WO2016198469A1 - Pénétration d'acides alpha-hydroxylés à partir d'émulsions anhydres - Google Patents

Pénétration d'acides alpha-hydroxylés à partir d'émulsions anhydres Download PDF

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WO2016198469A1
WO2016198469A1 PCT/EP2016/063065 EP2016063065W WO2016198469A1 WO 2016198469 A1 WO2016198469 A1 WO 2016198469A1 EP 2016063065 W EP2016063065 W EP 2016063065W WO 2016198469 A1 WO2016198469 A1 WO 2016198469A1
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topical formulation
alpha
formulation
skin
hydroxy acids
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PCT/EP2016/063065
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Åke LINDAHL
Niklas PALMKVIST
Lars Pettersson
Anders SJÖDIN
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Hpf Ip Holding S.A.
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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention generally relates to topical formulations of water-free emulsions for penetration of alpha-hydroxyl acids, in particular lactic acid.
  • Inflammatory reactions often cause an increase of pH in the skin, or an increase of pH in the skin causes inflammation in the skin.
  • Chronic pruritus affects millions of people worldwide, although solid epidemiological data is very limited. For example, one study reported that 8-10% of the population of Oslo suffer from chronic pruritus from several different causes (F. Dalgard et al, J. Investig. Dermatol. Symp. Proa, 2004, 9(2): 120-5).
  • Chronic pruritus is also a prevalent symptom in cutaneous T-cell lymphoma (68-93%), a disease that includes mycosis fungoides and Sezary syndrome (N. Meyer et al, Acta Derm.
  • Pruritus is the most common dermatological complaint in elderly patients (S. Beauregard and B. A. Gilchrest, Arch. Dermatol, 1987, 123:1638-43). Itch is also often the side effect of certain drugs, such as EGF receptor antagonists.
  • Antihistamines can sometimes effectively treat itch due to acute urticaria, but many chronic pruritic diseases respond poorly to conventional HI receptor antagonists (Tey H. L. and G. Yosipovitch; Br. J. Dermatol, 2011, 165(1):5-17). In addition to marginal efficacy, systemic antihistamines can also cause intolerable drowsiness.
  • Other current therapies possess various limitations. For example, anticonvulsants such as gabapentin inhibit spinal mechanisms in the perception of itch, but their use is limited due to their slow onset of action (5-6 weeks) (Metz and Stander, 2008).
  • Opiate receptor antagonists such as naloxone, nalmefene, and naltrexone decreased pruritus symptoms in patients with liver and kidney disease, although significant central nervous and gastrointestinal side effects occurred (Metz and Stander, 2008; N. V. Bergasa et al, Hepatology, 2006, 44(5): 1317-23).
  • Substance P the endogenous ligand for the neurokinin- 1 (NK-1) receptor, is a significant mediator of pruritus (T. Andoh et al, J. Pharmacol. Exp. Ther., 1998, 286:1140-5).
  • Intradermal injection of substance P elicits an itch sensation in human subjects, and an associated itch response in mice.
  • the substance P-induced itch-associated response in mice is not inhibited by antihistamines (B. Amatya et al., Skin Pharmacol. Physiol, 2010; 23:133- 138; C. Weidner et al, J. Invest. Dermatol, 2000, 115:1015-1020).
  • Ohmura et al. reported that tachykinin NK-1 receptor antagonist, BIIF 1149 CL, inhibited scratching behaviour in a picrylchloride- induced dermatitis model inNC/Nga mice (Eur. J. Pharmacol, 2004, 491:191-194; U.S. Patent Application No. 2003/100565).
  • Aprepitant an NK-1 receptor antagonist
  • NK-1 receptor antagonist is approved by the FDA for use in the prevention of chemically induced nausea and vomiting (emesis) after chemotherapy.
  • Duval and Dubertret first reported that oral aprepitant (80 mg daily) had utility in treating pruritus in three patients with Sezary syndrome (N. Engl. J. Med., 2009, 361(14): 1415-6).
  • Torres et al. disclosed similar results (J. Am. Acad. Dermatol, 2012; 66(l):el4-5). Stander et al.
  • Atopic dermatitis is an inflammatory skin condition with severe pruritus as a central feature. Many factors are likely to contribute to the severe pruritus in AD, thereamong the on-going inflammatory process, which results in the release of various pruritogens, including histamine, bradykinin and serotonin (5-HT). Another central feature and a key contributor to pruritus in AD is the skin dryness. This is also suggested from animal models, in which skin dryness sensitizes the skin for pruritic stimuli (Akiyama T, Carstens MI,
  • AD skin Enhanced scratching evoked by PAR-2 agonist and 5-HT but not histamine in a mouse model of chronic dry skin itch. Pain. 2010;151(2):378-83).
