Gastro-retentive Drug Delivery Systems: Formulation Perspective
Submitted in partial fulfillment of the requirements of
Study in Advance Topics
Sumeet V. Katke (2017H1460160H)
Under the supervision of
Dr. Swati BiswasAssistant Professor
Department of Pharmacy
BIRLA INSTITUTE OF TECHNOLOGY & SCIENCE, PILANI
ACKNOWLEDGEMENTI would like to express my special thanks to Dr. Swati Biswas, who gave me the opportunity to learn and present the topic of Study in Advance Topics on Gastro-retentive Drug Delivery Systems: Formulation perspective.
I would also like to thank my friends who helped me during the course of the work.
TOC o “1-3” h z u ACKNOWLEDGEMENT PAGEREF _Toc512559217 h 2Introduction: PAGEREF _Toc512559218 h 3Basic anatomy and physiology of stomach: PAGEREF _Toc512559219 h 6Potential drug candidates for GRDDS PAGEREF _Toc512559220 h 8Unsuitable drug candidates for GRDDS PAGEREF _Toc512559221 h 9Strategies for delaying drug transit through GIT PAGEREF _Toc512559222 h 9Marketed Formulations PAGEREF _Toc512559223 h 15Pre-clinical Study PAGEREF _Toc512559224 h 16Clinical Study PAGEREF _Toc512559225 h 17References PAGEREF _Toc512559226 h 18
TOC h z c “Figure” Figure 1 Anatomy of stomach PAGEREF _Toc512559950 h 6Figure 2 Blood supply to stomach PAGEREF _Toc512559951 h 8Figure 3 Types of gastro-retentive dosage forms PAGEREF _Toc512559952 h 9Figure 4 High density systems PAGEREF _Toc512559953 h 10Figure 5 Floating system PAGEREF _Toc512559954 h 11Figure 6 Raft forming system PAGEREF _Toc512559955 h 12Figure 7 Mucoadhesive system PAGEREF _Toc512559956 h 13Figure 8 Swelling system PAGEREF _Toc512559957 h 13Figure 9 Expandable system PAGEREF _Toc512559958 h 14
TOC h z c “Table” Table 1 Motor functions of GIT PAGEREF _Toc512560006 h 8Table 2 Potential drug candidates PAGEREF _Toc512560007 h 9Table 3 Unsuitable drug candidates PAGEREF _Toc512560008 h 9Table 4 Marketed formulations PAGEREF _Toc512560009 h 16
Introduction:The goal of any drug delivery system is to provide a therapeutic amount of drug to proper site in the body to achieve promptly and then maintain a desired drug concentration. Many orally administered drugs display poor bioavailability when administered as a conventional dosage form, i.e. the rate and extent to which the drugs are absorbed is less than desirable. To compensate for this effect, a large dose is often administered so that absorption of therapeutically required quantity of drug can occur. This technique may prove costly with expensive drugs and also poorly absorbed drugs may show variability in inter and intra bioavailability.
Rationale for the use of Gastro-retentive Drug Delivery System (GRDDS):
Improved half life
Reduced frequent dosing
Sustained or prolonged release
Increase gastric retention time
Reduced drug waste
Increased therapeutic efficiency
Advantages of Gastro-retentive Drug Delivery:
Increase in bioavailability and curative efficiency of drugs and economic usage of dose.
Minimised factor of risk in resistance in antibiotics owing to stabilised therapeutic levels over prolonged periods removing fluctuations.
Optimised release in case of short half-life drugs causes flip flop pharmacokinetics and also ensures patient compliance with reduced dosage frequency. They are advantageous against drawbacks of the gastric retention time (GRT) as well as the gastric emptying time (GET).
Efficient in treating stomach and small intestine related problems as it avails local therapy for these organs.
This method provides with a systematic and controlled drug delivery system which minimises chances of drug over exposure at the diseased site.
Providing a narrow curative index, the gastroretentive dosage forms minimises variance in concentrations of drugs and effects.
This system provides higher efficiency due to reduced counter activity by body.
Disadvantages of Gastro-retentive Drug Delivery:
Floating systems has limitation, that they require high level of fluids in stomach for floating and working efficiently. So more water intake is prescribed with such dosage form.
