INTRODUCTION:

Oral drug delivery has been the most predominant mode of administration over the years due to its main significance such as providing a maximum active surface area for the administration of various types of drugs (1,2). But, the dosing pattern of the conventional oral dosage forms has reported fluctuation in therapeutic drug plasma levels which leads marked side effects in some instances.

An uncontrolled immediate release of the drug may initiate local gastrointestinal or systemic toxicity (2). Conventional delivery of some drug had major drawbacks such as reduced oral bioavailability due to the presence of food, Gastric pH stabilisation, Degradation by Gastric enzymes, GI motility changes etc. (3-5). To overcome the above disadvantages of conventional dosage form, sustained/controlled drug delivery system was introduced. One excellent example is the oral osmotically controlled drug delivery system (CR) which work on the principle of osmotic pressure for controlled delivery of active agents (6,2).

Considering the inefficiency of a conventional dosage forms in delivery of certain drugs and the excellence of Osmotic systems in controlled release of drugs the FODDS was introduced which operates on the principle of osmotic pressure to float on the gastric fluid (7). FODDS is a once-a-day regimen developed on the basis of two technologies i.e. floating and osmotic mechanism (8). Since the floating osmotic pump mainly depends upon the principle of gastric retention in Gastrointestinal tract (GIT) which is determined by factor called Gastric retention time (GRT), it is necessary to understand the gastrointestinal physiology. The GRT lies typically between 6-8 hrs depending upon the fed state of the subject (8,9). It was found that large dosage forms possess longer gastric retention in fed state compared to fasting state. It is essential for developed once-a-day regimen to possess the characteristic retention up to 24 hrs in GIT which extends the absorption period of the drugs (10,8). Gastric retention time is an important parameter which has a significant influence over the drug bioavailability (11,12). A shorter gastric retention period for drugs which acts locally in the proximal region of the GIT can result in incomplete absorption of the drug, therefore, leading to reduced efficiency of the administered dose (12-14). Thus longer residence time will drastically improve the performance of the administered dose by increasing the number of active agents penetrating through the gastric mucous membrane (12).

The ability to extend the gastric emptying time or GRT is an essential feature for the dosage forms because gastric emptying of the dosage forms are highly variable nature. This characteristic feature enables the dosage forms to reside for more extended periods in the stomach than the conventional delivery systems. Further enhanced gastric retention increases the drug bioavailability, Diminishes drug wastage and increases drug solubility which is less soluble under High pH conditions. Gastro retention is a novel way to increase the availability of new products with therapeutic possibilities and significant benefits to patients (15).

The controlled release dosage forms like osmotically controlled systems show a typical drug release patterns in which the concentration of the drug is maintained within the Minimum effective concentration (MEC) and Maximum safe concentration (MSFC) for a prolonged duration thereby maintaining a constant therapeutic action. This results in an In vitro drug release pattern which is comparable to in vivo rate of drug release which leads to a perfect in vitro/in vivo correlation. Osmotically controlled systems open up new possibilities for drugs with a wide range of aqueous solubilities. Floating Osmotic systems offers both the benefits of Floating and Osmotic principles along with a prominent advantage such as the ability to deliver drug independent to physiological conditions like pH of gastric fluid (16).

Components of FODDS (7,17,18)

FODDS contains both the essential parts of Floating and Osmotic system to provide characteristic features of both the systems. It comprises of an osmotic pressure regulated drug delivery device and inflatable floating support in a bio-erodible capsule FODDS precisely consists for 3 major components

· The outer coat

· A Drug Reservoir compartment

· The inner coat

The Outer Coat comprises of gas generating and gel-forming agents which provides the floating action to FODDS

A Drug reservoir compartment comprises active agents along with a shape retaining semi permeable membrane and this portion possess a delivery orifice for delivery of the drug.

The inner coat comprises of the Osmotic agents along with other excipients which is responsible for the controlled release action using the osmotic pressure.

The whole system is encapsulated within a bio-erodible capsule.

Figure 1: Floating osmotic drug delivery system

Concept of FODDS:

FODDS comprises of an osmotic pressure regulated drug delivery device and inflatable floating support in a bio-erodible capsule.

The Floating mechanism:

After administration, the capsule rapidly disintegrates itself to release the intragastric osmotically-controlled drug delivery device. The inflatable floating support is made up of a deformable hollow polymeric shell which interacts with gastric fluid that initiates a spontaneous generation of CO2 occurs due to the presence of gas-forming agent and generated gas is contained within the swelled gel. This results in buoyancy of system due to reduced density (less than 1g/ml) (17,18).

The Osmotic mechanism:

After the device gets inflated, the water from the gastric fluid secreted in the stomach continuously pass through the semipermeable membrane and enters into the osmotically active compartment to dissolve the osmotically active salt. Thus an osmotic pressure is created that forces the drug reservoir compartment to reduce its volume by acting on the collapsible bag and initiate the release of drug solution through the delivery orifice (17, 18). Initially, a concentrated solution of the drug is formed due to the flow of fluid which passes through the semipermeable membrane and Secondary expulsion of the drug through the orifice is due to the osmotic pressure developed within the osmotic core (7)

The bio-erodible capsule present in the floating support erodes after a predetermined period to deflate the support. The deflated drug delivery system is then removed from the stomach (17).

