Ointments &pastes

Ointments and pastes

1. Ointments & Pastes Pharmaceutical ointments termed unguents are semisolid systems that are applied externally, primarily to the skin and also to mucous membranes. Medicated ointments are used for the treatment of infection, inflammation and pruritus. Non-medicated ointments are used as emollients and lubricants. Pastes are composed of ointment base that contain a high concentration of dispersed drug ( > 50% w/w) The viscosity of pastes are greater than that of ointments.

2. Factors determining the choice of ointment base The site of application. The required rate of drug release. The chemical stability of drug. The effect of the therapeutic agent on formulation viscosity.

3. Types of base for ointments and pastes Hydrocarbon bases. Absorption bases. Water-miscible/removable bases. Water-soluble bases.

4. Hydrocarbon bases – Paraffins Non-aqueous having the properties: Emollients , prevents water loss by forming occlusive film Excellent retention on the skin. Predominantly hydrophobic, so difficult to remove from the skin and also difficult to be applied on the moist surface. Not more than 5% of water could be incorporated with careful mixing. Chemically inert. Hard paraffin, white/yellow soft paraffin, liquid paraffin, microcrystalline wax.

5. Hard paraffin is white or colourless microcrystals wax. Melting point 47 – 65. used to enhance the rheological properties of ointment base. White/yellow soft paraffin is semisolid, consists of hydrocarbons derived from petroleum. Melting point 38 – 60 and can be used as an ointment base without a dditional components. Liquid paraffin; usually formulated with soft paraffin to achieve the required viscosity. It requires incorporation of antioxidant. Microcrystalline wax ; semisolid used to enhance the viscosity of ointments and creams. It has greater physical stability and when provided to liquid paraffin it reduces the bleeding of liquid component.

6. Absorption bases Contain significant amount of an aqueous phase. May be: Non-aqueous formulation to which an aqueous phase may be added to produce water in oil emulsion ( non-emulsified bases). Water in oil emulsions that can facilitate the incorporation of an aqueous phase without inversion or cracking. They are still difficult to be removed by washing. Non-emulsified bases; lanolin (wool fat), wool alcohols, beeswax. Water in oil emulsions ; hydrous lanolin

7. Non-emulsified bases are hydrophobic formulations to which water may be added. Good spreading properties. They are emollients. They are composed of 1/ paraffins 2/ a sterol based emulsifying agent. [lanolin ( wool fat), lanolin alcohols ( wool alcohols) and beeswax]. Lanolin is mixed with vegetable oil or paraffin to produce an ointment base that can absorb twice of it weight of water to produce water in oil emulsion. The usual concentration of lanolin in simple ointment is 5 -10 % w/w. Wool alcohols is added to a mixture of hard and soft paraffin to produce the required consistency. Inclusion of wool alcohol 5% w/w results in a 300% increase in the concentration of water that may be incorporated in paraffin bases. Bees wax consists of esters of aliphatic alcohols C24 – C36 even numbers . Combined with paraffins to produce non-emulsified bases.

8. Absorption bases – water in oil emulsion. Excipient used in this ointment base is hydrous lanoline which is a mixture of lanoline and water 25 -30 %. It is incorporated into paraffins and oils that can incorporate the subsequent addition of aqueous phase. Oily cream BP is water in emulsion ointment base that is composed of wool alcohol and water 50% each.

9. Water-miscible / removable bases Used to form water in oil emulsion for topical application. They are able to accommodate large volumes of water ( edema – wounds). They are not occlusive. Easily to be washed and removed out. They are aesthetically pleasing.

10. BP water-miscible/removable bases: Emulsifying ointment Cetrimide emulsifying ointment. Cetomacrogol emulsifying ointment. Each containing liquid paraffin20%, white soft paraffin 50% and emulsifying wax 30%. Types of emulsifying wax: Anionic emulsifying wax. Non-ionic emulsifying wax. Cationic emulsifying wax.

