Formulation And Evaluation Of Clotrimazole And Ketoconazole Combination Loaded Microsponge Gel Using Different Polymers For Topical Drug Delivery

Abstract

A microsponge delivery system (MDS) is highly crosslinked, porous, polymeric, microsphere, polymeric system made up of porous microspheres that can store a variety of active substance and then release them gradually and in reaction to a trigger on the skin. Microsponge has ability to retain in skin cell and prevent the dose dumping in blood circulation, which may cause side effects. Ketoconazole and clotrimazole have broad spectrum antifungal which shows fungi active static activity. Ketoconazole loaded microsponge will be prepare by the quasi-emulsion solvent diffusion method using different polymers will be varies drug polymer ratio. The microsponge will be characterize by the SEM, TEM, XRD, FTIR and will be evaluated for drug content, particle size, % entrapment efficiency, in vitro drug release, in vivo drug release. Microsponge will be prepare as a promising delivery system offering prolong release ketoconazole and clotrimazole using will be treating antifungal drug activity.

Keywords

Microsponge, Polymer, Skin, Antifungal, Ketoconazole, Clotrimazole, In-Vitro Drug Release, Antifungal, Diffusion Method

Introduction

NOVEL DRUG DELIVERY SYSTEM

The novel drug delivery systems have been increasingly investigated to achieve targeted and controlled release of drugs as many of conventional delivery systems require high concentrations of active agents to be incorporated for effective therapy because of their low efficiency as delivery systems. Microsponges are highly cross-linked, patented, porous, polymeric microspheres that acquire the flexibility to entrap a wide variety of active ingredients that are mostly used for prolonged topical administration and recently for oral administration. Microsponges are designed to deliver a pharmaceutically active ingredient efficiently at minimum dose and also to enhance stability, elegance, flexibility in formulation, reduce side effects and modify drug release profile.

Topical Drug Delivery 

Topical application has been used for centuries for the treatment of localized skin diseases. In this skin is most partially accessible organs on human body. Topical preparations avoid the gastro-intestinal irritation and metabolism of drug.1 A therapeutic system is applied topically and the drug diffuses passively out of its carrier or vehicle and, depending on physiochemical parameters of the drug and biological properties associated with the skin. Topical preparations are applied to the skin surface for local or systemic effects.

Topical delivery includes:

• External topical that are spread, sprayed, or dispersed on to cutaneous tissues to cover the affected area.
• Internal topical that are applied to the mucous membrane orally, vaginally or on anorectal tissues for local activity.

Advantages of topical drug delivery system.

• Avoidance of first pass metabolism
• Convenient and easy to apply
• Ability to easy terminate the medications, when needed
• Ability to deliver drug more selectively to specific site
• Avoidance of gastro intestinal incompatibility
• Providing utilization of drug with short biological half-life, narrow therapeutic window
• Improving physiological and pharmacological response
• Improve patient compliance
• Provide suitability for self-medication
• Disadvantages of topical drug delivery systems. 
• Skin irritation of contact dermatitis may occur
• Possibility of allergic reaction
• Drugs of large particle size not easy to absorb through the skin

SKIN

The skin completely covers the body and is continuous with the members lining the body orifices. It contains sensory nerve endings that enable discrimination of pain, temperature and touch. It is involved in the regulation of body temperature.

Structure of the Skin:

The skin is the largest organ in the body and has a surface area of about 1.5- 2m2 in adults. In certain areas, it contains accessory structures: glands, hair and nails. There are two main layers; the epidermis, which covers the dermis.

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    Figure 1: Structure of skin

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Microsponge Drug Delivery System

A microsponge delivery system (MDS) is highly cross-linked, porous, polymeric microspheres, polymeric system consisting of porous microspheres that can trap wide range of actives ingredients and then release them onto the skin over a time and in response to trigger. These days more developments in delivery systems are being desegregated to optimize the drug efficacy and cost-effectiveness of the therapy. Microsponge delivery system (MDS) has been successively addressed for the controlled release of drug onto the outer layer of skin (epidermis). Drug loaded microsponge consist of microporous beads, typically 10-25µm in diameter that possess a versatility to entrap wide range of active agents (drug or therapeutic agents). Microsponge systems are based on microscopic, polymer-based microsphere that can suspend or entrap a wide variety of substance. Microsponge technology offers entrapment of substances and to contribute towards reduced side effects, improved stability, increased smoothness, and enhanced formulation flexibility. In addition, microsponge systems are non-irritating, non-allergic and non-toxic. MDS technology is being used currently in cosmetics skin care, sunscreen. One of the best features is it is self-sterilizing. It also expands its application in oral drug delivery, bone and tissue engineering.

