For formulations ME4 a drastic change in absorbance values were observed indicating instability of droplets with time. Results showed in Table 5.

 

In-vitro drug release: Further sumatriptan succinate microemulsion formulations ME1, ME2, ME3, and ME4 were subjected for in-vitro drug release studies, by the procedure mentioned in materials and methods.  % drug release was calculated and the data was depicted in Figure 3.

 

Figure 3: In vitro % drug release of all formulations

Sumatriptan succinate microemulsions prepared with 3:1 ratio of surfactant, cosurfactant and oil (ME2) was found to have the highest % drug release amongst the formulations ME1-ME4 i.e., 74.2±0.95% of drug release at 12 hrs and 86% drug release at the end of 24 hrs.

 

FT-IR spectrum:

By comparing the FTIR spectra of pure sumatriptan succinate with its optimized formulation it was observed that there was no considerable difference in their spectral values. This was justified by the presence of three characteristic peaks of sumatriptan succinate O-H groups, aromatic C-H and C=C, N=H scissoring groups at around 3110.2cm-1, 2903.06cm-1, 963.04cm-1 and 3376.93cm-1 respectively in polymer mixer. Similarly, aliphatic C-C stretches and C-O stretch, O-H deformation, C-H out of plane bending, ring deformation of the aromatic groups peaks in polymer mixture were seen at around 839.22,1705.9, to1297.8, 1137.79, 1419.86, since there is no change in the position of the end of the bonds it was concluded that the drug maintains its identity It indicated the incorporation of sumatriptan succinate in the formulation its showed good compatibility of drug with optimized formulation. The FT-IR spectrum of pure drug and optimized formulation was showed in Figure 4.

 

Figure 4: IR-Spectrum of A. drug and B. optimized formulation

 

CONCLUSION:

Thus, from all the above observations, it was concluded that ME2 formulation has shown highest bioavailability, then other formulations. The best formulation sumatriptan succinate microemulsion ME2 showed improved in-vitro bioavailability than that of pure drug which strongly suggests the use of sumatriptan succinate microemulsion as drug delivery system to improve bioavailability of the drugs like sumatriptan succinate.

 

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Received on 12.04.2020            Modified on 11.06.2020

Accepted on 05.08.2020         © RJPT All right reserved