Floating In Situ Gels for Gastroretentive Drug Delivery Systems (GRDDS): Advances, Mechanisms, and Therapeutic Potential (2024)

Abstract

Administering medications orally to target specific areas of the gastrointestinal tract can be challenging due to low effectiveness with traditional forms of medication, which is caused by incomplete drug release and a short amount of time for the drug to be absorbed. To address this issue and increase the oral uptake of these medications, new methods for delivering drugs have been created. Gastroretentive systems like floating systems, mucoadhesive, high-density, expandable, have been created to offer controlled drug delivery with extended time in the stomach. Liquid oral medications are more likely to have low bioavailability in stomach-specific drug delivery compared to other oral forms, because they pass through the stomach and duodenum more quickly. To create a long-lasting release version of a liquid medication, a liquid in-situ floating gel system could significantly improve the oral formulation. Gel formation relies on factors such as temperature changes, pH adjustments, the existence of ions, and exposure to ultraviolet light, leading to the gradual and regulated release of the drug. This detailed article includes methods, substances, products on the market, patents, natural methods, and recent developments of in situ gel.

Keywords

In situ gel, floating, gastroretentive.

Introduction

Polymeric formulations that form gel in thebodyare drug deliverysystems that are in solution or liquid form before being introduced into the body, once given undergoes gelation in place to create a gel. In-place gel Forming systems have been extensively studied as meansof long-term drug release.^[1] The new and innovative method of drug delivery. It involves a Floating Drug Delivery System (FDDS), which can provide sustained release of medication. The latest trend in FDDS. In-situ gelling systems can be used in various ways of giving medicine, such as through the mouth, nose, eye, by mouth, through the rectum, through the vagina, and also through injection. Benefits of in situ forming polymeric drug delivery systems include easy administration, higher local bioavailability, and decreased dosage. Frequency, enhanced patient adherence, and simpler production process make it cost-effective. Gastroretentive floating drug delivery systems have a lower density than stomach fluid, which allows them to float in the stomach without impacting the rate at which the stomach empties for an extended period. When the gel that has formed floats on the stomach Release the drug slowly at the desired rate from the gel that floats in fluid. A gel is a soft, steady, or firm substance that includes at least two parts, with one being a liquid in large amount.

Figure no.1 : Classification of GRDDS

Floating Drug Delivery

In situ formation based on physiological stimuli :

Thermally triggered system :

Temperature-sensitive hydrogels represent one of the most extensively studied categories of environment-sensitive polymer systems in drug delivery research. Utilizing a biomaterial that transitions from a sol to a gel state in response to an increase in temperature offers an appealing approach for in-situ formation. ^[9]The ideal critical temperature range for such a system is near ambient and physiological temperatures, allowing for easier clinical handling without the need for an external heat source, as body heat alone can trigger gelation. A well-designed system should be adaptable to slight variations in local temperature, such as those that may occur on skin surfaces, appendages, or within the oral cavity. ^[10]

pH triggered systems :

Another type of in situ gel formation based on physiological stimuli occurs when gelation is triggered by pH changes. pH-sensitive polymers contain acidic or basic groups that either accept or release protons as the environmental pH changes. Polymers with a high number of ionizable groups are referred to as polyelectrolytes. In hydrogels with weakly acidic (anionic) groups, swelling increases as the external pH rises, while swelling decreases for polymers with weakly basic (cationic) groups. ^[11]

Most anionic pH-sensitive polymers are typically derived from poly(acrylic acid) (PAA), such as Carbopol® or carbomer. Similarly, poly(vinyl acetal diethyl amino acetate) (AEA) solutions exhibit low viscosity at pH 4 and form hydrogels at neutral pH. Liquid formulations of drugs often face challenges such as limited bioavailability and rapid removal. To enhance drug delivery, a PAA solution that gels at pH 7.4 was developed. However, at high concentrations necessary for gelation, the acidic nature of PAA solutions could potentially damage the eye surface before being neutralized by tear fluid. This issue was partially addressed by combining PAA with hydroxypropyl methylcellulose (HPMC), a viscosity-enhancing polymer, resulting in pH-responsive mixtures that remain in solution at pH 4 and form a gel at pH 7.4. Mixtures of poly(methacrylic acid) (PMA) and poly(ethylene glycol) (PEG) have also been utilized as pH-sensitive systems to achieve gelation. ^[12]

