FORMULATION AND DEVELOPMENT OF HYDROCHLOROTHIAZIDE FLOATING MICROSPHERES
RAVIKUMAR R. PATEL1, Dr. JAYVADAN K. PATEL2
1 Research Scholar, Jodhpur National University, Jodhpur
2 Principal and Professor, Nootan Pharmacy College, Visnagar, Mehsana, Gujarat.
AIM OF PRESENT INVESTIGATION
Now a day most of the pharmaceutical scientists are involved in developing an ideal drug delivery system with an objective of not only curing the disease but also to achieve patient compliance. Approximately 50 % of the drug delivery system available in market is oral drug delivery system. Conventional oral dosage forms provide a specific drug concentration in systemic circulation without offering any control over drug delivery. Over the past three decades, the pursuit and exploration of devices designed to be retained in the upper part of gastrointestinal tract has advanced consistently in terms of technology and diversity, encompassing a variety of systems and devices such as floating systems.
Hydrochlorothiazide is a thiazide diuretic commonly prescribed for treatment of hypertension, congestive heart failure and edema. It is mostly absorbed from the duodenum and the first part of the jejunum1. Bioavailability of hydrochlorothiazide was enhanced when given with food through delaying of gastric emptying in both cases. Bioavailability was lower from SR formulation such as pellets compared to an IR tablet, because the SR formulation passed the drug absorption sites before from completed the drug release. These studies support the absorption window theory for hydrochlorothiazide and therefore a higher bioavailability of the drug in a GRD can be expected if there is a prolonged gastric residence time1. The above information supports the theory that hydrochlorothiazide has an absorption window, which makes it a good candidate for intragastric floating drug delivery system.
Gastro retentive systems extend significantly the period of time over which the drugs may be released. Thus not only prolong dosing interval but also increase patient compliance beyond the level of existing controlled release dosage forms. Most of the old age population in India suffers from hypertension, heart diseases, and angina pectoris. Antihypertensive agents and calcium channel blockers are mainly used to treat those geriatric patients. These cardiovascular drugs suffer from low bioavailability problems, short half life due to extensive first pass metabolism therefore short duration of action; this makes discomfort to old age people. Recent development in novel drug delivery system, a new approach Gastro retention is solution to these problems of cardiovascular drugs. Floating microspheres have a bulk density less than gastric fluid and so remain buoyant in the stomach for a prolonged period of time. While the system floats over gastric contents, the drug is released slowly at the desired rate from the system, therefore improving bioavailability of drug and better control over the fluctuations in plasma drug concentration. Thus it not only reduces dosing frequency but also reduces side effects like gastric irritation and major problem like dose dumping thereby greatly increasing patient compliance.
The gastroretentive drug delivery system can be retained in the stomach and assists in improving the oral sustained delivery of the drugs that have and absorption window in a particular region of the GI tract, these systems help in continuous releasing the drug before it reaches the absorption window, thus ensuring optimal bioavailability. Several approaches are currently used to prolong gastric retention time .These include floating drug delivery system, swelling and expanding systems, polymeric bioadhesive system, high –density and other delayed gastric-emptying devices2. The principal of buoyant preparation offers a simple and practical approach to achieve increased gastric residence time for dosage from and sustained drug release3. The present investigation describes the formulation development of an intragastric floating drug delivery system of Hydrochlorothiazide.
The objective of the present study is to develop suitable gastroretentive floating microspheres of Hydrochlorothiazide and to study release kinetics of drug with a view to reduce the dose frequency and to achieve a controlled drug release via gastric retention with improved bioavailability.
