WO2019233722A1 - Pharmaceutical composition comprising tacrolimus - Google Patents

Pharmaceutical composition comprising tacrolimus Download PDF

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Publication number
WO2019233722A1
WO2019233722A1 PCT/EP2019/062533 EP2019062533W WO2019233722A1 WO 2019233722 A1 WO2019233722 A1 WO 2019233722A1 EP 2019062533 W EP2019062533 W EP 2019062533W WO 2019233722 A1 WO2019233722 A1 WO 2019233722A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
emulsifier
oil
composition according
amount
Prior art date
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PCT/EP2019/062533
Other languages
French (fr)
Inventor
Michael Edgar HERBIG
Dirk-Heinrich Evers
Melanie KÖLLMER
Sabine Fielhauer
Stefanie HAHN
Original Assignee
Almirall, S.A.
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Application filed by Almirall, S.A. filed Critical Almirall, S.A.
Publication of WO2019233722A1 publication Critical patent/WO2019233722A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present invention relates to a pharmaceutical composition comprising tacrolimus which is suitable for administration to the skin.
  • Tacrolimus is a 23-membered macrolide lactone that was first described in 1987 from the fermentation broth of a Japanese soil sample that contained the bacterium Streptomyces tsukubaensis.
  • the chemical name of tacrolimus is
  • tacrolimus 13, 19,21 ,27-tetramethyl-17-(prop-2-en-1 -yl)-11 ,28-dioxa-4- azatricyclo[22.3.1.0 4 9 ]octacos-18-ene-2,3,10,16-tetrone.
  • the structure of tacrolimus is shown below.
  • Tacrolimus is an immunosuppressive drug that acts via calcineurin inhibition. In systemic therapy it is mainly used after allogeneic organ transplantation to lower the risk of organ rejection. Topically, it is used as an ointment for the treatment of other T cell-mediated diseases, primarily atopic eczema or atopic dermatitis, but it is also used off-label in vitiligo and lichen sclerosus. Tacrolimus is currently the most effective drug for the topical treatment of atopic eczema. However, it is only available as a relatively greasy, sticky and occlusive ointment (Protopic®). Despite its lower efficacy, pimecrolimus cream (Elidel®) is therefore often used to provide a cosmetically more attractive formulation to patients.
  • Protopic® ointment is available in two strengths, 0.03% and 0.1 % tacrolimus monohydrate.
  • the ointment consists of polar solvent droplets (propylene carbonate) that are dispersed within a lipophilic matrix of liquid paraffin, white soft paraffin, hard paraffin and beeswax. While acting as a solvent and release modifier for tacrolimus, propylene carbonate is also classified as potential irritant that could further disrupt already compromised skin.
  • the absence of water in Protopic® reduces the risk of chemical degradation due to hydrolysis, isomerization, or pH incompatibility.
  • US 2013/0116271 describes an oil-in-water emulsion comprising tacrolimus, medium chain triglycerides, ethylene glycol salicylate and/or diethyl sebacate, an emulsifying agent with an HLB value of at least 12 and a hydrophilic polymer.
  • WO 2017/174530 describes a complex oil-in-water emulsion comprising two distinct discontinuous oil phases: (i) a first oil phase comprising a first oil and tacrolimus and (ii) a second oil phase comprising a second oil.
  • the oil-in-water emulsion described in WO 2017/174530 contains two different types of oil droplets.
  • the present invention is based on the finding that an acceptable cosmetic profile can be achieved, while avoiding excessive tacrolimus degradation, by formulating tacrolimus using a specific oil-in-water emulsion comprising two different emulsifiers and a solvent/antisolvent mixture in the oil phase.
  • the new formulation also achieves acceptable skin penetration and pharmacokinetic characteristics.
  • the invention therefore provides a pharmaceutical composition which is an oil-in- water emulsion comprising oil-phase droplets dispersed in an aqueous phase,
  • oil-phase droplets contain:
  • oil-in-water emulsion further comprises (a) a first emulsifier and a second emulsifier, wherein the first emulsifier is more hydrophilic than the second emulsifier, or (b) a polymeric emulsifier and a non-polymeric emulsifier, and
  • oil-in-water emulsion comprises water in an amount of from about 30.0 to about 75.0 wt% based on the total weight of the pharmaceutical composition.
  • the invention also provides the pharmaceutical composition for use in the treatment of the human or animal body.
  • the pharmaceutical composition may be for use in the treatment or prevention of atopic dermatitis, atopic eczema, psoriasis, vitiligo or lichen sclerosus.
  • the pharmaceutical composition may comprise a first emulsifier and a second emulsifier, wherein the first emulsifier is more hydrophilic than the second emulsifier.
  • first emulsifier is more hydrophilic than the second emulsifier.
  • hydrophilicity of a emulsifier correlates with a decrease in its lipophilicity.
  • second emulsifier is more lipophilic than the first emulsifier.
  • Emulsifiers suitable for pharmaceutical and cosmetic formulations are known in the art and the hydrophilicity and lipophilicity of known emulsifiers (sometimes described as surfactants) is widely reported in the literature.
  • the degree to which a emulsifier is hydrophilic may be defined, for example, by reference to the hydrophilic-lipophilic balance (HLB) value of the emulsifier.
  • HLB hydrophilic-lipophilic balance
  • the first emulsifier typically has an HLB value which is higher than the HLB value of the second emulsifier.
  • the first emulsifier has an HLB value which is at least 1 HLB unit, more preferably at least 2 HLB units, higher than that of the second emulsifier.
  • the first emulsifier typically has a hydrophilic-lipophilic balance (HLB) value of about 8.0 or greater (for instance from 8.0 to 18.0).
  • HLB hydrophilic-lipophilic balance
  • the first emulsifier may have an HLB value of 10.0 or greater, or an HLB value of 12.0 or greater.
  • the first emulsifier has an HLB value of from 14.0 to 17.0.
  • the second emulsifier typically has a hydrophilic-lipophilic balance (HLB) value of about 6.0 or less (for instance from 0.5 to 6.0).
  • the second emulsifier may have an HLB value of 5.5 or less.
  • the second emulsifier has an HLB value of from 4.0 to 5.5.
  • the first emulsifier is Steareth-21 and the second emulsifier is Steareth-2.
  • the weight ratio of (first emulsifier):(second emulsifier) is typically from 1.0:2.0 to 1.0:20.0, for instance from 1.0:10.0 to 1.0:15.0.
  • the first emulsifier is present in an amount of from about 0.01 to 2.0 wt% based on the total weight of the pharmaceutical composition.
  • the second emulsifier is present in an amount of from about 0.1 to 5.0 wt% based on the total weight of the pharmaceutical composition.
  • the first emulsifier may be present in an amount of from 0.05 to 0.5 wt% and the second emulsifier may be present in an amount of from 1.0 to 3.0 wt% based on the total weight of the pharmaceutical composition.
  • the total amount of the first and second emulsifiers is typically at least 1.5 wt% based on the total weight of the pharmaceutical composition, for instance from 1.8 to 3.0 wt%.
  • the pharmaceutical composition may alternatively comprise a polymeric emulsifier and a non-polymeric emulsifier.
  • the non-polymeric emulsifier may be lipophilic or hydrophilic.
  • the HLB value of the non-polymeric emulsifier may be 6.0 or less (i.e. a lipophilic non-polymeric emulsifier) or 8.0 or greater (i.e. a hydrophilic non-polymeric emulsifier).
  • the non-polymeric emulsifier may be as defined above for the first or second emulsifier.
  • the non-polymeric emulsifier may for instance be Steareth-21 or Steareth-2.
  • the polymeric emulsifier has a weight average molecular weight of at least 2000 g/mol.
  • the polymeric emulsifier may be a copolymer.
  • the polymeric emulsifier may be a copolymer of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol.
  • Examples of polymeric emulsifiers of this type include Pemulen® emulsifiers.
  • the polymeric emulsifier is typically a Pemulen emulsifier.
  • the Pemulen emulsifier may be Pemulen TR-1 or Pemulen TR-2.
  • the polymeric emulsifier is typically present in an amount of from 0.1 wt% to 2.0 wt% based on the total weight of the composition, for instance from 0.2 wt% to 1.0 wt%.
  • the non-polymeric emulsifier is typically present in an amount of from 0.01 wt% to 5.0 wt% based on the total weight of the composition, for instanced from 0.1 wt% to 2.5 wt%.
  • At least a proportion of oil-phase droplets in the pharmaceutical composition comprises components (i) to (iii) as defined above.
  • the proportion of oil- phase droplets which contains components (i) to (iii) in the oil-in-water emulsion is at least 50% by weight, preferably at least 80% by weight, based on the total weight of the oil-phase droplets in the oil-in-water emulsion.
  • the proportion of the oil-phase droplets which contains components (i) to (iii) in the oil-in-water emulsion is at least 95% by weight based on the total weight of the oil-phase droplets in the oil-in-water emulsion.
  • substantially all of the oil-phase droplets in the oil-in-water emulsion contain components (i) to (iii) as defined above.
  • the oil-in-water emulsion comprises an aqueous phase which is continuous and a single discontinuous oil phase dispersed in the aqueous phase, which single discontinuous oil phase comprises components (i) to (iii) as defined above.
  • the oil-in-water emulsion typically does not comprise a second discontinuous oil phase which is also dispersed in the aqueous phase.
  • Such an emulsion is typically obtainable by dispersing in an aqueous phase a single oil phase comprising components (i) to (iii) as defined above.
  • the pharmaceutical composition of the invention is substantially free (for instance less than 0.1 wt%), preferably completely free, from propylene carbonate.
  • the pharmaceutical composition of the invention is substantially free (for instance less than 0.1 wt%), preferably completely free, from any skin irritant.
  • the solvent is a liquid in which the macrolide compound is soluble.
  • the macrolide compound may be freely soluble in the solvent.
  • the anti-solvent is a liquid in which macrolide compound is not soluble.
  • the term “not soluble’’ does not mean that the macrolide compound is completely insoluble in the antisolvent with a solubility of exactly 0 mg/mL at 25°C. Rather, the antisolvent is a liquid in which the macrolide compound has poor solubility, for instance a liquid in which the macrolide compound is substantially insoluble at 25°C.
  • the macrolide compound is not freely soluble in the antisolvent.
