gastroretentive Drug delivery systems and applications

gastroretention in drug delivery

1. GASTRORETENTIVE DRUG DELIVERY SYSTEMS By Dr Sumant saini M pharm phd

2. Introduction Definition: Gastroretentive drug delivery systems (GRDDS) are designed to prolong the residence of drugs in the stomach. Significance: Improved therapeutic efficacy for drugs with short half-lives or narrow therapeutic windows Reduced dosing frequency Enhanced patient compliance

3. Gastrointestinal Physiology

4. Gastric emptying: Food composition: The type and amount of food ingested can significantly affect gastric emptying. High-fat meals, for example, tend to delay gastric emptying, while carbohydrates and liquids accelerate it. Gastric motility: The contractions of the stomach muscles, known as peristalsis, propel food into the small intestine. Factors like stress, medications, and certain diseases can affect gastric motility and, consequently, gastric emptying .

5. Gastric emptying: Hormonal regulation: Hormones such as gastrin, secretin, and cholecystokinin (CCK) play a role in regulating gastric emptying. These hormones are released in response to various stimuli, including the presence of food in the stomach and the ph of the intestinal contents. Disease states: Certain diseases, such as gastroparesis (delayed gastric emptying) and irritable bowel syndrome (IBS), can disrupt gastric emptying.

6. Factors that can slow down gastric emptying Factors that can accelerate gastric High-fat meals Fiber-rich foods Stress Certain medications Underlying medical conditions Carbohydrates Liquids Certain medications Underlying medical conditions

7. Importance of Gastric Emptying Time and Its Impact on Drug Delivery Efficacy Gastric emptying time (GET) plays a crucial role in drug delivery and absorption. It significantly influences the rate at which drugs reach the small intestine, where most absorption occurs. Understanding the factors affecting GET and its impact on drug delivery is essential for optimizing therapeutic outcomes.

8. Factors Affecting Gastric Emptying Time (GET) Food composition : The type and amount of food ingested can significantly influence GET. High-fat meals, for example, tend to delay gastric emptying, while carbohydrates and liquids accelerate it. Gastric motility : The contractions of the stomach muscles, known as peristalsis, propel food into the small intestine. Factors like stress, medications, and certain diseases can affect gastric motility and, consequently, GET.

9. Factors Affecting Gastric Emptying Time (GET) Hormonal regulation : Hormones such as gastrin, secretin, and cholecystokinin (CCK) play a role in regulating gastric emptying. These hormones are released in response to various stimuli, including the presence of food in the stomach and the pH of the intestinal contents. Disease states : Certain diseases, such as gastroparesis (delayed gastric emptying) and irritable bowel syndrome (IBS), can disrupt GET.

10. Factors Affecting Gastric Emptying Time (GET) Drug absorption: GET directly affects the rate at which drugs reach the small intestine, where most absorption occurs. Delayed gastric emptying can lead to delayed drug absorption, potentially reducing therapeutic efficacy. Drug release: some drug delivery systems, such as enteric-coated tablets or capsules, are designed to release their contents in the small intestine. If GET is delayed, these systems may not function as intended, resulting in suboptimal drug release.

11. Factors Affecting Gastric Emptying Time (GET) Drug stability: the acidic environment of the stomach can degrade certain drugs. Delayed gastric emptying can increase the exposure of these drugs to the acidic environment, potentially reducing their stability and effectiveness. Therapeutic outcomes: the overall therapeutic efficacy of a drug can be influenced by its absorption rate and the concentration of the drug at its target site. GET plays a critical role in determining these factors.

12. Factors Affecting Gastric Emptying Time (GET) Formulation modifications: formulating drugs as immediate-release or sustained-release preparations can help to manage the impact of GET on drug delivery. Meal timing: administering drugs at specific times relative to meals can optimize their absorption based on the known effects of food on get.

