1. KAUSAR AHMAD KULLIYYAH OF PHARMACY Cream Formulation http://staff.iium.edu.my/akausar 1 PHM4153 Dosage Design 2 2011/12

2. Contents PHM4153 Dosage Design 2 2011/12 Ideal formulation Types of excipients Properties 2

3. Examples of Creams PHM4153 Dosage Design 2 2011/12 Benzophenone, hydroquinone Fruit extracts Whitening Collagen, seaweed extract Liposome Anti- ageing Fish Herbs Virility 3

4. Formulation PHM4153 Dosage Design 2 2011/12 Process whereby drugs are combined with other substances (excipients) e.g. preservative to produce dosage forms e.g. cream suitable for administration to or by patients. 4

5. Ideal formulation PHM4153 Dosage Design 2 2011/12 5 Non-irritantNon-allergenicNon-staining Easy to apply Pleasant feeling to the skin Non-toxic Non-harmful Incapable of microorganism growth Free from side- effects

6. Formulation requirement: efficacy, safety, and quality PHM4153 Dosage Design 2 2011/12 Contain accurate dose Convenient to take or administer Provide drug in a form for absorption or other delivery to the target Retain quality throughout shelf life & usage period Manufactured by a process that does not compromise performance and that is reproducible and economical 6

7. Factors to be considered in formulation PHM4153 Dosage Design 2 2011/12 Physicochemical properties Waxes and oils or emulsions Choice of vehicle Provide essential part of the dosage form Prevent degradation of the formulation Categories of excipients Stability 7

8. Choice of vehicle PHM4153 Dosage Design 2 2011/12 Bases from mixtures of low and high MW PEG LiposomesMicroemulsions Multiple emulsions Fluorocarbon emulsions – ultra low  i 8

9. Examples of Oils & Fats PHM4153 Dosage Design 2 2011/12 9 Cyclomethicones Dimethicones Silicones Castor oil Glyceryl tricaprylate Triglycerides/ vege oils Octyl stearate Isopropyl palmitate Simple esters

10. Advantages of Silicones PHM4153 Dosage Design 2 2011/12 10 Chemical and physical stable, colourless, odourless Cosmetic Skin-feel, gloss/matte Dermo-toxicology Not sensitizing, non-comedogenic,

11. Examples of Lipids PHM4153 Dosage Design 2 2011/12 11 Mineral oil Hydrocarbons Beeswax Wax Dicaprilyl ether Ether Cetyl alcohol Alcohols Stearic acid Acids

12. Properties Limitation PHM4153 Dosage Design 2 2011/12 Emollient effect Shine Lubricity Spreadability Solvency Drying Odour Colour Viscosity Miscibility with other oils Toxicity Impurities Cost 12 Choosing Oils

13. Non-polar Polar PHM4153 Dosage Design 2 2011/12 Lasting emollient effect Barrier effect Inert Stable against oxidation Shine Spreadability cheap Varying emollient effect Little barrier effect Varying stability against oxidation Good absorption Good delivery expensive 13 Polarity of oils

14. Excipients PHM4153 Dosage Design 2 2011/12 Other components other than API added to formulation 14

15. Categories of excipients PHM4153 Dosage Design 2 2011/12 Provide essential parts of dosage form & enhance bioavailability Emulsifiers Viscosity modifier Prevent degradation of the formulation: protect, improve safety & enhance stability Anti-oxidants Anti-bacterials Preservatives UV absorbers Aid processing during manufacturing Assist product identification  colour 15

16. Choosing excipients PHM4153 Dosage Design 2 2011/12 physiological inertness physical and chemical stability conformance to regulatory agency requirements no interference with drug bioavailability absence of pathogenic microbial organisms commercially available at low cost 16

17. Emulsifiers PHM4153 Dosage Design 2 2011/12 17 w/oo/w

18. Penetration enhancers PHM4153 Dosage Design 2 2011/12 Disturb packing of SC lipid bilayer Examples: surfactants Disruption of skin barrier Extraction of skin lipids with apolar solvents e.g. acetone Physical stripping Physically or chemically induced irritation 18 Increase delivery of active substance by:

19. Hydration PHM4153 Dosage Design 2 2011/12 Hygroscopic effect NaCl Sorbitol PPG glycerol Alter water-binding capacity of corneocytes Low MW glycerols 19 Q. How does urea moisturise the skin?