In situ formation based on physical mechanism

Ion crosslinking :

Specific ion-responsive polysaccharides like Carrageen, Gellan gum (Gelrite®), Pectin, Sodium Alginate as Na⁺ and Cl^-, water undergoes phase transition from liquid to solid at 0 degrees Celsius ion exchange. When marine algae are treated with an acid, they release alginic acid. This acid can then undergo ion exchange to produce sodium alginate, which is used in various industrial and food applications. As K⁺, Ca⁺², Mg⁺², Na^+[14] For example, alginic acid goes through ion exchange. When ocean seaweed are exposed to an acid, they let go of alginic acid. This acid can then undergo ion exchange to create sodium alginate, which is utilized in different industrial and food uses solidification in the presence of two or more cations such as divalent/polyvalent ions. Calcium ion as a result of the interaction with guluronic acid block in alginate links or bindings.^[15]

Swelling and Diffusion:

Swelling of polymer due to water absorption leads to gel formation. specific eco-friendly fat material For example, myverol (glycerol mono-oleate) creates a gel in place. during such occurrence.[6] Polymer solution like N –Methyl pyrrolidone (NMP) includes the spread of a cleaning agent from polymer solution into the tissue around it and outcomes during the process of rain or when a liquid turns into a solid in a polymer material^.[17]

Enzymatic crosslinking:

Some natural enzymes that work effectively under normal circumstances without the necessity for potentially toxic substances like monomers and catalysts offers a convenient method for managing the pace of gel creation, which permits the blends to be inserted prior to the creation of gel in the location^.[18]

Photo-polymerisation :

An acrylate or other monomer solution polymerizable functional groups and a catalyst like 2,2 sensitizer is then activated by exposure to visible light. This process is known as photopolymerization and is commonly used in dentistry for curing dental materials such as composites and dental adhesives. This technique allows for quick and efficient curing of materials when a dental curing light is used to activate the sensitizer^.[20]

pH dependant gelling:

Another type of in situ gel is created by altering in acidity level Some types of polymers like PAA (Carbopol®) Carbomer or its related compounds, Polyvinylacetal, diethylaminoacetate (AEA), Mixtures of poly (methacrylic acid) (PMA) and poly (ethylene glycol) (PEG)24 change from a liquid to a solid with a change in pH.^[22] The hydrogel grows bigger when the outside pH goes up with weakly acidic (anionic) groups, but gets smaller if the polymer has weakly basic (cationic) groups_.^[21]

Temperature-Induced Gelation :

Certain polymers undergo gelation at physiological temperatures (around 37°C). When the solution is administered, the increase in temperature triggers polymer-polymer interactions, leading to gel formation. Polymers are Pluronic F-127, chitosan, methylcellulose, and applications are often used for injectable drug delivery and for thermosensitive formulations in ocular and nasal routes.^[27]

Enzyme-Responsive Gelation :

Gelation is triggered by enzymes present in the target area that break down specific groups within the polymer, leading to gel formation. This allows for highly localized gelation. Polymers used are hyaluronic acid derivatives or peptide-based polymers responsive to specific enzymatic cleavage, and applications are effective for site-specific delivery, especially in targeted cancer therapy. ^[28]

Polymers Used In This Study

Sodium alginate:

Sodium alginate is a natural polymer of sodium and alginic acid. It is commonly used in various industries such as food, pharmaceuticals, and textile printing due to its thickening, gelling, and emulsifying properties. In the food industry, sodium alginate is used as a thickener and stabilizer in products like ice cream, yogurt, and salad dressing. In pharmaceuticals, it is used as a gelling agent in the formulation of tablets and capsules. In textile printing, sodium alginate is used to thicken the dye and prevent it from spreading beyond the intended area of ?–D-mannuronic acid and ?-L-glucuronic acid molecules connected by 1,4-glycosidic bonds. the mixture of alginates in Water can create solid gels when di- or trivalent ions are present, for example, magnesium and calcium ions. a chemical compound primarily derived from brown seaweed or algae. primarily used for creating gel-based formulations Answer, for transport of the medications, peptides and proteins. Alginate salts are viewed as the best option because of The product is environmentally friendly and safe, with extra features adhesive quality. ^[29] This shows that the alginate secrete dense formations when the ionic radical of the concentration of ions is reduced the level of ions decreases. Sodium alginate used pharmaceutically as a water-soluble substance so helpful in long-lasting liquid medications for mouth use management, function as a stabilizing substance; thickening agent.

Gellan gum :

Gellan gum is a water-soluble negative-charged complex sugar commonly called Phytagel or Gelrite in commercial terms can be used as a gelling agent in food products approved by the FDA, produced by the Sphingomonas elodea (Pseudomonas elodea) and chemically has a negative charge. Polysaccharide with tetrasaccharide repeated and deacetylated. Units consist of beta-D-glucuronic acid (1 unit), alpha-L-rhamnose (1 unit), and beta-D-glucose (2 units) residues. Gellan gum forms a gel when there is a change in Temperature or because of the existence of cations (for example, Na+Potassium, Calcium, and Magnesium ions (K⁺, Ca2⁺, and Mg2⁺). Gellan gum can be used water-soluble polymer with pharmaceutical properties. Possible vehicle for various long-lasting oral floatation forms for delivering doses. ^[30]

Carbopol :

Carbopol is a polymer that depends on pH and creates a gel. The gel has high thickness at basic pH but remains in liquid form at acidic level of pH. ^[31]create a gel structure for pharmaceutical and personal care products. HPMC is combined with Carbopol to form a gel structure used in pharmaceutical and personal care items, Add the thickness to Carbopol solution while decreasing the sourness of the liquid. Different Aqua triblock Copolymers alter their solubility as they change ambient temperature.

Xanthan gum :

Xanthan gum has a large molecular weight and is produced outside of cells. Polysaccharide made by xanthomonas campestris. ^[32] It is essentially important to maintain a balanced diet in order to stay healthy and prevent illness. Eating a variety of fruits, vegetables, whole grains, and lean proteins can help support overall health and wellbeing. In addition, drinking plenty of water and limiting the consumption of processed foods and added sugars can contribute to a healthy lifestyle. Regular exercise is also crucial for maintaining a healthy body and mind. Finding a balance between healthy eating and physical activity is essential for optimal health a lengthy polymer of sugar with a high quantity of triple sugar side chains. ^[33]

Chitosan :

Chitosan is a natural and flexible positively charged polymer achieved through alkaline deacetylation of chitin, Chitosan is a cationic polymer that is pH dependent and biocompatible stays dissolved in water solutions with a pH of 6.2 or lower. Neutralizing a chitosan water solution to a certain pH Exceeding 6.2 causes the creation of a gel-like substance that has absorbed water cause something to happen suddenly increase the likelihood of something happening suddenly, cationic polysaccharides that gel can affect pH level of solutions change with heat dependent gel-forming water-based solutions by adding Polyol salts, with no chemical alteration. ^[34]

Characterization Of In Situ Gel

Ph:

In this study, the pH was measured using a digital pH meter. The prepared in situ gel formulation was placed in a 100 mL beaker, and the digital pH meter was immersed into the beaker containing the formulation to determine the pH value. ^[35]

Viscosity :

Brook Field The synthesized formulations' viscosities were measured using a viscometer. 50 milliliters of the sample were measured and transferred to Nessler's cylinder and sheared using spindle number 63 at room temperature at speeds of 50 and 60 rpm. The viscosity of each sample was measured three times. ^[36]

Sol to gel :

Using a USP (Type II) dissolution device with 500 mL of 0.1N HCl (pH 1.2) at 37±0.5°C, the in vitro gelation time was calculated. When the formulation came into contact with 0.1N HCl and time was recorded, it changed from sol to gel. Gelling time is the amount of time needed for the in-situ gelling system's first gelation. The gel was seen to float on the buffer solution in a matter of seconds. ^[37]

Floating lag time (buoyant time):

The amount of time it takes for the gel to rise from the bottom of The floating lag time (buoyant time) is the definition of the dissolution flask. Visual examination was used to determine the floating lag time of gel in a USP type II dissolution test device with 500 cc of 0.1 N HCl (pH 1.2) at 37±0.5°C.

