INTRODUCTION:

Nanoparticulate drug delivery systems signify a promising drug delivery system of controlled and targeted drug release. They are especially designed to release the drug in the surrounding area of goal tissue.

They exist as particulates or globular dispersions with a size in the series of 10-1000nm. In nano drug delivery systems, the drug or active component is dissolved, entrapped, encapsulated, adsorbed or attached to the matrix system.

Nano sized materials^[5,6] have more advantages over other dosage forms with larger particle size, as it can provide more surface area and increased solubility. It also provides the facility to control the drug release along with the ability to deliver the entrapped therapeutic agents to the desired site of action. Nano drugs are widely investigated for the oral delivery of drugs. Oral drug delivery is the much favored route of drug administration^[7] due to expediency, better patient fulfillment and cost-effectiveness. This system has been also used to increase bioavailability of drugs having poor bioavailability. However, due to the small size, extensive research was carried out on administration of these systems by various parenteral routes like intravenous, intra muscular and subcutaneous routes. The drugs loaded in nano drug delivery system were also reported to exhibit improved shelf life and stability.

MERITS OF NANO DRUG DELIVERY SYSTEMS:

1. They can be enabled with site specific delivery of drugs.

2. Site specific delivery of drugs facilitates enhanced therapeutic response and reduction in adverse effects.

3. Drug degradation by enzymatic action can be prevented.

4. Active and passive targeting of drug can be achieved by manipulating the particle size and surface characteristics.

5. Suitable for incorporation of wide range of therapeutic agents ranging from inorganic, organic, synthetic, semi-synthetic compounds, lipids and proteins.

6. They can be utilized for administration by oral, nasal, parenteral and ocular routes.

7. Controlled release of drug can be achieved

8. Surface modification using ligands can be made to improve the specificity of drug targeting.

DEMERITS:

1. Aggregation of particles due to their small size and huge surface area, however, this problem can be overcome by adjustment of surface charge (zeta potential) of the nanoparticles by addition of suitable surface active agents.

2. Difficult to handle in liquid forms (nanosuspensions). Freeze drying (lyophyllisation) had facilitated the maintenance of nanoparticles in dry form with enhanced stability.

3. Due to their ultra-small size they have limited drug loading capacity.

4. These are susceptible to bursting and leakage of drugs.

5. Scaling up problems due to the equipment’s used in the preparation and need for maintenance of uniform ultrafine size.

TYPES:

Nano drug delivery systems are classified based on the morphological characters, structure, composition as well as the arrangement of drug and polymer in the formulation:

1. Polymeric Nanoparticles:

The polymeric nanoparticles can be further classified into two types:

1. Nanospheres, which are polymeric matrix systems which consist of the drug that is dispersed physically and uniformly. The polymeric nano sized spherical matrix system provides effective control of the loaded drugs.

2. Nanocapsules^[8] are those systems containing vesicle’s in which the preparation is restrained to a cavity enclosed by a polymer membrane. In nanocapsules, the polymeric membrane encapsulates the core material, usually a drug.

Gymnemic acid was cut off from the leaves of Gymnema sylvestre (Asclepiadaceae). They are sweetness inhibitors. Once the leaves were eaten, sugar solutions sugar taste similar to water.

Chemically, they are triterpenoid glycosides. The fundamental configuration is the aglycone gymnemagenin (C₃₀H₅₀O₆). This is decked through a sugar for example glucuronic acid and by means of assorted ester groups. These variations give rise to the different gymnemic acids. More than 20 homologs of gymnemic acid are known.

Gymnemic acid it have the uppermost anti-sweet property. It suppresses the sweetness of mainly of the sweeteners as well as strong synthetic sweeteners like aspartame and natural sweeteners such as thaumatin, a sweet protein. The anti-sweet activity is reversible, but sugarinessrevival on the tongue can acquire more than 10 minutes.

The mechanism of the drug is during stimulus in insulin secretion beginning pancreas. It also exerts a parallel effect by delay the glucose assimilation in the blood.

Chitosan polymer is used here, which exhibit Biocompatible, biodegradable, non-toxic, anti-microbial and soluble in wide range of solvents.

