Formulation Strategies Part 1 PDF

Formulation strategies: Part 1 Mignon Cristofoli Overview What is an active? How do we know if it works? How can we increase the delivery of actives? Active & passive strategies How does a molecule enter into and move through the skin? Fick’s law Physicoche...

Formulation strategies: Part 1 Mignon Cristofoli Overview What is an active? How do we know if it works? How can we increase the delivery of actives? Active & passive strategies How does a molecule enter into and move through the skin? Fick’s law Physicochemical characteristics Solubility parameters Higuchi What are cosmetic actives? There is no legal definition, so it is subject to interpretation. Is glycerol an active? A definition which applies very strict criteria: “Those materials for which it is possible to carry out controlled experiments in which a baseline cosmetic effect is measurably enhanced by the addition of the active in a defined concentration.” Dr K. Lintner, PCIE Conference, Dusseldorf, 2003 Is the active working? The efficacy of any product containing an active is determined by: Intrinsic activity of the active molecule (i.e. the ability of the active to cause a response in a specific biological modele.g. antioxidant, collagen production enhancer) - determined in vitro Delivery of the active to the site of action (e.g. viable epidermis) Can be determined in vitro eg using diffusion cells, also in vivo tests eg tape stripping, confocal raman spectroscopy Assessed indirectly, using product efficacy testing (corneometerⓇ, cutometerⓇ)  A "cosmetic product" shall mean any substance or mixture intended to be placed in contact with the various external parts of the Where are we delivering to? human body (epidermis, hair system, nails, lips and external genital organs) or with the teeth and the mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their external parts of the human body: epidermis appearance and/or correcting body odours and/or protecting them or keeping them in good condition. (Article 2 of the UK Cosmetics Regulation (EC) No. 1223/2009) Possible locations: UV filters – skin surface Humectants – Stratum corneum Lightening actives – melanocytes Anti-ageing actives – viable epidermis? what about dermis?  Delivery of the active Skin absorption of most actives is very low (typically 2-4%; in the case of retinoids around 1% of the quantity applied) In some cases, it is 0%. WHY? Stratum corneum is a thin, but extremely effective barrier, evolved to keep water in and external materials out Some molecules may be too big (> 500 Da) Some active ingredients ionise - and it is very difficult for ionised molecules to partition into a lipid environment Active has a greater affinity for the formulation than the skin What can we do to increase delivery of the active? 2 approaches : active and passive not to be confused with the active ingredient! Active: uses more physical methods eg iontophoresis (application of a current), phonophoresis (use of ultrasound), microneedles (make holes/ channels through with the formulation can pass), physical occlusion (patches) Passive: focus on the formulation Passive strategies: formulation Includes: penetration enhancers - eg fatty acids, urea, alcohol, DMSO, Azone, terpenes formulation type eg emulsion (nano or microemulsions), micelles, liposomes etc supersaturation to induce increased thermodynamic activity ion pairing - the use of oppositely charged ions that are drawn together without forming ionic or covalent bonds, but are close enough together that their charges are masked optimisation of formulation, balancing: concentration of the active (need enough in the formulation that can be delivered to achieve its desired effect, this depends on the potency of the active - remember LD50 ?) AND the thermodynamic activity of the active in the formulation How do molecules pass through the SC? 3 possible routes: Intercellular * transcellular appendageal (hair follicles, sebaceous glands, sweat glands) Intercellular route Intercellular route (dominant) Contains alternating aqueous and lipid domains Once it has partitioned into the SC, an active must also be able to partition into alternating aqueous and lipid domains to move through the skin i.e. it cannot be exclusively hydro- or lipophilic diffusional pathlength is far greater than the thickness of the SC (± 15 - 20 μm); it is estimated at ± 300 - 900 μm Fick’s Laws of diffusion the movement of a compound through the skin occurs via passive diffusion can be described using Fick’s laws of diffusion Fick’s 1st law of diffusion takes account of partition, diffusion, change in concentration of active and pathlength J = flux = permeation of the active 1st step is partition into SC, followed by (µg/cm2) diffusion. This occurs repeatedly as the K = partition from the formulation into molecule moves across the alternating the skin - 1st step! lipid and aqueous phases D = diffusion (2nd step) L = path length while there are other layers of the ∆C = change in concentration epidermis, it is the SC that provides the kp = permeation coefficient = (K x D)/L main barrier properties When formulating we need to consider the following characteristics of the active: Molecular weight (MW) Melting point Partition coefficient Solubility (and potency) Active’s ability to leave the formulation and partition into the skin Physicochemical characteristics In general: MW of compound should be less than 500 Da compounds with lower melting points result in higher partition into the skin compounds should have both lipid and aqueous solubility, those