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WO2024209073A1 - Formulation de nanoémulsion présentant une stabilité de tacrolimus et une pénétration cutanée améliorées - Google Patents

Formulation de nanoémulsion présentant une stabilité de tacrolimus et une pénétration cutanée améliorées Download PDF

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Publication number
WO2024209073A1
WO2024209073A1 PCT/EP2024/059365 EP2024059365W WO2024209073A1 WO 2024209073 A1 WO2024209073 A1 WO 2024209073A1 EP 2024059365 W EP2024059365 W EP 2024059365W WO 2024209073 A1 WO2024209073 A1 WO 2024209073A1
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Prior art keywords
formulation
months
nanoemulsion
tacrolimus
active agent
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PCT/EP2024/059365
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English (en)
Inventor
Montserrat FOGUET
Mirella Gwarek
Lars MÖLLMANN
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Biofrontera Bioscience GmbH
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Biofrontera Bioscience GmbH
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Priority claimed from PCT/EP2023/059292 external-priority patent/WO2024208434A1/fr
Application filed by Biofrontera Bioscience GmbH filed Critical Biofrontera Bioscience GmbH
Priority to AU2024249973A priority Critical patent/AU2024249973A1/en
Priority to CN202480024241.1A priority patent/CN120981222A/zh
Publication of WO2024209073A1 publication Critical patent/WO2024209073A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/046—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/12—Aerosols; Foams
    • A61K9/124—Aerosols; Foams characterised by the propellant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
    • A61K2800/21—Emulsions characterized by droplet sizes below 1 micron
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A61K8/062—Oil-in-water emulsions
    • 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
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams

Definitions

  • Nanoemulsion formulation with improved Tacrolimus stability and skin penetration with improved Tacrolimus stability and skin penetration
  • the present invention relates to a composition
  • a composition comprising an oil in water nanoemulsion and a highly lipophilic macrolide lactone as an active agent, such as tacrolimus, dissolved in the nanoemulsion.
  • an active agent such as tacrolimus
  • tacrolimus can be fully dissolved, rather than suspended, and shows an improved stability in terms of active substance content, pH, particle size and particle size homogeneity.
  • Dispersions are colloidal systems, which include micelles, liposomes, virosomes, emulsions and micro-, nanoemulsions, suspensions and polymer solutions.
  • Emulsions or micro emulsions can be oil in water, water in oil or middle phased dispersions, often containing surfactants as emulsifiers.
  • Nanoemulsions are a subgroup of the emulsions that contain very fine oil in water dispersions. Nanoemulsions are highly homogeneous, transparent, and slightly opalescent.
  • the dispersed droplets (liquid) or vesicles in such emulsions are composed of a lipid core surrounded by at least one surfactant or emulsifier monolayer.
  • Nanoemulsions are characterized by a mean particle or vesicle size of less than 200 nm, often less than 100 nm and a narrow monodisperse particle or vesicle size distribution.
  • Nanoemulsions are generally thermodynamically more stable than conventional emulsions, they are often not stable in stress situations such as high temperature or freezing conditions. Nanoemulsions can be in a metastable state and the structure depends often on the manufacturing process, making them complicated to formulate to a pharmaceutical composition with a long shelf-life under different storage conditions. If destabilized they can become heterogeneous, milky and/or exhibit phase separation. On the other side, nanoemulsions can provide useful applications in skin care in that they may exhibit good textural and sensual properties due to the very fine droplet or globule size.
  • Nanoemulsions are often manufactured by mechanical fragmentation of an oily phase in an aqueous phase in the presence of a surfactant.
  • the very small size of the oily globules is often obtained by virtue of at least one pass through a high-pressure homogenizer or a sonicator.
  • Tacrolimus (also termed herein “TC”) is a macrolide lactone molecule harvested from the soil bacterium Streptomyces tsukubaensis. In pharmaceutical medicine, it is described as a calcineurin inhibitor with immunosuppressant capacity. It is applied topically to treat immune system mediated skin conditions such as atopic dermatitis or psoriasis.
  • TC is a molecule with a molecular weight of 804.03 g/mol and very lipophilic properties (logP > 3), i.e. by six orders of magnitude more lipophilic than ALA. Due to its very lipophilic nature, TC has been formulated in mixtures of mineral oil, paraffin, propylene carbonate, white petrolatum and white wax. TC in aqueous compositions has been formulated as suspensions and it has previously been found to
  • SUBSTITUTE SHEET (RULE 26) be weakly stable in aqueous formulations (approx. 3 months at room temperature or up to 9 months at 5°C).
  • Liquid formulations of TC in predominately water-based systems have not been commercialized as finished drug product by pharmaceutical companies so far, likely hampered by the challenges of solubilizing and stabilizing it in such formulations.
  • a topical formulation of TC two additional challenges exist. The first being the high lipophilicity, which may hinder its release from a fat-based formulation into the skin. The other being its weak ability to distribute in the skin’s watery compartments (such as living cells).
  • a first aspect of the invention relates to a formulation comprising (a) a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1 ) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol; and (b) an active agent, wherein the active agent is a highly lipophilic macrolide lactone.
  • Another aspect of the invention relates to the formulation of the first aspect for use in medicine.
  • Another aspect of the invention relates to the formulation of the first aspect for use a method of treatment or prevention of a dermatological, ophthalmic or autoimmune disease or condition, or for the prevention of organ rejection after transplantation.
  • the terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, Leuenberger, H.G.W, Nagel, B. and Kdlbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
  • Formulating a pharmaceutical composition is a highly complex process, which needs to take account of different aspects, such as pH, solubility, polymorphism, applicability, and overall stability of the pharmaceutical composition. Additionally, one must consider the benefits and constraints of the active pharmaceutical ingredient (API), excipients, the interaction of all components and the manufacturing process.
  • API active pharmaceutical ingredient
  • oil in water nanoemulsion formulations there are two different phases, which may need to be stabilized and compliant with patients: one is the hydrophobic carrier component, which is usually the carrier and needs to stabilize and release the API and the other one the aqueous component. All these aspects lead to complex formulations with a large number of ingredients.
  • One rather attractive property oil in water nanoemulsion formulations is its ability to enhance penetration of active ingredients.
  • aqueous pharmaceutical formulations of TC as suspensions with short stability (approx. 3 months at room temperature or up to 9 months at 5°C).
  • prior art fails to teach a pharmaceutical aqueous composition able to solubilize tacrolimus, a highly lipophilic active agent. Furthermore, prior art fails to teach aqueous formulations (in solution or suspension) for tacrolimus with an extended stability over 24 months.
  • nanoemulsions tend to coalesce under certain circumstances, such as exposure to extreme temperature differences, leading to bigger droplet sizes and harm the nanoemulsion quality.
  • active agent includes an active pharmaceutical agent (herein also termed “pharmaceutical active agent” or “active pharmaceutical ingredient”, “API”) and an active cosmetic agent (herein also termed “cosmetic active agent”).
  • an active pharmaceutical agent is defined as the chemical, biological, mineral or any other entity or component responsible for the therapeutic (pharmacological, physiological, physical, etc.) effects in a product.
  • an active cosmetic agent is defined as the chemical, biological, mineral or any other entity or component responsible for the cosmetic effects in a product.
  • the active agent may be a plant extract.
  • the active agent may be present as a pharmaceutically acceptable salt.
  • the active agent may be present as a cosmetically acceptable salt.
  • compositions of the invention comprise two phases:
  • a first aspect of the invention relates to a formulation comprising
  • a carrier component comprising:
  • highly lipophilic refers to a compound having a logP value that is at least 3, wherein P is the octanol-water partition-coefficient.
  • the active agent has a logP value of 3 or higher, such as 3.0 to 7.0 or 3.0 to 5.0.
