Development and optimization of mucoadhesive microballons of nizatidine for management of peptic ulcer

Ulcers are characterized histologically as a part in the mucosa of the GI tract through the muscularis mucosae into the submucosa or more inside part of GI trat mucous membrane. Ulcer can affect any part of the gastrointestinal tract contact with more secretion of acid peptic juices [1]. The gastric ulcer are generalized into Aphthous ulcers, Esophageal ulcers and Peptic ulcer based on their affected area in gastrointestinal tract in mouth, throat and stomach or the duodenum separately [2].


Introduction
Ulcers are characterized histologically as a part in the mucosa of the GI tract through the muscularis mucosae into the submucosa or more inside part of GI trat mucous membrane.
Ulcer can affect any part of the gastrointestinal tract contact with more secretion of acid peptic juices [1]. The gastric ulcer are generalized into Aphthous ulcers, Esophageal ulcers and Peptic ulcer based on their affected area in gastrointestinal tract in mouth, throat and stomach or the duodenum separately [2].
These are three kinds for example Aphthous ulcers create within the lips and cheeks or underneath the tongue. They are also called aphthae, aphthosis, aphthous stomatitis and infection. Mouth ulcers are generally have family ancestry (up to 40%) and are ordinarily because of injury (in view of not appropriate fi tting of false teeth, broke teeth, or fi llings),anemia, measles, viral contamination, oral candidiasis, incessant diseases, throat malignant growth, mouth malignant growth and vitamin B defi ciency [3,4]. Esophageal ulcers are injuries that happen toward the fi nish of throat because of Gastroesophageal Refl ux Sickness (GERD) with 10 % frequency.
They can be produce pain directly underneath the breastbone [5,6].

Abstract
The mucoadhesive microballons prepared by using combination of Poly Acrylic Acid (PAA), Poly Vinyl Pyrrolidone (PVP) polymers by polymer-polymer combination with solvent diffusion method. It is managing the discharge rate of Nizatidine between therapeutic absorption windows by extended the gastric emptying time of formulation. The delivery systems make certain accessibility of drug content at the assimilation site for the preferred period of time. The present work was justifi ed effect of various parameters as polymer (PAA-PVP) concentration, drug concentration, internal phase/external phase ratio, surfactant concentration, stirring speed, stirring time. PAA-PVP polymeric combinations microballons were prepared by solvent dispersion technique. The effect of internal/external phase ratio on preparation of microballons shows that content of water in the internal phase played a key role in the formation of microballons. The particle size found to be decreased upon increasing the concentration of surfactant (span 80) in oil phase. This might be due to the increase the surface tension of aqueous phase which ultimately seem to allow the formation of micro size range. The present work confi rmed that any criteria can be effect the result of the shape, size and size distribution, entire medication load of microballons. There are atleast two main targets which could be used for anchoring of delivery system through mucoadhesive in the GIT, the mucosal tissue and mucosal gel layer. The mucos layer is the fi rst surface encountered by particulate system and its complex structure offers many opportunities for the development of adhesive interaction with small polymeric particles either through non specifi c or specifi c interaction between complimentary structures. Due to all above advantages Microsphere delivery is an better choice for drug delivery in colon [12].

Research
Microballons are small round particles; having diameter in the range of micrometer (1μm to 1000μm or 1mm).
Microballons are in also called as microparticles. Microballons are characterized as "the solid circles or API was spread all over the matrix or molecular dispersion of particles". Mucoadhesion release, thus will be effective for drug delivery through oral mucosa for peptic ulcer management [13][14][15].

Materials
The drug nizatidine was generously supplied as a gift coeffi cient and FTIR study [16,17].

Solubility profi le
The solubility determination of nizatidine hydrochloride was carried out in various common solvents. A defi nite quantity (10 mg) of the drug was taken in a series of 25 ml volumetric fl asks and 10 ml of each solvent was added to these fl asks. The fl asks were clamped and shaken in vortex shaker for 6 hours at room temperature till equilibrium. The fl asks were observed visually for the presence of insoluble particle of drug. The supernatant was taken and fi ltered. Quantitative determination of nizatidine hydrochloride was carried out after suitable dilution using UV/Visible spectrophotometer (Shimadzu 1800, Japan). The experiment was repeated with the different volume of the solvents to obtain more appropriate degree of solubility [16,17]. The profi le of solubility of nizatidine HcL in different solvent is given in Table 1. The immiscible liquid phases were separated after some time and the aqueous phase was analysed for amount of drug after appropriate dilution with UV spectrophotometer. The results are presented in Table 2.

