OINTMENTS, CREAMS AND PASTES; How they work on skin?

Most of the drugs discussed in this section are applied on the skin. The skin has various functions:

Functions of skin

1. protects internal body structure from hostile external environmental hazards (pollution, temperature, humidity  and radiation)
2. limits passage of chemicals into and out of the body
3. acts as a microbilogical barrier
4. stabilizes blood pressure and temperature
5. mediates sensation of heat, cold, touch and pain
6. Expresses emotions, e.g. embarrassment, anger, and anxiety (by sweating)
7. Identifies the individual (color, hair, odor, and texture)

The dispersed systems in this section include Ointments, creams, pastes and suppositories. Others are transdermal drug delivery systems, lotions, topical solutions, linients, powders, gels, tinctures and aerosols.

Ointments are semisolid Preparations for external use which can be applied on skin or mucosae with or without inunction. Ointments act as protective and emollients on skin, but also may serve as vehicles for topical application of medicinal substances and cosmetics. There exist also ophthalmic ointments which are sterile to be applied in the eye.

Characteristics of ointments: Ointments should soften on application but should not melt.

Usually, ointments are oleaginous (containing fatty substances) but the definition of ointments includes substances of same consistence although they may differ in appearance and containing no fatty substances. White Ointment is Oleaginous while Polyethylene glycol (PEG) ointment if free from oleaginous substances.

Creams  are semisolid emulsions, usually medicated for external applications. They can be oil-in-water (O/W) or water-in-oil (W/O). There are also rectal and vaginal creams to be applied in the rectum and vagina respectively.

Pastes are creams and ointments containing a large amount of powder (solid material) and therefore are much thicker or stiffer.

 Preparations are applied to the skin for their physical activities like

• Acting as protectants, lubricants or emmolients
• Drying effect
• Specific medicinal agents (antibiotics, antifungals, antivirals, antiseptics)

Preparations sold Over-the-Counter (OTC) contain mixtures of medicinal substances used in the treatment of such conditions as minor skin infections, itching, burns, diaper rashes and other rashes, insect stings, and bites, skin diseases (e.g. eczema, psoriasis, athlete’s foot and acne)

Prescription skin preparation usually contain a single medicinal agents intended to counter a specific diagnosis condition, but now combination therapies are increasingly becoming common ( eg Quadriderm, Gentriderm, and Gentrisone).

Historical Background.

In ancient history, fats of animals were the basic vehicles for formulating ointments. Evidence fro excavations in the tombs of Egyptians Kings have given evidence of existence of ointments dating from 3000 -5000 BC. Later on honey, wax, gums and resins and balsams and mucilages from plants were used as bases for ointments.

The modern concept of ointments is a product of long development. Earlier, liquids and semisolid such as cerates, poultices and pastes preparations were all termed as ointments, but during the 13^th century, separate definitions were developed.

In the 19^th C, the concept of ointment began to broaden as natural bases were purified and used, and artificial bases were developed. In 1858, Translucent jelly was prepared by heating glycerin and starch. This is known as Unguentum glycerin BP.

1873 – Cosmolin and paraffin oil (Petrolatum)

1876 – Stearic acid (a substitute for white wax in over the counter products(

1885 – Wool fat (lanolin) was rediscovered

1920 -  Hydrogenated oils, sulfated sulfonated  hydrogenated oils, polyethelene glycols

(PEG) and their esters wwere discovered

1945 – Surface active agents (SAA) plastibase, attapulgite, silicones, and veegum

1960 – Emulsion type especiallyecially oil-in-water. These proved to be easily washed or

removed, promote percutaneous absorption. Thus various creams are now found in pharmacopoeia eg Cold Cream, Iodochlorohydroxyquin creams.

In summary, during the Greco-Roman time, ointment meant anything to smear whether aqueous or oily. In modern times, ointment has a broader meaning, including both fatty and aqueous hydrocarbon bases, e.g. vanishing cream.

Medications used for treatment on the skin include drugs for treatment of allergy, burns, local itchiness and superficial skin disease. But other medications are used to treat inner areas of the skin or even to provide systemic effects by penetrating through the skin.