Characteristics of microsponge drug delivery system.

• Microsponge are stable over the pH 1 to 11
• Microsponges are compatible with many of active ingredients and excipients
• Average pore size of microsponge is 25µ, so there no need of sterilization
• Approximately 40 to 60 % of drugs may entrapped in microsponge
• Microsponges must be either fully miscible in a monomer or capable of being made miscible by the addition of a small amount of a water-immiscible solvent
• It must be inert to monomers and should not increase the viscosity of the mixture throughout formulation of polymerization

Advantages of Microsponges.

• Microsponges are non-toxic
• It improves the flexibility of the formulation
• Microsponges are non-mutagenic
• These formulations can extend the release of drug; it can release the drug up to 12 hours continuously
• Microsponges are non-allergic
• It increases the patient compliance
• Microsponges are non- irritating formulation
• It also reduces irritation

Limitations

• The preparation uses organic solvents as porogens, which pose an environmental hazardous as some may be highly inflammable, posing a safety hazardous
• In some cases, the traces of residual monomers observed which is toxic and hazardous to health
• Properties of the active pharmaceutical product for the entrapment into microsponges
• API should be fully miscible in a monomer or should be miscible when the small amount of a co solvent is added to it
• API should not be miscible in water or should be only slightly soluble in water
• API should be unreactive to monomers
• It should not increase the viscosity of the mixture during formulation
• When it comes in contact with the polymerization catalyst it should be stable

Clinical uses of micro sponges

Sunscreens: It protects against sunburns and injury caused by sunrays.

Antiacne:

It increase the efficacy of skin. Decrease skin irritation. Decrease skin sensitization.

(e.g.)-benzoyl peroxide.

Anti-inflammatory:

It reduces skin allergic response and dermatosis and show long lasting activity. (e.g.- hydrocortisone).

Antidandruffs activity:

It prevents bad odor with increase efficacy and safety and also lower the irritation. (e.g.- zinc pyrithione, selenium sulphide).

Skin depigmenting activity:

It prevents the oxidation of skin with aesthetic agent (e.g.- hydroquinone).

Rubifacient:

It reduce irritation, greasiness and unpleasant odor.

Antifungals:

used as antifungals where it sustained the release of drug.

GEL

Gel is a semi solid formulation that has a pair of components which is liquid phase in rich. After the application of gel, the liquids are drying by the evaporation and, gels of drug are covering the skin.  According to USP definition of gels “Gels are semisolid system consisting of the dispersion made of either small inorganic particle or large organic particles enclosing and interpenetrated by liquid”. Gels are bi-phasic system in which inorganic particles are not soluble or dissolved but merely. It will have dispersed the continuous phase randomly coiled in the flexible chains. Gels are as compare to the creams and other ointments give better drug release. These are highly bio-compatible that’s why minimum risk of adverse reaction and inflammation. The dermatological use of gels has many properties as thixotropic, easily remove, non-greasy, desirable spreadable, non-staining, emollients, compatible with the many excipients. Topical drug delivery systems are applying as directly on the body surface as external part by spraying rubbing, spreading.

Ideal properties of gels:

• It should be inert with healthy skin
• Site specific drug delivery
• It should be less greasy. Their absorption should be better
• It should be water washable
• Topical gel should not be tacky and should show better spreadability
• It should be stable during storage condition

Advantage of gels

• Gels can be self- applied by patient to the affected area
• Applied only disease effected area
• Minimum risk of adverse effect
• Low inflammation
• Natural polymer may be used
• Effective cost
• It is for local therapeutic effect
• Easily washed from applied area due to irritation
• It is achieved cutaneous and percutaneous drug delivery
• It is avoiding gastrointestinal drug absorption
• These are also avoiding enzymatic activity

Disadvantage of gels

• Longer or time-consuming treatment
• Stability as well as storage problem
• Possible to allergic reaction
• Time taking preparation
• Low permeability of some drugs through skin                             

Pharmaceutical Gel

A gel is a solid or semisolid system made up of at least two components that contains a condensed mass and is interpenetrated by a liquid. Gels and jellies are made up of a tiny quantity of solids scattered in a big amount of liquid, however they have a solid-like rather than a liquid-like consistency. The presence of some type of epidermal structure, which gives jelly and gel their solid like qualities, is a distinguishing feature.

Advantages

• Stay away from the first-pass metabolism.
• Convenient, acceptable, and simple to implement.
• Ability to more precisely distribute medications to a specific location.
• Allowing for the use of medicines with a short biological half-life.
• Improving the drug's physiological and pharmacological response.
• Increase patient adherence.
• It can be used for self-medication.
• It is easily able to terminate the medications, when needed.