In supine posture (like sleeping), floating dosage form may swept away (if not of larger size) by contractile waves. So patient should not take floating dosage form just before going to bed.
Drugs having stability problem in high acidic environment, having very low solubility in acidic environment and drugs causing irritation to gastric mucosa cannot be incorporated into GRDDS.
Drugs which have stability and solubility problems in GIT are not suitable candidates for these types of systems.
Bio/mucoadhesives systems have problem of high turnover rate of mucus layer, thick mucus layer & soluble mucus related limitations.
Swellable dosage form must be capable to swell fast before its exit from stomach and achieve size larger than pylorus aperture. It must be capable to resist the housekeeper waves of Phase III of MMC.
Gastric retention is influenced by many factors such as gastric motility, pH and presence of food. These factors are never constant and hence the buoyancy cannot be predicted.
There is also possibility of esophageal binding with bioadhesive drug delivery systems.
Basic anatomy and physiology of stomach:The stomach is a J shaped enlargement of the GIT directly inferior to the diaphragm in the upper left part of the abdominal cavity.
Figure 1 Anatomy of stomachStomach has 3 parts:
Fundus: contains gas, produces slow and steady pressure on gastric content to press them down the stomach.
Body: the largest part of the stomach and acts as a reservoir for ingested foods and liquids
Antrum: lowest part of stomach and it is almost like a funnel shaped organ
The distal or antral portion of stomach has a wall composed of thicker muscle and is concerned with regulation of emptying solids by contracting and act as homogenizer and grinder.
The antral part co-ordinates with the body in the propulsion of gastric contents towards the pylorus.
Pyloric sphincter has two functions – it sieves the chyme and prevents large particles from being emptied from stomach and it also helps from duodenal contents from refluxing into stomach (bile and pancreatic enzymes may damage the gastric mucosa.
Motor functions of the GIT:
The different smooth muscle layers are responsible for performing the motor functions of the GIT, i.e. gastric emptying and intestinal transit. During the fasting state an interdigestive series of electrical events take place which cycle both through stomach and intestine every 2-3 hours, which is called as interdigestive myloelectric cycle or migrating myloelectric cycle (MMC) which is further divided in to four phases.
Table 1 Motor functions of GITBlood supply to the stomach:
Figure 2 Blood supply to stomachArterial blood is brought to the stomach by many branches of the celiac trunk. Blood from the stomach is returned to the venous system via the portal vein which carries the blood through the liver.
Potential drug candidates for GRDDSSr. No. Suitable Drug candidates Example
1. Drugs acting locally in the stomach. Antacids, Anti-ulcer drugs, drugs against H. Pylori, Misoprostol, Clarithromycin, Amoxicillin.
2. Drugs with narrow absorption window in Gastrointestinal tract (GIT). Cyclosporine, Methotrexate, Levodopa, Repaglindine, Riboflavin, Furosemide, Para-aminobenzoic Acid, Atenolol, Theophyllin,
3. Drugs having unstable properties in the intestinal or colonic environment. Captopril, Ranitidine HCl, Metronidazole, Metformin HCl.
4. Drugs caused imbalance of normal colonic microbes. Antibiotics against H. Pylori, Amoxicillin Trihydrate.
Table 2 Potential drug candidatesUnsuitable drug candidates for GRDDS
S. No. Unsuitable Drug Candidates Example
1. Drugs having very limited acid solubility. Phenytoin
2. Drugs that exhibits instability in the gastric environment. Erythromycin
3. Drugs that are used for selective release in the colon. 5- amino salicylic acid and corticosteroids
Table 3 Unsuitable drug candidatesStrategies for delaying drug transit through GIT
Figure 3 Types of gastro-retentive dosage formsHigh Density Systems:
Formulation of dosage forms with density that must exceed density of normal stomach content (1.004 g/ml). When the density of the pellets is more than the density of gastric fluids, they settle rapidly in the rugae and the contractions won’t be able to remove the pellets until they are eroded and completely released.
