Topical Creams Contain One Or More Drug Substances Biology Essay

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Topical creams are generally a semi-solid dosage form containing one or more drug substances dissolved or dispersed in a suitable base used for topical administration of the drug. It can be also described as an 'emulsion system that contains more than 20% water and volatiles and/or less than 50% of hydrocarbons, waxes, or polyethylene glycols as the vehicle for external application to the skin' [1].Depending upon either oil as dispersion phase or water as dispersion media or vice versa., appearance and rheological characteristics of topical cream get changed. As w/o (water in oil ) emulsion gives non greasy appearance while o/w (oil in water) emulsion makes cream greasy.

Route of administration:

Topical creams are applied to the skin, mucous membranes of buccal tissues, rectal membrane, vaginal mucosa, urethral membrane, ear lining and cornea. When drug is applied to skin it diffuses through skin barriers i.e. three layers of skin, first is stratum corneum, outer hydrophobic thick layer (10-20µ) which act as permeability barrier. Then second one is viable epidermis made up of keratinocytes layer and serve as barrier for intercellular pathway. Third layer is dermis an acellular part of skin with blood vessel and lymphatic vessel and nerve endings with sebaceous gland, hair follicle and sweat gland. The drug penetrates through skin by fallowing pathways [2,3],

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Excipients are the essential part of any drug formulation, which do not contribute in any therapeutic effect but improves its integrity as a dosage form by avoiding physical and chemical incompatibility. Excipients are generally used to improve the pharmaceutical characteristic of active ingredients such as dissolution, disintegration, flowability, bioavailability, stability compressibility, taste and elegance. As per their function they are categorized as disintegrating agent, binders, emulsifier, glidant, preservatives, sweeteners and colouring agents. [4]

Ideal properties of excipients:

An ideal excipient should be inert, physically, chemically stable and should not react with active pharmaceutical ingredient. As well as excipients should be non toxic and harmless to human. Finally last but not least excipients should be cost effective. [4]

Excipients used in topical formulation:

Hydrocarbons and Hydrocarbon wax:

Hydrocarbons in the form of petrolatum and mineral oil are extensively used to compound oil bases of semisolid dosage forms. Petrolatum is a complex mixture of semisolid hydrocarbons, while mineral oils are the byproduct of the petroleum. Hydrocarbon waxes such as paraffin's are used to improve the viscosity. They act as emollient by forming a greasy film on skin which prevent water loss and hydrate the skin and improves absorption of drug through skin [3, 5].

Vegetable oil bases:

Vegetable oils such as peanut oil, almond oil, olive oil can be used as oil bases but they are prone to oxidation which may hamper the stability of cream [3].

Fatty acid and alcohols:

Fatty acids are the long polymeric chains of saturated or unsaturated carbons or a mixture of fatty acids such as stearic acid, cetyl and stearyl alcohol used in topical cream as a base. Stearic acid also acts as emulsifier to develop consistency in emulsion, to endow a better spreadability to cream. Stearyl alcohol and cetyl alcohol are also widely used in cream formulation to give additive effect as emulsifier[3].

Emulsifying agent:

These are the substances used to ensure stability of the aqueous and oil and water phase in the topical cream by forming an interfacial film around the dispersed phase. Emulsifying agents classified into three broad categories [3],

1. Surfactants

2. Hydrophilic colloids

3. Finely divides solids.

Surfactants:

'Surfactant' as the name indicates they are surface active agents, which are used to reduce surface tension between lipid and water phase. Surfactants are further classified as per their ionization in aqueous media into anionic, cationic and non-ionic surfactants [7].

Anionic surfactant:

Anionic surfactants dissociates in aqueous media to form negative ions or anions which gives stability to the emulsion. These surfactants are most widely used in industries due to their cost effectiveness. Some of the important anionic surfactant groups are, Alkali metal and ammonium soaps, Carboxylic acids, Sulfuric acid esters and Substituted alkyl amides [5].

Cationic surfactant:

Cationic surfactant dissociates in aqueous media to form cation or positively charged ions to give stability to the emulsion. Quaternary ammonium compounds are the most important group of the cationic surfactant and prominently used in oil in water type of emulsions [5].

