Formulation and in vitro evaluation of gastroretentive drug delivery systems of amoxicillin trihydrate

 

Mohammed Ehtesham Ur Rahman¹*, Mohammed Abdul Haseeb², Mohammed Saleem³, Abdul Naveed⁴

¹King Abdulaziz University, Jeddah

²Deccan School of Pharmacy, Hyderabad

³Bhaskar Pharmacy college, Hyderabad

⁴Malla Reddy College of Pharmacy, Hyderabad

*Corresponding Author E-mail: ehteshamchem@gmail.com

 

Amoxicillin trihydrate has a short biological half life. Floating drug delivery systems of this drug were prepared with the objective of increasing overall gastric retention time in order to prolong the release. The floating tablets were prepared by using Hydroxy Propyl Methyl Cellulose (HPMC) polymers at different drug to polymer ratio with gas generating agents like sodium bicarbonate and citric acid. The granules were prepared by wet granulation technique using polyvinyl pyrrolidone (PVP) K30dissolved in isopropyl alcohol and were compressed into tablets. Initially the granules were evaluated for characteristics like bulk density, true density, angle of repose, true density and Carr’s index. The prepared tablets were evaluated for hardness, friability, uniformity of weight, in vitro buoyancy and in vitro drug release. The studies revealed that the optimized formulation F11 containing the drug and HPMC K4M polymer in the ratio 1:1, lactose, sodium bicarbonate and citric acid showed floating lag time of 22 minutes and remained buoyant for more than 24 hrs and it released 42.88 % of the drug in 6 hours. The results indicate that the prepared floating tablets of amoxicillin trihydrate provide a better option for increasing the bioavailability than the conventional dosage forms and appear suitable for further pharmacokinetic and pharmacological studies.

 

 

 

INTRODUCTION:

Amoxicillin trihydrate is a β lactam antibiotic which is effective for treatment of bacterial infections like tonsillitis, pneumonia, bronchitis, gonorrhea, ear infection, urinary tract infection, ulcers and skin infection.¹ These infections are primarily caused by Helicobacter pylori which mainly reside in gastric mucosal layer.  So the concentration and resident time of amoxicillin is important for complete eradication of H. Pylori.

 

The conventional delivery system for amoxicillin has short resident time in stomach and may be degraded in gastric acid.² A good way to improve the effectiveness of therapy is to develop a drug delivery system which can reside in the stomach for longer duration and release drug as long as possible in the ecological niche of the bacterium, and hence Gastroretentive Drug Delivery System (GRDDS) is an ultimate solution for this.³ Previously attempts have been made for sustained release of amoxicillin by researchers. Floating tablets were made by Hilton and Deasy, Sustained release minimatrices by Atul C. Badhan et al, and bioadhesive approaches by Durig T, Fassihi R and        Moes AJ.^4-7

 

The purpose of this research was to prepare gastroretentive floating tablets of amoxicillin trihydrate. To achieve gastroretention and sustained release HPMC polymers were used. For floating gas generating agents viz. Sodium bicarbonate and citric acid were used.

 

MATERIALS AND METHODS:

Amoxicillin trihydrate was obtained from Dr. Reddy's Laboratories Limited, Hyderabad. HPMC K4M and K15M were kindly gifted by Colorcon Asia Pvt. Ltd. Magnesium Stearate, Talc, Sodium bicarbonate, Citric acid, polyvinyl pyrrolidone (PVP)  K30, Lactose, Microcrystalline cellulose (MCC), Dicalcium phosphate (DCP) and Isopropyl alcohol were procured from S. D. Fine Chemicals, Mumbai, India. All the chemicals and reagents used were of analytical grade.

 

Preparation of Gastroretentive floating tablets of Amoxicillin trihydrate

Wet granulation method was employed to prepare granules of Amoxicillin trihydrate with HPMC (various grades) at different drug to polymer ratio as per the composition given in the Table 1. MCC, Dicalcium phosphate and lactose were used as diluents along with sodium bicarbonate and citric acid as gas generating agents. PVP-K30 dissolved in sufficient isopropyl alcohol was used as a granulating agent; Magnesium stearate was used as lubricant and talc as a glidant.

