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FORMULATION AND EVALUATION OF ITOPRIDE HCL SUSTAINED RELEASED PELLETS

 

Clinical courses

ABOUT AUTHORS:
Shankar Soni1*, Dr. Puspendra singh Naruka1, Sunil kumar ola2
1B N College Of Pharmacy, Udaipur
2Goenka College Of Pharmacy, Laxmangarh
*slsoni85@gmail.com

ABSTRACT
The present work was aimed at formulation development, evaluation and comparative study of the effects of ethyl cellulose in Itopride HCL CR pellets. The controlled release polymers used for the present study were Ethylcellulose N-14 and Ethylcellulose N-20. The formulated pellets were evaluated for various pellet properties, like hardness, bulk density, tapped density, cars index and dissolution rate. Comparative evaluation of the above-mentioned parameters established the superiority of the pellets formulated with Ethylcellulose those formulated with different grades.
The main objective of this work is to develop and explore formulation as sustained release pellets of Itopride hydrochloride.From the literature it was found that different carriers like ethyl cellulose N-20, Ethyl cellulose N-50 were used to prepare controlled release pellets of water soluble drugs. Hence, in the present investigation it is aimed to test the suitability of using ethyl cellulose in the development of gastric retentive systems and for controlling the drug release from the pellets.

Reference Id: PHARMATUTOR-ART-1977

INTRODUCTION
A peptic ulcer is a hole in the Gut lining of the stomach, duodenum, or esophagus. A peptic ulcer of the stomach is called a gastric ulcer of the duodenum, a duodenal ulcer, and of the esophagus, an esophageal ulcer. An ulcer occurs when the lining of these organs is corroded by the acidic digestive juices which are secreted by the stomach cells.

Peptic ulcer disease is common, affecting millions of Americans yearly Proton pump inhibitors (or "PPI"s) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production.


These drugs are utilized in the treatment of many conditions such as Dyspepsia, Peptic ulcer disease (PUD), Gastroesophageal reflux disease Laryngopharyngeal Reflux Disease, Barrett's esophagus, prevention of stress gastritis. Gastrinomas and other conditions that cause hypersecretion of acid, Zollinger-Ellison syndrome.


Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPas) or more commonly just gastric proton pump) of the gastric parietal cell. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion.

1.1. INTRODUCTION OF DRUG DELIVERY SYSTEM:
The aim of any drug delivery system is to provide therapeutic amount of drug and maintain it constant through out the period of treatment from decades an ACUTE OR CHORONIC illness is being clinically treated through the delivery of the drugs to the patient in the form of various dosage forms like Tablets, Capsules, Ointments, Syrups, Suspositories, Aerosols, Pills, Liquids, Gels etc.


New drug delivery systems can be over looked as

  • Delayed Release System
  • Controlled  Release System
  • Sustained  Release System
  • Prolonged Release System
  • Site Specific And Receptor Targeting

1.2. DELAYED RELEASE SYSTEM:
Use repetitive, intermittent dosing of a drug from one or more immediate release units, incorporated into a single dosage form. The two types of delayed release systems are

  1. INTEESTINAL RELEASE SYSTEM
  2. COLONIC PELEASE SYSTEM

a. Intestinal release systems:
A drug may be enteric coated for intestinal release for several known reasons such as to prevent gastric irritation, prevent destabilization in gastric pH etc.

b. Colonic release systems:
Drugs are poorly absorbed through colon but may be delivered   to such a site for two reasons
a) Local action in the treatment of ulcerative colitis and
b) Systemic absorption of protein and peptide drugs

Advantage is taken of the fact that PH sensitive bio degradable polymers like poly methacrylates release the medicament only at the alkaline pH of colon or use of divinylbenzene cross-linked polymers that can be cleaved only by the azo reductase of colonic bacteria to release free drug for local effect or systemic absorption.

eg. Repeat action tablets, enteric-coated tablets.

1.3. CONTROLLED DRUG DELIVERY (PRE PROGRAMED):

  • Controlled drug delivery is delivery of drug at a rate or at a location determined by needs of body or disease state over a specified period of time.
  • Activation modulated
  • Feed back regulated
  • Site targeting
  • Provides constant drug levels with zero order kinetics.

1.3.1. Advantages:
1. Improved patience compliance and convince due to less frequent drug administration
2. Increased safety margin of high potency drugs due to better control of plasma levels.
3. Reduction in health care costs through improved theory, shorter treatment period, less frequency of dosing and reduction in personnel time to dispense Administer and monitor patient.