 Medications used in treatment via skin

1. Surface treatment (camouflage, sunscreen, skin barriers to prevent chapping, cosmetic application, topical antibiotics, antiseptics, and deodorants). The surface bioavailability requires the formulation to release (not bind to) medicament.
2. Stratum corneum treatment: to improve emolliency or stimulate sloughing (keratolysis)
3. Skin appendage treatment: to reduce hyperhydrosis of the sweat glands with antiperspirants (Aluminium chloride), treatment of acne with salicylic acid, tretinoin, or isotretinoin, topical antibiotics (eg framycetin and neomycin sulphate) and anti-fungals (clotrimazole, miconazole  and ketoconazole)
4. Epidermis and dermis treatment:  steroidal and non steroidal anti-inflammatory agents and corticosteroids used in treatment of psoriasis, anaesthetics (benzocaine, amethocaine), antipruritis and antihistamins. May need penetration enhacers such as stratagems
5. Transcutaneous immunization using topical vaccine antigens e.g.
6. Systemic treatment via transdermal patches. This is a difficult approach because drugs are absorbed slowly, may be lost by washing or wiped by clothing, or by the sheded corneum scales. Also penetration depends on age, subject, conditions and sex. But there are examples in which this approach is followed e.g. nitroglycerin patches, nicorrete patches, transdermal scopolamine, nitroglycerin, oestradiol, clonidine and fentanyl.

PERCUTANEOUS ABSORPTION

Percutaneous absorption is a phenomenon associated with penetration of medicament into and through skin to blood stream. There are several ways in which drug penetrate the skin:

§  Between cells of stratum corneum,

§  Through cells of stratum corneum,

§  Through sweat glands,

§  Through sebaceous gland or

§  Through walls of hair follicles

Broken or abraded skin allow penetration easily but such penetration is not  true percutaneous absorption.

After passage through the stratum corneum, (and through the fatty layer and deeper epidermal layer finally into the dermis, drug may reach vascularised dermal layer and become available for absorption into general circulation. Subcutaneous layer behaves like a semi permeable membrane, and drug molecules penetrate by passive diffusion.

When medications are applied on the skin the following processes take place:

1.      Drug must be released from the vehicle/base

2.      Drug must penetrate into the skin layers

3.      Pharmacological action will be elicited.

 

SKIN SECTION        MODE OF PENETRATION             EXAMPLES OF

TREATMENT

 

Skin surface        Drug may dissolve, diffuse or                      Camouflage, protective layer.

    just be released from the vehicle                Insect repellants, antimicrobial    

and antifungal.

Stratum corneum      Partition of drug or diffusion                         Emolliency, Keratosis

To the stratum corneum                      (Exfolients)

Appendages                                                                           Antiperspirant, exfolient

(through pilosebaceous                                                           antibiotic antifungal

unit or ecrine gland)                                                                depilatory

 

Viable epidermis        Partition or diffusion                          anti-inflammatory

                                    through viable epidermis                     anaesthetic,

 Antihistamine

Dermis                        Partition or diffusion                          Antipruritic    

                                    through viable epidermis                     PUVA and PDT

                                                                                               

Circulation                 Removal via circulation                      Patch system

                                                                                                Nitroglycerin

Factors affecting percutaneous absorption or Properties influencing Transdermal drug delivery:

Percutaneous absorption is affected by

Ø  The condition of skin,

Ø  Nature of the drug,

Ø  Nature of the vehicle in which the drug is contained and

Ø  hydration of the skin

Ø  area where drug is applied

Ø  length of time the drug remains on skin, friction with which the drug is applied on skin

Anatomy and physiology of skin

 Skin Structure is complex. It has three layers:

1.      Epidermis (avascular, cellural).

2.      Dermis (conectve tissue)

3.      Hypodermis Subcutaneous (fat)

In addition there are skin appendages (eccrine sweat glands, apocrine sweat glands, hair and hair follicles and sebaceous glands)

(a)                Epidermis – this is the external, outer surface, about 0.1mm – 1mm

                                                -  Covered with discontinuous film of lipids

                                                -  Acidic (pH 4.5 – 6.5)

There are 5 layers – stratum corneum (horny layer),  S. lucidium (barrier zone) s. granulosum (granular layer) S. malpighii (prickle cell layer) s. germinatioum (basal cell layer).

S. corneum:   10 – 50µ, general layers of flattened keratinized cells which ore   constantly shed and replaced.

                                                -  offer Mechanical protection, retards water loss, control           entry of drugs.