  • Yet another feature of AD skin is its abnormally high pH, which, similar to the skin dryness, might be related to a deficient skin barrier function.
  • the mean pH value of lesional AD skin was 6.13 ⁇ 0.52 as compared to 5.24 ⁇ 0.40 in the healthy control group (Knor T, Meholjic- Fetahovic A, Mehmedagic A. Stratum corneum hydration and skin surface pH in patients with atopic dermatitis. Acta Dermatovenerol Croat. 2011;19(4):242-7).
  • the complex interplay between inflammation, skin dryness and abnormal pH in relation to pruritus in AD is currently not investigated thoroughly.
  • One object of the invention is to reduce inflammation by maintaining an acidic environment in and on the skin.
  • Alpha-hydro xy acids are used for this purpose.
  • a topical formulation has been developed which generates a large release of the acid from the formulation.
  • An aspect of the invention is a water free emulsion including a polar phase that can dissolve alpha-hydroxy acids and a lipid phase that can generate protective occlusion of the compromised skin barrier and facilitate penetration of other medically active agents.
  • the topical formulation dissolves alpha-hydroxy acids and in particular lactic acid. If lactic acid is not dissolved, the acid will not penetrate the skin. Occlusive substances, lipids, do not dissolve lactic acid and therefore an emulsion is preferred having a lipid continuous phase and a discontinuous phase in which the lactic acid is soluble.
  • the discontinuous phase does not contain water (water is not to be added to this phase). The reason is that the acid will be charged and charged molecules do not penetrate into the skin readily. If, however, the discontinuous phase contains polar compounds in which lactic acid is soluble, a high penetration of lactic acid may be generated.
  • the polar phase may include alcohols and/or esters exemplified but not limited to diols, triols and esters of alpha hydroxy acids.
  • Triols are polar and can form stable emulsions with lipids such as paraffin oil provided proper emulsifiers are used.
  • triols such as glycerol do not facilitate skin penetration of lactic acid and we have found that diols are useful in generating both release and skin penetration of alpha hydroxy acids, including lactic acid.
  • the discontinuous phase of the formulation may contain a diol in order to facilitate the release of an alpha-hydroxy acid, exemplified by but not limited to lactic acid, from the formulation.
  • an alpha-hydroxy acid exemplified by but not limited to lactic acid
  • the increased release of alpha-hydroxy acids facilitated by the topical formulation described may help maintain a low pH ( ⁇ pH 6), and help maintain an acidic environment in and on the skin.
  • such increased release of alpha-hydroxy acids facilitated by the topical formulation described maintains an acidic environment in and on the skin for several hours.
  • the formulation should preferably contain about 20 to 90% of continuous phase, more preferably 40 to 75%, and most preferably 50 to 60%>, in order to facilitate physical stability and occlusion.
  • One further aspect of the invention is to include a medically-active compound intended for the treatment or relief of dermatological conditions.
  • a medically-active compound intended for the treatment or relief of dermatological conditions.
  • Such compounds can be dissolved in either the lipid phase or in the polar phase.
  • Non-limiting examples of such compounds are nuclear receptor agonists, nuclear receptor antagonists, non-steroidal antiinflammatory drugs, kinase inhibitors, phosphatase inhibitors, ion channel blockers, immunomodulators, G-protein coupled receptor antagonists, G-protein coupled receptor agonists, monoamine transporter blockers, enzyme inhibitors, anti-fibrotics or anti-infective substances, exemplified by but not limited to Mometasone, Diclofenac, Doxepin, Pramoxine, Calcipotriol, Apremilast, Tacrolimus, Tofacitinib, Pirfenidone, Desloratadin,
  • the emulsion is formed and stabilized by the use of emulsifiers.
  • the emulsifier should have a HLB (hydrophile lipophile balance) value of 4 to 12, more preferably 5 to 11, and most preferably 5 to 9.
  • HLB hydrophile lipophile balance
  • the emulsion can be formed by a single emulsifier or by the use of a combination of several emulsifiers when HLB is calculated by methods known to a person skilled in the art.
  • Another related aspect of the invention is a water- free emulsion characterized by a continuous phase, comprising, consisting essentially of or consisting of one or several lipids, and a discontinuous phase, comprising, consisting essentially of or consisting of polar esters and alcohols and alpha-hydroxy acid compounds creating a pH of less than 5.5 when exposed to water, both phases being emulsified by surfactants said product being useful for restoring skin humidity and decrease itch.