  • the antisolvent is typically an antisolvent other than water, for instance an organic antisolvent or a hydrocarbon antisolvent. Typically, the antisolvent is a lipophilic anti-solvent.
  • the solubility of the macrolide compound in the antisolvent is about 1.0 mg/mL or less at 25°C.
  • solubility of the macrolide compound in the antisolvent is 0.1 mg/mL or less at 25°C or 0.01 mg/mL or less at 25°C.
  • references to specific solubility values for the macrolide compound in a liquid are references to the solubility of the macrolide compound in that liquid on its own, rather than to the solubility of the macrolide compound in the environment of the pharmaceutical composition of the invention.
  • the solubility of the macrolide compound in a solvent as used herein may be determined by: (i) suspending an excess of the macrolide compound in 1 mL of the solvent; (ii) stirring the solvent and macrolide compound at 25°C for 24 ⁇ 4 hours; (iii) removing undissolved macrolide compound from the solvent by centrifugation and/or filtering; and (iv) determining the mass of macrolide compound dissolved in the 1 ml_ of solvent, optionally by ultra performance liquid chromatography (UPLC).
  • UPLC ultra performance liquid chromatography
  • the antisolvent is liquid paraffin, petrolatum, liquid wax, a silicone or a mixture thereof.
  • the antisolvent is liquid paraffin.
  • the antisolvent may alternatively be squalene, squalane, or a partially fluorinated alkane.
  • Liquid paraffin (“ Paraffinum liquidum”) is a mixture of saturated aliphatic and alicyclic non-polar hydrocarbons which typically have a carbon number of greater than or equal to 15. Liquid paraffin may also be referred to as mineral oil. Typically, liquid paraffin comprises higher alkanes, for instance straight-chain alkanes having greater than or equal to 15 carbon atoms (for instance from 15 to 30 carbon atoms). A commercially available form of liquid paraffin is PIONIER ® 2071 P.
  • Liquid paraffin typically has (i) a relative density of from 0.8 to 0.9 at 15°C as measured by ASTM D4052, (ii) a kinematic viscosity at 40°C of from 60 to 80 mm 2 /s as measured by ASTM D445 and (iii) a kinematic viscosity at 100°C of from 5 to 15 mm 2 /s as measured by ASTM D445.
  • Petrolatum is a semi-solid mixture of saturated aliphatic and alicyclic non-polar hydrocarbons which typically have a carbon number of greater than or equal to 25 (for instance from 25 to 40).
  • the melting point of petrolatum is typically in the range of 35 to 45°C.
  • liquid wax includes waxes which are liquid at room temperature (for instance 25°C).
  • the wax is typically naturally derived (for instance an animal wax such as beeswax or a vegetable wax such as soy wax).
  • Waxes typically comprise higher alkanes (for instance at least 15 carbon atoms) and lipids (for instance fatty acid esters).
  • a silicone is a liquid or semi-solid polysiloxane compound.
  • a silicone has the formula [F ⁇ SiOJn where R is C1-4 alkyl or phenyl and n is from 10 to 500.
  • C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.
  • the silicone may be dimethicone or cyclomethicone.
  • the antisolvent is present in an amount of from about 5.0 to 30.0 wt% based on the total weight of the pharmaceutical composition.
  • the amount of the antisolvent may be from 10.0 to 15.0 wt% based on the total weight of the pharmaceutical composition.
  • the amount of the antisolvent may be from 22.5 to 27.5 wt% based on the total weight of the pharmaceutical composition.
  • the oil-phase droplets comprise a solvent.
  • the solvent may be a single solvent or a mixture of miscible solvents.
  • the solvent is a mixture of two or more miscible liquids such as two or more oils.
  • the solvent may be a mixture of triglycerides and an ester of a mono- or di-carboxylic acid, which ester comprises at least 4 carbon atoms.
  • the solubility of the macrolide compound in the solvent is about 10.0 mg/mL or greater at 25°C.
  • the solubility of the macrolide compound in the solvent is 15.0 mg/mL or greater at 25°C.
  • the solubility of the macrolide compound in the solvent may be from 15.0 mg/mL to 80.0 mg/mL at 25°C.
  • the oil-phase droplets comprise a mixture of both the solvent and the antisolvent.
  • the solubility of the macrolide compound in the oil-phase comprising the solvent and the antisolvent will therefore be intermediate between the solubility of the macrolide compound in the solvent and the solubility of the macrolide compound in the antisolvent.
  • the solubility of the macrolide compound in the oil-phase droplets i.e. the oil phase comprising the solvent and the antisolvent
  • the solubility of the macrolide compound in the oil-phase droplets may be from 5 to 20 mg/mL at 25°C.
  • the solvent comprises: (i) one or more triglycerides and/or (ii) an ester of a mono- or di-carboxylic acid, which ester comprises at least 4 carbon atoms.
  • the solvent may comprise one or more triglycerides, or the solvent may comprise one or more triglycerides and an ester of a mono- or di-carboxylic acid, which ester comprises at least 4 carbon atoms.
  • the one or more triglycerides may be present in an amount of from about 10.0 to 30.0 wt% based on the total weight of the pharmaceutical composition, for instance from 17.5 to 25.0 wt%.
  • the ester may be present in an amount of from about 5.0 to 20.0 wt% based on the total weight of the pharmaceutical composition, for instance from 5.0 to 15.0 wt%.
  • the triglyceride is typically an ester formed from glycerol (propane-1 , 2, 3-triol) and three fatty acids (which may be the same or different).
  • a fatty acid is a linear or branched aliphatic carboxylic acid compound comprising from 4 to 30 carbon atoms. Fatty acids may be saturated or partially unsaturated (for instance comprising 1 to 4 double bonds).
  • a fatty acid is a compound of formula RCOOH where R is a linear Ce-24 alkyl group or a linear Ce-24 alkenyl group comprising from 1 to 3 double bonds.
  • fatty acids include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid or docosahexaenoic acid.
  • the one or more triglycerides typically have the formula:
  • R is a linear or branched C4-18 hydrocarbyl group
  • R' is a linear or branched C4-18 hydrocarbyl group
  • R" is a linear or branched C4-18 hydrocarbyl group.
  • a linear or branched C4-18 hydrocarbyl group is an organic group which consists of hydrogen and carbon atoms and which contains from 4 to 18 carbon atoms.
  • the hydrocarbyl group is aliphatic (non-aromatic) and not cyclic.
  • the linear or branched C4-18 hydrocarbyl group is a linear or branched C4-18 alkyl group or a linear or branched C4-18 alkenyl group comprising from one to three double bonds.
  • each of R, R' and R" may independently be a linear C4-18 alkyl group such as butyl, hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl or octadecyl.
  • the one or more triglycerides are medium chain triglycerides.
  • Medium chain triglycerides also known as mid chain triglycerides
  • each of the three fatty acid residues comprise from 6 to 12 carbon atoms, for instance from 8 to 10 carbon atoms.
  • Medium chain fatty acids accordingly are compounds of formula:
  • R is a linear C6-12 alkyl group
  • R' is a linear C6-12 alkyl group
  • R" is a linear C6-12 alkyl group.
  • linear C6-12 alkyl groups include hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
  • Medium chain triglycerides are commercially available.
  • the medium chain triglyceride may be Kollisolv ® MCT 60 or Kollisolv ® MCT 70.
  • the ester of a mono- or di-carboxylic acid which ester comprises at least 4 carbon atoms, is typically an ester having a molecular mass of from 150 to 350 g/mol.
  • the ester is formed from (i) an alcohol and (ii) a fatty acid having from 6 to 18 carbon atoms or a diacid having from 4 to 12 carbon atoms.
  • the alcohol is typically a C1 -6 alcohol.
  • the solvent may comprise an ester which is formed from: (i) an alcohol which is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec- butanol, isobutanol, tert-butanol and n-pentanol; and (ii) an acid which is caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid or docosahexaenoic acid, or a di
  • the ester is typically a compound of formula:
  • R A is a linear or branched C4-18 hydrocarbyl group
  • each R B is independently a linear or branched C1 -6 alkyl group
  • R c is a linear or branched divalent C1 -8 hydrocarbyl group.
  • the linear or branched C4-18 hydrocarbyl group R A is a linear or branched C4-18 alkyl group or a linear or branched C4-18 alkenyl group comprising from one to three double bonds.
  • the R A -C(0)0- group may be derived from one of the fatty acids defined above.
  • each R B is independently methyl, ethyl, propyl or isopropyl. Both R B may be ethyl or both R B may be isopropyl.
  • a linear or branched divalent C1 -8 hydrocarbyl group is an organic group derived by removing two hydrogen atoms from a C1-8 hydrocarbon compound, typically which hydrocarbon compound is aliphatic.
  • R c is a group of formula -(CFteJm- where m is an integer from 2 to 8.
  • the ester is diisopropyl adipate, diethyl sebacate, isopropyl myristate or isopropyl palmitate.
  • the ester is diisopropyl adipate or diethyl sebacate. More preferably, the ester is diisopropyl adipate.
  • the solvent typically comprises: medium chain triglycerides in an amount of from 10.0 to 30.0 wt% based on the total weight of the pharmaceutical composition;
  • the oil phase accordingly typically comprises diisopropyl adipate, liquid paraffin and medium chain triglycerides.
  • paraffin (medium chain triglycerides) may be (from 20 to 30):(from 20 to 30):(from 40 to 60), for instance 25:25:50.
  • the solvent may further comprise triethyl citrate, optionally in an amount of 2.5 to 10.0 wt% based the total weight of the pharmaceutical composition.
  • the solvent may comprise triethyl citrate and medium chain triglycerides.
  • the optimum pH for the stability of tacrolimus is in the range of about 3.5 to 5.5.
  • the pH of the pharmaceutical composition is according typically from 3.5 to 5.5.
  • the pH of the pharmaceutical composition is in the range of 4.25 to 5.0 as this is closer to the physiological pH of skin. pH is as measured using an appropriate pH meter at a temperature of 25°C.
  • the oil-in-water emulsion comprises an aqueous phase.
  • the aqueous phase comprises water and the oil-in-water emulsion comprises water in an amount of from about 30.0 to 75.0 wt% based on the total weight of the pharmaceutical composition.
  • the amount of water is from 40.0 to 60.0 wt% or from 45.0 to 55.0 wt%.
