A REVIEW ON MICROSPHERES AS DRUG CARRIERS

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[Find the meaning and references behind the names: Low, Main, Pace, Sunita]

Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 800 A REVIEW ON MICROSPHERES AS DRUG CARRIERS V. Gulghane, Sunita N. Vaidya, V. Satote, S. Waghde, S. Kale Datta Meghe College of Pharmacy Salod (H), Datta Meghe Institute of Higher Education Research (DU), Wardha, Maharashtra, India Abstract Orally modified-release multiple-unit dosages have consistently shown themselves to be a more successful therapeutic choice than other dosage types. Novel medication delivery systems have several advantages over conventional multidose therapy. Current trends indicate that the use of micro particles in drug delivery systems can result in regulated or delayed release formulations for oral use with minimal risk of dose dumping, variable blending to achieve different release patterns, and predictable and short stomach residence time. In addition to their prolonged release, microspheres garnered significant interest for their capability to specifically target drugs. It has been demonstrated that oral modified-release multiple-unit dosage is a more efficacious treatment option in comparison to traditional or quick-release single-unit dosage forms. Innovative drug delivery methods are superior to traditional multidose therapy in a number of ways. According to current trends, the use of microparticles in drug delivery systems can lead to formulations that are regulated or released gradually for ingestion with a low risk of dose dumping, blending that can be adjusted to achieve diverse release patterns, and a stomach residence period that is predictable and brief. In addition to their extended release, microspheres attracted a lot of attention due to their capacity to target medications precisely Keywords: Diagnostic microspheres, magnetic microspheres, microsphere, polymeric microspheres, therapeutic magnetic microspheres Address for correspondence: Sunita N. Vaidya, Datta Meghe College of Pharmacy Salod (H), Datta Meghe Institute of Higher Education and Research (DU), Wardha, Maharashtra, India. Phone:+91-9284591082 E-mail: sunitavaidya 06@gmail.com Received: 20-03-2024 Revised: 04-07-2024 Accepted: 25-07-2024 INTRODUCTION M icrosphere-based drug delivery methods have garnered significant attention in recent times. Researchers have investigated the prospect of controlled or sustained release for microspheres made of both biodegradable and nonbiodegradable polymers, depending on the final application. The main characteristic of microspheres is their microphase separation shape, which permits controlled variability in the release of medication and the pace of disintegration [1] “A structure composed of a continuous state of one or more mixable polymer in which drugs are disseminated at the molecule or microscopic level is referred to as a monolith sphere or medicinal material that dispersed into the matrix or a particle’s molecular dispersal. Microspheres are little, spherical particles that range in size from one to a thousand millimeters, or micrometres. Microspheres can occasionally be formed by starches, gums, proteins, lipids, and waxes. Natural polymers include albumin and gelatine, whereas artificial polymers include polyglycolic acid and polylactic acids. The solubility and stabilities of the polymers and medications, as well as process safety and economic considerations, were taken into consideration while choosing the solvents used to dissolve the polymeric components [2] MICRO PARTICULATE DELIVERY SYSTEMS When a polymeric or proteinic envelope wraps the particles and solidifies, microcapsules can develop. Microparticulatedelivery technologies aim to control and extend the release of the active component from the coated particle without attempting to change the normal biodestination of the active molecules in the body after administration and absorption. The distribution of these molecules within the body and their REVIEW AR TICLE

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[Find the meaning and references behind the names: Long]