A novel floating osmotic system has the ability to release the first active agent in the outer coat immediately followed by the consistent, controlled delivery of the second active agent from the osmotic core as the system floats in the gastric medium present in the stomach. The above principle works when the Floating Osmotic system contains a compressed core of primary active agent, a semipermeable membrane which is permeable to surrounding fluids and it is impermeable to active agent, and the outer coat consists of a gas generating ingredient, a gelling agent and a secondary active agent. These floating osmotic systems may contain same or different primary and secondary active agents.

The Floating Osmotic Systems are profoundly effective for those drugs which can act locally in the gastrointestinal tract or systematically by the absorption via stomach and small intestine which takes place through the immediate release of one drug followed by consistent, controlled delivery of the drug present in the osmotic core. The rate of release of drug from the osmotic core depends upon the presence of an osmotic gradient between the contents of core and the fluid in the gastrointestinal tract. The release rate of the drug does not depend upon the physiological conditions of the body like PH and the gastrointestinal motility. The active agents are released at a constant rate as long the osmotic gradient remains constant and release gradually reduces as the gradient falls. The release ceases when the gradient reaches zero after which the remaining inert components present in the shell are excreted through faeces (19).

Figure 2: Representation of FODDS mechanism

Why FODDS is Effective than other GRDDS:

· FODDS was found to be effective when compared to tablets and pellets for increased retention and bio-adhesion used in the treatment of gastric disorders which are prepared using natural gums, plant extracts, sucralfates, acrylic acid or methacrylic acid derivatives (20). However, these bioadhesive systems were abandoned due to the fact these mucoadhesive polymers were not able to significantly decrease the gastric transit time of solid delivery systems (21,19).

· Another report (22) states the success of the low-density systems of pellets and tablets, but these systems fail to provide an extended period of gastric residence when not taken with a meal (19).

· Since the FODDS is the based on Osmotic, mechanism it provides a greater advantage over the other GRDDS. The better control over in vivo release of the active agent is achieved in the case of an osmotic system since they follow zero order kinetics (23) and they possess a significant in-vitro/in-vivo correlation (24,25,19).

· Osmotic delivery has been proved to be useful in the controlled delivery of various active agents. Reports have shown that Gastrointestinal Therapeutic System of nifedipine (26) and glipizide(27) were significantly more effective when compared to their corresponding immediate release formulations. Many other Osmotic delivery systems claim the same. Thus incorporating the Osmotic release Mechanism in a Floating System will provide a better release potential provided the retention factor due to Floating Mechanism, in turn, improves the bioavailability of the Local and Systemic acting drugs. (19).

Advantages:

· One of the first benefits of FODDS for various drugs is that it enhances the absorption of drugs in the stomach and upper intestine thereby increasing the therapeutic activity. Thus FODDS mechanism is highly applicable to drugs like Methyldopa, captopril, Furosemide and riboflavin which has stomach and upper region of the intestine as the specific sites of absorption. However, this route has a limitation that the absorption may not be uniform throughout the Gastrointestinal tract (19,28, 29).

· Floating Osmotic systems utilises the phenomenon of Gastric residence time (GRT) or Transit time in the Gastrointestinal tract. Drugs which are majorly dependent upon the GRT can get benefited by FODDS. The Sparingly soluble drugs which have to be administered several times a day due to their inadequate dissolution can employ FODDS mechanism to extend the duration of gastric residence and thereby significantly improving the drug dissolution and absorption (19).

· In Special cases, drugs like Ciprofloxacin and Ofloxacin which are intended for the treatment of infections and disorders specific to gastric region extensively utilises FODDS mechanism. Since in these cases the drugs have to be retained in the stomach with high concentration for optimum efficiency of the treatment. A classic example is the treatment of chronic and peptic ulcers which is caused by Helicobacter pylori. Even though the bacterium is sensitive to most of the antibiotics, it requires maintenance of a high concentration of drug within the gastric mucosa for effective eradication of the bacteria (19, 28, 30).

· FODDS is particularly effective for drugs that are acid soluble in nature (31), drugs that are unstable in intestinal fluids(32) and drugs which undergo immediate change due to its pH-dependent solubility which arise due to conditions like food, age and pathological conditions of Gastrointestinal tract. Drugs like Bromocriptine can be incorporated in a controlled release system such as FODDS for the potential treatment of parkinsonism. It was found that about 30% of the drug dose was absorbed from the gastrointestinal tract (33). Thus low absorption potential of the drug results in low dose usage which can be significantly enhanced by Floating Systems like FODDS.

Limitations:

Floating Osmotic systems fail to operate efficiently under the presence of low level of fluids in the stomach. A high level of fluid is required for efficient working of these floating systems. However, this limitation can be overcome by taking 200-250ml of water along with the dose (27,28).

· Floating Osmotic Systems cannot incorporate drugs which irritate gastric mucosa (28).

· Drug substance that has stability and solubility issues in the gastric environment of the stomach cannot utilise the Floating Osmotic Mechanism (28).

