Preparation and evaluation of pulsatile drug delivery system for paracetmol

Preparation and evaluation of pulsatile drug delivery system for paracetmol

preparation and evaluation of pulsatile drug delivery system for paracetmol

Project Abstract

The objective of the present study is to obtain a programmed drug delivery system which contains two pulses of doses in a single tablet.

In present study two pulse release tablets of paracetamol was to be formulated, A-J. The formulations A-J are having two pulses of Paracetamol in which polymers used are Croscarmellose Sodium, Cross Povidone, Sodium Starch Glycolate, Starch USP, Carboxy methyl cellulose, Starch 1500, Alginate, Methyl cellulose, Guar gum and Hydroxy Propyl Methyl Cellulose. First pulse is having dose of 250 mg and second pulse which is core tablet is having the dose of 250 mg coated with Opadry film.

The aim of the study to determine which formulation is giving a good lag time and a desirable drug release from both the second and first pulses of the tablets is determined by both invitro and invivo model.

Acknowledgement

‘Words’ are very poor comforters to express the deep debt of gratitude which

one feels in one’s inner corner of the heart when one is helped to achieve the goal in

this boundless and endless field of research work, but since there is no other way

which can better express one’s feeling of gratitude than this. I must have to recourse it and express my deep debt of gratitude with honorable regards to esteemed superviser Ms.Enoche oga (School of Pharmacy and Biomedical Sciences, University of Central Lancashire) Lecturer, constant encouragement and philosophical suggestions made me possible to submit my dissertation. I wish to extend my gratitude to Mr.Abdullah Isreb (School of Pharmacy and Biomedical Sciences, University of Central Lancashire).

Table of Content

Pages

1.Introduction 1-20

· Pulsatile drug delivery system.

· Classification of pulsatile drug delivery system.

· Advantages & Disadvantages.

· Disease targeted pulsatile drug delivery system.

· Recent advances.

· Aim of the study.

· Drug profile.

2.Materials and Methods 21-27

· List of ingredients

· List of equipments used

· Calibration curve of paracetamol

· Formulation of two pulse release tablet

· Characterization and evaluation of tablets

3.Results&Discussion 28-

· Calibration curve of paracetamol

· Scanning Electron Microscopy

· XRD

· TGA

· Post formulation studies

4.Conclusion 29

5.Bibliography 30

INTRODUCTION

PULSATILE DRUG DELIVERY SYSTEM

Oral controlled drug delivery systems are the prominent form of drug delivery systems, it has many pros over oral route of drug delivery system. This drug delivery systems release their medicament in a sustained manner. This kind of drug delivery system offers many pros over other drug delivery system such as constant release of drug at targeted site, avoid the fluctuations in drug release, amount of drug & dose frequency also reduced, side effects are decreased, and improves patient compliance.

Figure 1: Drug release profile of Pulsatile Drug Delivery Systems

Chronopharmacokinetic

Chronopharmacokinetics involves study of drug absorption, distribution, metabolism and excretion. Pharmacokinetic parameters can be influenced by changes in the physiological functions of circadian rhythm. examples of circadian rhythm are secretion of gastric acid, gastrointestinal motility, blood flow in GI, drug protein binding, liver enzyme activity, renal blood flow etc…

Classification of pulsatile drug delivery systems: (Gupta Anuj, 2012)

Pulsatile drug delivery system can be broadly classified into three classes.

I. Time controlled pulsatile drug delivery.

II. Stimuli induced pulsatile drug delivery.

III. Externally regulated pulsatile drug delivery.

I. Time controlled pulsatile drug delivery.

A. Single unit pulsatile systems

1. Capsule based systems

E.g. Pulsincap system

2. Capsular system based on Osmosis

a. ‘Port’ System

b. System based on expandable orifice.

c. Delivery by series of stops.

d. Pulsatile delivery by solubility modulation

3. Pulsatile system with Erodible or soluble barrier coatings.

a. The chronotropic system

b. ‘Time clock’ System.

c. Compressed tablets

d. Multilayered Tablets

4. Pulsatile system with rupturable coating

B. Multiparticulate / Multiple unit systems:

1. Pulsatile system with rupturable coating

E.g. Time –controlled Explosion system (TCES)

2. Osmotic based rupturable coating system

E.g. Permeability controlled system

3. Pulsatile delivery by change in membrane permeability

E.g. Sigmoidal release system.

A. Single unit pulsatile system

1. Capsule based systems:

Pulsincap was comprises of a water-insoluble capsule enclosing the drug reservoir. When this capsule come in contact with the dissolution fluid, it swells; and after a predetermined lag time, the plug pushed itself from the capsule and rapidly released the drug. Here the lag time is controlled by the plug. Some of the examples for hydrogel plug are.

