INTRODUCTION:

WHO declared that H. pyloriis a carcinogen due to its association with gastric adenocarcinoma¹. Known as king of spices, reports have suggested that black pepper has effect on common cold and cough,also on gastro-intestinal disorders such as colic and dysentery. It has found its use in treatment of various inflammations as well².

Floating drug delivery system (FDDS) extends the time of drug in stomach and offers added advantage of availability of drug for localized action in stomach. In the stomach, Effervescent floating systems can be made to float by integratingfloating chamber containinginert gas, vacuum or air³.

In one of the studies, pet ether extract of Piper nigrum showed anti-ulcer activity in mice through antioxidant mechanism by preventingthe gastric mucosal damage in ethanol induced ulcer model⁴. In another study, it has been reported that anti-inflammatory activity shown by capsaicin and piperineagainst gastritis induced by H. pylori in Gebrilsand this was independent of direct anti-bacterial effects. This study concluded its usage in chemoprevention of H. pylori linked gastric carcinogenesis⁵. Recently, the gastro-retentive microspheres of Piperine which was evaluated for hepato-protective and anti-ulcer properties in rats is also reported⁶. The aqueous extract of black pepper inhibited ulcers induced by Aspirin in rabbits⁷. With this in view, we aimed at preparation and evaluation of floating formulations of Black pepper extract.

MATERIAL AND METHODS:

Plant extract and Crude drugs:

The dried fruits of Piper nigrum extract with batch no. FPN-1808001 having the lab reference/reportno. PC1808203 was received as gift sample from Natural Remedies Private Limited, Bangalore. Colophony was purchased from anAyurvedic shop in local market of Udupi.

Chemicals:

HPMC K100M was obtained from Rolex Laboratory, Hyderabad. Sodium bicarbonate and Talc was obtained from Sisco Research Laboratories Pvt. Ltd., Mumbai. Lactose was procured from Labort Fine Chem Pvt. Ltd, Surat. Magnesium stearate was obtained from Modern Chemical Corporation, Ahmedabad.

Instruments:

Shimadzu make IRAffinity software-version 1.20 Jan 2009 and UV-Vis spectrophotometer of model UV-2450, Shimadzu Analytical, New Delhi – 110082, India, Cat.No. 208-24301-93 were used in the experiment for incompatibility and drug absorbance studies respectively. Cadmach tablet punching machine with single punch was used for punching the tablets.

FTIR studies for drug excipient interactions:

Compatibility of the drug viz, Pepper extract alone, Pepper extract + HPMC K100M and Pepper extract + Colophony along with the other individual excipient was determined using FTIR spectrophotometer, by recording the spectrum range of 4000 – 400 cm^-1. Weighed amount of sample was compressed into a disc with with excipients in a ratio of 1:1 in 2% KBr. Then the spectrum was recorded using solution by placing the disc in the path of light.

Characterization of tablet blends:

Tablet blends were characterized for the various parameters such as bulk density, tapped density⁸, angle of repose, Carr’s compressibility index, and Hausner ratio⁹.

Formulation of tablets:

In this study, all the tablet formulationswere prepared by means of direct compression method in presence of pepper extract (22.2% w/w of piperine), HPMC K100M, lactose, sodium bicarbonate, talc, magnesium stearate and colophony. All the ingredients were made to pass through sieve no. # 80 as per The Ayurvedic Formulary of India and were weighed accurately. The drug, polymers as well as other excipients were taken in required quantities and weighed accurately. The extract was kept separately. Polymers such as HPMC K100M and colophony were thoroughly mixed with sodium bicarbonate. After mixing the pepper extract with the polymer mixture, a blend of uniform distribution was achieved using talc and magnesium stearate as glidants. The blended mixture was weighed individually according to the formula and compressed to tablets through a single punch tablet making machine (Cadmach, Ahmedabad). The level of polymers was optimised to obtain a formulation which can release 95% of drug around 10 hours would have a potential as twice daily dosage form. Different formulations viz F1 to F5 were fabricated as per the procedure and signified in Table 1 and Table 2 respectively. In our earlier studies, the method described for the preparation and evaluation floating tablets of Liquorice extracthas been modified and used in this experiment, as colophony is exceptional.

