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______Review Article Topical Sprays: Novel Delivery System

Prakarsha Chavan, Amrita Bajaj and Akkshata Parab* Department of Pharmaceutics, SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (West), Mumbai - 400 056, Maharashtra, India. ______ABSTRACT Topical systems have been found to have many advantages over oral drug delivery systems such as avoidance of first pass metabolism, gastro intestinal irritability, slow onset of action, etc. The clinical evidence indicates that conventional topical formulations possess certain short comings like irritancy, allergies due to the variety of excipients used. This review deals with all detailed information regarding rational approach to novel topical formulations like topical/ sprays and their formulation, fabrication and evaluation parameters.

Keywords: Topical sprays, Metered dose transdermal spray, Advanced Preservative Free Container.

INTRODUCTION followed by fabrication of a drug delivery system Over the last few decades the treatment of that meets all the stringent needs that are illness has been accomplished by administering specific to the drug molecule (physicochemical to via various other routes in and stability factors), the patient (comfort and addition to traditional oral and sublingual routes cosmetic appeal), the manufacturer (scale up like rectal, parenteral, topical, , etc. and manufacturability) and most important the With the advent of new era of pharmaceutical economy. Topical preparations are used for the dosage forms, topical drug delivery systems localized effects at the site of their application by have established themselves as integral part of virtue of drug penetration into the underlying novel drug delivery products. Topical drug layers of skin or mucous membranes3. delivery systems (TDDS) are gaining increase in popularity and several drugs have been Advantages of Topical Drug Delivery successfully delivered by topical/transdermal Systems4 route for both local and systemic action.  Avoidance of first pass metabolism. Topical/transdermal drug delivery systems offer  Convenient and easy to apply. the non-invasive delivery of medication from the  Achievement of efficacy with lower total daily surface of skin, the largest and most accessible dosage of drug due to continuous drug organ of human body-through its layers, to the input. circulatory system1. Topical delivery is the  Avoidance of gastro-intestinal application of a drug containing formulation to incompatibility. the skin to directly treat cutaneous disorders or  Improve patient compliance. other effects within the skin. Topical drug delivery systems offer many advantages over Limitations of Topical Drug Delivery conventional and oral methods. It Systems5 reduces the load that the oral route commonly  Skin irritation and contact dermatitis may places on the digestive tract and liver. It occur due to the drug and/or excipients. enhances patient compliance and minimizes  Can be used only for drugs which require harmful side effects of a drug caused due to very small plasma concentration for action. temporary overdose2.  Drugs of larger molecular size are not easy The development of TDDS is multidisciplinary to be absorbed by the skin. activity that encompasses fundamental feasibility studies starting from the selection of Topical dosage forms, an alternative to drug molecule to the demonstration of sufficient conventional formulations, are becoming popular drug flux in an ex vivo and in vivo model because of their unique advantages. The topical

