Semisolids

Semisolids- ointments, creams, pastes and gels

1. SEMISOLID DOSAGE FORMS Presented By: Mr.Naresh Gorantla , M.Pharm , ( Ph.D ) Assoc. Professor, Departmernt of Pharmaceutics Balaji college of pharmacy, Anantapuramu

2. CONTENTS Introduction Anatomy of skin Routes of drug transport Factors affecting penetration Formulation Manufacturing Evaluation

3. DEFINITIONS OINTMENT: T hese are semi solid preparations meant for external application to the skin/ mucous membrane. PASTE: T hese are semisolid preparations containing high amounts of solid ingredients intended for external application to skin . CREAM: T hese are viscous semisolid emulsions meant for external use. GELS: T hese are semisolid aqueous dispersion systems which may contain suspension of either small /large organic molecules dispersed in a suitable liquid.

4. The skin is very effective as a selective penetration barrier. The epidermis provides the major control element for drug penetration.

5. Epidermis The superficial, thinner portion composed of keratinized stratified squamous epithelial tissue Epidermis consists of different layers a) Stratum corneum (Horney layer) Barrier to Percutaneous absorption b) Stratum lucidum (Barrier zone) Barrier to transfer of water across skin, damage resulted in increased permeability. c) Stratum granulosum (Granular layer) Participate in keratinisation d) Stratum spinosum e) Stratum basale (Stratum germinativum ) Melanocytes the pigment-producing cells of the epidermis ,

6. B. Dermis : The sensitive connective tissue layer of the skin located below the epidermis, containing nerve endings, sweat and sebaceous glands, and blood, hair follicles, fibroblast, histocytes and lymph vessels . Composed of strong connective tissue containing collagen (for strength) and elastin (for stretch ) Play major role in temperature regulation.

7. Hypodermis (SC fatty layer) Below the dermis is hypodermis also called subcutaneous layer . Sub mean under and cutaneous mean skin. Loose layer of connective tissue which is anchored to the underlined tissue ( muscle and bones). Most fat cells are present in hypodermis (adipose tissues) acts as insulator to protect the body from excessive heat and cold environment

8. Skin appendages 1.Sweat glands The sweat glands are coiled tubules in the dermis which open on to the skin surface; they can be sub-divided in to two classes; Eccrine glands: The sweat glands which are involved in the regulation of body temperature by water elimination. About two million eccrine sweat glands Apocrine sweat glands : Are larger than eccrine sweat but few in number. They are mainly located in the hairier regions of the maxillae and around the nipples. Apocrine sweat differs in composition from eccrine and may be cloudy and colored

9. 2.Hair follicles Hair follicles are sebum-filled openings from which keratinous hair filaments protrude. Follicles occupy about 0.1% of the skin surface area; absent from plantar and palmar surfaces, the red areas of the lips, and parts of the genitalia. 2.Sebaceous glands: More in number and size on face Palms, soles doesnot contain Sebaceous glands Sebum is composed of Glycerides, Free fatty acids, Cholesterol, Cholesterol esters, wax esters and Squalene .

10. Mechanism of drug penetration through skin Three potential entry routes of drugs to the viable tissue: Transepidermal route ( Across the continuous stratum corneum ) Transappendageal route Epidermal route

11. Transepidermal route Polar pathway When the therapy is required to target horny layer of the skin Emollients and Exfolients Diffusion is passive process i.e. follows concentration gradient. Low molecular weight molecules penetrate through stratum corneum to some extent.

12. Transepidermal route Intrafollicular pathway For ions and large molecules with low diffusion coefficients which crosses S.Corneum with difficulty ( Polar steroids and antibiotics) Antiperspirants like Aluminium chloride Topical Antibiotics like Tetracycline, Clindamycin Antifungals like Clotrimazole , Miconazole Depilatories like Strontium sulphide, Barium sulphide and Thioglycolates . Topical exfolients like Salicylic acid, Retinoic acid

13. Epidermal route Intercellular pathway Drugs like Topical steroids, NSAIDs and corticosteroids Anaesthetics like Benzocaine Antihistamines and Antipruritics Antimalignants like Methotrexate, 5-flouro uracil

14. Low molecular weight molecules penetrate through stratum con e um to some extent. Skin appendages are main route for Electrolytes, polar steroids, antibiotics and colloidal particles. Particles of 3-10 µ m can penetrate through hair follicle and particles less than 3µ penetrate through stratum con e um . Hair follicle route may be important for ions and large polar molecules. Topically applied agents such as steroids, hexachlorophane, griseofulvin, sodium fusidate and fusidic acid may form a depot or reservoir by binding within the stratum corneum.