Gulghane, et al .: A review on microspheres as drug carriers Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 801 elimination will be exclusively dictated by their physical and chemical properties. Consequently, pharmacological target is to reduce overall dosage and cost while optimizing therapeutic efficacy Microspheres Microspheres are biodegradable, free-flowing powders with a preferred particle size of <200 mm that are formed of synthetic polymers or proteins [3] A needle with an 18 or 20 number can be used to inject them [4] Microspheres, which are extensively dispersed throughout the gastrointestinal tract (GIT) and consist of tiny particles smaller than 200 mm in size, improve drug absorption and reduce the adverse effects that irritant medications have on the gastrointestinal mucosa [5] PROPERTIES OF AN IDEAL MICROSPHERE [6] Stated that some requirements have to be met for the preparation of microspheres: • The stability of the product following synthesized with a clinically appropriate shelf life • The capacity to incorporate comparatively high amounts of the drug • Particle size and dispersibility control in aqueous injection vehicles • Balanced biodegradability and biocompatibility • Adaptability to changes in composition • Control over the publication of content • Boost the effectiveness of treatment • Decrease in toxicity • Reduction in toxicity • Bior absorbency ADVANTAGES [7,8] Reported many advantages of microsphere such as: 1. Microspheres have a long-lasting and consistent therapeutic impact 2. masking an unpleasant taste or smell 3. Boost the stability of the stomach enzymes and the body 4. Increased drug use will increase bioavailability and decrease the frequency or severity of side effects 5. Thus, less dose intervals lead to better patient compliance 6. Decreased toxicity 7. High absorption window considering the drug’s properties in the GIT 8. Decreased metabolism on the first pass 9. Longer biological half-life 10. All aspects of microsphere morphology are dependent on controlled variations in drug release and breakdown DISADVANTAGE [9,10] Reported some disadvantages of microsphere: 1. The adjusted release from the mixtures [11] 2. Since controlled release formulations often have larger drug loads, any compromise to the dosage form’s release properties could potentially be hazardous 3. Numerous factors, including diet, the rate of transit through the stomach, and internal and external factors, could be responsible for the altered release from the formulation 4. Because controlled release formulations typically carry a larger drug load, any compromise to the dosage form’s integrity during release could result in dosage dumping, therapy failure, and possible toxicity 5. These kinds of dosage formulations should not be eaten or crushed CLASSIFICATION OF POLYMERS Microspheres used usually are polymers. They are classified into two types- [12] • Artificial polymers It is divided into two types • Non-biodegradable polymers e.g. Epoxy polymers, Acrolein, Glycidyl methacrylate, and Polymethyl methacrylate (PMM) • Biodegradable polymers e.g. Lactides, poly alkyl Ciano the acrylates, poly anhydrides, and glycosides and their co-polymers • Natural polymers: It is obtained from different sources such as proteins, carbohydrates and chemically modified carbohydrates Proteins: Albumin, Gelatine, and Collagen Carbohydrates: Agarose, Carrageenan, Chitosan, Starch. Chemically modified carbohydrates: Poly dextran, Poly starch [Figures 1 and 2] TYPES OF MICROSPHERES Bio-adhesive microspheres [13] Adhesion is defined as the drug’s capacity to cling to a membrane by means of the sticky feature of polymers soluble in water. The adherence is “bio adhesion” of a drug delivering device to a mucosa membrane, such as the oral, ocular, nasal, or rectal. Due to their extended residency length, these microspheres establish close contact with their absorption.

