Semisolid Dosage Forms Flashcards
What is in the he lipid bilayer in the stratum corneum?
Mainly ceramide, fatty acids, cholesterol, cholesterol esters and cholesterol sulfate
How does the structure and components of the stratum corneum relate to its barrier to drug absorption?
Stratum corneum consists of highly cross linked keratinocytes which are surrounded by an insoluble cornified cell envelope
Corneocytes are linked together by cormeodesmosomes. This provides support and stability for the stratum corneum.
Corneocytes have a unique oval structure, making them impermeable to solute.
What is ceramide?
The predominan lipid in the bilayer of the stratum corneum.
It has 9 different subclasses with hydrocarbon chains ranging from 14-36 carbons
What is the function of lipids in the stratum corneum?
To control and prevent transepithelial water loss.
What is natural moisturing factor?
NMF. This comprises 20-30% the dried weight of corneocytes.
It is water soluble and allows the skin to maintain hydrated
What is the main concept of transdermal and topical drug delivery?
Diffusion of the drug through various layers of the skin into systemic circulation.
What is topical (dermal) drug delivery?
Targeting of pathological sites within skin.
The disease is usually located within the skin e.g. Skin cancer, psoriasis, eczema
What are semisolids?
Formulations having viscosity and rigidity intermediate between that of a solid and liquid.
These are applied to the skin or mucous membrane for therapeutic, protective or cosmetic action
What is the semisolid dosage form mainly used for?
Localised effects,
However systemic absorption must not be overlooked. .e.g in pregnant women, some side effects may arise.
Semisolids can also be used for transdermal effects e.g. Progesterone cream used for postmenopausal hot flushes. It has poor systemic bioavailability
What are ointments?
Semisolid greasy preparations intended for external application or the skin or mucous membrane
These are Anhydrous with the active ingredient dissolved or dispersed in the base.
They can be medicated or non medicated
What are the common uses of ointments?
Acts as physical barrier to environment
Acts as emollient to soften skin and make it more pliable.
Carrier of medicament
What are the main classifications of ointment bases?
Hydrocarbon bases or oleaginous bases Fats and fixed oil bases Absorption bases Silicones Emulsifying bases Water soluble bases
What are the general property of ointment bases?
Anhydrous. Will not absorb water
Water resistant, not easily washed away
Forms greasy film on skin surface that inhibits moisture loss and improves skin hydration.
They also aid in the percutaneous absorption of drugs
What do hydrocarbon or oleaginous gases consist of?
Soft paraffin or a mixture of hard paraffin.
Water and aqueous ingredients may be incorporated into such gases in small amounts with difficulty.
What are the sources and forms of hydrocarbon bases?
Sources:
Vegetable oil-mineral oil
Animal fact-oleic oil
Petrolatum
Forms:
Liquid hydrocarbon-mineral oil
Semisolid hydrocarbon-Vaseline
Solid hydrocarbon-paraffin
What is petrolatum (Vaseline)?
A type of hydrocarbon base.
There are two forms:
1) petrolatum USP (yellow petrolatum or jelly petrolatum)
2) white petrolatum (decolourised petrolatum or white Vaseline)
These are a mixture of semisolid hydrocarbons with a MP between 38°C and 60°C
MP increases with increasing chain length
What are plastibases?
A series of hydrocarbons containing polyethylene
Forms structural matrix
It is soft, smooth, homogenous, neutral, odourless, non irritating and stable
Easy to spread and remove from the skin with good adhesion.
What are fats and fixed oils?
Non volatile oils, particularly of vegetable origin.
E.g. Mono and diglyceride mixtures of unsaturated and saturated fatty acids like sesame oil, almond oil.
These decompose upon exposure to air, light and high temeperatures,
Requires the addition of antioxidants like butylated hydroxytoluene, vitamin E etc.
What are the 7 main types of sesame oil?
Palmitic Palmitoleic Stearic Oleic Linoleic Linolenic Eicosenoic
How are silicones used?
They are nice corporates into barrier creams to protect the skin from water soluble irritations
E.g. Dimethicone, dimethyl polysiloxane
What are absorption (emulsifying bases) like?
Absorb water to form w/o emulsion while retaining their semisolid consistency
They are classified into two categories
What are the two categories that absoprtion/emulsifying bases are classified into?
1) Those that are water free and have ability to accommodate water resulting in w/o emulsion. (I.e. a hydrocarbon low HLB emulsifier + water results in w/o emulsion aka semisolid)
2) hydrocarbon base that has already absorbed small amounts of water and resulted in w/o emulsion. These may absorb more water and can result in 3x the weight of the original base. (Lanolin 0.25% water is composed mainly of long chain waxy esters)
What are emulsifying (water removeable bases?)