1.3.2. Disadvantages:
1.  Poor in vitro –in vivo correlations.
2. Possibility of dose dumping due to food, physiologic formulation variables or chewing or grinding of oral formulation by the patient and thus increased risk of toxicity
3. Retrieval of drug is difficult in conc. of toxicity poisoning or hypersensitivity reaction

The oral controlled release systems are classified as follows:
A) Continuous release systems.
B) Delayed transit and continuous release systems.

1.4. SUSTAINED DRUG DELIVERY (PROGRAMED):
The aim of any drug delivery system is to provide therapeutic amount of drug to appropriate site in the body to achieve immediate therapeutic response and to maintain the desired drug concentration.

In the recent years sustained release (SR) dosage forms continue to draw attention in the research for improved patient compliance and decreased incidence of adverse drug reactions.

Sustained release, sustained action, prolonged action, extended action are the terms used to identify drug delivery system that are designed to achieve a prolong therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.

1.4.1. Advantages:
1.Improvement of patient compliance because of decreased frequency of dosage.
2. Avoidance of costly interventions such as laboratory services.
3. Allowing patients to receive medications as outpatients.
4. Optimization of duration of action of drug.
5. Controlling the site release.

1.4.2. Disadvantages:
1.Increased   variability among dosage units.
2. Stability problems.
3. Increased cost per unit dose.
4. More rapid development of tolerance.
5. Need of additional patient education and counseling.

Figure 1: Plasma drug concentration profiles for conventional tablet or capsule formulation, a sustained release formulation and a zero order controlled release formulation.

1.5. PROLONGED RELEASE:
Provide extended release, but not necessarily constant drug levels.  May not follow perfect Zero Order.

1.6. SITE SPECIFIC AND RECEPTOR RELEASE:
Targeting drug to the particular organ or tissue of the body. For receptor release   target is particular receptor for a drug within an organ or tissue.

1.7. PELLETIZATION

Pellets:
Pellets can be defined as small, free flowing spherical or semi-spherical solid units, typically from about 0.5 mm to 1.5 mm, and intended usually for oral
Administration, manufactured by the agglomerates of fine powders or granules of   bulk drugs and Excipients using appropriate processing equipment. Pellets can be prepared by many methods, the compaction and drug-layering being the most widely used today.

Regardless of which manufacturing process is used, pellets have to meet the following requirements. They should be near spherical and have a smooth surface both considered optimum characteristics for subsequent film coating. The particle size range should be as narrow as possible. The optimum size of pellets for pharmaceutical use is considered to be between 600 and 1000mm.

The pellets should contain as much as possible of the active ingredient to keep the size of   the final dosage form within reasonable limits. They should be near spherical and have a smooth surface both considered optimum characteristics for subsequent film coating. The particle size range should be as narrow as possible. The optimum size of pellets for pharmaceutical use is considered to be between 600 and 1000mm.

The pellets should contain as much as possible of the active ingredient to keep the size of the final dosage form within reasonable limits. Regardless of which manufacturing process is used, pellets have to meet the following requirements. They should be near spherical and have a smooth surface both considered optimum characteristics for subsequent film coating.

The particle size range should be as narrow as possible. The optimum size of pellets for pharmaceutical use is considered to be between 600 and 1000mm. The pellets should contain as much as possible of the active ingredient to keep the size of the final dosage form within reasonable limits. They should be near spherical and have a smooth surface both considered optimum characteristics for subsequent film coating.

1.8. Significance of Pellets:
Pellets may have varied applications in varied industries. It just requires an innovative bend to use it to derive maximum profitability. The smooth surface & the uniform size of the pellets allow uniform coating not only for each pellet but also from batch to batch. Highlighted below are some of the few instances where smooth surfaced uniform pellets are being successfully used.

1. Pellets ensure improved flow properties, and flexibility in formulation development and manufacture.

2. The coating material may be colored with a dye material so that the beads of different coating thickness will be darker in color and distinguishable from those having fewer coats.

3. The beads or granules of different thickness of coatings are blended in the desired proportions to give the desired effect.

4. The thickness of the coat on the pellets dictates the rate at which the drug contents are released from the coated particles.

5. By selecting the proper formulation, processing conditions and processing equipment it is possible to attain smooth surfaced & uniform pellets.

