IJCRR

IJCRR - 14(8), April, 2022

Pages: 16-25

Date of Publication: 19-Apr-2022

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Preliminary Study on the Composition of Nanoparticles for the Treatment of Peptic Ulcer

Author: Shubhrajit Mantry, Sahil Shaikh, Shubham Shinde, Shital Bidkar, Ganesh Dama

Category: Healthcare

Abstract:One of the most frequent gastrointestinal issues is a gastric ulcer. Throughout their lives, peptic ulcer disease affects more than 10% of the adult population in Western countries. The pathogenesis of peptic ulcer disease is based on an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide, and other peptides and growth factors) and hazardous chemicals (acid and pepsin). Certain acid-related illnesses can be addressed and prevented by lowering gastric acidity or improving mucosal protection. In the treatment of stomach ulcers, nanoparticles are being developed for antiulcer drug delivery. Other treatments, such as nanotechnology, are gaining prominence as a result of the challenges in treating peptic ulcers. Different types of nanoparticles have strong antibacterial properties, polymeric nanoparticles have advantages in drug delivery and drug protection and membrane-coated nanoparticles have prominent properties of indirect targeting, demonstrating the importance of nanotechnology in the development of new peptic ulcer treatments. The pharmacokinetic performance and ulcer healing response of an antiulcer medicine in the form of nanoparticles were evaluated in Wistar rats with produced ulcers during characterization. The size distribution of the drug-filled particles was limited, with a size of approximately 200 nm.

Keywords: Proton Pump Inhibitor, Peptic Ulcers Disease, Gastro-intestinal track, Nanoparticles, Nonsteroidal Anti-inflammatory Drug, Nano- Materials

Full Text:

Introduction

Acids and pepsin cause ulcers on the lining of the duodenum and stomach, causing peptic ulcers (PUD). PUD is caused by an imbalance between protective factors such as prostaglandins, blood flow, and cell regeneration and aggressive factors such as alcohol abuse, smoking, Helicobacter pylori colonization, and the use of nonsteroidal anti-inflammatory drugs.¹

Peptic ulcer (PUD) is a term used to describe a wound in the gastrointestinal tract (GIT) that reaches the inner, submucosal, and possibly outer muscle layers, causing perforation and death. Organ wall lead. The disease affects a significant portion of the world's population and increases public health costs. Ulcers are a common condition that affects people around the world. Symptomatic treatment of ulcers hurts health due to unpleasant side effects. Many herbs and secondary metabolites are currently used to treat ulcers.²

Traditional oral treatments are well known. However, drug degradation in the gastrointestinal environment, reduced oral bioavailability and lack of drug delivery to the target site can reduce the effectiveness of this treatment. After this approach, it becomes attractive to use tactics to improve the effectiveness of these traditional medicines.¹ For better effect, the particle size of the formulation in the nanometer range is preferred for high penetration efficiency. Therefore, the composite material is prioritized over the nanoparticles formed. Nanomaterials are gaining importance in innovation due to their adjustable physical, chemical, and biological properties, and their superior performance compared to bulk materials. The size, composition, shape, and origin of nanomaterials are all factors that need to be considered.³

Role of nanoparticles in peptic ulcer-

Nanoscale devices less than 50 nanometresin diameter can easily penetrate most cells, while devices less than 20 nanometresin diameter can easily exit the blood arteries as they circulate through the body. Due to their small size, nanoscale devices can easily interact with biomolecules both on the surface and inside the cell. As a result, it is made of high molecular weight nanoparticles that can be used to treat ulcers.⁴The production of high molecular weight nanoparticles by high-speed homogenizer and ultrasonic technology increases the solubility and absorption of the drug, increasing its availability at the action site and the therapeutic index.⁵In peptic ulcers, sucralfate is a topically active chemical that combines with hydrochloric acid in the stomach in an acidic environment to produce a pasty, viscous crosslinker capable of serving as an acid buffer for up to 6 to 8 hours after a single dose in an acidic environment⁶. This project creates polymeric nanoparticles, reducing the available particle size and increasing treatment efficiency⁷. Due to the formation of a polymeric coating, the absorption rate is also increased in the stomach and intestine.⁸ Using an ultrasonic homogenizer is very efficient in reducing soft and hard particles. Homogeneity is based on cavitation⁹. When a liquid undergoes intensive sonication, the sound waves propagate through the liquid, causing alternating high-pressure and low-pressure cycles (approximately 20,000 cycles/sec).¹⁰