with a log P of between 1-3 are suitable for percutaneous delivery log P experiments show you how likely your unionised molecule is like partition into the aqueous phase and how much into the lipid phase log P = log [active octanol] [active water] This Photo by Unkno wn Author is licensed under CC BY-SA Potency of the active In toxicology the LD50 value of a drug compound told us how much of the compound when administered orally, would kill 50% of the test population. We were able to compare this with other molecules to determine how potent it was eg NaCl (sodium chloride i.e. table salt) is about 3000 mg/ kg while botulinus toxin is 0.00001 mg/kg. As only a tiny amount of botox is needed, it is clearly much more potent than NaCl. Thus, as cosmetic formulators, you want to determine how much of your active is required to partition into the skin to achieve the desired outcome If only a small amount partitions, you need to optimise your formulation Obviously, this is subject to cosmetic legislation Solubility of the active Our active is not administered orally. As it is applied topically, it needs to be in solution (formulation) If only a small amount of the active partitions, you may need a high concentration of it in your formulation eg if 2% partitions - and your formulation contains a [5%] of the active this would equate to 0.001% partitioning; if a [1%], this would amount to 0.0002% partitioning (5 times less) 1st step: select solvents in which our active will be highly soluble how do we do this without testing saturated solubility of our active in each and every possible solvent? a selection tool known as “solubility parameters”  Solubility parameters (SP) The solubility parameter is a numerical value that indicates the relative solvency behavior of a specific solvent. This numerical value can be an indicator that the solute- solvent or solvent- solvent are more likely to interact Works on the principle of “like dissolves like” It is derived from the cohesive energy density of a molecule cohesive energy density is a value associated with the forces required to keep molecules close together in a condensed state (eg solid or liquid)  Hildebrand SPs one way to determine this value has been derived from the heat of vaporization Heat of vaporisation is the additional energy added into a system to take it from boiling point to vaporization (gaseous state) this is the basis of the Hildebrand SP Hildebrand’s SP was based on van der Waal’s forces. 𝛿 = Solubility parameter c = Cohesive energy density ΔH = Heat of vaporization R = Gas constant T = Temperature Vm = Molar volume  Hansen SPs This approached was developed by Hansen who divided cohesive energy density into three components: hydrogen bonding (H) , dipole- dipole interactions (P) and van der Waal’s forces (D). Hansen Solubility Parameters (HSP) 𝛿t = SP 𝛿t2 = 𝛿d2 +𝛿p2 + 𝛿h2 𝛿d = London dispersion / van der Waal’s forces 𝛿p = polar forces (dipole-dipole) 𝛿h = hydrogen bonding forces Hansen’s SP Hansen developed a 3D spherical solubility model, with a radius of interaction very simply, it was suggested that if the SP values for another molecule fell within this sphere, they would be soluble/ miscible Once you have identified HSPs for your active and the solvent, calculate the Distance (Ra) between them by using the equation: 𝛿t = SP 𝛿d = London dispersion / van der Ra2 = 4(𝛿d1 - 𝛿d2 )2 + (𝛿p1 - 𝛿p2 )2 + (𝛿h1 - 𝛿h2)2 Waal’s forces 𝛿p = polar forces (dipole-dipole) 𝛿h = hydrogen bonding forces If the distance is less than the radius of interaction, then they should be soluble/ miscible (if the distance is greater, then not likely to be soluble/ miscible) The radius of interaction is usually determined through experimentation Solubility parameters: general There is software that will calculate these values (SPs). There are different models eg Hansen and Van Krevelen and Hoftyzer Most important thing is that we should stick with one approach We often use this tool in a very simplistic way i.e. if the numerical values are close, we use it as an indicator that the solute- solvent or solvent-solvent are more likely to interact SC is attributed a solubility parameter value = ± 10 (cal/ cm3 )1/2 (Liron and Cohen, 1984). As accepted SI units are MPa1/2, the value would be 20.455 MPa1/2 Propylene glycol (PG), 1–2 pentanediol (1-2P), 1–5 pentanediol (1-5P), 1–2 hexanediol (HEX), isopropyl alcohol (IPA), isopropyl myristate (IPM), glycerol (GLY) Transcutol® (TC), Capryol 90® or propylene glycol monocaprylate (PGMC) Type II, Lauroglycol 90® or propylene glycol monolaurate (PGML) Type II,Labrafac® or medium chain triglycerides of caprylic (C8) and capric (C10) acids, dipropylene glycol (DiPG), tripropylene glycol (TriPG). The solubility parameter of EA was calculated as 15.4 ((cal/cm3)1/2) it has been reported that the solubility parameter of the skin, is 10 (cal/ cm3)1/2 So far we have considered: Molecular weight (MW) ✓ Melting point ✓ Partition coefficient ✓ Solubility (and potency) ✓ Active’s ability to leave the formulation and partition into the skin Higuchi: the percutaneous absorption process from creams and ointments (Higuchi, 1960) Fick’s 1st law of diffusion The rate controlling barrier is the skin in considering the equation for flux: While the permeability coefficient (K x D) is important - it is really K, the partition coefficient that is most important. K = partition from the formulation into the skin - (1st step) K is very sensitive to molecular structure and size Higuchi 1 If the vehicle itself isn’t affecting the skin, what determines the movement of the active