  • the pharmaceutical composition typically comprises a buffer.
  • the aqueous phase may comprise an aqueous buffer having a pH of from 3.5 to 5.5 or of from 4.25 to 5.0.
  • the buffer may be a citrate buffer, a lactate, a tartrate, or a phosphate buffer or a citrate-phosphate, citrate-lactate or citrate-tartrate buffer, preferably a citrate buffer.
  • the buffer (i) provides an optimum pH of from 4.0 to 5.0 in order to stabilise the macrolide compound, (ii) might act as a chelating agent to improve the stability of the macrolide compound and (iii) provides a slightly acidic pH which generally have favourable effects on atopic skin.
  • the buffer typically comprises water and citrate (in the form of citric acid or a salt of citric acid).
  • the buffer may comprise water, citric acid and sodium hydroxide. The production of appropriate buffers is well known in the art.
  • the oil-in-water emulsion typically further comprises a chelating agent (which may be the citrate in the buffer).
  • a chelating agent which may be the citrate in the buffer.
  • the chelating agent may be citrate, tartrate or EDTA.
  • the pharmaceutical composition further comprises a thickener, optionally in an amount of from 0.1 to 3.0 wt% based on the total weight of the pharmaceutical composition.
  • the thickener may for instance be a gum such as xanthan gum.
  • the thickener is present in the aqueous phase.
  • the pharmaceutical composition further comprises one or more
  • preservatives optionally in an amount of from 0.1 to 4.0 wt% based on the total weight of the pharmaceutical composition, for instance from 0.5 to 2.5 wt%.
  • the preservative may for instance be phenoxy ethanol.
  • the macrolide compound is typically tacrolimus monohydrate.
  • the pharmaceutical composition typically comprises the macrolide compound in an amount of from 0.005 to 0.3 wt% based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition may comprise the macrolide compound in an amount of about 0.03 wt% or about 0.1 wt% based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition is typically suitable for topical administration to the skin.
  • the oil-in-water emulsion may comprise:
  • the pharmaceutical composition is an oil-in-water emulsion comprising oil-phase droplets dispersed in an aqueous phase
  • oil-phase droplets contain:
  • a solvent which is medium chain triglycerides in an amount of from 17.5 to 25.0 wt% and optionally diisopropyl adipate in an amount of from 10.0 to 12.5 wt%;
  • an antisolvent which is liquid paraffin in an amount of from 10.0 to 30.0 wt%;
  • the oil-in-water emulsion further comprises a first emulsifier which is steareth-21 in an amount of from 0.1 to 0.2 wt% and a second emulsifier which is steareth-2 in an amount of from 1.5 to 2.5 wt%;
  • the oil-in-water emulsion comprises a water phase in an amount of from 40.0 to 60.0 wt% based on the total weight of the pharmaceutical composition;
  • medium chain triglycerides are compounds of formula:
  • R is a linear C6-12 alkyl group
  • R' is a linear C6-12 alkyl group
  • R" is a linear C6-12 alkyl group
  • the amounts are based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition is an oil-in-water emulsion comprising oil-phase droplets dispersed in an aqueous phase
  • oil-phase droplets contain:
  • a macrolide compound which is tacrolimus, or a pharmaceutically acceptable salt or solvate thereof, in an amount of from 0.005 to 0.3 wt%;
  • a solvent which is medium chain triglycerides in an amount of from 20.0 to 25.0 wt% and diisopropyl adipate in an amount of from 10.0 to 12.5 wt%;
  • an antisolvent which is liquid paraffin in an amount of from 10.0 to 12.5 wt%;
  • the oil-in-water emulsion further comprises a first emulsifier which is steareth-21 in an amount of from 0.1 to 0.2 wt% and a second emulsifier which is steareth-2 in an amount of from 1.5 to 2.5 wt%;
  • the oil-in-water emulsion comprises a water phase in an amount of from 40.0 to 60.0 wt% based on the total weight of the pharmaceutical composition;
  • medium chain triglycerides are compounds of formula:
  • R is a linear C6-12 alkyl group
  • R' is a linear C6-12 alkyl group
  • R" is a linear C6-12 alkyl group
  • the pharmaceutical composition is an oil-in-water emulsion comprising oil-phase droplets dispersed in an aqueous phase
  • oil-phase droplets contain:
  • an antisolvent which is liquid paraffin in an amount of from 20.0 to 30.0 wt%;
  • the oil-in-water emulsion further comprises a first emulsifier which is steareth-21 in an amount of from 0.1 to 0.2 wt% and a second emulsifier which is steareth-2 in an amount of from 1.5 to 2.5 wt%;
  • the oil-in-water emulsion comprises a water phase in an amount of from 40.0 to 60.0 wt% based on the total weight of the pharmaceutical composition;
  • medium chain triglycerides are compounds of formula
  • R is a linear C6-12 alkyl group
  • R' is a linear C6-12 alkyl group
  • R" is a linear C6-12 alkyl group
  • the amounts are based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition of the invention typically comprises less than 0.75% of the impurity of formula (I), which is the regio-isomer, and/or less than 0.15% of the impurity of formula (II), which is the 8-epimer:
  • the invention provides a pharmaceutical composition according to the invention for use in the treatment of the human or animal body.
  • the invention also provides a pharmaceutical composition according to the invention for use in the treatment or prevention of atopic dermatitis, atopic eczema, psoriasis, vitiligo or lichen sclerosus.
  • the composition is for use in the treatment of atopic eczema.
  • the invention provides use of a pharmaceutical composition according to the invention in the manufacture of a medicament for use in the treatment or prevention of atopic dermatitis, eczema, psoriasis, vitiligo or lichen sclerosus.
  • a disease selected from the group consisting of atopic dermatitis, eczema, psoriasis, vitiligo or lichen sclerosus
  • Tacrolimus monohydrate (referred to as tacrolimus throughout the Examples) is practically insoluble in water and in hexane, freely soluble in ethanol and very soluble in methanol.
  • the partition coefficient in n-octanol/water system is greater than 1000.
  • the solubility of tacrolimus in a number of different solvents was determined by suspending an excess of the substance in 1 mL of correspondent solvent. The samples were stirred for 24 ⁇ 4 h at ambient conditions. The undissolved residue was separated from the liquid by centrifugation and additional filtration (ultrafree-MC 0.45 pm filter vials). The clear filtrate was further diluted in an adequate way in order to prepare it for UPLC analysis.
  • the solubility of tacrolimus in the various solvents is shown in Table 1 below.
  • tacrolimus The stability of tacrolimus is complex and needs to be assessed in real formulations rather than in single excipients. From a theoretical point of view it can be concluded that due to the presence of an ester functional group, the pH optimum is in the slightly acidic range. The half acetal is typically most stable in neutral environment, but may be kinetically stabilized in the ring structure.
  • tacrolimus is more difficult to stabilize in the presence of water as compared to water-free systems such as the Protopic ® ointment or the Prograf ® Concentrate Solution for Infusion. Stabilization against isomerization and re-arrangement reactions was expected to be challenging. The separation of isomers is also an analytical challenge, especially in the context that tacrolimus is devoid of a good chromophore and, therefore, a very weak UV absorber resulting in low sensitivity of classical UPLC analysis.
  • the hydrolysis driven degradation products of tacrolimus are shown in the scheme below.
  • compositions of the present invention set out in the tables below were produced as oil-in-water emulsions. The values given are wt. % based on the total weight of the composition. These formulations are numbered as formulations I- XI.
  • Sub batch 01 Tacrolimus was weighed in under the safety cabinet, wet with the triethyl citrate and dissolved in the solvent at 70°C.
  • Sub batch 02 Mid chain triglycerides, liquid paraffin, and steareth-2 were melted at 70°C.
  • Sub batch 01 was added to sub batch 02 at 70°C.
  • Sub batch 03 Buffer solution was added to the mixing vessel, then phenoxyethanol and Steareth-21 were added and heated to 70°C. Alternatively to using a
  • prefabricated buffer solution this may be generated in situ by adding the appropriate amounts of citric acid and sodium citrate or citric acid and sodium hydroxide to water. The solution was homogenized for 5 min.
  • Sub batch 01 Tacrolimus was weighed under the safety cabinet, wet with the diisopropyl adipate and dissolved in the solvent at 70°C.
  • Sub batch 02 Mid chain triglycerides, liquid paraffin, and steareth-2 were melted at 70°C
  • Sub batch 01 was added to sub batch 02 at 70°C
  • Sub batch 03 Buffer solution was added to the mixing vessel, then phenoxyethanol and Steareth-21 and heated to 70°C. Alternatively to using a prefabricated buffer solution, this may be generated in situ by adding the appropriate amounts of citric acid and sodium citrate or citric acid and sodium hydroxide to water. The solution is homogenized for 5 min.
  • Formulation VI was compared with Protopic® in the Hamburg model with an analysis of an extended number of skin compartments. The results are shown in the table below with the values representing the mass of tacrolimus per mass of skin (ng API/mg skin).
  • Formulations III and I were selected for pig pharmacokinetic studies and compared with Protopic®. Five naive male Gottingen minipigs were used for each formulation. Formulations were applied to 10 % of the body surface and removed after 8 hours. The last of a total of 14 sampling time points was after 76 hours. The results are shown in the Table below.
  • Formulation XIII was investigated for skin penetration in the Hamburg model and compared with Protopic® ointment 0.1 %. As shown in the table below, a higher degree of penetration into the skin compartments was found for formulation XII as compared to Protopic® ointment.
  • formulation XIII was selected for pig pharmacokinetic studies and compared with Protopic® ointment 0.1 %. Two naive male Gottingen minipigs were used for each formulation. Formulations were applied to 10 % of the body surface and removed after 8 hours. The last of a total of seven sampling time points was after 24 hours. The systemic exposure, both in Cmax and AUC was significantly higher than for Protopic® which may be attributed to the higher degree of saturation in formulation XIII.
  • Example B and G which have the compositions set out in the table below.
  • tacrolimus was significantly more chemically stable with respect to degradation to the regio-isomer and the 8-epimer when formulated in the pharmaceutical composition according to the invention compared with the formulation of WO 2017/174530.