  • the term “macrolide lactone” refers to a compound comprising or consisting of a macrocyclic lactone ring.
  • One or more deoxy sugars can be attached to the lactone ring.
  • the macrocyclic lactone ring comprises at least one cyclic half acetal, one 1 ,2-dicarbonyl substructure as well as one piperidine substructure.
  • the macrocyclic lactone ring comprises two methoxy ligands at position 14 and 16.
  • the macrolide lactone is not halogenated.
  • the active agent has immunosuppressant capacity.
  • the active agent is Tacrolimus, Pimecrolimus, Everolimus or Sirolimus, preferably Tacrolimus, a derivative, an isomeric form, a tautomeric form, a precursor, a metabolite, hydrate, and/or a pharmaceutically acceptable salt thereof.
  • Tacrolimus also termed “TC” herein, is identified by CAS number 104987-1 1 -3 and has the following chemical formula:
  • Tacrolimus is a macrolide lactone molecule harvested from the soil bacterium Streptomyces tsukubaensis. In pharmaceutical medicine, it is described as a calcineurin inhibitor with immunosuppressant capacity. It is applied topically to treat immune system mediated skin conditions such as atopic dermatitis or psoriasis.
  • TC is a molecule with a molecular weight of 804.03 g/mol and very lipophilic properties (logP > 3), i.e. by six orders of magnitude more lipophilic than 5-aminolevulinic acid (ALA). Due to its very lipophilic nature, TC has been formulated in mixtures of mineral oil, paraffin, propylene carbonate, white petrolatum and white wax. TC has previously been found to be weakly stable in aqueous formulations (approx. 90 days at room temperature).
  • Formulations of TC in predominately water-based semisolid systems have not been put to pharmaceutical use so far, likely hampered by the challenges of solubilizing and stabilizing it in such formulations.
  • the pharmaceutical use of TC two challenges exist. The first being the high lipophilicity, which may hinder its release from a fat-based formulation into the skin. The other being its weak ability to distribute in the skin’s watery compartments (such as living cells).
  • a precursor of TC is e.g. Pre-Tacrolimus, which has the following chemical formula:
  • Sirolimus is identified by CAS number 53123-88-9 and has the following chemical formula:
  • a precursor of Sirolimus is e.g. Pre- Sirolimus, which has the following chemical formula: Pimecrolimus is identified by CAS number 137071 -32-0.
  • Everolimus is identified by CAS number 159351 -69-6.
  • the formulation is a pharmaceutical formulation.
  • the formulation is a lotion, a spray, a foam, an emulsion, a nanoemulsion, a gel or a cream.
  • the formulation is a lotion.
  • a lotion is a low-viscosity topical preparation intended for application to the skin.
  • a lotion has a lower viscosity than a cream or a gel due to its higher water content.
  • the lotion has a viscosity of ⁇ 8 Pa s (pascal-second), ⁇ 6 Pa s, ⁇ 5 Pa s, ⁇ 4 Pa s, ⁇ 3 Pa s, ⁇ 1 .0 Pa s, or ⁇ 0.5 Pa s.
  • the viscosity is determined as described in the examples section.
  • the formulation may be for topical, ophthalmic or systemic use. In preferred embodiments, the formulation is for topical use.
  • the aqueous component comprises an aqueous phase or forms an aqueous phase.
  • the carrier component comprises or consists of nanovesicles.
  • the carrier component can also be referred to as the lipid phase of the nanoemulsion.
  • the active agent is dissolved in the lipid phase of the nanovesicles. In other words, the active agent is dissolved in the lipid phase of the nanoemulsion.
  • the active agent may be present as a salt, hydrate or derivative.
  • the nanoemulsions and formulations comprising nanoemulsions of the present invention are transparent. Further, the nanoemulsion and formulations comprising nanoemulsions of the present invention can carry active agents such as tacrolimus more efficiently and, thus, become increasingly important in the field of medicine and pharmacy.
  • “Aging” as used herein, refers to alteration, disintegration and/or degradation of the formulation, affecting chemical and physical stability during storage, in particular under stressed conditions. Such physical or chemical changes due to storage may include, but are not limited to Ostwald ripening, flocculation, coalescence and/or breaking, which may lead to a change in vesicle size or polydispersity index.”
  • tacrolimus can surprisingly be dissolved, rather than suspended, in the aqueous formulations of the present invention containing nanoemulsion.
  • the formulations of the present invention are surprisingly stable and resistant to aging.
  • the formulations of the present invention are stable in terms of TC content and particle size and particle size distribution even after storage, for example for 24 months at 2-8°C.
  • duration is described as “one month, two months, three months” etc., this is meant to include embodiments in which the duration is “at least one month, at least two months, at least three months” etc.
  • a “nanovesicle emulsion” or a “nanoemulsion” is a dispersion of oil in water (oil- in-water dispersion, oil-in-water emulsion, O/W emulsion).
  • the nanoemulsion can be monophasic, transparent and/or slightly opalescent.
  • the nanoemulsions of the present invention can be colloidal systems, which include dispersed nanovesicles comprising a lipid core surrounded by at least one surfactant or emulsifier monolayers.
  • the nanoemulsions and the formulations comprising the nanoemulsions of the present invention are characterized by a mean particle or nanovesicle size of less than 500 nm less, than 200 nm, or less than 100 nm.
  • the nanoemulsions and the formulations comprising the nanoemulsions of the present invention has a narrow (homogeneous) nanovesicle size distribution, for example a nanovesicle size distribution characterized by a polydispersity index of less than or equal to 0.4.
  • lipid vesicle As used herein, “nanovesicle”, “nano vesicle”, “lipid vesicles”, “oil droplets”, “droplets” and “oil globules” are interchangeable and refer to small oil droplets in an oil in water emulsion.
  • a lipid vesicle of an average size (see above, e.g., below 500 nm, 200 nm, 100 nm) that is compiled of a monolayer of a surfactant and a lipid core.
  • the nanovesicles can have a size of less than or equal to 500 nm, or less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm.
  • nanoparticle or “nano particle”, is distinguished from “nanovesicles”, and refers to solid particles, which are not described in this invention.
  • the formulation of the present invention may be a formulation which is essentially free of nanoparticles. “Essentially free of nanoparticles” means, that the formulation comprises less than or equal to 2% by weight, or less than or equal to 1% by weight of, or does not comprise nanoparticles. Nanoparticles are mainly inorganic, solid lipids or polymeric solid particles may have a size of below 100 nm, below 200 nm, or below 500 nm. The size can be determined by the methods as described herein. For example, the formulation may be essentially free of nanoparticles with a diameter of less than 100 nm, as determined by dynamic light scattering.
  • topical use or “topical treatment” of the formulation of the invention describes an application to a particular place on or in the body, in particular the human body. This includes, but is not limited to administration of the formulation to body surfaces such as the skin or mucous membranes.
  • the topical use can be epicutaneous, meaning that the formulation is directly administered to the skin.
  • the topical use is a pharmaceutical use.
  • systemic use or “systemic treatment” of the formulation of the invention describes an application in which the active agent is distributed throughout the body via the blood or lymphatic system, for example after an injection or oral intake.
  • the “stability” of a formulation comprising nanovesicles, as described herein includes, but is not limited to the physical and chemical stability.
  • a formulation is stable if the integrity of the nanovesicles is found to be stable.
  • a measure known to the skilled person to describe integrity of the nanovesicles is the size, as for example determined by dynamic light scattering, as described herein.
  • the nanovesicles produced according to the invention can have a size below 100 nm, preferably below 50 nm, more preferably in the range of 20 nm to 30 nm, immediately after manufacture.
  • the formulation as described herein is stable if the nanovesicles in the formulation of the present invention have a size (or diameter) of less than or equal to 500 nm or less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm.