 S. lucidium:     Acts as main barrier to skin penetration (even water). Thought as extension of S. corneum. Following penetration of this zone, penetrant is exposed to living tissues below.

S. gerninatium:   Growth of cells begin here, multiply push against cells above them, progress, change shape and composition and becomes horny.

           

(b)        Dermis: this is known as true skin. It is joined to epidermis but differ in

Composition/morphology. It has Collagen + Elastin fibres in gelatinous mucopolysacacharide medium

Also Blood and Lymph vessels are contained here. There are also Hair follicles, and sebaceous gland.

            (c)        Hair follicles, sweat glands, sebaceous glands

Potential pathway for drug penetration through skin, but not important – why?  There three times more sweat glands on palms/soles yet tehse are less permeable (except for water) than the rest of skin.

(d) Sebaceous glands. Play no significant role. They are richly supplied

with blood vessels. They are known to synthesize lipids.

1. Skin, skin condition and other biological factors.

Skin components complicate the whole action of drug release and final absorption. Absorption of drugs will be influenced / affected by

                                i.      Skin condition

                                                              i.      Presence of fats under the skin,

                                                            ii.      enzymes,

                                                          iii.      presence of lymphatic vessels,

                                                          iv.      interstitial fluids,

                                                            v.      hair follicles and

                                                          vi.      sweat glands.

                              ii.      Activity in skin e.g.  cell division, cell transport , cell surface loss will affect drug absorption in one way or another.

                            iii.      Disease of the skin (eczema, psoriasis),

                            iv.       skin damage (scars, scratches, cuts, blisters),

                              v.      presence of Cellular debris, sweat, sebum and surface contaminants bring other unwanted effects.

                            vi.      Skin thickness: Regional skin sites differ. Eg thickness of stratum corneum of the face, armpit, behind ear (or postauricular area) have better absorptive rates, but palm, soles are not good sites. Postauricular area has advantages: the layer is thinner, there are more sweat glands and sebaceous glands per unit area, and capillaries are closer to the surface and has relatively high temperature. )

                          vii.      Biological factors

                                                              i.      Blood flow

                                                            ii.      Skin metabolism (some medicines are metabolized under the skin and reduce the concentration gradient e.g. steroids, and some chemical carcinogens.

                                                          iii.      healing process

                        viii.      Inter-individual differences (some individuals sweat profusely, some skins are softer, some are more hairy)

                            ix.      presence of chemicals, solvents

2. Nature of the drug. (partition coefficient of the drug between vehicle and skin part, and aqueous /liquid solubility of the drug.

Absorption of the drug is said to be by passive diffusion and therefore all factors that affect passive diffusion will affect percutaneous absorption.

The diffusion process.

The rate of transfer of materials per unit area, J, is proportional to the concentration gradient. This is expressed by Fick’law:

           

J = -DδC/δχ

where C is the concentration of diffusing substance, x is the space coordinate measured normal to the section and D is the diffusion coefficient. The negative sign indicate that the flux is in the direction of decreasing concentration.

Thus diffusion does not only depend on concentration gradient and the area on which the drug is applied or even  the skin thickness but also partition coefficient between drug and skin, skin characteristics and diffusion coefficient . Additionally there is a series of strata in the skin and hence diffusion is not simple. Thus the diffusion resistance in all skin layers must be considered:

 R_T =    1     =   h₁        +         h₂          +          h₃

                                                

                                                P_T           D₁K ₁                  D₂K ₂                       D₃K ₃

Where R_T is the total resistance to permeation_, P_T is the thickness-weighted permeability coefficient, K is the partition coefficient of drug and in vehicle and skin and the numerals refer to the separate skin layers.

Unless on layer is extremely permeable compared to other layers, the diffusion process is not simple but rather complex. Furthermore the skin is selective, being easily penetrated by certain substances and resistant to penetration by others. All physiological and physicochemical characteristics must be considered by formulators.

Passive diffusion:

Movement across skin is by passive diffusion. This is evidenced by the fact that

1.      Skin remains impermeable long after removal from animal.

2.      Fick’s law is obeyed. The rate of diffusion is proportional to difference in concentration of penetrant in and out of the skin.