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Abstract

The present invention relates to a pharmaceutical composition which is an oil-in- water emulsion comprising oil-phase droplets dispersed in an aqueous phase, wherein at least a proportion of the oil-phase droplets contain: (i) a macrolide compound which is tacrolimus, or a pharmaceutically acceptable salt or solvate thereof; (ii) a solvent in which the macrolide compound is soluble; and (iii) an antisolvent in which the macrolide compound is not soluble; wherein the oil-in-water emulsion further comprises (a) a first emulsifier and a second emulsifier, wherein the first emulsifier is more hydrophilic than the second emulsifier, or (b) a polymeric emulsifier and a non-polymeric emulsifier, and wherein the oil-in-water emulsion comprises water in an amount of from 30.0 to 75.0 wt% based on the total weight of the pharmaceutical composition.

Description

PHARMACEUTICAL COMPOSITION COMPRISING TACROLIMUS
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising tacrolimus which is suitable for administration to the skin. BACKGROUND TO THE INVENTION
Tacrolimus is a 23-membered macrolide lactone that was first described in 1987 from the fermentation broth of a Japanese soil sample that contained the bacterium Streptomyces tsukubaensis. The chemical name of tacrolimus is
(1 R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1 ,14-dihydroxy-12-[(1 E)-1- [(1 R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1 -en-2-yl]-23,25-dimethoxy-
13, 19,21 ,27-tetramethyl-17-(prop-2-en-1 -yl)-11 ,28-dioxa-4- azatricyclo[22.3.1.04 9]octacos-18-ene-2,3,10,16-tetrone. The structure of tacrolimus is shown below.
Figure imgf000002_0001
Tacrolimus is an immunosuppressive drug that acts via calcineurin inhibition. In systemic therapy it is mainly used after allogeneic organ transplantation to lower the risk of organ rejection. Topically, it is used as an ointment for the treatment of other T cell-mediated diseases, primarily atopic eczema or atopic dermatitis, but it is also used off-label in vitiligo and lichen sclerosus. Tacrolimus is currently the most effective drug for the topical treatment of atopic eczema. However, it is only available as a relatively greasy, sticky and occlusive ointment (Protopic®). Despite its lower efficacy, pimecrolimus cream (Elidel®) is therefore often used to provide a cosmetically more attractive formulation to patients.
Protopic® ointment is available in two strengths, 0.03% and 0.1 % tacrolimus monohydrate. The ointment consists of polar solvent droplets (propylene carbonate) that are dispersed within a lipophilic matrix of liquid paraffin, white soft paraffin, hard paraffin and beeswax. While acting as a solvent and release modifier for tacrolimus, propylene carbonate is also classified as potential irritant that could further disrupt already compromised skin. The absence of water in Protopic® reduces the risk of chemical degradation due to hydrolysis, isomerization, or pH incompatibility.
However, the lack of water and the presence of paraffin and beeswax are also the reason for the poor cosmetic profile of the formulation.
Several attempts have been made to develop cream formulations comprising tacrolimus. US 2013/0116271 describes an oil-in-water emulsion comprising tacrolimus, medium chain triglycerides, ethylene glycol salicylate and/or diethyl sebacate, an emulsifying agent with an HLB value of at least 12 and a hydrophilic polymer. WO 2017/174530 describes a complex oil-in-water emulsion comprising two distinct discontinuous oil phases: (i) a first oil phase comprising a first oil and tacrolimus and (ii) a second oil phase comprising a second oil. Thus, the oil-in-water emulsion described in WO 2017/174530 contains two different types of oil droplets.
Other formulations are described in WO 2011/042485, US 2005/0249757,
EP0753297, WO 98/36747 and Yamanaka et al (International Journal of
Pharmaceutics 464 (2014) 19-26). However, it has been found that known cream formulations involve an unacceptable level of chemical degradation of the tacrolimus active agent.
There is a need to develop a cream formulation comprising tacrolimus which is cosmetically appealing to patients, and in which tacrolimus is chemically stable. It is also desirable to develop a formulation which does not require potential irritants such as propylene carbonate. There is also a need to develop a cream formulation comprising tacrolimus which has acceptable skin penetration and pharmacokinetic properties. SUMMARY OF THE INVENTION
The present invention is based on the finding that an acceptable cosmetic profile can be achieved, while avoiding excessive tacrolimus degradation, by formulating tacrolimus using a specific oil-in-water emulsion comprising two different emulsifiers and a solvent/antisolvent mixture in the oil phase. The new formulation also achieves acceptable skin penetration and pharmacokinetic characteristics.
The invention therefore provides a pharmaceutical composition which is an oil-in- water emulsion comprising oil-phase droplets dispersed in an aqueous phase,
wherein at least a proportion of the oil-phase droplets contain:
(i) a macrolide compound which is tacrolimus, or a
pharmaceutically acceptable salt or solvate thereof;
(ii) a solvent in which the macrolide compound is soluble; and
(iii) an antisolvent in which the macrolide compound is not soluble; wherein the oil-in-water emulsion further comprises (a) a first emulsifier and a second emulsifier, wherein the first emulsifier is more hydrophilic than the second emulsifier, or (b) a polymeric emulsifier and a non-polymeric emulsifier, and
wherein the oil-in-water emulsion comprises water in an amount of from about 30.0 to about 75.0 wt% based on the total weight of the pharmaceutical composition.
The invention also provides the pharmaceutical composition for use in the treatment of the human or animal body. The pharmaceutical composition may be for use in the treatment or prevention of atopic dermatitis, atopic eczema, psoriasis, vitiligo or lichen sclerosus.
DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutical composition may comprise a first emulsifier and a second emulsifier, wherein the first emulsifier is more hydrophilic than the second emulsifier. Generally, an increase in the hydrophilicity of a emulsifier correlates with a decrease in its lipophilicity. Typically, therefore, the second emulsifier is more lipophilic than the first emulsifier.
Emulsifiers suitable for pharmaceutical and cosmetic formulations are known in the art and the hydrophilicity and lipophilicity of known emulsifiers (sometimes described as surfactants) is widely reported in the literature. The degree to which a emulsifier is hydrophilic may be defined, for example, by reference to the hydrophilic-lipophilic balance (HLB) value of the emulsifier.
The first emulsifier typically has an HLB value which is higher than the HLB value of the second emulsifier. Preferably, the first emulsifier has an HLB value which is at least 1 HLB unit, more preferably at least 2 HLB units, higher than that of the second emulsifier.
The first emulsifier typically has a hydrophilic-lipophilic balance (HLB) value of about 8.0 or greater (for instance from 8.0 to 18.0). The first emulsifier may have an HLB value of 10.0 or greater, or an HLB value of 12.0 or greater. Preferably, the first emulsifier has an HLB value of from 14.0 to 17.0.
The second emulsifier typically has a hydrophilic-lipophilic balance (HLB) value of about 6.0 or less (for instance from 0.5 to 6.0). The second emulsifier may have an HLB value of 5.5 or less. Preferably, the second emulsifier has an HLB value of from 4.0 to 5.5.
HLB values as used herein are typically as calculated by Griffin’s method (Griffin, W C, Journal of the Society of Cosmetic Chemists, 1 (5): 311-26 (1949) and Journal of the Society of Cosmetic Chemists, 5 (4): 249-56 (1953)). Griffin’s method uses the formula HLB = 20 c Mh/M where Mh is the molecular mass of the hydrophilic portion of the emulsifier molecule and M is the molecular mass of the whole emulsifier molecule. HLB values for certain emulsifiers are stated below.
The first emulsifier may for instance be Steareth-21 (HLB = 15.5), PEG-8 dioleate (HLB = 8), Sorbitan Laurate (HLB = 8.6), PEG-40 Sorbitan Peroleate (HLB = 9), Laureth-4 (HLB = 9.7), PEG-7 Glyceryl Cocoate (HLB=10), PEG-20 Almond
Glycerides (HLB = 10), PEG-25 Hydrogenated Castor Oil (HLB = 10.8), Stearamide MEA (HLB = 11 ), Polysorbate 85 (HLB = 11 ), PEG-7 Olivate (HLB = 11 ), Cetearyl Glucoside (HLB = 11 ), PEG-8 Oleate (HLB = 11.6), Polyglyceryl-3 Methyglucose Distearate (HLB = 12), Oleth-10 (HLB = 12.4), Oleth-10 / Polyoxyl 10 Oleyl Ether NF (HLB = 12.4), Ceteth-10 (HLB = 12.9), PEG-8 Laurate (HLB = 13), Cocamide MEA (HLB = 13.5), Polysorbate 60 NF (HLB = 14.9), Polysorbate 60 (HLB = 14.9), Polysorbate 80 (HLB = 15), lsosteareth-20 (HLB = 15), PEG-60 Almond Glycerides (HLB = 15), Polysorbate 80 NF (HLB = 15), PEG-20 Methyl Glucose Sesquistearate (HLB = 15), Ceteareth-20 (HLB = 15.2), Oleth-20 (HLB = 15.3), Steareth-20 (HLB = 15.3), Ceteth-20 (HLB = 15.7), lsoceteth-20 (HLB = 15.7), Polysorbate 20 (HLB = 16.7), Polysorbate 20 NF (HLB = 16.7), Laureth-23 (HLB = 16.9), PEG-100 Stearate (HLB = 18.8), Steareth-100 (HLB = 18.8) or PEG-80 Sorbitan Laurate (HLB = 19.1 ).
The second emulsifier may for instance be Steareth-2 (HLB = 4.9), Glycol Distearate (HLB = 1 ), Sorbitan Trioleate (HLB = 1.8), Propylene Glycol Isostearate (HLB = 2.5), Glycol Stearate (HLB = 2.9), Sorbitan Sesquioleate (HLB = 3.7), Glyceryl Stearate (HLB = 3.8), Lecithin (HLB = 4), Sorbitan Oleate (HLB = 4.3), Sorbitan Monostearate NF (HLB = 4.7), Sorbitan Stearate (HLB = 4.7), Sorbitan Isostearate (HLB = 4.7), Oleth-2 (HLB = 4.9), Glyceryl Laurate (HLB = 5.2), Ceteth-2 (HLB = 5.3), PEG-30 Dipolyhydroxystearate (HLB = 5.5), Glyceryl Stearate SE (HLB = 5.8), Sorbitan Stearate (and) Sucrose Cocoate (HLB = 6) or PEG-4 Dilaurate (HLB = 6).