  • “Stability” can also refer to the absence of processes above described as aging, leading to a loss of pharmaceutical functionality or quality.
  • the composition described in this invention is functional or pharmaceutically functional, as long as the vesicle size is less than or equal to 500 nm or less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm.
  • “stability” can refer to the stable content of the active agent, in particular tacrolimus.
  • the content of the active agent is, for example, considered stable if at least 70%, at least 80% or at least 90% of the content of the active agent is still present, when stored, for example, at stressed conditions, as described herein.
  • the content of the active agent may be
  • the active agent of the invention can be stable for at least one month, at least 3 months, at least 6 months, at least 9 months, at least 12 months or at least 24 months, at 2-8°C, or at about 5°C.
  • the formulation of the invention can be stable for at least one month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 24 months, at 2-25°C, at 2-8°C, at 15-25°C, at 25°C or at about 5°C.
  • the formulation of the present invention may have a nanovesicle size of less than or equal to 500 nm, or less than or equal to 300 nm, or less than or equal to 200 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm, when stored for 3 months at 40°C.
  • the formulation of the present invention may have a nanovesicle size of less than or equal to 500 nm, or less than or equal to 300 nm, or less than or equal to 200 nm, preferably in the range of 5 nm to 100 nm, when stored for 24 months at 25°C.
  • the active agent has a content of more than or equal to 80%, preferably more or equal to 85%, more preferably more or equal to 90% when a) stored for one month, two months, three months, six months at 2-25°C; or b) stored for one month, two months, three months, six months, twelve months, eighteen months or twenty-four months at 2-8°C.
  • the nanoemulsion comprises nanovesicles, wherein the nanovesicles have a size of less than or equal to 500 nm, preferably less than or equal to 200 nm, more preferably in the range of 5 nm to 100 nm when a) stored for one month, two months, three months, six months, twelve months, eighteen months, or twenty-four months at 2-25°C; or b) stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months, or thirty-six months at 2-8°C.
  • the polydispersity index of the formulation is less than or equal to 0.4 when a) stored for one month, two months, three months, six months, twelve months, eighteen months, or twenty-four months at 2-25°C. b) stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months, thirty-six months at 2-8°C.
  • the size or diameter of the nanovesicles as described herein can be expressed as the Z-average (also termed “z-average”).
  • the size distribution of the nanovesicles can be characterized by the polydispersity index. These parameters are well known to the skilled person, and are widely used in the art to characterize particle or vesicles in emulsions, suspensions and/or polymeric solutions.
  • the size of the nanovesicles can be determined by dynamic light scattering (also referred as Photon Correlation Spectroscopy (PCS) or Quasi-Elastic Light Scattering (QELS)).
  • dynamic light scattering also referred as Photon Correlation Spectroscopy (PCS) or Quasi-Elastic Light Scattering (QELS)
  • PCS Photon Correlation Spectroscopy
  • QELS Quasi-Elastic Light Scattering
  • the total aqueous component can present in an amount of 50% to 99% w/w, based on the total weight of the nanoemulsion (a), preferably from 70% to 95% (w/w), and more preferably from 75% to 95% (w/w), or 80% to 95%.
  • weight per weight means the weight concentration or mass concentration of a component in a formulation described herein.
  • the weight or mass of a component is expressed as a percentage of a reference formulation.
  • the weight or mass of a component can be expressed as a percentage of the total weight or mass of the formulation of the invention, or as a percentage of the total weight or mass of the nanoemulsion (a).
  • the aqueous component can comprise at least one pH buffering agent. Any suitable buffering agent may be used. Suitable buffering agents are known to the skilled person.
  • the at least one pH buffering agent can be selected from the group consisting of citrate, phosphate, acetate and carbonate.
  • the pH of the aqueous component can be in the range of 2-9.
  • the pH of the aqueous component can also be preferably in the range of 2-6, such as 2, 3, 4, 5 or 6, more preferably in the range of 3-6, such as 3, 4, 5 or 6, or 3-5, such as 3, 4 or 5.
  • the pH of the aqueous component can also be in the range of 4-10, or 5-7, preferably about 7.4.
  • the pH of the formulation is 2- 7, preferably 2-6, more preferably 3-5.
  • the pH of the formulation is 4-10, or 5-7, preferably about 7.4.
  • the at least one lipophilic component can be selected from triglycerides and mixtures thereof.
  • the at least one lipophilic component is a lipid, a synthetic oil, a vegetable oil and/or an animal oil.
  • Suitable lipids according to the present invention are physiologically acceptable lipids such as ceramide, mono-, di- and triacylglycerin (triglycerides).
  • the at least one lipophilic component is a triglyceride, preferably a triglyceride comprising a Cs- fatty acid, or a mixture thereof.
  • the at least one lipophilic component is a caprylic and/or capric triglyceride and/or a mixture thereof, particularly preferably Miglyol (such as Miglyol 812, available e.g., from IOI Oleochemical) or Myritol (such as Myritol 318, available e.g., from BASF).
  • Miglyol such as Miglyol 812, available e.g., from IOI Oleochemical
  • Myritol such as Myritol 318, available e.g., from BASF.
  • Suitable vegetable and animal oils e.g., are sunflower oil, soybean oil, peanut oil, rape oil, fish oil and/or cetaceum.
  • the at least one lipophilic component can be present in an amount of from 0.1% to 30% (w/w) based on the total weight of the nanoemulsion (a), preferably from 0.25% to 15% (w/w), preferably from 0.25% to 10% (w/w), and more preferably from 0.5% to 8% (w/w) or 3% to 8% (w/w). Also preferred is the at least one lipophilic component being present in an amount of from 10 % to 30% (w/w) based on the total weight of the nanoemulsion (a), more preferably 15-30%, or 10-20%.
  • the at least one surfactant may be any suitable surfactant known to the skilled person.
  • HLB hydrophilic/lipophilic balance
  • lipophilic emulsifiers are used for water-in-oil emulsions and hydrophilic emulsifiers for oil-in-water emulsions.
  • emulsifiers or mixtures of them are suited for the preferred vehicles and purpose of the composition.
  • combinations of emulsifiers might be advantageous.
  • a suitable membrane-forming surfactant is a phospholipid, a lysophospholipid, a ceramide and/or a mixture thereof.
  • the phospholipid is lecithin or cephalin from soybeans or hens’ eggs.
  • the at least one surfactant is a phospholipid, more preferably lecithin, most preferably soy lecithin.
  • the phospholipid in particular phosphatidylcholine, the lysophospholipid, the ceramide and/or the mixture thereof can be present in an amount of from 0.1 % to 10% (w/w), based on the total weight of nanoemulsion(a), preferably from 0.15% to 5% (w/w), and more preferably from 0.2% to 3% (w/w) or from 0.2% to 4% (w/w), most preferably from 2.5% to 4% (w/w).
  • the lecithin has a phosphatidylcholine content of at least 80% by weight, more preferably of at least 90% by weight, and most preferably of at least 94% by weight.
  • the quality of the lecithin, namely its phosphatidylcholine content, plays a crucial role for the size of the vesicles of the nanoemulsion. The higher the phosphatidylcholine content of the lecithin, the smaller is the size of the vesicles of the nanoemulsion.
  • anionic, nonionic, cationic and/or amphoteric surfactants are suitable as well as block copolymers.
  • Suitable anionic surfactants are soaps, alkylbenzene sulphonates, alkane sulphonates, alkylsulfates and/or alkyl ether sulfates.
  • Suitable cationic surfactants are quaternary ammonium compounds, preferably having one or two hydrophobic groups (e.g., cetyltrimethylammonium bromide and cetyltrimethylammonium chloride) and/or salts of tong-chain primary amines.