· Drugs like Nifedipine are not applicable to Floating Osmotic Systems since they undergo the first-pass metabolism and with Floating Osmotic systems, they may produce reduced bioavailability due to slow gastric emptying (28, 34).

· Osmotic release Mechanism may produce irritation or ulcer due to the release of saturated drug solution (76).

· For the preparation of orifice in Floating Osmotic system requires the use of special instruments and is not cost effective method (35).

Criteria for selection of drugs:

1. According to the principle of osmotically controlled release.

Drugs which have a shorter half-life are preferred for the Floating Osmotic system development.M ost of the Antihypertensive class of drugs lies under this category(35). Eg Diltiazem HCl(36), Metoprolol(37), Oxprenolol, Nifedipine (38), Glipizide (39), Carbamazepine.

2. According to the Principle of floating drug release (28,40-52)

· Drugs which have better local action in the stomach. E.g. Misoprostol, antacids etc.

· Drugs which have a narrow absorption window in the Gastrointestinal tract. E.g. L-DOPA, Riboflavin, Para amino benzoic etc

· Drugs which have the stomach and upper portion of the GI tract as the primary site of absorption. E.g. Calcium Supplements.Chlordiazepoxide and cinnarazine

· Drugs which are unstable in other parts of the Gastrointestinal tract, i.e. Colon and Intestine. E.g. Captopril and metronidazole.

· Drugs which tend to disturb colonic bacteria. E.g. Amoxicillin Trihydrate

· Drugs which are especially effective against infection agents like H.pylori.Their local availability can be prolonged by increasing their Gastric residence time in Stomach. It is seen in cases like the peptic ulcer.

· The drugs like NSAIDs tend to cause gastric lesions hence cannot be incorporated in the Floating Osmotic system.

· Also, the drugs those are unstable in acidic environment present in the stomach are not suitable for Floating Osmotic system since they degrade under acidic conditions. Further, the drugs which are absorbed throughout all the parts of Gastrointestinal tract offer no advantage when incorporated in Floating Osmotic systems hence are not generally considered for Floating Osmotic system.

Formulation aspects:

Floating Osmotic system is made up of basic ingredients which are essential for its functioning. Those include the Active ingredient, Osmotic agent, semipermeable membrane, plasticiser, gas generating agent, swelling agent and gelling agent. A primary preference for the composition of the Floating Osmotic System is given in the Table below:-

Table 1: Preferred Composition of FODDS

S. No	Composition	Amount
1	Active ingredient	3-72%
2	Osmotic agent	5-10%
3	Semi permeable membrane material	2-8%
4	Plasticiser	2-10%
5	Gas generating agent	5-15%
6	Swelling agent	2-10%
7	Gelling agent	2-10%

The percentage amount mentioned in the above table is the percentage weights of the ingredients which based on the total weight of the composition (%w/w)

Further, the active ingredients present in the outer coat should be preferably between 3-12%, and the active ingredients present in the osmotic inner coat should be preferably (45-60%).

Floating Osmotic system comprises of specific main components for which their purpose and examples are given below

Osmotic agents:

They are preferably added when the active agents have limited solubility in the fluid present within the environment of delivery. They can entirely or partially solubilise the active agent. When the active agent is only partially or completely dissolved in the fluid, the active agents can be released as a suspension once the sufficient fluid passes through or absorbed by the core to form a suspension.

Examples: Salts of acids and bases, Sugars, Sugar alcohols, Sodium chloride, potassium chloride, calcium Sulfate, Sodium Sulfite, magnesium chloride, magnesium Sulfate, calcium bicarbonate, d-mannitol, Sodium Sulfate, calcium lactate, urea, Sucrose, lactose, dextrose.(6,19)

(most preferred being Sodium chloride: 5-10% or 7-9% or 8.5% based on the weight of total composition.)

Semipermeable membrane:

They consists of polymers which possess a selective permeability characteristic by allowing the movement of water but not the solute

Examples: Cellulose esters such as cellulose acetate (acetyl content 32%,38%), cellulose acetate butyrate, cellulose triacetate and ethyl cellulose and Eudragits.(6,19,51,52)

(Most preferred being cellulose triacetate 5-10% or 3-7% or 5% based on the weight of total composition)

Plasticizers:

Plasticizers are used to alter the properties and characteristics of the polymers used in the coating which can influence the permeability.(79,53).

Examples: glycol ethers, poly(propylene glycol), block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticisers, triacetin, propylene glycol, and glycerin. Ethylene glycol, 1,2-butylene glycol, diethylene glycol, triethylene citrate, and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, diethylene glycol monoethyl ether, Sorbitol lactate, ethyl lactate, butyl lactate, and ethyl glycolate.

(Most preferable being Polyethylene glycol 400: 2-10% or 5-8% or 6% based on the weight of the total composition)(19).

Swelling agent: -

The swelling agent can swell several folds higher than its original volume on contact with the fluid present in the environment.

Examples: Starch, Sodium Starch glycolate, crosslinked carboxymethylcellulose, crosslinked polyvinyl pyrrolidone, and partially pregelatinised Starch.