15. Once drug permeates through horny layer it readily enters living tissue and systemic circulation. The average residence time of drug in dermis may be 1 min before it is washed away by blood. NSAIDS reach far down to muscles to form depots.

16. Factors influencing dermal penetration of drugs I. Biological factors: Skin condition Skin age Blood flow Regional skin site Moisture content and environmental temperature II. Physicochemical factors : 1. Drug-skin Skin hydration Drug-skin binding 2. Vehicle -skin Type/Nature of vehicle Temperature Penetration enhancers 3. Drug - Vehicle

17. BIOLOGICAL FACTORS: 1. Skin condition : Injuries, Chemicals and Defatting . The intact, healthy skin is a tough barrier but acids and alkalis injure barrier cells and thereby promote penetration. Mixtures of non-polar and polar solvents, such as chloroform and methanol, remove the lipid fraction and molecules pass more easily. Disease alters skin condition, skin inflamed, with loss of stratum corneum thus permeability increases. 2 . Skin age Skin of the young and the elderly is more permeable than adult tissue. Children are more susceptible to the toxic effects of drugs and chemicals, because of their greater surface area per unit body weight; thus potent topical steroids, Causes severe side-effects and death.

18. 3.Blood flow: An increased blood flow could reduce the amount of time a penetrant remains in the dermis, and also raise the concentration gradient across the skin . 4 . Regional skin sites : Variations in permeability depend on the thickness and nature of the stratum corneum and the density of skin appendages. Permeabilities depend on thickness of stratum corneum and the overall thickness of the tissue. Facial skin in general is more permeable than other body sites

19. 5. Moisture content of Skin and environmental temperature: If the moisture content of the skin is high then penetration is also high. When the drugs are applied to a completely hydrated skin, their penetration rates are high. Environmental temperature also affects the drug absorption through s kin , drugs like Aspirin and glucocorticoids absorbs 10 times faster at 37 c than at 10 c.

20. Physicochemical factors : Drug-skin interactions 1. Skin hydration: When water saturates the skin the tissue swells, softens and wrinkles and hydration of the stratum corneum increases permeability . A compound which hydrates the skin efficiently can also improves penetration. Substances like free fatty acids, pyrrolidone carboxylic acids, urea, sodium, potassium and calcium lactates are used as natural moisturizers. Dusting powders or lotions, provide a large surface area for evaporation and therefore dry the skin .

21. Physicochemical factors 2 . Drug - Skin Binding : Drugs which are having binding capacity with skin and skin constituents also affects the penetration. Drugs like Surface active agents, Sunscreens and some topical steroids bind with skin and form reservoirs in the s.corneum and releases slowly.

22. Physicochemical factors : Vehicle-skin interactions 1. Type and Nature of the vehicle : Occlusive vehicles like fats and oils reduces water loss, increases moisture content and promotes penetration. Lipophilic vehicles like paraffins , waxes, fatty acids, and alcohols also prevents water loss. W/O emulsions are also occlusive in nature. O/W emulsions are slightly less occlusive but also promotes penetration. 2. Effect of Temperature: Increased temperature can increases penetration. Occlusive vehicles can increase temperature on application. Minor effect compared to hydration.

23. 3. Effect of penetration enhancers : Substances which temporarily diminishes the impermeability of the skin and enhances the penetration rate of drugs are called as penetration enhancers. DMSO, DMF and DMA commonly used but have irritant effect, toxicity and bad odor . Pyrrolidones can be used as effective enhancers. Surfactants especially anionic surfactants alters the penetration by interacting with protein helics of the skin. Combination of oleic acid with propylene glycol. Considering the safety and effectivity water is the best penetration enhancer.

24. Physicochemical factors : Drug – Vehicle interactions This factor is considered when release of drug from the vehicle is the rate determining factor. The affinity between the drugs and the base determines the release rate of drugs. The substances having lower solubility in the vehicle may releases rapidly.