Non ionic surfactant:

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Non ionic surfactants are used in both o/w and w/o type of emulsion, and as they are less toxic as compared to other surfactant they are also used in oral and parenteral dosage forms. Some important nonionic groups are, Glycol and glycerol esters and Fatty alcohol polyglycol ethers [5].

2. Hydrophilic colloids:

Hydrophilic colloids are water sensitive and get swelled in presence of water with improved viscosity. These surfactants are mostly used as auxiliary surfactant to aid other surfactant and improve viscosity of emulsion and mainly used in cosmetic industry. Hydrophilic colloids are susceptible to PH changes and favors o/w type of emulsion and quite useful in complex w/o/w type of emulsion. Some important hydrophilic colloids are, Natural and synthetic clay and Natural hydrocolloids [3].

3. Finely divides solids:

A finely divided solid includes polar inorganic solids such as heavy metal hydroxides non-swelling clays and pigments and some non-polar solids. They act as a wetting agents rather than primary surfactant, so most of the time used as auxiliary surfactant in combinations[3].

Emollient:

An emollient agent is used in the cream formulations to provide to soften the skin or site of action. They also enhance the penetration of drug through the skin.

Preservatives:

These are the compounds used to prevent microbial growth within a cream to improve the stability and shelf life of product.

Hydrophile-Lipophile Balance (HLB) :

All surfactants have hydrophilic head and hydrophobic tail portion because of which they have surface activity. Hydrophile -lipophyle balance (HLB) is an indication of a solubility of surfactant. HLB is ratio of oil loving portion to water loving portion of surfactant. This balance is measure on the basis of molecular weight of surfactant. This theory was introduced by Griffith in 1954 and extended by Davies in 1957. The hydrophilic surfactants favour O/W emulsions while hydrophobic surfactants favors W/O emulsion. HLB number is assign to surfactant is characteristic of its relative polarity. The application of HLB value is, it tells about chemistry of surfactant and predicts its behavior. Like HLB value of water insoluble surfactants falls in 4-6 range and mostly used in W/O emulsion. Partially soluble in water have HLB value in 6-9 range used as wetting agent. Translucent to clear solubility in water surfactants have HLB value in 10-12 range and used as detergents. Very soluble surfactants have HLB value 13-18 range and used in O/W emulsions [5, 7, 8].

Stability of emulsion:

A stable emulsion is define as a system in which distributed phase can retain their initial character and remains uniformly distributed throughout continuous phase. Separation of emulsion into its constituent phases caused under gravity, when there is difference between oil phase and aqueous phase. Emulsions are thermodynamically unstable system; there are various factors which affect stability of emulsion which result is phase separation. Some of factors that cause emulsion to break are addition of chemical agent which is incompatible with emulsifying agent, bacterial growth specially on a non-ionic surfactants and protein material and temperature changes cause denaturation of protein emulsifying agent and changes solubility characteristics of emulsifying agents. The instability of emulsion is distinguished as a physical instability phenomenon such as sedimentation/creaming, flocculation, Ostwald ripenining, coalescence and phase inversion [5,7,8].

Fig. 3 Schematic diagram representing destabilization of emulsion.

Accessed from http://sparror.cubecinema.com/cube/cola/chemistry/cola1.htm#15

Creaming/ Sedimentation

Creaming or sedimentation of emulsion happens due to density difference in density of two phases under gravity. Creaming is occurred in W/O emulsion when density of aqueous droplets is higher than the oil phase. Sedimentation is most likely occurring in O/W phase where density of oil droplets is higher than aqueous phase. Creaming rather than sedimentation occur most frequently because most of oils have densities less than continuous aqueous phase. A decrease in creaming rate is achieved by homogenising emulsion to reduce globule size, increasing the viscosity of continuous phase by addition of thickening agent and decreasing density difference between two phases [5,7,8]

Flocculation

Flocculation may occur depending types of interaction (attractive and repulsive) between droplets. Under condition when Van Der Walls attractive forces exceeds repulsive forces to form aggregates of two or more droplets to form floccules. The globules do not coalesce and may be redispersed by shaking. The flocculation process enhances the gravitational instability rate and lead to coalescence. It decreases the shelf life of emulsion [5,8,9].

