Department of Pharmaceutics, P.S.G.V.P. Mandal’s College of pharmacy, Shahada-425409, Dist.-Nandurbar, Maharashtra, India.
Mucoadhesive nasal microspheres represent a promising drug delivery system designed to enhance the bioavailability and therapeutic efficacy of drugs administered via the nasal route. These microspheres are typically composed of biocompatible and biodegradable polymers, which adhere to the mucosal lining of the nasal cavity, allowing for controlled drug release and prolonged retention time. This innovative approach not only improves the drug's absorption but also minimizes side effects, as it bypasses the first-pass metabolism. The mucoadhesive properties of the microspheres facilitate sustained drug release, making them particularly suitable for both local and systemic delivery of therapeutic agents. In addition to their ability to deliver a wide range of drug types, including proteins, peptides, and small molecules, the microspheres offer advantages such as ease of administration, non-invasive nature, and patient compliance. This paper discusses the formulation, characterization, and potential applications of mucoadhesive nasal microspheres in various therapeutic fields, including pain management, vaccines, and the treatment of chronic diseases. The future of mucoadhesive nasal microspheres lies in their ability to offer a targeted, efficient, and patient-friendly alternative to traditional drug delivery systems.
The history of nasal drug delivery dates back to earlier topical applications of drugs intended for local effects. Nasal therapy also called "Navya karma has been recognized form of treatment in the Ayurvedic system of Indian medicines.(1) Nasal route is easily accessible, convenient, and reliable with a porous endothelial membrane and a highly vascularised epithelium that provides a rapid absorption of compounds into the systemic circulation, avoiding the hepatic first pass elimination. In addition, intrananal drug delivery enables dose reduction, rapid attainment of therapeutic blood levels, quicker onset of pharmacological activity, and fewer side effects.(2,3) The nasal route is conventionally used for drug delivery for treatment of local diseases such as nasal allergy, nasal congestion and nasal infections(4,5). But in the recent years, this route has received special attention as a convenient and reliable method for the systemic delivery of drugs, especially those that are ineffective by oral route due to their metabolism in the gastrointestinal tract or by first-pass effect and must be administered by injection.(6) Among other promising non-parenteral routes, the nasal route of administration may perfectly satisfy the pre-requisites for non-oral, non-parenteral systemic medication purpose(7) Microspheres are solid spherical particles ranging in size from 1-1000µm. They are spherical free flowing particles consisting of proteins or synthetic polymers. The microspheres are free flowing powders consisting of proteins or synthetic polymers, which are biodegradable in nature. There are two types of microspheres; microcapsules and micromatrices, which are described as, Microcapsules are those in which entrapped substance is distinctly surrounded by distinct capsule wall and micromatrices in which entrapped substance is dispersing throughout the microspheres matrix. Solid biodegradable microspheres incorporating a drug dispersed or dissolved through particle matrix have the potential for the controlled release of drug. They are made up of polymeric, waxy, or other protective materials, that is, biodegradable synthetic polymers and modified natural products.(8)
MATERIAL AND METHODS
MATERIAL:
1. Synthetic Polymers
Poly alkyl cyano acrylates is a potential drug carrier for parenteral as well as other ophthalmic, oral preparations. Poly lactic acid is a suitable carrier for sustained release of narcotic antagonist, anti-cancer agents such as cisplatin, cyclophosphamide, and doxorubicin. Sustained release preparations for anti-malarial drug as well as for many other drugs have been formulated by using of co-polymer of poly lactic acid and poly glycolic acid. Poly anhydride microspheres (40μm) have been investigated to extend the precorneal residence time for ocular delivery. Poly adipic anhydride is used to encapsulate timolol maleate for ocular delivery. Poly acrolein microspheres are functional type of microspheres. They do not require any activation step since the surfacial free CHO groups over the poly acrolein can react with NH2 group of protein to form Schiff’s base(24) Synthetic polymers are divided into two types.