13. Drug delivery systems: using drug delivery systems that can overcome the challenges posed by GET, such as floating or mucoadhesive systems, can improve drug absorption and therapeutic efficacy. Disease management: addressing underlying diseases or conditions that affect get can help to optimize drug delivery and improve patient outcomes. Factors Affecting Gastric Emptying Time (GET)

14. Physicochemical Factors Pka of the drug As per the ph -partition hypothesis, the ionization state of a drug depends on its dissociation constant and the ph of the fluid at the absorption site. Thus, weakly acidic drugs ( pka 2.5-7.5), which remain unionized in the acidic medium are predominantly absorbed from the stomach. Solubility Most drugs are absorbed by passive diffusion in their unionized form. One of the prerequisites for passive diffusion is that the drug should be in the solubilized state. Thus, drugs with higher solubility in the acidic medium are predominantly absorbed from the stomach. Stability The ph of the GI segment affects the stability of many drugs. The degrada - tion of the drug at a particular site retards its absorption, and hence differ- ence in drug absorption from various regions in the GI tract is observed. Thus, drugs which are stable in the acidic medium show their absorption window usually in the stomach

15. 6.1.2.4 Enzymatic Degradation Various enzymes present in the particular GI segment can cause drug deg- radation , resulting in regional variability during drug absorption. Thus, the drugs which are not substrates to the enzymes present in the stomach are absorbed from gastric region. 6.1.3 Physiological Factors 6.1.3.1 Mechanism of Absorption Absorption of certain drugs can be enhanced by local active and facilitated transport mechanisms present only at a particular site of GI tract. 6.1.3.2 Microbial Degradation Degradation of certain drugs by microflora is also responsible for regional variability in absorption from the GI tract.

16. Importance of Increased Gastric Transit Time Benefits of prolonged drug residence: Increased drug absorption Sustained therapeutic levels Reduced systemic side effects Therapeutic applications: Gastrointestinal disorders (e.g., ulcers, gastritis) Antibiotic therapy

17. Gastroretention : Definition and Mechanisms Definition: Gastroretention refers to the retention of a drug or delivery system in the stomach for an extended period.

18. Floating systems: Utilize low-density materials to maintain buoyancy In buoyant state in gastric fluids without influencing GRT for extended periods of time ( tamizharasi et al. 2011). When the system remains in the flotation state, the drug is released in a slow, continuous, but controlled fashion ( singh et al. 2017). After the release of the drug, the residual system gets emptied from the stomach. This increases GRT, whereby the plasma drug level variability can be controlled. An FDDS owes its buoyancy either to its lower density than the stomach contents or due to the gaseous phase formed inside the system after it comes in contact with the gastric environment (figure 6.6a). A floating dds , also known as a hydrodynamically balanced system ( hbs ), must comply with three major criteria ( bansal et al. 2016b):

19. Noneffervescent Systems The floatation of noneffervescent FDDS can be either because of i ) low den- sity due to swelling or ii) inherent low density. Low density due to swelling This type of system involves the admixture of a drug with a gel, which, after swallowing, swells due to imbibitions of gastric fluid, attaining a bulk density lower than the outer corona. The entrapped air provides the necessary floatation to the dosage forms. The most commonly used polymers include the gel forming or highly swellable cellulose type hydrocolloids, matrix- forming materials and polysaccharides, which also work as bioadhesive polymers such as carbopol and chitosan This technology involves encasing of a drug reservoir in a microporous compartment with apertures along its upper as well as lower walls, as depicted in figure 6.3.

20. Inherent Low-Density Systems The system initially settles down, and then comes to the brim after a spe - cific lag time, thus poses a plausible risk of premature emptying from the stomach. Therefore, there is an ardent need of a system that floats imme - diately as soon as it comes in contact with gastric fluids. This can only be accomplished with the provision of a low-density device since its inception. Low-density systems are generally made by air entrapment. Watanabe et al. (1976) prepared a single-unit FDDS with inherent low density, consisting of a hollow core (empty, hard gelatin capsule, polystyrene foam, or pop rice grain) coated with two layers: a subcoat of cellulose acetate phthalate, and an outer drug-containing coating of ethyl cellulose (EC)/hydroxypropyl methylcellulose (HPMC). This type of system is very useful for low-dose drugs but may not be suitable if larger amounts of drug are needed for an effective therapy.