Ostwald Ripenining

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Ostwald ripening is disproportion mechanism specially occurs in a polydispersed mechanism facilitated by presence of micelles in continuous phase. Micelles increase solubility of small oil droplets than larger once which get dissolve on storage and get deposited on larger droplets. Ostwald ripening decrease by reducing size of droplets, increasing viscosity of dispersed medium and lowering the densities between two phases and creating energy barrier between oil and water interphase [5,7,8].

Coalescence

Emulsions are thermodynamically instable. Coalescence is a phenomenon in which two or more droplets merge together to form single large droplet which is thermodynamically stable. It occurs when the droplets are close together and due to thinning or disruption of interfacial membrane around droplets. Coalescence always happens when droplets are close together at this point attractive forces are greater than repulsive forces which make interfacial membrane difficult to protect droplets. Unlike the flocculation coalescence is an irreversible process, so droplets cannot be redispersed after shaking [7, 9].

Phase inversion

Phase inversion is a destabilisation process where dispersed phase and dispersed medium forms continuous phase and dispersed droplets from continuous phase. Excessive amount of dispersed phase may involve phase inversion or cracking of emulsion. Addition of electrolyte to anionic and cationic surfactants can alter the HLB of emulsifying agent and may alter the emulsion type. Heating of emulsion stabilize by non-ionic surfactant cause breaking of Hydrogen bonds responsible for hydrophilic bonding thus HLB gets altered and thus emulsion gets invert[5,7,8].

Shelf life assessment:

Stability studies perform a key role in the research and development of a new pharmaceutical entity. Classically, word "stability" indicates strength to stand or endure any physical or chemical changes and in pharmaceutical world stability refers as capacity to resist any susceptible changes which may affect quality, efficacy and efficiency of active medicament [10,11]. Stability studies gain an uttermost importance in the formulation and development of pharmaceutical dosage form, as they give the final verdict on your investment of years of hard work, money and knowledge. Stability testing gives us opportunity to test our final products to their limits before facing the market and corroborate you are delivering the best. One more interesting feature of stability study reveals in some inevitable circumstance such as if any drug produces instability and that leads to any harm to any patients. These consequences may cause a huge economical set back to manufacturer in the form of substantial product and process investigation with recall of the product, which may associated with the lawsuit and legal proceedings of regulatory authorities. Therefore, stability testing is useful to avoid such circumstances and establishing standards for storage conditions, shelf life and expiry date [12].

Types of stability studies are as fallow,

1. Stability studies of active pharmaceutical ingredient.

2. Stability studies to support formulation development.

3. Stability studies to support clinical and preclinical trial.

4. Stability studies to support drug registration.

5. Stability studies to support marketed product.

Shelf life assessment by centrifuge :

In accelerated stability testing of emulsion systems 'centrifugation' proved to be a key player due to its ability of prediction and accuracy of results. Also it provides you a large set of data in short time span without any complex procedure and calculation.

In case of any emulsion system under normal storage condition if stored for prolong time; then emulsion becomes prone to the process of demulsification, starting with aggulation of particle and ends with sedimentation, flocculation, coalescence or creaming. And these demulsification parameters are functions of gravity as per the Stoke's law.

where µ is the viscosity of the medium (water for O/W emulsions and oil for W/O emulsions).

In centrifuge with the help high rotation frequencies and effective acceleration we can achieve gravitational force which can mimic physical stress experienced by emulsion on prolong storage. Thus centrifugation is the most efficient way to accelerate these processes and predict the stability.

Emulsions are composed of one or more immiscible phases dispersed in dispersion media hence size distribution of droplets influence characteristic properties of emulsion and these characteristic properties are rheology of emulsion, texture, colour, viscosity and stability.

Creaming and sedimentation is governed by gravity .the amount of gravitational force depends upon the radius of particle and density difference between the aqueous phase and lipid phase exceeds the Brownian diffusion ultimately causing sedimentation.[7]

4/3Ï€R3DrgL >> kT .Where L is the height of the container, R is radius.