a. non-biodegradable polymers: e.g. Poly methyl methacrylate (PMMA) Acrolein Glycidyl methacrylate Epoxy polymers
b. Biodegradable polymers: e.g. Lactides, Glycolides & their co polymers, Poly alkyl cyano acrylates, Poly anhydrides.(24)
2. Natural polymers
Albumin is a widely distributed natural protein .It is considered as a potential carrier of drug or protiens (for either their site specific localization or their local application into anatomical discrete sites). It is being widely used for the targeted drug for the targeted drug delivery to the tumour cells. Gelatin microspheres can be used as efficient carrier system capable of delivering the drug or biological response modifiers such as interferon to phagocytes(24,25) Starch belongs to carbohydrate class. It consists of principle glucopyranose unit, which on hydrolysis yields D-glucose. It being a poly saccharide consists of a large number of free OH groups. By means of these free OH groups a large number of active ingredients can be incorporated within as well as active on surface of microspheres. Natural polymers are divided into different sources like proteins, carbohydrates and chemically modified Carbohydrates, Proteins: Albumin6, Gelatin7, and Collagen. Carbohydrates: Agarose, Carrageenan, Chitosan, Starch. Chemically modified carbohydrates: Poly dextran, Poly Starch. In case of non-biodegradable drug carriers, when administered parenterally, the carrier remaining in the body after the drug is completely released poses possibility of carrier toxicity over a long period of time(25)
Methods:
The microspheres can be prepared by using any of the several techniques given below but choice of the technique mainly depends on the nature of the polymer used, the drug, the intended use and the duration of therapy
1) Single Emulsion Technique (8)
The micro particulate carriers of natural polymers i.e., those of proteins and carbohydrates are prepared by single emulsion technique. The natural polymers are dissolved or dispersed in aqueous medium followed by dispersion in non-aqueous medium e.g., oil. In the second step of preparation cross-linking of the dispersed globule is carried out. The cross linking can be achieved either by means of heat or by using the chemical crosslinkers. The chemical cross linking agent used include gluteraldehyde, formaldehyde, terephthaloyl chloride, diacid chloride, etc. Croslinking by heat is carried out by adding the dispersion, to previously heated oil. Heat denaturation is however, not suitable for the thermolabile drugs while the chemical cross-linking suffers disadvantage of excessive exposure of active ingredient to chemicals if added at the time of preparation.
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Fig.1. Microspheres By Single Emulsion Technique
2) Double Emulsion Technique (9,10)
Involves the formation of the multiple emulsions or the double emulsion of type w/o/w and is best suited to the water-soluble drugs, peptides, proteins and the vaccines. This method can be used with both the natural as well as the synthetic polymers. The aqueous protein solution is dispersed in a lipophilic organic continuous phase. This protein solution may contain the active constituents. The continuous phase is generally consisted of the polymer solution that eventually encapsulates of the protein contained in dispersed aqueous phase. The primary emulsion is then subjected to the homogenization or the sonication before addition to the aqueous solution of the polyvinyl alcohol (PVA). This results in the formation of the double emulsion. The emulsion is then subjected to the solvent removal either by solvent evaporation or by solvent extraction process. The solvent evaporation is carried out by maintaining emulsion at reduced pressure or by stirring the emulsion so that the organic phase evaporates out. In the latter case, the emulsion is added to the large quantity of water (with or without surfactant) into which organic phase diffuses out. The solid microspheres are subsequently obtained by filtration and washing. A number of hydrophilic drugs like luteinizing hormone releasing hormone (LH-RH) agonist; vaccines, proteins/peptides and conventional molecule are successfully incorporated in to the microspheres using the method of double emulsion solvent evaporation/extraction.
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Fig.2. Microspheres by Double emulsion technique
3) Spray Drying and Congealing Technique (9,10)
Spray drying and spray congealing methods are based on the drying of the mist of the polymer and drug in the air. Depending upon the removal of the solvent or the cooling of the solution, the two processes are named spray drying and spray congealing respectively. The polymer is first dissolved in a suitable volatile organic solvent such as dichloromethane, acetone, etc. The drug in the solid form is then dispersed in the polymer solution under highspeed homogenization. This dispersion is then atomized in a stream of hot air. The atomization lead to the formation of small droplets or the fine mist from which the solvent evaporates leading to the formation of microspheres in a size range 1-100µm. Microparticles are separated from the hot air by means of the cyclone separator while the traces of solvent are removed by vacuum drying.