Floating duration :

Floating duration is the amount of time it takes for the gel to develop and float on the dissolving medium's surface. Visual inspection using a dissolution test device USP (Type II) with 500 mL of 0.1N HCl (pH 1.2) at 37±0.5°C allowed for the determination of the gels' floating time. ^[39]

Gel strength :

The gel is made from the sol form in a beaker. Pushing a rheometer probe gently into the gel is necessary because the beaker containing the gel rises at a specific rate. Changes in the load on the probe as a function of the probe's depth of immersion beneath the gel surface can be used to measure it. ^[40]

Fourier transform infra-red spectroscopy and thermal analysis :

Conduct infrared spectroscopy using the Fourier transform technique. Investigate the interaction between drugs and excipients.^[41] Differential scanning calorimetry is utilized for the purpose of determining if there have been no alterations in the optimized formulation, in comparison to the use of completely natural ingredients, suggesting the communications.

In-vitro drug release studies:

An in vitro dissolution study was performed to evaluate the release kinetics of the drug. The study utilized USP Type II dissolution testing equipment with a paddle apparatus, set to rotate at 50 RPM. A disintegration medium of 900 ml at pH 1.2 was prepared using 0.1N HCl, and the temperature was maintained consistently at 37 ± 0.2°C. At various time intervals, 1 ml samples of the dissolution medium were taken and replaced with fresh medium to maintain the volume. The drug concentration in these samples was then measured using a spectrophotometer for analysis. ^[42]

Stability Study :

The storage condition for room temperature was maintained at 25 ± 5°C with 65% relative humidity (RH), while accelerated stability studies were conducted at 40 ± 2°C with 75 ± 5% RH. The stability assessment was carried out over a period of 30 days.^[43]

CONCLUSION

Floating in situ gels have emerged as an innovative drug delivery system, providing prolonged and controlled drug release with increased gastric retention. By transforming into a gel upon contact with gastric fluids, they enable localized drug action, reduce dosing frequency, and improve patient compliance. Their floating properties ensure that the gel remains buoyant for extended periods, enhancing bioavailability by maintaining therapeutic levels of the drug at the desired site. Overall, floating in situ gels offer promising potential for improving the effectiveness and efficiency of various medications, especially for drugs requiring sustained release or targeted delivery in the stomach.

REFERENCES.