25. Ointments DEF: Ointments are semisolid preparations meant for external application to skin or mucous membrane. FORMULATION OF OINTMENTS: Active pharmaceutical ingredients Ointment bases Antioxidants Preservatives Humectants Perfumes

26. Classification of ointments Based on penetration Epidermic- Meant for action on epidermis Endodermic- Action on deeper layers of cutaneous tissue Diadermic- Meant for deep penetration According to therapeutic uses (API) Antieczematous like Hydrocortisone, coal tar and Ichthammol . Antibiotic s like Bacitracin, Neomycin Antifungal s like Benzoic acid, salicylic acid, Nystatin Antiinflammatory like Betammethasone , Triamcenolone Antipruritic s like Benzocaine, coaltar Astringent s like calamine, Zinc oxide and Tannic acid Counter irritants like Capsaicin, Iodine, Methyl salicylate Keratolytic s like Resorcinol, Salicylic acid and Sulphur Paraciticides like Benzyl benzoate, Gamma benzene hexa chloride.

27. An ointment is a substance or part of an ointment which serves as a carrier or vehicle for the active ingredient. They should be: Compatible with skin pH and drug Inert, non irritating and non sensitizing Good solvent and/or emulsifying agent Emollient, protective , non greasy and easily removable Release medicaments easily at the site of administration Pharmaceutical elegant and possess good stability.

28. B AS E S OL E A GINOUS BASE A B S O RP T ION BASE EM U LSI O N BASE WATER S O L UB L E BASE

29. 1. Oleaginous ( hydrocarbon) bases: They consist of a combination of more than one oleaginous material such as water insoluble hydrophobic oils and fats Disadvantages: Greasy, sticky-non washable Retain body heat Do not increase absorption They are anhydrous, do not absorb water & insoluble in water . Emollient action on skin. These bases include: Hard Paraffin , Soft paraffin, Liquid paraffin

30. A ) Hard paraffin: A mixture of solid saturated hydrocarbons that are derived from petroleum. It is a colourless or white wax-like material that is physically composed of a mixture of microcrystal. The melting temperature of hard paraffin is between 47 and 65 o c and, used to enhance the properties of ointment bases . B) Soft paraffin (Petrolatum): This is purified mixture of semisolid hydrocarbons obtained from petroleum. Types Yellow soft paraffin – M.pt=38 C, used in ophthalmic ointments. White soft paraffin- M.pt=56 C, obtained from bleaching Yellow soft paraffin.

31. c) Liquid paraffin (white mineral oil/ liquid petroleum): mixture of liquid hydrocarbons obtained from petroleum by distillation. White, transparent, tasteless, oily liquid. USE - Combine with hard/ soft paraffin to harden/soften ointment base, and also as levigating agent.

32. 2. Absorption base s : Absorption bases, unlike the hydrocarbon types, are hydrophilic-absorb considerable amounts of water or aqueous solutions. These bases do not absorb water on contact, but with sufficient agitation, they absorb aqueous solutions and may become W/O type emulsions. Less occlusive than hydrocarbon bases, but have emollient action. Not easily removable from skin. To incorporate small amounts of aqueous solutions.

33. Wool fat(Anhydrous lanolin): This is fat from wool of sheep ovis aries Can absorb 50% water of its weight . , more sticky nature. USE: ointment base preparation, ophthalmic ointments. Wool alcohol: Wool fat is alkalized to separate cholesterol & alcohol . It contains NLT 30 % of cholesterol. USE: ointment base preparation Bees wax: Wax from honey comb of bees. 2 types- yellow & white bees wax USE: stiffening agent in paste & ointments. Hydrous wool fat: Purified fat from wool of sheep. Insoluble in water, soluble in ether, chloroform. Contains 70% wool fat+ 30% water. USE: Emollient.

34. Advantages of Absorption bases Compatible with most of the medicaments Absorb large quantity of water or aqueous substances Relatively heat stable Easily spreadable Less occlusive and good emollients Aqueous substances can be incorporated Disadvantages Undesirable due to greasy nature Chances of microbial contamination.