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Gulghane, et al .: A review on microspheres as drug carriers Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 802 They provide more therapeutic action since they stay at the application site longer Magnetic microspheres [14] This type of medication delivery method is essential since it precisely addresses the illness’s location. This suggests that a smaller quantity of magnetically focused medication can take the place of more freely circulating medicine in greater quantities. Magnetic carriers such as dextran, chitosan, and others exhibit magnetic responses when exposed to contained materials in a magnetic field Therapeutic magnetic microspheres They work to treat liver tumors with chemotherapy. Medication such as peptides and proteins can also be targeted with this technique Diagnostic microspheres By producing supra magnetic iron oxides at the nanoscale, it can be used to identify bowel looping from other abdominal structures and view liver metastases Floating microspheres [15] Floating types float in the stomach without slowing down the rate at which food is discharged since their bulk density is lower than that of gastric fluid. The medication is released gradually and at the proper rate if the system floats on stomach content, increasing gastric residence and producing swings in plasma concentration. This also reduces the possibility of dosage dumping and striking. This results in a longer-lasting therapeutic effect that reduces dosage frequency. This is how the medication (ketoprofen) is given Radioactive microspheres [16] The 10–30 nm-sized microspheres used in radioembolization therapy are bigger than capillaries and are tapped into the first capillary bed they come across. The arteries that supply the target tumor are injected with them. In each of these scenarios, radioactive microspheres deliver high radiation doses to the targeted areas without posing a threat to adjacent healthy tissues. Since radioactivity acts inside a radioisotope’s typical distance rather than being discharged from microspheres, it differs from a drug delivery system. Radiological microspheres come in three main varieties: α , ß, and γ emitters Polymeric microspheres The many types of polymeric microspheres can be classified into two groups: synthetic microspheres and biodegradable microspheres BIODEGRADABLE POLYMERIC MICROSPHERES [17] Because natural polymers like starch are naturally sticky, biocompatible, and biodegradable, this is the rationale behind employing them. Biodegradable polymers stay in contact with mucous membranes for longer lengths of time and form gels because they have a high degree of swell property when in contact with aqueous medium. The drug’s release rate and extent are determined by both the prolonged release pattern and the polymer concentration. The primary disadvantage is the challenging drug loading efficiency of biodegradable microspheres in therapeutic environments, which makes managing drug release challenging. They do, however, have a variety of applications in treatments based on microspheres. synthetic polymeric microspheres [18] SYNTHETIC POLYMERIC MICROSPHERES [18] The use of synthetic polymeric microspheres in therapeutic settings is quite common. It has also been demonstrated to be safe and suitable for use as a filler, bulking agent, Figure 2: Types of microspheres Figure 1: Structure of microsphere

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Gulghane, et al .: A review on microspheres as drug carriers Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 803 embolic particles, drug delivery vehicles, etc. However, these microspheres’ main flaw is that they tend to spread out from the injection site, increasing the chance of embolism and further organ damage EMULSION SOLVENT EVAPORATION TECHNIQUE With this approach, the drug is dissolved in a polymer that has previously been dissolved in chloroform, and the resulting solution is then added to the aqueous phase that has 0.2% sodium PVP as an emulsifying agent. The medication and polymer were separated into fine droplets after 500 rpm of agitation. These droplets were then gathered by filtration, rinsed with demineralized water, and allowed to dry for a full day at room temperature. Solvent evaporation was used to make the solidified microspheres [19] SINGLE EMULSION TECHNIQUE The microparticle carriers of natural polymers, like proteins and carbohydrates, are made using the single emulsion approach [ Figure 3]. Natural polymers are dispersed in a non-aqueous medium after first being dissolved or spread in an aqueous medium, like oil The next step involves cross-linking the dispersed globules, which can be accomplished chemically or by heating them. By preheating the oil and combining it with the dispersion, one may control the heat-induced linkage. Chemical crosslinking has the active ingredient to significant volumes of chemicals when added during preparation and then centrifuged, cleaned, and separated. It is inappropriate to heat denaturation when using thermolabile medications [20] DOUBLE EMULSION TECHNIQUE [20] This technique needs the preparation of numerous emulsions or double emulsions of type w/o/w and is effective with water-soluble drugs, peptides, proteins, and vaccines [Figure 4 ]. The lipophilic organic continuous state in which the protein aqueous solution is dispersed is usually composed of the polymer solution that finally envelops the protein present in the dispersed aqueous phase. The main emulsified is then combined with the PVA aqueous solution after being homogenized. This results in the creation of a double emulsion, which is then subjected to solvent removal, either by solvent evaporation, which maintains the emulsion at a lower pressure, or stirring to cause the organic phase to evaporate away. Proteins, vaccine hydrophilic drugs such as luteinizing hormone-releasing hormone agonists are a few examples APPLICATIONS Microspheres in vaccine delivery Immunity to the microorganism or any of its dangerous metabolites is necessary for immunization. The ideal vaccination should fulfill the following requirements: it should be inexpensive, simple to administer, safe, and effective. Safety and reducing adverse effects are complex subjects [21] Both the safety factor and the degree of antibody response are directly impacted by the application method. Parenteral vaccinations using biodegradable delivery technology may be able to mitigate some of the shortcomings of conventional vaccines [22] Parenteral carriers — subcutaneous, intramuscular, and intradermal — are of interest because they offer a number of advantages, including: (1) Antigen stabilization; (2) Antigen release modulation; and (3) enhanced antigenic qualities through adjuvant activity. (4) Targeting with microparticulate carriers the well-established concept of site-specific medicine delivery, or targeting, is gaining a lot of interest. The efficacy of a medicine as a treatment depends on its capacity to selectively bind to and activate its target receptors. The primary mechanism of pharmacological activity is the ability to depart the pool in a predictable, efficient, and targeted way, which is mediated by the use of a carrier system. When particles are positioned in distinct anatomical compartments, they are kept due to the physical properties of the surrounding environment or the particles’ biophysical interaction with the cells of the target Chemoembolization Chemoembolization is a type of endovascular therapy in which a targeted arterial embolization of a tumor is combined with Figure 4: Microspheres by double emulsion technique Figure 3: Microspheres by single emulsion technique