1. Miyazaki S., Hirotatsu A., Kawasaki N., Wataru K. and Attwood D. (1999). In situ gelling gellan formulations as vehicles for oral drug delivery. J. Control Rel., 60:287–295.
2. B. Padmasri, R. Nagarju, D. Prasanth. a comprehensive review on in situ gels: Int J App Pharm, Vol 12,2020: pp.24-25.
3. Nilesh P. Salunkhe et.al., Oral in-situ floating gelling system:Review on.World. J. Pharm.Pharma. Sci. 2019,8[4],478-496
4. Bhardwaj T.R., Kanwar M., Lal R. and Gupta A. Natural gums and modified natural gums as sustained release carriers. Drug Devel. Ind. Pharm., 2000, 26:1025-1038.
5. Guo J., Skinner G., Harcum W. and Barnum P. Pharmaceutical applications of naturally occurring water soluble polymers. Pharm Sci. & Technol. Today, 1998, 1:254-261
6. Esposito E. and Carratto V. Comparative analysis of tetracycline containing dental gels; poloxomers and monoglycerides based formulation. Int. J. Pharm, 1996, 142:9-23.
7. Geraghaty P. and Attwood D. An investigation of parameters influencing the bioadhesive properties of myverol 18-99/ water gels. Biomaterials, 1997, 18:63-70
8. Podual K. and Peppas N.A. Dynamic behavior of glucose oxidase-containing microparticles of poly(ethylene)- grafted cationic hydrogels in an environment of changing pH. Biomaterials, 2000, 21:1439-1450.
9. Burkoth A. and Anseth K. A review of photocrosslinked polyanhydrides: In situ forming degradable networks. Biomaterials, 2000, 21:2395- 2404.
10. Soppimath K., Aminabhavi T., Dave A, Kumbar S. and Rudzinski W. Stimulus-responsive ?smart? hydrogels as novel drug delivery systems. Drug Dev. Ind. Pharm., 2002, 28: 957- 974.
11. Aikawa K., Mitsutake A., Uda H., Tanaka S., Shimamura H. and Aramaki Y. Drug release from pH-response polyvinylacetal diethyl aminoacetate hydrogel, and application to nasal delivery. Int. J. Pharm., 1998, 168:181- 189.
12. Whitehead L., Fell J. and Collett J. Development of a Gastroretentive Dosage Form. Eur. J. Pharm. Sci., 1996, 4:182-187.
13. Deshpande A., Shah N., Rhodes C. and Malick W. Development of a novel controlled release system for gastric retention. Pharm Res, 1997, 14: 815-824
14. Bhatt P, Khatri N, Kumar M, Baradia D, Misra A. Microbeads mediated oral plasmid DNA delivery using polymethacrylate vectors: an effectual groundwork for colorectal cancer. Drug delivery. 2015;22(6):849-61.
15. Bromberg LE, Ron ES. Temperature-responsive gels and thermogelling polymer matrices for protein and peptide delivery. Adv Drug Deliv Rev, 1998; 31:197-221.
16. Suryawanshi A, Hiremath SP. Floating Drug Delivery Systems - A Review. American Journal of PharmTech Research, 2012; 2:138-153.
17. Cappello J, Crissman JW, Crissman M, Ferrari FA,Textor G, Wallis O. In-situ self-assembling protein polymer gel systems for administration,delivery, and release of drugs. J Control Release, 1998; 3:105-17
18. Soppimath KS, Aminabhavi TM, Dave AM,Kumbar SG, Rudzinski WE. Stimulus-responsive“smart” hydrogels as novel drug delivery systems.Drug Dev Ind Pharm, 2002; 28:957-74.
19. Aikawa K, Mitsutake A, Uda H, Tanaka S,Shimamura H, Aramaki Y. Drug release from pH-response polyvinylacetal diethyl aminoacetate hydrogel, and application to nasal delivery. Int J Pharm, 1998; 168:181-188.
20. Kumar S, Himmelstein K. Modification of in-situ gel behaviour of Carbopol solutions by hydroxypropylmethylcellulose.J.Pharm.Sci, 1995; 84:344-8.
21. Alexandridis P,Lindman B,Amphiphilic block polymers. Amsterdam: Elsvier;2000.
22. Patel JK, Chavda JR, Modasiya MK. Floating in situ gel based on alginate as carrier for stomach-specific drug delivery of famotidine. International Journal of Pharmaceutical Sciences, 2010; 3(3):1092- 1104.
