Development, In-Vitro and In-Vivo Evaluation of Gastro Retentive Formulations for Moxifloxacin HCl

 

Raghavendra Kumar Gunda¹*, A. Vijayalakshmi², K. Masilamani³

¹Research Scholar, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Pallavaram, Chennai, Tamil Nadu, India- 600117.

²Department of Pharmacognosy, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Pallavaram, Chennai, Tamil Nadu, India- 600117.

³Department of Pharmaceutics, Jaya College of Paramedical Sciences, College of Pharmacy, Thiruninravur, Chennai, Tamil Nadu, India- 602024.

 

ABSTRACT:

The objective of current study is to develop gastro retentive formulation for Moxifloxacin. HCl using various drug release modifiers and performing In-vitro, In-vivo evaluations. Moxifloxacin, novel synthetic fluoro quinolone, antibacterial agent. Floating, Muco Adhesive tablets of Moxifloxacin. HCl were prepared using variable amounts of HPMCK100M, Lannea coromandelica gum (LCG) by direct compression technique, Wet Granulation technique respectively. Amount of release modifiers required to obtain the prolonged release of drug shows impact on objective of the study. Formulations were developed and are checked for pharmacopoeial tests. Results shows that all the formulations were lie within the standard limits. Dissolution parameters of all formulations were subjected to kinetic fitting, various statistical parameters were determined. Formulation GRSOF containing 50mg of HPMCK100M and 50mg of LCG, is the best formulation showing similarity f₂=71.734, f₁=4.271 with the marketed product (AVELOX). It follows Higuchi’s kinetics, Non-Fickian Diffusion first order kinetics (n= 0.717). In-vivo studies were performed for the GRSOF with 6 healthy rabbits and pharmacokinetic parameters were determined, compared with AVELOX and found that GRSOF produced similar results. GRSOF expected to improve patient compliance by means of providing good clinical outcome.

 

 

 

INTRODUCTION:

Gastric emptying is a dynamic process and gastro retentivity of dosage form results improved clinical response^[1-3]. Gastric transit time in humans, influences absorption of drugs, can result inappropriate drug release from formulation leading to diminished clinical response. Gastro retentive dosage forms had the ability to sustain the release of drug at predictive rate, by retaining the drug in the acidic environment for a longer period of time. Gastro retentive dosage forms are suitable for local drug delivery to the stomach and small intestine^[4].

 

In case of many drugs which are released in the stomach have the greatest therapeutic effect while their release is prolonged in a continuous and controlled manner. This type of drug delivery system will have relatively less side effect and removes the need of repeated dosages^[5-6].

 

The controlled gastric retention of solid dosage forms was obtained by numerous mechanisms such as flotation, bioadhesion, High density (sedimentation), modified shape systems, expansion, or by simultaneous administration of pharmacological agents that delay gastric emptying^[7-8].

 

Bioadhesive delivery systems produce many more benefits over other oral modified release systems by virtue of gastro retentivity, localization by targeting drug product at a specific site. It also proven that bioadhesive systems, they provide intimate contact between absorptive mucosa and dosage form which results high flux of drug through the GI mucosa^[9-15].

 

Floating Drug Delivery Systems (FDDS) have a bulk density is lower than gastric fluids and thus remain buoyant in gastric environment for prolonged period of time, without affecting the gastric emptying rate. Dosage form is stayed in stomach due to flotation mechanism, which results controlled rate of drug release. After the release of drug, the residual system is run out from the gastro environment; this will increases GRT and a better control of fluctuations in plasma drug concentrations^[16-19]. They also offer maintenance of C_ss longer period of time and minimizing the risk of resistance, this is very useful for delivery of antibiotics^[20].

 

Moxifloxacin. HCl, synthetic broad spectrum antibacterial agent belongs to the class of 4^th generation fluoroquinolone. It has a narrow absorption window and absorbed primarily in the proximal portions of gut, an ideal candidate for a gastroretentive drug-delivery system that will prolong the gastric transit time of formulation, results enhanced bioavailability^[21-22].

 

An attempt is made in current study to develop gastro retentive drug delivery system (preferably by Flotation) with the help of drug release rate modifiers (Natural- Lannea coromandelica gum (LCG), Semisynthetic-HPMCK100M) and effervescent mixtures^[23-25]. From the literature, very less work reported for LCG, though it is natural more benefits observed from economy point of view as well as risk incidence also low. Hence LCG selected as polymer for the formulation development of Moxifloxacin. HCl Gastro retentive delivery.