11. Anionic emulsifying wax: Composed of : cetosteryl alcohol 90 gm Sodium lauryl sulphate 10 gm Purified water 4 ml Cationic emulsifying wax: Cetosteryl alcohol 900 gm Cetrimide 100 gm Non-ionic emulsifying wax: Cetosteryl alcohol 800 gm Cetomacrogol1000 200gm

12. Water-soluble bases They are non-greasy, miscible with the excudates and compatible with majority of therapeutic agents. Prepared by mixing Polyethylene glycol 400 and polyethylene glycol 4000 in a ratio of 60%, 40% respectively then heat and controlled cooling. Used to incorporate solid therapeutic agent. Incorporation of 5% or more water will liquidify the base. To incorporate up to 25% aqueous phase, PEG 400 may be replaced by stearyl alcohol.

13. Additional / alternative solvents Liquid silicon : used in barrier ointments due to its water-repellent. Vegetable oils : may be used either to replace mineral oils or to enhance the emollient properties ( arachis oil, cocanut oil). Organic esters : isopropyl myristate is used to enhance the spreadability properties and enhance drug dissolution within the ointment base.

14. Preservatives Ointments / pastes that do not contain water do not require preservative. Preservatives for those containing water: Phenol 0.2-0.5%, chlorocresol 0.075 – 0.12% Benzoic acid and its salts 0.1 – 0.3% Methyl parabens and propyl parabens 0.2 -0.3% Concentration should equal or exceed the MIC Antioxidants Lipophilic Hydrophilic

15. Manufacture of ointments & Pastes Dispersal of the powdered therapeutic agent into the pre-heated hydrocarbon base using mechanical mixer. Hydrophobic component and hydrophilic components are dissolved separately in their liquid phases. The two phases are maintained at 70 C then mixed together either simultaneously or by adding the aqueous phase to the non-aqueous phase.

16. Lotions May be formulated as solution or suspension. It contains the therapeutic agent and + alcohol as co-solvent and coolant. + humectants to retain the moisture on the skin after application ( Glycerol). + vehicle purified water with or without buffer. + preservative. + component to stabilize the suspended therapeutic agents.

17. Liniments Alcohol-based liniment: act as counterirritants and rubefacient causing reddening of the skin and may act to increase the penetration of the drug through the skin. This will provide cooling effect; soap liniment. Oil-based liniment: employed in conditions of massage. Oil used is arachis oil and cottonseed oil ; camphor liniment, methyl salicylate liniment. Generally no other excipients are used.

18. Collodions Collodions are solutions of pyroxylin ( nitrated cellulose predominantly cellulose tetranitrate ), castor oil and colophony dissolved in an organic solvent composed of alcohol and ether. Normally applied to the skin by brush and after evaporation of the solvent will form occlusive film. Collodions may contain therapeutic agents as colliodion and salicylic acid and collodion. Collodion is a solution of pyroxylin in 3 ether + 1 alcohol. This will form firm film and may render flexible by adding 2% camphor and 3% castor oil. Salicylic acid collodion is a solution of salicylic acid 10% in flexible collodion and used for the treatment of warts.

19. Advantages of ointments and pastes Spreadability . Occlusive Lubrication and emollient Release of drug Hydrophobicity Pastes………….porosity Pastes opaque Stability of drug Cooling effect

20. Disadvantages Greasy Pastes thick Staining Liniment not applied to broken skin E xuding sites Limited solubility of drug in base Pastes to hair

21. Pharmaceutical Gels Definition: Semisolid system in which there is interaction either physical or covalent between colloidal particles within a liquid vehicle.

22. Gels – description The vehicle is continuous and interact with the colloidal particles within the 3 dimensional network formed by the bonds created between the adjacent particles. The vehicle may be aqueous, hydro-alcoholic, alcoholic or nonaqeous . Colloidal particles may be dispersed solids; kaolin, bentonite. Colloidal particles may be dispersed polymers. Xerogels are gels in which the vehicle had been removed leaving a polymer films.