Table 1. Floating tablet formulations composition

Ingredient	F1	F2	F3	F4	F5
Ingredient	mg
Pepper extract	500	500	500	500	500
Lactose	250	200	200	200	200
HPMC K100M	250	300	200	250	350
Sodium bicarbonate	250	200	250	200	200
Talc	15	15	10	15	15
Magnesium stearate	15	15	10	15	15

Table 2. Composition of F3 formulation

Ingredients	F3 (mg)
Ingredients	F3a	F3b	F3c
Pepper extract	500	500	500
Lactose	200	200	200
HPMC K100M	200	200	200
Sodium bicarbonate	250	250	250
Talc	10	10	10
Magnesium stearate	10	10	10
Colophony	10	20	50

Evaluation of tablets:

Assessment of self-fabricated tablets for various physical parameters viz diameter, thickness, friability, hardness and weight variation was carried out.

Calibration curve and Buoyancy time:

A stock solution with a concentration of 100µg/ml of piperine was prepared 0.1N HCl. From this stock solution, a serial dilution was made to get different concentrations ranging from 10 to 90µg/ml in different volumetric flasks. Absorbance was measured at 341nm using spectrophotometer.

Time taken by dosage form to rise on to the surface ofacid medium is known as “Floating Lag Time (FLT)” or Buoyancy Lag Time (BLT). Electrolab TDT-08L USP Type II (paddle) dissolution apparatus at speed 75rpm in 900mL 0.1N HCl at 37+0.5⁰C to mimic in vivo conditions was utilized to analyze floating behavior¹⁰.

In vitro dissolution studies:

USP Type I (basket) apparatus was used to carry out these studies where 900mL 0.1N HCl dissolution medium was kept under thermostatically controlled water bath at 37+0.5⁰C. After inserting each tablet into individual basket, it was kept under rotation at 75rpm. At varying time intervals, 5ml of sample was withdrawn. Dissolution medium was kept constant throughout the experiment by replacing equal volume of 5mL of 0.1N HCl into basket. The samples collected were labelled respectively and analyzed spectrophotometrically at 341nm against blank. A plot of cumulative drug release (%CDR) V/s time (hrs) was plotted¹⁰.

Selection of dose:

The percentage of piperine in the pepper extract is 22.2% w/w as per the Certificate of Analysis provided by Natural Remedies, Bangalore. Therefore, we have used 500mg of pepper extract, which contained 110mg of piperine. Conversion of rat dose of 20mg/kg¹¹ to Human equivalent dose as per FDA guidelines, the human dose for piperine was found to be 3.2mg/kg body weight. With a body weight of 70kg human, the required amount of piperine is 225mg. And hence 500 mg of extract was considered for preparing the floating formulations as a single dose and it will have a potential of two tablets per day.

RESULTS:

The peak at 1600 and 3300 in the spectrum indicates the presence of carbonyl and OH functional groups respectively. The FTIR results obtained from the peaks shows no or partial interaction between drug sample and excipients such as HPMCK100M, Lactose, Sodium bicarbonate, Magnesium stearate and Talc as presented in Figure 1 and 2. Whereas, the size, shape and intensity of the peaks are varied due to the weaker or physical forces of hydrogen bonding interaction between pepper extract and colophony, the OH group peak is disappeared as shown in the Figure3.

Figure 1. FTIR spectrum of Pepper extract alone

Figure 2. FTIR spectrum of Pepper extract with HPMC K100M

Figure 3. FTIR spectrum of Pepper extract with Colophony

The tablet mixture was analyzed for their bulk density, tapped density, angle of repose, Carr’s compressibility index as well asHausner’s ratio as given in Table 3.