International Journal of Pharma And Chemical Research I Volume 2 I Issue 2 I Apr – Jun I 2016 ISSN 2395-3411 Available online at www.ijpacr.com 103 drug delivery systems are mainly used in pain Introduction to Topical sprays management, contraception, infections, The history of aerosol technology is traced back allergies, inflammation and urinary incontinence. to the early years of the twentieth century. The Various novel topical dosage forms include: principles of aerosol technology were applied to  Topical the pharmaceutical aerosols in early 1950s. The  Topical sprays topical aerosol products were intended for  Topical patches application for treatment of burns, minor cuts,  Topical films bruises, infection and various dermatological conditions. Historically, developments in topical Topical gels drug delivery have been incremental, focusing Gels are transparent to opaque semisolids on overcoming problems associated with the containing a high ratio of solvent to gelling barrier properties of the skin, reducing skin agent. Gels are created by entrapment of large irritation rates and improving the aesthetics amounts of aqueous or hydroalcoholic in a associated with conventional topical drug network of colloidal solid particles, consisting of delivery systems. Regardless of the inorganic substances, such as aluminum salts or transdermal/topical drug delivery systems in organic polymers of natural or synthetic origin. development, the patient acceptability from an Depending upon the nature of colloidal aesthetic, safety and non-irritancy perspective substance and the liquid in the formulation, the will remain the main focus for the newer gels range in appearance from entirely clear to products entering the market. The non-invasive opaque. Most topical gels are prepared with character of transdermal drug delivery makes it organic polymers, such as carbomers, that accessible to a wide range of patient population impart an aesthetically pleasing, clear, and is a highly acceptable option for drug sparkling appearance to the product, and are dosing. easily washed off the skin with water6. Problems with existing technology Topical patches Transdermal/topical drug delivery systems (TDDS) such as patches, creams and gels still A topical patch is a medicated adhesive patch 8 that is placed on the skin to deliver a specific suffer from some limitations . The precision of dose of medication through the skin and into the dosing is particularly an issue with creams and bloodstream. The first commercially available gels, especially as it has also been topical prescription patch was approved by the demonstrated that altering the dose applied per U.S. Food and Drug Administration in December surface area can affect the drug delivery profile, although conflicting effects have been observed 1979, namely scopolamine patch for motion 9 sickness7. The adhesive is covered by a release when the area of application is increased . liner, which needs to be peeled off before Although precision of dosing might be less of an applying the patch on the skin. issue in patch systems, there is relatively little flexibility available for the dosing. Variability of Topical films dosing has also been highlighted as an issue with TDD systems. Most studies have focused These are medicated transparent polymeric 10 films similar to topical patches. The only on the intra-site variability of dosing that many difference is that films do not contain adhesive have attributed to the different levels of skin polymer. hydration found at various anatomical sites. It has also been shown that variations in Topical sprays temperature, possibly due to local Topical sprays are dosage forms in which microcirculation changes in the skin, can affect polymeric of drug is sprayed over the the drug delivery profile from TDDS. Variability intact skin so as to get a sustained release of of dosing has also been observed between different skin types, skin of different aged drug from the polymeric matrix. The drug is 11 12 present in saturated form in the polymer matrix. patients and diseased skin . As the organic solvent vehicle evaporates, Psychological stress has also been shown to slowly the drug diffuses through the polymer impact skin barrier recovery. The relatively high matrix and passes from the skin barrier. skin irritation rates that were associated with the earlier transdermal patches have been somewhat reduced, but the inherent occlusive nature of the products still dictates that this

International Journal of Pharma And Chemical Research I Volume 2 I Issue 2 I Apr – Jun I 2016 ISSN 2395-3411 Available online at www.ijpacr.com 104 remains an issue for TDDS13. The occurrence of component also enables the formulation to have sensitization reported has been up to 50% with uniform distribution on the skin over a defined clonidine patch and seen to increase with time of area after application, without leaving excess exposure14. As consumers become increasingly vehicle. Hence, this ensures that the dose can educated about product options, their be administered in a precise and highly expectations regarding skin irritation rates and reproducible manner and that aesthetic value patch size have also been increased. From the and transference issues are avoided. The patient‟s perspective, the large surface area for evaporation of some of the vehicle leads to an application, particularly for gels and creams, increase in concentration of the active drug and which is required to produce adequate dosing hence enhanced partitioning into the stratum levels, can also translate into aesthetic corneum. concerns. It is crucial that formulators consider The non-volatile component prevents the drug the aesthetics of the product after application, to from precipitating from solution as the volatile avoid unpleasant stickiness or greasiness and to solvent component evaporates. The minimize residue on the skin. A recent physicochemical properties of the nonvolatile development that attempts to overcome some of component have been selected so that it the limitations of TDDS involves application of partitions rapidly into the stratum corneum and the concept of evaporative delivery and serves to disrupt the ordered intercellular lipids formulating aerosol. and enhance permeation. Hence, this type of delivery system creates an invisible depot of The concept of evaporative delivery- topical drug and enhancer in the stratum corneum from aerosol sprays which the drug can be slowly diffused into the Traditionally, aerosols as topical spray systems skin. MDTS relies on the combination of newly were largely used as a medium for transdermal identified GRAS (Generally recognized as safe) drug delivery. Aerosols are those products that chemical penetration enhancers and the depend on the power of a compressed or accurate and precise topical dosing of volatile liquefied gas to expel the content from the and non volatile vehicles16. container. However, these propellants based The MDTS has the potential to offer enhanced sprays have now been replaced by propellant passive topical drug delivery system with little or free and polymer based Metered dose no skin irritation primarily as a result of its non- transdermal sprays (MDTS). occlusive nature and the skin tolerability. The MDTS is a topical solution made up of a Improved cosmetic acceptability compared to volatile and nonvolatile vehicle containing the patches, gels, and creams has been achieved drug dissolved as a single-phase solution. A through the judicious use of excipients. The finite metered-dose of the formulation applied to product is more convenient to use, since it is into intact skin results in subsequent evaporation of compact unit and can be applied easily and the volatile component of the vehicle, leaving the quickly. The MDTS features a small, discrete, remaining nonvolatile penetration enhancer and hand-held applicator that delivers a pre-set dose drug to rapidly partition into the stratum corneum of a proprietary formulation of drug to the skin during the first minute after application, resulting and the package is tamper proof system. It also in a stratum corneum reservoir of drug and prevents contamination of unused contents. The enhancer. It is diagrammatically represented in inherent dosage flexibility of the MDTS and the Figure 1. Following a once-daily application of simplicity of manufacture provide a significant the MDTS a sustained and enhanced cost-of-goods advantage relative to traditional penetration of the drug across the skin can be transdermal systems. achieved from the stratum corneum reservoir. This delivery system allows for patient friendly, Increases in drug diffusivity are related primarily discreet and convenient, dosing via topical to stratum corneum lipid fluidization or lipid administration, thus avoiding gastro-intestinal phase separation15. tract irritation. It provides many advantages over This formulation represents a micro-dose patches and gels, including a non-messy evaporative system that provides passive and application with little or no skin irritation. non-occlusive delivery. The system developed is Metered-dose transdermal spray has the a rapid-drying solution containing a volatile potential to expand the growth of TDDS by component that enables the volume per area of broadening patient acceptance and application to be precisely defined. This pharmaceutical applications for enhanced TDD.