In a preferred embodiment, the first emulsifier is Steareth-21 (HLB = 15.5),
Polysorbate 60 (HLB = 14.9), Polysorbate 80 (HLB = 15), lsosteareth-20 (HLB = 15), PEG-60 Almond Glycerides (HLB = 15), Polysorbate 80 NF (HLB = 15), PEG-20 Methyl Glucose Sesquistearate (HLB = 15), Ceteareth-20 (HLB = 15.2), Oleth-20 (HLB = 15.3), Steareth-20 (HLB = 15.3), Ceteth-20 (HLB = 15.7), lsoceteth-20 (HLB = 15.7) or Polysorbate 20 (HLB = 16.7) and the second emulsifier is Steareth-2 (HLB = 4.9), Sorbitan Oleate (HLB = 4.3), Sorbitan Monostearate NF (HLB = 4.7), Sorbitan Stearate (HLB = 4.7), Sorbitan Isostearate (HLB = 4.7), Oleth-2 (HLB = 4.9), Glyceryl Laurate (HLB = 5.2), Ceteth-2 (HLB = 5.3), PEG-30 Dipolyhydroxystearate (HLB = 5.5) or Glyceryl Stearate SE (HLB = 5.8).
Preferably, the first emulsifier is Steareth-21 and the second emulsifier is Steareth-2.
The weight ratio of (first emulsifier):(second emulsifier) is typically from 1.0:2.0 to 1.0:20.0, for instance from 1.0:10.0 to 1.0:15.0.
Typically, the first emulsifier is present in an amount of from about 0.01 to 2.0 wt% based on the total weight of the pharmaceutical composition. Typically, the second emulsifier is present in an amount of from about 0.1 to 5.0 wt% based on the total weight of the pharmaceutical composition. For instance, the first emulsifier may be present in an amount of from 0.05 to 0.5 wt% and the second emulsifier may be present in an amount of from 1.0 to 3.0 wt% based on the total weight of the pharmaceutical composition. The total amount of the first and second emulsifiers is typically at least 1.5 wt% based on the total weight of the pharmaceutical composition, for instance from 1.8 to 3.0 wt%.
The pharmaceutical composition may alternatively comprise a polymeric emulsifier and a non-polymeric emulsifier. The non-polymeric emulsifier may be lipophilic or hydrophilic. For instance, the HLB value of the non-polymeric emulsifier may be 6.0 or less (i.e. a lipophilic non-polymeric emulsifier) or 8.0 or greater (i.e. a hydrophilic non-polymeric emulsifier). The non-polymeric emulsifier may be as defined above for the first or second emulsifier. The non-polymeric emulsifier may for instance be Steareth-21 or Steareth-2.
Typically, the polymeric emulsifier has a weight average molecular weight of at least 2000 g/mol. The polymeric emulsifier may be a copolymer. For example, the polymeric emulsifier may be a copolymer of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol. Examples of polymeric emulsifiers of this type include Pemulen® emulsifiers. The polymeric emulsifier is typically a Pemulen emulsifier. The Pemulen emulsifier may be Pemulen TR-1 or Pemulen TR-2.
The polymeric emulsifier is typically present in an amount of from 0.1 wt% to 2.0 wt% based on the total weight of the composition, for instance from 0.2 wt% to 1.0 wt%. The non-polymeric emulsifier is typically present in an amount of from 0.01 wt% to 5.0 wt% based on the total weight of the composition, for instanced from 0.1 wt% to 2.5 wt%.
At least a proportion of oil-phase droplets in the pharmaceutical composition comprises components (i) to (iii) as defined above. Typically, the proportion of oil- phase droplets which contains components (i) to (iii) in the oil-in-water emulsion is at least 50% by weight, preferably at least 80% by weight, based on the total weight of the oil-phase droplets in the oil-in-water emulsion. Preferably, the proportion of the oil-phase droplets which contains components (i) to (iii) in the oil-in-water emulsion is at least 95% by weight based on the total weight of the oil-phase droplets in the oil-in-water emulsion. Most preferably, substantially all of the oil-phase droplets in the oil-in-water emulsion contain components (i) to (iii) as defined above.
In a preferred embodiment, the oil-in-water emulsion comprises an aqueous phase which is continuous and a single discontinuous oil phase dispersed in the aqueous phase, which single discontinuous oil phase comprises components (i) to (iii) as defined above. Thus, in this embodiment, the oil-in-water emulsion typically does not comprise a second discontinuous oil phase which is also dispersed in the aqueous phase. Such an emulsion is typically obtainable by dispersing in an aqueous phase a single oil phase comprising components (i) to (iii) as defined above.
Typically, the pharmaceutical composition of the invention is substantially free (for instance less than 0.1 wt%), preferably completely free, from propylene carbonate. Preferably, the pharmaceutical composition of the invention is substantially free (for instance less than 0.1 wt%), preferably completely free, from any skin irritant.
The solvent is a liquid in which the macrolide compound is soluble. The macrolide compound may be freely soluble in the solvent. The anti-solvent is a liquid in which macrolide compound is not soluble. As the skilled person will appreciate, the term “not soluble’’ does not mean that the macrolide compound is completely insoluble in the antisolvent with a solubility of exactly 0 mg/mL at 25°C. Rather, the antisolvent is a liquid in which the macrolide compound has poor solubility, for instance a liquid in which the macrolide compound is substantially insoluble at 25°C. The macrolide compound is not freely soluble in the antisolvent. The antisolvent is typically an antisolvent other than water, for instance an organic antisolvent or a hydrocarbon antisolvent. Typically, the antisolvent is a lipophilic anti-solvent.
Typically, the solubility of the macrolide compound in the antisolvent is about 1.0 mg/mL or less at 25°C. Preferably, solubility of the macrolide compound in the antisolvent is 0.1 mg/mL or less at 25°C or 0.01 mg/mL or less at 25°C.
References to specific solubility values for the macrolide compound in a liquid (for instance 0.1 mg/mL or less in the liquid at 25°C) are references to the solubility of the macrolide compound in that liquid on its own, rather than to the solubility of the macrolide compound in the environment of the pharmaceutical composition of the invention.
The solubility of the macrolide compound in a solvent as used herein may be determined by: (i) suspending an excess of the macrolide compound in 1 mL of the solvent; (ii) stirring the solvent and macrolide compound at 25°C for 24 ± 4 hours; (iii) removing undissolved macrolide compound from the solvent by centrifugation and/or filtering; and (iv) determining the mass of macrolide compound dissolved in the 1 ml_ of solvent, optionally by ultra performance liquid chromatography (UPLC).
Typically, the antisolvent is liquid paraffin, petrolatum, liquid wax, a silicone or a mixture thereof. Preferably, the antisolvent is liquid paraffin. The antisolvent may alternatively be squalene, squalane, or a partially fluorinated alkane.
Liquid paraffin (“ Paraffinum liquidum”) is a mixture of saturated aliphatic and alicyclic non-polar hydrocarbons which typically have a carbon number of greater than or equal to 15. Liquid paraffin may also be referred to as mineral oil. Typically, liquid paraffin comprises higher alkanes, for instance straight-chain alkanes having greater than or equal to 15 carbon atoms (for instance from 15 to 30 carbon atoms). A commercially available form of liquid paraffin is PIONIER® 2071 P. Liquid paraffin typically has (i) a relative density of from 0.8 to 0.9 at 15°C as measured by ASTM D4052, (ii) a kinematic viscosity at 40°C of from 60 to 80 mm2/s as measured by ASTM D445 and (iii) a kinematic viscosity at 100°C of from 5 to 15 mm2/s as measured by ASTM D445.
Petrolatum is a semi-solid mixture of saturated aliphatic and alicyclic non-polar hydrocarbons which typically have a carbon number of greater than or equal to 25 (for instance from 25 to 40). The melting point of petrolatum is typically in the range of 35 to 45°C.
The term liquid wax includes waxes which are liquid at room temperature (for instance 25°C). The wax is typically naturally derived (for instance an animal wax such as beeswax or a vegetable wax such as soy wax). Waxes typically comprise higher alkanes (for instance at least 15 carbon atoms) and lipids (for instance fatty acid esters).
A silicone is a liquid or semi-solid polysiloxane compound. Typically, a silicone has the formula [F^SiOJn where R is C1-4 alkyl or phenyl and n is from 10 to 500. C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. The silicone may be dimethicone or cyclomethicone.
Typically, the antisolvent is present in an amount of from about 5.0 to 30.0 wt% based on the total weight of the pharmaceutical composition. For instance, the amount of the antisolvent may be from 10.0 to 15.0 wt% based on the total weight of the pharmaceutical composition. The amount of the antisolvent may be from 22.5 to 27.5 wt% based on the total weight of the pharmaceutical composition.
The oil-phase droplets comprise a solvent. The solvent may be a single solvent or a mixture of miscible solvents. Typically the solvent is a mixture of two or more miscible liquids such as two or more oils. For instance, the solvent may be a mixture of triglycerides and an ester of a mono- or di-carboxylic acid, which ester comprises at least 4 carbon atoms.
Typically, the solubility of the macrolide compound in the solvent is about 10.0 mg/mL or greater at 25°C. Preferably, the solubility of the macrolide compound in the solvent is 15.0 mg/mL or greater at 25°C. For example, the solubility of the macrolide compound in the solvent may be from 15.0 mg/mL to 80.0 mg/mL at 25°C.
The oil-phase droplets comprise a mixture of both the solvent and the antisolvent. The solubility of the macrolide compound in the oil-phase comprising the solvent and the antisolvent will therefore be intermediate between the solubility of the macrolide compound in the solvent and the solubility of the macrolide compound in the antisolvent. Typically, the solubility of the macrolide compound in the oil-phase droplets (i.e. the oil phase comprising the solvent and the antisolvent) is 2.5 mg/mL or greater at 25°C. For instance, the solubility of the macrolide compound in the oil- phase droplets may be from 5 to 20 mg/mL at 25°C.
Typically, the solvent comprises: (i) one or more triglycerides and/or (ii) an ester of a mono- or di-carboxylic acid, which ester comprises at least 4 carbon atoms. For instance, the solvent may comprise one or more triglycerides, or the solvent may comprise one or more triglycerides and an ester of a mono- or di-carboxylic acid, which ester comprises at least 4 carbon atoms.