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[Find the meaning and references behind the names: Amine]

Gulghane, et al .: A review on microspheres as drug carriers Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 804 the local delivery of a chemotherapeutic medication, either simultaneously or later. The benefit of such embolization’s is theoretically that they will produce long-term therapeutic levels of chemotherapy in the tumorous regions in addition to vascular occlusion. Chemotherapy embolization is a development of traditional percutaneous embolization techniques Surface modified microspheres Many techniques have been used to alter the surface properties of carriers to prevent phagocytes from clearing them and to change how they are distributed across the body. The ability of the polyester, polyester, which is or polymethyl methacrylate (PPM) micro to absorb MPS is reduced and their hydrophilicity is enhanced with the absorption of poloxamer on their surface. Protein microspheres covalently treated with polyethylene glycol (PEG) derivatives show decreased immunogenicity and clearance. PEG derivative-covalently treated protein microspheres exhibit reduced immunogenicity and clearance. The surface modifications most thoroughly researched are: (1) Antibody fragments Amino Acid-Based Proteins, (2) Polysaccharides (poly-, oligo-, and mono-), (3) Chelating agents (such DTPA, EDTA, or deferoxamine) to the surface of microspheres Monoclonal antibodies (Mabs) mediated microspheres The molecules known as Mabs are highly selective. Microspheres containing bioactive compounds can be used to target specific locations with Mabs due to their high specificity. Mab spheres and microspheres can be directly coupled by covalent coupling. The free amino, hydroxyl, or aldehyde groups on the surface of the microspheres are suitable sites for the attachment of the antibodies. To attach the Mabs to microspheres, you can utilize any of the following methods. (1) Adsorption lacking specificity, (2) Specific Sorbent, (3) Direct communication, (4) Reaction mediated by agents Imaging Stomach retention in terms of words. Combining many methods, including genetic products and gene and gene sorting for safe, effective, and targeted in vivo administration, diseased cell sorting, supplementing, and diagnostics as microscopic representations of the body’s damaged organs and tissues, microspheres will be crucial for innovative medicine delivery in the future [23] The potential use of benzodiazepine-containing polymer films for oral drug administration in rabbits was investigated. The results indicated that a film that is similar to the current tablet dosage forms and has a drug-polymer ratio of 1:0.5 would be a practical method of dose. Because of the polymer’s ability to form films, film dosage forms may be developed using it rather than medication tablets. For the purpose of delivering medications orally, polymer is a unique type of polymer due to its sensitivity to pH and the reactivity of its major amine groups Microspheres for DNA delivery [24] Microspheres have recently been used as a delivery device to improve plasmid DNA transfer and stability in the bioenvironment. DNA-gelatine microspheres and nanoparticles are the building blocks of a novel gene delivery system that Truong-Le et al . (1998) found. These particles are produced by complex coacervation of plasmid DNA with gelatine FUTURE CHALLENGES Microspheres appear to present promising challenges in the medical field in particular because of their wide range of applications in molecular biology, such as the detection of six single-nucleotide polymorphisms, the prevention of tumors after liver transplantation, and the sophisticated method of delivering vaccines and proteins CRITERIA FOR MICROSPHERE PREPARATION One method for incorporating solid, liquid, or gas into various polymer coatings is micro encapsulation [25] The production of discrete microspheres through various techniques is contingent upon variables such as particle size, delivery channel, duration of drug release, and these attributes associated with rotating velocity, drug crosslinking, evaporation time, and co-precipitation [26] The following requirements should be met when preparing microspheres: (1) The ability to add a sizable amount of medication. (2) The mixture’s stability after synthesis and its capacity to last on a shelf for therapeutic usage. (3) The size and dispersibility of particles in aqueous injection vehicles. the active reagent-controlled release over an extended period of time. (4) Biocompatibility under suitable supervision. (5) Biocompatibility and (6) Vulnerability to alteration by chemicals Materials used [27] Synthetic polymers are divided into two types: i. Non-biodegradable polymers • Poly methyl methacrylate (PMMA) • Acrolein • Glycidyl methacrylate • Epoxy polymers