21. 6.2.2.4.1 Hollow Microspheres Hollow microspheres are low-density systems that immediately float as soon as they come in contact with the gastric fluid, causing gastroretention and thereby improving drug bioavailability ( Aloshi 2016). For instance, hollow microspheres ( microballoons ) consisting of Eudragit RS (an enteric polymer) containing the drug in the polymeric shell developed have been reported in the literature (Kawashima et al. 1989; Bansal et al. 2016a).

22. 6.2.2.4.2 Floating Beads Dosage forms containing spherical floating beads have been synthesized using lyophilized calcium alginate that can keep floating for 12 h. Floating beads have a prolonged gastroretention time of more than 5.5 h as compared to solid beads that show a shorter gastric retention of 1 h as diagrammati - cally represented in Figure 6.4. Both natural and synthetic polymeric sys- tems have been used in the preparation of multiple-unit FDDS. The floating properties of the devices strongly depended on the subse - quent drying process. Oven dried beads did not float, whereas lyophilized beads remained floating for >12 h in hydrochloride buffer pH 1.5 due to the presence of air-filled hollow spaces within the system ( Talukder and Fassihi 2004).

23. 6.2.2.6 Effervescent Systems 6.2.2.6.1 Volatile Liquid Containing Systems These systems incorporate an inflatable chamber containing a volatile liquid, such as ether or cyclopentane, which evaporates at body temperature lead- ing eventually to inflation of the chamber in the stomach. These inflatable GI systems contain a hollow expandable and deformable unit that consists of two chambers separated by an impermeable, pressure-responsive, and mov- able bladder. The first chamber contains the drug and the second chamber contains the volatile liquid. In the stomach, the volatile liquid evaporates and inflates the device, leading to drug release from the reservoir into the gastric fluid, as shown in Figure 6.6a. The device may also consist of a bioerodible plug made up of PVA, polyeth - ylene , etc. that gradually dissolves causing the inflatable chamber to release gas and collapse after a predetermined time to permit spontaneous ejection of the inflatable system from the stomach (Rahim et al. 2015).

24. 6.2.2.6.2 Gas Generating Systems These systems incorporate, apart from the drug and the swelling poly- mers , such as chitosan and methylcellulose, some effervescent compounds, e.g., sodium bicarbonate (NaHCO3), tartaric acid (C₂H₂O), and citric acid (CHO7) that liberate CO2 when they come in contact with acidic gastric con- tents. And, CO₂ in this case, gets entrapped in swollen hydrocolloids and provides buoyancy to the dosage forms (Mirani et al. 2016). Generally, the effervescent systems suffer from a specific disadvantage that they do not float immediately after swallowing, as gas generation takes some time. Therefore, they could be cleared from the stomach before becom - ing effective.

25. 6.2.2.7 Limitations of FDDS A. The performance of low-density, floating DDS is strongly dependent on the fed/filling state of the stomach. Nevertheless, this approach can successfully prolong the gastric retention time and has already led to the production of pharmaceutical products, which are com- mercially available in the market ( Talukder and Fassihi 2004). B. An FDDS requires sufficiently high levels of fluid in the stomach to float and work efficiently. However, this can be overcome by admin- istrating the dosage form with fluids (200-250 ml) and with frequent meals ( Taranalli et al. 2015).

26. Swelling systems: Absorb water and expand to increase gastric volume

27. Mucoadhesive systems: Adhere to the gastric mucosa through adhesive properties

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29. THEORIES OF BIOADHESION Electronic Theory This theory suggests that the formation of a double layer of electrical charge at the interface between the bioadhesive and the biological tissue is responsible for adhesion. The interaction of these charges can create a strong bond.  