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1.9. The Most Common Advantages of Pelletization Are
1. Improved appearance of the product and the core is pharmaceutically elegant.
2. Pelletization offers flexibility in dosage form design and development.
3. Pellets are less susceptible to dose dumping
4. It reduces localized concentration of irritative drugs.
5. It improves safety and efficacy of a drug.
6. Pellets offer reduced variation in gastric emptying rate and transit time.
7. Pellets ensure improved flow properties in formulation development.

The most important reason for the wide acceptance of multiple unit products is the rapid increase in popularity of oral controlled release dosage forms, Controlled release oral solid dosage forms are usually intended either for delivery of the drug at a specific site within the gastrointestinal tract or to sustain the action of drugs over an extended period of time.

The above mentioned goals can be obtained through the application of coating materials (mainly different polymers), providing the desired function or through the formulation of matrix pellets to provide the desired effect.

The advantage of multiple unit products as a controlled release dosage form is believed to be their behavior because of their advantageous dispersion pattern in the gastrointestinal tract and their special size characteristics.

1.10. Theory of Pellet Formation:
In order to judiciously select and optimize any pelletization granulation process, it is important to understand the fundamental mechanisms of granule formation and growth. Different theories have been postulated related to the mechanism of formation and growth of pellets.

As the conventional granulation, the most thoroughly studied, most classified pelletization process, which involves a rotating drum, a pan or a disc, has been divided into three consecutive regions, nucleation, transition and ball growth. However, based on the experiments on the mechanism of pellet formation and growth, the following steps were proposed: nucleation, coalescence, layering and abrasion transfer.

Method of Preparing Pellets
Compaction and drug layering are the most widely used pelletization techniques in harmaceutical industry of the compaction techniques, extrusion and spheronization is the most popular method. Recently, however, melt pelletization has been used frequently in making compaction pellets using a different type of equipment, e.g. a high-shear mixer and Other pelletization methods such as power layering, solution or suspension layering.

Powder layering:
Powder layering involves the deposition of successive layers of dry powders of drugs and excipients on preformed nuclei or cores with the help of binding liquids. As powder layering involves simultaneous application of binding agents and dry powders, hence it requires specialized equipments like spheronizer. The primary requirement in this process is that the product container should be solid walls with no perforation to avoid powder lose beneath the product chute before the powder is picked off by the wet mass of pellets that is being layered.

Solution or suspension layering:
Solution and suspension layering involves the deposition of successive layers of solution or suspensions of drug substances and binder over the starter and non-peril seeds, which is an inert material or crystals/granules of the same drug. In fact the coating process involved in general is applicable to solution or suspension layering technology. Consequently conventional coating pans, fluidized beds, centrifugal granulators, wurster coaters have been used successively to manufacture pellets by this method. The efficiency of the process and the quality of the pellets produced are in part related to the type of equipment used.

Pelletization By Extrusion And Spheronization:
The process involves first making the extrudes from the powder material and then converting the extrudes into beads using the spheronizer. The powder material could be any kind of powder (drug powder, ayurvedic powder, food ingredient powder, detergent powder, nuclear powder etc).  Beads as fine as 0.6mm can be made.

Fig2. formation of pellets by extrusion and spheronization

Other Pelletization Methods
Other pelletization methods such as globulation, cryopelletization, balling, and compression are also used, although a limited scale in the preparation of pharmaceutical pellets.

Globulation or droplet formation consists two related processes, spray drying and spray congealing.

Spray drying:
It is the process in which drugs in the suspension or solution without excipients are sprayed in to a hot stream to produce dry and more spherical particles. This process is commonly used for improving the dissolution rates hence bioavailability of poorly soluble drugs.

Spray congealing:
It is the process in which a drug is allowed to melt, disperse or dissolve in hot melts of gums, waxes or fatty acids, and is sprayed into an air chamber where the temperature is kept below the melting point of the formulation components, to produce spherical congealed pellets. Both immediate and controlled release pellets can be prepared in this process depending on the physiochemical properties of the ingredients and other formulation variables.

Cryopelletization:
It is a process in which the liquid formulation is converted in to solid spherical particles or pellets in the presence of liquid nitrogen as fixing medium. The shape depends up on the distance the droplet travel before contacting liquid nitrogen.

Compression:
It is one type of compaction technique for preparing pellets.Compacting mixtures or blends of active ingredients and excipients under pressure prepare pellets of definite sizes and shapes. The formulation and process variables controlling the quality of pellets prepared are similar to those used in tablets manufacturing.