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Fig. 1: Schematic representation of the partitioning process for a rapid-drying, topical spray formulation

Advantages of the Metered Dose Last two components are collectively called as Transdermal Spray Formulations packaging component.  The product is more convenient to use, since it is into compact unit and can be A. Product Concentrate applied easily and quickly. Product concentrate consists of a single or  It has potential to offer enhanced combination of active ingredients and contains passive topical drug delivery with little or other ingredients depending upon the type of no skin irritation primarily as a result of MDTS formulation. The product concentrate its non-occlusive nature and the skin comprises of the following: tolerability.  Improved cosmetic acceptability 1. Active Ingredient compared to patches, gels and creams The topical/transdermal route is an extremely has been achieved through the judicious attractive option for the drugs with appropriate use of excipients. pharmacology and physical chemistry. The  This technology can be used to evaluate foremost requirement of MDTS is that the drug the feasibility of topical delivery for possesses the right mix of physicochemical and newly developed drugs. biological properties for topical/transdermal drug delivery. Active ingredient used for metered Metering pumps are used now a day to provide dose topical spray must be therapeutically propellant free delivery.17 Pump technology has effective at a relative low dose and have a lower made enormous advances as a result of the molecular weight, be non irritating to the skin fluorocarbon ban in 1976. surface and should have some affinity for the When finger is pressed on the actuator, the skin, it should dissolve in the fatty matrix piston and clapper descend. The dose chamber between the skin cell. It should be stable and gets closed and further finger pressure causes compatible with the vehicle or solvents used in an increase in hydraulic pressure in the liquid the formulation. isolated in the dose chamber. As the liquid The MDTS is specially used in chronic pain cannot be compressed it counters the action of management, central nervous system disorders the spring and pushes back the clapper towards including nausea, anxiety-related conditions and the base, passes through the centre of the stem Alzheimer‟s and Parkinson disease, and gets atomized by the spray insert. menopause, female androgen insufficiency, male androgen insufficiency, contraception, Metered Dose Topical Spray Package urinary incontinence, cessation18. Components Some of the drugs incorporated in sprays Metered Dose Topical Spray aerosol product include , Nestorone, Fentanyl, Nicotine, comprises of four separate components. Buspirone, Granisetron, Testosterone, A. Product concentrate Hydrocortisone aceponate. B. Propellant C. Container D. Valve/ Metering pumps and actuator