30. THEORIES OF BIOADHESION Adsorption Theory This theory posits that bioadhesion is primarily due to intermolecular forces, such as van der Waals forces, hydrogen bonding, and electrostatic attractions. These forces act between the molecules of the bioadhesive and the biological tissue

31. THEORIES OF BIOADHESION Wetting Theory According to this theory, the ability of the bioadhesive to spread and wet the biological tissue surface is crucial for adhesion. A good wetting contact ensures that the bioadhesive molecules can interact closely with the tissue

32. THEORIES OF BIOADHESION Diffusion Theory This theory suggests that the bioadhesive molecules diffuse into the tissue, creating interpenetration and entanglement with the tissue components. This interpenetration can lead to strong adhesive bonds.

33. THEORIES OF BIOADHESION Fracture Theory This theory focuses on the mechanical properties of the bioadhesive and the tissue. It proposes that the strength of the adhesive bond depends on the energy required to fracture the bond.

34. THEORIES OF BIOADHESION Additional Considerations Mechanical Interlocking : In some cases, the bioadhesive may physically penetrate into the pores or irregularities of the tissue, creating a mechanical interlocking effect. Dehydration Theory : This theory suggests that the bioadhesive may cause dehydration of the tissue surface, leading to closer contact between the bioadhesive and the tissue.  

35. THEORIES OF BIOADHESION Additional Considerations ADVANTAGES Stability : Bioadhesive dosage forms tend to increase stability of certain drugs by localizing the drug to an optimal site of its maximal stability. Also, these systems by disallowing a proper contact of drug with food components may protect the former from attack by the latter

36. THEORIES OF BIOADHESION Additional Considerations ADVANTAGES Improved Bioavailability : Also, the bioadhesive systems have been successfully employed to improve the consistency of the drugs like atenolol by regulating their drug absorption and reducing fluctuation of their plasma levels

37. THEORIES OF BIOADHESION Additional Considerations ADVANTAGES Peptide Delivery : The susceptibility of the peptides to the diverse pH ranges is known to challenge their efficacy. The GR systems have been attempted in case of melatonin to effectively deliver them via an oral route

38. THEORIES OF BIOADHESION Additional Considerations ADVANTAGES Mucosal Protection : Bioadhesive dosage forms could protect the GI mucosa from ulceration caused by NSAIDs

39. Disadvantages of Bioadhesives Ion-/pH- Sentivity Polyanionics as polyacrylic acid are highly sensitive to the ionic environment. Thus, the use of polyacrylates in an ion-rich environment may interfere with the adhesive properties of the polymer. Sufficient adhesiveness may be obtained at a specific pH range only. Rheological properties of Carbopol 934 samples were found to be substantially influenced by the environmental pH.

40. Disadvantages of Bioadhesives High Viscosity Due to the high viscosity of the polymers, these systems could impede the delivery of the drug to the absorbing surface

41. Disadvantages of Bioadhesives Loss of Mucoadhesive Activity An increased wetting of the polymer may lead to the formation of nonadhesive , slippery mucilage that may cause loss of mucoadhesive activity. Due to this, bioadhesive system may move past the absorption site. Besides, mucoadhesion during the GI transit of the DDS will be limited by a relatively

42. Characterization of Gastroretentive Dosage Forms Challenges Faced/Anticipated in Characterization of Gastroretentive Dosage Forms The performance of the GR formulation is highly dependent on the physiological conditions of the stomach. A number of factors affect the gastric retention of the dosage form and hence the prediction of drug release pro- file is difficult. The high variability of gastric emptying time poses major challenge in determining the GR behavior of formulations. For instance, the presence of food that extends the GRT is represented by a higher gastric emptying time in the fed condition as compared to the fasting condition. The in- vitro-in-vivo correlation (IVIVC) often becomes difficult as the formulation

43. Characterization of Gastroretentive Dosage Forms In-Vitro Characterization and Gastroretention Study Effective in-vitro characterization plays a crucial role in ensuring the quality and predicting the clinical utility of the developed formulations. In addition to routine evaluation parameters for final dosage form, like hardness, friability, general appearance, assay, uniformity of content, and weight variation for tablets, the following methods have also been reported to evaluate peculiar formulation characteristics accountable for gastric retention.