3.      Evidenced that diffusional resistance is in stratum corneum, Sodium, water are actively absorbed in stratum corneum.

Fick’s Law:

dQ/dt = DA (C₁-C₂)

                        x

dQ = quantity of drug transferred across the membrane

dt = change in time, A = area where diffusion is taking place.

C₁ and C₂ = concentration of drug on either side, x = thickness of skin

D = diffusion coefficient.

Since DA/x is a constant,

dQ/dt = P (C₁-C₂) where P = permeability constant.

When C_{1 =} C₂  the dynamic equilibrium is reached.

Here the main characteristics of the penetrant which determines its rate of penetration  is partition coefficient, P_k,  and effective diffusivity in the skin, D. Of these, P_k is more sensitive to molecular structure and size.

Formulation variables are not important except the thermodynamic activity of the drug in the vehicle, which increase up to saturation for a given vehicle.

2.1    Thus Drug concentration in the vehicle is important. Percutaneous absorption increase with increased concentration of the drug in the vehicle.

2.1.1 Systems where the rate controlling step to absorption is in the skin (the vehicle not appreciably affecting the skin).

dq = P.C. C DA         PC =  Effective distribution

                                       dt                x                      Coeff. of drug  between vehicle and skin.

                                                C          =          (in the vehicle)

                                                D         =          Average diffusivity in barrier

                                                A          =          X-sectional area

                                    x          =          Thickness of barrier

Here the main characteristics  of penetrate which determine its rate of penetration = PC and . Of these factors, PC is more important (varies greatly than D) and  is very sensitive to molecular structure and size.

Formulation variable are not important except the thermodynamic activity of drug in the vehicle  which increase up to saturation for a given vehicle.

2.1.2        Systems where the rate-controlling step is in the applied base (drug is fine, insoluble and in suspension, C<A), large concentration gradient develop in applied phase. Amount of drug released is proportional to square root of concentration of drug per unit volume.

√ drug concentration or        

                                                            Volume                                               

Drug solubility, diffusion constant and time are not proportional to derug concentration. The instantaneous rate of absorption at time t,

                                                            dq/dt = √ADC

                                                                            2t

Here, skin properties not important (directly) but mostly – drug  concentration (A), Diffussion coeficient.D, and solubility Cs.  : Rate is controlled by regulating A,D,Cs

                                    A          –         no problem

D         -           ( inversely proportional to Stoke –Einstein Equation and

varies with viscosity)

Cs        -           Changes according to  pH and presence of co-solvents

or Complexing agents

2.1.2        Percutaneous absorption increase when a drug is applied over a large area of the skin.

2.1.3        Percutaneous aborption is higher if the time of contact of the application is increased. The longer the time the higher the application.

2.1.4        Concentration of the drug in vehicle and hence concentration gradient increase percutaneous absorption

2.1.5        The higher the Diffusion coefficient of a drug in skin the higher the percutaneous absorption.

2.1.6        Ionization of the drug: only unionized species of a drug are absorbed. Ionization is affected by temperature and pH.

2.1.7        Partition coefficient (the stratum corneum –to-vehicle partition coefficient). Although triamcinolone is more active than hydrocortisone when administered systemically, but is only 1/5^th active topically. In this context, also presence of micelles or surface active agents has their effects.

2.1.8        Molecular size and shape. The smaller the size of the drug molecule the more the penetration.

2.1.2         

1. SKIN HYDRATION.

Protein, and protein degradation products of the outer skin sorbs water very well, the amount of bound water being a direct function of the relative humidity at a given temperature.  (Not absolute amount of moisture in the atmosphere).

Hydration may physically alter the skin tissue, also change diffusion coefficient and Activity Coefficient of the penetrating drug, hence increase   rate of passage through the skin.

Therefore, ointments with available water for hydration e.g. o/w bases, can     increase percutaneous absorption of some drugs.  In the same sense, bases which tend to dehydrate the S. corneum (or do not maintain hydration of the skin   decrease percutaneous absorption, For example PEG is not a suitable base for water-soluble medicaments.

Bases e.g. Petrolatum, w/o emulsions which leave occlusive films, induce hydration through sweat accumulation.  Degree of occlusion is even greater with plastic film e.g Saran Wrap, especiallyecially with steroids (Dexamethasone, triamcinolone acetonide.  Here Minimal Effective Concentration (MEC) is reduced by a factor of 100.