 

Most of the Tablets were manufactured by utilising Direct Compression Technique. But drug release retardation also influenced by method of manufacture, literature survey proved that Gastro retentive formulations were prepared by Wet Granulation Technique also^[26].

 

The development of gastro retentive drug delivery system of Moxifloxacin. HCl using polymers which increases the gastric transit time, improve penetrability of drug via mucosa thereby improving the clinical efficacy of the active ingredient.

 

Hence an attempt is made in this research work to formulate gastro retentive floating (GRF), Muco Adhesive tablets of Moxifloxacin. HCl using HPMCK100M, LCG by Direct Compression technique, Wet Granulation method Respectively.

 

MATERIALS AND METHODS:

Materials:

A gift sample of Moxifloxacin. HCl was procured from Macleods Pharmaceutical Ltd, Mumbai, India. HPMCK100M was obtained from Loba Chemie Pvt. Ltd, Mumbai, India. Lannea coromandelica Gum was gifted from Sarada Pharmaceuticals, Guntur. All other excipients such as Sodium bicarbonate, Lactose, Emcompress, Magnesium stearate, Talcwere obtained from S.D. Fine Chem. Ltd, Mumbai, India.

 

Formulation Development of Moxifloxacin. HCl Gastro Retentive  Tablets:

Preparation of Moxifloxacin HCl Muco Adhesive Tablets (GMAF):

Granules were prepared by wet granulation method. Moxifloxacin HCl, polymers were dry mixed for period of 15 min. Distilled water was added as granulating liquid. The cohesive mass obtained was passed through sieve no # 12. The wet granules were dried at 60⁰C for 15 min. The dried granules were passed through sieve no # 16 and were mixed with lubricants. Granules showing promising preformulation properties were subjected to compression using rotary tablet punching machine (RIMEK), Ahmadabad. The composition is shown in Table 1.

 

Table 1: Formulae for the preparation of Moxifloxacin HCl Gastro retentive Tablets

Name of the Ingredients	Quantity for single Tablet (mg)
	GMAF	GRSOF
Moxifloxacin. HCl	436.8	436.8
Emcompress		47.2
Lactose	47.2	-
HPMCK100M	-	50
HPMCK15M	-	-
Lanneacoromandelica gum (LCG)	150	50
Sodium bicarbonate	-	50
Talc	3	3
Magnesium Stearate	3	3
Total Weight	640	640

 

Preparation of Moxifloxacin HCl Floating Tablets (GRSOF):

Direct compression technique was utilised for the preparation of floating tablets, each containing 436.8 mg Moxifloxacin HCl equivalent to 400 mg Moxifloxacin Accurately weighed ingredients (except Moxifloxacin HCl) were screened (# 40 mesh) for obtaining uniform size to ensure proper mixing, to obtain polymer mixture. The drug was then mixed with the polymer mixture for 10 minutes for uniform mixing of powder blend. Blend was lubricated with magnesium stearate. The formulae for Moxifloxacin HCl floating tablets were shown in Table 1. Powder blend was subjected to preformulation analysis. Results show good flow properties. Powder blend was subjected to compression with the help of rotary tablet compression machine (Tablet Minipress).

Compressed tablets were examined as per official standards and unofficial tests. Tablets were packaged in well closed light resistance and moisture proof containers.

 

Evaluation of Moxifloxacin. HCl Gastro Retentive Tablets^[27]:

Hardness:

The breaking/crushing strength of the tablets was determined by measuring diametric breakdown of tablet using a Monsanto Tablet Hardness Tester.

 

Friability:

The friability of the tablets was carried with the help of Roche friabilator. 20 tablets were weighed noted as initial weight (W₀), these were subjected to 100 free falls from a fixed height and weighed (W) again. % friability was calculated by using following formula. The friability result should not be more than 1%.

 

Weight loss (%) = [W₀- W / W₀] x 100:

 

Assay:

Assay was performed by triturating stated number of tablets in Indian pharmacopoeia (20) converted to powder, powder equivalent to 100mg of drug was added in 100ml of 0.1 N HCl, followed by sonication. The solution was filtered through a 0.45μ membrane filter, suitable aliquots were prepared, and the absorbance of the resultant solution was measured spectrophotometrically at 288nm using 0.1 N HCl as blank^[28].

 

Thickness:

Thickness formulations were determined by using vernier calipers, by placing tablet between two arms it.

 

In vitro buoyancy studies:

This test is performed by placing the tablets in a beaker containing 100mL of 0.1 N HCl (SGF). The time required for the upward movement of tablet to float on the 0.1 N HCl (SGF) was noted to be floating lag time ^[30].

