A Research on Formulation and Evaluation of Transdermal Patches for Peptic Ulcer

Peptic ulcer disease is a problem of the gastrointestinal tract characterized by mucosal damage secondary to pepsin and gastric acid secretion. It usually occurs in the stomach and proximal duodenum, it occurs in the lower esophagus, the distal duodenum or the jejunum as in unopposed hypersecretory states such as Zollinger-Ellison syndrome. The word ‘peptic’ refers to pepsin a stomach enzyme that break down proteins. Peptic ulcer located in stomach is called gastric ulcer.

Peptic ulcers, despite being a common gastrointestinal disorder, have a complex and multifactorial etiology. Understanding the various factors contributing to ulcer formation is crucial for effective management and prevention. The primary causes of peptic ulcers include Helicobacter pylori (H. pylori) infection, the use of nonsteroidal anti-inflammatory dru(NSAIDs) and less commonly stress-related mucosal damage.

NSAIDs: NSAIDs are commonly used for their analgesic, anti-inflammatory, and antipyretic properties. However, their use is associated with an increased risk of peptic ulcer perforation (PPU). Approximately 25% of chronic NSAID users will develop peptic ulcer disease (PUD), and 2%-4% may experience bleeding or perforation.

H. Pylori: Recurrent peptic ulcer disease (PUD) predominantly occurs in patients with H. pylori infection, suggesting that H. pylori play a significant role in the development of PUD and its complications. While proton pump inhibitor therapy significantly reduces the risk of recurrent H. pylori infection, its efficacy in reducing ulcers is modest in NSAID users.

Smoking: Tobacco is thought to inhibit pancreatic bicarbonate secretion, leading to increased acidity duodenum. It also inhibits the healing of duodenal ulcers. However, in some studies, there was no difference in tobacco use between patients with non-H. pylori, non-NSAID duodenal ulcersand those with H. pylori related ulcers, indicating a limited role of smoking. This indicated that smoking did not increase the risk of ulcer recurrence once the H. pylori had been eradicated.

MATERIALS AND METHODS

MATERIALS:

METHOD OF FORMULATION

SOLVENT EVAPORATION METHOD:

The polymers were accurately weighed and dissolved in 10 ml of ethanol and in the case of Eudragit L100, the chloroform: methanol (1:1) solution was also used and kept aside to form a clear solution. Drug pantoprazole sodium was dissolved in the above solution and mixed until the formation of a clear solution. Then the plasticizer and the permeation enhancers were added to the formulation step by step and mixed uniformly. The resulted uniform solution was cast on the petri dish, which was lubricated with glycerine and dried at room temperature for 24 h. An inverted funnel was placed over the petri dish to prevent fast evaporation of the solvent. After 24 h, the dried patches were taken out and stored in a desiccator for further studies.

Pre-formulation study

1. Weight variation: Weight variation was carried out by weighing three different patches individually using an electronic balance. The average weight and SD of the patch was recorded.
2. Surface pH: To determine surface pH, three patches of each formulation were allowed to swell for two hours on the surface of an agar plate. Surface pH was measured by using pH paper placed on the surface of the swollen patch as per reported method. A mean of three readings was recorded.
3. Flatness: The prepared patches were cut longitudinally into strip. The initial length of the patch was measured and then kept on the glass slide at room temperature for 30mins. After 30minutes final length of patch was measured. The variation of non-uniformity between both length was measured. Flatness was calculated by measuring both the lengths.
4. Folding endurance: A Particular area of the strip (2x2 cm) was cut uniformly and folded over and over until it broke. The value of the folding endurance was determined by the number of times the film was folded at the same location either to break the film or to develop visible cracks.
5. Thickness: The thickness of the transdermal patches was measured using a screw gauge at three different places, and the mean value along with SD was calculated.
6. Drug content uniformity: Transdermal patch of specified area was cut into small pieces and dissolved in 100ml of phosphate buffer pH 7.4. The solution containing patch was mixed with magnetic beads operated by magnetic stirrer for 6 hours to allow the whole drug to dissolve then 1ml was withdrawn from stock solution in 10ml of volumetric flask with phosphate buffer pH - 7.4 up to the mark. The solution was filtered and analysed spectrophotometrically at 281nm wavelength for obtained concentration of drug in solution.^[34]
7. Percentage moisture content: The prepared transdermal films were individually weighed and stored in a desiccator containing fused calcium chloride at room temperature for 24 h. After 24 h, the films were removed and reweighed accurately, and the percentage moisture content was determined from the following formula.

Percentage Moisture Content =

Initial weight − Final weight x100

Final weight ^[35]

8. Moisture uptake: The prepared films were weighted accurately and kept in a desiccator containing a saturated solution of sodium chloride at relative humidity of 80% at room temperature for 48h. After 48h the patches were removed and reweighed. % moisture uptake is calculated by using following formula

Percentage Moisture Content =

Initial weight − Final weight x100

Final weight

1. In vitro drug release studies: The dissolution study was carried out using USP Type-2 rotating paddle dissolution test apparatus. Therefore, to provide sink condition, 100 ml of 7.4 pH phosphate buffer was taken as the dissolution medium in a 250 ml glass beaker maintained at 37 ± 0.5 0 C which was stirred at 50 rpm. 2 cm in diameter film was fixed by using acyanoacrylate adhesive on the glass disk. At the bottom of the dissolution vessel the disk was kept so that the film remains on the upper side of the disk. At pre-determined time intervals 5 ml samples withdrawn and replaced with same volume of dissolution medium. These samples have been filtered using 0.45μm filter and diluted suitably with 7.4 pH phosphate buffer and assayed spectrophotometrically 281 nm respectively ^[24].

