INTRODUCTION:

Solid lipid Microparticles were firstly developed in 1990 and it considered being a promising drug carrier system especially for the incorporation of the active drug substance and to promote the sustained and controlled drug delivery¹. Soli lipid Microparticles are solid spherical in shape and size ranging from 1-1000μm and that can be suspended in suitable aqueous solvent system.

Due to its special size dependent character of solid lipid microparticles offers the possibility to develop improved new therapeutic product². The ability to incorporate drug into micro carriers offers to develop new drug delivery system for site specific targeting. Hence a solid lipid Microparticles reaches to the target site at controlled rate and show controlled release for better therapeutic result. This drug delivery system are prepare to obtained prolonged sustained or controlled drug delivery, to improves bioavailability, to enhance stability and to reduce toxic effects follows with target drug at specific site³. Microparticles are prepared mostly by two types of polymers especially natural polymer or synthetic polymer that assist in transportation of active compound. Ethyl cellulose and sodium alginate is natural polymer that obtained from the marine brown algae. This is biocompatible, biodegradable and non-toxic, and widely used in oral and topical formulation⁴. Biodegradable polymer microparticles, either microspheres or microcapsules are often used as a support for the delivery of bioactive compounds. While triglyceride and cholesterol is synthetic polymer which shows detrimental effect on incorporating peptides and proteins during manufacturing of formulation. These polymers are biocompatible, biodegradable and non-toxic in nature. Microparticles vary widely in quality, sphericity, and uniformity of particle and particle size distribution. The ranges of techniques for the preparation of microparticles offers the variety of opportunity to control various aspect of drug administration and to facilitates the accurate delivery of small quantity of the potent drugs, and to avoid the unexpected concentration of drug at the site other than the target site. The behavior of the drug component can be manipulated according to need by coupling the drug to a carrier particle. The clearance kinetics, tissue distribution, metabolism and interaction of drug are strongly depends on the behaviour of the carrier. The primary goal of drug delivery system is to obtain the therapeutic response with minimal side effect, that condition achievable by delivering drug at the specific site with pre determined rate and over specified period of time in the body.

The oral drug delivery system is the most convenient route because of ease in administration and more patient compliance. To develop the oral doses form it is important to improve both the residence time as well as release of drug from the dosages forms. Drugs that easily absorbed from gastric intestinal tract and having short half life are eliminated faster from blood stream, to avoid this problem oral control drug delivery system develop as they release drug slowly and maintain constant drug concentration in serum for longer period of time that finally improves the bioavailability of drug. A well designed controlled drug delivery system overcome some of the problems related to conventional therapy and enhance the maximum therapeutic efficacy, it become necessary to deliver the drug to target site in appropriate amount at right time to avoid the side effect and maximize the therapeutic effects⁵. Ideally microspheres having particle size less than 200μm and can be injected by an 18 or 20 number needle. Many methods are used for the preparation of solid lipid microparticles (SLMs) are homogenization technique, solvent evaporation technique, Solvent Extraction Technique, encapsulation technique, phase Separation Co-acervation Technique, spray drying method and many more⁶. There are numerous analytical techniques used for the characterization of microspheres are scanning electron microscopy technique, differential scanning calorimetric technique and Fourier transformed infra red spectroscopy (FTIR). This FTIR technique is used for the characterization of drug loaded formulation⁷. The in-vitro drug release was studied using rotator basket method which is described in the 5th edition of the European Pharmacopoeia, with the help dissolution apparatus. The study carried out at 150 rpm in phosphate buffer solution of pH 7.4 at⁸.

Fig. 1 Microsphere

ADVANTAGES:

1. SLM improve the absorption of poorly absorbed drug.

2. SLM improve the bioavailability, reducing adverse effect, and showing constant target drug release.

3. SLM improve the stability of drug, scale up and sterilized easily.

4. SLM have high drug load and show constant and prolonged therapeutic effect.

5. SLM can prepare on large scale with relatively at low cost.

6. Incorporated active compound shows sustained drug release.

7. Due to special size dependent character and spherical shape microparticles can be injected into the body.

8. Application versatility⁹

LIMITATIONS:

1. The release rate of drug may vary from dose form that depends upon the polymers used.

2. Drug release profile may get altered by the presence of food and that further affects the drug transient time.

3. Changes in the integrity of formulations could affect the efficacy of doses forms and shows the possibility of toxic effects.