Oleaginous bases + high HLB surfactant
What are the three types of water removeable bases? What dictates these types?
Anionic (emulsifying ointment)
Cationic (cetrimide emulsifying ointment)
Non-ionic (cetomacrogol emulsifying ointment)
These depend on the type of surfactant incorporated into the oleaginous base
What are water soluble bases?
These do not not contain hydrocarbons or any other oleaginous components
They are a mixture of high and low MW polyethylene glycol (PEG)
These are non occlusive and can be easily washed from the skin surface
E.g. Macrogols ointment and PEG ointment
What is considered when choosing an appropriate base?
Desired release rate of drug
Desirability for transdermal or topical effect
Stability of drug in ion intent base
Effect of drug on consistency and other physical features of the base
Occlusive or washable nature
How are ointments prepared using the incorporation method?
Components of ointment are mixed together by various means until a uniform preparation has been achieved,
The ingredients are I mixed in a mortar and pestle or using a spatula and ointment slab.
The active ingredient can be added directly using a compatible levitating liquid like liquid paraffin in the case of petrolatum bases
Which rules should be followed (to ensure uniformity) in the incorporation method of ointment preparation?
Geometric dilution rules
When should the incorporation method be used?
When all ingredients can be triturated (no solid ingredients)
It is useful for altering the ointment e.g:
Diluting ointment base to reduce strength,
Adding liquid, adding powdered drug
Commonly used for dispensing small quantities
What are the limitations of the incorporation method?
It is very difficult to fix the product after initial formulation.
You can add more high/low viscosity component, keep triturating but in most cases you will probably have to start over.
What are the criteria for levitating agents used to prepare ointments?
Must be compatible with base (external phase)
Must not influence product viscosity
What are some common levigating agents used?
Mineral oil and glycerine
Some surfactants (polysorbate 80)
Coal tar
What is the fusion method for preparing ointments?
Ingredients are combined and melted together.
Components which are not melted can be added to the congealing mixture as it is cooled and stirred.
Heat labile substances and volatile constituents are added last when temperature is low enough to avoid decomposition
When is the fusion method used?
When you ingredients cannot be physically mixed easily. E.g. High viscosity ingredients or solids like beeswax, cetyl alcohol, paraffin, stearic acid, any fusible solid
What are limitations of the fusion method?
Ingredients cannot be overheated.
Lanolin and oleic acid can oxidise
Product should not discolour
Heat labile components can degrade.
Phases must be mixed at the same temperature
High melting ingredients can solidify
Phase separation can occur- need to reheat and stir vigorously
Often product has low viscosity-need to add high viscosity/MP ingredients like beeswax, paraffin, stearic acid.
Poor dispersion- need to reheat and add more surfactant
What are creams?
Semisolid emulsions for external applications in which the active ingredient if present is either dissolved or dispersed
Water containing absorption bases are often used,
What is an example of a cream which is a o/w emulsion?
Vanishing cream
What is an example of a cream which is a w/o emulsion?
Emollient and cleansing creams
What are water in oil creams?
These are preferred over ointments due to easy of spreading and removing
They are also less greasy.
Once rubbed onto skin an occlusive layer is formed which would reduce the water evaporation from the skin and would have an emollient effect
What are oil in water creams?
When rubbed onto skin the continuous phase evaporates which leaves a cooling sensation.
These are non occlusive but deposits lipids and other moisturisers on the subcutaneous to restore the tissues hydration ability
What are the limitations of creams?
Possible phase inversion or cracking when applied to surface of skin and on storage,
Difficult to determine true viscosity as they display non Newtonian flow
What are gels?
1) cross linked polymeric structure which is in penetrated by a
2) liquid
Solid or semisolid system with at least two constituents composed of low concentrations of gelator molecule (<15%) which, in the presence of an appropriate solvent self assembles via physical or chemical interactions into an extensive mesh network preventing solvent flow.
When is the product called a jelly?
Then the matrix of the gel system is rich in liquid
How are gels classified?
By the nature of the solvent:
There are organogels and hydrogels
What are hydrogels?
Semisolid formulation which has an external polar solvent phase immobilised within a 3D network structure.
I.e. A cross linked network of polymers
Have the ability to absorb large amounts of water and swell while maintaining their 3D structure
How can hydrogels be classified?
Based on the number and type of polymers in their structure
Mono polymeric hydrogels contain only one polymeric substance
Co polymeric hydrogels have two different types of polymers (at least one should be hydrophilic)
Multi polymeric hydrogels contain several different types of polymers in the structures
What is a stimuli responsive hydrogel?
Hydrogels can be triggered by several stimuli to absorb solvents and swell, delivering several functions.
This is done via three main mechanisms
What are examples of the stimuli hydrogels are responsive to?