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2. Solvents and Co-solvents 5. The polymer must be easy to Volatile solvents: It is most desirable that, after manufacture and it should yield itself application of the drug composition to the skin, into desired product and should allow the volatile component of the composition incorporation of large quantities of active evaporates and the area of skin to which the component without deteriorating its drug composition was applied becomes touch- mechanical properties. dry. 6. 6. Cost of polymers should not be Nonvolatile vehicle: Normally non volatile excessive. solvents are selected based on the miscibility with volatile solvents. The selection is also Different polymers used are: based upon the polymer solubility in solvent. Various grades of Eudragits (Eudragit type The solvent helps to spread the drug and the RSPO, L-100, RL-100, RLPO, S-100), polyvinyl penetration enhancer over the skin. For example acetate, cellulose acetate, poly vinyl alcohol, methanol, ethanol, acetone, isopropanol, ethyl povidone vinyl acetate, polyvinylnpyrolidone acetate, methylene chloride has been used as (Kollidon K-30, Kollidon K-25 and Kollidon VA solvent. 64), cellulose derivatives such as Ethyl Co-Solvents perform a variety of functions in cellulose, Hydroxy ethyl cellulose, Cellulose topical aerosol formulations. While selecting co- acetate phthalate, Hydroxy propyl methyl solvents various factors like stability, safety, cellulose type K4M and K15M, Carbomers, compatibility must be considered. Co-Solvents Poloxamer etc20. help to reduce vapour pressure of propellant. Co-Solvents also help in solubilizing the drug in 4. Penetration enhancers the system19. A dermal penetration enhancer is an agent that facilitates the passage of an active agent 3. Film forming Polymers through the skin. The dermal penetration These macromolecules are very large molecules enhancing compounds are of low toxicity to the consisting of many repeating units and are skin and thus are safe at high concentration, are formed by a process of polymerization which non-irritating, and excellent promoters of links together small molecules, monomers. For percutaneous absorption. These are example: Carbomer or carbopol, Poloxamer (or compounds, which promote skin permeability by pluronic), Polymethacrylates (Eudragits) etc. altering the skin as a barrier to the flux of a Such film forming polymers are utilized in the desired penetrant. Mainly used penetration development of Metered dose transdermal enhancers are terpenes, terpenoids or essential sprays. Diffusion of the drug through the oils, pyrrolidones and azones, fatty acids and polymer and absorption through the skin barrier esters, alcohols, glycols, glycerides, surfactants are the rate limiting steps. and phospholipids23. They are dissolved in to the non-volatile solvent along with permeation enhancer and the drug is 5. Solubilizers dissolved in volatile solvent. After evaporation of The solubilizers are used to dissolve or suspend solvent they form film onto the skin surface the drug in chosen vehicle. Solubility influences which releases the drug and this drug goes to a drug's dissolution, release kinetics, and systemic circulation to give effect. Following ultimately its bioavailability and thus plays a factors are taken into consideration during the major role in the formulation of drug delivery selection of polymer: systems. Many of the solubilizers also enhance 1. Molecular weight and chemical percutaneous penetration of the drug and/or act functionality of polymer must allow as humectants. Preferred solubilizers include proper diffusion and release of specific surfactants such as SLS (Sodium lauryl drugs. Increased polymer weight sulphate), polyhydric alcohols like propylene decreases drug diffusivity in polymers. glycol or polyethylene glycols, vitamin E TGPS 2. Polymer should not react with the drug. (tocopheryl polyethylene glycol 100 succinate) 3. The polymer and its degradation and labrasol etc. products must be non-toxic. 4. The polymer should not decompose on 6. Plasticizers storage or during the useful life of Plasticizers are additives that increase the device. plasticity or fluidity of a material. Plasticizers work by embedding themselves between the