1) They are not soluble, but the drug gets penetrate through swollen polymers (e.g., polymethacrylates)

2) Erodible compressed polymers (e.g., hydroxy propyl methyl cellulose, polyvinyl alcohol, Polyethylene oxide)

3) Congealed melted polymers (e.g., saturated polyglycolated glycerides, glyceryl mono oleate)

4) Enzymatically controlled erodible polymer (e.g., pectin).

Figure 2: Design of Pulsincap system

2. Capsular system based on Osmosis

a. ‘Port’ System

The Port system was developed by therapeutic system research laboratory Ann Arbor, Michigan, USA, and consists of a capsule coated with a semi permeable membrane. Inside the capsule consist of insoluble plug and the drug formulation. When this capsule expose to the solvent, the membrane present in the capsule absorbs the water, and it creates some osmotic pressure inside the capsule and the plug expelled after a predetermined lag time. Example are methylphenidate used for hyperactivity disorder.

Figure 3: Drug release mechanism from port system

b. System based on expandable orifice:

It is an osmotically driven capsular system in which the liquid drug is absorbed into highly porous particles, which release the drug through an orifice of a semi permeable capsule supported by an expanding osmotic layer after the barrier layer is dissolved. The capsular system delivers drug from the capsule osmotic infusion of moisture from the body. E.g. Elastomers, such as styrene-butadiene copolymer have been suggested Pulsatile release was achieved after lag times of 1 to 10 hrs, depending on the thickness of the barrier layer and that of semi permeable membrane. A capsule designed for implantation can deliver drug intermittently at intervals of 6 hours for 2 days.

Figure 4: System on expandable orifice

c. Delivery by series of stops: based

In this system drug and a water-absorptive osmotic engine that are placed into capsule and separated by a movable partition. This capsule consists of sequence of partitions which deliver drug pulse manner and the number and the frequency of dose depends on the number of partitions present in the capsule, drug release from capsule depends on the osmotic pressure created in the capsule. porcine somatotropin deliver the drug by using this delivery system.

d. Pulsatile delivery by solubility modulation:

This system consists of drug (salbutamol sulphate) and a modulating agent (sodium chloride). The amount of NaCl was such that it was less than the amount needed to maintain saturation in a fluid that enters the osmotic device. The pulsed delivery is based on drug solubility. Salbutamol has solubility of 275mg/ml in water and 16 mg/ml in saturated solution of NaCl, while NaCl has solubility of 321 mg/ml in water, and its saturation solubility is 320 mg/ml.

3. Pulsatile system with Erodible or soluble barrier coatings:

Most of the pulsatile drug delivery systems are reservoir devices coated with a barrier layer. This barrier erodes or dissolves after a specific lag period, and the drug is subsequently

released rapidly from reservoir core. The lag time depends on the thickness of the coating layer.

a. The chronotropic system:

The Chronotropic system consists of a drug core and coated with hydroxy propyl methyl cellulose (HPMC), which is responsible for a lag phase. The predetermined lag time is maintained by the thickness and using different grades of HPMC. The system is suitable for both tablets and capsules.

Figure 5: The chronotropic system

b. ‘Time clock’ System:

In this system the solid dosage form is coated with a aqueous dispersion. This coating is made up of water-soluble polymer know as hydrophobic-surfactant layer. When it come in contact with the dissolution medium the drug gets dispersed into the body. The delay time depends on width of film coated on the surface. After the lag time, the medicament present in the core gets released immediately.

Figure 6: ‘Time clock’ System

c. Compressed Tablets:

In this system both the core and the coat compressed directly, obviating needs for separate coating process and use of coating solutions. The outer compression-coated tablet provides the initial dose, rapidly disintegrating in the stomach and the inner layer is made up of components are insoluble in gastrointestinal media but they get dissolved in intestinal environment. The major cons of this system is it required large amount of coating material besides this cores tablet can’t be placed in the correct position.