MATERIALS AND METHODS:

Gymnemic acid, chitosan, poloxamer, ethanol, potassium dihydrogen phosphate, orthro phosphoric acid.

METHODS:

1. Preformulation studies:

Calibration graph for Gymnemic acid:

Preparation of calibration curve in pH 1.2, pH 7.4 and pH 6.8 buffers:

Weigh 100mgs of Gymnemic acid and dissolve it in a small volume of buffer solutions in 3 100ml volumetric flask and the volume is made up to 100ml with 1.2 pH buffer solution in volumetric flask numbered 1, in 2^ndvolumetric flask 7.4 pH buffer solution was used and in the third one 6.8 pH buffer was used to make up the volume. A categorization of standard containing the concentration ranges from 10 to 50 µg/ml of Gymnemic acid were prepared for 1.2 pH buffer, 7.4 pH buffer solution and 6.8 pH buffer solution individually, absorbance were calculated at 290nm and calibration graph was plotted by means of concentration against absorbance.

2. Drug-excipient compatibility study by DSC:

Differential scanning calorimetry (DSC):

Samples of individual components in addition to each drug-excipient be weighed (Mettler Electronic balance) unswervingly in pierce aluminum crucible pans (5-10 mg) and scanned in the 50-300°C range below static air, with heating rate of 10ºC/min, using Shimadzu DSC-60 equipment.

METHOD OF PREPARATION^[9-14]

Table 1. Formula used for the preparation of Gymnemic acid nanoparticles

S. NO	FORMULA-TION	DRUG (mg)	CHITOSAN (%V/V)	TWEEN (%V/V)
1.	GNP-1	100mg	0.5	5
2.	GNP -2	100mg	1.0	5
3.	GNP -3	100mg	1.5	5
4.	GNP -4	100mg	2.0	5
5.	GNP -5	100mg	2.5	5

METHOD:

Emulsion -droplet coalescence method:

· Dissolve Chitosan particles with 1% acetic acid and 100mg of Gymnemic acid in phosphate buffered saline. This solution is added to 10ml of liquid paraffin contain 5% v/v tween 20. The mixture was homogenized 3 minutes to form water in oil (w/o) emulsion.

· The resultant Gymnemic acid nanoparticles[9] were centrifuged at 3000 rpm for 60 mts and washed with ethanol and water, consecutively to eliminate residual liquid paraffin and surfactant.

· afterward on they were dried in air for 3 hour followed by hot air oven at 50° for 4 hour and store in a desiccator

· Some batches namely (GNP1, GNP2, GNP3, GNP4, and GNP5) be prepared by varying the drug and polymeric ratio and the result of polymer concentration on the encapsulation effectiveness and the drug loading capacity was studied.

CHARACTERIZATION STUDIES:

· Drug content

· Particle size and zeta potential

· Drug content

· Encapsulation efficiency

· In vitro drug release^[15]

Particle size and Surface charge:

Using Malvern-Zeta size the zeta- potential is calculated and the significance in surface charge of adhesion and interaction of particle with cells is noted. The prepared nanoparticles^[16,17] was evaluate for their particle size and surface charge by photon correlation spectroscopy (PCS) by means of zeta sizer and diluted to 1:1000 with the aqueous phase of the formulation to obtain a suitable kilo counts per second (kcps) and then it is analyzed at 25°C with an angle of detection of 90° six replicates was in use for the measurement.

Drug content:

Weigh 1gm of gymnemic acid nanoparticles^[18] exactly transfer into a 25ml volumetric standard flask and dissolve 5 ml with pH 6.8 phosphate buffer solution then dilute 1 ml to 25 ml of buffer solution and Then the usual and sample absorbance was measured at 290 nm using a UV-Visible spectrophotometer. The percentage of drug content was calculated.

Entrapment efficiency:

The drug infused nanoparticles are centrifuged at 15000 rpm for about 30 mins. 1ml of the separated supernant solution was diluted with water and the absorbance was noted at 290 nm and calculated for the quantity of gymnemic acid entrapped was calculated by subtracting the sum of untapped^[19,20]from the total gymnemic acid used for the preparation.