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[Find the meaning and references behind the names: Keshar]

Gulghane, et al .: A review on microspheres as drug carriers Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 805 ii. Biodegradable polymers [28,29] • Lactides, Glycosides and their co polymers • Poly alkyl cyan Acrylates • Poly anhydrides Natural polymers obtained from different sources such as proteins, carbohydrates, and chemically modified carbohydrates [30,31] a. Proteins • Albumin • Gelatine • Collagen b. Carbohydrates • Agarose • Carrageenan • Chitosan [32] • Starch c. Chemically modified carbohydrates • Poly dextran [33] • Poly starch METHODS In vitro methods The development of experimental methods that enable evaluation of a drug’s release characteristics and permeability via a membrane is crucial. For this purpose, several in vivo several reports of in vitro methods made. Pharmaceutical production, quality control methods, and product development are just a few areas where in vitro studies on drug release find application. Acquiring sensitive and consistent release data from hydrodynamically and physiochemically defined settings are necessary. Because of the influence of technology, specific conditions, and the difficulty of replicating in vivo situations, many in vitro release procedures for buccal formulations have been developed; nevertheless, a Standard in vitro approach is still lacking. Depending on the form and purpose of the dose form created, different professionals have employed various equipment designs in various settings Beaker method [34] The dosage form is constructed to stick to the bottom of a glass that holds the medium and is evenly swirled using an overhead stirrer. A variety of medium quantities (50–500 mL) and stirrer speeds, which range from 60 to 300 rpm, in the scientific literature. The interface diffusion system is the work of Dearden and Tomlinson. It is divided into four pieces. At first, the drug was in compartment A, which represents the oral cavity, in a buffer at the right concentration. within an intermediary. One octanol was found in compartment B, which stood in for the buccal membrane, whereas 0.2 M HCl was found in compartment C, which stood in for physiological fluids. One octanol’s phases were saturated with one another before to use. The samples were removed and placed in back in compartment A using a syringe Modified keshar chien cell [35] Compartment C, which stood for body fluids, contained 0.2 M HCl, whereas compartment B, which represented the buccal membrane, contained 1-octanol. Additionally, one octanol was found in protein binding compartment D. Before use, the 1-Octane and the water-based phasewere overpowered by one another. Using a syringe, the samples were taken out of compartment A and put back in. Dissolving apparatus: To analyse in vitro release profiles, standard USP or BP dissolving apparatus have been used, which include rotating elements, a paddle, [36] and a basket [37] The dissolving media used in the study has a volume range of 100–500 mL and a rotating speed of 50–100 rpm In vivo methods Methods for examining the permeability of intact mucosa include such as those that use the biological reaction of the organism either locally or systemically, or those that entail direct localized detection of the uptake or generation of penetrating agents at the surface. Drugs systemic pharmacological effects after being delivered to the oral mucosasome of the most significant and early research on mucosal permeability. Nevertheless, the most often used methods are buccal absorption tests, animal model-based in vivo studies, and drug permeability research using perfusion chambers Animal models The main applications of animal models are in drug screening, evaluating a range of formulations, and investigating the mechanism of action and application of permeation enhancers. There is a dearth of in vivo models, such as those created of dogs, rats, rabbits, cats, hamsters, pigs, and sheep, despite the fact that many animal representations have been described in the literature. The animal is normally given a general anesthesia before the dosage form is administered. Rats with knotted esophagus tubes are unable to absorb substances by routes other than the mouth mucosa. Blood is drawn and tested at different times Test for buccal absorption: In 1967, Beckett and Trigg created the test for buccal absorption. When mixing one or more substances, it is an easy and accurate way to estimate how much medication is lost from the mouth. The test has proven to be helpful in determining how important drug structure, contact time, starting drug concentration, and solution pH are in relation to each other when the drug is in the oral cavity [38] In vitro–in vivo correlations “ In vitro - in vivo correlations” are associations between the rates of dissolution in vitro and the quantity and rate