Press-coated pulsatile drug delivery systems:

1. This system is used to protect hygroscopic, light-sensitive, oxygen labile or acid-labile drugs.

2. Preparation procedure is simple and cheap.

3. Both the core and coat were compressed directly in this system.

4. Both hydrophobic, hydrophilic materials are used in press-coated pulsatile drug delivery system.

5. This system is used to separate the two incompatible drugs.

d. Multilayered Tablets:

The tablet contain two drug and they are separated by a layer separated by a drug-free gellable polymeric barrier layer. This three-layered tablet was coated on three sides with impermeable ethyl cellulose, and the top portion was left uncoated. Upon contact with dissolution medium, the initial dose incorporated into the top layer was released rapidly from the noncoated surface. The second pulse was obtained from the bottom layer after the gelling barrier layer of HPMC was eroded and dissolved. The rate of gelling and/or dissolution of the barrier layer control the appearance of the second pulse. The gelling polymers reported include cellulose derivatives like HPMC, methyl cellulose, or polyvinyl alcohols of various molecular weights and the coating materials include ethyl cellulose, cellulose-acetate-propionate, methacrylic polymers, acrylic and mehtacrylic co-polymers, and polyalcohols.

Figure 7: Multilayered Tablet

4. Pulsatile system with rupturable coating:

These systems depend on the rupturing of the coating for the release of drug. The pressure necessary for disintegration of the coating can be achieved by the effervescent excipients, swelling agents, or osmotic pressure. Citric acid and sodium bicarbonate used as effervescent excipient for the preparation of tablet core, and it is coated with ethyl cellulose. When the tablet come in contact with the dissolution medium it develops carbon dioxide helps in penetration of water into the core results in delivering of drug in pulsatile manner after disintegration of the coating. The release of drug and lag time depends on the thickness of coating layer and hardness of the core tablet.

B. Multiparticulate / Multiple unit systems:

Multiparticualte systems offer various advantages over single-unit systems. These include,

1. No dose dumping was observed.

2. Flexibility of blending units with different release patterns.

3. Reproducible and short gastric residence time.

The drug-carrying capacity is low in multiparticulate systems is due to presences of huge number of excipients.

1. Pulsatile system based on rupturable coating:

E.g. Time –controlled Explosion system (TCES):

This is a multiparticulate system in which drug is coated on non-pareil sugar seeds followed by a swellable layer and an insoluble top layer. Super-disintegrants agent used as swelling agents examples are sodium carboxymethyl cellulose, sodium starch glycolate, L-hydroxypropyl cellulose. Polymers used for preparation of this are polyvinyl acetate, polyacrylic acid, polyethylene glycol, etc. when coming to effervescent tablet it is made up of mixture of tartaric acid and sodium bicarbonate. Upon penetration of media into the tablet, the swellable layer get expanded, further the drug gets released due to the rupture of film. The release of drug does not depend on drug solubility and pH of environment. The lag time of the tablet depends on thickness of coating or amounts of plasticizer in the outermost layer.

2. Osmotic based rupturable coating system:

This system is based on mechanism of osmotic and swelling effects. The core made up of drug, a solid and/or lipid material (eg, mineral oil) followed by disintegrating agent. It is coated with cellulose acetate. When aqueous medium come in contact with this system, the media get penetrates into the core displacing lipid material. After the depletion of lipid material, internal pressure is created inside the core which results in rupture of coating. Another system large number of pellets are encapsulated in capsule or tablet. Each pellet consist of core that is made up of therapeutic agent and a water-soluble osmotic agent. The osmotic agents dissolve in the water causing swelling of pellets, thereby regulating the rate of drug dispersion. This system most commonly used for antihypertensive drug (eg.diltiazem).

3. Pulsatile delivery by change in membrane permeability:

A Sigmoidal release system (SRS) is reported due to the interaction of acrylic polymers with quaternary ammonium groups in the presence of other counter ions. SRS system consists of pellet cores having drug and succinic acid, it is coated with ammonio-methacrylate copolymer USP/NF type (B). When media come in contact with system the medium dissolves succinic acid. This system was used to design an acid containing core with good in vitro/in vivo correlation of lag time was observed.

II. Stimuli induced pulsatile drug delivery:

The release of the drug is based on the stimulation of biological factor such as temperature, chemical stimuli.

1. Temperature induced systems

2. Chemical stimuli induced pulsatile systems

a. Glucose-responsive insulin release devices.

b. Inflammation-induced pulsatile release.

c. Drug release from intelligent gels responding to antibody concentration.

d. pH sensitive drug delivery system.

1. Temperature induced systems:

a. Thermo-responsive hydrogel systems:

In these systems the polymer undergoes swelling or deswelling phase in response to the temperature which modulate drug release in swollen state.

