1. SEMI-SOLID

2. Anatomy and Physiology of skin
Skin is divided into 3 layers:
Epidermis
Dermis
Subcutaneous tissue (hypodermis)
EPIDERMIS:
External layer of the skin.
Thickness is from 0.16 mm to 0.8 mm.
Acts as a protective barrier against bacteria, chemical irritants, allergen etc.

3. Consists of 5 layers:
Stratum corneum: (horny layer)
-outermost layer
Stratum lucidum: (barrier zone)
Stratum Granulosum: (granular layer)
-keratinization
Stratum Spinosum (Prickle cell layer)
Stratum Germinativum ( Basal Cell layer)

4. Dermis:
3 to 5 mm thick.
Synthesizes proteins, collagen and elastin.
Supports Epidermis.
Contains blood vessel, lymph vessel, hair follicles, Sebaceous gland, sweat gland, muscle and nerve fibers.
Subcutaneous Fat Tissue ( Hypodermis):
-Innermost layer of skin.
-Fat storage

5. PERCUTANEOUS ABSORPTION
Involves the transfer of drug from the skin surface into the stratum corneum, under the support of concentration gradient and its subsequent diffusion through the stratum corneum and underlying epidermis, through the dermis and into the microcirculation.
Route of Penetration:
Between the cells of stratum corneum
Through the walls of hair follicles
Through the sweat gland
Through the sebaceous gland
Through the cells of stratum corneum
(Figure from Sprowl’s American Pharmacy)

6. PERCUTANEOUS ABSORPTION
So, in a simplified way, it can be said that-
Percutaneous absorption is the penetration of a substance from outside into the skin and then through the skin into the bloodstream.

7. Factors Affecting Percutaneous Absorption
PHYSICOCHEMICAL FACTORS:
1.Concentration of drug in the vehicle:
-the amount of drug percutaneously absorbed per unit of S.A per time interval increases, if the
concentration of drug in the vehicle increases.
2.Surface area of the skin:
-the larger the area of application, the more drug is absorbed.
3. Aqueous Solubility:
-Increase in aqueous solubility of a drug, enhances its absorption.

8. PHYSICOCHEMICAL FACTORS:
Diffusion Co-efficient:
-Percutaneous absorption usually occurs by passive diffusion and this process may be governed by Fick’s Law of diffusion
dQ/dT= DA(C2-C1)/ x
Here,
dQ/dT= rate of diffusion
D= diffusion co-efficient
A=area
X= thickness
C2= concentration of drug
C1= concentration of medium

9. PHYSICOCHEMICAL FACTORS:
Partition co-efficient:
-Here, skin and base act as 2 different phases.
-Drug is incorporated with the vehicle.
-If the attraction between drug and molecule and vehicle is stronger than the attraction between the drug molecule and skin, then drug molecule do not enter inside the skin.
-So the partition co-efficient value should be favorable for the absorption of the drug.

10. PHYSICOCHEMICAL FACTORS:
6. Activity Co-efficient: -The activity of the drug in the vehicle is the product of the drug concentration and the activity co-efficient of the drug in vehicle. - The highest activity of the drug in a vehicle is needed to obtain the maximum rate of penetration.

11. PHYSICOCHEMICAL FACTORS:
7. Penetration Enhancer:
-certain substances temporarily diminish the impermeability of the skin and are used clinically to enhance the penetration rate of drug. Ex:
DMSO
DMA
DMF

12. PHYSICOCHEMICAL FACTORS:
Vehicle Composition:
-The percutaneous absorption of some drugs (corticosteroids) is markedly affected by changes in vehicle composition.
-The influence of vehicle on percutaneous absorption is related to an effect
On the solubility of the drug in the vehicle
On the activity coefficient of the drug
On the vehicle or skin permeation coefficient
rather than on the effect of the vehicle on the skin itself.

13. PHYSIOLOGICAL FACTORS:
Skin thickness:
- If skin thickness is high, rate of percutaneous absorption is less.
2. Skin Hydration:
Higher the amount of water in skin, higher the hydration state, higher will be the rate of percutaneous absorption.
3.Skin Condition:
-The intact skin is an effective barrier to penetration.
-Keratolytic agents accelerate percutaneous absorption by softening the keratinized cell matrix of stratum corneum.

