DEVELOPMENT AND EVALUATION OF FLOATING TABLETS OF CIPROFLOXACIN HCL - INTRODUCTION

 CHAPTER -1

INTRODUCTION

 

            Oral delivery of drugs is by far the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in formulation, etc. Many of the drug delivery systems, available in the market are oral drug delivery type systems. Oral drug delivery systems have progressed from immediate release to site-specific delivery over a period of time. Every patient would always like to have a ideal drug delivery system possessing the two main properties that are single dose or less frequent dosing for the whole duration of treatment and the dosage form must release active drug directly at the site of action.^{1, 2}

 

            Thus the objective of the pharmacist is to develop systems that can be as ideal system as possible. Attempts to develop a single- dose therapy for the whole duration of treatment have focused attention on controlled or sustained release drug delivery system.

 

            Attention has been focused particularly on orally administered sustained drug delivery systems because of the ease of the administration via the oral route as well as the ease and economy of manufacture of oral dosage forms, Sustained release describes the delivery of drug from the dosage forms over an extended period of time. It also implies delayed therapeutic action and sustained duration of therapeutic affect. Sustained release means not only prolonged duration of drug delivery and prolonged release, but also implies predictability and reproducibility of drug release kinetics. A number of different oral sustained drug delivery systems are based on different modes of operation and have been variously named, for example, as a dissolution controlled systems, diffusion controlled systems, ion-exchange resins osmotically controlled systems, erodible matrix systems, pH- independent formulations, swelling controlled systems, and the like.

 

            Drugs that are easily absorbed from the G.I.T and having a short half-life are eliminated quickly from the blood circulation. To avoid this problem the oral controlled release formulations have been developed, as these will release the drug slowly into the GIT and maintain a constant drug concentration in the serum for a longer period of time.³

 

                 More than 50% of drug delivery systems available in the market are oral drug delivery systems. These systems have the obvious advantages of case of administration and patient acceptance. One would always like to have ideal drug delivery systems that will possess two main properties: ^{4, 5}

1. It will be a single dose for the whole duration of treatment, and
2. It will deliver the active drug directly at the site of action.

 

            It is suggested that compounding narrow absorption window drugs in a unique pharmaceutical dosage form with gastro retentive properties would enable an extended absorption phase of these drugs. After oral administration, such a dosage form would be retained in the stomach and release the drug there in a controlled and prolonged manner, so that the drug could be supplied continuously to its absorption sites in the upper gastrointestinal tract. This mode of administration would best achieve the known pharmacokinetic and pharmacodynamic advantages of controlled release dosage form for these drugs.

          

            Controlled release or Extended-release dosage forms with prolonged residence times in the stomach are highly desirable for drugs which are, ^{6, 7, 8}

1. Administered two or more time a day.
2. Only absorbed in the upper GI regions.
3. Targeted at sites in the upper GI tract.
4. Bio available through active transport mechanisms.
5. Irritating to the mucosa.
6. Imbalancing, irritating, or unsafe in the lower GI region.
7. More effective when plasma levels are more constant.
8. Drugs that are locally active in the stomach.
9. That has an absorption window in the stomach or in the upper small intestine,
10. That are unstable in the intestinal or colonic environment.
11. Have low solubility at high pH values.

 

Biological aspects of stomach anatomy:

            The main function of the stomach is to process and transport food. It serves as a short‐term storage reservoir, allowing a rather large meal to be consumed quickly. Substantial enzymatic digestion is initiated in stomach, particularly of proteins. Vigorous contractions of gastric smooth muscle mix and grind foodstuffs with gastric secretions, resulting in liquefaction of food. As food is liquefied in the stomach, it is slowly released into the small intestine for further processing. ⁹

 

            Anatomically the stomach is divided into 3 regions: fundus, body, and antrum (pylorus). The proximal part made of fundus and body acts as a reservoir for undigested material, whereas the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions.¹⁰

            It has been reported that the mean value of pH in fasted healthy subjects is 1.1± 0.15. But when food comes into the stomach, the pH may rise to levels in the 3.0 to 4.0 level due to the buffering capacity of proteins. However, in fasted state, basal gastric secretion in women is slightly lower than that of men.¹¹

 

            Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the 2 states. During the fasting state an inter digestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours. This is called the inter digestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases: ¹²

 

Phase I (Basal phase): lasts from 30 to 60 minutes with rare contractions.

 

Phase II (Preburst phase): lasts for 20 to 40 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.

