LIQUID-LIQUID SUSPENSION POLYMERIZATION

MICROSPONGE DRUG DELIVERY SYSTEM

PRESENTED BY Karad B. B. M Pharm- I Sem

GUIDED BYMrs. Barhate A.N.SVPMSCollege of Pharmacy, Malegaon (BkII) Tal.Baramati, Dist. Pune 2015-2016

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CONTENTSIntroductionNeed of microsponge delivery systemMethods of preparationCharacteristics of microspongesRelease mechanismAdvantages & limitationsApplicationsEvaluation ParametersMarketed formulationsReferences

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Introduction 1,5,12MICROSPONGE: Microsponges are polymeric delivery systems composed of porous microspheres. They are tiny sponge-like spherical particles with a large porous surface. Microsponge is recent novel technique for control release and target specific drug delivery system.

They are desire to deliver API efficiently at the minimum dose and also to enhance stability, reduce side effect and modify drug release.Typically in 5-25 m in diameter.

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Microsponge as Topical drug delivery

The human skin is a large and complex organ that protects internal tissue from environmental exposure. As the interface between the organism and the external world, the skin is susceptible to injuries from the environment or from other organisms.

Topical drug delivery systems are formulated either to give local effect or to enter in to the systemic circulation, where skin serves as the portal of entry to the drug and various formulations made available in the market are creams, gels, lotions, ointments etc.

Skin4

Main drawbacks of topical preparations for local action are they may readily absorbed and hence, less duration of action and decreased activity. Similarly topical preparations for systemic action have drawback like drug doesnt reaches the systemic circulation in sufficient amounts. To overcome this problems MDS technique plays imp. Role.A Microsponge Delivery System (MDS) is patented, highly cross-linked, porous, polymeric microspheres that can entrap wide range of actives and then release them with desired rate. This system is applicable for the improvement of performance of topically applied drugs. When microsponge delivery system applied to the skin, the release of drug can be controlled through diffusion or other variety of triggers, including rubbing, moisture, pH, friction, and skin temperature. Thus the microsponge should remain maximum time at the skin and below the epidermis and release the medicament slowly.5

Typical view of Microsponges

Fig.Highly porous nature of Microsponge

Fig.Retinol entrapped in Microsponge6

NEED FOR MICROSPONGE DELIVERY SYSTEMMicrosponges consist of non-collapsible structures with porous surface through which active ingredients are released in a controlled manner.Their characteristic feature is the capacity to adsorb orload a high degree of active materials into the particle and on to its surface.To prevent excessive accumulation of ingredients within the epidermis and the dermis.Controlled release of drug on to epidermis does not enter the systemic circulation in significant amounts. 7

METHODS OF MICROSPONGE PREPARATION1,4,6,11,23Drug loading in microsponges can take place in two ways, one-step process or by two-step process ; based on physico-chemical properties of drug to be loaded.

Following techniques are commonly used

Liquid-liquid suspension polymerization Quasi-emulsion solvent diffusion 8

Preparation of microspongeDrug loading in microsponge

One step processTwo step processLiquid -liquid suspension polymerisationQuasi emulsion solvent diffusionBased on physico-chemical properties of drug to be loaded

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Liquid-liquid suspension polymerization

Microsponges are prepared by suspension polymerization process in liquid-liquid systems (one-step process).In their preparation, the monomers are first dissolved along with active ingredients in a suitable solvent solution of monomer and are then dispersed in the aqueous phase, which consist of additives (surfactant, suspending agents, etc. to aid in formation of suspension).Once the suspension is established with distinct droplets of the preferred size then, polymerization is initiated by increasing temperature as well as irradiation.After polymerization process is complete, the liquid is removed which is permeate within preformed microsponges then, incorporates the variety of active substances like anti fungal, anti acne, anti inflammatory etc. which act as a topical carriers.

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1. LIQUID-LIQUID SUSPENSION POLYMERIZATION

Fig.:- Reaction vessel for microsponge preparation by liquid-liquid Suspension Polymerization11

The various steps in the preparation of microsponges are summarized as:Selection of monomer or combination of monomers.

Formation of chain monomers as polymerization begins

Formations of ladders as a result of cross linking between chain monomers

Folding of monomer ladder to form spherical particles

Agglomeration of microspheres, which give rise to formation of bunches of microspheres

Binding of bunches to form microsponges.