44. Characterization of Gastroretentive Dosage Forms In-Vitro Characterization and Gastroretention Study The study is performed in USP dissolution apparatus containing 900 mL of deionized water, 0.1N hydrochloric acid or more preferably simulated gastric fluid (SGF) as the dissolution medium at a temperature of 37 ± 0.5°C, with or without stirring. For tablet dosage forms, the time required by tablet to start floating (floating lag time) and the total duration for which the tablet remains floating (floating time) are often measured. For floating mic- roparticulate drug delivery systems, the carrier is dispersed in continuously stirred testing medium for target duration. Subsequently, the floating as well as settled fraction of these carriers are separated and their dry weights (WF and Ws , respectively) are measured to calculate percent buoyancy as a measure of gastric retention Percentage Buoyancy = WF + WS × 100

45. Characterization of Gastroretentive Dosage Forms Mucoadhesion Study The mucoadhesive property of gastroretentive formulations is evaluated by measuring the strength, with which the formulation attaches to mucus lining of biological tissue samples and measuring the force required to detach the formulation as a measure of mucoadhesive strength. A universal tensile tester is often utilized to sensitively measure the detachment force for tablets while modified dynamic contact angle analyser or microtensiometer is utilized for individual microparticles Alternatively, an in-vitro wash-off test is also performed for multiparticulate systems, where the tissue is mounted on a glass slide, a predefined number of particles are allowed to attach to moistened tissue and their mucoadhesive strength is challenged by

46. Characterization of Gastroretentive Dosage Forms In-Vitro Drug Release The paddle or basket type dissolution test apparatus is commonly utilized for in-vitro drug release Study using 0.1N HCI, FaSGF (SGF fasted condition) or FeSGF (SGF fed condition) as a release medium at 37 ± 0.5° C. FaSGF contains pepsin, sodium taurocholate, and lecithin at pH around 1.5, while FeSGF contains milk or buffer at pH 5, in combination to other ingredients of FaSGF .

47. Characterization of Gastroretentive Dosage Forms Swelling Index The immersion method is used to study the swelling behavior of a GR systems. The method involves immersion of formulation in SGF at 37°C and the change in dimension, volume, or weight is measured at predetermined time points as a measure of swelling. The percent swelling is calculated by, where M o and. M₁ are the measurements recorded initially and at time t, respectively: Percent swelling =[(M 1 -Mo)/Mo] × 100

48. Characterization of Gastroretentive Dosage Forms Density of the Dosage Form The density of formulation is calculated as mass to volume ratio. For instance, the density of a capsule shaped tablet is calculated by putting weight (M), radius (r) and side length (a) of the tablet, Density = M/[(4/3)πr²( r+a )]

49. DRUG RELEASE KINETIC MODELING

50. Dissolution controlled drug delivery systems A drug with a slow dissolution rate is inherently sustained and for those drugs with high water solubility, we can decrease dissolution through appropriate salt or derivative formation. The rate limiting step for dissolution of drug is the diffusion across the aqueous boundary layer. The solubility of the drug provides the source of energy for drug release which is countered by the stagnant fluid layer. The dissolution process at steady state would be described by Noyes-Whitney equation, dc/dt = K(Cs - Cb ) Where, dc/dt = Dissolution rate. K= Dissolution rate constant. Cs = concentration of solution at solid surface Cb = The concentration of drug in bulk of the solution

51. Dissolution and diffusion controlled drug release system Drug encased in a partially soluble membrane (Ethyl cellulose & PVP mixture) Pores are created due to dissolution of soluble parts of membrane. It permits entry of aqueous medium into core & drug dissolution take place. Diffusion of dissolved drug out of system. Example-mixture of ethyl cellulose and PVP they get dissolve in water and create pores of insoluble ethyl cellulose membrane

52. Mathematical modelling The mathematical modeling of drug delivery has a significant potential to facilitate product development and help to understand release behavior of complex pharmaceutical dosage forms. The models are based on the main factors which affect the drug release such as the particle size distribution, the physical state and the concentration profile of the drug inside the polymeric particles, the viscoelastic properties of the polymer–penetrant system and the dissolution–diffusion properties of the loaded drug. Any one particular theory cannot be made applicable to any drug delivery system as the systems may also involve combination of models.