 

Measurement of Detachment force (Muco adhesion Strength):

Measurement of Detachment force is a measure of Adhesion strength. It is determined with the help of Texture Analyzer^[19].

 

In-Vitro drug release Study:

The In vitro dissolution rate study for formulation trails were performed using USP XXIII type-II dissolution test apparatus containing 900ml of 0.1 N HCl operated under conditions like temperature 37±0.5°C and rotated at a speed of 50rpm. At predetermined time intervals, 5ml of the samples were withdrawn as per the pharmacopoeial procedure. The resultant samples were analyzed for estimation of drug release by measuring the absorbance at 288nm using UV-Visible spectrophotometer after suitable aliquots. The samplings were performed in triplicate manner (n = 3)^[21,22,28].

 

The dissolution profile of all the formulations was subjected to kinetic modeling such as zero-order, first-order, Higuchi, and Korsmeyer–Peppas models to know the drug release mechanisms^[29-30].

 

Swelling Index Study:

To evaluate swelling index, tablet was placed in USP dissolution apparatus II with 900ml 0.1N HCl after measuring the weight of tablet (W₁). Then weight of tablet (W₂) was determined by virtue of time i.e. at different time intervals viz. 0, 2, 4, 6, 8, 10, 12h after using blotting paper to remove surplus fluid. Swelling Index was calculated using following formula.

 

Swelling Index (%) = [(W₂- W₁) / (W₂)] x 100

 

In-Vivo Evaluation:

In order to ascertain the Pharmacokinetic parameters and Clinical outcome, the In-vivo evaluation of GRSOF (Optimized) containing 436.8mg of Mopxifloxacin. HCl equivalent to 400mg of Moxifloxacin was performed. A Single dose Crossover, Non-Blended, Open Label and Randomized Block Study was designed and conducted using 6 healthy Rabbits with a washout period of 15 days. Prior ethical clearance was obtained from Institutional Animal Ethical Committee which is certified by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) and approved by Institutional Animal Ethical Committee ref. no. 1987/PO/Re/S/17/CPCSEA.Exp.No.5. Blood samples were collected at 0, 0.5, 1, 2, 4, 8, 12, 16, 20, 24 hours from the marginal vein. Collected samples were subjected to centrifugation by using Remi’s Micro Centrifuge-209 operated at 3000±500rpm for 10 minutes. After centrifugation the samples were preserved at refrigeration Conditions until the analysis was carried out. After analysis data processed for the determination of Pharmacokinetic parameters such as C_Max, T_Max, AUC etc The Pharmacokinetic Data obtained for GRSOF is compared with Avelox-400^[31-32].

 

RESULTS AND DISCUSSION:

Gastro retentive tablets of Moxifloxacin. HCl were formulated with the help of various drug release modifiers (HPMCK100M, LCG) along with effervescent mixtures. Formulation design was presented in Table 1.  All trials have 436.8mg of Moxifloxacin. HCl (equivalent to 400mg of Moxifloxacin) as a gastro retentive tablet dosage form prepared by direct compression technique as well as Wet Granulation Techniques. All final batches were subjected to various finished product evaluation tests like drug content, floating lag time, Adhesion Time, mean hardness, Muco adhesion Strength, total floating time, mean thickness, friability as per pharmacopoeial methods, and subjective results were summarized in Table 2.1, 2.2. Results reveals that all formulations were lie within the acceptance criterion. Swelling study was performed on all formulation Trials about 12 hours. From the swelling study it is found that GRSOF had highest swelling property and the data for swelling evaluation was presented as Figure 1.

 

Drug release studies were performed for finished batches using pH 1.2 buffer (0.1 N HCl) as a dissolution fluid as operated under standard set of conditions at 50rpm (Paddle), 37±0.5°C. Dissolution plots were presented in Figure 2 (Kinetic Plots). % CDR for formulations at 24 h were found to be 99.25±0.66-99.31±2.1%. The result revealed that the release rate of drug was inversely proportional to quantity of polymers and vice versa^[33]. Hence desired drug release was achieved by manipulating composition of Polymers.

 

Dissolution profiles of Moxifloxacin. HCl tablets were subjected to kinetic modeling. The results were presented (statistical parameters) as Table3. Formulation (GRSOF) is the identical product shows similarity factor (f2) 71.73, difference factor (f1) 4.27, t_cal is <0.05 when compared with marketed product (AVELOX).