Basis for the project:

This project is a small part of a formulation and development program run by SERENTIS ltd. SERENTIS ltd is a small pharmaceutical company which is embarking a new topical cream formulation. They were interested to select combination of surfactants and additives from bunch of selective basic excipient to formulate stable cream formulation in shortest time span. In addition to this their interest was to observe effect of varying concentrations of surfactant on the overall stability of cream formulation.

Excipient

(%W/W)

Cetostearyl alcohol

7.200

Polysorbate 60

1.800

White soft parafin

15.00

Liquid Parafin

6.000

Isopropyl myristate

5.000

Glycerol

5.000

Natrosol 250 HX

0.200

Phenoxyethanol

1.000

Water

58.80

Table : Basic formulation provided by SERENTIS ltd.

Material and methodology:

Material: Cetostearyl alcohol, Polysorbate 60, White soft paraffin, Liquid paraffin, Isopropyl myristate, glycerol, Natrosol , phenoxyethanol, sodium dodecyl sulphate (SDS),sodium methacrylate and Berberine hydrochloride all ingredients are pharmaceutical grade and purchased from sigma Aldrich ,UK.

Method of formulation:

Lipid phase preparation:

A glass beaker (400ml) weighed on a tarred balance and labelled as vesse1. Then white soft paraffin (15 g) was weighed into vessel 1 on tarred balance. Cetostearyl alcohol (7.2g) was weighed and added to Vessel 1. Liquid paraffin ( 6g) was placed into a glass vial and poured directly into vessel 1 on the tarred balance. After that Isopropyl myristate (5g) was placed into glass vial and pour directly into beaker on the tarred balance. Polysorbate 60 (1.8g) was added to vessel 1 on tarred balance.

Aqueous phase preparation

Another glass beaker (400ml) was weighed on tarred balance and label as vessel 2. Glycerol (5g) was weighed with glass vial and poured into vessel 2. Natrosol 250 HX was weighed using weighing boat and then transferred into vessel 2 and stirred by using spatula until a homogeneous slurry was observed. Then Distilled water (58.8g) was weighed and poured directly into vessel 2 and stirred well. Phenoxyehanol (1g) was weighed using glass vial and mixed well into vessel 2.

Heating and homogenising process:

At the same time Vessel 1 (oil phase) was heated up to 60-650C into pre-heated water bath until clear melt mixture is observed. The time for heating is approximately 20 min., during this time mixture in vessel 1 was stirred every 5 min for the homogenous melting of oil phase. Once the clear melt mixture observed in vessel 1 and vessel 2, the contents of vessel 1(Oil phase) was then poured into vessel 2 (Aqueous phase) into pre heated bath up to 60-65oC. The mixture from vessel 2 was removed from water bath and homogenised for 4 min by using a silverson L4RT homogeniser. Homogenised mixture in vessel 2 was then transferred to the Heidolph stirrer. The stirring was continued until the vessel was cooled to room temperature.

Variations in cream formulations:

All the cream formulation were formulated as per noted methodology above; but as stated in the objective to observe the effect of variations in concentration of surfactant and other additives, some changes had been done. Chart below summarises the changes done.

Samples 1 to 5 are formulated with variations in cetostearyl alcohol. Sample1 (6.4%), Sample 2 (6.8%), Sample 3 (7.2%). Sample 4 (7.6%), Sample 5 (8%) of cetostearyl alcohol.

Sample 6,6A and 7,7A formulated with same basic formulation, but with active drug mimic Berberine hydrochloride

Sample 8 with red dye ( oil o red )

Sample 9,10 and 11 with 1%,0.75% and 0.50% of sodium dodecyl sulfate respectively replacing polysorbate 60 from basic formulation.

Sample 12, 12A and 13,13A with 0.5% and 1 % of sodium dodecyl sulfate with 0.5% of berberine hydrochloride.

Sample 14,15and 16 with 0.5%, 0.75% and 1% of sodium methacrylate.

Sample 17, 18, and 19 with 0.5%, 0.75% and 1% of sodium methacrylate and 0.5 % of berberine hydrochloride in each formulation.