4. Less reproducibility¹⁰.

Description of Curcumin:

Curcumin, 1, 7-bis (4-hydroxy- 3-methoxyphenyl) -1, 6- heptadiene-3, 5-dione), is a small molecular weight, natural hydrophobic polyphenolic compound, isolated from the rhizomes of Curcuma longa, family Zingiberaceae. The structural formula of curcumin was first described in 1910 by Lampe and Milobedesk¹¹. Various curcuminoids are found in curcumin. The curcuminoids founds are about 5% bisdemethoxycurcumin, 15% demethoxycurcumin, and 80% Curcumin. When curcumin is taken orally, 75% of it excreted in the feces while only traces of curcumin appear in Urine. The long list of uses of Curcumin includes antioxidant, anti-inflammatory, anticancer, antimalarial, antiseptic, rheumatism arthritis, asthma, diabetes, analgesic and wound healing activities¹².

Fig.2 Structure of Curcumin

Mode of action:

Curcumin has shown an effective therapeutic agent and defence mechanism against Alzheimer’s disease by the ability to destabilize Aβ plaque formation and through increase the phagocytosis of Aβ plaque¹³.

Methodology:

Preformulation study of curcumin:

Preformulation study in which we determine the physiochemical property of the active compound that could affects the drug performance and development of efficacious, safe and stable dosages form. It is an optimizing process. These studies help in rational designing of formulation. In Preformulation study, we study the organolaptic character of active compound like: colour, order, taste, solubility, melting point, entrapment efficacy, compatibility study, pharmacokinetic study, thin layer chromatography and calibration curve. All these studies avoid the maximum chances of error or any kind of incompatibility during formulation.

Authentication of the procured curcumin:

Several parameters were taken in consideration for the authentication of the drug.

Melting point:

The Melting point study of the drug was determined by capillary fusion method. The observed melting point values of drug were same as the reference value, which describe that the drug was pure. The results are shown in Table.

Table1. Melting point of curcumin

Method Used	Experiment Value	Observe Value
Capillary Fusion Method	182 ◦C ± 1.28	179 ± 175oC

Thin layer chromatography (TLC):

The TLC plate was prepared by precoating with Silica G. A spot of test solution was applied on the silica plate (20×10cm) above 0.5cm from the bottom and placed in the TLC chamber, which was saturated with solvent system contains chloroform: benzene: methanol (80:15:5) as shown in table 2.

Table 2: Thin layer chromatography

Thin layer chromatography

Rf Value (Observed)

Observe Value

(n=3)

Curcumin

0.87

0.90

Fourier Transforms Infra-Red Spectroscopy (FTIR):

The FTIR spectra in the range (4000 – 400) cm-1 were recorded. The sample were taken with KBr and then compressed into tablet. The drug KBr pellet were analyzed that will provide spectra¹⁴.

Fig 1: Reference FTIR Spectra of Curcumin

Table 3: Interpretation of FTIR (drug)

Reported (cm-1)	Wave No (cm-1)	Functional group	Inference
3510.2cm^-1	cm^-1	OH Phenol	Stretching
1627.8cm^-1	cm^-1	C=O Ketone	Stretching
1596cm^-1	cm^-1	C=C Aromatic	Stretching
1276cm^-1	cm^-1	C-O	Stretching

Preparation of Solid lipid Microparticles:

By Hot melt microencapsulation technique:

Solid Lipid Microparticles (SLMs) were prepared by using hot melt microencapsulation technique (which can be carried out by normal or phase inversion technique). Stearic acid (lipid) was melted in beaker, by putting beaker on hot plate at 70^oC. Curcumin was added in the melted Stearic acid under continuous stirring on magnetic stirrer to form hot melt mixture. The hot mixture was emulsified into an aqueous surfactant solution and was heated above the lipid melting point to form oil/water emulsion. Different grades of surfactant (Span 20, Span 60, Span 80 and Tween 80) were used at different concentration (0.5ml, 1ml, 1.5ml). The o/w emulsion was poured into a 100ml of ice-cooled aqueous phase maintained at 2^oC- 5^oC and was finally allowed to cool in an ice bath. Hardened microparticles were allowed to settle down and after 15 min aqueous phase was decanted, microparticles were filtered, rinsed with water and freeze dried.

