Chapter 8 medicated applications

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Presented by:

Asst. Prof. MA. LOURDES LICSI-MOJARES, RPh

CEU School of Pharmacy

USES OF TOPICAL PHARMACEUTICALS

VEHICLES FOR TOPICALLY – APPLIED DRUGS

( Non-medicated ointment bases)

EMOLLIENTS – provide soothing / softening effects on the surface tissues

PROTECTIVES / OCCLUSIVE DRESSINGS

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FACTORS INFLUENCING ABSORPTIONOF DRUGS THROUGH THE SKIN

A. Partition Coefficient of Drugs through the Skin

Substances possessing both water

and lipid solubility are favorably absorbed through the skin.

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B. Moisture and Temperature in the Environment of the Skin

B.1 Moisture Balance in the Skin

It is found in the stratum corneum layer of the epidermis.

It prevents the NMF (Natural Moisturizing Factor) from being stripped from the skin.

NMF prevents skin from drying out, even during excessive contact of the skin with water.

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B.2 Insensible Perspiration

The skin constantly releases water in the skin surface, which evaporates quickly without being noticed.

When the surrounding environment has a high moisture content, the rate of evaporation of sweat is slowed down, and the person becomes aware of the clammy moist sensation on his skin.

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C. Pathological Injury to the Skin

Skin penetration has been enhanced by abrasions or when the skin is stripped of its barrier layer.

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D. Type of Vehicle Used

Skin penetration of drug substances may be enhanced by the use of a suitable semisolid base.

The vehicle may help increase the rate of penetration of a drug substances into the skin.

It serves as a carrier for the API.

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RAW MATERIALS IN THE FORMULATION OFMEDICATED APPLICATIONS

FDA approves chemical substances and states the maximum concentration considered safe for food and cosmetics

(GRAS grade).

The supplier of these drug substances supplies brochures / information which indicates that FDA APPROVAL SAFETY TESTS are conducted.

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THE FREQUENT RAW MATERIALS FOR MEDICATED SEMISOLIDS

HYDROCARBONS

Petrolatum and Mineral oil are the MOST WIDELY USED substances in semisolids, next to water.

PETROLATUM– a complex mixture of semisolids containing hydrocarbon aliphatic, cyclic, saturated, unsaturated, branched and unbranched substances in varying proportions.

MINERAL OIL – derived from petroleum acid. It is less tacky and with lower viscosity.

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HYDROCARBON WAXES

1. Help increase the viscosity of hydrocarbons such as petrolatum and mineral oil

2. prevent separation of hydrocarbons from the ointment.

Examples: paraffin, beeswax, ceresin wax (mixture of paraffin and

ozokerite).10


OLEAGINOUS SUBSTANCES

Vegetable fixed oils which contain glycerides of mixtures of saturated and unsaturated fatty acids (MCT’s and FA’s).

These are employed for its EMOLLIENT and SKIN-LUBRICATING effects.

Examples: Fixed oils of peanut, olive, sesame, cottonseed, coconut, corn

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FATTY ACIDS and ALCOHOLS

Functions as; 1. auxiliary emulsifiers 2. viscosity –builders

Examples: Stearic acid – emulsifiers in water-removable

creams

Stearyl / Cetyl Alcohols - emollients, provides the necessary firmness / softness in consistency

of creams.12


EMULSIFIERS

Substances that;

a. Prevent Coalescence

b. act as Product stabilizers

Examples: Triethanolamine stearate, SPANS, TWEENS, Carbowax

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POLYOLS

Used as Humectants, prevents dehydration and “Crusting” on top of creams and ointments in jars.

Examples: Glycerin, PG, Sorbitol 70%,

PEG (lower MW)

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INSOLUBLE POWDERS

These must be uniformly dispersed throughout the semisolid vehicle to assure product homogeneity.

These solids must be impalpable to the touch..

Particles less than 74 microns Particles less than 74 microns (equivalent to 200 mesh) is said to be (equivalent to 200 mesh) is said to be impalpable to most peopleimpalpable to most people. .