23. Esposito E, Carratto V. Comparative analysis of tetracycline containing dental gels, poloxomers and monoglycerides based formulation. Int. J. Pharm, 1996; 142:9-23.
24. Geraghaty P, Attwood D. An investigation of parameters influencing the Bioadhesive properties of Myverol water gels. Biomaterials, 1997; 18:63-7.
25. Motto F, Gailloud P. In-vitro assessment of new embolic liquids prepared from preformed polymers and water miscible solvents aneurysm treatment. Biomaterials, 2000.
26. Bhardwaj TR, Kanwar M, Lal R and Gupta A. Natural gums and modified natural gums as sustained release carriers. Drug Devel Ind Pharm, 2000; 26:10 25-38.
27. Guo J-H, Skinner GW, Harcum WW, Barnum PE. Pharmaceutical applications of naturally occurring water-soluble polymers. Pharm Sci & Technol Today, 1998; 1:254-61.
28. Schoenwala RD, Smlen VF. Drug absorption analysis from Pharmacological data: Transcorneal biophasic availability of Tropicamide. J Pharm Sci, 1971; 60:1039-1045
29. Durrani AM, Davies NM,Thomas M, Kellaway IW. Pilocarpine bioavailability from a mucoadhesive liposomal ophthalmic drug delivery System. International Journal of Pharmaceutics, 1992; 88:409.
30. Kumar S, Himmelstein K., Modification of in-situ gel behaviour of Carbopol solutions by hydroxypropylmethylcellulose, J. Pharm.Sci, 1995, 84, 344-8.
31. Nirmal HB, Bakliwal S, Pawar SP. In-Situ gel: New trends in Controlled and Sustained Drug Delivery System. Int J Pharm Tech Res 2010; 2: 1398-1408.
32. Dasharath MP, Divyesh KP, Chhagan NP. Formulation and evaluation of floating oral in-situ gelling. International Scholarly Research Network, 2011.
33. Harish NM, Prabhu P, Charluyu RN, Subramanyam EVS. Formulation and evaluation of in-situ gel containing Clotrimazole for oral candidiasis, J Pharm Sci 2012; 4: 1885- 1889.
34. Rahul N, Venkatakrishnakiran P, Dhanalakshmi P, Prasannaraju Y. Formulation and evaluation of in-situ gelling systems for ocular delivery of Doxycycline hyclate. Journal of Innovative Trends of Pharmaceutical Science 2012; 3: 1-7.
35. Sonjoy KMJ, Thimmasetty GL, Prabhu S, Geetha MS. Formulation and evaluation of an in-situ gel forming ophthalmic formulation of Moxiflaxin hydrochloride. Int J Pharma Investig 2012; 2: 2
36. El-sayed AI, Sayed I, Gihan F, Omar S, Khaled H, Noura HA.
37. Development and characterization of thermosensitive pluronic based Metronidazole in-situ gelling formulations for vaginal application. Acta Pharm 2012; 62: 59–70.
38. Wagh VD, Deshmukh KH, Wagh KV. Formulation and evaluation of in-situ gel drug delivery system of Sesbania grandiflora flower extract for the treatment of bacterial conjunctivitis. J Pharm Res 2012; 4: 1880-1884.
39. Kavitha K, Rajas NJ. Sustained ophthalmic delivery of Levofloxacin hemihydrate from an ion activated in-situ gelling system. Int J Pharm Tech Res 2011; 3: 702-706.
40. Ramesh CN, Rakesh K, Dhanawat M, Pandit JK. Modified PLA nano in-situ gel: A potential ophthalmic drug delivery system. Colloids and Surfaces B: Bointerfaces 2011; 86: 28–34.
41. Shi-Lei C, En C, Qi-Zhi Z, Xin-Guo J. A novel nasal delivery system of a chinese traditional medicine, Radix Bupleuri, based on the concept of ion-activated in-situ gel. Arch Pharm Res 2007; 30: 8.
42. Padma PJ, Karthika K, Rekha NR, Khalid E. Formulation and evaluation of in-situ ophthalmic gels of Diclofenac sodium. J Chem Pharm Res 2010; 2: 528-535.
43. Hitendra SM, Saurabh KS, Sanjay J, Surana J. Nasal in-situ gel containing hydroxy propyl ?-cyclodextrin inclusion complex of Artemether: Development and in-vitro evaluation. Incl Phenom Macrocycl Chem 2011; 70: 49

