 Introduction  Topical Formulations  Intranasal Formulations  Summary and Questions.

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Transcript of  Introduction  Topical Formulations  Intranasal Formulations  Summary and Questions.

Clinical Formulations in The Dispensary

Clinical Formulations in The Dispensary AgendaIntroduction Topical FormulationsIntranasal FormulationsSummary 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 methodsRecently Safety Assessment (GSK) has been involved in different routes of dosing, which have used the proposed clinical formulation Topical dosingIntranasal and Oropharyngeal dosingClinical formulations generally use a wider variety of excipients with more complicated, multi stage preparation methodsHistorically these were supplied by Pharmaceutical Development from within a GMP environmentBoth 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 CarboxymethylcelluloseEmulsions - 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 WaterStiefel 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

OintmentsSemisolid, 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 paraffinAbsorption bases i.e. beeswaxWater soluble bases i.e macrogolsWater 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

GelsContain continuous long chain structures, which provide solid like properties.

A simple gel is water thickened with one of the following:

Natural gums tragacanth, xanthanSemisynthetic material carboxymethylcelluloseSynthetic material Carbopol 934PClays 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

EmulsionsAre 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 IngredientsEach topical formulation may contain one or more of these six functional categories:-Polymeric ThickenersCelluloses. i.e HPMCGums. i.e. xanthanColloidal solids. i.e silicaAcrylic acids. i.e. carbomersHydrogels. i.e. polyvinyl alcoholOil Phase. i.e mineral oil, white soft paraffin, Sophiderm SurfactantsNonionic. i.e. TweenAnionic. i.e SLSCationic. i.e BKC SolventsPolar. i.e water, propylene glycolNon polar. i.e. isopropyl alcohol PreservativesAntimicrobial. i.e BKC, potassium sorbate, methylparabenAntioxidant. i.e ascorbic acidChelating agents. i.e citric acid pH adjusters. i.e sodium hydroxide, sodium phosphate

11Transfer of Topical Formulations into the Dispensary Topical formulations previously provided by Pharmaceutical Development (mainly based in Canada) prepared to GMPThree stage hand over:-Initially PD provided all formulations for Safety Assessment studies to GMPNext PD supplied placebo (control) and the high dose formulation to GMP and Dispensary prepared the lower concentrations to GLP by serial dilution with the placeboFinally Dispensary prepare all formulations for Safety Assessment studies to GLP also conduct formulation GLP stability testingReasons for hand over:Regulators expect, that were capability exists, formulations used on GLP studies should be prepared within a GLP environmentPharmaceutical Development Canada closed down limited UK based supportStiefel has taken over however, they have no in house facilities for formulation preparationTherefore, Dispensary has taken over the role of producing topical formulations for Safety Assessment studies

Challenges in taking on this rolePractical:-Specialised equipment such as mixers and pH probes needed to be acquiredSourcing of a wide variety of excipients a lot of which are were new to the DispensaryTraining and generation of SOP to address the novel formulation challenges

Knowledge Base:-Needed to increase our understanding over the rational for excipient selectionDealing with international collaborators and partnership companies (Stiefel) in sourcing information on the formulations Formulation PreparationFormulation 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: Creamwhite 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-10Solvents = propylene glycol and hexylene glycolAqueous phase = waterCyclomethicone

Example of a FormulationWeigh out test material into container 1.Add solvents to container 1 and stir magnetically may not go totally into solutionAdd aqueous phase to container 1 and stir magneticallyHeat container one and the pre made Oily phase to approximately 60C (5C).Temperature to be recorded using a thermometerAdd Oily Phase to container 1 and mix on the Ultra Turrax for approximately 2-3 minutesWeigh out cyclomethicone into a glass syringe and add to container 1Continue 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)Watch to ensure the formulation does not set on the Turrax mixerMeasure pH using special probe, allow to cool and setAllow formulation to cool at room temperature and stir with spatula intermittently throughout cooling process until formulation thickens.Sample when cooled and thickened.

Dispensary ConsiderationsCurrent formulation tests:- Test chemical stability at both ambient and fridge storage for up to 28 daysTest 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 timeFormulation 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 troublesomeNeed 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 dosingAnalysisFormulations generally do not dissolve in analytical diluent, therefore, centrifuging and extraction methods needed

Topical Formulations SummaryThere are 3 types of topical formulations:-OintmentsGelsEmulsionsEach formulation contains a variety of excipients each with a role to playTopical formulations for Safety Assessment studies have moved from GMP to GLP areas, in response to regulatory needsRecently RTP has also increased involvement in topical studies. Therefore, both the UK and US Dispensaries are now able to suppor