 

All the ingredients sufficient for a batch of 15 tablets according to formula were passed through sieve no.20. In order to enhance the flow and compaction properties and drug was triturated with polymer in a glass mortar and pestle for 15 minutes to achieve a homogenous blend, further it is granulated by using 1% polyvinyl pyrrolidone solution dissolved in iso-propyl alcohol. The wet mass was passed through sieve no.18 and the granules were dried in a hot air oven at not more than 60°C until LOD (loss on Drying) reached within 2 to 3%. Dried granules were passed through sieve no.18. The blend was mixed and lubricated with magnesium stearate to ensure complete mixing, then mixed with talc as glidant. Tablets were compressed by using tablet punches on a tablet compression machine⁸ (Rimek minipress machinery Co. Pvt. ltd., India) at hardness of 4 to 6 kg/cm².

 

 

EVALUATION

Evaluation of granule properties: Initially the granules were evaluated for characteristics viz. bulk density, true density, angle of repose, true density and Carr’s index⁹. The results are given in the table 2.

 

Evaluation of tablets: After preparation the tablets were evaluated for post compression parameters viz. hardness (Monsanto tester), friability (Roche type friabilator), uniformity of weight^{10, 11}, in vitro buoyancy and in vitro drug release. The results are shown in table 3

The content uniformity test is mandatory for tablets whose average weight is below 50mg. In the present study this test was not performed because the average weight of tablets was far greater than 50mg.

 

In vitro buoyancy studies: In- vitro buoyancy studies were performed for all the formulations. Randomly selected tablets from each formulation were introduced in a 100ml beaker containing simulated gastric fluid, pH 1.2 as per USP. The time taken for the tablet to ascend to the surface and float was taken as floating lag time (FLT). The time for which the dosage form continuously remained on the surface of medium was determined as the total floating time (TFT) ¹². The results are illustrated in Table 3

 

In-Vitro Dissolution Studies: The release rate of the drug amoxicillin from floating tablets was determined using USP dissolution apparatus II (Lab Hosp India). The test was performed using 900 ml of 0.1N hydrochloric acid, at 37 ± 0.5°C and 50 rpm. Aliquots of 5ml were collected at predetermined time intervals and replenished with an equivalent volume of fresh medium. The samples were filtered through a 0.45 μm membrane filter and diluted suitably with 0.1N HCl and were analyzed using Elico UV/Visible spectrophotometer at λ_max 272 nm¹³. The results are illustrated in Figure 1and Figure 2.

 

Table 1: Formulae of Amoxicillin Trihydrate GFDDS Prepared with HPMC (various grades) for 15 tablets

Ingredients	Formulation code (Quantity in gram)
	F10	F11	F12	F13	F14	F15	F16	F17
Amoxicillin  trihydrate	3.75	3.75	3.75	3.75	3.75	3.75	3.75	3.75
HPMC K4M	3.75	3.75	3.75	3.75	3.75	3.75	3.75	3.75
Lactose	0.75	0.75	-	-	-	-	-	-
Microcrystalline cellulose	-	-	0.75	0.75	-	-	0.75	0.75
Dicalcium phosphate	-	-	-	-	0.75	0.75	-	-
Sodium bicarbonate	0.75	1.5	0.75	1.5	0.75	1.5	1.5	1.5
Citric acid	-	0.75	-	-	-	-	0.75	0.75
PVP K30	1%	1%	1%	1%	1%	1%	1%	1%
Talc	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3
Magnesium stearate	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3

 

 

RESULTS AND DISCUSSION:

The formulated granules were evaluated for Bulk density, true density and Carr’s index and all the values were found to be within the standard limits as seen in the table 2. Angle of Repose was found to be between 25 and 30, so the flow property is said to be GOOD¹⁴.

 

Post compression parameters such as hardness, friability, percentage weight variation, floating lag time, in vitro dissolution studies are shown in the table 3. The hardness and friability of the formulations was found to be in the range of 3.5 to 5 and 0.22 to 1.46 respectively. It indicates the sufficient strength of tablet to withstand wear and tear during handling. Percentage Weight variation (uniformity of weight) is an important evaluation parameter for tablets. Any deviation from the prescribed limits may adversely affect the content uniformity of the formulation the prepare formulations were evaluated for weight variation using eagle electronic balance and was found to be within the IP limits.

