introduction topical formulations intranasal formulations summary and questions
TRANSCRIPT
Clinical Formulations in The
Dispensary
Agenda
Introduction
Topical Formulations
Intranasal Formulations
Summary and Questions
IntroductionHistorically, within Safety Assessment (GSK), standard formulations are
generally used for:-
– oral (1% (w/v) aqueous methylcellulose)
– intravenous (saline)
– inhaled formulations (lactose)
Normally 1 or 2 excipients and 3 step preparation methods
Recently Safety Assessment (GSK) has been involved in different routes of dosing, which have used the proposed clinical formulation
– Topical dosing
– Intranasal and Oropharyngeal dosing
Clinical formulations generally use a wider variety of excipients with more complicated, multi stage preparation methods
Historically these were supplied by Pharmaceutical Development from within a GMP environment
Both sets of formulations have common factors, however, they have unique challenges
Topical Formulations
A topical formulation is applied to the surface of the skin and generally used for local action.
Routinely 3 types of formulation which are applied to the skin:
Ointments – Anhydrous mixes containing fatty material (water free)
Gels – Water containing a thickening agent such as Carboxymethylcellulose
Emulsions - two or more immiscible liquids. Creams and lotions.
Within GSK there have been 3 approaches to topical formulations, each with different excipients:-GSK Pharmaceutical Development
i.e. White Soft Paraffin, Mineral Oil, Emulsifier 10, ST-eEastomer-10, Cyclomethicone, Propylene Glycol, Hexylene Glycol in Purified Water
Stiefel
i.e Butylated Hydroxy Toluene (BHT), Eumulgin B2, Sophiderm, Phenoxyethanol, Carbopol 980NF, Pemulen TR-1, Propylene Glycol in Purified Water, final formulation pH adjusted to pH 5 (± 0.2), using Trolamine
GSK Biopharmaceuticals
i.e. Myritol, Capryol, Labrasol, Tween 80, in pH buffer
Ointments
Semisolid, homogeneous, viscous and anhydrous mix containing fatty material.
The primary vehicle of an ointment is known as the ointment base. The choice of a base depends upon the clinical indication for the ointment.
The different types of ointment bases are:
– Hydrocarbon bases i.e soft white paraffin
– Absorption bases i.e. beeswax
– Water soluble bases i.e macrogols
– Water removable or emulsion bases i.e cetrimide
Hydrocarbon bases are the only truly anhydrous forms.
The cooling rate of ointments, once prepared, is important. Too slow a cooling rate causes the formation of a few large crystals (thickening the mix), whilst rapid cooling leads to the formation of lots of smaller crystals (more fluid mix).
Example:
White Soft Paraffin, Mineral Oil, Steareth 2, St.Emulsifier 10, St.Elastomer-10, St. Cyclomethicone-5NF, Labrasol, Propylene Carbonate and Propylene Glycol
Gels
Contain continuous long chain structures, which provide solid like properties.
A simple gel is water thickened with one of the following:
– Natural gums – tragacanth, xanthan
– Semisynthetic material – carboxymethylcellulose
– Synthetic material – Carbopol 934P
– Clays – silicates, hectorite
To attain maximum thickening of a gel the thickening agent, i.e. Carbopol 934P, must be uncoiled.
Uncoiling of the thickening agent can be aided by adding a simple inorganic base (i.e. NaOH) to aqueous and polar solvent mixes or by adding amines (i.e. Triethanolamine) to less polar or non polar solvent based mixes
Example:
Isopropyl Myristate, Carbopol 934P, Triethanolamine, Propylene Glycol, Laureth-4, Purified Water, Methyl Paraben, Propyl Paraben
Emulsions
Are mixtures of two or more immiscible liquids. The most common type of emulsion used in topical formulations are creams. Lotions are also a form of emulsion, tending to have a greater proportion of water then creams.
Two phase preparations in which one phase (the dispersed or internal phase) is finely dispersed in the other (the continuous or external phase).
The dispersed phase can be either hydrophobic based, oil in water (O/W) or aqueous based water in oil (W/O).
Physical stability is maximised by the use of an emulsion-stabilizing system (i.e. Emulsifier 10 or Cyclomethicone), to stop flocculation.
Flocculation is the close accumulation of two or more droplets of a dispersed phase, usually caused by Van der Waals forces, leading to the eventual complete separation of the two phases.