23. Main categories of pharmaceutical Gels Categorization was based in the nature of the three dimensional network of particles. Dispersed solid gels. Hydrophilic polymer gels

24. Dispersed solid gels . When dispersed particles undergo flocculation throughout the system, a continuous solid particle network is established, with the liquid vehicle dispersed in the void volume between the particles. The nature of the interaction between the particles in the network may be van der Waals e.g Aluminium hydroxide gel . OR electrostatic bonding e.g Kaolin, bentonite, Al.Mg silicate. The particles exhibit plate-like crystal structure with electronegative charges at the face and electropositive charges at the edges. The bonding strength between the particles is weak which can be broken by shaking resulting in liberation of individual particles. On removal of stress the rheological properties return. This recovery is time-dependent and termed thioxytropy .

25. Hydrophilic polymer gels Dispersion of hydrophilic polymer within appropriate aqueous vehicle. There are two types: 1- types 1 gels. 2- type 2 gels.

26. 1- types 1 gels . Termed as hydrogel.( type 1 chemical) The interaction between the polymer chain is covalent and is mediated by molecules that cross-link the adjacent chains ( cross-linker). Example of a cross-liked hydrogel and monomer is hydroxyethylmethacrylate and the cross- linker ethyleneglycol dimethacrylate . It has the ability to absorb a considerable mass of aqueous fluid whilst still retaining the3D structure. It exhibit robust mechanical structure being resistant to fracture up to 1 kpa . Having excellent flexibility Hydrogels in which the aqueous been removed is termed xerogels . It is brittle and the aqueous phase is used as plasticizer.

27. Type 1 gels do not exhibit flow when exposed to and applied stress due to inability of the stress to destroy the covalent bonds. This elastic properties enable the energy utilized to be stored and utilized after removal of stress to return to equilibrium. Hydrogels are used in wound dressings, as lubricants coating in urethral catheters and as soft contact lenses. Used for the controlled delivery of therapeutic agents at the site of implantation.

28. 2- type 2 gels . The bonds are either hydrogen bond, ionic association or van der Waals interactions. These bonds are weaker bonds. So, interactions between polymer chains are reversible. Application of stress can result in flow. So it shear – thinning system. Being pseudoplastic , on removal of stress, the intermacromolecules bonds are reformed. This type 2 gels are used in formulations: Cellulose derivatives. Polysaccharides from natural origin. Polyacrylic acid

29. Cellulose derivatives. Methyl cellulose Hydroxyethyl cellulose Hydroxypropyl cellulose. Sodium carboxymethylcellulose .

30. Polysaccharides from natural origin. Carrageenan derived from red seaweed. They are lambda, iota and kappa. Which differ in the location of sulphate group and absence of anhydroglactose . Kappa carrageenan exhibit excellent gelling properties. 0.3 – 1% w/w. Alginic acid / sodium alginate derived from algae. addition of calcium ions to aginate solution will result in a viscous gel. It is incompatible with basic drugs. Poly ( acrylic acid); produced following polymerization of acrylic acid and cross-linking with allyl sucrose or ally ethers of pentaerythritol.0.5 -2% w/w polyacrylic acid neutralized with an appropriate base is used. It is incompatible with basic therapeutic agents. Its viscosity is adversely affected by medium and high concentration of electrolyte.

31. Factors affecting gelation of type 2 gels Concentration of hydrophilic polymer. Molecular weight of the polymer. Nature of the solvent. pH of the solvent. Ionic strength of the solvent phase. Temperature. Ionic gelation.

32. Concentration of hydrophilic polymer . At low concentrations, the hydrophilic polymer exhibit Newtonian flow due to the limited number of polymer-polymer interactions. As the concentration increases, the number of polymer-polymer interactions increases and at a definite concentration, the flow properties become non-Newtonian --- this the gel point. Further increase lead to increase in the junction zones and increase resistance to applied stress. Therefore, the physiochemical and rheological properties of a pharmaceutical gel may be readily manipulated by altering the concentration of hydrophilic polymer.

33. Molecular weight of the polymer As the molecular weight of the hydrophilic polymer increases at a definite concentration, there are a greater number of available sites on the polymer chains that may e ngage in the polymer-polymer interactions. As a result the viscosity of the formulation increases.

34. Nature of the solvent . In good solvents, the chains of the polymer exist in the expanded state. In poor solvent, the polymer chain exist in coiled state. The viscosity of the polymer solution depend on the expansion of the polymer chains. Therefore, the physiochemical properties of the gel are dependent on the solvent system into which the hydrophilic polymer is dissolved. In poor solvents gelation will not occur.