Table 4: Evaluation of formulated tablets*

Formulation	Diameter (mm)	Thickness (mm)	Hardness kgf/cm²)	Friability (%)	Uniformity of weight (g)	Buoyancy time ( min)
F1	17±0.4	6.600±0.004	2.33±0.03	0.18±0.003	1.280±0.168	-
F2	17±0.4	6.614±0.002	2.66±0.04	0.238±0.004	1.230±0.157	-
F3	17±0.4	6.726±0.002	2.33±0.02	1.027±0.001	1.170±0.862	0.69+0.03
F4	17±0.4	6.158±0.003	2.50±0.02	0.542±0.002	1.180±0.352	-
F5	17±0.4	6.610±0.003	2.66±0.05	1.031±0.002	1.280±0.568	-

*Average of three determinations

Table 5: Evaluation of optimized formulated tablets*

Formulation	Diameter (mm)	Thickness (mm)	Hardness (kgf/cm²)	Friability (%)	Uniformity of weight (g)	Buoyancy time (min)
F3a	17±0.4	6.626±0.002	2.72±0.08	0.628±0.024	1.180±0.014	0.35±0.02
F3b	17±0.4	6.656±0.003	2.74±0.06	0.554±0.022	1.190±0.017	1.54±0.03
F3c	17±0.4	6.716±0.002	2.74±0.06	0.576±0.022	1.220±0.015	0.96±0.01

*Average of three determinations

Buoyancy time:

The buoyancy time of the successful formulation F3 was found to be less than one minute. Whereas, the other formulations did not float or break after 10 minutes in the acid medium.

In vitro drug release study:

0.1N Hydrochloric acid as the dissolution medium in USP dissolution apparatus was used to study the drug release of floating tablets. The selected formulations (F3, F3a, F3b and F3C) showed cumulative drug release (CDR) more than 98% in the dissolution medium and followed First order kinetics and the n values are 0.952, 0.942, 0.950 and 0.977 respectively and these formulations followed Non-Fickian type of diffusion. The integrity of the tablet was maintained for more than 10 hours in the dissolution medium.Results are shown in Figure 4.

Figure 4. Dissolution study of floating tablets of Pepper extract

DISCUSSION:

Gastric microbiology bloomed after the research of H. pyloriby Marshall and Warren from gastritis patient¹².Piperine has a synergistic action with ciprofloxacin in showing antibacterial action when combined. Even in the multi-drug resistant strains, piperine inhibits the bacterial growth and also bacterial drug efflux pum^13-15. Piperine acts as anti-bacterial agent which inhibited the growth of H. pylori and its adhesion¹⁶. Reports suggest that piperine is actively involved against cancer initiation^17-19. Black pepper comprises 5-9% of piperine²⁰ and daily intake of about 600 mg pepper could prevent the infection throughH. pyloriand also gastric carcinogenesis²¹.

Oral drug delivery system is among the most sought out route foradministration of drugs as it is easier, has good compliant and flexible²². Floating Drug Delivery Systems (FDDS) is designed to retain forms in GI tract and to increase its residence time²³. FDDS offers advantage of local drug action in the stomach²⁴. P. nigrum extract contains piperine as the major constituent and therefore to retain its floating formulation in the stomach, which can be more effective for the treatment of gastric ulcers and carcinogenesis. As in one of the studies, it is reported that capsaicin and piperine showed anti-inflammatory activity on H. pylori induced gastritis in gebrils and independent of direct anti-bacterial activity on H. pylori and thus may possess potential in chemoprevention of H. pylorilinked gastric carcinogenesis⁵. There are also reports that piperine inhibit the growth of H. pylori and its adhesion. It also decreases the motility due to suppression of the flhA and flgE expressions¹⁶.

NDDS in particular, floating technology in the preparation of gastro-retentive tablets for the synthetic molecules, a good literature is available. For example, effervescent technology was applied to prepare and evaluate the floating tablets of Lafutidine using various polymers xanthan gum, guar gum, and sodium alginate²⁵. This technology was also applied to develop floating tablets of Domperidone to have a sustained release²⁶. In another research work, floating tablets of Levocetirizine were developed and evaluated for increasing the gastric retention time²⁷. Effervescent technology was also applied to develop the Glipizide tablets²⁸. To prolong the gastric residence of Ofloxacin, stable floating tablets were prepared with guar gum, locust bean gum alone or in combination with HPMC K100M. Sodium bicarbonate was used as gas generating agent²⁹. In order to enhance the oral bioavailability of Metformin hydrochloride, floating tablets were prepared and evaluated³⁰. Formulation and evaluation of floating tablets of Baclofen, a skeletal muscle relaxant were developed to deliver the drug in a controlled manner in GIT and into systemic circulation³¹.