The entrapment efficiency was calculated based on the formula given below

In vitro release:

Using Franz diffusion cell the invitro study was performed for about 24 hrs using a dialysis membrane. The equipped gymnemic acid nanoparticles^[21,22]are kept inside the membrane and it is immersed in phosphate buffer with pH of 6.8 and the sample was withdrawn at programmed time interval and the quantity of gymnemic acid released was determined by measured using UV-Visible spectrophotometer at 290 nm absorbance. Based on the absorbance results a cumulative % of drug release was calculated and the results were discussed.

RESULTS AND DISCUSSION:

Preformulation studies^[23]:

Preparation of calibration graph for Gymnemic acid:

Standard calibration data of Gymnemic acid in pH 1.2, 7.4 and 6.8 buffers at 285 nm

Table 2. Absorbance of Gymnemic acid in buffer solutions

S. No	Concentration	Absorbance
S. No	Concentration	pH 1.2	pH 7.4	pH 6.8
1	10	0.025	0.031	0.101
2	20	0.052	0.063	0.204
3	30	0.076	0.095	0.302
4	40	0.104	0.122	0.406
5	50	0.124	0.155	0.505

Fig. 1. Calibration curve of Gymnemic acid in pH 1.2, 7.4 and 6.8buffers

Standard calibration curve of Gymnemic acid was carried out in 1.2 pH, 7.4 pH and 6.8 pH buffer at 220 nm. The r²value in the entire medium shows nearly 1, which signifies linearity.

DSC analysis:

The melting point of gymnemic acid and the physical mixture of other ingredients showed a similarity index in thermogram graph DSC analysis. Hence from the DSC study, it was found no interaction between Gymnemic acid and other excipients used in the formulation.

The DSC thermogram be given in the Fig. 2 and 3

Drug –Excipients compatibility analysis - Physical observation and assay:

Based on the study the material of drug-excipient has no characteristic color change and there is no significant changes in the chemical evaluation this indicates that the drug and ingredients added are compatible with each other.the results are given below in the table 3

Table 3 Physical characteristics of Gymnemic acid

S.No	Physical parameter	Results
1	Description	Dark brown colour powder
2	Melting point	198.8⁰C
3	Loss on drying	0.08%
4	Assay	99.58%

Table 4 Physical characteristics of individual drug and excipients[21]

S.No	Sample ID	Initial description	Final description
1.	Gymnemic acid	Dark brown colour powdered	No changes
2.	Chitosan	Off-white powder	No changes

Table 5 Physical characteristics of drug-excipient mixture

S.No	Sample ID	Initial description	Final description
1.	Gymnemic acid	Dark brown colour powdered	No changes
2	Gymnemic acid+ Chitosan	Brown colour powders	No changes

Table 6 Chemical characteristics of drug-excipient mixture

S.No	Sample ID	Initial assay (%)	Final assay (%)
1.	Gymnemic acid	99.58%±0.26	99.54%±0.21
2.	Gymnemic acid+ Chitosan	99.55%±0.64	99.51%±0.43

n = 3; Mean ± S.E.M.

Table 7 Drug content and entrapment efficiency Particle size and zeta potential of Gymnemic acid nanoparticle.

Trial	Zeta potential (mV)	Particle size(nm)	Entrapment Efficiency (%)	Drug Content(%)
GNP1	17.9	190.1	58.67	99.53
GNP 2	16.7	192.6	68.73	99.51
GNP 3	15.6	195.0	85.71	99.57
GNP 4	14.2	196.5	86.24	99.54
GNP 5	13.6	197.3	86.71	99.52

· As a result, the zetapotential rate for GNP3 was obtained maximum of 19.6 mV.

· The particle size has no changes ^[24].

· Particle size and entrapment efficiency of the Gymnemic acid nanoparticles(GNP1- GNP5) were greater than before with increasing Chitosan concentration.

· This is because of elevated quantity of availability of Chitosan to encapsulate the drug, in the lead increase the Chitosan concentration, number of layers coated the drug was improved, thus results in increased particle size and entrapment efficiency^[25].

· Further increase in the Chitosan concentration (GNP4-GNP5), has no more augment in the entrapment efficiency because the accessibility of the drug to be included is small which is not enough for further encapsulation of drug by Chitosan.