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[Find the meaning and references behind the names: Liu, Law, Park, Mahmood, Ramesh, Singh, Sahil, Yadav, Marcel, Prasanth, Gupta, Jiang, Fatima, Ghulam, Naveed, Colon, Jain, Urs, Prakash, Kaur, Jansen, Yamamoto, Kavitha, Varghese, Mathew, Meena, Sunny, Zhou, Dev, Ion, Yang, Bhai]

Gulghane, et al .: A review on microspheres as drug carriers Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 806 of availability of the drug or its metabolites as established by urine excretion and/or blood concentration. These correlations can be used to generate bioavailability-based product specifications [39-41] CONCLUSION Microspheres have been shown to be a superior pharmaceutical delivery technique when compared to several other varieties because of its advantages of improved patient compliance and specificity of target. As can be shown from the above, microspheres represent a feasible alternative for sustained and targeted drug delivery in a variety of organs, including the liver, colon, nose, pulmonary system, and eyes. Microspheres generated by ion-tropic gelation hold potential as a gastric retention technique. Many companies are focusing on commercializing this strategy even though there are still many obstacles to be settled in order to achieve long-stomach retention in terms of words. Combining several techniques, such as genetic products and gene and gene sorting for safe, targeted, and efficient in vivo administration, diagnostics, diseased cell sorting, and supplementation as tiny models of damaged organs and tissues in the body, In the future, microspheres will be essential for creative drug delivery REFERENCES 1. Guiot P, Couvreur P. Polymeric Nanoparticles and Microspheres. New York, USA: CRC Press; 1986. p. 207 2. Chein YW. Oral Drug Delivery Systems: In Novel Drug Delivery Systems. Vol. 50. New York: Marcel Dekker, Inc.; 1992. p. 139-77 3. Vyas SP, Khar RK. Targeted and Controlled Drug Delivery. 7 th ed. New Delhi, India: Vallabh Prakash An; 1990. p. 418 4. Brahmana DM, Jaiswal SB. Biopharmaceutics and Pharmacokinetics. 2 nd ed. 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An examination of factors affecting the size, distribution and release characteristics of polymer microbeads made using electrostatics. J Control Release 1997;43:183-96 17. Cleland JL, Duenas ET, Park A, Daugherty A, Kahn J, Kowalski J, et al . Development of poly-(D, L-lactideco-glycol ide) microsphere formulations containing recombinant human vascular endothelial growth factor to promote local angiogenesis. J Control Release 2001;72:13-24 18. Jain NK. Controlled and Novel Drug Delivery. 4 th ed. New Delhi, India: CBS Publishers; 2010. p. 236-7 19. Irom BC, Kavitha K, Rupeshkumar M, Singh SD. Natural polymeric microsphered for drug delivery: A review. Int J Pharm Res Dev 2012;4:31-7 20. Pradesh TS, Sunny CM, Varma KH, Ramesh P. Preparation of microstructure hydroxyapatite microspheres using oil in water emulsion. Bull Matter Sci 2005;28:383-90 21. Funded Berg HH, Stites DP, Caldwell JL Wells JV. Basic and Clinical Immunology. 2 nd ed. 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[Find the meaning and references behind the names: Raju, Gangadhar, Anil, Sunder, Patil, Naveen, Kumar, Choudhary, Mani, Sudha, Venkatesh, Kiran, Ganesh, Veena, Sai, Nil, Shweta, Naik, Rupa, Pak]

