gastroretentive drug delivery system

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GASTRORETENTIVE DRUG DELIVERY SYSTEMS (GRDDS):

-:Prepared by:- Parth Joshi M.Pharm (Sem-2) Department of Pharmaceutics Atmiya Institute of Pharmacy Rajkot GASTRORETENTIVE DRUG DELIVERY SYSTEMS (GRDDS) GRDDS

CONTENTS:

Introduction Advantages Limitations Techniques Evaluation Conclusions References Study Question CONTENTS 2 GRDDS

INTRODUCTION:

Conventional oral delivery is widely used in the pharmaceutical field to treat the disease. However conventional delivery had many draw back and major drawback is non site specificity. Some drugs are absorbed at specific site only. They require release at specific site or a release such that maximum amount of drugs reaches to the specific site. INTRODUCTION 3 GRDDS

Slide 4:

Gastro-retentive delivery is one of the site specific drug delivery for the delivery of the drugs at the stomach. It is obtain by retaining dosage form in to stomach and drug is being released at controlled manner to specific site. 4 GRDDS

ADVANTAGES :

Enhanced bioavailability Reduced frequency of dosing Reduced fluctuations of drug concentration Reduced counter-activity of the body ADVANTAGES 5 GRDDS

Slide 6:

Targeted therapy for local ailments in the upper GIT Improved selectivity in receptor activation Minimized adverse activity at the colon Site specific drug delivery 6 GRDDS

LIMITATIONS:

It is not recommended for drugs which are unstable at gastric/acidic pH, insoluble or very low soluble drugs and drugs which causes gastric irritation. For floating high level of fluid is required in GIT. Also sleeping condition is favorable for the better results of GRDDS. Adhesive systems cannot prevail longer due to high turn-over rate of mucus layer and presence of soluble mucin. For swelling systems, it is necessary that the formulation should not exit before the appropriate swelling. LIMITATIONS 7 GRDDS

Factors Affecting Gastric Retention :

Density :- Less than 1 gm/cm 3 for better GRT. Size :- DF diameter more than 7.5mm increased GRT. Shape of dosage form :- Tetrahedron and ring shaped better GRT. Fed or unfed state :- Fed state GRT is longer. Factors Affecting Gastric Retention 8 GRDDS

Slide 9:

Nature of meal :- Feeding of indigestible polymers or fatty acid salts decreasing the gastric emptying rate and prolonging drug release . Caloric content :- Proteins and fats GRT can be increased by 4 to 10 hours. Gender :- GRT in males is less compared with female. Age :- Elderly people significantly longer GRT . Posture :- GRT can vary between supine and upright . 9 GRDDS

DRUGS THOSE ARE UNSUITABLE FOR GASTRORETENTIVE DRUG DELIVERY SYSTEMS:

1) Drugs that have very limited acid solubility . e.g. Phenytoin 2) Drugs that suffer instability in the gastric environment . e.g. Erythromycin 3) Drugs intended for selective release in the colon . e.g. 5- amino salicylic acid and Corticosteroids DRUGS THOSE ARE UNSUITABLE FOR GASTRORETENTIVE DRUG DELIVERY SYSTEMS 10 GRDDS

POTENTIAL DRUG CANDIDATES FOR GASTRORETENTIVE DRUG DELIVERY SYSTEMS:

Drugs those are locally active in the stomach. e.g. Misroprostol, Antacids Drugs that have narrow absorption window in gastrointestinal tract (GIT). e.g. L-DOPA, Para amino benzoic acid, Furosemide, Riboflavin Drugs those are unstable in the intestinal or colonic environment. e.g. Captopril, Ranitidine HCl POTENTIAL DRUG CANDIDATES FOR GASTRORETENTIVE DRUG DELIVERY SYSTEMS 11 GRDDS

Slide 12:

4) Drugs that disturb normal colonic microbes . e.g. Antibiotics against Helicobacter pylori 5) Drugs that exhibit low solubility at high pH values . e.g. Diazepam , Verapamil HCl 12 GRDDS

TECHNIQUES:

Floating drug delivery systems B. High-density systems C. Bioadhesive or mucoadhesive systems D. Swelling And Expanding Systems TECHNIQUES 13 GRDDS

Slide 14:

14 A. Floating drug delivery systems 1. Effervescent systems 2. Non Effervescent systems a) Colloidal gel barrier system b) Microballoons / Hollow microspheres c) Alginate beads d) Microporous compartment system GRDDS

The major requirements for floating drug delivery system :

It should release contents slowly to serve as a reservoir. It must maintain specific gravity lower than gastric contents (1.004 – 1.01 gm/cm 3 ). It must form a cohesive gel barrier. The major requirements for floating drug delivery system 15 GRDDS

A. Floating Drug Delivery System :

Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents , the drug is released slowly at the desired rate from the system . After release of drug, the residual system is emptied from the stomach . A. Floating Drug Delivery System 16 GRDDS