Antibody PH Temperature Metal Light Glucose Ionic strength Electric and magnetic field
What are the three mechanisms of of hydrogel absorption of solvents to deliver their function?
Mechanical motion:
Information transmission:
Mass movement
What is mechanical motion?
where physiological variants like temperature, exposure to magnetic field causes the polymer to swell. This can be exploited, e.g. To repair artificial muscles where a change in the environment causes it to swell etc to generate movement.
What is information transmission?
which can be done by either shape memory or optical activity. In shape memory. Gels remember their original shape, which they can return to via heating even after swelling or shrinking. In optical activity, the colour change of gels is reversible. We can add a pH sensitive material in the structure of cells and the gel can be used to indicate the pH of the environment,
What is mass movement?
This is the most important mechanism for drug movement and refers to the movement of drug in and out of the polymeric network of the gel.
Raises in body temperature can result in swelling of the gel which then releases antipyretic drugs,
Some polymers can react with glucose in the blood whih causes them to swell and release insulin.
What are organogels?
Semisolid formulation having external organic solvent phase which is immobilised within a 3d network structure
What are the two main classes of gelators in organogels?
Low molecular weight gelator
Polymeric gelator
What are low molecular weight gelators?
Physical
These include solid fiber matrix and liquid fibre matrix
What is the difference between solid fibre and liquid fibre matrices?
Solid fibre matrix is strong and more robust due to permanent solid like networks.
The junction points are relatively large. These are referred to as pseudocrystalline micro domains
Liquid fibre matrix have transient networks where junction points are most often chain entanglements. Liquid fibre matrices may exhibit kinetic features like dynamic change of gelator molecules with bulk liquid as well as chain breaking/recombination
What is the polar solvent addition method for forming an organogel?
Non polar solvent and surfactant are mixed. Reverse micelles are formed.
Hydrogen bonding occurs upon addition of polar solvent.
This forms tubular reverse micelles.
Upon more addition of polar solvent, a 3D gel network with immobilised apolar phase is produced
What is the heating method for forming an organogel?
Non polar solvent and a solid organogelator are mixed together and heated, forming a non polar solution of organogelator.
This is then cooled to room temperature. The organogelator precipitates out as fibres which undergo physical interaction with each other to form a 3D network
What are the two methods for forming an organogel?
Polar addition method
Heating cooling method
What are examples of organogelators?
Lethicin is used transdermally (diclofenac, piroxicam, tetrabenzamidine)
Glyceryl fatty acid esters are used transdermally (levonorgestrel, ethinyl estradiol)
Sorbitan momosterate is used nasally, orally, subcutaneously and intramuscuarly (propranolol, cyclosporin A)
What are lethicin organogels?
Composed of hydrated phospholipids and appropriate organic liquid with polar solvent.
Can be incorporated into wide range of substances with diverse physicochemical characteristics e.g. Chemical nature, solubility, molecular weight, size.
They form spontaneously, (thermodynamically stable) and allows modification of skin barrier function
Moisture insensitive so resist microbial contamination
Very low skin irritancy potential
What is lethicin?
A phospholipid from soy bean and egg yolk
Biocompatible surfactant
Used in everyday life including in human and animal food, medicine, cosmetics and various industrial applications
What are the disadvantages of using lethicin in gels?
Transfer into gels has only been demonstrated for non aqueous solutions of naturally occurring unsaturated lethicins
Synthetic lethicins containing residues of saturated fatty acids have not succeeded informing organogels
Gels also cannot be formed with hydrogenated soy bean lethicin.
Why is unsaturated phospholipid molecules a desired property in the formation of lethicin organogels?
This would result in better hydration of the polar head group which favours the formation of reverse micelles
Why are organic solvents used in lethicin organogels?
Organic solvents can be linear, branched and cyclic alkanes, ethers, esters, fatty acids, or amines.
Isopropyl myristate and isopropyl palmitate are commonly used.
They exhibit skin penetration enhancing effects and are both biocompatible and biodegradable
Why would polar solvents be used in lethicin organogels?
They can act as a structure forming and stabilising agent
Water, glycerol, ethylene glycol and formamide are commonly used
What are the required properties of the polar solvent to be used in lethicin organogels?
High surface tension
High dielectric constant
Solvent polarity
Strong tendency toward hydrogen bonding
What are limitations of lethicin organogels?
Level of lethicin and organic solvent is fairly high
Requires ugh purity lethicin which is expensive
Incorporation of synthetic cosurfactants like pluronic gives an option for less pure lethicin. These are called pluronic lethicin based organogels (PLO)
What are pastes?
Ointment containing as much as 50% powder dispersed in a fatty base
They have good absorbing properties.