35. 3. Water Removable bases: Water removable bases and are of O/W emulsions that resembles creams in appearance. Ability to absorb water, serum discharges . Can be diluted with water. Advantage s: Miscible with exudates from lesions Does not interfere with skin function Good contact with skin because of surfactant content High cosmetic acceptability. Easy removable from the hair.

36. Hydrophilic ointment: White petrolatum 250 gm Stearyl alcohol 250 gm Propylene glycol 120 gm SLS 10 gm Methyl Paraben 0.25 gm Propyl paraben 0.25 gm Purified water 370 gm

37. 4. Water soluble Bases: ( Grease less Base ) Do not contain oleagenous substances and contain completely water soluble ingredients. Greaseless and become softer on addition of water. Carbo waxes 200,300…1500. (For viscous liquids) Carbo waxes 1540, 3000.. 6000(For Viscous solids) Pectin, Tragacanth & Cellulose derivatives (Form plants) Gelatin (Animal) Silica Gel, Bentonite (Chemical) For low viscosity - Glycerin, Glyceryl mono stearate.

38. Carbo waxes (Macrogols/ Polyethylene glycols) General formula CH 2 OH. (CH 2 OCH 2 )n . CH 2 OH These are mixtures of polycondensation products of ethylene oxide and water Average Molecular weight is represented by numbers Macrogols 200, 300, 400 Macrogol 1500 -- viscous liquids -- greasy semi solid Macrogols 1540, 3000,4000, 6000 -- waxy solids Liquids Clear and colourless Faint characterisitic odour Miscible with water, alcohol and other glycols

39. So l ids White or cream in colour Hard lumps or flakes Soluble 1 in 3 in water and 1 in 2 in alcohol Solidifying points range from 40 to 60°c Macrogols Properties: Non-toxic and non-irritating pH – 4 to 7.5 Can be sterilised by heat (solids – dry heat, liquids – autoclave) water soluble, non-volatile and inert substances. Different carbowax mixture produces different consistency.

40. Selection of an appropriate ointment base Pharmaceutical Factors Stability Solvent properties Consistency Dermatological Factors Effect on skin function Miscibility Compatibility Irritation Emolliency Ease of Application & Removal

41. Formulation of ointments Cont.. Antioxidants: When there is a possibility of oxidative degeneration. BHT, BHA and propyl gallate . Preservatives: These are selected based on irritancy and toxicity. Benzoic acid derivatives are used commonly. But for nasal administration they are not used because of irritation, Quaternary ammonium compounds like Phenyl mercuric nitrite is used. Chelating Gents: To chelate the trace amounts of metal ions, chelating agents like Citric acid, Phosphoric acid, Maleic acid, Tartaric acid are used. Perfumes: To give a pleasant odour.

42. MANUFACTURING Ointments are prepared by Incorporation or Trituration method Fusion method Chemical reaction method Emulsification method

43. Incorporation method Incorporation of solids Incorporation of Liquids Ointment tile and Spatula made up of metal, rubber are used. The method involves steps like Size reduction Levigation Trituration Levigating agents mineral oil for oleagenous bases and Glycerin for other bases. Mortar and pestle is used for levigation . After levigation the paste of the drug is incorporated into ointment base. While incorporating liquids, the capacity of base to absorb and retain liquids must be considered.

44. FUSION METHOD When ointment base consists of number of solid ingredients. When the melting point differences are more. All the ingredients are subjected to heat to melting. Melting is done in the decreasing order of the melting points. Heat sensitive or any volatile substances are added last. Porcelain dish or glass beaker is used in small scale, and Steam jacketted kettle is used in large scale.

45. EMULSIFICATION METHOD Fats , oils and waxes an melted together to a temperature and 70 c. Aqueous solution of the heat stable, water soluble compounds is also heated to the same temperature. Aqueous Solution is slowly added to the melted bases, with continuous stirring until cool. Emulsifying agent is needed to make a stable emulsion Water soluble soaps are commonly used as emulsifier for semisolid o/w emulsions. Combination of triethanolamine stearate soap and cetyl alcohol is used in o/w emulsion Bees wax and divalent calcium ions used in w/o emulsion.