Slide 17:

17 This results in an increased GRT and a better control of the fluctuations in plasma drug concentration. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal. To measure the floating force kinetics , a novel apparatus for determination of resultant weight (RW) has been reported in the literature. GRDDS

Slide 18:

The RW apparatus operates by measuring continuously the force equivalent to F (as a function of time) that is required to maintain the submerged object. The object floats better if RW is on the higher positive side. This apparatus helps in optimising FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of intragastric buoyancy capability variations. 18 GRDDS

Slide 19:

RW or F = F buoyancy - F gravity = (Df - Ds) gV where RW = total vertical force, Df = fluid density, Ds = object density, V = volume and g = acceleration due to gravity. 19 GRDDS

1. Effervescent systems:

1. Effervescent systems Floatability can be achieved by generation of gas bubbles. These buoyant systems utilize matrices prepared with swellable polymers such as Polysaccharides (e.g. chitosan) Effervescent components (e.g. sodium bicarbonate, citric acid or tartaric acid) 20 GRDDS

Slide 21:

21 The optimal stoicheometric ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76: 1. In this system carbon dioxide is released and causes the formulation to float in the stomach. GRDDS

Effervescent (gas generating) systems:

Effervescent (gas generating) systems 22 GRDDS

Drug release from effervescent (gas generating) systems:

Drug release from effervescent (gas generating) systems 23 GRDDS

2. Non-effervescent Systems:

Non-effervescent floating drug delivery systems are normally prepared from :- gel-forming or highly swellable cellulose type hydrocolloids, polysaccharides or matrix forming polymers like polyacrylate, polycarbonate, polystyrene and polymethacrylate. In one approach, intimate mixing of drug with a gel forming hydrocolloid which results in contact with gastric fluid after oral administration and maintain a relative integrity of shape and a bulk density less than unity within the gastric environment. 2. Non-effervescent Systems 24 GRDDS

Slide 25:

The air trapped by the swollen polymer confers buoyancy to these dosage forms. Excipients used most commonly in these systems include Polyacrylates Polyvinyl acetate Carbopol Agar Sodium alginate Calcium chloride 25 GRDDS

(a) Colloidal gel barrier system:

These systems contains drug with gel-forming hydrocolloids meant to remain buoyant on the stomach content. This prolongs GRT and maximizes the amount of drug that reaches its absorbtion sites in the solution form for ready absorption. These are single-unit dosage form, containing one or more gel-forming hydrophilic polymers. E.g.:- HPMC , HEC , HPC , NaCMC (a) Colloidal gel barrier system 26 GRDDS

(b) Microballoons / Hollow microspheres:

Microballoons / hollow microspheres loaded with drugs in their other polymer shelf were prepared by simple solvent evaporation or solvent diffusion /evaporation methods to prolong the gastric retention time (GRT) of the dosage form. Commonly used polymers to develop these systems are polycarbonate, cellulose acetate, calcium alginate, agar. Buoyancy and drug release from dosage form are dependent on quantity of polymers, the plasticizer polymer ratio and the solvent used for formulation. (b) Microballoons / Hollow microspheres 27 GRDDS

Slide 28:

The microballoons floated continuously over the surface of an acidic dissolution media containing surfactant for more than 12 hours. At present hollow microspheres are considered to be one of the most promising buoyant systems because they combine the advantages of multiple-unit system and good floating. 28 GRDDS

Formulation of floating hollow microsphere or microballoon:

Formulation of floating hollow microsphere or microballoon 29 GRDDS

(c) Alginate beads:

(c) Alginate beads Preparation of Alginate beads :- 30 GRDDS

Slide 31:

These beads improve gastric retention time (GRT) more than 5.5 hrs. Example :- Calcium alginate/ Pectinate beads Calcium Alginate + Pectinate Gel beads Calcium Alginate + Chitosan gel beads 31 GRDDS

(d) Microporous compartment system:

This approaches based on the principle of the encapsulation of a drug reservoir inside a micro porous compartment with pores along its top and bottom walls. The peripheral walls of the device were completely sealed to present any direct contact of the gastric surface with the undissolved drug. In the stomach the floatation chamber containing entrapped air causes the delivery system to float in the gastric fluid (d) Microporous compartment system 32 GRDDS

B. High Density Systems :

Density should be more then stomach content i.e. 3 g/cm 3 Capable to withstand with peristaltic movement of stomach Prepared by coating or mixing drug with heavy inert material Diluents such as… Barium sulphate (density = 4.9) Zinc oxide Titanium dioxide Iron powder must be used to manufacture such high-density formulations. B. High Density Systems 33 GRDDS

High Density Systems:

High Density Systems GRDDS 34

C. Bioadhesive System:

Here, the drug is incorporated with bio/ Muco-adhesive agents, enabling the device to adhere to the stomach walls, Thus resisting gastric emptying. However, the mucus on the walls of the Stomach is in a state of constant renewal, Resulting in unpredictable adherence. Thus, this approach is not widely used. C. Bioadhesive System 35 GRDDS

Slide 36:

36 GRDDS

Slide 37:

Mechanism of bioadhesion: Hydration-mediated adhesion Bonding-mediated adhesion Receptor-mediated adhesion. Problem of muco adhesive system: Rapid removal of mucus. Not sure weather the Dosage Form will adhere to the mucus or epithelial cell layer Dosage Form may adhere to esophagus resulting in drug induced injuries 37 GRDDS

D. Swelling And Expanding Systems :

Also called ‘ PLUG SYSTEM’ Size of the formulation more than Pyloric sphincter It should expand for gastric retention Should be Collapsed after lag time The swelling is usually results from osmotic absorption of water and the dosage form is small enough to be swallowed by the gastric fluid. D. Swelling And Expanding Systems 38 GRDDS

Slide 39:

Swelling And Expanding Systems 39 GRDDS

Drug release from swellable systems:

Drug release from swellable systems 40 GRDDS

EVALUATION :

Various parameters that need to be evaluated in gastro retentive formulation include Dissolution profiles Specific gravity Content uniformity Hardness Friability in case of solid dosage forms. EVALUATION 41 GRDDS

Slide 42:

In case of multi particulate drug delivery systems, Differential scanning calorimetry Particle size analysis Flow properties Surface morphology Mechanical properties are also performed. The tests for floating ability and drug release are generally performed in simulated gastric fluids at 37° C. 42 GRDDS

Methods to asses gastroretentivity of GRDFs:

Magnetic Resonance Imaging (MRI) It is a noninvasive technique and allow observation of total anatomical structure in relatively high resolution. The visualization of GI tract by MRI has to be further improved by the administration of contrast media. For solid Dosage Forms , the incorporation of super paramagnetic compound such as ferrous oxide enables their visualization by MRI. Methods to asses gastroretentivity of GRDFs 43 GRDDS

Slide 44:

Radiology (X-Ray) In this technique a radio-opaque material has to be incorporated in the Dosage Form, and its location is tracked by X-ray picture. Gastroscopy Gastroscopy is commonly used for the diagnosis and monitoring of the GI tract. This technique utilizes a fiber optic or video system and can be easily applied for monitoring and locating Gastro Retentive Dosage Forms in the stomach. 44 GRDDS

Slide 45:

Swelling studies Tablets weighed individually (W 1 ) and placed in Petri dishes containing 15ml of 0.1N HCl. At regular intervals they are removed from Petri dishes and excess surface water was removed using filter paper. The swollen tablets were reweighed (W 2 ). The swollen tablets are dried at 60° C at 24hrs in an oven and kept in desiccators for 24hrs and reweighed (W 3 ). Degree of swelling = W 2 - W 1 / W 1 %Erosion = W 1 - W 3 X 100 / W 1 45 GRDDS

Conclusions:

The development of GRDDs can be advantageous for the administration of some important drugs and significantly improves their therapeutic outcome. Gastroretentivity of a Dosage Form can be achieved by the development of devices that can be significantly, Expand their volume by unfolding or swelling Adhering to gastric mucosa The suitable density to sink or float over the gastric fluids. Conclusions 46 GRDDS

Commonly used drug in formulation of gastro retentive dosages forms:

Commonly used drug in formulation of gastro retentive dosages forms Dosage forms Drugs Floating Tablets Acetaminophen,Acetyl salicylic acid, Ampicillin Floating Capsules Furosemide, L-DOPA and Benserazide,Nicardipine Floating Microspheres Aspirin, Griseofulvin Floating Granules Diclofenac sodium, Indomethacin 47 GRDDS

Gastro retentive products available in the market:

Gastro retentive products available in the market Brand Name Drug Company Mandopar ® Levodopa and Benserazide Roche, USA Conviron ® Ferrous sulphate Ranbaxy, India Cifran OD ® Ciprofloxacin Ranbaxy , INDIA Cytotech ® Misoprostal Pharmacia, USA 48 GRDDS

REFERENCES :

Floating drug delivery systems: a review. AAPS PharmSciTech. 2005;6 (3) Article 47. N.K. Jain Progress in controlled and Novel drug delivery system, CBS Publisheres, 1 st edition,2004, Page no: 76-97 Floating Drug Delivery System: An Approach to Gastroretension. Latest Reviews. 2007;5(1). Gatroretentive dosage forms: Overview and special case of Helicobacter pylori. J Control Release. 2006;111:1-18. REFERENCES 49 GRDDS

STUDY QUESTION:

Write advantages of GRDDS? What is GRDDS? How it can be achieved? Write a note on FDDS? STUDY QUESTION 50 GRDDS

Slide 51:

51 GRDDS THANK YOU