2. Chemical stimuli induced pulsatile systems:

a. Glucose-responsive insulin release devices:

This system has pH sensitive hydrogel containing glucose oxidase. When glucose concentration in the blood increases glucose oxidase get converted glucose into gluconic acid which results in change in the pH of the system. Due to changes in the pH the polymer get swollen which results in insulin release. Insulin by virtue of its action reduces blood glucose level and consequently gluconic acid level also gets decreased and system turns to the deswelling mode thereby decreasing the insulin release. Examples for pH sensitive polymers are N, N-Dimethyl aminoethyl methacrylate, chitosan, polyol etc.

b. Inflammation-induced pulsatile release:

During inflammation, hydroxyl radicals are produced from these inflammatory cells. Yui and co-workers focused on the inflammatory-induced hydroxyl radicals and designed a drug delivery system, which responded to the hydroxyl radicals and get degraded in a desired manner. They used hyaluronic acid (HA) which is specifically degraded by the hyaluronidase or free radicals. Degradation of HA via the hyaluronidase is very low in a normal state of health but they get degraded rapidly during inflammatory diseases state. This system is used to treat various inflammatory diseases such as rheumatoid arthritis; using anti-inflammatory drug incorporated HA gels as a implant.

c. Drug release from intelligent gels responding to antibody concentration:

Recently, novel gels were developed which responded to the change in concentration of bioactive compounds to alter their swelling/reselling characteristics. Special attention was given to antigen-antibody complex formation as the cross-linking units in the gel since such interactions are very specific. Utilizing the difference in association constants between polymerized antibodies and naturally derived antibodies towards specific antigens, reversible gel swelling/deswelling and drug permeation changes occurs.

d. pH sensitive drug delivery system:

This system consists of two components.

1. Immediate release type

2. Pulsatile release-In which the drug released is based on the change in pH.

pH dependent polymers are used to release the drug at specific site. For example, cellulose acetate phthalate, polyacrylates, and sodium carboxymethylcellulose are used as pH dependent polymers. These polymers are used as enteric coating materials so that the drug get released in the small intestine.

III. Externally regulated pulsatile drug delivery:

In this pulsatile drug delivery system, the drug release regulated by external stimuli like magnetism, ultrasound, electrical effect, and irradiation. In magnetic regulated system a magnetic bead is placed in the implant. On application of the magnetic field, drug release occurs because of magnetic beads.

ADVANTAGES AND DISADVANTAGES (Singh et.al, 2011)

There are numerous advantages of the pulsatile drug delivery systems such as:

· These systems can be used for extended day time or nighttime activity.

· They reduce the dose frequency, dose size and cost, which ultimately reduces side effects, thereby improving patient compliance.

· Drug adapts to suit circadian rhythms of body functions diseases.

· Drug targeting to a specific site, like the colon, can be achieved.

· They protect mucosa from irritating drugs.

· Drug loss by extensive first pass metabolism is prevented.

· They provide constant drug levels at the site of action and prevent the peak-valley fluctuations.

· Predictable, reproducible, and short gastric residence time.

· Less inter- and intra-subject variability.

· Improve bioavailability.

· Limited risk of local irritation.

· No risk of dose dumping.

· Flexibility in design.

· Improve stability.

Disadvantages are:

· Low drug loading capacity and incomplete release of drugs.

· Multiple manufacturing steps.

· Lack of manufacturing reproducibility and efficacy.

· Large number of process variables.

· Batch manufacturing process.

· Higher cost of production.

· Trained/skilled personal needed for manufacturing.

Diseases targeted for Pulsatile Drug Delivery System: (S.R.Tajane et.al, 2012)

Diseases presently targeted for chronopharmaceutical formulations are those for which there are enough scientific backgrounds to justify PDDS- compared to the conventional drug administration approach. They include hypercholesterolemia, asthma, cancer, duodenal ulcer, arthritis, diabetes, neurological disorders, cardiovascular diseases (e.g., hypertension and acute myocardial infarction) and colonic delivery.

All these conditions demand a time-programmed therapeutic scheme releasing the correct amount of dose of the drug at the appropriate time. This requirement is usually fulfilled by PDDS.

Table 1: Diseases required pulsatile delivery (Vipul p. Patel et.al)

Table 2: Marketed Dosage Forms of Pulsatile Drug Delivery

RECENT ADVANCES IN ORAL PULSATILE DELIVERY TECHNOLOGY (Anantha nayaki ravula et.al, 2011)

1. ACCU-BREAK TECHNOLOGY

In ACCU-T-CR Trilayer tablets contains a controlled-release (CR) medication is separated by a drug-free break layer, allowing the CR dose to be divided into equal half doses. Additionally, it contains a immediate release (IR) component can be added to CR tablets.

2. SODAS TECHNOLOGY

Spheroidal Oral Drug Absorption System is also known as Elan’s Multi particulate drug delivery system. The system consists of uniform spheroidal beads of 1-2mm in diameter containing drug & excipients and it is coated with controlled release polymers. The drug gets released in a pulsatile manner.