20. PHM4153 Dosage Design 2 2011/12 20

21. PHM4153 Dosage Design 2 2011/12 21

22. pH adjustment PHM4153 Dosage Design 2 2011/12 22 TriethanolamineNaoH

23. Preservatives PHM4153 Dosage Design 2 2011/12 23 Sodium methyl/butyl/propyl paraben Imidazolidinyl urea

24. Anti-oxidant PHM4153 Dosage Design 2 2011/12 24 Butyl hydroxy toluene Butyl hydroxy anisole

25. UV filters PHM4153 Dosage Design 2 2011/12 25 Zinc oxideTitanium dioxideBenzophenone

26. Other types of excipients PHM4153 Dosage Design 2 2011/12 26 Soothing Allantoin Anti-free radicals Polyphenols

27. Effects of excipients PHM4153 Dosage Design 2 2011/12 texture and consistency phase behaviour of the component emulsifiers. physicochemical properties rheological, thermal and microscopical 27

28. Physicochemical properties PHM4153 Dosage Design 2 2011/12 Oils susceptible to oxidation Add antioxidants E.g. BHT, BHA Aqueous solutions support microbial growth Add preservatives E.g. methyl and propyl paraben BUT these may affect the endocrine….. 28

29. Physical and chemical properties of excipients PHM4153 Dosage Design 2 2011/12 29 solubilityhygroscopicityswelling hydration capacity particle size distribution bulk & tap density specific surface area complexation infrared spectrum microbes

30. PHM4153 Dosage Design 2 2011/12 30 10  m, porous 7  m, empty spheres Polyamide: Carrier for insoluble ingredients; Protector for sensitive ingredients; Slow delivery & long lasting effect

31. Excipient: Particle size distribution PHM4153 Dosage Design 2 2011/12 31

32. Excipient: Pore volume & pore diameter PHM4153 Dosage Design 2 2011/12 32

33. Incompatibility PHM4153 Dosage Design 2 2011/12 33 ChemicalpH/dissociation pH/disperse systems polyvalent cationscomplexation cationic and anionic compounds of high MW reducing agents (cause fading of dyes) PhysicalImmiscibilityInsolubilityPackaging Formulation and packaging materials

34. Detection of Incompatibility PHM4153 Dosage Design 2 2011/12 Cracked cream Hydrolysis or oxidation DiscolorationPrecipitation 34

35. Effect of type of preparation: Absorption of retinyl palmitate PHM4153 Dosage Design 2 2011/12 Exercise: 18% absorbed from acetone vehicle compared to only 4% absorbed from o/w emulsion Q WHY? 35

36. Exercise: Determine functions of excipients PHM4153 Dosage Design 2 2011/12 Nizoral cream Ketoconazole PPG Stearyl alcohol Cetyl alcohol Sorbitan stearate Polysorbate Isopropyl myristate Sodium sulfite Purified water Elomet cream 0.1% Mometasone furoate White petrolatum White wax PPG stearate Stearyl alcohol Ceteareth-20 Hexylene glycol Titanium dioxide Al starch octenylsuccinate Purified water Phosphoric acid 36

37. References PHM4153 Dosage Design 2 2011/12 Bugay, D. E. (1999). Pharmaceutical excipients : characterization by IR, Raman, and NMR spectroscopy. RS201E87B931P Kibbe, A. H. (2000). Handbook of pharmaceutical excipients. RS201E87H236K Rowe, R. C., Sheskey, P. J. & Owen, S. C. (2006). Handbook of pharmaceutical excipients RS201E87H236K Rowe, R. C. (2009). Handbook of pharmaceutical excipients. RS201E87H236K 37

38. PHM4153 Dosage Design 2 2011/12 38 Some materials sourced from the following: http://www.eastman.com/Markets/Pharmaceutical/Excipients/Excipients_intro.asp http://www.pharmaceutical-technology.com/contractors/materials/uniqema/ http://www.pformulate.com/ http://images.vertmarkets.com/CRLive/files/Downloads/89FB7970-7376-44A0- B6B6-4B171E4B978B/InsolubleKollidon.pdf Thank you to contributors.