 

Design for performing In-Vivo test was presented in Table 4. The mean Plasma Drug Concentration Profile of (In-Vivo) GRSOF, Marketed Product shows similarity or nearly super imposable. Results for Pharmacokinetic Evaluation were summarized in Table 5, Figure 3. C_max of Formulations was founded to be in the range of 18.29±0.5-18.65±0.4.T_max was founded to be 12 Hours. AUC_0-t was founded to be in the range of 195.79±12.51-209.62±15.78AUC_0-∞196.79±12.55-214.78±16.29.K_E values were founded to be in the range of 0.222±0.002- 0.332±0.001.

 

Table 2.1.: Final product quality assurance parameters for the Formulations (n= 3)

S. No	Formulation Code	Hardness (kg/cm2)	Thickness (mm)	Friability (%)	Average Weight (mg)	Drug Content (%)
1	GMAF	5.62±0.23	6.23±0.06	0.24±0.13	642±2	97.53±0.36
2	GRSOF	5.263±0.17	6.18±0.03	0.33±0.09	644.5±4.15	99.3±0.39

 

Table 2.2: Final product quality assurance (Gastro Retentive) parameters (n=3)

S. No	Formulation Code	Floating lag time (sec)	Total floating time (h)	Force of detachment (mN)	Adhesion Time (hr)
1	GMAF	-	-	453.39±9.61	25
2	GRSOF	51.95±1.45	24	-	-

 

Table 3: Regression analysis of Moxifloxacin HCl Gastro Retentive Tablet formulations (Kinetic Modelling)

S. No	Formulation Code	Kinetic Parameters
		Zero order			First Order			Higuchi			Korsemeyer-Peppas
		a	b	r	a	b	r	a	b	r	a	b	r
1	GMAF	22.637	3.581	0.962	2.096	0.067	0.924	2.035	20.079	0.998	1.072	0.716	0.932
2	GRSOF	29.247	3.576	0.924	2.071	0.082	0.984	6.699	20.703	0.990	1.116	0.717	0.912
3	MP	30.379	3.578	0.915	2.214	0.109	0.935	7.465	20.831	0.987	1.122	0.718	0.897

 

Table 4: Study Design (In Vivo) for the determination of Pharmacokinetic Parameters

 

Table 5: In-Vivo Pharmacokinetic Data for Moxifloxacin HCl Gastro Retentive Formulations

 

Fig. 1: % swelling with respect to time Chart

 

Fig. 2: Kinetic plots

 

Fig. 3: Comparative Plasma Drug profiles of Formulations

 

CONCLUSION:

On the basis of the current research study, the use of macro molecules (Natural and Semisynthetic polymers) in combination had its own advantages of maintaining integrity and buoyancy of tablets. Gastro retentive tablet dosage form of Moxifloxacin. HCl was formulated successfully using HPMCK100M, Lannea coromandelica gum. The effervescent based FDDS is a promising formulation to obtain gastro retentivity by using gel forming polymers employing sodium bicarbonate as gas generating agent. Among the various Gastro retentive formulations studied, the formulation (GRSOF) showed the best result in terms of the required % cumulative drug release, Floating lag time and total floating time and is considered as the ideal formulation. GRSOF follows First order release, Non-Fickian Diffusion. It shows good retaining characteristics. Plasma drug concentrations were maintained well. It also avoids first pass effect and also improves patient compliance by reducing the dosing frequency, which will ultimately improve the clinical outcome.

 

ACKNOWLEDGMENT:

Authors acknowledge sincere thanks to the management and Staff of School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Chennai for the facilities granted, support for the successful completion of research work.

 

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ABBREVATIONS AND SYMBOLS USED

GR           -       Gastro Retention

HPMC      -       Hydroxy Propyl Methyl Cellulose

LCG         -       Lannea Coromandelica Gum

C_Max         -       Peak Plasma Concentration

T_Max         -       Peak Time

BCS         -       Biopharmaceutical Classification

FDDS       -       Floating Drug Delivery Systems

MADDS   -       Muco Adhesive Drug Delivery Systems

MP           -       Marketed Product

L              -       Litre

kg            -       Kilo Gram

cm           -       Centi Meter

µg            -       micro gram

mL           -       milli litre

%CDR      -       Percentage Cumulative Drug Release

H             -       Hour

ºC             -       Degree Centigrade

#              -       Sieve Number

mm          -       milli meter

t_1/2            -       Half Life

t_50%          -       Time taken to release 50% drug from dosage form

t_90%          -       Time taken to release 90% drug from dosage form

 

 

 

Received on 01.10.2019           Modified on 14.12.2019

Accepted on 25.02.2020         © RJPT All right reserved