Fig. Steps in the preparation of microsponges12

Quasi-emulsion solvent diffusion:

Porous microspheres (microsponges) are 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 35C and plasticizer such as triethylcitrate (TEC) is 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 is filtered to separate the microsponges. The product (microsponges) was washed and dried in an air- heated oven at 50C for 24 hr.13

2. QUASI-EMULSION SOLVENT DIFFUSION

Fig.: Preparation of microsponges by quasi emulsion solvent diffusion method 14

CHARACTERISTICS OF MICROSPONGES10,15,17Microsponge formulations are stable over range of pH 1 to 11.It is stable at the temperature up to 130 c.They are compatible with most vehicles and ingredients.They are self sterilizing as their average pore size is 0.25m where bacteria cannot penetrate.Microsponge formulations have high entrapment upto 50 to 60%.It is free flowing and can be cost effective reduced irritation and hence improved patient compliance.

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Drug explored in Microsponge drug delivery system 1,17IbuprofenFluconazoleBenzoyl peroxideKetoprofenParacetamolDicyclomineFlurbiprofenKetoconazoleTretinoinTrolamineRetinolSalicylic acid16

CHARACTERISTICS OF MATERIALS ENTRAPED IN MICROSPONGES10,23,15,17They should be completely miscible in monomer.They should be water immiscible or at most only slightly soluble.They should be inert to monomers.They should be stable in contact with polymerization catalyst and conditions of polymerization

Mostly liquid or soluble ingredients can be entrapped In the microsponge. 17

Release Mechanisms2,4,17,6PressureTemperature changeSolubilitypH triggred system18

Pressure:Rubbing/ pressure applied can release active ingredient from microsponges onto skin. The amount released depends upon various characteristics of the sponge. Temperature change: Some entrapped actives can be too viscous at room temperature to flow spontaneously from Microsponges onto the skin. Increased in skin temperature can result in an increased flow rate and hence release. 19

Solubility: Microsponges loaded with water-soluble ingredients like anti-perspirants and antiseptics will release the ingredient in the presence of water. The release can also be activated by diffusion taking into consideration the partition coefficient of the ingredient between the microsponges and the outside system.

pH triggered systems:Triggering the pH-based release of the active can be achieved by modifying the coating on the microsponge. 20

ADVANTAGES OF MICROSPONGE1,2,5,15Microsponge systems are non-irritating, non-mutagenic, non-allergenic and non-toxic.

Improved formulation flexibility.

Extended release of drug continuous upto 12 hours.

Reduce irritation and improve patient complience.

Microsponge drug delivery can improve bioavailability of drug.

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ADVANTAGES OF MICROSPONGEThey have better thermal, physical and chemical stability.Allows incorporation of immiscible product.Advance oil control.Easy to formulate.

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LIMITATIONS2,5The preparation methods usually use organic solvents as porogens, which pose an environmental hazard, as some may be highly inflammable, posing a safety hazard.

In some cases, the traces of residual monomers have been observed, which may be toxic and hazardous to health. 23

Sr.No.Active AgentsApplications1.SunscreensImproved Protection Against Sunburns and Sun Related Injuries.2.Anti-acne:E.g. Benzoyl peroxideMaintained Efficacy with Decreased Skin Irritation and Sensitization. 3.Anti-inflammatory:E.g. hydrocortisone Long Lasting Activity With Reduction of Skin Allergic Response and Dermatoses. 4.Anti-dandruffs: E.g. zinc pyrithione, selenium sulfide. Reduced Unpleasant Odour with Lowered Irritation with Extended Safety and Efficacy .

Applications2,3,1124

Sr.No.Active AgentApplications5.AntipruriticsExtended and improved activity.

6.Skin depigmenting: E.g.hydroquinone. Improved stabilization against oxidation with improved efficacy and aesthetic agents .7.RubefacientsProlonged activity with reduced irritancy, greasiness and odour. 8.Anti-fungalsSustained release of active ingredients.