 

Phase III (burst phase): lasts for 10 to 20 minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave.

 

Phase IV: lasts for 0 to 5 minutes and occur between phases III and I of 2 consecutive cycles.    

Factors Affecting Floating Drug Delivery System^{13, 14}

Density- GRT is a function of dosage form buoyancy that is dependent on the density of a dosage form which affects the gastric emptying rate. A buoyant dosage form should have a density of less than that of the gastric fluids floats. Since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period.

 

Size- Dosage form units having a diameter of more than 7.5mm are reported to have an increased gastric residence time compared with those having a diameter of 9.9mm Gastric retention time of a dosage form in the fed state can also be influenced by its size. Small tablets are emptied from the stomach during the digestive phase while large .size units are expelled during the house keeping waves.

 

Single or multiple unit formulation- Multiple unit formulations show a more predictable release profile and insignificant impairing of performance due to failure of units, allow co-administration of units with different release profiles or containing incompatible substances and permit a larger margin of safety against dosage form failure compared with single unit dosage forms.

Effect of buoyancy- On comparison of floating and non floating dosage units, it was concluded that regardless of their sizes the floating dosage units remained buoyant on the gastric contents throughout their residence in the gastrointestinal tract, while the non floating dosage units sank and remained in the lower part of the stomach. Floating units away from the gastro-duodenal junction were protected from the peristaltic waves during digestive phase while the non floating forms stayed close to the pylorus and were subjected to propelling and retropelling waves of the digestive phase.

 

Fed or unfed state: Under fasting conditions, the GI motility is characterized by periods of strong motor activity or the migrating myloelectric complex (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach and, if the timing of administration of the formulation coincides with that of the MMC, the GRT of the unit can be expected to be very short. However, in the fed state, MMC is delayed and GRT is considerably longer. It was concluded that as meals were given at the time when the previous digestive phase had not completed, the floating form buoyant in the stomach could retain its position for another digestive phase as it was carried by the peristaltic waves in the upper part of the stomach.

 

Nature of meal:  feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.

 

Caloric content: GRT can be increased by four to 10 hours with a meal that is high in proteins and fats.

 

Frequency of feed: The GRT can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC.¹³

 

Gender: Mean ambulatory GRT in males (3.4±0.6hours) is less compared with their age and race matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface.

 

Age: elderly people, especially those over 70, have a significantly longer GRT.

 

Posture: GRT can vary between supine and upright ambulatory states of the patient. When subjects were kept in the supine position it was observed that the floating forms could only prolong their stay because of their size; otherwise the buoyancy remained no longer an advantage for gastric retention.

 

Biological factors: diabetes and Crohn’s disease, Etc.

 

Concomitant Drug administration & interaction: Anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride. In order for a hydrodynamically balanced dosage forms to float in the stomach. The density if the dosage forms should be less than the gastric contents .However, the floating force kinetics of such dosage form has shown that the bulk density of a dosage form is not the most appropriate parameter for describing its buoyant capabilities. The prolongation of the gastric residence time by food is expected to maximize during drug absorption from the dosage form due to increased dissolution of the drug and longer residence at the most favourable sites of absorption. However, literature data on the relationship between device size and gastric residence time are contradictory.

 

APPROACHES TO GASTRIC RETENTION ^{3, 15}

            A number of approaches have been used to increase gastric retention time (GRT) of a dosage form in stomach by employing a variety of concepts.

    

 

 

 

 

a) Floating Systems

            Floating Drug Delivery Systems (FDDS) have a bulk density lower than gastric fluids and thus remain buoyant in stomach for a prolonged period of time, without affecting the gastric emptying rate. While the system floats on gastric contents, the drug is released slowly at a desired rate from the system. After the release of drug, the residual system is emptied from the stomach. This results in an increase in gastric retention time and a better control of fluctuations in plasma drug concentrations. Floating systems can be classified into two distinct categories, non effervescent and effervescent systems.

 

b) Bio/Muco-adhesive Systems

            Bio/muco-adhesive systems are those which bind to the gastric epithelial cell surface or mucin and serve as a potential means of extending gastric residence time of drug delivery system in stomach, by increasing the intimacy and duration of contact of drug with the biological membrane.

