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