 

The initial Gastroretentive Drug delivery formulations of Amoxicillin trihydrate formulation containing drugs and different polymers of different ratios (F₁, F₂, F₃, F₄... F₉ etc.) using HPMC K15Mwith gas generating agents sodium hydroxide and citric acid the floating lag time varied from 60min to 120min and remained under floating conditions for >24hours. Owing to its long floating lag time this batch of tablets was casted off.

 

The Final Formulations which were prepared using varying concentrations of polymer (HPMC K4M) (F10 to F17,) have shown floating lag time between 22min -38min. When Sodium bicarbonate and citric acid were used in ratio of (100:50) as in formulations ( F_11, F_16,F₁₇) floating lag time has been reduced considerably from 1hr-10min.It was observed that when an optimum concentration of Sodium bicarbonate and citric acid used, there was reduction in floating lag time, where the dissolution medium was imbibed into the matrix, the interaction of acidic fluid with Sodium bicarbonate and citric acid resulted in the formation of CO₂ gas within the swollen gel, thus causing floating as the matrix volume expanded and its density decreased providing buoyancy.

 

Therefore it can be concluded that optimum concentration of Sodium bicarbonate along with citric acid were found to be essential to achieve optimum in-vitro floating of GRDDS of Amoxicillin trihydrate.

 

 

Table 2: Evaluation results of various parameters of granules

Formulation code	Bulk density (g/cm3 )	True density (g/cm3 )	Angle of repose (θ)	Carr’s consolidation index (%)
F10	0.34	0.317	28.61	25.36
F11	0.36	0.393	28.61	20.85
F12	0.35	0.261	29.98	19.27
F13	0.42	0.295	28.61	20.10
F14	0.39	0.211	30.00	11.39
F15	0.40	0.248	29.50	11.11
F16	0.34	0.236	25.82	14.36
F17	0.34	0.363	28.61	21.38

 

Table 3: Results for Post compression parameters

Formulation code	Hardness (Kg/cm2)	Friability (%)	% Weight variation	Floating lag time	Floating time (Hrs)
F10	5	0.26	+4	34 Min 19 sec	>24
F11	5	0.26	+4	22 Min 21 sec	>24
F12	4.5	0.22	+1.33	26 Min 33 sec	>24
F13	4.5	0.27	0	38 Min 48 sec	>24
F14	3.5	1.46	-1.34	29 Min 41 sec	>24
F15	3.5	1.30	+2.66	31 Min 53 sec	>24
F16	5	0.35	+1.33	23 Min 06 sec	>24
F17	4	0.48	+2.66	27 Min 11 sec	>24

 

 

From the above results of dissolution studies it was observed that with increase in concentration of polymer, there is a decrease in the drug release which may be attributed to increased viscosity of the gel as well as the gel layer with longer diffusion path. This could cause a decrease in effective diffusion coefficient of the drug and a reduction in the drug release rate.

 

Among the various formulations studied, the formulation F₁₁ was considered as an ideal formulation which exhibited 42.88% of drug release in 6 hours with a floating time of  >24hours.

 

CONCLUSION:

Among the various formulations prepared and studied, the formulation F11 containing drug polymer ratio (1:1) prepared with HPMC, K4M showed promising results releasing equivalent 42.88 % of the drug in 6hrs with a floating lag time of 22 Minutes and floating time of over 24 hrs and has been considered as an ideal formulation.

 

Finally, it may be concluded that this novel drug delivery system i.e., Gastroretentive Floating Drug Delivery Systems of amoxicillin offers a valuable dosage form which delivers the drug at a controlled rate and at a specific site. They provide a better option for increasing the bioavailability and reliability by allowing a better control of fluctuations observed with conventional dosage forms. The Formulation F11 appears suitable for further pharmacokinetic and pharmacological studies to evaluate clinical safety to these tablets in suitable animal and human models.

 

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Accepted on 14.09.2013         © RJPT All right reserved