14. MISCELLANEOUS FACTORS
The site of absorption:
The drug penetrated readily where the outer keratin layer is thin.
Length of time of the use of drug
Multiple dosing
Skin temperature
State of ionization of medicaments
pH pf the applied preparation and pH of the skin

15. ADVANTAGES OF PERCUTANEOUS ABSORPTION OF DRUG
They can avoid GI drug absorption difficulty caused by GI pH, enzymatic activity and drug interaction.
They can avoid first pass effect.
Drug therapy may be terminated rapidly.
When oral route is unsuitable (vomoting, diarrhoea) then this route can be used.
Frequent dose can be administered.

16. Purpose of Giving Semisolid drug to Topical route
General purpose:
Emollient effect
To make the skin smooth
Disease:
-Antibiotic, antihistamin, anti inflammatory, analgesic activities.
Systemic Effect:
TDDS

17. Types of pharmaceutical semi-solid preparations:
Ointments
Creams
Gels
Pastes

18. OINTMENTS
Ointments are semi-solid preparations intended for external use.
They are easily spread and their plastic viscosity may be controlled by modification of the formulation.
Ointments are typically used as
Emollients – that make the skin more pliable
Protective barriers – which prevent harmful substances from coming in contact with the skin
Vehicles – in which to incorporate medication.

19. Ointment Bases
Ointment bases is the fatty substance which is employed as vehicle or carrier for medicaments, emollients to soften or render the skin more pliable to prevent the skin from moisture, air and chemicals.
Examples:
Acne treatment: Resorcinol
Antibiotic: Neomycin, Bacitracin
Antifungal: Benzoic acid, Salicylic acid
Anti-inflammatory: Hydrocortisone
Analgesic: Methyl salicylate
Protective agent: Calamine, ZnO

20. CHARACTERISTICS OF AN IDEAL OINTMENT BASE
Stable
Neutral in nature
Non greasy
Non-toxic
Non-irritant
Non dehydrating
Non hygroscopic
Non staining
Non pH dependent
Non degreasing in action
Water removable

21. CHARACTERISTICS OF AN IDEAL OINTMENT BASE
12. Compatible with all medicaments 13. Free from objectionable odor 14. Efficient on all types of skin 15. Capable of stock preparation for extemporaneous use 16. Melting or softening at body temperature 17. Capable of holding at least 50% water 18. Composed of readily available ingredients of known chemical composition.

22. CLASSIFICATION OF OINTMENT BASES
Ointment bases are classified into four general groups:
Oleaginous Bases
Absorption Bases
Emulsion Bases
Water-soluble Bases

23. 1.Oleaginous Bases Characteristics:
Lipophilic or hydrophobic in nature.
They cannot absorb water, they do not contain water and are not washable in water.
Hydrocarbon bases are retained on the skin for prolonged periods.
Inhibits evaporation of skin moisture.
act as occlusive dressings. They do not "dry out" or change noticeably upon aging.

24. Petrolatum Petrolatum is a good base for oil-soluble ingredients.
a mixture of semisolid hydrocarbons obtained from petroleum
an unctuous mass, varying in color from yellow to white
It forms an occlusive film on the skin, absorbs less than 5% water under normal conditions and does not become rancid.
- Wax may be incorporated to stiffen the base.
- It may be used alone or in combination with other agents as an ointment base.
- Commercial product is Vaseline.

25. Petrolatum

26. Parrafin
A purified mixture of solid hydrocarbons obtained from petroleum.
A colorless or white, more or less translucent mass that may be used to harden or stiffen oleaginous semisolid ointment bases.
Paraffins form a greasy film on the skin, inhibiting moisture loss and improving hydration of the horny layer in dry scaly conditions.
This hydration is also a main reason why ointments are so effective in encouraging percutaneous absorption of a drug.

27. Parrafin

28. Liquid paraffin
A colorless, odorless oily liquid consisting of a mixture of hydrocarbons obtained from petroleum.
Has the same character with paraffin .
Can be used in combination with paraffin to adjust viscosity.

29. Plastibases
The plastibases are a series of hydrocarbon bases, containing polyethylene, which forms a structural matrix in systems which are fluid at the molecular scale but are typical dermatological semi-solids.
They are soft, smooth, homogenous, neutral, colorless, odorless, non-irritating, non-sensitizing, extremely stable vehicles.
Compatible with most medicaments and they maintain their consistency even at high concentrations of solids and at extreme temperatures.