3. IPDAS Technology

The Intestinal Protective Drug Absorption System is intended for use with GI irritant

compounds. The IPDAS® technology is composed of numerous high density-controlled release beads, which are compressed into a tablet form. Once an IPDAS® tablet is ingested, it gets disintegrated and dispersed beads containing a drug in the stomach, further it transported through duodenum and along the gastrointestinal tract in a controlled manner.

4. CODAS TECHNOLOGY

The Chronotherapeutic Oral Drug Absorption System is developed to attain delayed release of drug. This system is developed to release the drug after a pre-determined lag time, a drug release pattern depends on circadian rhythms. E.g.Verapamil is formulated as VERELAN. The drug is released after 4-5 hours after ingestion; the lag time achieved by using coating drug beads with polymer. This kind of technique is used for arrhythmia drug.

5. PRODAS TECHNOLOGY

Programmable Oral Drug Absorption System is a multi-particulate technology which combines the benefits of tableting technology within a capsule. Here, the release rate of the drug can be preprogrammed.

6. TMDS TECHNOLOGY

The Time Multiple Action Delivery System provides control release rate of multiple ingredients within a single tablet.

7. DMDS TECHNOLOGY

The Dividable Multiple Action Delivery System allows the tablet to be broken down into equal portions so that each portion of the tablet will achieve similar release profile as that of the tablet.

8. PMDS TECHNOLOGY

The Programmable Multiple Action Delivery System technology enables the active ingredient delivered in a controlled manner.

9. GEOCLOCK TECHNOLOGY

This press-coated tablets which consist of active ingredient, and it is coated with mixture of hydrophobic wax and brittle material to maintain pH independent lag time. E.g., LODOTRA – used in rheumatoid arthritis.

10. GEOMATRIX TECHNOLOGY

This technology enables the simultaneous release of 2 different drugs and at different rates from a single tablet. This is achieved by constructing a multilayered tablet. The combination of layers, each with different rates of swelling, erosion is responsible for the rate of drug release within the body.

11. PULSYS TECHNOLOGY

This technology is used for once daily pulsatile dosing. A compressed tablet that contains pellets designed to release drug at different regions in the GI tract in a pulsatile manner is prepared. E.g. Amoxicillin is formulated in this way, and showed improved bactericidal action.

12. OSDRC TECHNOLOGY

One Step Dry Coating technology is a unique, innovative, low cost and high quality

technology. The OSDRC rotary tableting machine has a variable double punch configuration which allows production of tablet within a tablet (cored tablets).

13. INTELLIMATRIX TECHNOLOGY

Contains a unique composition of several different intelligent polymers such as HEC and enables precise profile control and site-specific drug delivery.

14. EURAND’S PULSATILE AND CHRONO RELEASE SYSTEM

This system can provide one or more rapid release pulses with predetermined lag times. For e.g, Propranolol Hcl is formulated as this system and is used in the treatment of cardiovascular diseases. When administered at bedtime, the drug is released after an initial delay such that maximum plasma concentration levels occur in the early morning hours, when the patient is more at risk.

15. EURAND’S DIFFUCAP MULTI PARTICULATE SYSTEM

In system the first layer is active drug and core is made up of sugar/cellulose spheres, and then applying one or more rate controlling, functional polymers to produce spherical multilayered particles. E.g. Innopran is a diffucap formulation containing propranolol and verapamil which are released approximately 4-5 hours after ingestion. The delay is introduced by the level of release controlling polymer applied to the drug loaded beads.

16. DIFFUTAB TECHNOLOGY

This technology is useful for sustained and targeted pulsed delivery. This system incorporates a blend of hydrophilic polymers that control drug release via diffusion and erosion of a matrix tablet.

17. ORBEXA TECHNOLOGY

This is a multi-particulate system in which huge amount of drug is loaded and products obtained is granulated by using spheronizer. The granules were coated with polymer containing functional groups membranes for additional release rate control and may be filled into capsules. This technology can be used for sensitive drugs such as proteins.

18. EURAND’S MINITABS TECHNOLOGY

Multi particulate are used for the preparation of mini tablets which are cylindrical in shape. Those tablets are coated with coating agent to maintain control release of drug.

19. BANNER’S VERSETROL TECHNOLOGY

In this system both hydrophilic or lipophilic matrix are incorporated in to soft gelatin capsule shell in order to attain desired drug release profile.

Aim of the study:

The main aim of this studies is to formulate the paracetamol in pulsatile drug delivery system and evaluate the paracetamol tablets by using invitro anvivo models.