53. Factors affecting the drug release kinetics Drug related factors Drug solubility Dose or drug content molecular weight and size particle size and shape diffusion in polymer and media Formulation variables Formulation geometry (size & shape) formulation excipients additives quantities and their roles Polymer related factors An increase in polymer proportion increases the viscosity of the gel and, thereby, increases the diffusional path length. Hence diffusion coefficient decreases and rate of drug release falls .

54. Zero order release kinetics It refers to the process of constant drug release from a drug delivery device independent of the concentration. Zero order release can be represented as Q = Q₀ + K₀t Where Q is the amount of drug released or dissolved Q₀ is the initial amount of drug in solution, K₀ is the zero order release constant. Graphical representation of fraction of drug dissolved verses time will be linear. The slope of the curve gives the value of K in zero order release kinetics

55. Zero order release kinetics is mainly expressed by

56. First order release kinetics The first order equation describes the release from system where release rate is concentration dependent, it is expressed by the equation: Dc / dt = - kt Where K is first order rate constant. This equation can be expressed as: Log c’= log c₀ – k t / 2.303 Where, c₀ is the initial concentration of drug and c’ is the concentration of drug in solution at time t. The equation predicts a first order dependence on the concentration gradient (co – c’) between the static liquid layer next to the solid surface and the bulk liquid.

57. The plot made: log cumulative of % drug remaining vs time which would yield a straight line with a slope of –K/2.303. The dosage forms containing water soluble drug in porous matrices follows this profile.

58. Higuchi Model The first example of a mathematical model aimed to describe drug release from a matrix system was proposed by Higuchi in 1963. This model is applicable to study the release of water soluble and low soluble drugs incorporated in semisolid and solid matrices, transdermal patches or films for oral controlled drug delivery Model expression is given by the equation: Q= [ d. Ε / τ . (2a- ε c s ) c s t ] 1/2 Where Q is the amount of drug released in time t per unit area A Ε is the porosity of matrix, Τ is the capillary tortuosity factor C is the initial amount of drug contained in the dosage form Cs is the solubility of active agent in the matrix medium D is the diffusion coefficient in the matrix medium

59. Simplified higuchi model describes the release of drugs from insoluble matrix as a square root of time dependent process Q= k h t 1/2 The data obtained were plotted as cumulative percentage drug release versus square root of time. The slope of the plot gives the higuchi dissolution constant K H

60. Hixson Crowell cube root law It was first proposed as a means of representing dissolution rate that is normalized for the decrease in solid surface area as a function of time. It describes the release from systems where there is a change in surface area and diameter of particles or tablets. Provided there is no change in shape. As a suspended solid dissolves, its surface decreases as the two-thirds power of its weight The cube root law can be written as : Q o 1/3 - q t 1/3 = k hc t Where, qt denotes the remaining weight of solid at time t Qo is the initial weight of solid at time t = 0, K HC represents the dissolution rate constant

61. The graphical plot of the cubic root of the unreleased fraction of the drug verses time should yield a straight line. This model is used by assuming that release rate is limited by the drug particles dissolution rate and not by the diffusion. The assumptions made for the validity of the law by hixson and crowell can be summarized as follows: The law is claimed to be more suitable for monodispersed systems. The dissolution takes place normal to the surface. The difference in rates at different crystal faces is considerably less and the effect of agitation of the liquid against all parts of the surface remains same. The liquid is agitated intensely to prevent stagnation in the nearest places of the dissolving particle thus resulting in a slow rate of diffusion.

62. Peppas Model (Power Law) Ritger and peppas , korsmeyer and peppas developed an empirical equation to analyze both fickian and non- fickian release of drug from swelling as well as non swelling polymeric delivery systems. M t /M α = Kt n Also can be written as: Log[ M t /M α ] =Log[K] + nLog[t] where Mt/M∝ is fraction of drug released at time t n is diffusion exponent indicative of the mechanism of transport of drug through the polymer K is kinetic constant incorporating structural and geometric characteristics of the delivery system. The power law model is useful for the study of drug release from polymeric systems when the release mechanism is not known or when more than one type of phenomenon of drug release is involved. .