 

            Binding of polymers to mucin/epithelial surface can be divided into three broad categories:

• Hydration-mediated adhesion.
• Bonding-mediated adhesion.
• Receptor-mediated adhesion.

c) Swelling and Expanding Systems

These are dosage forms, which after swallowing, swell to an extent that prevents their exit from the pylorus. As a result, the dosage form is retained in stomach for a long period of time. These systems may be named as “plug type system”, since they exhibit tendency to remain logged at the pyloric sphincter.

 

d) High density systems

            These systems with a density of about 3 g/cm3 are retained in the rugae of stomach and are capable of withstanding its peristaltic movements. A density of 2.6- 2.8 g/cm3 acts as a threshold value after which such systems can be retained in the lower parts of the stomach. High-density formulations include coated pellets. Coating is done by heavy inert material such as barium sulphate, zinc oxide, titanium dioxide, iron powder etc.

 

e) Incorporation of passage delaying food agents

            Food excipients like fatty acids e.g. salts of myristic acid change and modify the pattern of stomach to a fed state, thereby decreasing gastric emptying rate and permitting considerable prolongation of release. The delay in gastric emptying after meals rich in fats is largely caused by saturated fatty acids with chain length of C10-C14.

 

f) Ion exchange resins

Ion exchange resins are loaded with bicarbonate and a negatively charged drug is bound to the resin. The resultant beads are then encapsulated in a semi-permeable membrane to overcome the rapid loss of carbon dioxide. Upon arrival in the acidic environment of the stomach, an exchange of chloride and bicarbonate ions take place. As a result of this reaction carbon dioxide is released and trapped in the membrane thereby carrying beads towards the top of gastric content and producing a floating layer of resin beads in contrast to the uncoated beads, which will sink quickly.

 

g) Osmotic regulated systems:                                                                                                                

            It is comprised of an osmotic pressure controlled drug delivery device and an inflatable floating support in a bioerodible capsule. In the stomach the capsule quickly disintegrates to release the intragastric osmotically controlled drug delivery device. The inflatable support inside forms a deformable hollow polymeric bag that contains a liquid that gasifies at body temperature to inflate the bag. The osmotic controlled drug delivery device consists of two components drug reservoir compartment and osmotically active compartment.

h) Raft system

            It incorporates alginate gels that have a carbonate component and upon reaction with gastric acid, bubbles form in the gel enabling floating.

 

TYPES OF FLOATING DRUG DELIVERY SYSTEM ^{16, 17, 18, 19, 20}

            Based on the mechanism of buoyancy, two distinctly different technologies have been utilized in the development of FDDS which are:

1. Effervescent system
2. Non-effervescent system

 

A.  EFFERVESCENT SYSTEM

            Effervescent systems include use of gas generating agents, carbonates (eg. Sodium bicarbonate) and other organic acid (e.g. citric acid and tartaric acid) present in the formulation to produce carbon dioxide (CO2) gas, thus reducing the density of the system and making it float on the gastric fluid. These effervescent systems further classified into two types.

I. Gas generating systems

a. Intra gastric single layer floating tablets or

Hydrodynamically Balanced System (HBS)

            These are as shown in figure and formulated intimately mixing the CO2 generating agents and the drug with in the matrix tablet. These have a bulk density lower than gastric fluids and therefore remain floating in the stomach unflattering the gastric emptying rate for a prolonged period. The drug is slowly released at a desired rate from the floating system and after the complete release the residual system is expelled from the stomach. This leads to an increase in the GRT and a better control over fluctuations in plasma drug concentration.

 

The HBS must comply with following three major criteria

1. It must have sufficient structure to form cohesive gel barrier.
2. It must maintain an overall specific density lower than that of gastric     contents.
3. It should dissolve slowly enough to serve as reservoir for the delivery system.

 

b. Intra gastric bilayered floating tablets:

            These are also compressed tablet as shown in figure and contains two layer i.e.

 

 

i.                    Immediate release layer and

ii.                  Sustained release layer.

c. Multiple Unit type floating pills:

            These systems consist of sustained release pills as ‘seeds’ surrounded by double layers. The inner layer consists of effervescent agents while the outer layer is of swellable membrane layer. When the system is immersed in dissolution medium at body temp, it sinks at once and then forms swollen pills like balloons, which float as they have lower density.

 

II. Volatile Liquid / Vacuum Containing Systems

a. Intragastric floating gastrointestinal drug delivery system

These system can be made to float in the stomach because of floatation chamber, which may be a vacuum or filled with air or a harmless gas, while drug reservoir is encapsulated inside a microporus compartment.