FTIR spectrum of nizatidine hydrochloride
The drug sample of nizatidine hydrochloride was identifi ed by infrared spectroscopy (Alpha, Bruker, USA       The different concentration solution was measured using spectrophotometer (Shimadzu 1800, Japan) at  max 228 nm and create the calibration curve (Table 4, Figure 4).

SIF (pH 6.8) determination of absorption maxima ( max ):
Standard stock solution of 10 μg/ml with phosphate buffer (pH 6.8) was scanned between 200-400 nm for the absorption maxima by UV/visible spectrophotometer (Shimadzu 1800, Japan). The absorption maximum was obtained at 313 nm as shown in Figure 5.          Citation: Jain Table 8 and graphically shown in Figure 10.

Effect of internal phase/external phase ratio:
The effect of internal/external phase ratio was justifi ed by selection of P2D2 formulation. The microballons were prepared with change of ratio 1:1, 1:5 and 1:10 of both internal and outer phase ratio as constant parameter. The effect of phase ratio on the particle size and percentage drug entrapment effi ciency is reported in Table 9 and shown in Figure 11.  Table 10 and shown in Figure 12.  Table   11 and Figure 13.  Table 12 and Figure 14.

Results and discussion
The    Figure 11: Effect of solvent ratio on particle size and drug entrapment effi ciency.      The result was observed that with increasing the drug concentration, the entrapment effi ciency of drug in microballons were also increased up to 40/100 mg. If the concentration of drug was increased more than 40/100 mg, the entrapment effi ciency gradually decreased. This was due to saturation of PAA-PVP with the drug and the particle size of microballons does not signifi cantly change. The observation recorded in Table 8 and shown in Figure 10.
The effect of internal/external phase ratio on preparation of microballons showed that amount of water act as internal phase was effected. The mixing amount of ethanol starts to diffused out into the oil phase, and water act as important part for preparation core of the emulsion droplets. The result was justifi ed that, the content of water directly affects the solidifi cation time of the microballons. If the phase volume ratio was selected more than 1:5, the solidifi cation time of the microballons increased. This was due to the using relatively large quantity of oil phase during mixing. This was decreased the collision frequency between the incompletely solidifi ed microballons (Table 9 and Figure 11).
The particle size of microballons was decreased, while increasing the concentration of surfactant (span 80) in oil phase. The surface tension of aqueous phase was increased, this allow the formation of micro size range. The optimum size of microballons was 112.6±2.5μm and drug entrapment effi ciency was 92.4±1.8% at using 1.5% v/v surfactant concentration. As the amount of surfactant increased the particle size of microballons was decreased due to formation of micelles. The drug entrapment effi ciency also decreased because of the leaching out of the drug particles during optimization process (Table 10 and Figure 12).
The effect of stirring speed was identifi ed by increasing speed from 300 to 500 rpm. The average particle size was decreased from 135.2 μm to 99.5 μm, because of more stirring speed enhances the energy, and thus breaks up the emulsion droplets and formed small droplets. The result was concluded that as stirring speed increases, an average particle size of microballons was decreased. At 500 rpm formulation P2D2I2E3S3 shaped narrowest size distribution 110.2±3.5 μm with spherical shape with drug entrapment effi ciency was 90.3±3.5 %. The observation documented in Table 11 and showed in Figure 13.
The average particle size of PVP-PAA microballons reduces with increasing stirring time during mixing. Narrow particle size was found 107.5±1.6μm with entrapment effi ciency 91.6±2.1% of formulation P2D2I2E3S3T4 after 4 h stirring time duration. Stirring time for more than 4h origin separation of aqueous phase, thus agglomeration of the polymers was produced. The observations are recorded in Table 12 and shown in Figure 14.

Conclusion
Mucoadhesive microballons is one of dosage forms, which make available the opportunity of increase the bioavailability. The present study was concluded that the prepared mucoadhesive microballons was advanced example of current formulation by solvent dispersion technique. The present work was justifi ed the effect of various parameters as polymer combination and its concentration (PVP-PAA), drug concentration, internal phase/external phase ratio, surfactant concentration, stirring speed, stirring time. The polymeric mixture was mixed in oil then this mixture stirred in a blend of ethanol/water mixture. The interpolymer complex beads start to solidifi ed and convert to hardening material as ethanol water mixture diffused out. The concentration of drug the entrapment effi ciency gradually changed. The effect of internal/external phase ratio as internal phase played a key role in the formation of microballons. The particle size found to be decreased as the ratio of surfactant (span 80) change as surface tension of aqueous phase allow the formation of micro size balloons.
The stirring speed decreased the particle size with enhancing the stirring time to format agglomeration of the polymers.
The outcomes proposed that these factors confi rm impact on the shape, size and size distribution, entire medication load effectiveness of microballons.