Table 4: Composition of curcumin targeted Solid lipid microparticles

Formulation	Drug (mg)	Stearic acid	Surfactant Span 80
F1	125	2	0.5
F2	125	2	1.0
F3	125	2	1.5
			Span 60
F4	125	2	0.5
F5	125	2	1.0
F6	125	2	1.5
			Span 20
F7	125	2	0.5
F8	125	2	1.0
F9	125	2	1.5
			Tween 80
F10	125	2	0.5
F11	125	2	1.0
F12	125	2	1.5

Characterization of the solid lipid microparticles:

Encapsulation Efficiency:

Curcumin loaded microspheres were crushed and extracted using ethanol by ultra sonication method 30 min. The supernatant containing unentrapped curcumin was withdrawn and measured UV spectrophotometrically at 432nm against ethanol. The amount of curcumin entrapped in microspheres was calculated by following equation

Mass of drug in microspheres

Encapsulation = ---------------------------------------- X 100

efficiency Initial mass of drug

Determination of Percentage yield:

The prepared microparticles firstly dried, then collect and weighed accurately. The actual weights of microparticles were divided by the total amount of all components which were used for the formulation of solid lipid microparticles¹⁵.

Mass of obtained microspheres

Percentage = -------------------------------------------- X 100

yield Initial mass of drug+ Initial mass of polymer

Fig 2: FTIR of curcumin + stearic acid+ span 60

Calibration Curve of Curcumin in 0.1N HCl (1.2pH):

Calibration curve of curcumin was plotted in 0.1 N HCl (1.2pH) at λmax 432nm medium by using UV-Spectrophotometer (Shimadzu-1800). The results are shown in Table 9. A graph was plotted between concentration and absorbance. Regression coefficient was calculated R²=0.998 as shown in fig.

Table 5: Calibration curve data of Curcumin in 0.1N HCl (1.2pH) at Max 432nm.

Sr. No.	Concentration (μg/mL)	Absorbance at max432 nm
1	5	0.218 ± 0.004
2	10	0.452 ± 0.003
3	15	0.665 ± 0.002
4	20	0.884 ± 0.004
5	25	1.072 ± 0.003
6	30	1.251 ± 0.002

Fig 3: Standard Plot of Curcumin in 0.1 N HCl (1.2pH) at max 432nm.

Calibration Curve of Curcumin in Phosphate Buffer (7.4pH).

Calibration curve of curcumin was plotted in phosphate buffer (7.4pH) at max 432nm and the results are shown in Table 10. A graph was plotted between concentration and absorbance. Regression coefficient was calculated as the R²=0.999 as shown in figure

Table 6: Calibration Curve data of Curcumin in Phosphate Buffer (7.4pH) at max 432nm

Sr. No	Concentration (μg/mL)	Absorbance at max432nm
1	5	0.293 ± 0.005
2	10	0.462 ± 0.003
3	15	0.611 ± 0.004
4	20	0.860 ± 0.002
5	25	1.083 ± 0.004
6	30	1.323 ± 0.005

Fig 4: Standard Plot of Curcumin in Phosphate Buffer (7.4pH) at max 432nm

Solubility study of Curcumin:

Solubility study of curcumin was performed by using mechanical shaker in 0.1N HCl (pH1.2), phosphate buffer (pH 7.4) and methanol by equilibrium solubility method. The results are shown in Table.

Table 7: Solubility of Curcumin

S. No	Solubility Study	Concentration (mg/mL)
1	0.1N HCl	0.65± 0.06
2	Phosphate Buffer	2.68 ± 0.039
3	Methanol	4.21 ± 0.056

Development of curcumin loaded microspheres by hot melt microencapsulation technique:

Various batches of formulation were successfully formulated by using hot melt microencapsulation technique. In this technique curcumin were taken.

with 2gm Stearic acid and varied quantity of surfactant then melted in beaker at 70^oC. Now o/w emulsion was formed and poured into a 100ml of ice-cooled aqueous phase maintained at 2^oC - 5^oC and was finally allowed to cool in an ice bath.