Balling:
It is the pelletization process in which pellets are formed by a continuous rolling and tumbling motion in pans, discs, drums or mixtures. The process consists of conversion of finely divided particles in to spherical particles upon the addition of appropriate amounts of liquid.

Non Pareil Seeds (Neutral Pellets):

Sugar Spheres:
Sugar spheres contain not more than 92% of sugar, calculated on dry basis. The remainder consists of maize starch defined according to European pharmacopoeia.
Possibility to analyze the sugar spheres according to the NF and JP.
Produced accordance with the GMP.

Enteric coating:
Enteric coatings are those which remain intact in the stomach, but will dissolve and release the contents once it reaches the small intestine. Their prime intension is to delay the release of drugs which are inactivated by the stomach contents or may cause nausea or bleeding by irritation of gastric mucosa.

Cracking of the film either during application or on storage will result in a loss of enteric properties. Therefore, consideration must be given to the mechanical properties of the applied film. Cracking problems can be effectively overcome by plasticization. Plasticizer can also be used to reduce the permeability of the polymer films to water vapor. The choice of suitable Plasticizer is restricted to non-water soluble materials because these are likely to be most effective.

An evaluation is made of the solubility parameters of species together with an assessment of the intrinsic viscosity of dilute solutions of the polymer on the plasticizers. This determines the maximum interaction between polymer and Plasticizer, and indicates which Plasticizer is likely to be most effective. A general rule to follow is to use 1 part Plasticizer to 10 parts polymer.

One should also consider viscosity of the plasticizer, its influence on the final coating solution its effect on film permeability, tackiness, flexibility, solubility and taste and its toxicity, compatibility with other coating solution components and stability of the film and the final coated product.

Enteric coating materials:
Enteric coatings work because they are selectively insoluble substances they won't dissolve in the acidic juices of the stomach, but they will when they reach the higher pH of the small intestine.

5.5.Commonly-used enteric coatings may be made from:
Methacrylic acid copolymers
Cellulose acetate (and its succinate and phthalate version)
Polymethacrylic acid and acrylic acid copolymer
Hydroxypropyl methyl cellulose phthalate
Polyvinyl acetate phthalate
Hydroxyethyl ethyl cellulose phthalate
Cellulose acetate tetrahydrophtalate
Acrylic resin
Shellac

The earliest enteric coatings utilized formalized gelatin, this was unreliable because of the polymerization of gelatin could not be accurately controlled. Another was shellac, disadvantage was polymerization with time, resulting in poor dissolution of the coating.

1.5 COATING EQUIPMENTS:
Most of the coating processes use one of three general types of equipments.
1. The standard Coating pan
2. The Perforated Coating pan
3. The Fluidized bed coater

Conventional pan system:
The standard coating pan system consists of a circular metal pan mounted somewhat angularly on a stand, the pan is rotated on its horizontal axis by a motor, the hot air is directed into the pan and onto the bed surface, and is exhausted by means of ducts positioned through the front of the pan .Coating solutions are applied by spraying the material on the bed surface.

The Perforated Coating pan:
Neocota is an automatic coating system for tablets and pellets. Neocota is a completely updated automatic coating system having a batch capacity of 500 g to 1 kg. This model efficiently carries out the following operations: Aqueous film coating of tablets and pellets Non-aqueous organic solvent based film coating of tablets and pellets and enteric film coating of tablets and pellets.

The basic units of the system are: Coating pan has perforations along its cylindrical portion. It is driven by a variable speed drive with a flame-proof motor. Supply of hot air and exhaust of drying air are arranged to facilitate the coating system through stainless steel plenums positioned on both sides of the perforated coating pan. The pan is enclosed in a cylindrical airtight housing provided with a suitable door and front glass window.

This housing of pan with drive is a stainless steel cabinet accommodating the gearbox, AC variable drive, power panel, hot air unit, ex-haust unit and an air fitter. Liquid spray system is complete with stainless steel liquid storage vessel, variable flow-rate liquid dosing pump, automatic spray gun, and inter-connecting flexible hoses.