International Journal of Pharma And Chemical Research I Volume 2 I Issue 2 I Apr – Jun I 2016 ISSN 2395-3411 Available online at www.ijpacr.com 107 chains of polymers, spacing them apart valves presently available. Specially designed (increasing the "free volume"), and thus glass bottles having „V‟ shape carved at the significantly lowering the glass transition base are used. The dip tube of the pump fits in temperature for the polymer and making it this „V‟ shape cavity such that the last drop of softer. Plasticizer includes triethyl citrate, the spray can also be sprayed out. There are dimethly isosorbide, castor oil, polyhydric also customized containers available from alcohols such as propylene glycol or various manufacturers24. polyethylene glycol. 2. Metering Valves/ Pump 7. Humectants Aerosol valves are used for dispensing aerosol In the presence of water the permeability of skin products as sprays, foams and semisolid increases significantly. Hydration is the most streams. The MDTS technology utilizes metered important factor which increases the permeation dose valves for delivering definite amount of capacity of skin. Hence, humectants are used in drug per actuation or per spray. Metered valves the formulation of topical/transdermal have been developed to dispense given formulations. Humectants used includes quantities of medication, thus metering and polyhydric alcohols e.g. propylene glycol, controlling the dose delivered. The use of polyethylene glycol, glycerol, sorbitol, butylene metering pumps helps to deliver propellant free glycol and polyvinylpyrrolidone21, 22. delivery as external pressure is required to actuate the content present inside the container. B. Propellants The metered aerosol pump ensures accurate The propellant is the “Heart” of the aerosol dosing onto the intact skin and eliminates many product. The propellant is defined as “liquefied of the administration problems. Pumps are gas with a vapour pressure greater than designed to accurately deliver volumes as low atmospheric pressure at a temperature of 105° as 25μl and as high as 0.5 to 1 ml per actuation. F”. For the topical aerosols, the propellant is one Two types of pumps namely VP7 and VP3 are of the essential but now optional components of available in markets which are made up of the entire package. It performs dual functions: pharmaceutically acceptable materials such as supplies the necessary pressure to expel polypropylene and polyethylene. A special range material from the container when the valve is of VP7 pumps such as VP7H (as in Figure 2) opened and helps to convert the product into the which is resistant to hydrocarbons has also been desired physical form for its end use. Propellant developed by Aptar Pharma28. Functions of the is necessary for developing proper pressure metering valves are to meter accurately and within an aerosol container and for expulsion of repetitively small volumes of liquid containing the composition when the valve is open. It is the drug and to seal the pack against undue also responsible, together with the valve, for leakage of propellant vapour and to deliver dispensing the product as a fine spray. product in the desired form.

C. Packaging Components MDTS has three packaging components: 1. Container 2. Metering valve/ pump 3. Actuator

1. Containers Various containers have been used for pharmaceutical aerosols. Because of esthetics and excellent compatibility with drugs, glass, stainless steel and aluminium containers are selected. MDTS formulation makes use of Fig. 2: Vertical Action Valve plastic coated glass bottles ranging in size from 10ml to 30ml for solution aerosols. Clarity of the Pumps have two main functions content can be checked in the path of strong A. Dynamic Function light using glass containers. All commercially Delivers metered dose of liquid or viscous available glass bottles have 20 mm neck finish pharmaceutical formulation. Spray (liquid) or and adapt easily to all of the metered aerosol

International Journal of Pharma And Chemical Research I Volume 2 I Issue 2 I Apr – Jun I 2016 ISSN 2395-3411 Available online at www.ijpacr.com 108 dispense (viscous product) with ergonomically and concentration of drug/enhancer per unit designed actuators. In some instances, pumps area of skin. also participate in the product protection (oxidation/contamination).

B. Static Function Closure: Sealing of the container and protection of the content at rest Compatibility: No absorption/ adsorption, low level of extractables or leachables from components of the pump.

3. Actuators Fig. 3: Representative Picture of Actuator Precision molded plastics constructed from a variety of polyethylene or polypropylene Selection of Container materials by injection molding. Accurate APF Plus (Advance preservative free) screw-on dimensional control is required for critical areas spray container from Aptar pharma (as seen in like spray orifice to ensure absence of leakage figure 4) was procured for delivering the and correct spray performance during discharge. accurate amount of drug from container. Spring Topical spray actuators of different shapes and loaded tip seal mechanism acts as a physical sizes are available25. Actuator incorporates the barrier avoiding crystallization and discharge orifice or spray nozzle and a socket to contamination of the product, clogging of engage and form a seal with the metering valve nozzles can be avoided. Micro filter membrane system. In case of metered dose topical spray in the air flow prevents the product from formulations, a centrifugal type spray nozzle (as contamination. The APF Plus spray system in Figure 3) controls the spray angle (a) and ensures accurate dosing and elimination of nozzle shroud controls the height (h) of the many of the administration problems. The spray nozzle above the skin. The nozzle shroud concept of propellant and preservative free also ensures the nozzle orifice is kept metered delivery offers a new dimension to perpendicular to the surface of the skin. By deliver potent therapeutic agents. controlling the parameters like concentration of drug and enhancer in the vehicle, the spray APF PLUS Advantages volume, angle and height, the formulator can  Fine mist control the total application area of the spray  Round spray pattern  Long and stable fully developed phase of spray