Reference

1. Miyazaki S., Hirotatsu A., Kawasaki N., Wataru K. and Attwood D. (1999). In situ gelling gellan formulations as vehicles for oral drug delivery. J. Control Rel., 60:287–295.
2. B. Padmasri, R. Nagarju, D. Prasanth. a comprehensive review on in situ gels: Int J App Pharm, Vol 12,2020: pp.24-25.
3. Nilesh P. Salunkhe et.al., Oral in-situ floating gelling system:Review on.World. J. Pharm.Pharma. Sci. 2019,8[4],478-496
4. Bhardwaj T.R., Kanwar M., Lal R. and Gupta A. Natural gums and modified natural gums as sustained release carriers. Drug Devel. Ind. Pharm., 2000, 26:1025-1038.
5. Guo J., Skinner G., Harcum W. and Barnum P. Pharmaceutical applications of naturally occurring water soluble polymers. Pharm Sci. & Technol. Today, 1998, 1:254-261
6. Esposito E. and Carratto V. Comparative analysis of tetracycline containing dental gels; poloxomers and monoglycerides based formulation. Int. J. Pharm, 1996, 142:9-23.
7. Geraghaty P. and Attwood D. An investigation of parameters influencing the bioadhesive properties of myverol 18-99/ water gels. Biomaterials, 1997, 18:63-70
8. Podual K. and Peppas N.A. Dynamic behavior of glucose oxidase-containing microparticles of poly(ethylene)- grafted cationic hydrogels in an environment of changing pH. Biomaterials, 2000, 21:1439-1450.
9. Burkoth A. and Anseth K. A review of photocrosslinked polyanhydrides: In situ forming degradable networks. Biomaterials, 2000, 21:2395- 2404.
10. Soppimath K., Aminabhavi T., Dave A, Kumbar S. and Rudzinski W. Stimulus-responsive ?smart? hydrogels as novel drug delivery systems. Drug Dev. Ind. Pharm., 2002, 28: 957- 974.
11. Aikawa K., Mitsutake A., Uda H., Tanaka S., Shimamura H. and Aramaki Y. Drug release from pH-response polyvinylacetal diethyl aminoacetate hydrogel, and application to nasal delivery. Int. J. Pharm., 1998, 168:181- 189.
12. Whitehead L., Fell J. and Collett J. Development of a Gastroretentive Dosage Form. Eur. J. Pharm. Sci., 1996, 4:182-187.
13. Deshpande A., Shah N., Rhodes C. and Malick W. Development of a novel controlled release system for gastric retention. Pharm Res, 1997, 14: 815-824
14. Bhatt P, Khatri N, Kumar M, Baradia D, Misra A. Microbeads mediated oral plasmid DNA delivery using polymethacrylate vectors: an effectual groundwork for colorectal cancer. Drug delivery. 2015;22(6):849-61.
15. Bromberg LE, Ron ES. Temperature-responsive gels and thermogelling polymer matrices for protein and peptide delivery. Adv Drug Deliv Rev, 1998; 31:197-221.
16. Suryawanshi A, Hiremath SP. Floating Drug Delivery Systems - A Review. American Journal of PharmTech Research, 2012; 2:138-153.
17. Cappello J, Crissman JW, Crissman M, Ferrari FA,Textor G, Wallis O. In-situ self-assembling protein polymer gel systems for administration,delivery, and release of drugs. J Control Release, 1998; 3:105-17
18. Soppimath KS, Aminabhavi TM, Dave AM,Kumbar SG, Rudzinski WE. Stimulus-responsive“smart” hydrogels as novel drug delivery systems.Drug Dev Ind Pharm, 2002; 28:957-74.
19. Aikawa K, Mitsutake A, Uda H, Tanaka S,Shimamura H, Aramaki Y. Drug release from pH-response polyvinylacetal diethyl aminoacetate hydrogel, and application to nasal delivery. Int J Pharm, 1998; 168:181-188.
20. Kumar S, Himmelstein K. Modification of in-situ gel behaviour of Carbopol solutions by hydroxypropylmethylcellulose.J.Pharm.Sci, 1995; 84:344-8.
21. Alexandridis P,Lindman B,Amphiphilic block polymers. Amsterdam: Elsvier;2000.