Gulghane, et al .: A review on microspheres as drug carriers Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 807 techniques. Effect of polymer viscosity on microcapsule characteristics. Pak J Sci 2009;22:291-300 27. Li SP, Kowalski CR, Feld KM, Grim WM. Recent advances in microencapsulation technology and equipment. Drug Dev Ind Pharm 1988;14:353-76 28. Dandarid PM, Mastiholimath VS, Patil MB, Gupta MK. Biodegradable microparticulate system of captopril. Int J Pharm 2006;307:83-88 29. Gangadhar CB, Sunder RS, Varma MK, Raju MS, Sai Kiran M. Formulation and evaluation of indomethacin microspheres using natural and synthetic polymers as controlled release dosage forms. Int J Drug Discov 2010;2:8-16 30. Mazumder R, Nath LK, Anwarul H, Maity TS, Choudhary PK, Shreshta B. Formulation and in vitro evaluation of natural polymers-based microsphere for colonic drug delivery. Int J Pharmacy Pharm Sci 2010;2:211-9 31. Kavitha K, Veena CP, Anil Kumar SN, Tamizh Mani T Formulation and evaluation of trimetazidine hydrochloride loaded Gelatin microspheres. Int J Pharmacy Pharm Sci 2010;2:67-70 32. Lorenzo-Lamosa ML. Design of microencapsulated chitosan microspheres for colon drug delivery. J Control Release 1998;52:109-18 33. Sudha Mani T, Naveen Kumar K. Preparation and evaluation of ethyl cellulose microspheres of ibuprofen for sustained drug delivery. Int J Pharma Res Dev 2010;2:120-1 34. Shalaka D, Naik SR, Amruta A, Parimal K. Vitamin E loaded pectin alginate microspheres for cosmetic application. J Pharm Res 2009;2:1098-02 35. Senthilnathan B. Design development and evaluation of pulsatile. Int J Drug Discov 2011;4:1614-6 36. Nagpal M, Maheshwari DK, Rakha P, Dureja H, Goyal S, Dhingra G. Formulation development and evaluation of alginate microspheres of ibuprofen. J Young Pharm 2012;4:13-6 37. Shweta K, Kumar SP. Recent Advancement in Chitosan Best Formulation and its Pharmaceutical Application. Vol. 1. Rajasthan: Pelagia Res Library; 2010. p. 195-210 38. Venkatesh DP, Roopa K, Jha SK. Formulation and evaluation of microspheres contain Fluvastatin sodium. Int J Drug Dev Res 2012;4:306-14 39. Sochan GN, Gavina V. Formulation and evaluation of mucoadhesive microspheres of macromolecular polymers using flurbiprofen as a model drug. Pharm Lett 2012;4:1560-6 40. Ganesh SN, Venkatesh G, Hanumanthachar J, Jayanthi C. Developed an alternative drug delivery system in the form of mucoadhesive microspheres. Int J Pharmacy Pharm Sci 2012;5:1562-8 41. Oedemic N, Tilkan MG. Investigation of the parameters affecting the release of flurbiprofen from chitosan microspheres. Braz J Pharm Sci 2017;53:12 Source of Support: Nil. Conflicts of Interest: None declared.

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