  • a suitable amphoteric surfactant Is N-(acylamidoalkyl)betaine, N-alkyl-p-aminopropionate, phosphate-alkyl-ammonium compounds, and/or amine-N-oxide.
  • a suitable copolymer building block for example, is propylene oxide.
  • a nonionic surfactant is particularly preferred as O/W emulsion-forming surfactant.
  • the surfactant is a polyoxyethylene-type surfactant.
  • the at least one surfactant can be any a polyoxyethylene-type surfactant.
  • a suitable nonionic surfactant can be selected from the group consisting of fatty alcohol polyglycolether, alkylphenol polyglycolether, alkylpolyglucoside, fatty acid glucamide, fatty acid polyglycolether, ethylen oxide-propylene oxide-block polymer, polyglycerol fatty acid ester, fatty acid alcanolamide and (ethoxylated) sorbitane fatty acid ester (sorbitane).
  • a particularly preferred ethoxylated sorbitane fatty acid ester is polyoxyethylene sorbitane monooleate, most preferably Polysorbate 80.
  • the at least one surfactant such as the polyoxyethylene-type surfactant, can be present in an amount of from 0.1 % to 10% (w/w), based on the total weight of the nanoemulsion (a), more preferably from 0.2% to 5% (w/w), and most preferably from 1% to 5% (w/w) or 0.5% to 5% (w/w).
  • the formulation of the invention can comprise as least one hydrophilic surfactant with an HLB of 9 to 17, more preferably 12-16, particularly polysorbate 80 to form a nanoemulsion.
  • the at least one surfactant can be a sugar-based surfactant.
  • Sugar-based surfactants are a group of non-ionic surfactants using hydrophilic sugars to which hydrophobic tails are bound.
  • One common substance of this class is n-dodecyl-p-D-maltoside, a member of the maltoside surfactants so named because the sugar unit used is maltose.
  • An example of a pyranoside surfactant is n-octyl-p-D-thioglucopyranoside. This class uses pyranose as the sugar unit.
  • glycoside surfactants are octyl glucoside, decyl glucoside, and lauryl glucoside.
  • Tween surfactants are based on a sorbitan sugar, which is why they are commonly referred to as polysorbate surfactants.
  • Tween surfactants Three oligo(ethylene glycol) side groups of varying lengths are bound to the sugar increasing the hydrophilicity of the head group. This structure forms the core of all Tween surfactants. They deviate in the hydrophobic tail, which is a fatty acid coupled via an ester to four oligo(ethylene glycol) tail. In Tween 20 this fatty acid is lauric acid; in Tween 80 it is oleic acid.
  • the at least one surfactant is selected from the group consisting of a phospholipid, in particular phosphatidylcholine, a lysophospholipid, a ceramide and/or a mixture thereof.
  • the at least one surfactant is a polyoxyethylene-type surfactant.
  • the at least one surfactant is phosphatidylcholine.
  • the formulation comprises a phospholipid as surfactant and a polyoxyethylene-type surfactant.
  • the formulation comprises phosphatidylcholine as surfactant and a polyoxyethylene-type surfactant.
  • the formulation comprises phosphatidylcholine and polysorbate 80 as surfactants.
  • the at least one surfactant is phosphatidylcholine.
  • the formulation comprises from 0.5% to 5% (w/w), preferably from 1% to 4% (w/w), more preferably from 1 .2% to 3.5% (w/w) phosphatidylcholine.
  • the formulation comprises from 0.1 % to 10% (w/w), preferably from 0.15% to 5% (w/w), more preferably from 0.25% to 4.5% (w/w) phosphatidylcholine.
  • the at least one alcohol comprises at least three carbon atoms.
  • the at least one alcohol preferably independently has 3-5 (i.e. no more than 5) or 3-4 (i.e. no more than 4) carbon atoms.
  • the at least one alcohol can be at least one monohydric alcohol.
  • Particularly suitable alcohols having 5 carbon atoms are 1 - pentanol and/or 4-methyl-2-pentanoL
  • Suitable alcohols having 4 carbon atoms are 1 -butyl alcohol, /so-butyl alcohol (2-methyl-1 -propanol), tert-butyl alcohol (2-methyl-2-propanol) and/or sec-butyl alcohol (2-butanol).
  • the alcohol is not propylene glycol.
  • the at least one alcohol has 3 carbon atoms, i.e. is selected from the group consisting of 1 -propanol or 2-propanol (isopropyl alcohol) and mixtures thereof.
  • a preferred alcohol is 2- propanol.
  • the alcohol may present in an amount of from 0.1 % to 10% w/w based on the total weight of the nanoemulsion (a), preferably from 0.5% to 5% (w/w), and more preferably from 1% to 2% (w/w).
  • the formulation as described herein may comprise a gelling agent. Any suitable gelling agent may be used. Suitable gelling agents and mixtures thereof are known to the skilled person.
  • the gelling agent may be selected from the group consisting of poloxamer, xanthan, bentonite, sodium carboxymethylcellulose, hydroxymethyl cellulose, carbomer, hydroxypropyl cellulose, gellan gum, guar gum, pectin, poly(ethylene)oxide, polycarbophil, alginate, tragacanth, povidone, gelatin, and mixtures thereof.
  • the gelling agent is selected from poloxamer, xanthan and/or mixtures thereof.
  • the gelling agent is xanthan (xanthan gum).
  • the gelling agent is a poloxamer.
  • Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (polyethylene oxide)).
  • Commercially available are Poloxamer 407 and Poloxamer 188.
  • Poloxamer 407 can have an average molecular weight of about 12600 Dalton.
  • Poloxamer 188 can have an average molecular weight of about 8400 Dalton.
  • a preferred poloxamer is Poloxamer 407.
  • the gelling agent may be present in an amount of from 0.1 % to 10% (w/w), based on the total weight of the formulation, preferably from 0.25% to 5% (w/w), and more preferably from 0.5% to 4% (w/w) or 1 % to 4% (w/w).
  • the formulation as described herein may comprise one or more preservatives. Any suitable preservative or a mixture thereof may be used. Suitable preservatives are known to the skilled person.
  • the preservative can be selected from benzoate, tocopherol or derivatives and any mixtures thereof, citric acid, EDTA, potassium sorbate, vitamin C and/or derivatives and any mixtures thereof, wherein the preservative is preferably sodium benzoate.
  • Suitable aqueous mixtures of sodium benzoate and potassium sorbate are commercially available, for example EuxylTM K 712 preservative (Ashland). These components can be part of the aqueous component and/or of the nanovesicles.
  • the preservative can be present in the formulation as described herein in an amount of from 0.01% to 10% (w/w), 0.01 % to 7% (w/w), 0.01% to 5% (w/w), 0.01 % to 3% (w/w) based on the total weight of the formulation, preferably from 0.2% to 2% (w/w) or 0.1 -2% (w/w), and more preferably from 0.2% to 1 .5% (w/w).
  • the formulation of the present invention may be a gel formulation.
  • a ”gel is a two-phase elastic colloidal material, consisting of a dispersed liquid incorporated in the solid phase often constituted by a gelling agent. Suitable gelling agents, such as xanthan, are described herein.
  • the formulation of the present invention may be provided in a container or dispenser. Suitable dispensers and containers are known to the skilled person.
  • the dispenser may be a squeeze tube, comprising the formulation as described herein.
  • the squeeze tube may contain the gel formulation as described herein.
  • the dispenser may also be a metered dose dispenser or a foam dispenser or spray dispenser.
  • the container or dispenser may comprise a propellant, wherein the propellant is provided to pressurize the container or dispenser.
  • a propellant Any suitable propellant may be used. Suitable propellants and mixtures thereof are known to the skilled person.
  • the propellant is selected from propane, isobutane, n-butane and mixtures thereof.