Fig. 4: Advanced preservative free Plus Container

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Evaluation of Metered Dose Topical Spray incorporating dilute solution of methylene blue in Formulations the formulation and spraying on a Whatmann The quality control tests on the metered dose paper placed at a definite distance. This paper is topical spray formulations are performed mainly clipped on a board and the spray formulations to optimize the drug delivery systems and to are sprayed at the distance of 15cm. Whatmann improve the efficiency of delivery of the paper is used for evaluating the spray pattern as medicinal agent. dye gives a distinct blue coloration which shows The metered dose topical spray formulations are the spray pattern on white background of evaluated on the basis of tests indicated for Whatmann paper after application of the spray27. aerosol preparations as per monographs in IP, BP and USP [26]. Tests related to propellants e. Evaporation time/ Film formation time are not carried out, as the developed metered The evaporation time or time required for the dose topical spray formulations do not contain spray film to dry is recorded. Time required for propellants in the system. getting totally dry film is noted. a. Viscosity f. pH The viscosity of the is measured at The pH of the metered dose topical spray 25±1°C using Brookfield viscometer. The spindle formulations are recorded by pH meter. is rotated at 1 rpm. g. Ex- vivo Physical Evaluation b. Volume of solution delivered upon each Placebo batches are actuated on left hand actuation palms of three healthy human volunteers of 21– The volume of solution delivered upon each 27 years in age, four times every 10 s from a actuation is calculated using eq. 1. distance of 15cm. Time required for film formation, appearance of film, flexibility of film, AL = (Wt –Wo)/ Dn ………….. (1) feeling of warmth and subsequent cooling sensation, irritation potential and water Where AL is the volume of solution delivered washability are recorded. The appearance of the upon each actuation, Wt is weight of formulation film is graded as shiny and transparent (+) or after actuation, Wo is the initial weight of the shiny and translucent (++) or dull and opaque formulation before actuation, and Dn is the (+++). Dermal adhesion, flexibility and water density of the formulation. An average weight of washability of the film are graded as poor (+), five actuations is calculated. moderate (++) or good (+++). To check dermal adhesion of the film, the palms c. Spray angle of each volunteer are rotated for 10 min in anti- The method of impingement of spray on a piece clock wise direction with occasional opening and of paper is used for the study. Sudan red (10 closing of palm, after 8min of actuation of the mg) is dissolved in formulation to facilitate spray. During the study (720 min), the nature of visualization. The sprays are actuated in the film is carefully evaluated for any fracture, horizontal direction onto a white paper mounted separation or removal. After 720 min, water at a distance of 15 cm from the nozzle. The washability of the film is checked. radius of the circle, formed on the paper, is recorded in triplicate from different directions. CONCLUSION Spray angle (θ) is calculated by eq. 2. Topical drug delivery systems offer several advantages over oral delivery systems. This Spray angle (θ) = tan-1 (l/r)……………… (2) review explains added advantage of the novel drug delivery systems like the topical sprays Where „l’ is the distance of paper from the using metered dose transdermal spray system. nozzle, and r is the average radius of the circle. These topical spray formulations are easy to formulate and fabricate possessing targeted d. Spray Pattern drug delivery, uniform dosing, patient Characterization of spray pattern is important for compliance, aesthetic appeal, good efficacy and evaluating the actuator, spray pump non irritancy. Such novel formulations can be a performance as well as deposition pattern of better future prospective in topical dosage forms formulation. Spray pattern of the metered dose over the conventional dosage forms. topical spray formulations is checked by

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