In the recent past, developments had taken part in the field of novel drug delivery system (NDDS) in plant extracts and active moieties to overcome to enhance patient compliance³². Over the last decade, major advances have been made on development of NDDS from plant actives and extracts³³. For example, emulgel of ginger extract were prepared and evaluated for antimicrobial activity³⁴. Another example, the floating tablets of amla alcoholic extract, ginger aqueous extract, fenugreek, psyllium husk, HPMC K100M, sodium bicarbonate, talc and magnesium stearate were prepared by direct compression method and evaluated³⁵.

With this background, floating tablets of black pepper extract for the management of gastric ulcers were prepared. Pre-formulation aspects were studied to know any interactions between the extract and the excipients. The flow property of the powder blends F1 to F5 was observed to be satisfactory with the exception of F1 and F4 which had angle of repose more than 30. Only the formulation F3 showed passable compressibility index (25.33±1.6) and Hausner ratio (1.33±0.4). Whereas, the other formulations showed high values indicating very poor flowability properties as depicted in Table 3. As colophony was used in the formulation, direct compression was made use of for punching the tablets. Blends of extract were prepared by using HPMC K100M, lactose, sodium bicarbonate, talc, magnesium stearate and colophony. In the present study, two approaches were used for the formulation development. The first approach was to optimize the floating behavior of the dosage form for more than ten hours and the second approach was to optimize release characteristics of the drug from matrix system. Carbon dioxide generated from the reaction between sodium bicarbonate with the acid will remain in gellified swollen polymer that produces an upward motion of tablet to maintain the buoyancy^36-37. HPMC K100M was used as hydrophilic polymer and colophony as the hydrophobic polymer in the formulations. Both the polymers were used to find out the optimum polymer levels which can modify the overall drug release to fulfil the desired objective. Lactose was used in the formulations for improving the compressibility property. The lubricants used in the formulations were talc and magnesium stearate. Only in the F3 formulation, at particular quantity of ingredients, the formulation has shown desired results with respect to floating behavior or drug release.

The optimization of formulations was done by changing the required quantity of various ingredients in different trials. In the prepared formulations from F1-F5, only formulation F3 showed promising results with respect to floating behavior with floating lag time of 10 seconds. The other formulations did not float or got disintegrated within 3-5 minutes. Therefore, F3 formulation was studied for dissolution and it showed the maximum release at 4 h. We added colophony, to extend the release in the prepared formulations F3a, F3b and F3c. F3a showed the drug release up to 6 h and F3b has released the drug up to 9 hours. In F3c formulation, due to high concentration of colophony, the drug release got reduced to 4 h. We have arrived at a conclusion that optimum concentration of colophony promises the desired drug release pattern as shown in the Figure 4.

CONCLUSION:

An attempt was made to prepare floating tablet formulations of pepper extract with prolonged gastric residential time. Release of piperine from successful formulation is inversely proportional to the concentration of hydrophobic polymer used. We conclude that HPMC K100M, sodium bicarbonate in combination with colophony could be the promising ingredients in developing the floating formulations of pepper extract. Also the developed formulations can be used effectively against H. pylori and to manage/treat gastric ulcers and in the prevention of gastric carcinogenesis.

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Received on 25.06.2021 Modified on 12.04.2022

Research J. Pharm. and Tech 2023; 16(8):3733-3738.

DOI: 10.52711/0974-360X.2023.00616

Formulation	Bulk density (g/cc)	Tap density (g/cc)	Angle of repose (⁰)	Carr’s Index (%)	Hausner’s Ratio
F1	0.60±0.10	0.52±0.4	32.22±1.6	-14.28±2.3	0.87±0.1
F2	0.56±0.06	1.89±0.6	25.42±1.4	70.37±3.4	3.37±0.8
F3	0.58±0.08	0.78±0.2	25.16±1.3	25.33±1.6	1.33±0.4
F4	0.53±0.02	2.05±0.2	33.07±1.5	75.60±1.6	4.12±0.3
F5	0.53±0.02	1.87±0.2	23.93±1.4	71.65±1.6	3.52±0.3