The epithelium of the small and large intestines is in intimate contact with ingested material to absorb nutrients. Disaccharides, peptides, fatty acids, and monoglycerides are produced in the small intestine, then converted and absorbed in the villi. Due to electrostatic repulsion and trapping means, charged particles such as carboxylate polystyrene nanoparticles or those made from positively charged polymers have limited oral bioavailability ¹¹. The smaller the diameter of the particles, the faster they can pass through the mucus and reach the colon cells; a Diameter of 14 nm penetrates in 2 min, the diameter of 415 nm penetrates in 4 min. particles look 30 min while 1000 nm particles cannot shift this barrier.12

Ulcer Anatomy & Pathophysiology-

An ulcer is a continuous rupture of the covering epithelium, whether it is the skin or the mucosa, due to molecular death. An ulcer is a rupture or rupture of the inner lining of the body that prevents a membrane-bound organ from continuing to function normally. An imbalance between protective and destructive factors in the gastrointestinal tract lining causes peptic ulcer disease. duodenum (PUD). Risk factors for PUD include H. pylori infection, NSAID use, first-degree relative with PUD, migration from developed countries, and African-American/Hispanic ethnicity. A mucosal defect extending to the muscular mucosa is common with peptic ulcers. The inner layers are susceptible to acid when the mucous membrane that protects the surface is damaged. The ability of mucosal cells to release bicarbonate is also impaired. H. pylori is known to localize and inflame the gastric mucosa. H. pylori also inhibits bicarbonate release, promotes metabolism, and increases gastric acidity.¹²

Preliminary test for peptic ulcer-

Stool monoclonal antigen tests-

When using a laboratory-certified monoclonal test, fecal antigen screening uses a monoclonal antibody that is as accurate as of the urea breath test ¹⁶. The urea breath test is more expensive and requires more equipment. Similar to how a urea breath test only detects an existing infection, a stool antigen test can be used as a curative test. PPIs should avoid for two weeks before testing, but stool antigen testing is not as affected as urea breath tests using PPIs. ¹⁷

Mechanism of Action of drug -

Finally, PPIs work by reducing gastric acid secretion. These drugs are absorbed near the small intestine and then released into the circulation, where they affect the stomach’s parietal cells.¹⁸ The enzyme H+/K+ ATPase, or proton pump, is found in parietal cells and is blocked by PPIs. The penultimate stage in gastric acid secretion is this enzyme. PPIs are active precursors in the acid-secreting tubules of parietal cells only after acid-catalyzed cleavage. PPIs are broken down by the liver enzyme P450.¹⁹ Though there are slight differences in which the P450 enzyme predominates in breaking down some PPIs, CYP2C19 is the most common.¹⁴Understanding how PPIs are metabolized can help us understand why certain PPIs work better for some people than others. For example, people of Asian descent have higher bioavailability of PPIs and should start at a lower dose. The bioavailability of PPIs increases with age. Therefore, the dosage in the elderly should be checked frequently and changed as necessary. PPIs are the most effective drugs to reduce acid production in the stomach.¹⁵

Figure. 3 - Schematic representation of the major pathophysiological mechanisms involved in the pathogenesis of peptic ulcer disease and the sites of action of the most commonly used pharmacological treatment options for peptic ulcer disease. CCK2 = cholecystokinin receptor; PGE2 = prostaglandin E2; PGI2 = prostaglandin I2; EP3 = prostaglandin E3 receptor; HIST = histamine. ²¹

Role of additives for nanoparticles drug targeting-

Organic Solvent-

Organic solvents recognized as neurotoxins include hexane, tetrachlorethylene, and toluene. Fatty and aromatic hydrocarbons, amines, esters, ethers, ketones, and nitrated or chlorinated hydrocarbons are all examples of organic solvents.¹⁶

Polymer-

Allows the modification of ligand surfaces for stealth and drug delivery, ensuring the stability of labile molecules. e.g. Gelatine, lecithin, albumin17.

Surfactant-

Surfactants reduce the average particle size by changing the surface energy of the particles. As a result, the surface tension decreases, and the Kelvin barrier changes, allowing more particles to avoid agglomeration18.

Aq. Solvent-

The aq. Solvents are used to dissolve the surfactant and form a solution19.