Protein and protein degradation of the outer s (occlusion of skin increases hydration. Compare skin patches and ointments and creams or protective films).

3.1 Drugs with more affinity to the skin than to the vehicle leave the vehicle

easily and are absorbed better.

3.2 drug absorption appears to be enhanced from vehicles that easily cover

the skin surface, mix readily with sebum and bring the drug into contact with tissue cells for absorption.

3.3 Vehicles that increase skin hydration generally increase percutaneous

absorption of the drugs. Oleagenous vehicles and /or occlusive bandages act as moisture barriers therefore hydrate the skin

2. Other factors
1. Site of application – where keratic layer is thin, drugs pass readily – e.g. scrotal skin Vs palms, soles.
2. Length of time the application remains on skin – absorption of time, the rate    time as tissue saturates
3. Amount of inunction used in application.  The larger the period, the greater the absorption.
4. Skin temperature:  This varies with conditions in sparsely haired animals e.g. man.  In cold weather rate is decreased, while in hot    conditions rate  is increased twice per 10^o increase.

Ointment Bases

Characteristics of an ideal base:

• Non irritating, non sensitizing
• Non dehydrating
• Non greasy
• Compatible with common ingredients
• Stable
• Water washable (removable)
• Absorptive
• Absorb water
• Smooth and pliable
• Inert
• Readily release incorporated medicament
• Acceptable odour (free from objectionable odours)
• Easy to compound

There is no ointment base with all these qualities. But a pharmacist should be able to recommend depending on the physical – chemical properties, site of application as well as actors affecting absorption from dermatological vehicles.

CLASSIFICATION OF BASES

A: Bases can be classified according to TYPE (based on composition)

            I. Oleaginous ointment base            

i. Anhydrous

                                                            ii does not absorb water readily (hydrophobic)

                                                            iii insoluble in water

                                                            iv not water removable

Examples of oleaginous bases

                                                              i.      Fats and Fixed Oils:

a.      Lard (purified internal fat of abdomen of hog was used extensively in the past but now obsolete.

b.      Fixed oils:Olive, Cotton seed, Sesame. Persil, Sunflower oils.

Advantages:    Emollient properties (induce hydration)

Disadvantages:            Low WATER, WATER absorbing capacities

                                    Rancidity (glycosides of fatty acids)

                                                            ii.      Hydrocarbon Bases

a. Petrolatum, liquid petrolatum, with wax.

                        -           Wide range of melting points

                        -           Compatible with many ingredients

-           Stable, odourless, tasteless, chemically inert

-           Same as occlusive coverings, induce hydration, vehicle for ophthalmic ointments, antibiotics – are unstable in WATER e.g Bacitracin.

                        -           Do not rancidity

                       

DISADVANTAGE:  Greasy.

b. Plastibase – combination of mineral oils + heavy

hydrocarbon  waxes

                        -                       Soft, unctuous, colourless, jelly-like

                                    Melts at 90 – 91º, good consistency between -15º – 60º

-           Does not liquefy tropics does not harden in low temperatures

                        -           Makes more elegant Ung than paraffin

-           Release more drug than petrolatum when exposed to o/w interface.

-           No smooth consistency with wax.

 c.  Silicones:

Synthetic polymer – basic structure O-Si-O-Si-O and may be liquid, resin or rubber depending on the type of organic group attached.

-           Demethylpolysiloxane (DC 200 fluid) + L-45

-           All insoluble in WATER (and are water repellant)

-           Inert physiologically, non-toxic, non irritant.

-           Used widely in protective creams and lotions.

            II Absorption ointment base

i.        Anhydrous

ii.      Absorbs water (hydrophilic)

iii.    Insoluble in water

iv.    Most are not water removable

Absorption here means water absorbing properties – NOT action on skin.

-          Are anhydrous, capable of absorbing large quantity of water while retaining their consistence.

-           Could be W/O emulsion e.g. hydrous lanolin

            Anhydrous lanolin        ,wool alcohol, aquabase

            Hydrophilic petrolatum (o/w).

            White wax, stearyl alcohol  (have high Heat stability and high water absorption capability)

            Wool alcohols

·         The  ADVANTAGES  of the bases is that one can increase water in aqueous solutions of drugs, have high Index of compatibility, are heat stable and can be elmulisified with WATER to increase  emolliency

DISADVANTAGES They are still greasy although they can be readily removed from skin than Oleagenous bases.