They can absorb noxious chemicals like the ammonia that bacteria release from urine,
They have a high viscosity to localise the effect of irritant or staining materials and are less greasy than ointment as the powder absorbs some of the fluid hydrocarbons
What are the three types of ultraviolet radiationL
UVA
UVB
UVC
What is UVA radiation ?
The longest wavelength 315-400nm
Penetrates deep into skin surface
Releases free radicals can lead to DNA mutation, hence carcinogenic
What is UVB radiation?
Long wavelength (280-315nm)
Reaches the skin surface
Can cause tanning, burning, skin ageing
What is UVC radiation?
Short wavelengths (100-280nm) Do not penetrate the earth zone
What are the three main types of sunscreens?
UV absorbing materials
UV reflective material
UV reflective nano particles
What are UV absorbing materials?
Sunscreen may contain chemical absorbants which absorb incoming radiation
What are UV reflective materials?
Where some of the incoming radiation is reflected or scattered and some of the UV radiation is absorbed
What is UV reflective nano particlesl
Most of the incoming radiation is reflected resulting in less UV radiation penetrating the subcutaneous layer e.g. Physical sunscreen
What are the organic sunscreen components?
Fairly abundant and diverse in comparison to inorganic components.
The advantage is that they give manufacturers flexibility with characteristic of the formulation such as the SPF, water resistance and product feel
What are the disadvantages of organic sunscreens components?
They absorb UV radiation so they are vulnerable to photodegradation and generating free radicals.
They also have potential for photo irritant or photo sensitising reactions in susceptible individuals.
P amino benzoic acid has been removed from most products
What are the advantages of inorganic sunscreen components
Absorb, reflect and scatter UV radiation. Good physical barrier,
More effective than absorption of UV radiation alone
Cover a broad spectrum of UV rats so their addition can simplify the formulation. Lower number of components needed compared to organic components.
Beneficial for those with sensitivity or skin irritation issues
What is a disadvantage of inorganic sunscreen components?
They have poor dispersion
What are examples of common sunscreen components?
Organic:
Oxybenzone, enzulizole, octisalate, oxtinoxate,
Inorganic:
Titanium dioxide, zinc oxide
Avobenzone
What are the properties of avobenzone?
Oil soluble
Used to absorb full spectrum of UVA rays
Highly degradable in presence of sunlight
Often paired with photo stabiliser in sunscreen formulations
What are the properties of oxybenzone?
Absorbs UVB and partial UVA
Potential harmful and likely photo carcinogen
Derivative of benzophenone which is a known carcinogen as it produces free radicals
What are the properties of enzulizole?
Protects against UVB and minimally against UVA
Water soluble
Used in formulations for light non greasy feeling
What are the properties for octisalate?
Formed by condensation of salicylic acid and 2-ethylhexanol
Salicylic portion absorbs UVB radiation
2-ethylhexanol portion adds water resistance properties
What are the properties of octinoxate?
Absorbs UVB
Water insoluble, hence useful for waterproof formulations
What are the properties of titanium dioxide?
Forms aggregates which reflect extensive UVB and considerable UVA
Delivers greater SPF than zinc oxide
What are the properties of zinc oxide?
Reflect extensive UVB and UVA
Covers broader UVA spectrum than titanium
What is the sun protection factor?
A measure of sunscreen effectiveness.
E,g, SPF 30 sunscreen means that the sun exposure of 30x greater is necessary to produce erythema compared to a situation in which the user is not photoprotected
How is the SPF calculated?
It is a numerical ratio between the minimal erythemal dose of sunscreen protected skin applied to the amount of 2mg/cm^2 and the minimal erythemal dose of unprotected skin,
What is MED?
Minimal erythemal dose. But is measured as the minimal amount of UV that produces redness 24 hours after exposure
I.e. How much UV light is required to produce redness on protected skin
What are the limitations of using sunscreens?
Sunscreen use tend to extend exposure time in the sun thus increasing risk of skin cancers,
Most people use 1/4 to 1/2 of the recommended amount of sunscreen and then do not reapply it as frequently as recommended.
Most sunscreens block UVB but allow UVA to penetrate deeply into skin (more dangerous)
There are also concerns about safety of chemicals used, even those which are considered safe by the environmental working group
Potential to inhibit vitamin D production
How is vitamin D produced?
7-dehydrocholesterol is converted into cholecalciferol D3 upon UVB exposure,
Or ergocalciferol D2 is obtained from food
Liver converts both of these to 25-hydroxy vitamin D
Kidney then converts this to
1,25-hydroxy vitamin D
This can then exhibit biological action
What are the requirements for successful sunscreen formulation?
Provide efficient protection against UVB and UVA radiation
Be stable to heat and UV radiation
Be user friendly to encourage frequent application and provide reliable protection
Be cost effective
What must a sunscreen contain to be effective against both UVA and UVB radiation?
A combination of active ingredients within a complex vehicle matrix