Reference Id: PHARMATUTOR-ART-1218
2.1 INTRODUCTION TO FLOATING MICROSPHERES
Microspheres can be defined as solid, approximately spherical particles ranging in size from 1 to 1000 micrometer. The Microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers, which are biodegradable in nature. Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of drugs4. Microspheres are small in size and therefore have large surface to volume ratios. The concept of incorporating microscopic quantities of materials within microspheres dates back to the 1930s and to the work of Bungerberg de joing and co-workers on the entrapment of substances within coacervates. The potential uses of microspheres in the pharmaceutical have been considered since the 1960’s and have a number of applications. The use of microspheres in pharmaceuticals have a number of advantages Viz., Taste and odor masking, conversion of oils and other liquids to solids for ease of handling, protection of drugs against environment (moisture, heat, light and oxidation), separation of incompatible materials, to improve flow of powders, production of sustained release, controlled release and targeted medications. The most important physico-chemical characteristics that may be controlled in microspheres manufacture are; particle size and distribution, polymer molecular weight, ratio of drug to polymer, total mass of drug and polymer.5, 6
A number of different substances both biodegradable as well as non-biodegradable have been investigated for the preparation of microspheres; these materials include polymers of natural origin or synthetic origin and also modified natural substances. A range of microspheres prepared using both hydrophilic and hydrophobic polymers. Hydrophilic polymers includes gelatin, agar, egg albumin, starch, chitosan, cellulose derivatives; HPMC, DEAE cellulose. Hydrophobic polymers include ethyl cellulose, polylactic acid, PMMA, acrylic acid esters etc7. The number of polymers and range of formulation variables available to control the rate of drug release from controlled release devices are broad. Selection among these variables is based upon the desired release rate and duration, physical and chemical properties of the drug and the intended site of administration. In general polymers are selected from one of several classes as follows:
Non-Biodegradable Hydrophobic Polymers:
These materials are inert in the environment of use, are eliminated or extracted intact from the site of administration, and serve essentially as a rate limiting barrier to the transport and release of drug from the device. Common examples of such materials include polyethylene vinyl acetate (EVA), Polydimethyl siloxane (PDS), Polyether urethane (PEU), Ethyl cellulose (EC), Cellulose acetate (CA), Polyethylene (PE) and Polyvinyl chloride (PVC), Acrycoat, Eudragit S etc.8, 9
Hydrogels: These polymers swell but do not dissolve when brought in contact with water. They are obtained from natural or synthetic sources. As with the hydrophobic polymers, hydrogels are inert, removed intact from the site of administration, and function by forming a rate limiting barrier to the transport and release of drugs. Common examples include polyhydroxy ethyl methyl acrylate (PHEMA), cross-linked poly vinyl alcohol (PVA), cross linked poly vinyl pyrrolidone (PVP), poly acryl amide etc.10
Soluble polymers:These are moderate molecular weight (less than 75,000 Daltons) uncross linked polymers that dissolve in water. The rate of dissolution decreases with increasing molecular weight. These materials can be used alone or in combination with hydrophobic polymers to provide devices that slowly erode over time. Examples include polyethylene glycol (PEG), uncross linked poly vinyl alcohol or poly vinyl pyrrolidone, hydroxyl propyl methyl cellulose (Methocel) and copolymers of metha acrylic acid and acrylic acid methyl ester (Eudragit L) etc.
Biodegradable polymers:These materials also slowly disappear from the site of administration; however it occurs in response to a chemical reaction such as hydrolysis. Examples of biodegradable polymers include polylactic acid (PLA), poly glycolic acid (PGA), Polycaprolactone (PCL) and several generic classes such as the poly anhydrides and poly orthoesters.11
The range of techniques for the preparation of microspheres offers a variety of opportunities to control aspects of drug administration. Microspheres can be prepared by:
Single Emulsion Technique, Double Emulsion Technique, Polymerization technique, Phase Separation coacervation technique, Spray Drying and Spray Congealing, Solvent Extraction12
Floating microspheres are gastro-retentive drug delivery systems based on non-effervescentapproach. Floating microspheres are in strict sense, spherical empty particles without core. These microspheres are also termed as “Microballoons” due to its characteristic internal hollow structure and excellent floatability in vitro.
Gastro-retentive floating microspheres are low-density systems that have sufficient buoyancy to float over gastric contents and remain in stomach for prolonged period. As the system floats over gastric contents, the drug is released slowly at desired rate resulting in increased gastric retention with reduced fluctuations in plasma drug concentration 13.
Advantages of Floating Microspheres:
• Improves patient compliance by decreasing dosing frequency.
• Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration is avoided, a desirable plasma drug concentration is maintained by continuous drug release.
• Better therapeutic effect of short half-life drugs can be achieved.
• Gastric retention time is increased because of buoyancy.
• Drug releases in controlled manner for prolonged period.
• Site-specific drug delivery to stomach can be achieved.
• Enhanced absorption of drugs which solubilizes only in stomach.
• Superior to single unit floating dosage forms as such microspheres releases drug uniformly and there is no risk of dose dumping. 12
• Avoidance of gastric irritation, because of sustained release effect, floatability and uniform release of drug through multiparticulate system.
• The flow characteristics and packability of the resultant microballoons are much improved when compared with the raw crystals of the drug.
• Drug targeting to stomach can be attractive for several other reasons 14
For the weakly basic drugs with poor solubility in the basic environment, the floating systems may avoid any chance of solubility to become the rate-limiting step in the release by restricting the drug to the stomach.
Any solute released in the stomach will empty along with the fluids such that the whole surface of the small intestine is available for absorption. This is particularly useful when an absorption window exists in the proximal small intestine15.
The positioned gastric release is useful for all substances intended to produce a lasting local action onto the gastroduodenal wall.
Limitations of floating Microspheres
• The major disadvantage of floating systems is requirement of sufficiently high levels of fluids in the stomach for the drug delivery16.
• The dosage form should be administered with a minimum of glass full of water8.
• Floating system is not feasible for those drugs that have solubility or stability problems in gastric fluids.
• Single unit floating capsules or tablets are associated with an “all or none concept,” but this can be overcome by formulating multiple unit systems like floating microspheres or microballoons17.
• Drugs that irritate the mucosa, those that have multiple absorption sites in the gastrointestinal tract, and those that are not stable at gastric pH are not suitable candidates to be formulated as floating dosage forms.13
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