  • the formulation comprises a propellant and is comprised in a pressurized container.
  • the formulation of the present invention comprised in a pressurized container has a high foaming capacity and forms a stable foam (long collapse time) when released from the pressurized container, even in the absence of a fatty alcohol or another foam adjuvant.
  • the formulation of the present invention comprised in a pressurized container is highly stable with regard to nanovesicle size, even in the absence of a gelling agent or in the presence of only low concentrations of a gelling agent.
  • the formulation of the present invention comprised in a pressurized container is highly stable with regard to the concentration of the active agent, even in the absence of a gelling agent or in the presence of only low concentrations of a gelling agent.
  • the formulation of the present invention comprised in a pressurized container is surprisingly resistant to aging at stressed conditions in respect to API content and nanoemulsion vesicle size, compared to a formulation.
  • the term “petrolatum” relates to a semi-solid mixture of hydrocarbons derived from the distillation of petroleum.
  • the hydrocarbons that make up petrolatum mainly comprise at least 25 carbon atoms.
  • the CAS number of petrolatum is 8009-03-8.
  • the formulation of the first aspect of the invention comprises essentially no petrolatum.
  • the formulation of the present invention may be prepared as a foamable formulation.
  • the formulation of the present invention may be prepared as a pressurized formulation, wherein a propellant is provided to pressurize the formulation. Any propellant as described herein can be used.
  • the formulation of the present invention may be prepared as a pressurized, foamable formulation, wherein a propellant is provided to pressurize the formulation. Any propellant as described herein can be used.
  • the formulation of the invention may be provided in a foam dispenser, as described herein.
  • the foam dispenser comprises a container, wherein said container comprises the formulation as described herein, and a propellant.
  • the propellant is provided to pressurize the foam dispenser. Any suitable propellant may be used, as described herein.
  • a foam-generating device is mounted on the container.
  • the formulation is prepared as a foamable formulation.
  • Said foamgenerating device can comprise a valve for releasing and dosing of the formulation, and a push button for actuating the valve. Upon actuating the push button, the formulation can be released and can form a foam.
  • Suitable dispensers are known to the skilled person.
  • the formulation of the invention may be provided in a spray dispenser, as described herein.
  • the spray dispenser comprises a container, wherein said container comprises the formulation as described herein, and a propellant.
  • the propellant is provided to pressurize the spray dispenser. Any suitable propellant may be used, as described herein.
  • a spray-generating device is mounted on the container.
  • the formulation is prepared as a sprayable formulation.
  • the invention also provides a foam, comprising the formulation of the present invention, as described herein.
  • the active agent in the formulation of the invention is a highly lipophilic active agent, such as tacrolimus.
  • the active agent may be present in an amount of from 0.001% to 25%, 20%, 15%, 10% or 5% w/w, based on the total weight of the formulation.
  • the active agent may be present in an amount of from 0.001% to 10% w/w, based on the total weight of the formulation, 0.005% to 5%, or 0.01% to 0.5% w/w, based on the total weight of the formulation.
  • the formulation is a topical formulation and the active agent is present in an amount of from 0.001% to 0.5% w/w, preferably 0.005% to 0.2% w/w, more preferably 0.01% to 0.1 % w/w, based on the total weight of the formulation.
  • the formulation is a systemic formulation and the active agent is present in an amount of from 0.005% to 25% w/w, preferably 0.01% to 10% w/w, more preferably 0.01% to 5% w/w, even more preferably 0.01% to 2% w/w, based on the total weight of the formulation.
  • the systemic formulation may be a formulation for injection or an oral formulation.
  • the systemic formulation is diluted with a pharmaceutically acceptable buffer prior to injection, resulting in a final concentration of 0.01 % to 1% w/w based on the total weight of the formulation.
  • the formulation is an ophthalmic formulation, in particular eyes drops, and the active agent is present in an amount of from 0.001% to 0.5% w/w, preferably 0.005% to 0.2% w/w, more preferably 0.01% to 0.1 % w/w, based on the total weight of the formulation.
  • the formulation of the invention comprises essentially no fatty alcohol.
  • the expression “comprises essentially no” “is essentially free of’ specifies that the formulation is either free of a compound or comprises less than 0.5% (w/w), less than 0.4% (w/w), less than 0.3% (w/w), less than 0.2% (w/w), less than 0.1% (w/w), less than 0.08% (w/w), less than 0.07% (w/w), less than 0.06% (w/w), less than 0.05% (w/w), less than 0.04% (w/w), less than 0.03% (w/w), less than 0.02% (w/w), or less than 0.01% (w/w) of a compound based on the total weight of the formulation.
  • Fatty alcohols have been described to work as foam adjuvants. They are used in prior art formulations, in particular in foamable formulations.
  • the formulation comprises essentially no fatty alcohol and essentially no fatty acid.
  • fatty alcohol relates to alcohols having at least 6 carbon atoms, usually 6-28 carbon atoms. Fatty alcohols can be saturated or unsaturated and unbranched or branched. Fatty alcohols are usually straight-chain primary alcohols.
  • fatty alcohol as used herein relates to fatty alcohols in their standalone form and does not include esters comprising fatty alcohols.
  • fatty acids relates to carboxylic acids with an aliphatic chain of at least 6 carbon atoms, usually 6-28 carbon atoms. Fatty acids can be saturated or unsaturated and unbranched or branched. Most naturally occurring fatty acids have an unbranched chain of carbon atoms.
  • fatty acid as used herein relates to fatty acids in their standalone form and does not include esters comprising fatty acids.
  • the formulation is either free of a fatty alcohol (in its standalone form, or in other words as isolated molecule) or comprises less than 0.5% (w/w), less than 0.4% (w/w), less than 0.3% (w/w), less than 0.2% (w/w), less than 0.1 % (w/w), less than 0.08% (w/w), less than 0.07% (w/w), less than 0.06% (w/w), less than 0.05% (w/w), less than 0.04% (w/w), less than 0.03% (w/w), less than 0.02% (w/w), or less than 0.01% (w/w) of a fatty alcohol (in its standalone form, or in other words as isolated molecule) based on the total weight of the formulation.
  • the formulation is either free of a fatty acid and a fatty alcohol (in their standalone form, or in other words as isolated molecules) or comprises less than 0.5% (w/w), less than 0.4% (w/w), less than 0.3% (w/w), less than 0.2% (w/w), less than 0.1% (w/w), less than 0.08% (w/w), less than 0.07% (w/w), less than 0.06% (w/w), less than 0.05% (w/w), less than 0.04% (w/w), less than 0.03% (w/w), less than 0.02% (w/w), or less than 0.01% (w/w) of a fatty acid and a fatty alcohol (in their standalone form, or in other words as isolated molecules) based on the total weight of the formulation.
  • the formulation comprises essentially no foam adjuvant.
  • the formulation can be free of foam adjuvant or comprises less than 0.5% (w/w), less than 0.4% (w/w), less than 0.3% (w/w), less than 0.2% (w/w), less than 0.1 % (w/w), less than 0.08% (w/w), less than 0.07% (w/w), less than 0.06% (w/w), less than 0.05% (w/w), less than 0.04% (w/w), less than 0.03% (w/w), less than 0.02% (w/w), or less than 0.01 % (w/w) of a foam adjuvant based on the total weight of the formulation.
  • the term “foam adjuvant” relates to compounds capable of increasing the foaming capacity of a formulation and/or stabilizing a foam.
  • the term “foam adjuvant” relates to fatty acids and fatty alcohols having at least 6 carbon atoms.
  • the formulation of the present invention may comprise or consist of:
  • an aqueous component present in an amount of 70% to 95% w/w, based on the total weight of the nanoemulsion (a).
  • the formulation can comprise two surfactants, more preferably soy lecithin and Polysorbate 80.