Figure 4 High density systemsThese formulations are prepared by coating drug on a heavy core or mixed with heavy inert material such as iron powder, zinc oxide, titanium dioxide, barium sulphate.
Floating drug delivery systems (FDDS) have a bulk density lower than gastric fluids and thus remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. Floating property can be based on principles like low density due to swelling, low density due to gas generation and entrapment of gases in the polymer.
A single unit floating controlled drug delivery formulated as a tablet consists of a foam powder (polypropylene foam powder), matrix forming polymer (HPMC, polyacrylates, sodium alginate, corn starch, carrageenan, gum guar and gum arabic), optional filler and API.
Types of floating drug delivery systems:
Effervescent gas generating system:
The drug is formulated along with a gas generating agent such as NaHCO3 or CaCO3+ Citric/Tartaric Acid.
These are formulated in such a way that when they come in contact with gastric content, CO2 is liberated and gets entrapped in swollen hydrocolloid which provides buoyancy to dosage form.
Volatile liquid containing system:
These have an inflatable chamber which contain a liquid e.g. ether, cyclopentane, that gasify at body temperature to cause the inflation of the chamber in the stomach.
There are two chambers in the system first contain the drug and the second chamber containing the volatile system.
Figure 5 Floating systemThese systems possess inflatable chamber containing liquid ether which gasifiers at body temperature to inflate the stomach. Inflatable chamber contains bio erodible polymer filament (e.g. Copolymer of poly vinyl alcohol and poly ethylene) that gradually dissolves in gastric fluid and finally cause inflatable chamber to release gas and collapse.
Raft Forming Systems:
Raft forming system has received much attention for the delivery of antacid and drug delivery for gastro infection and disorders on contact with gastric fluid a gel forming Solution swells and forms a viscous cohesive gel containing entrapped CO2 bubbles. That forms raft layer on top of gastric fluid which releases drug slowly in stomach (Often used for gastro oesophageal reflux treatment).
Figure 6 Raft forming systemMucoadhesive Systems:
These types of systems adhere to the biological membrane (mucosa) of the stomach and maintain intimate contact with the membrane for a longer time and hence retains in stomach for its prolonged release. These systems are formulated using bio adhesive polymers.
Materials commonly used for bioadhesion are poly acrylic acid, chitosan, cholestyramine, hydroxypropyl methylcellulose (HPMC) and polylactic acids.
Figure 7 Mucoadhesive systemSwelling Systems:
These are a type of non-floating gastro-retentive drug delivery system which when enters to stomach, swells (due to presence of swell able polymers) to an extent that cannot pass through the pyloric sphincter leading to its retention in the stomach.
Figure 8 Swelling systemIn every swellable hydrogel, there are mainly 3 layers: 1st swelling, 2nd diffusion and 3rd erosion layer.
Swelling index and swelling time is an important factor for such systems.
Swelling index means how much fold it can increase in volume.
These systems are capable of expanding and retain in the stomach for longer periods.
These are usually formulated as a capsule containing dosage form folded and compact form. After being exposed to stomach environment, capsule shell disintegrates and dosage form expands preventing its exit through the stomach. By using a suitable polymer, sustained and controlled drug delivery can be achieved.
Figure 9 Expandable systemSuperporous Hydrogels:
These materials have a swelling ratio of over 1000.Super porous hydrogels, average pore size ;100 micrometer, swell to equilibrium size within a minute, due to rapid water uptake by capillary wetting and are intended to have sufficient mechanical strength to withstand pressure by gastric contraction. This is achieved by co-formulation of a hydrophilic particulate material, Ac-Di- Sol (Crosscarmellose sodium).
In this type, the dosage form contains a small internal magnet, and a magnet placed on the abdomen over the position of the stomach.
In vivo human studies showed that, in the presence of an extracorporeal magnet, the plasma concentrations of acyclovir were significantly higher.
Furthermore, the mean AUC0 – 24 h was 2800 ng h/mL with the external magnet and 1600 ng h/mL without. Although these systems seem to work, the external magnet must be positioned with a degree of precision that might compromise patient compliance.