30. Plastibases The bases apply easily and spread readily
They adhere to the skin, imparting a velvety, non-greasy feel and can be readily removed.

31. Synthetic Esters
Synthetic esters are used as oleaginous base constituents, including
glyceryl monostearate
isopropyl myristate
isopropyl palmitate
butyl stearate and
butyl palmitate.
Long chain alcohols such as cetyl alcohol, steryl alcohol and polyethylene glycol (PEG) may also be used.

32. Lanolin derivatives
Lanolin derivatives are commonly used in topical and cosmetic preparations.
Examples include
lanolin oil (Lantrol)
hydrogenated lanolin

33. 2.ABSORPTION BASES
Absorption bases are anhydrous, water- insoluble and therefore not washable in water, however these bases can absorb water.
They permit the inclusion of water-soluble medicaments through prior solution and uptake of the solution as an internal phase.

34. Examples of Absorption Bases
Wool fat (anhydrous lanolin)
Wool fat (anhydrous lanolin) contains a high percent of cholesterol as well as esters and alcohol containing fatty acids.
may contain no more than 0.25% of water.
Insoluble in water but absorbs twice its weight in water
melts between 36°C and 42°C.

35. Examples of Absorption Bases-

36. Examples of Absorption Bases
Hydrophilic Petrolatum
Hydrophilic ointment is a white petrolatum combined with 8% white beeswax, 3% stearyl alcohol and 3% cholesterol which are added to a w/o emulsifier.
Has the ability to absorb water, with the formation of a water-in-oil emulsion.
Prepared forms include : Aquaphor which employs wool alcohol to render white petrolatum emulsifiable, Polysorb which uses sorbitan sesquioleate .

37. 3. Emulsion Bases Emulsion bases may be
w/o emulsions, which are water-insoluble and not washable in water but can absorb water because of their aqueous internal phase.
Ex: lanolin, cold cream
They are used as emollients.
The aq. phase hydrating the skin and the oil phase forms a occlusive layer covering which prevents water loss due to evaporation.

38. o/w emulsions which are water-insoluble but washable in water and able to absorb water in their aqueous external phase.
Ex: Hydrophilic ointment, Vanishing Cream

39. Examples of Emulsion Bases-
Hydrous wool fat (Lanolin)
Hydrous wool fat (lanolin) is a w/o emulsion containing about 25% water.
It acts as an emollient and forms occlusive films on the skin, effectively preventing epidermal loss.

40. Examples of Emulsion Bases
Cold cream
Cold cream is a w/o emulsion prepared by melting white wax, spermaceti and expressed almond oil together, adding hot aqueous solution of sodium borate, and stirring until cool.
Use of mineral oil rather than almond oil makes a more stable cold cream. However, cold cream prepared with almond oil makes a better emollient base.
This ointment should be freshly prepared.

41. Spermaceti

42. Mineral Oil
a mixture of liquid hydrocarbons.
It is useful as a levigating substance to wet and to incorporate solid substances into the preparation of ointments that consist of oleaginous bases as their vehicle.

43. Hydrophilic ointment
Hydrophilic ointment is an o/w emulsion employing sodium lauryl sulfate as an emulsifying agent.
It is readily miscible with water and thus can be removed from the skin easily.

44. Vanishing cream
Vanishing cream is an o/w emulsion, which contains a large percentage of water as well as humectant (e.g. glycerin, propylene glycol), which retards surface evaporation of the product.
An excess of stearic acid in the formula helps to form a thin film when the water evaporates.

45. 4. Water-soluble bases May be anhydrous or may contain some water.
Non-greasy and also known as greaseless ointment bases.
Water soluble
Water washable

46. PEG Ointment
PEG ointment consists of a blend of water-soluble polymeric glycols that forms a semisolid base capable of solubilizing water-soluble drugs and some water-insoluble drugs.
This base contains 40% PEG 4000 (solid) and 60% PEG 400 (liquid) and is prepared by the fusion method.
Only a small amount of liquid (<5%) can be incorporated without loss of viscosity. This base can be made stiffer by increasing the amount of PEG 4000 up to 60%.

47. general formula HOCH2[CH2OCH2]nCH2OH
Suitable combinations of high and low molecular weight polyethylene glycols yield products having an ointment like consistency which soften or melt when applied to the skin.
Much less occlusive than the absorption bases.