III Emulsion ointment base

w/o      hydrous, absorbs water, insoluble in water, not water removable

o/w      hydrous, absorbs water, water soluble, water removable

Semi-solid emulsions  can be o/w or w/o,

                        -           Can absorb water

-           Wide range of products due to big new organic compounds for use as wetting agents, emollient detergents, and emulsifiers – Surface Active Agents (SAA) can be ionic or non-ionic.

            Non ionic SAA  are widely used in demotologicals – They do not ionize (not affected by presence of ions e.g. hard water), less toxic, non-instant, more stable.

Lanolin (compatible with skin lipids

Cold cream USP uses spermacet from whales).

                        Hydrophillic oint USP

                        Emulsilying oint BP

-           They have tendency to lose water.  Add Glyecrin, PEG, or propylene Glycol as humectant.  These are Hygroscopic, reduce WATER loss through evaporation.

Anhydrous Emulsion bases  (emulsifiable solids) have been developed as a means of producing emulsions for extemporaneous compounding. These are powders (easy weighing)

Emulsifying wax BP is Used to make Emulsifying ointment which in turn is used in making Aqueous cream

            IV water soluble bases          Anhydrous adsorbs water, water soluble, and water

removable, greaseless.

-          Include bases prepared from higher ethylene glycol polymers – PEC compounds (Carbowax).

PEG:  HO-CH₂ (CWATERCH₂)x CWATERH

The macrogols are mixtures of polycondensation compounds of ethylone oxide and water, and are described by representing their average molecular weights.  Consistency varies from viscous liquids to waxy solids.

Macrogol 200 – 700 liquid

Mavrogol > 1000 semi solid

Macrogol >1500 waxy solids

-          Completely water soluble – easy removal from skin.

-          Non toxic, non- irritating, heat sterilizable, hygroscopic

-          Consistency modified by mixing liquids with solids e.g. Macrogol Oint BPC

Macrogol 300        65 parts

       Macrogol 4000      35 parts

            -    Absorbed by skin:  hence are good for drugs which need be absorbed.

-    Solvent power – can dissolve Hydrocortisone, Citric Acid, sulphonamides and sulfurs.

-     Free f rom greasiness, Eeasily spread

-     Do not hydrolyse, rancidify, or support microbial growth

-     Compartible with many ingredients e.g. lchthamol, Sulphur, Zinc Undecenoate

DISADVANTAGES:  Limited uptake of water – 5.8%.  Bases are thinned with liquid macrogol or propylene glycol.  If need to incorporate more water add higher alcohols e.g. cetostearyl alcohol.

-          Can reduce antibacterial activity of some agents e.g. Phenol, quartenary ammonium compounds, Penicillin

-          Not occlusive, therefore tend to dehydrate skin and decrease Percutaneous absorption.

           

Arbitrary included are semisolid preparations produced thrrough use of bentonite, colloidal magnesium silicate, pectin, sodium Algnate, also carbopol.

Pectin:  A WATER product, WATER soluble, absorb large quantity of WATER, useful in treating bedsores + stubborn ulcers.

Glyceryl monostearate:  - in cosmetic bases Additive  which increase water retaining capacity). It is Incompartible with Acidic substances

Cellulos ederivatives MeC, Na CarbMeCellulose stabilizer

Bentonite – insoluble in water but when mixed with 8 – 10 parts it gels (resemble petrolatum), BUT dries ,  and becomes unstable on standing. When 10% glycerin is added it becomes Humectant

Celloidal aluminium magnesium silicate is a thickener, stabilizer

Carbopol – Acid polymer, dispenses readily in water and is a thickener.

PREPARATION OF OINTMENTS

Objective:

To dispense uniformly throughout the vehicle a finely subdivided or dissolved drug substances – i.e no lumps, free from grittiness. Therefore methods of preparation must satisfy these criteria.

Two General Methods:

(i)                 Mechanical incorporation:

(a)                Ointment slab (also Ointment parchment)  - This method needs two spatulas – one with broad long blade (to provide a large rubbing surface) and a small one to remove accumulated material from the large one.