The Fluidized bed coater:
The Fluid Bed Technology offers a very efficient coating technique. The major advantage of the Fluid Bed Systems is that it is as per GMP standards it is a closed system. The second advantage of the Fluid Bed Systems is that not only coating but granulation and pellet formation is also possible in the same machine. Fluidized bed coating is a process that takes place inside a fluidized bed whereby a coat is introduced to cover the intended object in order to protect it or modify its behavior. Particulate coating is a form of fluidized bed coating involving the coating of solid Particles inside the bed. In the process, a layer is deposited onto the surface of fluidized solid particles by spraying with a solution of the coating material.

The fluidizing gas is also use to dry the deposited solution to form a coat on the surface of the particle. There is considerable diversity in methods of using fluidized bed technology. For e.g. liquids can be applied to fluidized particles in a variety of ways, including top, bottom and tangential spraying. For a given product, each method can offer markedly.

Fluidized beds for film coating can be divided into 3 groups.
Top-spray
Tangential-spray
Bottom-spray equipment.

Top spray:
The expansion chamber is lengthened to allow powder to remain fluidized longer and to move with a higher velocity, so that agglomeration is minimized The expansion chamber is conically shaped to allow uniform deceleration of air stream .The filter housing is larger and designed to shake the fines back into the bed interrupting fluidization this reduces agglomeration endencies.

The nozzle is positioned low in the expansion chamber so that coating material impinge on the fluidized particle a short distance from the nozzle; this reduces droplet spray drying and provides for longer subsequent drying of the coated particles. The top spray coater has been used to apply aqueous and organic solvent based film coatings, controlled release coatings.

Bottom spray coating: (wurster process, Make-GLATT)
The wurster machine employs a cylindrical product container with a perforated plate. Inside the container is a second cylinder (coating partition) with is raised slightly above the perforated plate, centered in the plate below this partition is a spray nozzle used to dispense the coating solution. The perforated plated is designed with large holes in the area under the coating partition and smaller holes in the remainder of the plate, except for one ring of large holes at the perimeter. The design allows the substrate particles to be pneumatically transported upward through the coating partition, and downward outside this partition.

Material passing through coating partition receives a layer of coating material, dries in the expansion chamber, and falls back in a semi fluidized state. Material circulates rapidly in this fashion and receives layer of coating material, dries in the expansion chamber, and falls back in a semi fluidized state material circulates rapidly in this fashion and receives a layer of coating on each pass through the coating partition. The ring of large holes on the periphery of perforated plate prevents the accumulation of material at the container wall. It has been used for coating small particles, pellets and tablets.

Table: 2 Parameters Used in Bottom Spray Equipment

Inlet temperature

38-42ºC

Product temperature

32-36ºC

Exhaust temperature

32-38ºC

Spray rate

8-12mg/min

Peristaltic pump

12-18 rpm

1.6 Fluid Bed Coating
Particles smaller than approx.2mm should be coated in fluid bed equipments, because with decreasing particle diameter the specific surface area of a substrate increase dramatically  thus, the required coating weight gain is much higher than tablet coating processes. In order to achieve acceptable process times, the high efficiency of fluid bed compared to pan coating equipment shows clear advantages in particles coating processes.

Shape
In order to achieve good flow properties, spherical particles with smooth surfaces are preferred, while needle shaped particles show poor flow properties and tend to form lumps. Another advantage of the latter is the increased risk of breakage during the coating process, creating un coated spaces and leading to an increased coating weight gain .besides crystals and pellets, granules can be used as substrates as a disadvantages we may have uneven surfaces and often increased abrasion compared to the shapes mentioned first, which can also lead to increased surface areas which requires higher amounts of coating.

Size
Usual particle sizes are in arrange of 0.2-1.2mm.smaller particles may have problematic flow properties in higher scale and may tend to break if the length and diameter-ratio is.2. Smaller particle size are required if particles are administered from sachets or incorporated into chewable tablets. in order to avoid damage by chewing, the coated particles  should have a maximum size of o.4mm smaller end products may given a better mouth felling but increasing specific surface areas requires higher coating amounts.

Top And Bottom Or Tangential Spray
The top spray method is known and used for particle coating and granulation processes. Compared to other fluid bed coating technologies, the top spray method is susceptible for porous film structure, especially if organic coating formulations are processed .bottom spraying (wurster process) is the usual method in particle coating .due to a more uniform particle movement, better film structures can be achieved compared to the top spray method, and the required polymer weight gain for a certain function is usually lower to some extent.