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TYPES OF SEMISOLID VEHICLESNON-MEDICATED BASES

Factors which Influence the Choice of

Semisolid Vehicles

1. Nature of the skin lesion

2. Skin Type

3. Solubility of the formulation components

4. Stability of the API’s

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HYDROCARBON BASES

Typically lipophilic Spreads easily onto the skin Difficult to remove / wash-off Act as occlusive dressings, since the

normal evaporation of insensible perspiration is inhibited.

Examples are White petrolatum, Mineral oil, White / Yellow Ointment, USP

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ABSORPTION / EMULSIFIABLE BASES

These are hydrophilic mixtures formed by the addition of substances that possess polar groupings ( sulfates, carboxyl, hydroxyl or ether linkages) to a Hydrocarbon Base.

Lanolin, Cholesterol, Sorbitan monostearate / monooleate are added to Hydrocarbon bases to make it hydrophilic.

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WATER – REMOVABLE / WASHABLE BASES

These are o/w emulsions referred to as Creams.

Upon application, there is little or no evidence of its presence onto the skin.

Best for moist skin lesions, since its o/w character tend to adsorb serous discharges.

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WATER – REMOVABLE / WASHABLE BASES

Vanishing creams, Foundation creams, Shaving Creams.

Vanishing creams type of vehicles are of o/w type.

Absorption bases are of w/o type.

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WATER-SOLUBLE / GREASELESS BASES

Prepared from mixtures of high and low MW PEG

No water is required in its preparation

Water soluble, due to many polar groups and ether linkages

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WATER-SOLUBLE / GREASELESS BASES

Suitable combinations of high and low MW PEG yield products having an ointment-like consistency, which soften or melt when applied topically.

Low MW PEG – liquids

Moderately high MW PEG – unctuous

Very High MW PEG - solids

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OPTHALMIC OINTMENTS

Semisolid ophthalmic vehicles frequently contain any of the ff. bases that have been sterilized;

1. petroleum jelly 2. absorption base (Lanolin or Lanolin Alcohol) 3. water-soluble base

Insoluble API powders should meet the requirements for IMPALPABILITY.

Ophthalmic ointments should be rendered STERILE and ISOTONIC.

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OTHER OPTHALMIC OINMENT BASES

Lanolin

Sterilized by Gamma Radiation or Sterilization by Filtration

Lanolin Alcohol

Possess emollient properties suitable for eye ointment formulation.

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PRESERVATION FROM MICROBIAL SPOILAGE

The chemical preservative for semisolids should be evaluated as to:

1. Stability with regard to formulation components

2. Container to be used.

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CHARACTERISTICS OF PRESERVATIVESFOR SEMISOLID PRODUCTS

Some preservatives become inactive in the presence of other ingredients.

Boric acid may be used in ophthalmic ointments against bacterial/ fungal contamination.

Bacterial counts should be made on the water supply, RM, pipelines, filling equipment and containers.

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USE OF ANTI-OXIDANTS

Anti-oxidants are added to semisolids, whenever oxidative deterioration is anticipated.

BHA, BHT, Propyl gallate

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USE OF ANTI-OXIDANTS

The choice of anti-oxidant is made upon consideration of the following factors:

1. toxicity / irritating potency

2. compatibility

3. odor

4. discoloration

5. solubility

6. stability

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MANUFACTURING PROCESS OFSEMI-SOLIDS

Factors to be controlled during the

Fusion Method:

1. Time of mixing

2. Temperature of mixing

3. Rate of agitation ( and other mechanical works)

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MANUFACTURING PROCESS OFSEMI-SOLIDS

FUSION METHOD

ANHYDROUS OINTMENTS are manufactured by this process, which is made by dissolving the API’s in the previously melted fats and waxes.

The melted mass must be mixed while cooling to ensure the homogenous distribution of the ingredients.

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STEPS IN FUSION METHOD

Step 1: PREPARATION OF THE OIL PHASE

Flake / pulverize the dry ingredients.

Heating is required to melt some ingredients (waxes), usually at 700C to 750C.

Blend in advance and disperse in mineral oil or silicone oil.