48. Propylene Glycol and Propylene Glycol-ethanol
forms a clear gel when mixed with 2% hydroxy-propyl cellulose. This base has become popular as a dermatologic vehicle.

49. Ophthalmic Ointments Vehicles should be non-irritating and sterile.
Petrolatum, Petrolatum-mineral oil and petrolatum-anhydrous lanolin bases are often used in ophthalmic ointments because of their low irritating potential.
Example:
Neomycin Ophthalmic ointment
Tobramycin Ophthalmic ointment

50. Preparation of an ointment
Insoluble powder Drug+ Small amount of Base
Mixture
Mixture + Remainder Base Ointment
Water soluble drug +water Solution + Lanolin Mixture
Mixture + Base Ointment

51. 2 Methods for preparation:
Levigation Method
Fusion Method

52. 1.levigation
The substance is incorporated into the ointment by levigation on an ointment slab.
A spatula with a long, broad blade should be used.
Insoluble substances should be powdered finely in a mortar and mixed with an equal amount of base until a smooth grit-free mixture is obtained. The rest of the base is added in increments.
Levigation of powders into small portion of base is facilitated by using a melted base or by the using a small amount of a compatible levigating agents such as mineral oil or glycerin.

53. 1.levigation Levigating agents:
Mineral oil for oily bases or bases where oil are the external phase.
Glycerin for bases where water is the external phase.
Levigating agent should be equal in volume to the solid material.
When liquid is added into an ointment, care must be taken to consider the capacity of the ointment in accepting the liquid.
When it is necessary to add an aqueous preparation to a hydrophobic base, the solution should be added into minimal amount of the hydrophilic base first. The mixture should be then added into the hydrophobic base

54. 1.levigation
Water soluble salts may be incorporated by dissolving them in the smallest possible amount of water and then incorporating the aqueous solution directly into the base.
Usually organic solvent such as ether, choloroform, or alcohol should not be used for dissolving the drug as the drug may crystallize out as the solvent evaporates.
Solvents should be used as levigating aids only if the solid is going to become a fine powder following the evaporation of the solvent.

55. 2. FUSION
This method is used when the base contains solids that have higher melting points such as waxes, cetyl alcohol and glyceryl monostearate.
This method is also useful for solid medicaments that are readily soluble in melted bases.

56. 2. FUSION
The oil phase should be melted separately, starting with materials having the highest melting point. All other oil-soluble ingredients are then added in a decreasing order of melting point.
The ingredients in the water phase are combined and heated separately to temperature equal to above that of the melted oil phase.
The two phases are them combined. If a w/o system is desired, the hot aqueous phase is incorporated into the hot oil phase with agitation. If a o/w system is desired, the hot oil phase is incorporated into the hot aqueous phase.

57. 2. FUSION
Volatile materials (e,g alcohol, menthol, iodine, camphor, parfumes etc) are added after the melted mixture cools to desired temperature.

58. PACKAGING Following points should be considered:
When using ointment jars, the container size should be such that the ointment fills the container but does not come in contact with the closure liner and should be ensure that the ointment fills air spaces.
If an ointment is made by fusion, it is usually packed while the ointment is still warm enough to be poured directly into the jar.
According to application the tubes are available with various tips i.e. eye tips, nasal tips, vaginal tips and rectal tips.

59. PACKAGING
Packaging of ointments on a large scale is carried out with automatic filling and crimping machine. The ends of the tubes are automatically folded, corrugated and code marked.
Ointments are usually packed in:
Ointment jars (glass or plastic)
Ointment tubes (tin or aluminium, variety of plastic)

60. DIFFERENCES BETWEEN OINTMENT, PASTE, CREAM AND GEL
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61. DIFFERENCES BETWEEN OINTMENT, PASTE, CREAM AND GEL
Generally Hydro-carbon based greasy semisolid
Basically ointment in which high percentage of insoluble solid has been added.
Semisolid preparation in which one or more medicaments are dissolved in either a W/O or O/W emulsion.
Semisolid preparation in which a liquid phase is trapped within a 3-D polymeric matrix.
Opaque
Transparent
Greasy
Less Greasy

62. REFERENCES Sprowl’s American Pharmacy (seventh edition)
The Theory and Practice of Industrial Pharmacy by Leon Lachman, Chapter -18, Page - 534