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Fig.3. Microspheres by Spray Drying technique
4) Polymarization Technique
It involves the reaction of various monomers at the interface between the two immiscible liquid phases to form a film of polymer that essentially envelops the dispersed phase. In this technique two reacting monomers are employed; one is dissolve in continuous phase while other is disperse in continuous phase (aqueous in nature) throughout which the second monomer is emulsified. Two conditions arise because of solubility of formed polymer in the emulsion droplet. That is formation is monolithic type of carrier if the polymer is soluble in droplet. Capsular type formed if the polymer is insoluble in droplet.
Proceeds using techniques like bulk, suspension precipitation, emulsion & micellar polymerization processes. In bulk polymerization, a monomer along with initiator is heated to initiate polymerization. Initiator is added to accelerate the rate of reaction. Drug is added during process of polymerization. The polymer so obtained is fragmented to microspheres.
Suspension polymerization is also called as bead/pearl polymerization. Carried out by heating the monomer or mixture of monomers with active principles (drug) as droplets dispersion in a continuous phase. The droplets may also contain an initiator & other additives. The emulsion polymerization differs from the suspension polymerization as due to presence of initiator in the aqueous phase, which later on diffuses to the surface of the micelles or the emulsion globules. The suspension & emulsion polymerization can be carried out at lower temperature since continuous external phase is normally water through which heat can easily dissipate. The processes also lead to the formation of higher molecular weight polymer at relatively faster rate.
5) Solvent Extraction (14)
Solvent evaporation has been extensively used for the preparation of PLA and PLGA microspheres which contain various drugs. Several variables are identified that can significantly affect microspheric characteristics, such as solubility of drug, internal morphology, type of solvent, diffusion rate, temperature, polymer composition, viscosity, and drug loading. The efficacy of this method relies on the effective entrapment of the active substance into the particles, and therefore this procedure is particularly efficient with drugs that are either insoluble or partially soluble in the liquid medium.
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Fig.4. Microspheres By Solvent Extraction Technique
6) Quasi Emulsion Solvent Diffusion (15)
Quasi-emulsion solvent diffusion method is used for the manufacturing of the controlled release microspheres of drugs with acrylic polymers. Microsponges can be manufactured by this method by using external phase which contains distilled water and polyvinyl alcohol. Internal phase consists of the drug, ethanol and polymers. Firstly, the internal phase is heated at 60ºC and added to the external phase in the room temperature. The mixture is stirred continuously for 2 hours. Then the mixture can be filtered for separation of the microsponges.
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Fig.5. Microspheres by Quasi-emulsion technique
Types Of Microspheres
Microspheres are classified into different types. They are of following
1. Bioadhesive microspheres (16)
Sticking of drug to the membrane by using the watersoluble property of the water-soluble polymers is called adhesion. Sticking or adhesion of drug delivery system to the mucosal membrane such as buccal, nasal, ocular, rectal etc can be termed as bioadhesion. This type of microsphere provides prolonged residence time at the target site and provide better therapeutic action.
2. Magnetic microspheres (17)
This type of delivery system localizes drug to the target site. In this type of delivery system, a drug or therapeutic radioisotope bound to a magnetic component is injected in the systemic circulation, which is then stopped with powerful magnetic field in the disease/target site. Magnetic microspheres are molecular particles which are small enough to move across capillaries without creating an esophageal occlusion
3. Floating microspheres (18)
In floating type, the bulk density is less than the gastric fluid and so remains buoyant in stomach without affecting gastric emptying rate. The drug is released slowly at the desired rate, and the system is found to be floating on gastric contents and decrease gastric residence and increases fluctuation in plasma concentration. Moreover, it also reduces chances of dose dumping. It produces prolonged effect and so reduces dosing frequencies.
4. Radioactive microspheres (19,20)
Radio embolization therapy microspheres sized 10-30nm are of larger than the diameter of the capillary bed when they come across. They are injected in the arteries that lead them to tumour of interest so all these conditions radioactive microspheres deliver high radiation dose to the targeted areas without damaging the normal surrounding tissues. Here radioactivity is not released from microsphere but acts within a radioisotope in typical distance. The different types of radioactive microspheres are α emitters, β emitters and ϒ emitters.