  • the at least one phospholipid, the at least one polyoxyethylene-type surfactant, the C3 to C 5 alcohol, the triglycerides, and the at least one preservative may be independently selected according to the herein-described disclosure.
  • formulation of the present invention may comprise, essentially consist of or consist of:
  • an aqueous component present in an amount of 70% to 95% w/w, based on the total weight of the nanoemulsion (a).
  • the formulation can comprise two surfactants, more preferably soy lecithin and Polysorbate 80.
  • the at least one phospholipid, the at least one polyoxyethylene-type surfactant, the C3 to C 5 alcohol, the triglycerides, and the at least one preservative may be independently selected according to the herein-described disclosure.
  • This formulation may comprise further components selected from EDTA, a-tocopheryl acetate and citric acid. These components can be part of the aqueous component and/or of the nanovesicles.
  • the formulation of the present invention may comprise or consist of:
  • an aqueous component present in an amount of 70-95% w/w, based on the total weight of the nanoemulsion (a).
  • a propellant wherein the formulation is comprised in a pressurized container and wherein the propellant is provided to pressurize the container to provide a pressurized formulation.
  • the present invention also relates to a nanovesicle, comprising, essentially consisting of or consisting of
  • a preferred nanovesicle of the invention comprises essentially consists of or consists of
  • the present invention also relates to a nanoemulsion, comprising, essentially consisting of or consisting of
  • aqueous phosphate buffer for example aqueous 5-100 mM phosphate buffer, pH 2-8, preferably pH 2-7, more preferably pH 2-5, ad 100%.
  • a preferred nanoemulsion of the present invention comprises, essentially consists of or consists of:
  • aqueous phosphate buffer (5 mM to 100 mM, preferably 10 mM to 50 mM), pH 6, ad 100%.
  • BF200 This nanoemulsion is termed herein “BF200”.
  • the BF200 nanoemulsion can be obtained by contacting a mixture of ingredients (a)-(d) in a total amount of 10% w/w and 90% w/w of an aqueous 10 mM phosphate buffer, pH 6, under condition allowing formation of a nanoemulsion, thereby forming the nanoemulsion.
  • An exemplary method for manufacture of the BF200 formulation is described in Example 1.
  • Another preferred nanoemulsion of the present invention comprises, essentially consists of or consists of:
  • BF215 This nanoemulsion is termed herein “BF215”.
  • the BF215 nanoemulsion can be obtained by contacting a mixture of ingredients (a)-(d) in a total amount of 15 % w/w and 85 % w/w of an aqueous 10 mM phosphate buffer, pH 6, under condition allowing formation of a nanoemulsion, thereby forming the nanoemulsion.
  • An exemplary method for manufacture of the BF215 formulation is described in Example 1.
  • Yet another preferred nanoemulsion of the present invention comprises, essentially consists of or consists of:
  • BF220 This nanoemulsion is termed herein “BF220”.
  • the BF220 nanoemulsion can be obtained by contacting a mixture of ingredients (a)-(d) in a total amount of 20% w/w and 80% w/w of an aqueous 10 mM phosphate buffer, pH 6, under condition allowing formation of a nanoemulsion, thereby forming the nanoemulsion.
  • An exemplary method for manufacture of the BF220 formulation is described in Example 1.
  • Yet another aspect of the present invention relates to the formulations, as described herein, for use in medicine.
  • Yet another aspect of the present invention relates to the formulations as described herein for use in medicine.
  • Yet another aspect of the present invention relates to the formulations as described herein, for use in a method of treatment and/or prevention of a dermatological, ophthalmic or autoimmune disease or condition, or for the prevention of organ rejection after transplantation.
  • the dermatological disease or condition to be treated with the formulation as described herein may include, but is not limited to, diseases or conditions of the skin, skin appendages or mucosa.
  • the dermatological disease or condition to be treated with the formulation as described herein may be selected from the group consisting of inflammatory, neoplastic, proliferative, infectious, and/or autoimmune diseases or conditions, and/or the cutaneous manifestation thereof, and/or diseases associated with single lesions or fields of lesions, neoplastic, proliferative and/or inflammatory changes.
  • the inflammatory dermatological disease or condition to be treated with the formulation as described herein may be selected from the group consisting of dermatitis, contact dermatitis, acne, atopic dermatitis, eczema, pustular dermatitis, seborrheic dermatitis, perioral dermatitis, chronic wound, urticaria, skin ulcer, rosacea, rash, drug eruptions, toxic epidermal necrolysis; erythema multiforme, erythema nodosum, granuloma annulare, and other cutaneous manifestations of inflammation.
  • the dermatological disease or condition may be an autoimmune dermatological disease or condition.
  • the autoimmune dermatological disease or condition, or the cutaneous manifestation of the autoimmune condition to be treated with the formulation as described herein, may be selected from the group consisting of psoriasis, pemphigus, systemic lupus erythematodes, lichen planus, morphea, sclerodermia, epidermolysis bullosa, dermatomyositis, graft-versus-host syndrome.
  • organ rejections after organ transplants such as heart, kidney, liver, lung transplants.
  • the ophthalmic disease or condition to be treated with the formulation as described herein may be selected from the group consisting of keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), dry-eye, corneal endothelial rejection after corneal transplantation.
  • ATC keratoconjunctivitis
  • VKC vernal keratoconjunctivitis
  • dry-eye dry-eye
  • corneal endothelial rejection after corneal transplantation corneal endothelial rejection after corneal transplantation.
  • Yet another aspect of the present invention is a method for the preparation of the formulation as described herein, comprising the following steps:
  • step (c) contacting the mixture obtained in step (a) with an aqueous component, under conditions allowing formation of a nanoemulsion.
  • the conditions allowing formation of the nanoemulsion may include mixing both phases at an appropriate temperature and stirring in a fashion to form nanovesicle.
  • suitable temperature and stirring conditions A vesicle size of less than or equal to 500 nm or less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm can be obtained.
  • the nanoemulsion of the present invention according to step (b) can be prepared without the use of high energy methods, which are well known in the art.
  • High energy method includes high-pressure homogenization, microfluidization, and ultrasonication (Prev Nutr Food Sci. 2019 Sep; 24(3): 225-234).
  • the method comprises a step of adding a lipophilic active agent to the lipid phase until complete solution.
  • the active agent is tacrolimus.
  • the method for the preparation the pharmaceutical formulation of the present invention can further comprise:
  • dispenser product or container product comprising the formulation as described herein.
  • the formulation of the present invention is provided in a container or dispenser.
  • Suitable dispensers and containers are known to the skilled person.
  • the dispenser may be a squeeze tube, comprising the formulation as described herein.
  • the squeeze tube may contain the gel formulation as described herein.
  • the dispenser may also be a metered dose dispenser or a foam dispenser or a spray dispenser.
  • the container or foam dispenser or spray dispenser may comprise a propellant, wherein the propellant is provided to pressurize the container or foam dispenser or spray dispenser.
  • a propellant Any suitable propellant may be used. Suitable propellants and mixtures thereof are known to the skilled person.
  • the propellant is selected from propane, isobutane, n-butane and mixtures thereof.
  • the dispenser product may be a foam dispenser or spray dispenser product, comprising a foam dispenser or spray dispenser, as described herein, the foam dispenser or spray dispenser comprises a container, wherein said container comprises the formulation as described herein, and a propellant.
  • the propellant is provided to pressurize the foam dispenser or spray dispenser. Any suitable propellant may be used, as described herein.
  • a foam-generating device or spraygenerating device is mounted on the container.
  • the formulation is prepared as a foamable formulation.
  • Yet another aspect of the present invention is the use of the formulation of the present invention, as described herein, for the manufacture of a medicament for topical or systemic treatment and/or prevention of a dermatological, ophthalmic, or autoimmune disease or condition in a subject or for prevention of organ rejection after transplantation.