63. The “n” value is used to characterize different release mechanisms. Peppas and Sahlin developed a release kinetics model and the equation is applicable to swellable systems. M t /M α = Kt m + Kt 2m Considering the right side of the equation, the first term represents the Fickian diffusional contribution, F, whereas the second term represents the Case II relaxational contribution, R.

64. BIOAVAILABILITY OR BIOEQUIVALENCE STUDIES the european agency provides biowaivers for the immediate release formu - lation of highly water-soluble drug releasing more than 85% drug within first 15 min, where gastroretentive dosage forms (GRDFS) don't fit due to controlled or sustained drug release. USFDA maintains the database of the biowaiver reports on approved federally compliant products that are used to prepare bioequivalence procedures as biowaivers; generating the relationship between the in-vitro and in-vivo data as IVIVC. This might aid in surmounting the problems associated with the biowaiver principles. In particular, a Level A correlation suits the best for extended release systems like GRDF, as it involves point to point comparison of dissolution data directly with plasma drug concentration-time profile to provide better prediction of in-vivo performance.

65. In-vivo Pharmacokinetics The GI tract demonstrates varying absorption characteristics based on its region-specific differences in physiology and anatomy. Thus, drug delivery to different regions of the gl tract significantly impacts the corresponding pharmacokinetic profiles As discussed earlier, the GRDF approach aims at providing continuous delivery of drugs to the upper part of the GL tract via overcoming the natural gastric activities responsible for evacuation of its content into the intestine The major approaches utilized so far for GRDF includes low-density systems that float in gastric fluid, high-density systems that sink

66. Magnetic systems: Utilize magnetic properties to be retained in the stomach

67. Bioadhesive systems: Adhere to biological tissues through specific interactions

68. Combination approaches: Utilize multiple mechanisms for enhanced gastroretention

69. Design and Development of GRDDS Formulation considerations: Drug solubility and release rate Excipient selection GRDDS design and fabrication

70. Materials and excipients: Polymers (e.g., chitosan, alginate) Floatable materials (e.g., microbubbles, hollow spheres) Mucoadhesive agents (e.g., carbomer, hyaluronic acid) Magnetic particles (e.g., magnetite)

71. Fabrication technique Hot melt extrusion Spray drying 3D printing

72. Evaluation of GRDDS In vitro evaluation: Dissolution studies Swelling studies Mucoadhesion studies Floating studies

73. in vivo evaluation: Animal models (e.g., rats, dogs) Human studies

74. Marketed GRDDS and Applications Examples of commercially available GRDDS: [Product names and descriptions] Therapeutic applications: Gastrointestinal disorders Antibiotic therapy Hormone replacement therapy

75. Evaluation of Gastroretention Using Imaging Techniques X-ray imaging: Principles and techniques Applications in GRDDS evaluation [X-ray images of GRDDS in the stomach]

76. Evaluation of Gastroretention Using Imaging Techniques Positron emission tomography (PET): Principles and techniques Applications in GRDDS evaluation [PET images of GRDDS in the stomach]

77. POLYMERS FOR GASTRORETENTIVE SYSTEMS Hydrocolloids hydrocolloids are gel-forming agent, which swells in contact with gastric fluid and maintains a relative integrity of shape and bulk density less than the gastric content e.G. , Acacia, pectin, agar, alginates, gelatin , casein, bentonite, veegum , methylcellulose (MC), HPMC, ethylcellulose (EC), HPC, hydroxyethyl cellulose, and carboxy methylcellulose sodium ( na CMC).

78. Inert fatty materials Edible, pharmaceutical inert fatty material, having a specific gravity

79. Release rate accelerants The release rate of the medicament from the formulation can be modified by including excipient like lactose and/or mannitol. These may be present from about 5% to 60% by weight. E.g., lactose, mannitol, etc.

80. Release rate retardants Insoluble substances such as calcium phosphate, talc, and magnesium stearate decreased the solubility and hence, retard the release of medicaments. E.g., dicalcium phosphate, talc, magnesium stearate, etc.