Production technique used in particles –

Solvent Evaporation Method –

Solvent evaporation was the original approach to producing macromolecular NPs from a prefabricated polymer. The production of an oil-in-water (o/e) emulsion is required for this process, which leads to the synthesis of nanoparticles ²⁵. The whole process is described, to begin with, an organic phase is produced using a polar organic solvent, in which the polymer is dissolved and the active ingredient (eg a drug) is decomposed. canopy. Both chloroform and dichloromethane have been used extensively in the past, but more often in the past. Due to their toxicity, they have been replaced by ethyl acetate, which is more toxic and therefore more suitable for biomedical applications ²⁰. Aqueous phases containing surfactants (eg polyvinyl acetate; PVA) were also frequently produced. The organic solution is emulsified in the aqueous phase with a detergent and processed into a nanodroplet dispersion using high-speed homogenization or ultrasonic waves. Evaporation of the polymeric solvent that can diffuse into the continuous phase of the emulsion results in a suspension of NP. The solvent is expelled either by continuous magnetic stirrer at room temperature (for more polar solvents) or constant depressurization (as for dichloromethane and chloroform). The cured nanoparticles can then be washed and collected by centrifugation, and after the solvent has evaporated, they can be lyophilized for long-term storage^21_.

Emulsions - Diffusion Method-

This is due to Leroux et al. The patented approach is a modified version of the salting-out process. The polymer was dissolved in a water-miscible solvent (propylene carbonate, benzyl alcohol) and then the solution was saturated with water ²⁸. The solvent phase saturated with polymer water is emulsified into an aqueous solution containing stabilizers²⁹. Then the solvent is removed by evaporation or filtration ³⁰. The advantages of this approach are excellent encapsulation efficiency (typically 70%), minimal homogenization requirements, high batch-to-batch reproducibility, easy scaling, simplicity, and limited size distribution³¹. The leakage of water-soluble drugs into the saturated aqueous outer phase during emulsification reduces encapsulation efficiency, which is a drawback of this approach ³².

Characterization of nanoparticles- 

Morphology-

Scanning and transmission electron microscopes (SEM and TEM) are widely used to learn more about the shape and size of polymer NPs. To analyse the morphology of NP, NP is often used in combination with cryofracture technology. Electron microscopy (TEM) is often used to distinguish between nanocapsules and nanospheres and to measure the wall thickness of nano-capsules. Nanospheres have a spherical, solid polymer structure, while nano-capsules have an oily core surrounded by a thin polymer shell (about 5 nm). Atomic force microscopy is another approach that has been used to analyse the surface morphology of macromolecular NPs (AFMs)³³.

Particle size and size distribution-

Microspheres were suspended in liquid paraffin and observed with an optical microscope. The size distribution of the microsphere was investigated using laser diffraction technology (Malvern Instruments Ltd., Malvern, UK). Average particle size was calculated and reported in micro-meters using cyclohexane as a dispersant ³⁴.

The yield of Nanoparticles-

The total weight of the nanoparticles produced was compared to the total weight of the copolymer and the drug to calculate the nanoparticle yield. 35

Entrapment efficiency-

The nanoparticles were separated from the dispersion by centrifugation at 22,000 rpm for 25 min. The supernatant obtained after centrifugation was appropriately diluted and analysed for free diazepam by UV-Visible spectrophotometer at specific nanometres. The trap effectiveness percentage is calculated as follows 36

Drug Content analysis-

Properly weigh 10 mg of microspheres into a clean 100 ml volumetric flask, dissolve in approximately 2 ml of acetone, adjust the volume with a pH 7.4 buffer, then increase the volume with a pH 7.4 buffer for marking. Rice field. completely. After filtration and dilution, samples were analysed spectrophotometrically to estimate drug concentrations in microspheres. The drug content of each sample was averaged in three separate tests. The containment efficiency of microspheres was estimated by dividing the actual drug content by the theoretical drug content of microspheres ³⁷

Stability of Nanoparticles-

The storage of optimal formulations at 4°C 1°C and 30°C 2°C in a stabilization chamber for 90 days determines the stability of the resulting nanoparticles. Samples were examined for drug content, drug release rate (t50%), and any changes in appearance after some time, such as 0, 1, 2, and 3 months ³⁸

Drug-Excipients Compatibility Studies-

Excipients are essential components of almost all pharmaceutical dosage forms, so it is essential to investigate any physical or chemical interactions between the drug and the excipients, as excipients can change in drug bioavailability and stability. To create a product that is stable, effective, attractive, easy to use, and safe, drugs and excipients must be compatible. Compatibility studies are especially important if the excipients are new and have never been used in formulations containing the active ingredient. To test drug compatibility with different excipients used, DSC and FTIR techniques have been widely used ³⁹