(Most preferable being partially pregelatinised starch: 2-10% or 5-8% or 6% based on the weight of total composition.)

Gelling agent:

Gelling agent on contact with gastric fluid gets converted into a viscous gel matrix which entraps the gas generated by a gas generating agent which in turn takes place on contact with Gastric fluid.

Examples:

hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, carbomer, carboxymethylcellulose, chitosan, and Sodium Alginate.

(Most preferable being hydroxypropyl methylcellulose (4000cps): 2-10% or 3-7% or 4% based on the weight of total composition.)(19).

Gas generating agent:

A gas generating agents otherwise known as effervescent agents generates carbon dioxide when they come in contact with the gastric fluid (54).

Examples:

Carbonate or Bicarbonate salts as sodium bicarbonate, Calcium Carbonate and Organic salts like citric acid, tartaric acid. Others include di-sodium glycine carbonate, nitroglycerine. (19)(55-57).

(The most preferable being Sodium bicarbonate and is present in an amount from 5-15% or 7-12% or 8.5% based on the weight of total composition) (19).

Table 2:- List of Suggested Therapeutic compound

Therapeutic compounds

antibacterial Substances, anti-inflammatory agents, anti-ulcer agents, antihistamines, antiparasitics, antivirals, proton pump inhibitor , antifungal, amoebicidal, analgesics, antidepressants, antiarthritics, antiasthmatics, anticoagulants, anticonvulsants, local anesthetics, antidiabetics, muscle relaxants, antipsychotics, antihypertensives, antiparkinson agents, hypnotics, Sedatives, antispasmodic, tranquilizers, anti-convulsants, muscle contractions, prokinetic agents,antimicrobials, antimalarials, hormonal agents, contraceptives, H2 receptor blockers, diuretics, hypoglycemics, and cardiovascular drugs

Laboratory scale preparation of FODDS:

The Preparation of Floating Osmotic system involves a 3 step process:

a) Direct compression

b) Semi permeable membrane coating process

c) final compression with Floating agents

The main active ingredient along with some other excipients like Hydroxy propyl methyl cellulose were mixed and passed through the required mesh size depending upon the nature of ingredients used. After the mixing process gets completed, the osmotic agent are thoroughly mixed and they are subjected to the tablet punching process. The coating solution is prepared based on the needs of the experiment. The coating is applied over the compressed tablets using a conventional coating pan. The process is done by maintaining the standard conditions like rpm, Temperature and Spray rate. (58). In the final step of preparation the floating agents like gas generating, Swelling agents were added to the die cavity in a determined ratio, and the pre-coated tablets are filled in the cavity and compressed. Formulator may add same or different active agent in the outer layer along with other ingredients (like floating agents) which act as the immediate release dose (19,16,59,60).

Figure 3 : Process of preparation

Evaluation parameters:

In-vitro studies:

Hardness, Friability, Assay, Content Uniformity:

Primary Evaluation of the Floating Osmotic tablets was performed according to the specifications mentioned in the monographs (61).

In Vitro Drug Release Study:

The Floating Osmotic systems were evaluated using the USP XXIV dissolution apparatus Type II to determine the in-vitro drug release characteristics. The Dissolution media used for the evaluation is a Simulated Gastric Fluid (SGF, with PH 1.2, Volume 900ml) to mimic the gastric conditions of the stomach and the temperature is maintained at 37±0.2°C with rotation maintained at 50 rpm. A measured amount (5ml) of the sample is withdrawn periodically at a different time interval, and the withdrawn amount is compensated with an equivalent volume of fresh medium. Then the dissolution samples are subjected to filtration process and were later analysed using a UV spectrophotometer. Additionally if needed the in vitro drug release is carried out in different PH varied media for example first 2h in PH 1.2, continued by 4.5PH for next 2hr later 2hr in 6.8PH and finally in 7.4PH for 2hr (62). The above method is done only under certain conditions to determine the effect of PH on the Drug release (16).

Floating Properties:

The time taken for Float Osmotic systems to float on the dissolution medium surface is noted as the Floating lag time and The duration of floating period till the Tablet sink in the dissolution medium is noted as the Floating log time (duration of floating). The above process is carried out in USP XXIV type II apparatus containing 500ml of Simulated Gastric Fluid (1.2PH) with the absence of pepsin at the temperature 37±0.5 °C with paddle rotation of 100 rpm (63).

Pharmacokinetic studies:

Pharmacokinetic studies are done to understand the pharmacokinetics of the administered systems which includes the AUC (Area under Curve), Cmax, and time to reach maximum plasma concentration (Tmax). These can also be estimated by using a computer and the statistical analyses performed using Student t-test (61,64).

In-vivo studies:

Gastroscopy:

Gastroscopy is a minimally invasive method for in-vivo evaluation of Floating Osmotic systems, and it is a peroral endoscopy. This method provides detailed information about the administered dosage forms by visual examination of Floating Osmotic systems in the Gastric cavity with the help of some optic fibres and a video camera (65,66). However, this method requires expertise in interpretation of results, and it also has a risk of inducing uncontrolled bleeding and retention of blood and food in the stomach and upper GIT (65).