Uses of Gel

Gels or gelling agents are used:

• As medication delivery methods for drugs that are taken orally.
• To provide a topical medication to the skin, mucous membranes, or eyes.
• Gels for dental care prophylactic like Sodium fluoride and Phosphoric acid gel.
• Gels as lubricant for catheters.

METHOD OF PREPARATION

Microsponges drug delivery system can be prepared in two ways, one-step process or by two-step process that is liquid-liquid suspension polymerization and quasi emulsion solvent diffusion techniques based that is based on physicochemical properties of drug to be loaded.

1. Liquid-liquid suspension Polymerization

The porous microspheres are prepared by suspension polymerization method in liquid-liquid systems. In this method the monomers which are immiscible are first dissolved along with active ingredients in a suitable solvent monomer and are then dispersed in the aqueous phases which consist of additives like surfactant, suspending agents to facilitate formation of suspension. The polymerization is then activated by increasing temperature or irradiation or by addition of catalyst. The polymerization process continues the formation of a reservoir type of system with spherical structure. After the polymerization process, the solvent is removed leaving the spherical structured porous microspheres, i.e., microsponges.

2. Quasi-emulsion solvent diffusion

Porous microspheres (microsponges) were also prepared by a quasi-emulsion solvent diffusion method (two-step process) using an internal phase containing polymer such as eudragit which is dissolved in ethyl alcohol. Then, the drug is slowly added to the polymer solution and dissolved under ultra-sonication at 35?C and plasticizer such as triethylcitrate (TEC) was added in order to aid the plasticity. The inner phase is then poured into external phase containing polyvinyl alcohol and distilled water with continuous stirring for 2 hours. then the mixture was filter to separate the microsponges. The product was washed dried by vacuum oven at 40?c for 24 hours.

3. Emulsion solvent diffusion method

In this method 2 phases are used in different proportion of organic and aqueous (ethyl cellulose and polyvinyl alcohol). The dispersed phase having ethyl cellulose and drug get dissolved in dichloromethane (20 ml) and a definite amount of polyvinyl alcohol added to 150 ml of aqueous continuous phase. Then, the mixture is stirred properly at 1000 rpm for 2hr. The required microsponges were collected by the process of filtration and kept for drying in oven at 40ºc for 24hr. microsponges which are dried were stored in desiccator and ensured of removal of residual solvents is done.

Evaluation Parameters

Percentage yield: the percentage yield of microsponges is calculated by using following equation

Yield = actual weight of product/ total weight of product×100

Morphology of microsponges:

the surface morphology of the microsponges can be studied by scanning electron microscopy (SEM). SEM of a fractured microsponge particle can also be taken to illustrate its ultra-structure.

Determination of loading efficiency and production yield:

the loading efficiency (%) of the microsponges can be calculated according to the following equation

Loading efficiency = actual drug content of microsponge ×100

Theoretical drug content:

the production yield of the micro particles can be determined by calculating accurately the initial weight of the raw materials and the last weight of the microsponges obtained.

Production yield = practical, mass of, microsponge×100

In vitro dissolution studies:

in vitro dissolution studies carried out using dissolution assembly (basket type) in 900 ml of pH   7.4 saline phosphate buffer solution at 37?C rotated at 50 rpm. specified number of aliquots withdrawn at hourly intervals up to 8h.

Drug – polymer compatibility: 

analyzed by DSC and FTIR.

CONCLUSION:

Fungal infection remains continuous and growing threat to human health, inappropriate and irrational use of antifungal chemotherapeutics resulted in the development of multidrug resistance fungal pathogen, unwanted toxicity and low therapeutic efficacy. continuous growth in the field of nanotechnology proposes in the new approach in the treatment of fungal skin infection. prolonged use of antifungal drugs are potential side effects, patients non- compliance, lower bioavailability.to solve this issue, safe and effective novel drug delivery system, which will reduce the dose with increase in concentration of drug in the target organ having low systematic concentration, is highly desirable. 