46. Chemical reaction method Preparation of some ointment involves chemical reactions Eg – (a)Iodine ointment (iodine free form) (b)Iodine ointment (iodine combined form with ointment base) (a)Ointments containing free iodine Iodine is slightly soluble in fats and vegetable oils. Readily soluble is potassium iodide solution in water due to formation of polyiodides (KI. I 2 , KI. 2I 2 , KI.3I 2 ) Poly iodides are readily soluble in water, alcohol and glycerin. These solutions may be incorporated with the molten absorption type ointment base.

47. (b) Ointments containing combined iodine Fixed oils and many fats obtained from vegetable and animal sources contain unsaturated constituents Iodine combines with double bonds CH 3 (CH 2 ) 7 CH=CH (CH 2 ) 7 COOH + I 2 (Oleic acid) CH 3 (CH 2 ) 7 CHI.CHI (CH 2 ) 7 COOH (Di-iodo stearic acid) Free iodine is not available, So ointments appear dark, greenish black in colour Leaves no stain when rubbed into the skin, Hence known as non- staining iodine ointment

48. EVALUATION OF OINTMENTS Drug content Release rate of medicament from base Penetration rate of medicament Absorption of medicament into blood stream Consistency of the preparation Irritant effect

49. 1. Drug content:-- Minimum fill test Select any 10 filled containers Weigh the required amount of ointment Medicament is extracted in to a suitable solvent Drug Content is determined by suitable analytical technique Results should be with in labeled quantity. 2. Release rate of medicament from base:-- Two in vitro techniques are used Agar cup plate method Diffusion method

50. Agar cup Plate method Used to determine the release rate of antibacterial ointment Tested in agar medium seeded with staphylococus aures. Zone of inhibition of bacterial growth is measured around circular cups

51. Diffusion method: Used to find the release rate of any type of medicament from the base A semi permeable membrane is tied at one end of glass tube Ointment is filled in the tube, properly spread on the membrane Tube is dipped in the distilled water maintained at 37±1 O C Samples are withdrawn after a specified period of time. Samples are immediately replaced with fresh distilled water Analyzed for the drug content Plot a graph between drug concentration and time

52. 3. Penetration rate of medicament: Determined by rubbing weighed amount into defined areas for a fixed time . Unabsorbed material is removed completely and weighed . Difference in weight provides total amount penetrated . Rate is then calculated . 4. Absorption of medicament into blood stream: Diadermic ointments are tested by in-vivo method. Determined by assaying drug content in either blood, urine, faeces or tissues after rubbing defined amount under standard conditions

53. 5. Consistency of the preparation: Determined by sliding a glass plate over the product by means of a pulley. Product is spread evenly on another glass plate fixed on a wooden block . Weights are added to the pan so that sliding of the movable glass plate is obtained . Ointment which require more weights to allow the plate to slide- over have high consistency or vice-versa .

54. 6. Irritant effect:-- Test is performed on skin and eyes of rabbit or human skin . Results are observed daily for a week Irritant effect of dermatological preparation is shown as lesions on cornea, iris and conjunctiva . Some times Rats are used and the ointments are injected to thigh muscles and sometimes under abdominal skin. Reactions are noted at intervals of 24,48, 72 and 96 hrs. Irritation can be identified by the presence of patches on skin.

55. PASTES

56. Pastes are semisolid preparations intended for application on to the skin and they differ from ointments that they generally contain a large amounts of finely powdered solid substances. These are thicker and stiffer than ointments and also less greasy than ointments and this is due to less amount of base. Stiffer in consistency and do not melt at body temperature. Less viscous than ointments and easy to stick. Due to high content of powdered substances pastes can absorb serous secretions and exudations.

57. Formulation of Pastes API Bases Absorbents Humectants Flavours/Perfumes Stabilizers

58. Paste base: Hydrocarbon bases:-- soft paraffin , liquid paraffin. Water miscible bases:-- glycerin, emulsifying ointment. Water soluble bases:-- poly ethylene glycols. Absorbents : To absorb wound exudates and secretions Ex: Zinc oxide, Light kaolin, Starch etc. Humectant: To maintain humidity in the preparation and to prevent drying. Ex: gl y cerin , sorbita l, propylene glycol.

59. GELS

60. GELS Gels are thin, transparent or translucent non greasy preparations consisting of dispersions of small or large molecules in an aqueous liquid vehicle. Lubricating (Surgical), Local anaesthetics, Antiseptic and Spermicidal (Non surgical) purposes. Gels are not suitable for water insoluble drugs.