Marketed FormulationsBRAND NAME ACTIVE INGREDIENTS Type of formulation Manufacturer
Cifran OD® Ciprofloxacin Floating tablet Sun PharmaMadopar® L-Dopa and BenserazideFloating, CR capsule Roche Laboratories
Valrelease® Diazepam Floating capsule. Roche Laboratories
Antacid Raft system Pierre Fabre Drug, France.
Almagate FlatCoat® Aluminium-magnesium
Antacid Raft system Liquid Gavision® Aluminium Hydroxide Raft system GSK
Conviron® Ferrous sulfate Colloidal gel forming FDDS. Ranbaxy, India.
Cytotec® MisoprostalFloating capsule. Pfizer
Table SEQ Table * ARABIC 4 Marketed formulationsPre-clinical and Clinical studies were studied through detailed literature search of Levodopa drug.
Levodopa was studied because it is a very important drug for the treatment of Parkinson Disease. It shows narrow absorption window and its bioavailability is seen to be enhanced by formulating it in a Gastro-retentive Drug Delivery System.
Pre-clinical StudySummary of experiment:
Due to its narrow absorption window, levodopa has to be administered continuously to the upper parts of the intestine in order to maintain sustained therapeutic levels. This may be achieved by a controlled release (CR) gastroretentive dosage form (GRDF). The aim of this work was to develop a novel GRDF, based on unfolding polymeric membranes, that combines extended dimensions with high rigidity, and to examine the pharmacokinetics of levodopa compounded in the GRDF. Levodopa CR-GRDFs were administered to beagle dogs pretreated with carbidopa. The CR-GRDF location in the gastrointestinal tract was determined by X-ray, and serial blood samples were collected and assayed for levodopa. Optimization of the pharmacokinetic profile of levodopa from the CR-GRDFs was carried out based on the in-vitro in-vivo correlation following modifications of the release rates (adjusted by various membrane thicknesses) and drug loads. The 21 successful CR-GRDF maintained therapeutic levodopa concentrations (500 ng ml ) over 9 h. In comparison to non-gastroretentive CR-particles and oral solution, mean absorption time was significantly extended. These outcomes demonstrate that the CR-GRDF may be used to improve levodopa therapy and can be applied to extend the absorption of ther narrow absorption window drugs that require continuous input.
Image: A picture of the gastro-retentive dosage form drawn out of dog stomach 15 minutes postadministration. The GRDF has unfolded almost completely to its original size.
The current study demonstrates prolonged absorption and sustained blood levels of narrow absorption window drugs, such as levodopa, can be achieved by the newly developed unfolding CR- GRDF.
It is expected that in addition to the drugs that are already marketed, this approach may be used for many potential active agents with a narrow absorption window, in which development is currently halted due to the lack of appropriate pharmaceutical CR-GRDF technologies.
Clinical StudySummary of experiment:
CR-Gastroretentive formulation was prepared similar to pre-clinical for clinical study in healthy human volunteers.
Purpose: To design novel expandable gastroretentive dosage form (GRDFs) and evaluate their gastroretentive properties. Then, to assess the pharmacokinetics of levodopa compounded in such a GRDF in healthy volunteers.
Methods: Thin (;0.07 cm), large-dimensioned (5 × 2.1 cm), multilayer dosage forms (DFs) with different rigid polymeric matrices and mechanical properties were folded into gelatin capsules and were administered to healthy volunteers with a light breakfast. GRDF unfolding and physical integrity were evaluated in vitro and in vivo (by gastroscopy and radiology). The pharmacokinetics of levodopa GRDF were compared to Sinemet CR® in a crossover design.
Results: The combination of rigidity and large dimension of the GRDFs was a decisive parameter to ensure prolonged gastroretentivity ( 5 h). Large-dimension DFs lacking rigidity had similar gastroretentivity as a nondisintegrating tablet (10 mm). The GRDFs rapidly unfolded and maintained their mechanical integrity. The absorption phase of levodopa was significantly prolonged following GRDF administration in comparison to Sinemet CR®.
Conclusions: The combination of size and rigidity of the novel GRDF enables a significant extension of the absorption phase of a narrow absorption window drug such as levodopa. This approach is an important step toward the implementation of such GRDFs in the clinical setting.
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