The one or more triglycerides may be present in an amount of from about 10.0 to 30.0 wt% based on the total weight of the pharmaceutical composition, for instance from 17.5 to 25.0 wt%. The ester may be present in an amount of from about 5.0 to 20.0 wt% based on the total weight of the pharmaceutical composition, for instance from 5.0 to 15.0 wt%.
The triglyceride is typically an ester formed from glycerol (propane-1 , 2, 3-triol) and three fatty acids (which may be the same or different). A fatty acid is a linear or branched aliphatic carboxylic acid compound comprising from 4 to 30 carbon atoms. Fatty acids may be saturated or partially unsaturated (for instance comprising 1 to 4 double bonds). Typically, a fatty acid is a compound of formula RCOOH where R is a linear Ce-24 alkyl group or a linear Ce-24 alkenyl group comprising from 1 to 3 double bonds. Examples of fatty acids include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid or docosahexaenoic acid. The one or more triglycerides typically have the formula:
Figure imgf000011_0001
wherein:
R is a linear or branched C4-18 hydrocarbyl group;
R' is a linear or branched C4-18 hydrocarbyl group; and
R" is a linear or branched C4-18 hydrocarbyl group.
A linear or branched C4-18 hydrocarbyl group is an organic group which consists of hydrogen and carbon atoms and which contains from 4 to 18 carbon atoms.
Typically, the hydrocarbyl group is aliphatic (non-aromatic) and not cyclic. Typically, the linear or branched C4-18 hydrocarbyl group is a linear or branched C4-18 alkyl group or a linear or branched C4-18 alkenyl group comprising from one to three double bonds. For instance, each of R, R' and R" may independently be a linear C4-18 alkyl group such as butyl, hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl or octadecyl.
Preferably, the one or more triglycerides are medium chain triglycerides. Medium chain triglycerides (also known as mid chain triglycerides) are triglycerides wherein each of the three fatty acid residues comprise from 6 to 12 carbon atoms, for instance from 8 to 10 carbon atoms. Medium chain fatty acids accordingly are compounds of formula:
Figure imgf000012_0001
wherein:
R is a linear C6-12 alkyl group;
R' is a linear C6-12 alkyl group; and
R" is a linear C6-12 alkyl group.
Examples of linear C6-12 alkyl groups include hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
Medium chain triglycerides are commercially available. For instance, the medium chain triglyceride may be Kollisolv® MCT 60 or Kollisolv® MCT 70.
The ester of a mono- or di-carboxylic acid, which ester comprises at least 4 carbon atoms, is typically an ester having a molecular mass of from 150 to 350 g/mol.
Typically the ester is formed from (i) an alcohol and (ii) a fatty acid having from 6 to 18 carbon atoms or a diacid having from 4 to 12 carbon atoms. The alcohol is typically a C1 -6 alcohol.
For instance, the solvent may comprise an ester which is formed from: (i) an alcohol which is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec- butanol, isobutanol, tert-butanol and n-pentanol; and (ii) an acid which is caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid or docosahexaenoic acid, or a di-acid which is succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelic acid or sebacic acid. Typically, the alcohol is ethanol or isopropanol. Typically, the acid is a diacid which is adipic acid or sebacic acid.
The ester is typically a compound of formula:
RA-C(0)0-RB or RB-0C(0)-Rc-C(0)0-RB, wherein:
RA is a linear or branched C4-18 hydrocarbyl group; each RB is independently a linear or branched C1 -6 alkyl group; and
Rc is a linear or branched divalent C1 -8 hydrocarbyl group.
Typically, the linear or branched C4-18 hydrocarbyl group RA is a linear or branched C4-18 alkyl group or a linear or branched C4-18 alkenyl group comprising from one to three double bonds. For instance, the RA-C(0)0- group may be derived from one of the fatty acids defined above.
Typically each RB is independently methyl, ethyl, propyl or isopropyl. Both RB may be ethyl or both RB may be isopropyl.
A linear or branched divalent C1 -8 hydrocarbyl group is an organic group derived by removing two hydrogen atoms from a C1-8 hydrocarbon compound, typically which hydrocarbon compound is aliphatic. Typically, Rc is a group of formula -(CFteJm- where m is an integer from 2 to 8.
Typically, the ester is diisopropyl adipate, diethyl sebacate, isopropyl myristate or isopropyl palmitate. Preferably the ester is diisopropyl adipate or diethyl sebacate. More preferably, the ester is diisopropyl adipate.
The solvent typically comprises: medium chain triglycerides in an amount of from 10.0 to 30.0 wt% based on the total weight of the pharmaceutical composition;
and/or diisopropyl adipate in an amount of from 5.0 to 20.0 wt% based on the total weight of the pharmaceutical composition. The oil phase accordingly typically comprises diisopropyl adipate, liquid paraffin and medium chain triglycerides. The weight ratio (diisopropyl adipate):(liquid
paraffin):(medium chain triglycerides) may be (from 20 to 30):(from 20 to 30):(from 40 to 60), for instance 25:25:50.
The solvent may further comprise triethyl citrate, optionally in an amount of 2.5 to 10.0 wt% based the total weight of the pharmaceutical composition. The solvent may comprise triethyl citrate and medium chain triglycerides.
It has been established that the optimum pH for the stability of tacrolimus is in the range of about 3.5 to 5.5. The pH of the pharmaceutical composition is according typically from 3.5 to 5.5. Preferably, the pH of the pharmaceutical composition is in the range of 4.25 to 5.0 as this is closer to the physiological pH of skin. pH is as measured using an appropriate pH meter at a temperature of 25°C.
The oil-in-water emulsion comprises an aqueous phase. The aqueous phase comprises water and the oil-in-water emulsion comprises water in an amount of from about 30.0 to 75.0 wt% based on the total weight of the pharmaceutical composition. Typically, the amount of water is from 40.0 to 60.0 wt% or from 45.0 to 55.0 wt%.
The pharmaceutical composition typically comprises a buffer. For instance, the aqueous phase may comprise an aqueous buffer having a pH of from 3.5 to 5.5 or of from 4.25 to 5.0. The buffer may be a citrate buffer, a lactate, a tartrate, or a phosphate buffer or a citrate-phosphate, citrate-lactate or citrate-tartrate buffer, preferably a citrate buffer. The buffer (i) provides an optimum pH of from 4.0 to 5.0 in order to stabilise the macrolide compound, (ii) might act as a chelating agent to improve the stability of the macrolide compound and (iii) provides a slightly acidic pH which generally have favourable effects on atopic skin. The buffer typically comprises water and citrate (in the form of citric acid or a salt of citric acid). The buffer may comprise water, citric acid and sodium hydroxide. The production of appropriate buffers is well known in the art.
The oil-in-water emulsion typically further comprises a chelating agent (which may be the citrate in the buffer). The chelating agent may be citrate, tartrate or EDTA.
Typically, the pharmaceutical composition further comprises a thickener, optionally in an amount of from 0.1 to 3.0 wt% based on the total weight of the pharmaceutical composition. The thickener may for instance be a gum such as xanthan gum.
Typically, the thickener is present in the aqueous phase.
Typically, the pharmaceutical composition further comprises one or more
preservatives, optionally in an amount of from 0.1 to 4.0 wt% based on the total weight of the pharmaceutical composition, for instance from 0.5 to 2.5 wt%. The preservative may for instance be phenoxy ethanol.
The macrolide compound is typically tacrolimus monohydrate.
The pharmaceutical composition typically comprises the macrolide compound in an amount of from 0.005 to 0.3 wt% based on the total weight of the pharmaceutical composition. For instance, the pharmaceutical composition may comprise the macrolide compound in an amount of about 0.03 wt% or about 0.1 wt% based on the total weight of the pharmaceutical composition.
The pharmaceutical composition is typically suitable for topical administration to the skin.
In the pharmaceutical composition, the oil-in-water emulsion may comprise:
tacrolimus monohydrate;
diisopropyl adipate or triethyl citrate;
mid chain triglycerides;
liquid paraffin;
steareth-2;
steareth-21 ; and
water.
In a preferred embodiment, the pharmaceutical composition is an oil-in-water emulsion comprising oil-phase droplets dispersed in an aqueous phase,
wherein substantially all of the oil-phase droplets contain:
(i) a macrolide compound which is tacrolimus, or a pharmaceutically
acceptable salt or solvate thereof, in an amount of from 0.005 to 0.3 wt%;
(ii) a solvent which is medium chain triglycerides in an amount of from 17.5 to 25.0 wt% and optionally diisopropyl adipate in an amount of from 10.0 to 12.5 wt%; and
(iii) an antisolvent which is liquid paraffin in an amount of from 10.0 to 30.0 wt%;
and wherein:
the oil-in-water emulsion further comprises a first emulsifier which is steareth-21 in an amount of from 0.1 to 0.2 wt% and a second emulsifier which is steareth-2 in an amount of from 1.5 to 2.5 wt%;
the oil-in-water emulsion comprises a water phase in an amount of from 40.0 to 60.0 wt% based on the total weight of the pharmaceutical composition;
the medium chain triglycerides are compounds of formula:
Figure imgf000016_0001
where R is a linear C6-12 alkyl group, R' is a linear C6-12 alkyl group and R" is a linear C6-12 alkyl group; and
the amounts are based on the total weight of the pharmaceutical composition.
In a preferred embodiment, the pharmaceutical composition is an oil-in-water emulsion comprising oil-phase droplets dispersed in an aqueous phase,
wherein substantially all of the oil-phase droplets contain:
(i) a macrolide compound which is tacrolimus, or a pharmaceutically acceptable salt or solvate thereof, in an amount of from 0.005 to 0.3 wt%;
(ii) a solvent which is medium chain triglycerides in an amount of from 20.0 to 25.0 wt% and diisopropyl adipate in an amount of from 10.0 to 12.5 wt%; and
(iii) an antisolvent which is liquid paraffin in an amount of from 10.0 to 12.5 wt%;
and wherein:
the oil-in-water emulsion further comprises a first emulsifier which is steareth-21 in an amount of from 0.1 to 0.2 wt% and a second emulsifier which is steareth-2 in an amount of from 1.5 to 2.5 wt%;
the oil-in-water emulsion comprises a water phase in an amount of from 40.0 to 60.0 wt% based on the total weight of the pharmaceutical composition;
the medium chain triglycerides are compounds of formula:
Figure imgf000016_0002
where R is a linear C6-12 alkyl group, R' is a linear C6-12 alkyl group and R" is a linear C6-12 alkyl group; and the amounts are based on the total weight of the pharmaceutical composition.