A disadvantage is that in case of nozzle blockage during the coating process, the product must be discharged before the nozzles can be cleaned. Tangential spraying system, which is commonly fitted with a rotating bottom plate, can achieve film quantities nearly as good as bottom spraying system. The rotation of the plate nicely supports product movement, so that the required air amount is mainly used for drying process and only to a smaller degree for the product movement.

Nozzles For The Particle Coating
Common spray gum  are air-borne with a round spray pattern. Some equipment is fitted with a double air supply which is used for common atomizing air and extra microclimate air, which surrounds the spray pattern, preventing over wetting of the product and reducing spray drying effects.

Pump System
Peristaltic pumps fitted with silicon tubing are standard. Tubing can be selected in a wide range of internal diameters in order to keep the flow speed high and hence to prevent sedimentation .therefore the use of tubing with small internal diameters recommended. Alternative pump systems include gear pumps and piston pumps.

Roating Disk Granulation
Granulation techniques utilizing centrifugal fluidizing drive has been studied only recently. These techniques have been extended to coating operations and combined with an expansion chamber to form the rotating disk granulator and coater fluid bed device.

The disk can be moved up or down to create a variable slit opening between the outer perimeter of the disk and the sidewall of the container. Air is drawn into the product container through the slit under negative pressure. This fluidizes the material along the circumferential surface of the product container. At the same time the disk rotates at varying speeds and moves the product by the centrifugal force to the outer portions where it is lifted by the fluidizing air stream into the expansion chamber.

As the material decelerates it descends to the center of the disk and repeats the same sequence. The fluidization pattern is often described as a spiraling helix or rope-like pattern around the inside of the rotor chamber. Spray nozzles can be immersed in the bed of fluidized material and spray applied in tangential fashion with respect to the particle flow.

DRUG PROFILE:

ITOPRIDEHCL:
Itopride (INN) is a prokinetic benzamide derivative unlike metoclopramide or domperidone. These drugs inhibit dopamine and have a gastrokinetic effect. Itopride is indicated for the treatment of functional dyspepsia and other gastrointestinal conditions.

It has the tradename GITUNE 50/150 MG and is marketed by INTAS PHARMACEUTICALS LTD. It has the tradename Ganaton and is marketed by Abbott Laboratories.

Itopride is not currently approved by the U.S. Food and Drug Administration (FDA) for use in the United States, nor is it yet approved in the United Kingdom. This may explain the apparent lack of patient information available in English compared to other similar classes of medication.

Physico Chemical Properties:

PHARACODYNAMICS:
Itopride HCl also has antiemetic action through interaction with D2 receptors located in the chemoreceptor trigger zone. Itopride HCl has been shown to accelerate gastric emptying in humans. The action of itopride HCl is highly specific for the upper GIT. It does not affect serum gastrin levels.

PHARMACOKINETICS:

Absorption:
Itopride HCl is rapidly and almost completely absorbed from the GIT. Relative bioavailability is calculated to be 60% due to liver first-pass metabolism. There is no effect of food on bioavailability.

Peak plasma levels (Cmax 0.28 mcg/mL) are reached after 30-45 min after 50 mg of itopride HCl. Following multiple oral doses ranging from 50-200 mg 3 times daily, itopride HCl and its metabolites showed linear pharmacokinetics over a treatment period of 7 days, with minimal accumulation.

Distribution:
Approximately 96% of itopride HCl is bound to plasma proteins .Albumin accounts for most of the binding. α1-acid glycoprotein accounts for <15% of binding.

Metabolism:
Itopride undergoes extensive hepatic metabolism in humans. Three metabolites have been identified, of which only 1 exerts minor activity without pharmacological relevance (approximately 2-3% of that of itopride). The primary metabolite in humans is the N-oxide generated by oxidation of the tertiary amine N-dimethyl group.

Itopride is metabolized by a flavin-dependent monooxygenase (FMO3). The abundance and efficiency of the human FMO-isozymes can be subject to genetic polymorphisms, which can lead to a rare autosomal recessive condition known as trimethylaminuria (fish odor syndrome).

The t½ of itopride may therefore be longer in trimethylaminuria patients. In vivo pharmacokinetic studies on CYP-mediated reactions revealed that itopride showed neither inhibitory nor inductory effect on CYP2C19 and CYP2E1, CYP content and uridine diphosphate glucuronosyl transferase activity were not altered with the administration of itopride.