  • Yet another aspect of the present invention is a method of treatment and/or prevention of a dermatological disease or condition in a subject, said method comprising administering to the subject, a pharmaceutically effective amount of the formulation as described herein.
  • the dermatological disease is a dermatological disease or condition as described herein.
  • the invention also pertains to the following items:
  • a formulation comprising (a) a nanoemulsion, said emulsion comprising:
  • a carrier component comprising:
  • an active agent wherein the active agent is a highly lipophilic macrolide lactone, preferably tacrolimus.
  • the nanoemulsion comprises nanovesicles, wherein the nanovesicles have a size of less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, preferably 5 nm to 100 nm when stored for one month, two months or three months at 40°C.
  • the nanoemulsion comprises nanovesicles, wherein the nanovesicles have a size of less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, more preferably 5 nm to 100 nm when stored for six months, twelve months, eighteen months or 24 months at 25°C.
  • the aqueous component is present in an amount of 50% to 99% w/w, based on the total weight of the nanoemulsion (a), preferably from 70% to 95% (w/w), and more preferably from 80% to 95% (w/w).
  • aqueous component comprises at least one pH buffering agent.
  • the at least one lipophilic component comprises a caprylic and/or a capric triglyceride or a mixture thereof.
  • the at least one surfactant comprises (a) a phospholipid, a lysophospholipid, a ceramide and/or a mixture thereof, and/or (b) a polyoxyethylene-type surfactant.
  • the polyoxyethylene-type surfactant comprises Polysorbate 80.
  • any one of items 26-30 wherein the polyoxyethylene-type surfactant is present in an amount of from 0.1% to 10% (w/w), based on the total weight of the nanoemulsion (a), more preferably from 0.2% to 5% (w/w), and most preferably from 0.5% to 5% (w/w).
  • any one of the preceding items wherein the at least one alcohol is present in an amount of from 0.1% to 10% (w/w), based on the total weight of the nanoemulsion (a), preferably from 0.5% to 5% (w/w), and more preferably from 1% to 2% (w/w).
  • the formulation of any one of the preceding items comprising at least one gelling agent.
  • any one of the preceding items wherein the gelling agent is selected from the group consisting of poloxamer, xanthan gum, bentonite, sodium carboxymethylcellulose, hydroxymethyl cellulose, carbomer, hydroxypropyl cellulose, gellan gum, guar gum, pectin, poly(ethylene)oxide, polycarbophil, alginate, tragacanth, povidone, gelatin, and mixtures thereof.
  • the gelling agent is selected from poloxamer, xanthan gum and/ or mixtures thereof.
  • any one of the preceding items wherein the gelling agent is present in an amount of from 0.1% to 10% (w/w), based on the total weight of the formulation, preferably from 0.25% to 5% (w/w), and more preferably from 1% to 4% (w/w).
  • the formulation of any one of the preceding items further comprising at least one preservative.
  • the formulation of item 38, wherein the preservative is benzoate, preferably sodium benzoate.
  • the formulation of item 38 or 39, wherein the preservative is present in an amount of from 0.01 % to 3% w/w, based on the total weight of the formulation, preferably from 0.2% to 2% (w/w), and more preferably from 0.2% to 1 .5% (w/w).
  • any one of the preceding items which is essentially free of parabens.
  • the formulation of any one of the preceding items characterized by a polydispersity index of less than or equal to 0.8, wherein the polydispersity index is determined by dynamic light scattering.
  • the formulation of any one of the items 1 -42 comprising:
  • an aqueous component present in an amount of 70% to 95% w/w, based on the total weight of the nanoemulsion (a).
  • the formulation for use of item 46 wherein the ophthalmic disease is selected from the group consisting of keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), dry-eye, corneal endothelial rejection after corneal transplantation.
  • the formulation for use of item 46, wherein the dermatological disease or condition includes diseases or conditions of the skin, skin appendages or mucosa. 49.
  • the dermatological disease or condition is selected from the group consisting of inflammatory, neoplastic, proliferative, infectious, and/or autoimmune diseases or conditions, and/or the cutaneous manifestation thereof, and/or diseases associated with single lesions or fields of lesions, neoplastic, proliferative and/or inflammatory changes.
  • inflammatory dermatological disease or condition is selected from the group consisting of dermatitis, contact dermatitis, acne, atopic dermatitis, eczema, pustular dermatitis, seborrheic dermatitis, perioral dermatitis, chronic wound, urticaria, skin ulcer, rosacea, rash, drug eruptions, toxic epidermal necrolysis; erythema multiforme, erythema nodosum, granuloma annulare, and other cutaneous manifestations of inflammation.
  • the formulation for use of item 49, wherein the autoimmune dermatological disease or condition, or the cutaneous manifestation of the autoimmune condition is selected from the group consisting of psoriasis, pemphigus, systemic lupus erythematodes, lichen planus, morphea, sclerodermia, epidermolysis bullosa, dermatomyositis, graft-versus-host syndrome.
  • a dispenser product comprising the formulation of any one of the items 1 -51 .
  • a container comprising the formulation of any one of the items 1 -51 .
  • a method of treatment and/or prevention of a dermatological disease or condition in a subject comprising administering to the subject, a pharmaceutically effective amount of the formulation of any one of the items 1 to 57.
  • Figure 1 Solubility of tacrolimus.
  • Top Solubility tests with tacrolimus (time point 0). From left to right: TC2 (1 mg TC/ml aqueous phosphate buffer), TC3 (20 mg TC/g lipid phase or carrier component), TC4 (2 mg TC/ml BF200 nanoemulsion), TC5 (1 mg TC/ml BF200 nanoemulsion); Bottom: Solubility tests with tacrolimus after 6 months storage at 5°C and 25°C. From left to right: TC4 stored at 5°C, TC4 stored at 25°C, TC5 stored at 5°C, TC5 stored at 25°C.
  • Figure 2 Tacrolimus assay in nanoemulsion formulations with different nominal TC content (0.1 %, 0.01%) after storage at 2-8°C, 25°C or 40°C.
  • Figure 4 Polydispersity index (PDI) of formulations with different nominal TC content (0.1 %, 0.01%) after storage at 2-8°C, 25°C or 40°C.
  • PDI Polydispersity index
  • Figure 5 In Vitro Release (SUPAC-SS) after 2.6 hours of tacrolimus formulations with nanoemulsion compared to commercially available tacrolimus ointments.
  • Figure 6 Epidermal penetration of tacrolimus formulation with nanoemulsion compared to commercially available tacrolimus ointment.
  • Example 1 Preparation of Nanoemulsions BF200, BF215 and BF220
  • Table 2 Composition of nanoemulsions BF200, BF215 and BF220
  • the manufacturing process for the nanoemulsions in a typical batch size consists of the following steps 1 -4:
  • Step 1 Preparation of phosphate buffer (aqueous component)
  • Phosphate buffer 1000 g was prepared and the phosphate buffer optionally sterilized.
  • Step 2 Preparation of the carrier component (lipid phase) containing the lipophilic component, the surfactants and the alcohol
  • Soy lecithin (17 g) was weighed in a suitable vessel, isopropyl alcohol (14 g) was added and the vessel was covered to avoid alcohol evaporation. Soy lecithin was dissolved under continuous stirring with a suitable stirrer at room temperature. Caprylic/capric triglycerides (35b g) and Polysorbate 80 (34 g) were weighed and added to the solution of soy lecithin. The mixture was stirred with a suitable stirrer at room temperature until a homogenous clear solution was obtained. This solution is the carrier phase to be included in the nanoemulsion containing all emulsifiers and lipid components of the nanoemulsion BF200. According to this procedure BF215 and BF220 was prepared by adapting the amount of the components (see Table 2).