In a preferred embodiment, the pharmaceutical composition is an oil-in-water emulsion comprising oil-phase droplets dispersed in an aqueous phase,
wherein substantially all of the oil-phase droplets contain:
(i) a macrolide compound which is tacrolimus, or a pharmaceutically
acceptable salt or solvate thereof, in an amount of from 0.005 to 0.3 wt%;
(ii) a solvent which is medium chain triglycerides in an amount of from 17.5 to 22.5 wt% and triethyl citrate in an amount of from 2.5 to 7.5 wt%; and
(iii) an antisolvent which is liquid paraffin in an amount of from 20.0 to 30.0 wt%;
and wherein:
the oil-in-water emulsion further comprises a first emulsifier which is steareth-21 in an amount of from 0.1 to 0.2 wt% and a second emulsifier which is steareth-2 in an amount of from 1.5 to 2.5 wt%;
the oil-in-water emulsion comprises a water phase in an amount of from 40.0 to 60.0 wt% based on the total weight of the pharmaceutical composition;
the medium chain triglycerides are compounds of formula
Figure imgf000017_0001
where R is a linear C6-12 alkyl group, R' is a linear C6-12 alkyl group and R" is a linear C6-12 alkyl group; and
the amounts are based on the total weight of the pharmaceutical composition.
After storage at a temperature of 40°C for 6 months, the pharmaceutical composition of the invention typically comprises less than 0.75% of the impurity of formula (I), which is the regio-isomer, and/or less than 0.15% of the impurity of formula (II), which is the 8-epimer:
Figure imgf000018_0001
Formula (I) Formula (II)
The invention provides a pharmaceutical composition according to the invention for use in the treatment of the human or animal body.
The invention also provides a pharmaceutical composition according to the invention for use in the treatment or prevention of atopic dermatitis, atopic eczema, psoriasis, vitiligo or lichen sclerosus. Typically, the composition is for use in the treatment of atopic eczema.
The invention provides use of a pharmaceutical composition according to the invention in the manufacture of a medicament for use in the treatment or prevention of atopic dermatitis, eczema, psoriasis, vitiligo or lichen sclerosus.
A method for treating or preventing a disease selected from the group consisting of atopic dermatitis, eczema, psoriasis, vitiligo or lichen sclerosus in a patient in need thereof, which method comprises applying a therapeutically effective amount of a pharmaceutical composition according to the skin of the patient. The invention will be described in more detail in the following Examples. EXAMPLES
Formulation study for tacrolimus Solubility of tacrolimus
Tacrolimus monohydrate (referred to as tacrolimus throughout the Examples) is practically insoluble in water and in hexane, freely soluble in ethanol and very soluble in methanol. The partition coefficient in n-octanol/water system is greater than 1000.
The solubility of tacrolimus in a number of different solvents was determined by suspending an excess of the substance in 1 mL of correspondent solvent. The samples were stirred for 24 ± 4 h at ambient conditions. The undissolved residue was separated from the liquid by centrifugation and additional filtration (ultrafree-MC 0.45 pm filter vials). The clear filtrate was further diluted in an adequate way in order to prepare it for UPLC analysis. The solubility of tacrolimus in the various solvents is shown in Table 1 below.
Table 1: Solubility profile of tacrolimus in selected pharmaceutical excipients
Figure imgf000019_0001
Stability of tacrolimus
Stability in solution (stress tests)
The stability of tacrolimus is complex and needs to be assessed in real formulations rather than in single excipients. From a theoretical point of view it can be concluded that due to the presence of an ester functional group, the pH optimum is in the slightly acidic range. The half acetal is typically most stable in neutral environment, but may be kinetically stabilized in the ring structure.
Therefore, it is evident that tacrolimus is more difficult to stabilize in the presence of water as compared to water-free systems such as the Protopic® ointment or the Prograf® Concentrate Solution for Infusion. Stabilization against isomerization and re-arrangement reactions was expected to be challenging. The separation of isomers is also an analytical challenge, especially in the context that tacrolimus is devoid of a good chromophore and, therefore, a very weak UV absorber resulting in low sensitivity of classical UPLC analysis. The hydrolysis driven degradation products of tacrolimus are shown in the scheme below.
Figure imgf000020_0001
„open ring" „19-epimer“ Further known degradation products of tacrolimus are shown in the scheme below.
Figure imgf000021_0001
eg o- somer
Tacrolimus-4-epimer-5,6-dien
Preparation of formulations
The pharmaceutical compositions of the present invention set out in the tables below were produced as oil-in-water emulsions. The values given are wt. % based on the total weight of the composition. These formulations are numbered as formulations I- XI.
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
Figure imgf000023_0001
Figure imgf000023_0002
Formulation process
The formulations according to the Examples were produced following the two protocols set out below.
Protocol A
Sub batch 01 : Tacrolimus was weighed in under the safety cabinet, wet with the triethyl citrate and dissolved in the solvent at 70°C.
Sub batch 02: Mid chain triglycerides, liquid paraffin, and steareth-2 were melted at 70°C. Sub batch 01 was added to sub batch 02 at 70°C.
Sub batch 03: Buffer solution was added to the mixing vessel, then phenoxyethanol and Steareth-21 were added and heated to 70°C. Alternatively to using a
prefabricated buffer solution, this may be generated in situ by adding the appropriate amounts of citric acid and sodium citrate or citric acid and sodium hydroxide to water. The solution was homogenized for 5 min.
Under mild stirring, the oil phase was added (sub batches 1 and 2) to the water phase (sub batch 3) and homogenized for two times 5 minutes and then cooled to room temperature under mild stirring. Protocol B
Sub batch 01 : Tacrolimus was weighed under the safety cabinet, wet with the diisopropyl adipate and dissolved in the solvent at 70°C.
Sub batch 02: Mid chain triglycerides, liquid paraffin, and steareth-2 were melted at 70°C Sub batch 01 was added to sub batch 02 at 70°C
Sub batch 03: Buffer solution was added to the mixing vessel, then phenoxyethanol and Steareth-21 and heated to 70°C. Alternatively to using a prefabricated buffer solution, this may be generated in situ by adding the appropriate amounts of citric acid and sodium citrate or citric acid and sodium hydroxide to water. The solution is homogenized for 5 min.
Under mild stirring, the oil phase was added (sub batches 1&2) to the water phase (sub batch 3) and homogenized for two times 5 minutes and then cooled to room temperature under mild stirring.
Pharmacokinetic data and skin penetration The skin permeation of the formulations of the invention was tested using the Hamburg Model and pharmacokinetic data was obtained from a minipig model.
Skin penetration
Hamburg model tests were carried out on pig ear skin (Herbig ME, Houdek P, Gorissen S, et al. A custom tailored model to investigate skin penetration in porcine skin and its comparison with human skin. Eur J Pharm Biopharm. 2015 Sep; 95:99- 1 ) to determine skin penetration of formulations according to the invention. As a comparison, the commercial formulation Protopic® was also tested.
Formulation VI was compared with Protopic® in the Hamburg model with an analysis of an extended number of skin compartments. The results are shown in the table below with the values representing the mass of tacrolimus per mass of skin (ng API/mg skin).
Figure imgf000025_0001
It was observed that the formulation according to the invention had better skin penetration than Protopic. Formulations VII and XII according to the invention were also compared with
Protopic® in the Hamburg model. The results are shown in the table below.
Figure imgf000025_0002
The penetration of the 0.1 wt% tacrolimus formulation I and the 0.03 wt% tacrolimus formulations was also compared with 0.03 wt% Protopic®. The results are shown for skin layers 4 to 6 in the table below.
Figure imgf000025_0003
This confirmed that formulations according to the invention have acceptable skin penetration.
Pharmacokinetic data
Formulations III and I were selected for pig pharmacokinetic studies and compared with Protopic®. Five naive male Gottingen minipigs were used for each formulation. Formulations were applied to 10 % of the body surface and removed after 8 hours. The last of a total of 14 sampling time points was after 76 hours. The results are shown in the Table below.
Figure imgf000026_0001
In the example of formulation XIII, isopropyl myristate (solubility 4.1 mg/mL) was used as the only solvent (together with paraffin as anti-solvent), resulting in a high degree of saturation of around 90%. This is in contrast to the examples shown above with higher solubility in the oil phase and, accordingly, lower saturation.
Composition of formulation XIII
Ingredient Commercial Name Formulation XIII
Tacrolimus 0,10
Steareth-2 Brij S2SO 1 ,00
Liquid paraffin Pionier 2071 10,00
Isopropyl myristate 30,00
Steareth-21 Brij S751 0,15
Phenoxyethanol 0,75
Xanthan gum Xantural 180 0,50
Citric buffer pH 4,5 57,50
Formulation XIII was investigated for skin penetration in the Hamburg model and compared with Protopic® ointment 0.1 %. As shown in the table below, a higher degree of penetration into the skin compartments was found for formulation XII as compared to Protopic® ointment.
Figure imgf000027_0001
In an exploratory study, formulation XIII was selected for pig pharmacokinetic studies and compared with Protopic® ointment 0.1 %. Two naive male Gottingen minipigs were used for each formulation. Formulations were applied to 10 % of the body surface and removed after 8 hours. The last of a total of seven sampling time points was after 24 hours. The systemic exposure, both in Cmax and AUC was significantly higher than for Protopic® which may be attributed to the higher degree of saturation in formulation XIII.
Figure imgf000027_0002
Comparative stability - Example 1
The chemical stability of tacrolimus in formulations I and III according to the invention was compared with that of tacrolimus in two formulations according to US
2013/0116271.
The two formulations selected from US 2013/0116271 were Example B and G, which have the compositions set out in the table below.
Figure imgf000027_0003
Figure imgf000028_0001
Samples of each of the formulations tested were stored for 24 weeks at either 5°C, 25°C, 40°C or 50°C. After storage, the amount of the regio-isomer degradation product in the formulations was determined using UPLC and mass spectrometry. The results (% tacrolimus regioismer relative to tacrolimus) are given in the table below.