Magnetic Resonance Imagining (MRI)

It is the most followed method for various diagnostic purposes due to its non-invasive strategy. It works on the principle of a powerful magnetic field to produce a detailed image of different parts of the human body. This same principle is used to identify the administered Floating Osmotic systems in the GIT by capturing the pictures of the System in the GIT. Commonly Iron powders are mixed with these systems, and then they are administered to the subject (65,67). It is safer than other techniques because it does not involve the use of dangerous radioisotopes for image capturing (65).

In-vivo radiology:

γ-Scintigraphy:

γ-Scintigraphy is one of the in-vivo buoyancy studies which is carried out to evaluate Floating Osmotic systems. This technique is done by administering a radioisotope to the subject which is encapsulated in the floating systems (i.e. Floating Osmotic system like 111In), and it is administered orally. The administered Radioisotope is then monitored using an external gamma camera which can produce a two- and three-dimensional images of the Floating Osmotic systems in the stomach. The image is generated by the radiation released from the body. This method can detect the actual position of the Floating Osmotic system and also its Gastric residence time by the interpretation of these images (65, 68). However, γ-Scintigraphy requires strict compliance with technical and safety measures, cases like ionisation radiations, low resolution, and complex manufacturing of radiopharmaceuticals (65).

Radiology:

Another method involved in the in-vivo evaluation of Floating Osmotic systems is the use of X-rays. The main advantage of Radiology is that it is safer, simple and cost friendly process when compared to γ-scintigraphy. A radio-opaque material like Barium sulphate is formulated with Floating Osmotic systems, and the X-ray images were taken to identify the position of the system in the GIT at various time intervals (65, 69). However, a larger amount of radio-opaque materials provides better resolutions (65).

Table 3:- List of the general tests for FODDS(65)

S. No	Test	Remarks
1	Description of the dosage form	A detailed description of product should be reported such as physical state, shape, colour etc.
2	Identification test of active moiety and colouring agent if available in composition	NIL
3	Uniformity of mass or uniformity of content	NIL
4	pH	NIL
5	Dissolution	NIL
6	Assay	NIL
7	Related substance content	If any
8	Residual solvent content	If any
9	Antimicrobial preservative content	If any

Table 4:- List of the Special tests for FODDS(65)

S.No	Test	Remark
1	Test for specific gravity	For floating system
2	Buoyancy/floating ability test	For floating system
3	Floating lag time	For floating system

Summary of works:

Many research studies have been carried out in Floating Osmotic Systems. Most of the studies were focused on areas of Formulation Development, In vitro characterisation, Computer Aided Optimization and Pharmacokinetic profile Evaluation. Some of the works emerged from the field of pharmacognosy with a scope to pharmaceutically improve the bioavailability of their crude extract using Floating Osmotic Technology.

In vitro Studies:

Ranitidine hydrochloride being one of the most suitable Active agents for Floating Osmotic systems was selected in a Research study carried by Pramod Kumar et al., (16) to develop and evaluate Ranitidine hydrochloride Floating Osmotic Drug Delivery System. In the corresponding study, the authors used the active ingredient as ranitidine since it is Histamine H2 receptor antagonist with a biological half-life of 2.5-3hrs which is favourable for a sustained release and it has poor absorption in the small intestine due to reduced solubility thus having good absorption window in the stomach. Ranitidine Hydrochloride was prepared in different batches by altering the quantity and type of excipients used. About four batches were prepared and their densities of these batches: I, II, III and IV were found to be 1.431g/cm², 1.485g/cm², 1.502g/cm², 1.542g/cm² respectively. A Compression Coating layer was added to these developed batches with different composition of the coating ingredients: CT1, CT2, CT3. HPMC K4M and SBC (sodium bicarbonate) were used as the coating mixture. Various In vitro studies were carried out to determine the best formulation from the prepared batches. It was finally concluded that developed formulations were influenced directly by the concentration of hydrophilic polymers in the core and the thickness of the Semipermeable membrane. All the prepared batches showed the desired lag time of fewer than two mins and remain floating for 12 hrs. Thus the lag time was directly proportional to SBC in compression coat and is inversely proportional to the density of FODDS. Batch III/80/CT3 was selected as an optimised formulation based on best correlation with desired release characteristic, and it had least lag time of 37s.

Similarly, Ramu Bandameedi et al., (60) developed Floating Osmotic tablets of Nizatidine. This study was specifically carried out on Nizatidine drug which is an H2 Receptor antagonist for the chronotherapy of the ulcer. The main aim of the study is to release the drug as two distinct phases separated by a lag time that achieves a plasma concentration profile varying in a circadian rhythm fashion. Floating Osmotic system were formulated using effervescence method consisted of three different steps – a) preparation of floating sustained release drug followed by b) time-lagged(4 hrs) coating with a hydrophobic rupturable polymer, ethyl cellulose and finally c) compression coating with immediate release dose of nizatidine and a supporting buoyant layer. Three ratios of Ethyl Cellulose to HPMC E15 (32.5:67.5,50:50 and 67.5:32.5) at three coating levels (5%,10%,15%)were used to optimize the lag time(4 hrs).For the preparation of buoyant layer carbapol 934p,cross-povidone and sodium bicarbonate were incorporated. The developed Floating Osmotic tablets were subjected to a series of evaluation: preformulation parameters, weight variation, thickness, hardness, friability, drug content, In-Vitro floating properties and In vitro drug release. Finally, based on the reports it was concluded that optimised formulation provided expected two-phase release pattern of Nizatidine with initial immediate dose release in 30 mins and then no drug release for 4hrs lag time followed by a sustained drug release for 8hrs in the stomach.