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Step 2: HYDRATION OF THE INGREDIENTS IN THE AQUEOUS PHASE

Emulsifiers, stabilizers, thickening agents are dispersed into water in a separate vessel.

Usually followed by a filtration procedure,

if needed.

Heating may be required to accelerate hydration.

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Step 3: FOAMING THE EMULSION

The aqueous and oil phases are blended under vigorous agitation, to form the emulsion.

Temperature is controlled between 300C to 400C.

Defoaming procedures are done to minimize foam formation after the product has emulsified.

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Step 4: DISPERSION OF THE ACTIVE/S

The API’s make up only a small proportion of the formulation.

It must be EFFICIENTLY DISPERSED to maximize yield and product effectiveness.

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PROCESS FLOW DIAGRAM ofTOPICAL PHARMACEUTICALS MANUFACTURE

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PLASTIC TUBE FILLING and SEALING MACHINE

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METHODS OF FILLING OPTHALMIC OINTMENTS

BLOW FILL SEAL METHOD (BFS)

SEQUENCE in ONE EASY OPERATION:

1. Fabrication of containers

2. Filling the product

3. Sealing

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METHODS OF FILLING OPTHALMIC OINTMENTS

FORM FILL SEAL METHOD (FFS)

The conventional method of filling opthalmic ointments.

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STRAIGHT- SIDED

GLASS and PET JARS for CREAMS and OINTMENTS

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FILLING MACHINE OINTMENT FOR OINTMENTS PRODUCTION

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COLLAPSIBLE TUBEFILLING AND SEALING MACHINE

Makes use of the

“Hot Melt” Sealing system.

Fills and Seals 85 collapsible tubes per minute.

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Specialty packaging for ointments intended for;

Nasal Rectal Vaginal Opthalmic

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STORAGE and LABELING

MICROBIAL SCREENING

( Microbial Limit Tests)

1. Staphylococcus aureus

2. Pseudomonas aeruginosa

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As per USP Requirements:

MINIMUM FILL Assessment of the Content Uniformity of

semi-solids.

Product weighing 60 g or mL – nlt 90% of the labeled amount.

Product weighing 60 g or mL to 150 g or mL – nlt 95% of the labeled amount.

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STANDARD ASSAYS of the API’s (Quantitative assay of % Purity or %

Content)

STERILITY TESTS 1. Membrane Filtration Technique 2. Test Tube Inoculation Method

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In vivo BA/BE – Dermatopharmacokinetic Studies (DPS)

Applicable to semisolids that contain: 1. Antifungals 2. Antivirals 3. Corticosteroids 4. Antibiotics 5. Topicals for vaginal use

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Not applicable to semisolids for; a. otic use b. opthalmic use c. that damage the stratum corneum of the

skin.

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It involves measurement of the ff.; 1. drug concentration in the stratum

corneum 2. drug uptake 3. apparent steady state 4. elimination after drug application onto

the skin

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As per Non- USP requirements

pH

Water Content (Karl Fisher Method)

Water affects the; a. physical stability b. chemical stability c. microbial stability

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Usual water limit: 0.5% to 1%

NMT 0.5% water content forOintments containing:1. Bacitracin2. Chlortetracycline HCl3. Nystatin

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NMT 1% water content for ointments, creams or gels containing;

1. Erythromycin2. Gentamycin sulfate3. Neomycin sulfate4. Tetracycline HCl

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Foreign Substances

Homogeneity ( also refers to Content

Uniformity by Minimum Fill testing)

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Metal Particle Detection Test – mandatory for opthalmic ointments

only.

Limits: NMT 3 tubes out of the 10 tubes

tested should contain 8 metal particles.

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Leaker Test Mandatory for opthalmic ointments

filled in collapsible tubes.

By Classical Blotting Paper Method

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Specs / Limits: NMT 1 tube out of the 10 tubes should leak. If MT 1 tube leaks, repeat the test on

20 additional tubes. NMT 1 tube out of the 30 tubes should leak.

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Health & Medicine

Chapter 8 medicated applications