10. Drug release kinetics: The drug release kinetic studies were done by various mathematical models (zero order, first order,Higuchi’s square root, Hixson-Crowell cube root law and Korsmeyer- Peppas model). The model that best fits the release data is selected based on the regression coefficient (R2) value in various models. The model that gives high ‘R2’ value is considered as the best fit of the release data. The release constant was calculated from the slope of the appropriate plots, and the regression coefficient (R2) was determined.

• Zero order: It describes the system in which the drug release rate is independent on its concentration as shown in equation:

Qt = Q? + K? t

Where,

Q? = Initial amount of drug in the solution (most times, Q0 = 0)

Q? = Amount of drug dissolved at time t

K? = Zero order release constant expressed in units of concentration/time.

To study the release kinetics, data obtained from in-vitro drug release studies were plotted accumulative % drug release versus time and R2 was calculated.

• First order: It describes the drug release from the systems in which the release rate is concentration dependent as described by equation:

Qt = Q? e-kt

Where,                      

Qt = Amount of drug dissolved in time t

Q? = Initial amount of drug in solution

K = First order release constant (hr-1)

Log C = log C? - Kt/ 2.303

Where,

K = 1st order rate constant expressed in units of time.

C? = initial concentration of drug

When the obtained data is plotted as Log cumulative percentage of drug release versus time, the obtained graph is a straight line; indicating that the release follows first order kinetics. The constant k can be obtained by multiplying 2.303 with the slope value.

• Higuchi Model:

This model is based on the hypotheses that.

1. Initial drug concentration in the matrix is much higher than drug solubility
2. Drug diffusion takes place only in one dimension (edge effect must be negligible)
3. Drug particles are much smaller than system thickness
4. Matrix swelling and dissolution are negligible
5. Drug diffusivity is constant
6. Perfect sink conditions are always attained in the release environment.

Qt = KH t1/2

Where,

Qt = Amount of drug released in time t KH = Higuchi dissolution constant.

The data obtained were plotted as cumulative % drug release versus square root of time.

• Korsmeyer-Peppas model:

Kors Meyer et al. developed a simple, semi empirical model which relates exponentially, the drug release to the elapsed time in order to understand the mode of release of drug from swellable matrices. The equation that describes Peppas model is:

M? / M = Ktⁿ

Where,

K = constant incorporating structural and geometrical characteristics of the drug from dosage form

n = Release exponent, indicative of the drug release mechanism.

The function of t is M?/ M?= Fraction of drug release at time t.

Equation can be simplified as:

Log M? / M?= Log K + n log t

When the obtained data is plotted as log of drug released versus log time, the graph obtained is a straight line with a slope equal to n and K can be obtained from the intercept.

This model is used to analyze the release from polymeric dosage forms, when the release mechanism is not well known or when there is a possibility of more than one type of release phenomenon being involved.

To study release kinetics, data obtained from in-vitro drug release studies were plotted as log cumulative % drug release versus log time.

FORMULATION TABLE:

Table: Various formulation of pantoprazole sodium transdermal patch.

RESULTS ANDDISCUSSION

PREFORMULATION STUDIES:

API characterization:

Table: Organoleptic properties of Pantoprazole sodium.

This study is important as organoleptic property determination is a preliminary test for each and every drug. Pantoprazole sodium as white to off white.

1. Solubility:

Solubility studies were carried out in different solvents as I.P and observations were showed.

Table: Solubility studies of Pantoprazole sodium.

Solubility analysis is important because the drug has to dissolve in the solvents and also in the dissolution medium used. Pantoprazole sodium was found to be freely soluble in water, slightly soluble in ethanol and soluble in methanol.

2. Melting Point:

Melting points were carried out and observations were shown in table.

Table: Melting point of Pantoprazole sodium.

This study is very much important as melting point is characteristic property of each drug and also helps in determining the purity of the drug. The melting point of pantoprazole sodium was found to be 160°C.

1. pH

The pH solubility profile of a pantoprazole sodium drug was found to be within range of 7.4

2. Determination of absorbance maxima i.e λ max of pantoprazole sodium: Pantoprazole sodium was estimated using UV Spectrophotometer measured at 288nm using distilled water.

Table: Standard calibration curve of Pantoprazole sodium with water

DRUG EXCEPIENT COMPATIBILITY STUDY

The compatibility study between drug and the carriers was carried out using FTIR spectrometer. The peak numbers of the drug exhibiting OH, C-C, S=O, C=O, C-C, C=C, COO, C-O-C, CH2, CN, C-H, stretching was observed and are depicted as below

Fig: FT-IR Spectrum of Pantoprazole sodium

Table: Interpretation of FT-IR spectral data of Pantoprazole Sodium

Fig: FT-IR spectrum of PVP K30

Table: Interpretation of FT-IR spectral data of PVP K30

Fig: FT-IR spectrum of Drug and polymer

Table: Interpretation of FT-IR spectral data of Drug and polymer

EVALUATION OF TRANSDERMAL PATCH

Table: In-vitro Dissolution studies of formulation F1-F6

Fig: In-vitro dissolution studies of formulation F1-F6

Fig: Zero order release kinetics of formulation F1-F6

Fig 24: First order release kinetics of formulation F1-F6

Fig 25: Higuchi release kinetics of formulation F1-F6

Fig 26: Kosermeyer Peppas release kinetics (Log T vs Log %CDR)

Table: In-vitro drug release kinetics studies of Pantoprazole sodium transdermal patch