Evaluation Parameter:

Evaluation of Solid lipid microparticles (SLMs) Solid lipid microparticles were evaluated for various parameters. These are given below as:

Drug loading, Percentage yield and entrapment efficiency¹⁶:

Drug loading, Percentage yield and entrapment efficiency was studied on twelve formulations. Assay for drug loading, Percentage yield and entrapment efficiency determination was done through UV spectrophotometer. The % drug loading was found to be 54.63 to 67.78%, Percentage yield was found 72.01 to 79.64 while entrapment efficiency was found to be 82.23 to 88.56 as given in table.

Table 8: Drug loading, Percentage yield data

S. No.	Formulation code	Drug loading (%)	Entrapment Efficiency (%)	Percentage Yield (%)
1	F1	53.34±0.43	60.56±0.85	82.37±0.39
2	F2	68.27±0.89	71.89±0.34	85.69±0.47
3	F3	72.71±1.05	89.32±0.76	89.38±0.58
4	F4	40.00±0.32	59.83±0.94	72.45±0.79
5	F5	54.46±0.54	67.90±0.34	74.56±0.91
6	F6	74.65±0.85	81.02±0.87	79.78±0.35
7	F7	20.12±0.99	48.34±1.54	53.45±0.73
8	F8	35.93±0.36	54.76±0.34	60.05±0.87
9	F9	47.20±0.59	63.95±0.54	66.21±0.21
10	F10	20.00±0.87	30.00±0.87	60.07±0.43
11	F11	21.49±0.23	37.49±0.23	68.56±0.98
12	F12	25.50±0.76	45.60±0.76	72.89±0.26

Weight Uniformity:

Weight of individual formulations of curcumin microsphere was checked for weight uniformity. The average weight uniformity of SLMs is given in Table 9.

Table 9: Average weight uniformity of SLMs

S. No.	Formulation code	Average weight (mg)
1	F1	2790
2	F2	2324
3	F3	2921
4	F4	2072
5	F5	2177
6	F6	2611
7	F7	2245
8	F8	2098
9	F9	2181
10	F10	2295
11	F11	2130
12	F12	2503

In-vitro drug release:

In-vitro drug release study was carried out by using 0.1N HCl (pH 1.2) and phosphate buffer (7.4pH) was used as dissolution medium (900ml). Sample withdrawn from dissolution medium were then analyzed through UV spectrophotometer at 432nm. The Results are shown in Table

Drug release profile of various formulations (F1- F3) of surfactant Span 80, (F4-F6) of surfactant Span 60 in table 15 and, (F7 - F9) of surfactant Span 20, (F10 - F12) of surfactant Tween 80 in Table

Table 10: In-vitro drug release of curcumin microsphere formulation from (F1-F12).