Example:
White Soft Paraffin, Mineral Oil, Emulsifier 10, ST-Elastomer-10, Cyclomethicone, Methylparaben, Propylparaben, Propylene glycol, Hexylene glycol, Sodium Phosphate Dibasic Anhydrous, Citric Acid Monohydrate in Purified Water
Emulsion - Cream
Emulsion - Lotion
Topical Formulation Ingredients
Each topical formulation may contain one or more of these six functional categories:-
Polymeric Thickeners
– Celluloses. i.e HPMC
– Gums. i.e. xanthan
– Colloidal solids. i.e silica
– Acrylic acids. i.e. carbomers
– Hydrogels. i.e. polyvinyl alcohol
Oil Phase. i.e mineral oil, white soft paraffin, Sophiderm
Surfactants
– Nonionic. i.e. Tween
– Anionic. i.e SLS
– Cationic. i.e BKC
Solvents
– Polar. i.e water, propylene glycol
– Non polar. i.e. isopropyl alcohol
Preservatives
– Antimicrobial. i.e BKC, potassium sorbate, methylparaben
– Antioxidant. i.e ascorbic acid
– Chelating agents. i.e citric acid
pH adjusters. i.e sodium hydroxide, sodium phosphate
Transfer of Topical Formulations into the Dispensary
Topical formulations previously provided by Pharmaceutical Development (mainly based in Canada) – prepared to GMP
Three stage hand over:-
– Initially PD provided all formulations for Safety Assessment studies to GMP
– Next PD supplied placebo (control) and the high dose formulation to GMP and Dispensary prepared the lower concentrations to GLP by serial dilution with the placebo
– Finally Dispensary prepare all formulations for Safety Assessment studies to GLP – also conduct formulation GLP stability testing
Reasons for hand over:
– Regulators expect, that were capability exists, formulations used on GLP studies should be prepared within a GLP environment
– Pharmaceutical Development Canada closed down – limited UK based support
– Stiefel has taken over – however, they have no in house facilities for formulation preparation
Therefore, Dispensary has taken over the role of producing topical formulations for Safety Assessment studies
Challenges in taking on this role
Practical:-
– Specialised equipment such as mixers and pH probes needed to be acquired
– Sourcing of a wide variety of excipients – a lot of which are were new to the Dispensary
– Training and generation of SOP to address the novel formulation challenges
Knowledge Base:-
– Needed to increase our understanding over the rational for excipient selection
– Dealing with international collaborators and partnership companies (Stiefel) in sourcing
information on the formulations
Formulation Preparation
Formulation and preparation process defined by Stiefel (previously Pharmaceutical Development)
The order in which the excipients are added together defines the formulation process of topical formulations.
Dispensary take the multi stage preparation method and tailor it to our computer system (Dispense) and GLP
Preparations are both time and resource intensive – 2/3 hour prep time per concentration
Ingredients are often pre combined prior to addition, see “Oiley phase” detailed below
Example: Cream
white soft paraffin, mineral oil, emulsifier 10, ST-elastomer-10, cyclomethicone, propylene glycol, hexylene glycol in purified water
Oily phase = white soft paraffin, mineral oil, emulsifier 10 and ST-elastomer-10
Solvents = propylene glycol and hexylene glycol
Aqueous phase = water
Cyclomethicone
Example of a Formulation
1. Weigh out test material into container 1.
2. Add solvents to container 1 and stir magnetically – may not go totally into solution
3. Add aqueous phase to container 1 and stir magnetically
4. Heat container one and the pre made “Oily phase” to approximately 60ºC (±5ºC).
5. Temperature to be recorded using a thermometer
6. Add “Oily Phase” to container 1 and mix on the Ultra Turrax for approximately 2-3 minutes
7. Weigh out cyclomethicone into a glass syringe and add to container 1
8. Continue to mix container 1 on the Ultra Turrax for approximately 5 minutes (note: heat Turrax head in hot water before mixing to avoid cooling the mix)
9. Watch to ensure the formulation does not set on the Turrax mixer
10. Measure pH using special probe, allow to cool and set
11. Allow formulation to cool at room temperature and stir with spatula intermittently throughout cooling process until formulation thickens.
12. Sample when cooled and thickened.
Dispensary Considerations
Current formulation tests:-
– Test chemical stability at both ambient and fridge storage for up to 28 days
– Test homogeneity – before and after storage (6 x 1 g samples taken)
Future formulation tests:-
– Physical stability, using a viscometer. Early indication of oil/water separation of the formulation. i.e paint left for a long time
Formulation preparation and supply:-
– Due to the preparation method, equipment used and high wastage, small amounts are difficult to prepare. Minimum of approximately 20 g per preparation, however, even this is troublesome
– Need to maintain a free flowing formulation throughout preparation, because once the viscosity increases its very hard to mix and ensure homogeneity is achieved – can use heat to reduce viscosity
– Pre load syringes due to wastage in dosing
Analysis
– Formulations generally do not dissolve in analytical diluent, therefore, centrifuging and extraction methods needed
Topical Formulations Summary
There are 3 types of topical formulations:-
–Ointments
–Gels
–EmulsionsEach formulation contains a variety of excipients – each
with a role to play
Topical formulations for Safety Assessment studies have moved from GMP to GLP areas, in response to regulatory needs
Recently RTP has also increased involvement in topical studies. Therefore, both the UK and US Dispensaries are now able to support Safety Assessment
Intranasal Formulations
Definition - Nasal spray products contain therapeutically active ingredients (drug substances) dissolved or suspended in solutions or mixtures of excipients (e.g., preservatives, viscosity modifiers, emulsifiers and buffering agents) in non-pressurised dispensers that use metering pumps. (FDA 1999.)
