In silico Biopharmaceutical Prediction of silver Nanoparticle and Ibuprofen Complex

 

Kailas M. Karande¹, Shivaji P. Gawade²

¹Department of Pharmaceutics, Satara College of Pharmacy, Satara, India.

²Principal, Late Narayandas Bhawandas Chhabada Institute of Pharmacy, Raigaon, Satara.

 

ABSTRACT:

Prevalence of silver nanoparticles in various sectors including healthcare is abundantly increasing. Several research articles are published focusing the synthesis and silver nanoparticle’s activities. Least literature is available about the long-term or short-term health consequences of these nanoparticles. While ionic and nanoparticulate silver are employed in several applications, information on their undesirable health effects are truly extremely scarce and roughly all concluded simply acute effects caused by short-range contact to very elevated doses. Few consequences are argyria and argyrosis, (bluish grey discolorations of skin and eye, respectively). Both situations are caused by the contact to a high dose of silver or to constant short doses of silver used for some months or even years. In contexts of this, we have worked on in silico ADME profile of silver nanoparticles and its complexation with ibuprofen using Gastroplus software. In order to make sure the reliability of in silico model used, we have validated it with the independent data from the literature. Pharmacokinetic parameters, like %Fa, %FDp, %F, Cmax, Tmax, AUC were determined and revealed the superiority of complex against the pure drug.

 

 

 

INTRODUCTION:

Prevalence of silver nanoparticle in various sectors including healthcare is abundantly increasing. Several research articles are published focusing the synthesis and silver nanoparticle’s activities. Least literature is available about the long-standing or short period health consequences of these nanoparticles. While ionic and nanoparticulate silver are employed in several applications, information on their undesirable health effects are truly extremely scarce and roughly all concluded simply acute effects caused by short-range contact to very elevated doses. Few consequences are argyrosis and argyria, (bluish grey discolorations of eye and skin, respectively). Both situations are caused by the contact to a high dose of silver or to constant short doses of silver used for some months or even years.

 

In contexts of this, we have worked on in silico ADME profile of silver nanoparticle and its complexation with ibuprofen. In order to make sure the reliability of in silico model used, we have validated it with the independent data from the literature.

 

Virtual screening (in silico) of ADME profile using Gastroplus software:

In silico pharmacology (otherwise called computational therapeutics, computational pharmacology) is a promptly developing field that internationally covers the advancement of procedures for utilizing programming to catch, examine and incorporate organic and clinical information from numerous differing sources. All the more explicitly, it characterizes the utilization of this data in the production of computational models or reproductions that can be utilized to cause forecasts, to recommend theories, and at last give disclosures or advances in medication and therapeutics.

 

Human pharmacokinetic (PK) forecast/predictions play a vital role in assessing the worth of prospective clinical candidate where the precise judgment of clearance, volume of distribution (Dv), bioavailability, and the plasma-concentration (Pc)-time profiles are the preferred conclusion points. While numerous methods for carrying out predictions exploit in vivo data, prediction may also be conducted productively from in vitro or in silico information, applying modeling and replication (simulation) techniques. The objective/s of current investigation was/were to screen individually the pharmacokinetic profile of silver nanoparticle and ibuprofen silver nanoparticle (IbuNS) complex. The virtual screening was done by means of commercially existing prediction software, GastroPlus which has been found to report a precise forecast ADME profile of small drug-like molecules. GastroPlus is a cutting-edge innovation PC program that mimics iv, gi, ocular, nasal as well as pulmonary ingestion, pharmacokinetics, and alternatively, pharmacodynamic impacts, for drugs dosed in Human (people) and animal.

 

Absorption – An Important Distinction:

For oral dosages, the portion absorbed in GastroPlus is characterized as the net part of the dose that is absorbed into the apical film of the epithelial cells in the gi tract, with regards to the cutting edge meaning of absorption by USFDA.

 

With the base of Fick's First Law, the GastroPlus permits exsorption (discharge from enterocytes to lumen, which has been reported in literature for IV dosage) as well as absorption (assimilation) from lumen to enterocytes. Consequently, the portion absorbed is determined as the net absorption (retention) and exorption.