22. Patel JK, Chavda JR, Modasiya MK. Floating in situ gel based on alginate as carrier for stomach-specific drug delivery of famotidine. International Journal of Pharmaceutical Sciences, 2010; 3(3):1092- 1104.
23. Esposito E, Carratto V. Comparative analysis of tetracycline containing dental gels, poloxomers and monoglycerides based formulation. Int. J. Pharm, 1996; 142:9-23.
24. Geraghaty P, Attwood D. An investigation of parameters influencing the Bioadhesive properties of Myverol water gels. Biomaterials, 1997; 18:63-7.
25. Motto F, Gailloud P. In-vitro assessment of new embolic liquids prepared from preformed polymers and water miscible solvents aneurysm treatment. Biomaterials, 2000.
26. Bhardwaj TR, Kanwar M, Lal R and Gupta A. Natural gums and modified natural gums as sustained release carriers. Drug Devel Ind Pharm, 2000; 26:10 25-38.
27. Guo J-H, Skinner GW, Harcum WW, Barnum PE. Pharmaceutical applications of naturally occurring water-soluble polymers. Pharm Sci & Technol Today, 1998; 1:254-61.
28. Schoenwala RD, Smlen VF. Drug absorption analysis from Pharmacological data: Transcorneal biophasic availability of Tropicamide. J Pharm Sci, 1971; 60:1039-1045
29. Durrani AM, Davies NM,Thomas M, Kellaway IW. Pilocarpine bioavailability from a mucoadhesive liposomal ophthalmic drug delivery System. International Journal of Pharmaceutics, 1992; 88:409.
30. Kumar S, Himmelstein K., Modification of in-situ gel behaviour of Carbopol solutions by hydroxypropylmethylcellulose, J. Pharm.Sci, 1995, 84, 344-8.
31. Nirmal HB, Bakliwal S, Pawar SP. In-Situ gel: New trends in Controlled and Sustained Drug Delivery System. Int J Pharm Tech Res 2010; 2: 1398-1408.
32. Dasharath MP, Divyesh KP, Chhagan NP. Formulation and evaluation of floating oral in-situ gelling. International Scholarly Research Network, 2011.
33. Harish NM, Prabhu P, Charluyu RN, Subramanyam EVS. Formulation and evaluation of in-situ gel containing Clotrimazole for oral candidiasis, J Pharm Sci 2012; 4: 1885- 1889.
34. Rahul N, Venkatakrishnakiran P, Dhanalakshmi P, Prasannaraju Y. Formulation and evaluation of in-situ gelling systems for ocular delivery of Doxycycline hyclate. Journal of Innovative Trends of Pharmaceutical Science 2012; 3: 1-7.
35. Sonjoy KMJ, Thimmasetty GL, Prabhu S, Geetha MS. Formulation and evaluation of an in-situ gel forming ophthalmic formulation of Moxiflaxin hydrochloride. Int J Pharma Investig 2012; 2: 2
36. El-sayed AI, Sayed I, Gihan F, Omar S, Khaled H, Noura HA.
37. Development and characterization of thermosensitive pluronic based Metronidazole in-situ gelling formulations for vaginal application. Acta Pharm 2012; 62: 59–70.
38. Wagh VD, Deshmukh KH, Wagh KV. Formulation and evaluation of in-situ gel drug delivery system of Sesbania grandiflora flower extract for the treatment of bacterial conjunctivitis. J Pharm Res 2012; 4: 1880-1884.
39. Kavitha K, Rajas NJ. Sustained ophthalmic delivery of Levofloxacin hemihydrate from an ion activated in-situ gelling system. Int J Pharm Tech Res 2011; 3: 702-706.
40. Ramesh CN, Rakesh K, Dhanawat M, Pandit JK. Modified PLA nano in-situ gel: A potential ophthalmic drug delivery system. Colloids and Surfaces B: Bointerfaces 2011; 86: 28–34.
41. Shi-Lei C, En C, Qi-Zhi Z, Xin-Guo J. A novel nasal delivery system of a chinese traditional medicine, Radix Bupleuri, based on the concept of ion-activated in-situ gel. Arch Pharm Res 2007; 30: 8.
42. Padma PJ, Karthika K, Rekha NR, Khalid E. Formulation and evaluation of in-situ ophthalmic gels of Diclofenac sodium. J Chem Pharm Res 2010; 2: 528-535.
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