REFERENCE

1. Roop K Khar, S P Vyas, Farhad J Ahmad, Gaurav K Jain. The theory and practice of industrial pharmacy. CBS Publishers. 2013; 4th edition:714-756
2. Mikari B. Formulation and evaluation of topical liposomal gel for fluconazole. Indian   J Pharm. Sci. 2010; 44(4): 324-325
3. Chadawar V, Shaji J. Microsponge Delivery System. Current Drug Delivery. 2007;4: 123-129
4. Pradhan SK. Microsponge as the versatile tool for drug delivery system. Int J Res Pharma   Chem. 2011; 1(2): 243-258.
5. RJ. (2012). Patel EK, Oswal Microsponges: a novel drug delivery system. IJRPC, 2(2), 237-238.
6. A.P. Pharma, Inc. Microsponge Technology, Topical Technology December 2001. Available at: http://www.appharma.com/PDFs/topicalsht.pdf.
7. Hainey P, Huxham I M, Rowatt B, Sherrington D C. Synthesis and ultrastructural studies of styrene-divinylbenzene polyhipe polymers macromolecules. A.C.S Publishers. 1991; (24): 117-121
8. Abdellatif AAH. A novel controlled release microsponges containing albendazole against haemonchus contortus in experimentally infected goats. Journal of Drug Delivery Science and Technology. 2018 (43): 469-476
9. Pandit AP. Design and devloped of nebivolol loaded microsponge gel for healing of diabetic wound. AAPS Pharma.Sci.Tech. 2016; (18): 846-854
10. Osmani RA. Design and devloped microsponges based novel drug delivery system for       augmented arthritis therapy. Saudi Pharma J. 2015; (23): 562-572
11. Mehta M, Panchal A. Formulation and vitro evaluation of controlled release microsponge gel for topical delivery of clotrimazole. International Journal of Advanced Pharmaceutics. 2012; 2(2): 93-101
12. Swati J, Dhaval B, Mahesh G. Formulation and evaluation of fluconazole soap strip for dermal infections. International Journal of Pharma Tech Research. 2011; 3(4): 2215-2221
13. Jain V, Singh R. Devlopment and characterization of drug loaded microsponge and its colonic delivery system containing paracetamol microsponge. Arch Pharma Research 2011; 34(5):733-740
14. John I. Topical Anti-inflammatory gels of fluocinolone acetonide entrapped in eudragit based microsponge delivery system. Research J. Pharma and Tech. 2008; 1(4): 502-506
15. Nokhodchi A, Jelvehgari M, Siahi M. Factors affecting the morphology of benzoyl peroxide microsponges. Micron Online Journal. 2007; (38): 834-840

 

16. Swati J, Dhaval B, Mahesh G. Formulation and evaluation of fluconazole soap strip for dermal infections. International Journal of Pharma Tech Research. 2011; 3(4): 2215-2221
17. Jain V, Singh R. Devlopment and characterization of drug loaded microsponge and its colonic delivery system containing paracetamol microsponge. Arch Pharma Research 2011; 34(5):733-740
18. John I. Topical Anti-inflammatory gels of fluocinolone acetonide entrapped in eudragit based microsponge delivery system. Research J. Pharma and Tech. 2008; 1(4): 502-506
19. Nokhodchi A, Jelvehgari M, Siahi M. Factors affecting the morphology of benzoyl peroxide microsponges. Micron Online Journal. 2007; (38): 834-840
20. Roop K Khar, S P Vyas, Farhad J Ahmad, Gaurav K Jain. The theory and practice of industrial pharmacy. CBS Publishers. 2013; 4th edition:714-756
21. Mikari B. Formulation and evaluation of topical liposomal gel for fluconazole. Indian   J Pharm. Sci. 2010; 44(4): 324-325
22. Chadawar V, Shaji J. Microsponge Delivery System. Current Drug Delivery. 2007;4: 123-129
23. Pradhan SK. Microsponge as the versatile tool for drug delivery system. Int J Res Pharma   Chem. 2011; 1(2): 243-258.
24. RJ. (2012). Patel EK, Oswal Microsponges: a novel drug delivery system. IJRPC, 2(2), 237-238.
25. A.P. Pharma, Inc. Microsponge Technology, Topical Technology December 2001. Available at: http://www.appharma.com/PDFs/topicalsht.pdf.
26. Hainey P, Huxham I M, Rowatt B, Sherrington D C. Synthesis and ultrastructural studies of styrene-divinylbenzene polyhipe polymers macromolecules. A.C.S Publishers. 1991; (24): 117-121
27. Abdellatif AAH. A novel controlled release microsponges containing albendazole against haemonchus contortus in experimentally infected goats. Journal of Drug Delivery Science and Technology. 2018 (43): 469-476
28. Pandit AP. Design and devloped of nebivolol loaded microsponge gel for healing of diabetic wound. AAPS Pharma.Sci.Tech. 2016; (18): 846-854
29. Osmani RA. Design and devloped microsponges based novel drug delivery system for       augmented arthritis therapy. Saudi Pharma J. 2015; (23): 562-572