Excretion:
Itopride HCl and its metabolites are primarily excreted in the urine. The urinary excretions of itopride and its N-oxide were 3.7% and 75.4%, respectively, in healthy subjects after oral administration of a single therapeutic dose.

Pharmacokinetic Properties:
1. HALF LIFE (T1/2): 5-6HOURS (BIOLOGICAL).
2. SHELF-LIFE: 36 MONTHS.
3. BIOAVAILABILITY: 60%
4. PH: 4-5
6. PROTEIN BINDING: 96%
7. ROUTE OF METABOLISM: HEPATIC METABOLISM CYTOCHROME P450 (CYP3A4)
8. ROUTE OF ELIMINATION: URINE 75.4%.

MECHANISAM OF ACTION:
Itopride has anticholinesterase (AchE) activity as wellas dopamine D2 receptor antagonistic activity and is beingused for the symptomatic treatment of various gastrointestinal motility disorders .It is well established that M3 receptors exist on thesmooth muscle layer throughout the gut and Acetylcholine(ACh) released from enteric nerve endings stimulates the contraction ofsmooth muscle through M3 receptors.

The enzyme AChE hydrolyses the released Ach inactivates it and thus inhibits the gastric motility leadingto various digestive disorders. Besides Ach dopamineis present in significant amounts in the gastro intestinaltractand has several inhibitory effects on gastrointestinalmotility, including reduction of lower esophageal sphincter and intragastric pressure. These effects appearto result from suppression of ACh release from themyenteric motor neurons and are mediated by the D2subtype of dopamine receptors.

Itopride, by virtue of its dopamine D2 receptorantagonism, removes the inhibitory effects on Achrelease. It also inhibits the enzyme AchE which preventsthe degradation of ACh .The net effect is anincrease in ACh concentration, which in turn, promotesgastric motility, increases the lower esophageal sphincterpressure, accelerates gastric emptying and improvesgastro-duodenal coordination. This dual mode of action of Itopride is unique .

THERAPEUTIC INDICATIONS:
Various prokinetic studies were conducted in patientsof NUD, reflux esophagitis and chronic gastritis, diabeticgastroparesis and functional dyspepsia. The results ofthese studies indicated that itopride is an effective prokinetic agent for the treatment of symptoms causedby altered gastrointestinal motility in all the above mentioned conditions.

Few studies have shown that itopride is superior in efficacy to metoclopramide and cisapride in patients of NUD. Sawantin a comparative trial found itoprideto be comparable in efficacy to Domperidone in the symptomatic management of NUD.

DOSAGE AND ADMINISTRATION:
The usual daily dosage for adults is 50mg of itopride hydrochloride orally in 3 divided doses before each meal (5).

CONTRAINDICATIONS AND PRECAUTIONS:
Itopride HCl is a relatively new drug and it is not currently approved for normal prescribed use or OTC use in either the US or the UK. However, this does not necessarily indicate that Itopride HCl is not effective or safe. Patients taking Itopride HCl should report any side-effects to their treating physician.

Itopride HCl is contraindicated in hypersensitivity to Itopride HCl or benzamides; lactation, GI hemorrhages, obstruction or perforation. Itopride HCl may not be indicated for those suffering from Parkinson's disease or other conditions involving dopamine regulation issues. Itopride HCl should be used with special caution in the young and the elderly. Little information is available at this time regarding the safe use of Itopride HCl during pregnancy.

SPECIAL PRECATIONS:
Itopride HCl enhances the action of acetylcholine and may produce cholinergic side effects. Data on long-term use are not available.

Use in pregnancy:
There are no adequate and well-controlled studies in pregnant women. Therefore itopride HCl should not be used during pregnancy unless the benefits outweigh the potential risks.

Labor and Delivery:
There are no known effects of Itopride HCl on labor or delivery.

Use in lactation:
Because Itopride is excreted in milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Use in children:
Safety of Itopride in children <16 years has not been established.

Use in the elderly:
In general, appropriate caution should be exercised in the administration and monitoring of Itopride HCl in elderly patients reflecting the greater frequency of decreased hepatic, renal function and of concomitant disease or other drug therapy.

ADVERSE DRUG REACTIONS:
Some common side-effects of itopride may include rash, diarrhea, giddiness,exhaustion, back or chest pain, increased salivation, constipation, abdominal pain, headache, sleeping disorders, dizziness, galactorrhea, and gynecomastia.

Other side effects may also be present.