Advantages of Microspheres: (21,22)
Disadvantages of Microspheres:(23)
Characterisation And Evaluation Of Microsphere:
Particle size was determined by optical microscopy with the help of calibrated eyepiece micrometer. The size of around 100 microspheres was measured and their average particle size determined. The average particle size was determined by using Edmundson's equation.
D mean = Σnd/Σn
Where, n = Number of microspheres checked; d = Mean size.
Median size of the microspheres formulations ranged from 15 to 40 um were considered to be suitable for nasal administration.
Microspheres containing of drug (5mg) were crushed and then these microspheres dissolved in distilled water with the help of ultrasonic stirrer for 3 hr, and then filtered and assayed by uv-visible spectroscopy and then entrapment efficiency is calculated. Entrapment efficiency is equal to ratio of actual drug content to theoretical drug content.
% Entrapment = Actual content/Theoretical content x 100
Percentage yield: The yield was calculated for each batch. The percentage yield of microspheres was calculated as follows.
{% Yield= Weight of Microspheres /Theoretical weight of drug and polymer x100}
The equilibrium swelling degree (ESD) of microspheres was determined by swelling 5gms of dried microspheres in 5 ml of phosphate buffer pH 6.8 overnight in a measuring cylinder. The swelling index of the microsphere was calculated by using the formula.
Swelling index= Initial weight – Final weight/ Initial weight × 100
The density of the microspheres can be measured by using a multi volume pychnometer. Accurately weighed sample in a cup is placed into the multi volume pychnometer.
Helium is introduced at a constant pressure in the chamber and allowed to expand. This expansion results in a decrease in pressure within the chamber. Two consecutive readings of reduction in pressure at different initial pressure are noted. From two pressure readings the density of the microsphere carrier is determined(26,27,28)
The samples for the scanning electron microscope (SEM) analysis were prepared by sprinkling the microspheres on one side of an adhesive stub. Then the microspheres were coated with gold before microscopy(28)
The drug polymer interaction and degradation of drug while processing for microencapsulation can be determined by FTIR
Ex-vivo drug permeation study was performed using a glass fabricated nasal diffusion cell. The water jacketed recipient chamber has a total capacity of 60 ml and flanged top of measured by a u-tube viscometer (viscometer constant at 400c is 0.0038 Mm2/s /s) at 25 ± 0.1 0c in a thermostatic bath. The polymer solutions are allowed to stand for 24 h prior to measurement to ensure complete polymer dissolution.(29,30)
Future Opportunities:
1. Drug Delivery Systems
2. Diagnostics
3. Biotechnology and Cell Culture
4. Materials Science
5. Cosmetics and Personal Care
6. Environmental and Industrial Applications
7. Advanced Manufacturing
8. Sustainability and Biodegradability
CONCLUSION:
In conclusion, microspheres represent a versatile and rapidly advancing technology with significant potential across various industries, including medicine, biotechnology, materials science, cosmetics, and environmental applications. Their ability to encapsulate and deliver active agents in a controlled and targeted manner holds particular promise for drug delivery systems, diagnostics, and tissue engineering. As research continues, innovations in microsphere materials and functionalities are expected to lead to more efficient, sustainable, and personalized solutions, with applications ranging from targeted therapies and gene delivery to advanced materials and eco-friendly products. The future of microspheres is poised to transform numerous fields, improving the quality of life, enhancing industrial processes, and contributing to environmental sustainability. However, as these technologies develop, ensuring their safety, efficacy, and environmental impact will be critical in maximizing their benefits and minimizing potential risks. With ongoing advancements, microspheres will continue to play a key role in shaping the future of science, healthcare, and technology.
REFERENCES
Ganesh Patel*, Sandip Tadavi, Dr. Sunil Pawar, Gopal Thakur, Arshiya Sharma, Aparna Thakur, Mucoadhesive Nasal Microspheres: A Novel Approach for Enhanced Drug Delivery, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 3, 2615-2627 https://doi.org/10.5281/zenodo.15093587
10.5281/zenodo.15093587