-          Mechanical action is employed– roll wrist in a figure 8.

-          One can warm base to facilitate (easier) the process (care with emulsion bases – over heating causes water loss.

-          Use small amount of levigating agent to form a concentrate then dilute geometrically with the remainder of the base

-          Water soluble drugs can be dissolved in a small amount of water, then incorporated in equal amount of lanolin.

(b)               Mortar and Pestle

Best when a liquid is to be incorporated or too large a quantity is to be handled.

-          Can warm the mortar to make the process easier.

-          The rest is similar as above.

(ii)               Fusion:

Used when harder, wax-like substances are to be incorporated with softer ones.  Use water-bath.

(a)                Older idea – progress from substances of highest melting point to lowest adding one at a time.

(b)               Recent:  Melt altogether – use lowest temperature and not too long, shorter time.

-           Melting time is shortened by grating wax components.

-           Remove discolored layer from base (oxidized part).

-           After melting, stir ingredients until congealed.  If lumpy, re-melt.

-           Can remove sediments by decanting, or use muslin or gauze in a warmed strainer.

-           Solid ingredient are added just near congealing pt.

-           Avoid vigorous shirring after ointment has started to thicken to avoid aeration

PRESERVATIVES:

To maintain potency and integrity of product, and to protect the health and safety by the consume a preservative is used.  USP suggests that products applied topically should be free from P. aerugunosa, S. aureus.

Parabens – methylparabens, Propylparaben

-          can sensitize.

SAFETY TOXICITY

Safety:            Condition of being safe from causing injury.

Toxicity:         (specific product) – adverse effect on a system caused by such a product acting for a given period of time of a specific dose level.

.  .  Ointment bases cause instant or allergic reactions. Tests should be done (especially for irritancy levels) both in animal and in man.

PACKAGING AND LABELLING

Ointment jars, metal or plastic tubes are used.

Ointment jars:

-          Straight sided screw cap jars on glass or plastic

-          Clear, amber, or opaque,

Or white opaque, plastic (high density polyethylene)

Tops – metal or composition plastic, inner liners (assure dust and air-tight closure), can be paper or plastic laminates.

-          Jars are filled less than capacity  to avoid or minimize contact between ointment and cap or liner.  For elegance use a flexible spatula to depress the centre (conically).

Ointment tubes:

May be made of tin or aluminum or plastic .

Advantage:                 Use of fingers is minimized.

Disadvantage:             Metal:  Metal contact and ion-catalysed instability.

Plastic:  May stain or discolor by immigration of coloured material onto plastic side wall. This can be minimized by internal coating (epoxy film).

LABELLING

Label should attach to itself (i.e completely, encircle the tube) to avoid obliteration, difficulty in reading or loss of label.   

On large scale – Expiry date, and code lot (batch number) are stamped on as part of tube crimping procedure.    

OPTHALMIC OINTMENTS

Ointments for application to the eyelids should be from specially selected and finely powdered chemicals.

(Vehicle must be of finest quality) –

      -  White/yellow, soft paraffin

                                         -  Mineral oil often with lanolin

                                         -  Non-irritating, permit diffusions, retain

             

- are applied outside and edges of eyelids, conjunctiva, and iris.

-  Should not contain particulate mater,   .therefore reduce amount of foreign particular matter contaminants

                        .  .  Tests to be done

                               50 particles for 10 tubes, 1 particle for

Should be sterile (harmful microorganism        loss of sugar) i.e. use sterilized ingredients under rigidly aseptic condition and must melt sterility test.

-          Containers must be sealed and temperature (to assess sterility) at time of first.

-          Leakage test – no significant leakage in of 10 tubes maintained at 60º for 8 hours.

Preparation.:

            Petrolatum vehicles and Medicaments are sterilized in heat in Hot air of 150ºC for 2 hours. Utensils for compounding are sterilized by autoclaving or wash slab with detergent, Empty tubes may be sterilized by storing them for 24 hours in 1:1000 solution of Benzalkonium chloride in 70% isopropyl alcohol and then to remove alcohol by   evaporation or just 70% ethanol for 24 hours.

Packing:         Use sterile disposable syringe (without a needle) to transfer semi-fluid ointments to ointment tube or sterile aluminum foil or powder paper. The procedure is carried out in laminar – flow hood to minimize contamination.