 

Pharmacokinetics in Gastro Plus:

A single-, two-, or three-compartment pharmacokinetic allows calculation of plasma concentration (Cp)-time profiles by means of suitable inputs, accounting for the interactions between absorption and pharmacokinetics seen with many drugs. Different properties considered in present investigation were the predictions from ADMET Predictor v9.5.0.0., ADMET Predictor pridicts over 140 different property including solubility, pKa, logP, CYP sites for metabolism, and Ames mutagenicity. ADMET Predictor is the most recent virtual computational tool, consisting the latest ideas and features which precisely predicts the ADMET property of a drug or dosage form. Predictor allows one to rapidly and easily create high quality QSAR/QSPR models based on the structural data provided. Software used in present investigation was proposed by Simulation Plus.

 

METHODS:

Plasma Concentration (Cp) Simulations:

The software GastroPlus^™ ver 9.7 (SimPlus Inc., Lancaster, CA, USA) was employed to predict oral absorption of silver nanoparticle (NS) and ibuprofen conjugate. For such, a database for the drugs was created in GastroPlus^™. Data used as Input data were consists of values taken from the (independent literature) literature available, including pKa, solubility, partition coefficient (Log P), supplementary parameters predicted employing the ADMET Predictor^™.

 

Properties were predictions from ADMET Predictor v9.5.0.0 and few were observed, which were shown in table 1

Table 1: Properties considered during in silico analysis

Sr. No.	Parameter	Value		Reference/Data Source
		NS	IbuNS
1	Molecular weight	108.88	314.15	ADMET Predictor v9.5.0.0
2	Solubility (mg/mL)	7.371	9.12	1ADMET Predictor v9.5.0.0 2Observed
3	pKa	4.40	4.40	ADMET Predictor v9.5.0.0
4	Log P	3.95	3.98	ADMET Predictor v9.5.0.0
5	Dose (mg)	100	100	ADMET Predictor v9.5.0.0
6	Effective permeability, Peff (cm/s × 10−4)	5.07	6.52	ADMET Predictor v9.5.0.0
7	Blood/plasma ratio	1.61	0.7	ADMET Predictor v9.5.0.0
8	Unbound plasma (%)	5.5	-	ADMET Predictor v9.5.0.0
9	Physiology	Human	Human	ADMET Predictor v9.5.0.0
10	Body weight (kg)	70	70	ADMET Predictor v9.5.0.0
11	Mean particle radius	25	70	Observed

 

In the GastroPlus^™ database records were created for three compounds silver, ibuprofen and Ibu NS. The simulations were performed in GastroPlus^™ to acquire the predicted values for the plasma concentration (Cp). Concentration curves were compared to each other (Ibu and Ibu NS) with respect to regression parameters generated by the software.

 

The pharmacokinetic parameters:

The pharmacokinetic parameters viz %F (% bioavailable, percent of dose that reached the systemic circulation), T_max, C_max, AUC (Area Under the Curve) were plotted by GastroPlus^™.

 

RESULTS AND DISCUSSION:

Plasma Concentration (Cp) Simulations:

The mechanism of absorption of silver nanoparticle is very complex phenomenon than of small molecules. The nanoparticles which are administered by oral route may be absorbed by paracellular transportation, transcytosis and M cell uptake in the GI tract, whilst macrophages and lymphatic uptake absorb primarily subcutaneous, intramuscular or inhaled nanoparticles [1].

 

Exposure routes for silver nanoparticles may include dermal, oral, and inhalational introduction, it should be marked that the bio-availability is generally low and depends on the dose, surface coating, particle size and soluble fraction. Bioavailability of silver nanoparticle is low than its salt [2]. Following oral exposure in rats, the bioavailability of silver nanoparticle was found to be 1.2 % and 4.2% for 1mg/kg and 10mg/kg dose respectively [3]. In present investigation, in silico model predicted approximately 94.51% bioavailability (results were shown in figure 1) after oral administration of silver nanoparticle, which may be on account of interaction of AgNp with approximately 7000 proteins and isoforms [4], moreover, its major excretion source was reported through feces [5]. Predicted bioavailability in present investigation and reference [6] bioavailability was found to be superimposed findings and may validate the model used.