Centrifuge analysis method:

Formulated cream samples by the above methodology were further subjected to centrifuge analysis. After formulation of cream, it was stored for one day (resting period) in laboratory drawer. On the next day 10 g of cream sample was transferred in centrifuge tube with help of spatula and tube was labelled. Afterwards labelled centrifuge tubes were placed in pre-calibrated 'Biofuge' centrifuge. Centrifuge machine was set at 7000 RPM (revolution per minute) for cumulative time of 10 min, 30min, 60 min, 90 min and 180 min. After each cumulative time interval of 10 min, 30min, 60 min, 90 min and 180 min samples were removed from centrifuge and observed by naked eye for any sign of demulsification or phase separation. If phase separation occurred height of displaced oil phase was measured by ruler and noted down with specific description.

Hot stage microscopy analysis method:

Using this analysis method sample 6 and 8 were analysed. sample 6 was formulated with active drug berberine hydrochloride and as it is yellow coloured water soluble compound there was not added any colour pigments .While in case of sample 8, cream sample was formulated by above mentioned method with addition of red dye (0.025g of 'oil O red') and stored for one day (resting period).

A small amount of sample was spread on a glass slide to form a thin layer and covered by cover slip. Afterward glass slide was placed on temperature controlled hot stage of microscope maintained at room temperature; lances and optical zoom of microscope were adjusted for clear vision. After all these necessary arrangements heating rate set up at the rate of 10 0c /min up to 40 0c, and then 10c /min up to maximum 650c at which cream melted. Simultaneously as heating started as per set up a snap shot( picture ) was taken at each change in morphology of cream, until cream melted to form a clear screen.

Result and Discussion:

In this section, results from centrifugation of formulated topical cream samples had presented in groups and discussed thoroughly below each section. Cream samples were formulated as per the given basic formula, with some variation in concentration of surfactant and other additives to compare their effect on the stability of cream. For all readings centrifugation speed kept constant that is, 7000 RPM (revolution per minute). All cream formulations had resting period of 1 day after which they were studied for stability study. In order to obtain precise result and to minimize the errors replicate of each formulation had formulated, but as obtained results for replicate were similar to each other, they had presented as a single reading.

From above obtained results, it is clear that there is no significant difference observed in stability of formulation differing from previous stability results of sodium methacrylate. Among formulated samples, sample 19 with 1% of sodium methacrylate shows the better stability profile in presence of 0.5% of active drug.

Conclusion:

Fast prediction of emulsion stability is important for formulation and development of topical cream, as it save essential time and cost of pharmaceutical companies. As shown by this study , centrifugation at 7000 rpm allowed to predict the stability of final product and to analyse the effect of varying concentrations of different surfactant and other additives.

Results obtained clearly shown that; the variations in-group of cetostearyl alcohol concentration suggests that, formulation with 8% of cetostearyl alcohol had shown better stability than 7.2% and other concentrations used. While, comparison between polysorbate 60 and sodium dodecyl sulfate shown that sodium dodecyl sulfate with 1% concentration was more compatible and stable in cream formulation with 0.5%ative drug rather than 1% active drug. Comparison between Natrsol and sodium methacrylate had shown that, cream formulation composed of 1% of sodium methacrylate with 0.5% of active drug was the more stable with longest shelf life.

Recommendations:

These are the recommendations to obtain a optimum stability and long shelf life for SERENTIS ltd. depicted from the conducted research study ,

Cetostearyl alcohol should be used as auxiliary emulsifier in concentration of 8% w/w.

Sodium dodecyl sulfate in concentration of 1%w/w is the best replacement for polysorbate 60.

Its better option to use active drug in 0.5% w/w rather than 1% w/w that had shown better compatibility and stability within all formulation.

Sodium methacrylate would be better choice instead of Natrosol.

Limitations of the project:

The main limitation of this project was unavailability of viscometer,and zeta potentiometer for semi solid preparation. Viscosity measurement and zeta potential calculation would have given better idea about the stability data. In addition, it would be helpful for validation of results.

Future work :

In future if some, researchers undertaking this project then they should try to increase radius of work through use of multisample analytical centrifuge which is more faster and more precise than conventional centrifuge. It would be helpful to carry out analysis of larger pool of cream formulation. They should also, try to use particle size analysis, zeta potential and rheological characteristics to validate their data.