  • nanoemulsion BF200 was used.
  • Step 3 Manufacturing of the nanoemulsion by mixing the aqueous component from Step 1 and the carrier from Step 2 for a lipid content of 10% (BF200)
  • Step 2 Manufacturing of an emulsion by mixing 900 g phosphate buffer (from Step 1 ) and 100 g carrier (from Step 2).
  • the aqueous component comprising the phosphate buffer was heated to approximately 45-60°C in a suitable vessel.
  • the carrier (concentrate) of step 2 was heated to approximately 45-60°C.
  • the carrier was poured to the phosphate buffer under continuous stirring with a propeller mixer resulting in the formation of a stable trombe (or spout) having the maximal possible diameter without causing foaming or sputtering.
  • the resulting nanoemulsion is stirred for 15 min.
  • the nanoemulsion was cooled down to room temperature.
  • nanoemulsion BF215 In nanoemulsion BF215, 850 g phosphate buffer (from Step 1 ) and 150 g carrier were mixed. In nanoemulsion BF220, 800 g phosphate buffer (from Step 1 ) and 200 g carrier were mixed.
  • Step 4 Preparation of the final formulation and primary packaging
  • the nanoemulsion can be sterilized.
  • a suitable pharmaceutical formulation e.g., by adding water, a suitable buffer, or an additional aqueous gel base with e.g., poloxamer 407 or xanthan gum.
  • Example 2 Preparation of a nanoemulsion formulation (BF220) containing 0.1% or 0.01% tacrolimus (TC) and 4% Poloxamer 407
  • the formulations were prepared according to Example 1 with the addition of the appropriate amount of an aqueous gel base with poloxamer 407 in step 4.
  • TC in an amount of 0.1 % or 0.01% was added to the lipophilic component of step 2 from example 1 .
  • Example 3 Determination of the solubility properties of tacrolimus in the nanoemulsion formulation
  • Tacrolimus was dissolved by mechanical techniques (stirring). Determination of a complete solution of substance was based on visual observation. A complete dissolution was defined as a clear solution with no signs of cloudiness or precipitation. The pure solvents were used as reference.
  • Example 4 Determination of vesicle size and polydispersity index by dynamic light scattering
  • the size of the nanovesicles, expressed as the z-average size (e.g., in nm), and the homogeneity of nanovesicle formulations, expressed as polydispersity index was determined by dynamic light scattering (sometimes referred as Photon Correlation Spectroscopy (PCS) or Quasi-Elastic Light Scattering (QELS)).
  • PCS Photon Correlation Spectroscopy
  • QELS Quasi-Elastic Light Scattering
  • the Zetasizer Nano ZS is instrumented with a 633 nm green laser and optics with a 173°scattering detector angle for size measurement.
  • the device may be operated under vacuum for measurements, but in these cases, vacuum was not applied to the samples for size and homogeneity measurements.
  • Example 5 In Vitro Release (SUPAC-SS) of tacrolimus formulations with nanoemulsion and tacrolimus ointments
  • In vitro release method is based on an open chamber diffusion cell system such as a Franz cell system.
  • the cylindrical glass Franz cell is a diffusion chamber comprising an upper and a lower part between which the synthetic membrane (e.g., EMD Millipore MF Membrane; 0.025 pm) is clamped.
  • the lower part (approx. 7 mL) is filled with an acceptor medium (EtOH/H 2 O 75:25 v/v%) maintained at a temperature of about 32°C in which the API has a sufficient solubility.
  • the acceptor medium is stirred (approx. 400 rpm) to ensure the partition and dissolution of the API.
  • the diffusion area of the membrane is approximately 1.8 cm 2 (25 mm diameter). Diffusion of tacrolimus from a topical product to and across the membrane was monitored (up to 2.6 hours) by assay using high-performance liquid chromatography (HPLC-UV).
  • Example 6 Epidermal penetration of tacrolimus formulation with nanoemulsion compared to commercially available tacrolimus ointment
  • the nanoemulsion formulation with 0.1 % tacrolimus was compared to the conventional 0.1 % ointment in a skin penetration study by assessing tacrolimus deposition in a layer wise assay using ex-vivo facial skin.
  • An established ex-vivo model was used to explore drug penetration into human skin from routine facial aesthetic surgery. The penetration test is dived into the following steps:
  • Sample preparation a. One non-occlusive dermal application to the ex vivo skin samples of 6 mm diameter. b. Approx. 28.3 mg (100 mg/cm 2 ) of test items c. After incubation at approx. 37°C and 5% CO2 in humidified atmosphere the test formulation was washed of samples with 70% ethanol. The samples were frozen in freezing medium at -80°C. d. Cryosectioning at -28°C with a thickness of 10 pm e. Extraction of tacrolimus with ACN at about 20°C for 24 hours and 450 rpm followed by centrifugation at 20°C.
  • Viscosity was measured by rotation (measuring geometry: cone/plate) with a constant shear rate of 90.0 s’ 1 at 20°C.
  • Tacrolimus (TC) content over time in BF220 with PX 4% as gelling agent at different temperatures
  • the nanoemulsion formulations were stored at 2-8°C, 25°C and 40°C.
  • the content of TC was determined at 0 (starting point) and various time points during the 24 months storage period. The results are shown in Figure 2.
  • Example 2 Formulation (Example 2) preserve the API (TC) content better than conventional aqueous formulations.
  • TC in formulation of Example 2 was found to be stable after 24 months storage at 2-8°C.
  • At 40°C TC in formulation of Example 2 is stable for at least 1 month.
  • the nanoemulsion formulations were stored at 2-8°C, 25°C and 40°C.
  • the particle size, particle size distribution and pH were determined at 0 (starting point) and various time points during the 24 months storage period. The results are shown in Figure 3 and Figure 4.
  • Samples were prepared as explained in Example D. The compound was dissolved in 10 mM Phosphate buffer (TC2) at defined concentration (see table below). For samples TC3, TC4 and TC5 the lipid phase (intermediate) of nanoemulsion BF200 was used as solvent. In a first step, Tacrolimus was dissolved in the lipid phase, followed by the preparation of the nanoemulsion by combining the aqueous phase with the lipid phase (containing Tacrolimus). Samples TC4 and TC5 were stored at 5°C and 25°C for a period of 6 months. The results of solubility tests for time point 0 and 6 months are shown in Figure 1 and Table 4.
  • Tacrolimus is highly soluble in the aqueous nanoemulsion (at least 90% water content) in a concentration of at least 2 mg/mL.
  • tacrolimus from the conventional lipophilic ointment containing 0.1% tacrolimus mainly stays on top of the skin, presumably associated to its formulation, and does not penetrate through the epidermis, while a higher tacrolimus deposition in the deeper skin layers can be achieved by the formulation with nanoemulsion (BF220) containing 0.1% tacrolimus. This outcome is in line with the results of Example C.

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Abstract

La présente invention concerne une composition comprenant une nanoémulsion d'huile dans l'eau et une lactone de macrolide hautement lipophile en tant qu'agent actif, tel que le tacrolimus, dissoute dans la nanoémulsion. Dans cette formulation, le tacrolimus peut être complètement dissous, plutôt que suspendu, et présente une stabilité améliorée en termes de teneur en substance active, de pH, de taille de particule et d'homogénéité de taille de particule.
PCT/EP2024/059365 2023-04-06 2024-04-05 Formulation de nanoémulsion présentant une stabilité de tacrolimus et une pénétration cutanée améliorées Pending WO2024209073A1 (fr)

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CN202480024241.1A CN120981222A (zh) 2023-04-06 2024-04-05 具有改善的他克莫司稳定性和皮肤渗透性的纳米乳制剂

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EP23214699 2023-12-06
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