A research was carried out on a plant extract Andrographis paniculata by Sanja et. al.,(70) which is incorporated in Floating Osmotic drug delivery for a sustained release. The predominant focus of the study is to formulate a novel osmotic capsule containing Andrographis paniculata extract (APE) to maintain a controlled extract level in the blood, prevent dose dumping and enhance the therapeutic efficacy. The Andrographis paniculata is a hepato stimulative agent which can also be used as a hepatoprotective agent. The Andrographis paniculata extract was prepared and stored. The preformulation studies were carried out for crude drug followed by preparation of Floating Osmotic capsule which takes place in 4 steps a) preparation of cross-linked hard capsule shell b) Filling of waxy material into the body c) Filling of the extract and osmogent and Finally d) Preparing extract releasing orifice and sealing of filled capsules. Various batches were prepared with varying type and concentration of excipients(P1-P8). The prepared batches were evaluated by carrying out numerous studies and it was finally concluded that the prepared Floating Osmotic capsules of Andrographis paniculata extract possessed a well-controlled release profile for about 12hrs. Further, it was inferred that Floating Osmotic capsule will be retained in the stomach; the extract will be continuously released in a controlled manner at the site of absorption thereby improving the therapeutic efficacy.

Diethylcarbamazine citrate(DEC) a water-soluble compound was utilised in a research study conducted by Zulfequar Ahamad Khan et al.,(8) on Floating Elementary Osmotic Pump Tablet (FOPT) for controlled delivery. This research study was conducted to investigate the suitability of the design of the Floating Osmotic Pump Tablet to extend the gastric residence of a highly water soluble drug. The Floating Osmotic Pump Tablet comprises of an Osmotic core(Active Ingredient (DEC), mannitol and hydrophilic polymers) surrounded by a coat of semipermeable layer (cellulose acetate) and gas generating gelling layer (sodium bicarbonate, hydrophilic polymers) and a final polymeric film (Eudragit RL 30D). The Evaluation parameters like physical parameters, floating lag time, duration of floatation and in vitro drug release to determine the effect of formulation variables. To Analyse the physiochemical change in the drug-excipient mixture specialised studies like Fourier transform infrared spectroscopy and X-ray diffraction studies were carried out. A Scanning electron microscopy image confirmed the integrity of the orifice and polymeric film. The data obtained on physical parameters provided a better understanding for the selection excipient for the formulation of FOPT and various other studies conducted like the role of hydrophilic polymers, the thickness of coating and level of gas generating agents provided insight about floating and mechanism of drug release. Based on the results of the above evaluation studies it was concluded that all the formulated Floating Osmotic Pump Tablets showed a lag time of fewer than 8 hours and a floating period of 2 hrs in the stomach. It was also found that Diethylcarbamazine citrate was released in Zero order fashion up to 24 hrs which is a characteristic of Osmotic Pump Tablets. Based on the results of accelerated stability testing it was concluded that the formulation was to remain stable up to 3 months at 40°C temperature and 75% relative humidity. From the overall results found it can be suggested that FOPT can be a platform for newer Osmotic drug delivery of the water-soluble class of drugs.

Recent work was carried out on plant extract by Fang Y et al.,(71) on the preparation of intragastric floating two-chamber osmotic pump tablets of total alkaloids of Coptis chinensis and Evodia rutaecarpa. The primary objective of the research is to develop a intragastric floating two chamber osmotic pump tablet of Coptis chinensis and Evodia rutaecarpa and to analyse it's in vitro release characteristics. The intragastric floating two chambered osmotic pump tablet was prepared using a mixture of Polyethylene Oxide and Hydroxypropyl methylcellulose as a ratio of 4:1 and Osmotic agent incorporated in the propelling layer contained sodium chloride (20 mg), Polyethylene glycol 400 in cellulose acetate,10%; Coating membrane in core tablet;9%. The developed tablets were then tested in in-vitro dissolution testing at standard testing conditions. Result of the current study indicated that the developed tablets had shown zero order release and the tablets have also shown a good controlled drug release behaviour. The Authors concluded the study by stating the developed Intragastric floating two chamber osmotic pump tablets has a good in vitro controlled release and the in vivo release behaviour still needs to be identified.