81. Buoyancy increasing agents Materials like EC, which has bulk density

82. Effervescent agents These are the agents which generate carbon dioxide after reacting with gastric acidic medium. E.g., sodium bicarbonate, citric acid, tartaric acid, di-sodium glycine carbonate, citroglycine , etc.[15,16]

83. On the basis of origin 1. Natural polymers like, chitosan, sodium alginate, etc. 2. Semi-synthetic polymers like, EC, HPMC, etc. 3. Synthetic polymers like, acrylic acid derivatives, lactic acid derivatives, etc.

84. CHITOSAN Chitosan (obtained by alkaline deacetylation of chitin) is a swellable, natural linear biopolyaminosaccharide . Chitin is a straight homopolymer composed of -(1,4)-linked N-acetyl-glucosamine units, while chitosan comprises of copolymers of glucosamine and N-acetyl-glucosamine. The emulsion cross-linking and the ionotropic gelation are most preferred and widely used methods for the preparation of floating microspheres. In both methods, cross-linking is required due to its ionic nature. Different grades of chitosan are available on the basis of their degree of deacetylation and molecular weight, and their solubility can also vary between slightly acidic medium to the aqueous medium.[17

85. SODIUM ALGINATE Alginate is a polysaccharide that is abundant in nature, as it is synthesized by brown seaweeds and soil bacteria.[40] It is widely employed in the food processing industry, often as a thickener or emulsifion stabilizer and in the pharmaceutical industry since it is the first byproduct of algal purification.[41,42] Sodium alginate consists of α-l-guluronic acid residues (G blocks) and β-d-mannuronic acid residues (M blocks), as well as segments of alternating guluronic and mannuronic acids (GM blocks). The guluronate residue blocks allow alginate fibres to form gels by binding Ca2+ ions and stomach H+ ions, which cross-link the fibers into a viscous polymer matrix.[43]

86. CALCIUM PECTINATE Pectin is an inexpensive, nontoxic polysaccharide extracted from citrus peels or apple pomaces, and has been used as a food additive, a thickening agent and a gelling agent. It also has bioadhesive properties toward other gastrointestinal tissues, which can be used as a drug delivery device on a specific site for targeted release and optimal drug delivery due to intimacy and duration of contact. Pectin has a very complex structure, which depends on both its source and the extraction process. Numerous studies contributed to elucidate the structure of pectin. Basically, it is a polymer of a-D-galacturonic acid with 1-4 linkages

87. GUAR GUM Guar gum is a natural nonionic polysaccharide derived from the seeds of Cyamopsis tetragonolobus (family Leguminosae). In pharmaceuticals, guar gum is used in solid dosage forms as a binder, disintegrant, and as a polymer in the floating drug delivery system.[80,81] Guar gum mainly consisting of polysaccharides of high molecular weight (50,000-8,000,000) composed of galactomannans, mannose: Galactose ratio is about 2:1. It consists of linear chains of (1-4)-b-D- mannopyranosyl units with a-D- galactopyranosyl units attached by (1-6) linkages

88. XANTHAN GUM Xanthan (a well-known biopolymer) is an extracellular heteropolysaccharide produced from bacterium Xanthomonascampestris which is a natural, biosynthetic, edible gum, and an extracellular anionic polysaccharide. Xanthan gum consists of glucose, mannose, and glucuronic acid, and is used in different foods as thickener and stabilizer.[88] Xanthan is a long-chained polysaccharide with a large number of trisaccharide side chains (composed of two mannose units and one glucuronic acid unit) and consists of a b-(1, 4)-D-glucose backbone. This gum develops a weak structure in water, which creates high-viscosity solutions at low concentration. Viscosity remains fairly constant from 0°C to 100°C

89. There are various excipients such as surfactants (sodium lauryl sulfate , poly vinyl alcohol, arlacel-60, tweens, spans etc.), gas generating agents (sodium bicarbonate, calcium carbonate), and pore forming agents (citric acid, silicates) are used in the formulation of floating drug delivery system.