from the formulation into the skin? Higuchi says that we need to consider the thermodynamic activity of the active in the formulation = 𝜶 and its activity coefficient in the skin (𝜸), such that 𝛼∙𝐷 𝐽= 𝛾∙𝐿  𝜶∙𝑫 Higuchi 2 𝑱= 𝜸∙𝑳 The driving force in the movement of the active from the vehicle into the skin, is the difference in thermodynamic potential between the vehicle (𝛼) and the skin (𝛾) It is this “activity” rather than absolute concentration that is important 𝜶 is often attributed a value of 1. Solute moves from areas of high activity to lower activity, so “activity” in the skin should be less than 1  saturated solubility of caffeine: solvent A : 0.2 mg/mL solvent B: 10 mg/mL Higuchi 3 𝜶 is often attributed a value of 1 - the maximum thermodynamic activity. the saturated solubility of a solute in a solvent is normally considered the highest thermodynamic activity - given the value of 1 For example: saturated solubility of caffeine in solvent A is = 0.2 mg/mL, in solvent B it is 10 mg/mL. The activity of these is now equivalent. Provided that the activity of caffeine in the skin would be less than 1, it should move equivalently from both vehicles into the skin. However, this is not always what happens. This is because the activity of the active is also related to its affinity for the vehicle “ solutes held firmly by the vehicle will exhibit low activity coefficients and slow rates of penetration” (Higuchi, 1960) In general, the higher the affinity, the lower the thermodynamic activity  saturated solubility of caffeine: solvent A : 0.2 mg/mL solvent B: 10 mg/mL Higuchi 4 What indicates affinity? an indicator of high affinity = high solubility and concentration in vehicle we don’t normally formulate at maximum solubility, it would be too unstable If we had 0.2 mg/mL caffeine in both solvent A and B: activity in A is high, but in B is very low “most energetic species will result in fastest penetration” WHY? The formulation and the active don’t like each other - so it moves to area (skin) where it has a greater affinity What does this mean in practice? Practical implications of thermodynamic activity 1 we still need to balance the concentration of our active and the thermodynamic activity why? even if a larger % of the active partitions from one solvent relative to another, if we can’t accommodate enough of the active in the vehicle, we won’t be able to deliver a sufficient quantity to the skin we can use SP as a tool to select our potential solvents - i.e. those in which our active is likely to be most soluble (high affinity) we can balance it with solvents with which it has a lower affinity (can use SP here too). Propylene glycol (PG), 1–2 pentanediol (1-2P), 1–5 pentanediol (1-5P), 1–2 hexanediol (HEX), isopropyl alcohol (IPA), isopropyl myristate (IPM), glycerol (GLY) Transcutol® (TC), Capryol 90® or propylene glycol monocaprylate (PGMC) Type II, Lauroglycol 90® or propylene glycol monolaurate (PGML) Type II,Labrafac® or medium chain triglycerides of caprylic (C8) and capric (C10) acids, dipropylene glycol (DiPG), tripropylene glycol (TriPG).  Generally: SP values closest to EA result in solubility parameters (cal/ cm3)1/2 skin 10 higher saturated solubility values of EA in that EA 15.4 PG 14.07 solvent Gly 17.14 IPA 11.23 Please note the y-axis, max value is 800 mg/ Hex ±12 mL PGML 9.44  solubility parameters (cal/ cm3)1/2 Please note the y-axis, max value is 10 µg/ cm2 skin 10 EA 15.4 PG 14.07 Gly 17.14 IPA 11.23 Hex ±12 PGML 9.44  The solubility parameter of EA was calculated as 15.4 ((cal/cm3)1/2) Saturated solubility decreases with the binary and ternary solvent combinations. Max y-axis value is now 600 mg/mL solubility parameters (cal/ cm3)1/2 skin 10 EA 15.4 PG 14.07 IPA 11.23 Hex ±12 PGML 9.44 Binary solvent systems: although the saturated solubility decreased, the y-axis now has a maximum value of 40 µg/ cm2 (for single solvents it was 10 µg/ cm2). This reflects that the amounts that permeated increased, despite a decrease in concentration. Ternary solvent systems: although the saturated solubility decreased, the y-axis now has a maximum value of 80 µg/ cm2 (for single solvents 10 µg/ cm2, binary 40 µg/ cm2). This reflects that the amounts that permeated increased even further, despite the decrease in concentration. solubility parameters (cal/ cm3)1/2 skin 10 EA 15.4 PG 14.07 IPA 11.23 Hex ±12 IPM 8.21 PGML 9.44 What happened here? Binary system and cumulative permeation values were aligned to single solvent systems. Why?  Supersaturation supersaturation is a technique sometimes used to increase the thermodynamic activity of an active in the formulation the formulation will contain a volatile component eg IPA in this case when the formulation is applied to the skin, the IPA evaporates and the concentration of the active in the formulation immediately increases this results in an increase in thermodynamic activity, driving the active from the formulation into the skin it can be a risky strategy, if the volatile solvent is required for the solubility of the active in the formulation if so, this may result in supersaturation, and a very unstable formulation. This may cause the active to precipitate out of solution Unless the active is in solution, it can’t partition into the skin => reduced permeation Conclusion Effective delivery of an active requires optimal conditions for its release from the formulation and its partition into the SC and beyond. References Higuchi, T., 1960. Physical chemical analysis of percutaneous absorption process from creams and ointments. J Soc Cosmet Chem, 11, pp.85-97.