General mechanism of action

Figure 8: General mechanism of paracetamol (Chhaya V Sharma et.al, 2021)

Drug profile

Name: Paracetamol.

IUPAC Name: N-(4-hydroxyphenyl)acetamide.

Molecular formula: C8H9NO2.

Molecular weight: 151.163g/mol.

Major route of administration: oral.

Description: odorless white crystalline solid.

Taste: Slightly bitter taste.

Boiling point:>500oC.

Melting point: 170oC.

Solubility: Very slightly soluble in cold water but greater solubility in hot water.

Density: 1.293 g/cu cm at 21 °C.

Category: Nonsteroidal Anti-inflammatory Drugs.

Half life: 4-8 hours.

Drug interaction: Leuprolide, Goserelin, Desmopressin, Daptomycin decrease the excretion rate of paracetamol which could result in high serum level.

Alcohol may increase the risk of hepatotoxicity.

Storage conditions: stored in a dry and cool place and away from direct sunlight.

Contraindications: liver failure, liver problems, renal impairment, inflammation in the liver because of hepatitis C virus.

MATERIALS AND METHODS

LIST OF INGREDIENTS

Paracetamol, Hypromellose, Methyl cellulose, Sodium starch glycolate, Alginate, Cross povidone, Talc, Magnesium Stearate, cross carmellose sodium, Hydrochloric acid and Microcrystalline cellulose was purchased from medex pharmaceuticals, Warwickshire, England, Polyvinyl pyrrolidone were obtained from OQEMA, England, Oxfordshire. Carboxy methyl cellulose, Hydroxypropyl methyl cellulose, Guar gum was obtained from Aqua-sol ingredients, Starch 1500 was obtained from VWR Chemicals, Sodium hydroxide pellets was purchased from LP Chemicals ,England, Cheshire, NaH₂PO₄ Anhydrous purchased from celtic chemicals, Nacl was purchased from Wilfrid Smith Ltd, England, Northamptonshire. Acetonitrile and Methanol was supplied by Rathburn Chemicals Ltd, Scotland. Eudragit L30 D-55 was obtained from Evonik industries, Greenford, London.

LIST OF EQUIPMENTS USED

Table 6: List of Equipments used

Calibration Curve of Paracetamol:

Diluent:

Mixed methanol and buffer (water, pH1.8, 6.5) (in the ratio 1:3)

Stock solution:

Weighed 100 mg of paracetamol and transferred into 100 mL of volumetric flask and added diluent up to the mark further sonicated for about 10 minutes. Transferred 10 ml of stock solution in to 100ml of volumetric flask and made up to the with phosphate buffer pH 6.5.

Transferred (100 µg/ml solution) 0.5ml, 1ml, 2ml, 3ml, 4ml, 5ml of stock solution in 10 ml of volumetric flask and made up to the mark with phosphate buffer 6.5.

FORMULATION OF TWO PULSE RELEASE TABLET:

Ten different formulations of tablet were formulated using different polymer using Opadry as coating layer for tablet.

It is bilayer tablet containing two drug containing layers separated by a drug-free polymeric barrier layer. Here the core tablet is coated with the Opadry film using fluidized bed coater. The initial dose is compressed on top of the coated surface. The second pulse was obtained from barrier layer by eroding and dissolving the coating layer. The rate of dissolution of the barrier layer controls drug release of second pulse.

Initial dose tablet (wet granulation):

Weight drug and excipient, transferred into blender and mixed well, add drop by drop binding solution to the content and mixed well, wet mix was prepared and passed through the sieve to prepare the granules, and these granules are dried under tray drying after drying the granules are passed through sieve to maintain the uniformity of granules.

Core tablet (Dry granulation):

Weighed both the drug and excipients, mixed to form a sludge and it is divided into small uniform particles by using powder mixer, the mixed content directly compressed into mini tablet machine and coated with Opadry.

Formulation composition

Diluent:

Preparation of fasted state simulating intestinal fluid

Dissolved 0.420 g of sodium hydroxide pellets, 3.438 g of NaH₂PO₄ Anhydrous, 6.186 g of NaCl, in 900 mL of purified water, Adjusted the pH of solution to 6.5 with 1 N NaOH and made up to 1000mL with purified water, Add 2.240 g of SIF Powder to 500mL of buffer. Stirred until powder is dissolved, Made up to 1000 mL with buffer solution.

Preparation of fasted state simulated gastric fluid

Dissolved 1.999 g of NaCl in 900 mL of purified water. Adjusted to pH 1.8 with HCl, made up to 1000mL with purified water, Add 0.060 g of SIF Powder to 0.5 L of NaCl solution. Made up to 1000 mL with NaCl solution.