Applications25

Evaluation parameters1,4,6,18Particle size (Microscopy)Morphology and Surface topographyDetermination of true density Loading efficiency and production yieldCharacterization of pore structure Compatibility studies Resiliency (viscoelastic properties) Drug release study26

Particle size analysis of loaded and unloaded microsponges can be performed by laser light diffractometer or any other suitable method. The values can be expressed for all formulations as mean size range. Cumulative percentage drug release from microsponges of different particle size must be plotted against time to study effect of particle size on drug release. Particles larger than 30m can impart gritty feeling and hence particles of sizes between 10 and 25m are preferred to use in final topical formulation. 1. Particle size determination :27

For morphology and surface topography, prepared microsponges can be coated with goldpalladium under an argon atmosphere at room temperature and then 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.

2. Morphology and surface topography of microsponges :

The true density of microparticles is measured using an ultra-pycnometer under helium gas and is calculated from a mean of repeated determinations. 3. Determination of true Density :28

4. Determination of loading efficiency and production yield :29

5. Characterization of pore structure :Mercury intrusion porosimetry can be employed to study effect of pore diameter and volume with rate of drug release from microsponges.

Porosity parameters of microsponges such as intrusionextrusion isotherms, pore size distribution, total pore surface area, average pore diameters, shape and morphology of the pores, bulk and apparent density can be determined by using mercury intrusion porosimetry.30

6. Compatibility studies :Compatibility of drug with reaction adjuncts can be studied by thin layer chromatography (TLC) and Fourier Transform Infra-red spectroscopy (FT-IR). Effect of polymerization on crystallinity of the drug can be studied by powder X-ray diffraction (XRD) and Differential Scanning Colorimetry (DSC).

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7. Resiliency :Resiliency (viscoelastic properties) of Microsponges can be modified to produce beadlets that is softer or firmer according to the needs of the final formulation. Increased cross- linking tends to slow down the rate of release. In vitro release studies can be performed using United States Pharmacopeial (USP) dissolution apparatus equipped with a modified basket consisted of 5 m stainless steel mesh at 37C. The release medium is selected according to the type of formulation that is, topical or oral, while considering solubility of active ingredients to ensure sink conditions.8.Invitro Drug Release study :32

Examples of MDS with their formulation 633MDSDrugsDisease treatmentGelsBenzoyl peroxideAnti-acne TreatmentFluconazoleAnti-fungalDiclofenac SodiumAnti InflammationTerbinafine HCLAnti-fungalLotionsBenzoyl PeroxideAnti-acne TreatmentCreamsHydroquinone and RetinolMelanomaOtherIbuprofenNSAIDMefenamic acidRhumatoid arthritis

Marketed formulation of the MDS1,3,11,18Product NameActive IngredientTreatmentManufacturerRetin-A-Micro0.1% and 0.4% tretinoin in an aq. gel. Acne vulgarisOrtho-McNeil Pharmaceutical, Inc.Cerac Cream, 0.5%0.5% flurouracil Actinic Keratoses (AK).Dermik Laboratories, Inc.Berwyn, PA 19312 USA Oil Control LotionNatural antibioticsAcne-Prone, oily skin conditions. Fountain Cosmetics

Ultra Guard DimethiconeProtect a babys skin from diaper rash. Scott Paper Company.Salicylic Peel 20

Salicylic Peel 30Salicylic acid 20%

Salicylic acid 30%Improve fine lines, pigmentation and acne concerns. Biophora.

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Product NameActive IngredientTreatmentManufacturerLactrex 12%Moisturizing Cream12% lactic acid as the neutral ammonium salt, ammonium lactate.Long lasting moisturization.SDR Pharmaceuticals,Inc., Andover, NJU.S.A. 07821.EpiQuin MicroRetinol and HydroquinoneMinimize skin irritation, Reduce age spot, sun spot etc.Skin Medica Inc.Line eliminator Dual Retinol Facial TreatmentRetinol (vitamin A)Diminish wrinkle, appearance of fine lines etc.AvonSportscream RS and XSTopical analgesic, anti-inflammatory and counterirritant.Management of Musculoskeletal conditions. Embil Pharmaceutical Co.Ltd.Micro peel plus /Acne peelSalicylic acid in forms of Microcrystals.Remove all dead cells doing no damage to skin. Biomedic.

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Ultra guardCerac creamEpiQuin MicroNeutrogenaShine stopperOil controlDermalogicaOil controlMuradMoisturizing creamImageSunscreenMarketed Preparations36

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