(a).Leukopenia, a reduction in the normal level of white blood cells, can be a potentially life-threatening reaction to itopride.

CARDIAC STUDIES:
Itopride belongs to the same benzamide group as cisapride, a drug which was found to affect QT interval and possibly predispose those using it to cardiac arrhythmias. This resulted in cisapride being voluntarily removed from the U.S. market on July 14, 2000 after a warning letter was issued by the FDA which mentioned these effects.

An obvious concern due to similarities between cisapride and itopride led to several preclinical studies being undertaken to evaluate the cardiac safety profile of itopride to see if it had a similar effect on QT interval in animals. These studies indicated that unlike cisapride, itopride was devoid of the potential to cause prolongation of the QT interval and posed no known risk of cardiac arrhythmias.

Later, in a study conducted with healthy adult volunteers, itopride was shown as unlikely to cause cardiac arrhythmias or ECG changes in part to the lack of significant interaction and metabolism via the cytochrome P450 enzyme pathway unlike cisapride and mosapride as it is metabolized by a different enzyme set.

New molecular studies on guinea-pig ventricular myocytes also supported the cardiac safety profile of itopride as it did not affect certain potassium mechanisms that may have been affected by cisapride or mosapride.

Moreover, Itopride has no affinity for the 5-HT4 receptors unlike other benzamides such as cisapride and mosapride which are 5-HT4 agonists. The affinity of cisapride for 5-HT4 receptors in the heart has been implicated in the undesirable cardiac effects of cisapride itsel.

INTERACTIONS:
Anticholinergic agents reduce the action of Itopride HCl. It is worth noting that Itopride HCl is a relatively new drug and that it is therefore possible that other drugs may interact with Itopride HCl which is not currently known.

TOLERABILITY:
Following the restriction imposed on cisapride us ageand the subsequent report of the arrhythmic potential of mosapride, safety of a prokinetic drug has been a cause of concern. Itopride is well tolerated with few minoradverse drug reactions in the form of diarrhea, headache,abdominal pain etc.

It has no significant effects on central nervous system and thus is devoid of extra pyramidal side effects and hyperprolactinaemia as is seen with other prokinetic drugs such as metoclopramide and domperidone.

It also has no effect on the cardiovascular system. Preclinical and clinical studie still date indicate that this drug is not having the potentialto cause prolongation of QT intervals unlike cisaprideand mosapride.

The affinity of cisapride for5HT4 receptors in the heart has been implicated in the undesirable cardiac effects of the drug but itopride has no affinity for 5HT4 receptors which makes this drug a better and safer prokinetic agent .Safety of this drug108 Vol has not been established in the pregnant females although no abnormalities in the organogenesis and foetal developments were observed in animal studies.

USES:
Itopride is Gastro intestinal prokinetic and it is used in the treatment of GI symptoms caused by reduced motility (Gastric fullness, Epigastric pain, anorexia, heart burn, Regurgitation, bloating, Nausea and vomitting.

  • Dyspepsia of a non-ulcer type (gastric "fullness", discomfort, and possible pain)
  • Anorexia
  • Heartburn
  • Regurgitation
  • Bloating
  • Nausea and vomiting
  • other possible gastric, prolactin, or dopamine related conditions

Itopride is typically taken three times a day. The dose is usually taken on an empty stomach about an hour before meals. However, the dosage and details of administration may vary depending on the patient’s age, symptoms, and other factors. Itopride was shown to significantly improve symptoms in patients with functional dyspepsia and motility disorders in placebo-controlled trials.

These studies concluded that the reduction in the severity of symptoms of functional dyspepsia after 8 weeks of treatment with Itopride indicated that Itopride was significantly superior to placebo and that Itopride yielded a greater rate of response than placebo in significantly reducing pain and fullness.

EXPERIMENTAL DETAILS:

Preformulation

Physical Characteristic

A) Determination of bulk density and tap density:
An accurately weighted quantity of the powder (W) was carefully poured into the granulated cylinder and volume (Vo) was measured. then the graduated cylinder was closed with lid .set into the density determination apparatus (bulk density apparatus)the density apparatus was set for  500 taps,750 taps , and 1250 taps .

After that the volume(Vf) was measured and continued the operation till the two consecutive reading were equal. The bulk density and the tapped density were calculated using the formulas.

Bulk Density – W/Vo
Tapped Density- W/Vf

Where W- Weight of the powder.
Vo - Initial volume(s)
Vf - Final volume.