Pharmacokinetic study-

We generated three groups of four Wistar rats (250-300 g) with ulcers. Drugs with NaHCO3 solution (5 mg/kg) or drug formulation (5 mg/kg) were administered to Wistar rats. Blood samples were obtained from the tail vein of each rat before drug treatment and at levels of 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 h after dosing. The supernatant was collected after centrifugation of the blood sample at 12,000 rpm for 10 min at 4 °C. Using acetonitrile and centrifugation, the drug formulation of each sample was extracted. The supernatant was collected, dried, and reconstituted using the mobile phase for HPLC analysis. The number of drug formulations that can be recovered from serum samples has been calculated. Using a non-inhibitory pharmacokinetic analysis model, pharmacokinetic parameters were calculated.⁴⁰

Pharmacodynamic study-

Wistar rats with ulcer-induced ulcers were divided into four groups (n = 4) and received saline (control group), drug solution, or capsule containing the drug formulation. For 7 days, the formulations were administered orally once daily. After 24 h, the mice were dead. The stomach was sectioned along the greatest curvature and its mucosal surface was cleaned with saline solution ⁴⁰. The total mucosal area and ulcerated area were measured using Axio Vision software after imaging the gastric mucosa. The equation used to determine ulcer index (IU)

Biodistribution of nanoparticles in stomach tissue-

Male Wistar rats weighing 250-300 gms were used in this investigation, and they were obtained from the local Laboratory Animal Center. All animal experiments followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals, and all procedures were reviewed by the Animal Research Ethics Board. During the night, the rats were fasted but were given free water. Oral doses of 100% ethanol (5 ml/kg) cause gastric ulcers. The ulcer-induced mice were divided into three groups, with four mice each (one control and two treatment groups). The treatment groups received ready-to-use drugs, while the control groups received only physiological saline. Formulas were used orally 1 h after ethanol administration⁴⁰ Four after receiving the dose, the rats were slaughtered. The stomach is opened longitudinally and saline solution is rubbed. Stomach tissue was divided into ulcerated and non-ulcerative sections, and freshly removed tissue was frozen using Tissue Tek. A CM3050 S cryostat was used to segment the molded tissue sample, which was then examined under a fluorescence microscope with an integrated digital microscopy system.⁴¹ Hematoxylin and eosin were also stained with hematoxylin and eosin to show healthy and ulcerated tissue morphology. The total mucosal area and ulcerated area were measured using Axio Vision software for quantitative determination. Ulcerated and non-ulcerative tissues were lyophilized separately in the dark. Each tissue sample was sonicated for 15 min after immersion in acetone. The supernatant was obtained after centrifugation of those tissue samples for 5 min at 2000 pm. Three times the extraction process was performed. Finally, the supernatant was diluted with acetone and examined with a fluorescence spectrometer at 430 nm and 490 nm. The absorption ratio of nanoparticles per cm2 of gastric tissue, whether ulcerated or not, was used to calculate the absorption of nanoparticles. ⁴²

Discussion-

According to evaluations of multiple papers, reducing the particle size of the dosage form increases porosity and permeability, which increases bioavailability and therapeutic efficacy, and this phenomenon is useful for treating peptic ulcers. Proton pump inhibitors are the best category of the drug in polymeric nanoparticle form, according to the review, and produce better results than other drug categories. When standard dose forms are compared to novel drug delivery systems (NDDS) dosage forms, we discover that NDDS is more effective and patient compliance is higher.

Conclusion-

We can treat PU with high drug potency, bioavailability and efficacy by using formulations containing NPs, resulting in reduced dosing frequency. A lot of research has been done to better understand how nanoparticles heal peptic ulcers, but one of the 4,444 hardest parts of characterizing is their microscopic size. The charge carriers are about 200 nm in size and narrow in size distribution. Nano-sized devices with a diameter of fewer than 50 nanometres can easily enter most cells, while those with a diameter of fewer than 20 nanometres can easily exit blood arteries as they travel. in the body. Nanoscale devices can easily interact with biomolecules both on the surface and inside cells due to their small size.

Acknowledgment-

The authors express their sincere gratitude to Sharad Chandra Pawar College of Pharmacy, College of Pharmacy, Our, University Libraries, and all other sources for their cooperation and advice in writing this review.

Source of Funding-

Self-Finance

Conflict of Interest: Nil

Author Contribution-

All authors contributed equally towards the data collection, data analysis & compilations.

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