Hr	F1	F2	F3	F4	F5	F6
1	11.23±0.38	12.32±0.32	23.02±0.56	08.79±0.78	09.01±0.85	11.03±0.49
2	15.85±0.67	20.74±0.84	39.56±0.64	12.56±0.89	13.98±0.64	34.85±0.67
3	25.79±0.59	35.47±0.56	48.75±0.38	28.02±0.34	15.44±0.67	42.5±0.89
4	37.23±0.81	40.65±1.22	60.89±0.94	38.52±0.56	16.79±0.94	55.85±0.29
5	48.23±0.87	46.89±0.72	73.05±1.05	42.89±0.78	17.07±0.92	68.57±0.38
6	55.45±0.48	52.74±0.29	78.96±0.98	62.12±0.98	24.12±0.28	75.07±0.91
7	60.22±0.62	57.98±0.62	80.63±0.82	51.59±1.23	28.18±0.48	79.56±1.05
8	64.78±1.24	63.45±0.67	81.36±0.61	58.27±0.58	40.71±1.25	80.14±0.54
9	67.36±0.87	68.55±0.78	82.25±0.31	61.77±0.89	52.74±0.37	81.54±0.76
10	67.91±0.74	72.45±1.08	84.23±1.04	67.65±1.09	67.65±1.09	82.21±0.98
11	71.23±0.39	75.23±0.49	85.89±0.67	70.08±0.55	75.81±0.83	83.36±0.34
12	73.37±0.82	78.95±0.67	88.12±0.82	75.19±0.87	79.01±0.68	85.15±0.55
Hr	F7	F8	F9	F10	F11	F12
1	2.21± 0.27	10.56±0.2	17.5±0.81	1.59±0.08	1.88±0.12	11.03±0.49
2	13.59±0.84	14.85±0.67	26.4±0.97	8.62±0.66	2.95±0.76	10.18±0.90
3	15.78±0.64	15.98±0.98	32.2±0.21	18.02±0.28	3.27±0.94	19.06±0.35
4	17.19±0.49	17.76±0.46	44.12±0.62	25.79±0.87	4.56±0.58	28.62±0.63
5	21.25±0.76	20.46±1.03	59.75±1.06	33.12±0.97	10.25±1.04	37.49±0.57
6	23.49±1.21	34.76±0.98	67.22±0.82	37.62±1.20	14.29±0.45	41.13±0.26
7	35.76±0.84	42.16±0.76	70.27±0.94	44.71±1.66	27.49±0.68	47.56±0.36
8	42.18±0.49	49.25±0.44	74.87±0.27	47.93±0.75	31.76±0.97	52.22±0.79
9	53.64±0.64	59.45±0.69	77.21±0.68	53.17±0.62	44.26±1.36	57.83±0.98
10	62.35±0.76	69.75±0.84	80.23±1.11	56.06±0.36	50.72±0.56	62.11±1.34
11	70.25±1.04	79.12±0.55	82.36±0.94	63.29±0.59	60.28±0.76	65.27±0.64
12	77.29±0.94	82.26±1.01	84.21±0.87	62.33±1.87	65.46±0.98	69.87±0.71

Fig.5: % Cumulative Drug Release of surfactant span 80 formulation (F1-F3)

Fig 6: % Cumulative drug release of surfactant span 60 formulation (F4-F6)

Fig 8: % Cumulative Drug Release of surfactant span 20 formulation (F7-F9).

Fig.9: % Cumulative Drug Release of surfactant Tween80 formulations (F10-F12).

Table 11: In-vitro drug release of best four formulations (F3, F6, F9 and F12).

Hour (hr)	F3	F6	F9	F12
0	0	0	0	0
1	23.2±0.56	11.03±0.49	17.5±0.81	3.07±0.54
2	39.56±0.64	34.85±0.87	26.4±0.67	10.18±0.90
3	48.75±0.38	42.5±0.38	32.2±0.47	19.06±0.25
4	60.89±0.94	55.85±0.290	44.12±0.28	28.62±0.63
5	73.05±1.05	68.57±0.68	57.75±1.05	37.49±0.57
6	78.96±0.98	75.07±0.91	67.22±0.98	41.13±0.26
7	80.63±0.82	79.56±0.47	70.27±0.82	47.56±0.65
8	81.36±0.61	80.14±0.67	74.87±0.61	52.22±0.36
9	82.25±0.38	81.54±0.28	77.21±0.38	57.83±0.79
10	84.23±1.04	82.21±1.11	80.23±1.04	62.11±0.18
11	85.89±0.67	83.36±0.67	82.36±0.67	65.27±1.36
12	88.12±0.82	85.15±0.82	84.21±0.82	69.87±0.71

Fig.10: %Cumulative Drug Release of best four formulations (F3, F6, F9 and F12). [(n=3), ± S.D.].

Based on encapsulation efficiency, percentage yield and percentage drug release the optimized formulations are F3 and F2. Therefore, F3 formulation was selected for measuring the size and shape of the microsphere.

Kinetic release of curcumin loaded microspheres:

Different models were applied on release of F3 formulation and best fit method was found to be Higuchi method

Table 12: Kinetic assessment of curcumin loaded microspheres (F3)

Formulation

code

Correlation co-efficient R2 value.