In- vitro drug release:

Table 8 In vitro release studies of Gymnemic acid nanoparticles

S. No	Time in (Hrs)	PERCENTAGE CUMULATIVE DRUG RELEASE
S. No	Time in (Hrs)	GNP1	GNP2	GNP3	GNP4	GNP5
1.	0.5	35.86± 0.47	30.25± 0.55	21.74± 0.33	12.75± 0.19	8.88± 0.24
2	1	50.81± 0.22	41.37± 0.23	36.85± 0.56	23.18± 0.27	17.63± 0.92
3	6	88.72± 0.19	72.36± 0.42	43.82± 0.72	32.15± 0.56	25.74± 0.34
4	12	99.51± 0.34	85.74± 0.19	56.89± 0.18	43.81± 0.15	32.81± 0.17
5	16	99.52± 0.67	97.32± 0.74	71.73± 0.88	57.93± 0.31	42.72± 0.35
6	20	99.53± 0.17	99.49± 0.11	84.88± 0.24	66.48± 0.71	51.95± 0.73
7	24	99.55± 0.89	99.51± 0.34	99.57± 0.31	78.82± 0.82	65.73± 0.62

mean±S.D, n=3

FIG. 6. Effect of Chitosan concentration on Invitro drug release of Gymnemic acid nanoparticles

From the in vitro drug release [26] study results, the highest drug release (99.57± 0.31) and at the closing stages of 24hwas observed with trial GNP3 which contains 1.5% w/v of Chitosan.

Below 1.5% w/v of Chitosan concentration as in the case of trials GNP1 and GNP 2 the maximum percentage drug release 99.51± 0.34 and 99.49± 0.11 were obtained at the end of 12 and 20hrs respectively which was not desirable^[27].

Above 1.5% w/v of Chitosan concentration^[28], reduction in drug release was observed as in the case of trial GNP4 and GNP5. The maximum percentage drug release for GNP4 and GNP5 were found to be 78.82± 0.82 and 65.73± 0.62 respectively at the end of 24h was obtained.

From the records obtained from in vitro drug release for GNP1- GNP5, it was concluded that increase in Chitosan concentration slows down the drug liberate due to improved particle size and decresed surface area of the prepared nanoparticles.

From all the above formulations, GNP3^[28] was preferred as best formulation due to its ideal particle size (195 nm), high entrapment efficiency (85.71%) and desirable drug release (99.57± 0.31% at the end of 24 h).

4. SUMMARY AND CONCLUSIONS:

The active pharmaceutical ingredient Gymnemic acid was evaluated for its organoleptic properties and solubility. The results obtained were satisfactory.

Gymnemic acid nanoparticles were prepared by emulsion -droplet coalescence method^[30] and the polymer concentrations were optimized by various trials

In the present study Chitosan nanoparticles containing Gymnemic acid was prepared. The effect of increase in Chitosan^[31] concentration in various parameters like particle size and invitro release profile were studied.

The Gymnemic acid nanoparticles were formulated and evaluated for its invitro drug release profile^[33]. The results showed that the in vitro drug release for GNP1, GNP2, GNP3, GNP4 and GNP5 was found to be 99.55± 0.89, 99.51± 0.34, 99.57± 0.31,78.82± 0.82 and 65.73± 0.62 respectively at the end of 24hrs.

Based on the in vitro study profile of Gymnemic acid nanoparticles formulations^[34] (GNP1-GNP5) formulation GNP3 was selected as finest formulation in which the particle size was 195 nm.

The % in vitro study of GNP3 formulation was 99.57± 0.31 and it was found to be suitable formulation to manage the condition of diabetes mellitus. Hence it can be concluded that the newly formulated controlled release nanoparticulate drug delivery^[35] systems of Gymnemic acid may be ideal and effective in the treatment of diabetes mellitus by allowing the drug to release continuously for 24 hrs.

5. CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 20.11.2018 Modified on 31.12.2018

Research J. Pharm. and Tech. 2019; 12(4): 1688-1694.

DOI: 10.5958/0974-360X.2019.00282.8