61. FORMULATION OF GELS Active ingredients: Local anaesthetics, Antiseptics, Spermicides- Nanoxynol-9 2. Gelling agents 3. Co-solvents/Dispersing agents 4. Preservatives 5. Water

62. Gelling agents These are organic hydrocolloids/ hydrophilic inorganic substances. Natural gelling agents– gum tragacanth, Alginates, starch , pectin, gelatin . Semi synthetic gelling agents – Cellulose derivatives Synthetic gelling agents– C arbomer s , poly vinyl alcohol, etc.,

63. 1.Tragacanth : Used for preparations of Lubricating, Medicated & Contraceptive Jellies. Concentrations used for Lubricating (2 to 3%) & Dermatological vehicle (5%). Tragacanth is poorly wettable On addition to water lumps are formed which is difficult to disperse Dispersing agent is generally used to get a homogenous product Alcohol, glycerol or volatile liquids are used as dispersing agent

64. Disadvantages : Obtained from natural sources , so vary in viscosity After evaporation, the film left on the skin tends to flake Loss of viscosity outside the pH range of 4.5 – 7 Can’t be stored for longer time Prone to microbial growth

65. 1.5 to 2% Used as Lubricant gel & Dermatological vehicle 5 To 10% Viscosity can be increased by adding soluble calcium salt Salting out is observed with high conc. 2-4% alcohol, glycerine, propylene glycol are used as dispersing agent Advantages over tragacanth Available in several grades of standard viscosity 2 . Sodium alginate :

66. 3 . Pectin : Good gelling agent suitable for acid ic products Used in many preparations including edible Jellies Glycerine is used as dispersing agent & humectant Pectin jelly is good medium for bacterial growth, add preservative Storage: Well closed container to prevent loss of moisture by evaporation

67. 4 . Starch : Used in combination with other Jelling agent . Provides a water soluble dermatological base . Starch + Gelatin = Glycerin jelly product is still used Glycerin (up to 50%) may be added which acts as preservative and humectant Note: Must be freshly prepared Well closed container to prevent loss of moisture by evaporation \

68. 5 . Gelatin : Insoluble in cold water (swells and soften) Soluble in hot water 2% gelatin forms jelly on cooling Stiff medicated Jellies can be prepared (15%) Melted before use and after cooling to desired temperature, applied with a brush. Affected area covered with bandage and left in place for several weeks Suitable preservative is required

69. 6 . Cellulose derivatives : Produce neutral jellies of very stable viscosity Afford good resistance against microbial growth High clarity & produce a soft film after drying Sodium CMC Used for preparation of lubricating & sterile jellies 1.5 - 5% - lubricant gels, 5% - Dermatological gels Withstand autoclaving temperature without deterioration Methyl cellulose – 3 %

70. Carbomer : High molecular weight water soluble polymers of acrylic acid which are crosslinked with allyl sucrose. 0.3-1% in lubricating gels & 0.5-5% as dermatological vehicle. These have high gelling efficiency and used in low concentrations. Poly vinyl alcohol (PVA): PVA gels provide protection as they dry quickly to form a strong residual film on skin. These are available in various grades and viscosities.

71. Preparation of Gels: Usually prepared by adding thickening agent along with dispersing agent. ex:Tragacanth,Carboxymethyl cellulose Thickening agent is added to aqueous solution in which drug has to be dissolved Mass is triturated in a mortar until a smooth product is obtained When coloured drug to be incorporated glass mortar is used Whole gum is preferred to powdered gum to get clear preparation of uniform consistency Remaining ingredients are added with stirring.

72. E x ampl e : R x Icthammol Tragacanth Alcohol (90%) Glycerine Water -20g -5g -10g -2g -qs 100g Send 100g Icthammol j elly Procedure : Tragacanth + alcohol motor  mucilage. Icthammol + glycerine + water Drug solution Drug solution + mucilage triturate Add water qs 100g Transfer into container, label & dispense.

73. PACKAGING OF SEMISOLIDS: The semisolid preparations are stored in a well closed amber colored container to protect against Temperature and Light. Ointment jars: Glass and porcelain Plastic 2. Collapsible plastic tubes

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