Pharmacokinetic Studies:

A pharmacokinetic research study was conducted by Fang Yu et al.,(72) to prepare and analyse the pharmacokinetics of Irbesartan Intragastric Floating Osmotic Pump(IFPOT) tablets in dogs. Irbesartan is an angiotensin II receptor antagonist used as an Antihypertensive agent. IFPOT was prepared by wet granulation coating method. Irbesartan IFPOT and a single dose 150mg Irbesartan tablets were given to six dogs in a randomised crossover design. HPLC fluorescence technique was adopted to determine the concentration of irbesartan in plasma before medication and 0.25, 0.5,0.75,1,1.5,2,3,4,6,8,12,24,36,48 and 72h after medication. DAS statistics software was used to calculate the pharmacokinetic parameters, and it was successful in evaluating the sustained release characteristics. The reports show that the developed Floating Osmotic tablets have a significant difference in tmax and cmax when compared to single dose Irbesartan tablets. It also possessed a significant relative bioavailability. From the above results, it can be presumed that IFPOT has a good sustained release effect in dogs.

A research was conducted using Dipyridamole as a model drug by Zhihong Zhang et al.,(73) for development and evaluation of a novel Floating Osmotic Pump Systems . The Floating Osmotic tablets (FOT) were developed and compared with matrix tablets (MT). The developed Floating Osmotic tablets were analysed for the effects of pH, Temperature and hydrodynamic conditions on drug release and floating behaviour. In vivo study was carried out using three crossover study design in 5 beagle dogs relative to Conventional Tablet (CT). The cumulative per cent input in vivo data was compared with that of in vitro release profile data. Based on the result it was clear that Both Floating Osmotic and matrix tablets were affected by pH of dissolution media but was not affected by temperature of the media. The Floating Osmotic tablets show a constant release under varying hydrodynamic condition, but the drug release from Matrix tablet was affected by stirring rate. Out of 3 batches of tablet (FOT,MT andCT) the Floating Osmotic tablet got the large Area Under Curve(AUC). A linear correlation was obtained between fraction absorbed in vivo and fraction dissolved in vitro for Floating Osmotic tablets which indicates a true zero order release of the drug whereas Matrix tablets obtained only a nonlinear pattern of drug release. These results supported the conclusion that Floating Osmotic Pump could be a novel delivery system for oral administration of drugs that have upper GIT as absorption window eg: Dipyridamole

Optimization studies:

An Optimization and Pharmacokinetic study was carried out to design a new model of Floating Osmotic Pump of Ambroxol Hydrochloride by Zhao F et al.,(74). The in vitro drug release and floating behaviour was assessed using the third method apparatus(Chinese Pharmacopeia 2010, appendix XD). Central composite design response surface methodology was utilised to optimise the formulation, Where Similarity factor (f2) between the release profile of the self-made formulation and target was taken as a dependent factor. The amount of glucose (A, mg), pore former (B,%) and weight of coating (C,%) were considered as the independent factors. The independent factors of the optimised formulation was A (100.99 mg), B (1.7%), C (4.21%). The similarity factors value of self-made capsule f2(89.14) was higher than that of marketed capsules (69.02) and self-made tablets (72.15). The self-made capsules also possessed a zero order release(r=0.9944) and almost complete drug release (>90%). From the results obtained in the in vivo study, it was clear that the tmax and Cmax value of the self-made capsules were notably lower than that of market capsules and self-made tablets. A correlation of 0.985 was obtained between in vivo fraction of absorption and in vitro release rate. Thus it was concluded from the results that self-made capsules exhibit a controlled release both in vitro and in vivo conditions.

An Optimization study was done on Dipyridamole as the active agent in the development of a new model of Floating Osmotic Pump System by Zhang et al.,(75). Apparatus three (Chinese Pharmacopeia 2005, appendix XD) was utilised for in vitro dissolution testing and to evaluate the Drug release and floating behaviour of the formulated system. Central Composite design response methodology was adopted for Optimization of the System where similarity factor (f2) between the release profile of the prepared formulation and target was taken as a dependent factor. Usage amount of polyoxyethylene (X1, mg), NaCl (X2, mg) and pore former (PEG4000, X3, %) were considered as independent factors. After evaluation of the dependent and independent data it was found that dissolution profile of formulated System could match the target dissolution profile under conditions of weight gain 8%-9%, X1 (20-34), X2 (30-57), X3 = 50. It was also found that the minimum usage percentage of pore former is 35.1%. Finally, it was reported that prediction results using the Central Composite design response methodology of the Optimization model were good in the experiments.

Manvendra S. Chauhan et al. developed an Osmotically regulated Floating Asymmetric membrane capsule of Ranitidine Hydrochloride.,(76) and the system was optimised using Central Composite Design. The study was conducted to develop an Osmotically regulated floating capsule containing a highly water-soluble drug like Ranitidine Hydrochloride to be released in a controlled manner with site specificity. The solubility of Ranitidine Hydrochloride was suppressed by following a technique called Common ion effect which involves using Optimized coated Sodium chloride as a formulation component. The Phase inversion technique was adopted to prepare the capsular wall of Floating Asymmetric membrane capsule (FAMC)in which the polymeric membrane was coated on glass pins by dipping them in a cellulose acetate solution followed by quenching. Central composite Design method was followed to analyse the effect of independent variables, such as level(s) of membrane former, pore former, and osmogen, on per cent cumulative drug release as the response variable. The evaluation of Asymmetric membrane by Scanning electron microscopy revealed the presence of a dense, nonporous outer region of the membrane supported by an inner porous region. Differential scanning calorimetry indicates the absence of drug excipient interaction. In vitro Drug release testing was carried out in three bio-relevant media, pH 2.5 (low fed state), pH 4.5 (intermediate fed state), and pH 6.5 (high fed state) revealed pH-independent drug release of Ranitidine Hydrochloride (p>0.05). Finally, the study was concluded with result that the Optimized FAMC9 with the floating ability for 12 hrs was visually analysed during the in vitro drug release studies and it exhibited a maximal drug release with zero-order kinetics.