Characterization and Evaluation of Tablets:

DSC- Differential Scanning Calorimetry:

Each individual components as well as each drug-excipient mixture were weighed (Mettler M3 Microbalance) directly in pierced Al pans (10–12 mg) and scanned between 30–200°C with a heating rate of 10 K min–1, using a Erweka equipped with a DSC 25 cell.

Thermogravimetric analysis:

The 10 mg of drugs were weighted and transferred to a platinum crucible, heating at 10oC/min under nitrogen atmosphere of at a flow rate of 100 mL/min.

Scanning electron microscopy:

The sample was mounted on a metal stub with double sided adhesive tape. The stubs were then placed in the coating chamber. The chamber was evacuated, refilled with argon and samples coated with gold emitted at 1.2 kV. The coated samples were placed into specimen holder of scanning electron microscope in a vacuum chamber. The chamber was evacuated, and a voltage of 15 kV was selected for accelerating the electrons from the electron gun onto the specimen. The image formed was viewed directly via a screen or recorded photographically.

X-ray diffraction:

The sample was filled onto the metal holder, which was previously grinded using mortar and pestle, and then smoothed with a spatula. A scanning rate of 0.04°29 s over the range of 10 to 70029 was used to produce each spectrum.

Hardness

Tablets require a certain amount of strength or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packing and shipping. The hardness of tablet was measured by Monsanto hardness tester. The tablets from each batch were used for hardness studies and results are expressed in Kg/cm3.

Thickness

The thickness of the tablets was measured by screw gauge. It is expressed in mm.

Weight variation test

Ten tablets were selected at randomly from the lot and weighed individually to check for weight variation.

Friability

It was performed in Erweka friability tester apparatus where the tablets were subjected to abrasion and shock by using plastic chamber that revolves at 25 rpm dropping the tablets at a distance of six inches with each revolution. weighted 20 tablets were placed into the Friabilator, subjected to 100 revolutions. The tablets are then dusted and reweighed. Pulsatile tablets that loose less than 0.5 to 1 % of their weight are generally considered acceptable.

%Friability=  x 100

Disintegration studies

Six tablets were taken from each batch and disintegration studies was performed using distilled water, FaSSGF (pH1.8), FaSSIF (pH 6.5) buffer, at 37 ˚C using disintegration Apparatus.

HPLC method:

Preparation of buffer solution:

Dissolved 5.75 g of monobasic ammonium phosphate in 800 ml of water, adjusted to pH to 3 using acetic acid, dilute to 1000 mL with distilled water.

Preparation of mobile phase:

Mixed acetonitrile and buffer solution in the ratio (40:60 v/v).

Waters HPLC with UV detector used to determine the content of paracetamol, Column: Supelco C18 (25cm×4.6mm),5 µm, Wavelength 242 nm, Mobile phase Acetonitrile: pH3 buffer solution (40:60), Retention time 3.8 minutes, Flow rate 1.5 ml/min, Injection volume 10 µL.

In Vitro drug release study

In vitro drug release study of two pulse tablets were performed for first pulse and later with second pulse was assessed using standard USP dissolution apparatus type II. The dissolution was performed by using distilled water, FaSSGF (pH1.8), FaSSIF (pH 6.5) buffer, the dissolution apparatus was filled with 900 mL of dissolution medium and maintained at a temperature of 37(0.5oC. The protocol of the dissolution apparatus was set to 5 mL for automatic withdrawal of sample and replacement of fresh media at predetermined time interval the dissolution apparatus. The collected samples were filtered through the 0.45µm millipore filter. The samples were analyzed for drug release using UV spectrophotometry at 242nm.

Pharmacokinetics studies

The blood samples were collected from 6 monkeys at different time intervals after single dose of oral administration of 20 mg/kg paracetamol, The blood sampling should be done at 15, 30, and 45 min (± 2 min), 1, 2, 3, 4, 6 h (± 5 min for hours 1, 2, 3, and 4; ± 10 min for hour 6) after the first paracetamol dose. After lag time second dose sampling should done at 30 min (± 2 min), 1, 2, 3, 4 and 6 h (± 5 min for hours 1, 2, 3, and 4; ± 10 min for hour 6). Blood samples was centrifuged, and the supernatant liquid was separated to determine the drug content at different time intervals using HPLC method. Bedside’s this Cmax, Tmax, T1/2 and AUC is calculated.

Shalini unnam

Project Assessment Form for: Drug Discovery and Development Preparation, evaluation and physiologically based pharmacokinetic modeling of a two of pulse drug release tablet for paracetamol

Date 09/08/21

Word count: 8500.