 

b. Inflatable gastrointestinal delivery systems

            In these systems an inflatable chamber is incorporated, which contains liquid ether that gasifies at body temperature to cause the chamber to inflate in the stomach. These systems are fabricated by loading the inflatable chamber with a drug reservoir, which can be a drug, impregnated polymeric matrix, then encapsulated in a gelatin capsule. After oral administration, the capsule dissolves to release the drug reservoir together with the inflatable chamber. The inflatable chamber automatically inflates and retains the drug reservoir compartment in the stomach. The drug continuously released from the reservoir into the gastric fluid. This system is shown in fig.

 

C. Volatile liquid containing system (osmotically controlled DDS)

As an osmotically controlled floating system, the device comprised  of  a  hollow  deformable  unit  that  was convertible from a collapsed to an expanded position and returnable  to  a  collapsed  position  after  an  extended period of time. A housing was attached to the deformable unit and it was internally divided into a first and second chamber with the chambers separated by an impermeable, pressure responsive movable bladder.  The first chamber contained an active drug, while the second contained a volatile liquid, such as cyclopentane or ether that vaporises at physiological temperature to produce a gas, enabling the drug reservoir to float. To  enable  the unit  to  exit  from  the  stomach,  the  device  contained bioerodible plug that allowed the vapour to escape.

  

D. Gas generating systems

            These buoyant delivery systems utilize effervescent reaction between carbonate/bicarbonate salts and citric/tartaric acid to liberate CO2 which gets entrapped in the jellified hydrochloride layer of the system, thus decreasing its specific gravity and making it float over chyme. These tablets may be either single layered wherein the CO2 generating components are intimately mixed within the tablet matrix or they may be bilayer in which the gas generating components are compressed in one hydrocolloid containing layer, and the drug in outer layer for sustained release effect. Multiple unit type of floating pills (Fig.14) that generates CO2, have also been developed. These kinds of systems float completely within 10 minutes and remain floating over an extended period of 5-6 hrs.

B. Non effervescent systems

            The non effervescent FDDS based on mechanism of swelling of polymer or bioadhesion to mucosal layer in GI tract. The most commonly used excipients in noneffervescent FDDS are gel forming or highly swellable cellulose type hydrocolloids, polysaccharides and matrix forming material such as polycarbonate, polyacrylate, polymethacrylate, polystyrene as well as bioadhesive polymer such as chitosan and carbopol 934. The various types of this system are as:

 

1. Single layer floating tablets:

            They are formulated by intimate mixing of drug with a gel-forming hydrocolloid, which swells in contact with gastric fluid and maintain bulk density of less than unity. The air trapped by the swollen polymer confers buoyancy to these dosage forms.

2. Bilayer floating tablets:

A bilayer tablet contain two layer one immediate release layer which release initial dose from system while the another sustained release layer absorbs gastric fluid, forming an impermeable colloidal gel barrier on its surface, and maintain a bulk density of less than unity and thereby it remains buoyant in the stomach.

3. Alginate beads:

Multi unit floating dosage forms were developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm diameter can be prepared by dropping a sodium alginate solution into aqueous solution of calcium chloride, causing precipitation of calcium alginate leading to formation of porous system, which can maintain a floating force for over 12 hours. These floating beads gave a prolonged residence time of more than 5.5 hour.

4. Floating Tablets:

Floating tablets (tabletss), loaded with ibuprofen in their outer polymer shells were prepared by a novel emulsion-solvent diffusion method. The ethanol: dichloromethane solution of the drug and an enteric acrylic polymer was poured in to an agitated aqueous solution of PVA that was thermally controlled at 40°.The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane formed in internal cavity in floating tablets of the polymer with drug. The tabletss floated continuously over the surface of acidic dissolution media containing surfactant for greater than 12 h in vitro.

 

Advantages of floating drug delivery system:^{21, 22}

Enhanced bioavailability

            The bioavailability of riboflavin CR-GRDF is significantly enhanced in comparison to the administration of non-GRDF CR polymeric formulations. There are several different processes, related to absorption and transit of the drug in the gastrointestinal tract, that act concomitantly to influence the magnitude of drug absorption.

 

Enhanced first-pass biotransformation

            In a similar fashion to the increased efficacy of active transporters exhibiting capacity limited activity, the pre-systemic metabolism of the tested compound may be considerably increased when the drug is presented to the metabolic enzymes (cytochrome P450, in particular CYP3A4) in a sustained manner, rather than by a bolus input.