35. pH of the solvent . The pH affects the ionization of acidic or basic polymers which in turn affects the expansion state of the polymer. In non-ionized state, acidic and basic polymers exist in a coiled state and gelation does not occur. The rheological properties of ionic polymers are optimal with range of pH values at which maximum expansion of chains occur. The rheological properties of non-ionic polymers are unaffected by the pH of the solvent, usually pH 4 – 10.

36. Ionic strength of the solvent phase . Presence of high concentration of electrolytes affects both ionic and non-ionic polymers. Non-ionic polymers may be salted out of solution due to desolvation of the polymer chains. At low concentration of electrolyte , shielding of the charge on the ionic polymer will occur, this will reduce the capacity of the polymer to interact with solvent resulting in compromised gel properties. If the concentration of the electrolyte is too high, salting out of ionic polymer will result.

37. Temperature Methyl cellulose and hydroxypropyl cellulose have been reported to undergo gelation at elevated temperature 50 – 60 ˚C . this transition has a limited biological relevance. Poly( oxyethylene )-poly( oxypropylene )block co-polymers undergo thermal transition at < 37˚C range. At temperature below this transition ( sol-gel) temperature T sol /gel , the solution of the polymer undergo Newtonian flow and low viscosity ( sol state). Above this T sol /gel is converted into gel with pronounced elasticity and viscosity. In solution at temperature below T sol /gel and above the critical micelle concentration , the polymer exists in a micellar state, elevation of temperature above T sol /gel , the micelles aggregate resulting in a gel. On lowering the temperature will result in deaggregation of micelles and reemergence of sol. This lead to their use as drug delivery system. Within the oral cavity and rectum.

38. Ionic gelation Certain hydrophilic polymers undergo gelation in the presence of inorganic metal ions. Polyvinyl alcohol polymers, gelation occur in the presence of borate , permanganate giving a gel of excellent mechanical strength due to the borate anion-mediated cross-link. ( toy Kid) Gelation of alginic acid occur in the presence of Mg, Ca, and Al ions.

39. Formulation of a pharmaceutical gels Choice vehicle. Inclusion of buffer. Preservatives. Antioxidants. Flavours / sweetening agents. Colours .

40. Choice of vehicle Purified water is the normally used in formulation of pharmaceutical gel. Co-solvent may be used as alcohol, propylene glycol, glycerol, poly ethylene glycol 400 to enhance the solubility of the therapeutic agent and to enhance permeation across the skin ( ethanol ). If the drug has poor chemical stability and/or poor solubility in water, pharmaceutical gel may be formulated using propylene glycol, glycerol, polyethylene glycol 400 and poly acrylic acid. In these systems gelation is facilitated by hydrogen bonding between hydroxyl and carboxylic acid groups and this results in: expansion of pendant groups on the polymer chain. Non-covalent cross-linking of adjacent polymer chain.

41. Inclusion of buffer Citrate and phosphate buffer may be included in aquous or hydroalcoholic gels to control the pH of the formulation. The solubility of buffer salts is decreased in hydroalcoholic -based vehicles.

42. Preservatives Same as ointments. It should be noted that parabens, phenolics interacts with the hydrophilic polymers used to prepare gels, thereby reducing the concentration of free ( antimicrobially active ) preservative. Thus, the concentration of these preservatives should be increased.

43. Antioxidants Used to increase the chemical stability that are prone to oxidative degradation. Selection of antioxidant depend on the nature of the vehicle used. Because majority of gels are aquous -based, water-soluble antioxoidant is used.( sodium metabisuphite , sodium formaldehyde sulphoxylate are commonly used)

44. Flavours / sweetening / coluring agents Refer to solutions.

45. Manufacturing of pharmaceutical gels Water soluble components are dissolved in the vehicle in a mixing vessel with mechanical stirring. The hydrophilic polymer is added to the stirring mixture slowly to prevent aggregation. Stirring is continued until complete dissolution of the polymer. Excessive stirring results in entrapment of air. Vacuum may be applied to remove the entrapped air.