Figure imgf000028_0002
n.d. - not detected
It was found that tacrolimus was significantly more chemically stable when
formulated in the pharmaceutical composition according to the invention compared with the formulations of US 2013/0116271. Comparative stability - Example 2
The chemical stability of tacrolimus in formulations III, VIII, IX, X and XI according to the invention was compared with that of tacrolimus in formulation according to WO 2017/174530.
The two formulations from WO 2017/174530 tested correspond to Sample 1 in that document. It is not stated in WO 2017/174530 whether Sample 1 is homogenised or stirred, and accordingly both homogenised and stirred versions of Sample 1 of WO 2017/174530 were prepared for comparison. The formulations of these two comparative Samples 1 are set out in the Table below.
Figure imgf000029_0001
Samples of each of the formulations tested were stored for 6 weeks at either 5°C, 25°C, 40°C or 50°C. After storage, the amount of the regio-isomer degradation product and the amount of the 8-epimer degradation product in the formulations was determined using UPLC and mass spectrometry. The results are given in the table below.
Figure imgf000029_0002
Figure imgf000030_0001
It was found that tacrolimus was significantly more chemically stable with respect to degradation to the regio-isomer and the 8-epimer when formulated in the pharmaceutical composition according to the invention compared with the formulation of WO 2017/174530.

Claims

1. A pharmaceutical composition which is an oil-in-water emulsion comprising oil-phase droplets dispersed in an aqueous phase,
wherein at least a proportion of the oil-phase droplets contains:
(i) a macrolide compound which is tacrolimus, or a
pharmaceutically acceptable salt or solvate thereof;
(ii) a solvent in which the macrolide compound is soluble; and
(iii) an antisolvent in which the macrolide compound is not soluble; wherein the oil-in-water emulsion further comprises (a) a first emulsifier and a second emulsifier, wherein the first emulsifier is more hydrophilic than the second emulsifier, or (b) a polymeric emulsifier and a non-polymeric emulsifier, and
wherein the oil-in-water emulsion comprises water in an amount of from 30.0 to 75.0 wt% based on the total weight of the pharmaceutical composition.
2. A pharmaceutical composition according to claim 1 , wherein the first emulsifier has a hydrophilic-lipophilic balance (HLB) value of 8.0 or greater.
3. A pharmaceutical composition according to claim 1 or 2, wherein the second emulsifier has a hydrophilic-lipophilic balance (HLB) value of 6.0 or less.
4. A pharmaceutical composition according to any one of the preceding claims, wherein the first emulsifier is Steareth-21 , PEG-8 dioleate, Sorbitan Laurate, PEG-40 Sorbitan Peroleate, Laureth-4, PEG-7 Glyceryl Cocoate, PEG-20 Almond
Glycerides, PEG-25 Hydrogenated Castor Oil, Stearamide MEA, Polysorbate 85, PEG-7 Olivate, Cetearyl Glucoside, PEG-8 Oleate, Polyglyceryl-3 Methyglucose Distearate, Oleth-10, Oleth-10 / Polyoxyl 10 Oleyl Ether NF, Ceteth-10, PEG-8 Laurate, Cocamide MEA, Polysorbate 60 NF, Polysorbate 60, Polysorbate 80, lsosteareth-20, PEG-60 Almond Glycerides, Polysorbate 80 NF, PEG-20 Methyl Glucose Sesquistearate, Ceteareth-20, Oleth-20, Steareth-20, Ceteth-20, Isoceteth- 20, Polysorbate 20, Polysorbate 20 NF, Laureth-23, PEG-100 Stearate, Steareth- 100 or PEG-80 Sorbitan Laurate.
5. A pharmaceutical composition according to any one of the preceding claims, wherein the second emulsifier is Steareth-2, Glycol Distearate, Sorbitan Trioleate, Propylene Glycol Isostearate, Glycol Stearate, Sorbitan Sesquioleate, Glyceryl Stearate, Sorbitan Oleate, Sorbitan Monostearate NF, Sorbitan Stearate, Sorbitan Isostearate, Steareth-2, Oleth-2, Glyceryl Laurate, Ceteth-2, PEG-30
Dipolyhydroxystearate, Glyceryl Stearate SE or PEG-4 Dilaurate.
6. A pharmaceutical composition according to any one of the preceding claims wherein the first emulsifier is Steareth-21 and the second emulsifier is Steareth-2.
7. A pharmaceutical composition according to any one of the preceding claims wherein:
the first emulsifier is present in an amount of from 0.01 to 2.0 wt% based on the total weight of the pharmaceutical composition; and/or
the second emulsifier is present in an amount of from 0.1 to 5.0 wt% based on the total weight of the pharmaceutical composition.
8. A pharmaceutical composition according to claim 1 , wherein (i) the polymeric emulsifier is Pemulen TR-1 NF or Pemulen TR-2 NF and/or (ii) the non-polymeric emulsifier is as defined for the first or second emulsifier in any one of claims 1 to 6.
9. A pharmaceutical composition according to any one of the preceding claims, wherein the solubility of the macrolide compound in the antisolvent is 1.0 mg/mL or less at 25°C, preferably 0.1 mg/mL or less at 25°C.
10. A pharmaceutical composition according to any one of the preceding claims, wherein the antisolvent is liquid paraffin, petrolatum, liquid wax, a silicone or a mixture thereof, preferably wherein the antisolvent is liquid paraffin.
11. A pharmaceutical composition according to any one of the preceding claims, wherein the antisolvent is present in an amount of from 5.0 to 30.0 wt% based on the total weight of the pharmaceutical composition.
12. A pharmaceutical composition according to any one of the preceding claims, wherein the solubility of the macrolide compound in the solvent is 10.0 mg/mL or greater at 25°C, preferably 15.0 mg/mL or greater at 25°C.
13. A pharmaceutical composition according any one of the preceding claims, wherein the solvent comprises:
(i) one or more triglycerides, optionally in an amount of from 10.0 to 30.0 wt% based on the total weight of the pharmaceutical composition; and/or
(ii) an ester of a mono- or di-carboxylic acid, which ester comprises at least 4 carbon atoms, optionally in an amount of from 5.0 to 20.0 wt% based on the total weight of the pharmaceutical composition.
14. A pharmaceutical composition according to claim 13, wherein the one or more triglycerides comprise a compound of formula
Figure imgf000033_0001
wherein:
R is a linear or branched C4-18 hydrocarbyl group;
R' is a linear or branched C4-18 hydrocarbyl group; and
R" is a linear or branched C4-18 hydrocarbyl group.
15. A pharmaceutical composition according to claim 13 or 14, wherein the one or more triglycerides are medium chain triglycerides.
16. A pharmaceutical composition according to any one of claims 13 to 15, wherein the ester is a compound of formula
RA-C(0)0-RB or RB-0C(0)-Rc-C(0)0-RB, wherein:
RA is a linear or branched C4-18 hydrocarbyl group;
each RB is independently a linear or branched C1 -6 alkyl group; and
Rc is a linear or branched divalent C1 -8 hydrocarbyl group.
17. A pharmaceutical composition according to any one of claims 13 to 16, wherein the ester is diisopropyl adipate, diethyl sebacate, isopropyl myristate or isopropyl palmitate.
18. A pharmaceutical composition according to any one of the preceding claims, wherein the solvent comprises:
medium chain triglycerides in an amount of from 10.0 to 30.0 wt% based on the total weight of the pharmaceutical composition; and
diisopropyl adipate in an amount of from 5.0 to 20.0 wt% based on the total weight of the pharmaceutical composition.
19. A pharmaceutical composition according to any one of the preceding claims, wherein the pH of the pharmaceutical composition is from 3.5 to 5.5.
20. A pharmaceutical composition according to any one of the preceding claims, wherein the oil-in-water emulsion further comprises a chelating agent, preferably wherein the chelating agent is citrate, tartrate or EDTA.
21. A pharmaceutical composition according to any one of the preceding claims, wherein the macrolide compound is tacrolimus monohydrate.
22. A pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is suitable for topical administration to the skin.
23. A pharmaceutical composition according to any one of the preceding claims, wherein the oil-in-water emulsion comprises:
tacrolimus monohydrate;
diisopropyl adipate;
citric acid or triethyl citrate;
mid chain triglycerides;
liquid paraffin;
steareth-2; steareth-21 ; and
water.
24. A pharmaceutical composition according to any one of the preceding claims which is an oil-in-water emulsion comprising oil-phase droplets dispersed in an aqueous phase,
wherein substantially all of the oil-phase droplets contain:
(i) a macrolide compound which is tacrolimus, or a pharmaceutically acceptable salt or solvate thereof, in an amount of from 0.005 to 0.3 wt%;
(ii) a solvent which is medium chain triglycerides in an amount of from 17.5 to 25.0 wt% and optionally diisopropyl adipate in an amount of from 10.0 to 12.5 wt%; and
(iii) an antisolvent which is liquid paraffin in an amount of from 10.0 to 30.0 wt%;
and wherein:
the oil-in-water emulsion further comprises a first emulsifier which is steareth-21 in an amount of from 0.1 to 0.2 wt% and a second emulsifier which is steareth-2 in an amount of from 1.5 to 2.5 wt%;
the oil-in-water emulsion comprises a water phase in an amount of from 40.0 to 60.0 wt% based on the total weight of the pharmaceutical composition;
the medium chain triglycerides are compounds of formula:
Figure imgf000035_0001
where R is a linear C6-12 alkyl group, R' is a linear C6-12 alkyl group and R" is a linear C6-12 alkyl group; and
the amounts are based on the total weight of the pharmaceutical composition.
25. A pharmaceutical composition as defined in any one of the preceding claims for use in the treatment of the human or animal body.
26. A pharmaceutical composition as defined in any one of claims 1 to 24 for use in the treatment or prevention of atopic dermatitis, atopic eczema, psoriasis, vitiligo or lichen sclerosus.
27. Use of a pharmaceutical composition as defined in any one of claims 1 to 24 in the manufacture of a medicament for use in the treatment or prevention of atopic dermatitis, atopic eczema, psoriasis, vitiligo or lichen sclerosus.
28. A method for treating or preventing a disease selected from the group consisting of atopic dermatitis, atopic eczema, psoriasis, vitiligo or lichen sclerosus in a patient in need thereof, which method comprises applying a pharmaceutical composition as defined in any one of claims 1 to 24 to the skin of the patient.
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