 

Sustained drug delivery/reduced frequency of dosing

            For drugs with relatively short biological half life, sustained and slow input from CR-GRDF may result in a flip-flop pharmacokinetics and enable reduced dosing frequency. This feature is associated with improved patient compliance and thereby improves therapy.

 

Targeted therapy for local ailments in the upper GIT

            The prolonged and sustained administration of the drug from GRDF to the stomach may be advantageous for local therapy in the stomach and small intestine. By this mode of administration, therapeutic drug concentrations may be attained locally while systemic concentrations, following drug absorption and distribution, are minimal.

 

Reduced fluctuations of drug concentration

            Continuous input of the drug following CRGRDF administration produces blood drug concentrations within a narrower range compared to the immediate release dosage forms. Thus, fluctuations in drug effects are minimized and concentration dependent adverse effects that are associated with peak concentrations can be prevented. This feature is of special importance for drugs with a narrow therapeutic index.

 

Improved selectivity in receptor activation

Minimization of fluctuations in drug concentration also makes it possible to obtain certain selectivity in the elicited pharmacological effect of drugs that activate different types of receptors at different concentrations.

Reduced counter-activity of the body

In many cases, the pharmacological response which intervenes with the natural physiologic processes provokes a rebound activity of the body that minimizes drug activity. Slow input of the drug into the body was shown to minimize the counter activity leading to higher drug efficiency.

 

Extended time over critical (effective) concentration

For certain drugs that have non-concentration dependent pharmacodynamics, such as betalactam antibiotics, the clinical response is not associated with peak concentration, but rather with the duration of time over a critical therapeutic concentration. The sustained mode of administration enables extension of the time over a critical concentration and thus enhances the pharmacological effects and improves the clinical outcomes.

 

Minimized adverse activity at the colon

Retention of the drug in the GRDF at the stomach minimizes the amount of drug that reaches the colon. Thus, undesirable activities of the drug in colon may be prevented. This pharmacodynamic aspect provides the rationale for GRDF formulation for beta-lactum antibiotics that are absorbed only from the small intestine, and whose presence in the colon leads to the development of microorganism’s resistance.

 

Site specific drug delivery

A floating dosage form is a feasible approach especially for drugs which have limited absorption sites in upper small intestine30. The controlled, slow delivery of drug to the stomach provides sufficient local therapeutic levels and limits the systemic exposure to the drug.

This reduces side effects that are caused by the drug in the blood circulation. In addition, the prolonged gastric availability from a site directed delivery system may also reduce the dosing frequency.

 

Disadvantages of floating drug delivery system²³

The main disadvantage of floating systems is that they require sufficiently high levels of fluid in the stomach for the DDS to float therein and work efficiently. However, this can be overcome by administrating the dosage form with a glass full of water (200-250 ml) with frequent meals or by coating the dosage form with bioadhesive polymers, thereby enabling them to adhere to the mucous lining of the stomach wall. The following consideration may help selecting the drug candidate for FDDS:

1. FDDS are not suitable for the drugs that have solubility or stability problems in   the gastric fluid.
2. Floating tablets are not suitable candidates for drugs with stability or solubility problem in the stomach.eg. nifedipine.
3. Drugs that are irritant to the gastric mucosa or induce gastric lesions are not good candidates for FDDS.
4. Requires the presence of food to delay gastric emptying.

 

Application of Floating tablets

1. Floating tablets are especially effective in delivery of sparingly soluble and         insoluble drugs.
2. For weakly basic drugs that are poorly soluble at an alkaline pH, floating tablets may avoid chance for solubility to become the rate-limiting step in     release by restricting such drugs to the stomach.
3. Drugs that have poor bioavailability because of their limited absorption to the             upper gastrointestinal tract can also be delivered efficiently thereby maximizing their absorption and improving the bioavailability.
4. The floating tablets can be used as carriers for drugs with so-called absorption windows, these substances. for example antiviral, antifungal and antibiotic agents (Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides and Tetracyclines).
5. For more effective oral use of peptide and protein drugs such as Calcitonin,           Erythropoietin, Vasopressin, Insulin, low-molecular-weight Heparin, and          LHRH.
6. Floating tablets of non-steroidal anti inflammatory drugs are very effective    for controlled release as well as it reduces the major side effect of gastric    irritation; for example floating tablets of Indomethacin are quiet beneficial for rheumatic patients.