Enteric coated polymer layer

Drug layer

Swelling layer

Rapid dissolving layer

ADDITIONAL INSTRUCTIONS FOR THE CLASS

SCORE A+ WITH HELP FROM OUR PROFESSIONAL WRITERS – preparation and evaluation of pulsatile drug delivery system for paracetmol

We will process your orders through multiple stages and checks to ensure that what we are delivering to you, in the end, is something that is precise as you envisioned it. All of our essay writing service products are 100% original, ensuring that there is no plagiarism in them. The sources are well-researched and cited so it is interesting. Our goal is to help as many students as possible with their assignments, i.e. our prices are affordable and services premium.

• Discussion Questions (DQ)

Initial responses to the DQ should address all components of the questions asked, including a minimum of one scholarly source, and be at least 250 words. Successful responses are substantive (i.e., add something new to the discussion, engage others in the discussion, well-developed idea) and include at least one scholarly source. One or two-sentence responses, simple statements of agreement or “good post,” and responses that are off-topic will not count as substantive. Substantive responses should be at least 150 words. I encourage you to incorporate the readings from the week (as applicable) into your responses.

• Weekly Participation

Your initial responses to the mandatory DQ do not count toward participation and are graded separately. In addition to the DQ responses, you must post at least one reply to peers (or me) on three separate days, for a total of three replies. Participation posts do not require a scholarly source/citation (unless you cite someone else’s work). Part of your weekly participation includes viewing the weekly announcement and attesting to watching it in the comments. These announcements are made to ensure you understand everything that is due during the week.

• APA Format and Writing Quality

Familiarize yourself with the APA format and practice using it correctly. It is used for most writing assignments for your degree. Visit the Writing Center in the Student Success Center, under the Resources tab in Loud-cloud for APA paper templates, citation examples, tips, etc. Points will be deducted for poor use of APA format or absence of APA format (if required). Cite all sources of information! When in doubt, cite the source. Paraphrasing also requires a citation. I highly recommend using the APA Publication Manual, 6th edition.

• Use of Direct Quotes

I discourage over-utilization of direct quotes in DQs and assignments at the Master’s level and deduct points accordingly. As Masters’ level students, it is important that you be able to critically analyze and interpret information from journal articles and other resources. Simply restating someone else’s words does not demonstrate an understanding of the content or critical analysis of the content. It is best to paraphrase content and cite your source.

• LopesWrite Policy

For assignments that need to be submitted to Lopes Write, please be sure you have received your report and Similarity Index (SI) percentage BEFORE you do a “final submit” to me. Once you have received your report, please review it. This report will show you grammatical, punctuation, and spelling errors that can easily be fixed. Take the extra few minutes to review instead of getting counted off for these mistakes. Review your similarities. Did you forget to cite something? Did you not paraphrase well enough? Is your paper made up of someone else’s thoughts more than your own? Visit the Writing Center in the Student Success Center, under the Resources tab in Loud-cloud for tips on improving your paper and SI score.

• Late Policy

The university’s policy on late assignments is a 10% penalty PER DAY LATE. This also applies to late DQ replies. Please communicate with me if you anticipate having to submit an assignment late. I am happy to be flexible, with advance notice. We may be able to work out an extension based on extenuating circumstances. If you do not communicate with me before submitting an assignment late, the GCU late policy will be in effect. I do not accept assignments that are two or more weeks late unless we have worked out an extension. As per policy, no assignments are accepted after the last day of class. Any assignment submitted after midnight on the last day of class will not be accepted for grading.

• Communication

Communication is so very important. There are multiple ways to communicate with me: Questions to Instructor Forum: This is a great place to ask course content or assignment questions. If you have a question, there is a good chance one of your peers does as well. This is a public forum for the class. Individual Forum: This is a private forum to ask me questions or send me messages. This will be checked at least once every 24 hours.

• Guarantee

  

• Zero Plagiarism
• On-time delivery
• A-Grade Papers
• Free Revision
• 24/7 Support
• 100% Confidentiality
• Professional Writers

• Services Offered

• Custom paper writing
• Question and answers
• Essay paper writing
• Editing and proofreading
• Plagiarism removal services
• Multiple answer questions

We will process your orders through multiple stages and checks to ensure that what we are delivering to you, in the end, is something that is precise as you envisioned it. All of our essay writing service products are 100% original, ensuring that there is no plagiarism in them. The sources are well-researched and cited so it is interesting. Our goal is to help as many students as possible with their assignments, i.e. our prices are affordable and services premium.

Looking for a Similar Assignment? Order a custom-written, affordable, plagiarism-free paper