A Recent study by Sanja et al.,(77) was focused on developing and optimising the Floating Osmotic Drug Delivery System (FODDS) of Diltiazem Hydrochloride. Since Diltiazem Hydrochloride is a highly water-soluble and a potent calcium channel blocker with a shorter half-life and its frequent dosing leads to patient noncompliance. This research was primarily focused on enhancing the bioavailability of the active agent and reducing its side effects and improved patient compliance. Diltiazem Hydrochloride is extensively used in the management of angina pectoris, arrhythmia and hypertension. This study was carried out using 32 Factorial Design method to determine the influence of KCL and HPMC K4M on the rate of drug release from the core tablet. HPMC K4M was incorporated into the core tablet to limit the release of active agent from core tablet. All the developed FODDS were subjected to preliminary characterisation and In vitro drug release study. All the developed formulations showed a zero order drug release. Optimised F3 formulation showed buoyancy lag time of 8 minutes, total floating of 8 hours and in vitro drug release of 98.21%. The developed F3 formulation was finally subjected to accelerated stability testing and was found to be stable after three months with no alteration in release pattern. It was subsequently reported that FODDS could be a new strategy for enhancing the oral bioavailability of Diltiazem Hydrochloride.

The Latest research was carried out on Antiviral agent Acyclovir by Mital Patel et al.;(78) with an aim to develop and optimise Floating Osmotic System of Acyclovir as a Single Unit Floating System. The capsules were prepared by crosslinking with vapours of formaldehyde for 24 hrs. The formulation was prepared by physical mixing of Acyclovir and Osmogent in different ratios. FTIR spectroscopic study confirmed the absence of drug-excipient interaction. The developed formulation was subjected to evaluations such as Floating lag time, total floating time and in vitro drug release. It was observed that the % drug release was increased with an increase in pore size and concentration of Osmogent. 3 Factors -2 level full factorial design was adopted for the optimisation of developed Capsules. Pore size and the ratio of Osmogent were taken as independent variables and % release of drug at 5 and 12 hours respectively were taken as response variables. The Result of the experiment indicated that % drug release of the optimised batch of floating osmotic capsule at 5 hours and 12 hours were 40.506% and 97.795% respectively. Thus based on the results obtained it was concluded that enhanced characteristics of optimised floating osmotic capsules make them suitable candidates for gastric targeting.

CONCLUSION:

Floating Osmotic system is based upon the controlled release mechanism of an osmotic pressure which differentiates itself from other Floating drug delivery Systems(FDDS). This dual phenomenon allows the Floating Osmotic system to find its place among modified Floating drug delivery system. Floating Osmotic systems, however, has both positive and negative aspects. Floating Osmotic system has a major advantage over the conventional dosage forms concerning drug bioavailability, drug usage and good patient compliance. Drugs which are acting locally in stomach and those drugs which have a small absorption window can be benefitted mainly by Floating Osmotic mechanism. In the case of Pharmacokinetic profile it offers a good correlation between in vitro and in vivo drug release rates which the is due to the Osmotically controlled release mechanism. Main drawback about these systems is that it involves the use of specialised tools such as usage laser or mechanical drilling for development of orifice. As seen in the results of Research studies the Floating Osmotic systems can be an excellent preference for controlled release for drugs with a shorter half-life and can be a successful modified FDDS where the traditional FDDS suffer from drawbacks seen in sinking systems, Swelling systems and Bio-adhesive systems. Thus with a deeper insight in physiochemical properties and pharmacological aspects of the drug along with a sound knowledge in formulation development one to develop a successful floating osmotic system of new drugs having various therapeutic possibilities.

CONFLICT OF INTEREST:

The authors confirm that this article content has no conflict of interest.

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80. Available from : https://www.drugs.com/availability/generic-coreg-cr.html.

Received on 24.09.2018 Modified on 18.10.2018

Research J. Pharm. and Tech 2019; 12(2):959-971.

DOI: 10.5958/0974-360X.2019.00160.4

S.No	Patent/Marketed products/Generic products	Company/Author	Date of approval/patent publication	Active agent	Category
1	Floating Osmotic device for controlled release	Bharat Pravinchandra Mehta., adhukant Mansukhlal Doshi., Milind Dattatraya Joshi	April 3, 2003	-	-
2	Coreg CR	GlaxosmithSmithKline	October 20, 2006	Carvedilol	Anti-hypertensive
3	Generic version of Coreg cr	Sun pharm industries	October 25, 2017	Carvedilol	Anti-hypertensive
4	Generic version of Coreg cr	IMPAX LABS inc	May 7,2018	Carvedilol	Anti-hypertensive