 

Silver nanoparticle were accumulated in the liver, lungs and kidney and elimination usually takes five to seven days after administration without showing any adverse effects. Silver nanoparticle showed a plasma half-life of 99 h. For humans it was predicted half-life of 15 days in the human liver. For complete clearance, silver nanoparticles may take 84 days [7]. In present in silico screening the plasma concentration (Cp Time profile) was screened for 24 h which revealed that the plasma concentration remains merely constant for 24h. It may be owing to uptake of particles by the MPS which increases with higher nanosilver concentration in the blood [8]. GastroPlus™ to build a compartmental pharmacokinetic (PK) model. PKPlus™ is an optional unit in GastroPlus™ which uses IV (intravenous) or oral CpT (plasma concentration–time) data to compute the most fitting modeling (one (1)-, two (2)-, or three (3)-compartmental models) and produce PK parameters for simulations [9].

 

In silico pharmacokinetic profile of ibuprofen was validated using the literature available [10] which revealed the successful application of in silico model.

 

In silico pharmacokinetic profile of IbuNS shown that the IbuNs would cause analgesic effects with a comparable onset of action as of ibuprofen, however with an additional area under curve 107.12 ng-h/ml. The results were shown in table 4.

 

The pharmacokinetic parameters

Table 2: In silico bioavailability of silver nanoparticle

Time (h)	0	2	4	6	8	10	12	14	16	18	20	22	24
Cp SilNm (ng/mL)	0	0.525	0.532	0.530	0.529	0.527	0.525	0.523	0.522	0.520	0.520	0.518	0.514

 

 

Figure 3: In silico bioavailability of Ibuprofen and Ibu-Nm

 

Table 3: In silico bioavailability of Ibu and Ibu-Nm

SimTime (h)	0	2	4	6	8	10	12	14	16	18	20	22	24
Cp-2- Ibu(ug/mL)	0	3.347	2.704	2.168	1.738	1.394	1.118	0.896	0.718	0.576	0.462	0.370	0.297
Cp-2-Sil-ibu(ug/mL)	0	3.584	3.191	2.822	2.496	2.208	1.953	1.727	1.528	1.351	1.195	1.057	0.935

 

Table 4: In silico pharmacokinetic profile NS, Ibu and Ibu-Nm

 

Simulation time was set to 24h with single dose administration of NS, IBU, and IBU-Nm. Fraction absorbed (Fa%) after gut metabolism, fraction absorbed (FDp%) after portal circulation, bioavailability (F) of NS were found to be same 94.491 which indicates the bypass of portal and gut metabolism for NS. Fa%, FDp% and Fa of IBU were found to be 99.987, 99.983 and 96.404 respectively, which indicates that there was gut and portal metabolism of IBU. Fa%, FDp% and Fa of IBU-Nm complex were found to be 99.962, 99.945 and 96.367 respectively, which indicates that there was gut and portal metabolism of IBU-Nm complex but the extent of metabolism was slightly lesser than the pure IBU. Cmax, which is maximum plasma concentration when a drug achieves in a particular compartment before the administration of a second dose. Cmax of NS was found to be 0.53428ng/mL while for IBU and IBU-Nm was observed to be 3.4447 and 3.722 respectively, which indicates that the Cmax for complex was slightly superior to the pure IBU. Tmax, maximum time required to achieve peak plasma concentration of NS was found to be 4h, while for IBU and IBU-Nm was found to be 1.44h and 1.76h respectively. AUC, drug amount absorbed systemically, of NS was found to be 822.86 which indicate the lowest clearance and accumulation of Nm for longer duration in the body. AUC for IBU and IBU-Nm was found to be 35.709 and 107.12 respectively. This clearly indicates the affirmative effect of complexation. AUC of complex was significantly more (approx. 3-fold) than the pure IBU.

 

CONCLUSION:

Cp simulations and pharmacokinetic parameters were determined using commercial software, Gastroplus. The model used was found to be valid. Pharmacokinetic parameters, like %Fa, %FDp, %F, Cmax, Tmax, AUC were determined and revealed the superiority of complex against the pure drug.

 

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Accepted on 13.07.2020           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(3):1736-1740.