Example 1 (2008):
Xylitol, Avicel CL611,Tween 80, Potassium Sorbate, EDTA, Sodium Citrate and Citric Acid (anhydrous) in water
Example 2 (2011):
Benzalkonium chloride and EDTA in 0.9% (w/v) aqueous sodium chloride
Why Intranasal Dosing
Local targets
i.e. established treatments such as corticosteriods for rhinitis
For systemic therapy can stop agents being metabolised in the GI tract
Potentially higher absorption then oral route
i.e. sumatriptan oral dose = 25, 50 or 100 mg but nasal dose = 5 or 20 mg.
Avoiding the need for subcutaneous dosing, therefore less invasive
Better for patient self administration
Intranasal Formulation Characteristics
Doses are up to 200 uL (clinical dose) – due to anything more being lost from absorptive area - swallowed or run out of nose
Ideally a solution is produced – better absorption
However, if solubility limits this, then suspensions are used
Suspensions have additional issues:-
– Crystal growth
– Physical stability
– Re-suspension
– Homogeneity
– Particle size distribution and morphology
– Sterile filtration not possible
pH usually aimed at pH 4-7.4 (SOP range = pH 4-11)
Intranasal Formulation Ingredients
Seven functional categories:-
Each formulation may contain one or more of these functional categories
Viscosity adjustment
– i.e carboxymethylcellulose
Tonicity adjustment
– i.e sodium chloride
Flavouring agent
– i.e menthol
Surfactants
– i.e Tween 80
Solvents (Solubility enhancers)
– i.e propylene glycol and ethanol
Preservatives
– i.e BKC, EDTA and methylparaben
pH adjusters/buffers.
– i.e sodium hydroxide and phosphates
Devices
Must be:-
–Compatible with the formulation
–Free from leachables (Only tested for Clinical dosing)
–User friendly
–Accurate and reliableDevices control the volume of spray, droplet size and angle
of administration
Suppliers include: Becton Dickinson, Rexam and Valois
The Preclinical devices typically dispense 50 and 100 uL
Device Head
Dispensary Considerations
Formulation tests:-
– Test chemical stability at both ambient and fridge storage for up to 28 days
– Test homogeneity – before and after storage (3 x samples taken)
– Test particle size of suspensions - certain excipients i.e Avicel, can interfere with some particle size analysis methods
Device test
– Test dispensing accuracy - 3 x 10 shots assessed
– Test need for device priming prior to dosing – done as part of accuracy check
– Assess the fill volume and dead within the device
– Ensure device testing is suitable for dosing method – i.e. dip tube removed for dog dosing, because device inverted during dosing
– Viscosity of the formulation effects all of the above
Throat (Oropharyngeal) Spray Formulations
Dose administered to the back of the throat
Uses specialised devices
Shares many similarities with intranasal:-
– pH range (pH 4-11)
– Stability/homogeneity testing
– Suspension v solution and associated challenges
Example:
Xylitol, Cremophor RH40, Copovidone, Sodium Benzoate, Xanthan Gum, Methylparaben, Propylparaben, Cetylpyridinium Chloride, Sodium Saccharin and Glycerol in water
Intranasal and Throat Spray Dosing Considerations
Dogs :-
– Similar devices to those used in the clinic, but with a smaller adaptor
– Devices deliver 50 or 100uL shots
– Device inverted during dosing, therefore, dip tube removed
– Multiple shots per nostril, i.e. 3 shots/nostril
– Multiple doses throughout the day i.e. 8 times daily
Rats:-
– Use a tube to administer drops of 10 uL
– Multiple drops/nostril
– Multiple doses throughout the day i.e. 4 times daily
General
– Often carried out in tandem with oral or iv dose, to provide systemic cover.
Intranasal Formulations Summary
Intranasal formulations offer advantages in drug delivery
Each formulation contains a variety of excipients – each with a role to play
Intranasal formulations for Safety Assessment studies have moved from GMP to GLP areas, in response to regulatory needs
Formulation testing and device testing performed by Dispensary to GLP
Summary
Topical, Intranasal and Oropharyngeal doses have provided the Dispensary with a series of challenges
More complicated, multi stage and resource intensive preparation methods
Wider variety of excipients used – potential sourcing complications and education on their role in the formulation
Formulation preparation has moved from a GMP into a GLP environment within the Dispensary - increasing Safety Assessment skill base and flexibility in study support
All formulation stability, homogeneity and Device testing is performed by the Dispensary to GLP as well
Questions