Zero order

(R2)

Zero order

(R2)

Higuchi type

(R2)

Korsmeyer

Pepper

release

0.8955

0.8311

0.9221

0.8719

Particle size of microparticles:

The particle size of microparticle formulations F3 was analyzed by Malvern Zeta- Sizer, which shows the average size of microparticles, which are within the range. The size ranged 23.70μm. The particle size was shown in figure

Morphology of Solid lipid microparticles:

Morphology of Solid lipid microparticles was studied using scanning electron microscopy (SEM). It was observed by SEM analysis that the optimized F3 formulation was smooth and spherical in shape. The outer surface of SLM is shown in figure

Fig 11. SEM image (shows morphology of microparticle) of curcumin solid lipid microparticles.

DISCUSSION:

Curcumin microspheres were designed with the objective of controlled and targeted release of drug to brain. Therefore, stearic acid polymer with various grades of surfactant (Span 20, 60, 80 and Tween 80) was chosen which assist the drug transportation and which also ensures the targeted effect. The identification of the procured drug was done by melting point determination which was found to be in the reference value range obtained from literature. Thin Layer Chromatography was also performed and the Rf value of the drug was almost same as reported in the literature confirmed the identity of the drug. The identification of the drug was further confirmed by its FTIR spectroscopy in which the spectrum was analyzed to confirm the presence of various functional groups present in curcumin and it same as reported in literature. Figure 14, 15 and 16 shows the standard calibration curve with regression value of 0.998 for 1.2pH [0.1 N HCl], 0.999 for 7.4pH [phosphate buffer] and 0.998 for methanol. The curves were found to be linear in the range of 5-30μg/mL at λ max of 432nm. During drug-excipient compatibility study by FTIR, there was no change in the major peaks. This suggested that there was no interaction between drug and excipient. Regarding solubility studies in different media as shown in table 12, it was found that solubility of curcumin was more in methanol (4.21± 0.056) as compared to Phosphate Buffer pH 7.4 (2.68± 0.039) than pH 1.2 0.1N HCl (0.65±0.06).

It was observed that the results of percentage yield and drug loading were within the limit with respect to variation of surfactant concentration of same formulations. The encapsulation efficiency of all formulations lies 82.23% to 88.56%, Percentage yield was 72.01% - 79.64% and drug loading was found to be 54.63% to 67.78%. Table 20 showed the results of each formulation.

The in-vitro drug release pattern of curcumin was carried out and shows in Figure 17, 18, 19, 20 and 21, and table 15 and 16 shows the pattern of drug release. F3 formulation showed maximum release up to 86.23%. The SPAN 80 containing microspheres of curcumin offered a high degree of positive results in relation of its constant drug release. The experimental design was optimized by using Hot melt microencapsulation technique.

Figure 23 shows the average size of F3 formulations i.e., 23.70μm. The results of Scanning Electron Microscopy revealed smooth and spherical structure of microsphere.

RESULT:

In the Preformulation study drug authentication was done with melting point, thin layer chromatography and FTIR spectroscopy. Compatibility study shows no change in the drug and excipient, this means drug does not show any kind of incompatibility with excipient. The calibration curve of curcumin was prepared in 0.1N HCl (pH 1.2), phosphate buffer (pH 7.4) and methanol. All the curves show linear line. The solubility study, TLC, FTIR spectroscopy is also performed. Curcumin SLM consist varied ratio of surfactant but constant ratio of polymer. The SLMs are prepared by using hot melt micro-encapsulation technique. The developed formulation were evaluated in terms of particle size, shape, entrapment efficiency, drug loading, percentage yield, in-vitro drug release and kinetic release of drug. Through Malvern Zetasizer particle size of formulation was determined. The SEM of curcumin microparticles reveals the spherical and smooth surface. All the formulation shows good entrapment efficiency. The in-vitro release studies of microparticles were carried out in USP-2 dissolution apparatus. The dissolution medium were kept at pH 1.2of 0.1N HCl, phosphate buffer (pH 7.4). The in-vitro release study revealed that there was burst release of drug in 12hr from the Microparticle formulation. The formulation was subjected to various kinetic models i.e. zero order, first order, Hiruchi and Pappas model.

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Received on 02.07.2021 Modified on 08.02.2022

Asian J. Pharm. Tech. 2022; 12(3):193-201.

DOI: 10.52711/2231-5713.2022.00032