  • a related aspect of the invention is an emulsion where the lipids can be defined by soft white paraffin, mineral and vegetable oils, and waxes suitable for pharmaceutical use.
  • Another aspect of the invention is an emulsion where the polar esters can be defined as diols, represented by propandiol, and triols represented by glycerol in a relation of 2: 1 to 1 :5.
  • Another aspect of the invention is a formulation including a medical agent suitable for the treatment of dermatological conditions.
  • Another aspect of the invention is a formulation including a medical agent suitable for the treatment of dermatological conditions involving inflammation.
  • the term "about,” as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, is meant to encompass, in addition to the measurable value, variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount.
  • a range e.g., a range from x to y
  • the measurable value is a range from about x to about y, or any range therein, such as about xi to about yi, etc.
  • the invention provides an essentially-anhydrous topical formulation.
  • the topical formulation comprises an emulsion, wherein the emulsion comprises a continuous phase and a discontinuous phase.
  • the continuous phase is preferably a lipid phase.
  • lipid phase refers to a non-polar or hydrophobic phase.
  • This hydrophobic phase preferably comprises hydrophobic or amphiphilic molecules, such as fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, triglycerides and/or phospholipids of natural or non-natural origin.
  • hydrophobic or amphiphilic molecules such as fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, triglycerides and/or phospholipids of natural or non-natural origin.
  • the continuous phase may contain one or more non-polar solvents, lipids and/or emulsifiers. Suitable components are di- and triglycerides or mixtures thereof, short chain monoglycerides (C8 to CI 2), fatty acid esters exemplified, but not limited to, cetyl esters, isopropyl esters of fatty acids esters such as isopropylmyristate or isopropylpalmitate.
  • the continuous phase contains a surfactant or a mixture of surfactants in order to facilitate the formation of an emulsion. Suitable surfactants or mixtures of surfactants have a hydrophile/lipophile balance of less than 9 and more than 4.
  • the emulsifier may contain saturated fatty acid esters exemplified but not limited to stearic, palmitic, myristic and lauric acids.
  • the continuous phase may contain one or more thickening agents suitable for use in lipids.
  • the continuous phase may contain thickening agents in the form of waxes, exemplified, but not limited to,
  • microcrystalline wax carnuba wax, cerosine wax and cetyl esters wax.
  • suitable types of thickening agents for lipids include, for example, polymeric thickeners such as ethylene vinyl alcohol copolymers and ethylene acrylic acid copolymers.
  • polymeric thickeners such as ethylene vinyl alcohol copolymers and ethylene acrylic acid copolymers.
  • lipophilic fused silica particles and polyethene or polyethylene particles are examples.
  • Suitable lipids for the continuous phase include soft white paraffin, paraffin oil, mineral and vegetable oils, and waxes suitable for pharmaceutical use.
  • the lipids are selected from medium chain triglycerides (e.g. whose fatty acids have an aliphatic tail of 6-12 carbon atoms) and paraffin oil.
  • the discontinuous phase is preferably a polar phase, more preferably an anhydrous (or essentially anhydrous) polar phase.
  • the polar phase preferably comprises one more polar compounds.
  • the polar phase preferably comprises one or more polar compounds (polar solvents) which are capable of acting as solvents for alpha- hydroxy acids (preferably for lactic acid).
  • the polar phase includes one or more alcohols and/or esters. Examples of suitable alcohols and esters include diols, trio Is and esters of alpha-hydroxy acids.
  • the discontinuous phase of the formulation contains a diol in order to facilitate the release of an alpha-hydroxy acid, exemplified by but not limited to lactic acid, from the formulation.
  • suitable diols include propanediol, hexanediol and dipropylene glycol.
  • Trio Is are polar and can form stable emulsions with lipids (e.g. paraffin oil) provided that proper emulsifiers are used.
  • lipids e.g. paraffin oil
  • trio Is such as glycerol do not facilitate skin penetration of lactic acid and we have found that diols are preferred for generating both release and skin penetration of alpha hydroxy acids, including lactic acid.
  • polar esters examples include polar citric acid and lactic acid esters.
  • suitable solvents include esters such as propylene carbonate and ethers such as dimethyl isosorbide (dimethyl ether of an anhydride of an isomer of sorbitol, also usable as a penetration enhancer). It has been found that, in some embodiments, solvents can be mixed to generate higher solubility than if a single solvent is used.
  • the polar solvents are selected from glycerol, propylene glycol, dipropylene glycol and triethyl citrate, or a mixture thereof.
  • Another embodiment of the invention is an emulsion where the polar esters can be defined as diols, represented by propandiol, and trio Is represented by glycerol in a relation of 2:1 to 1:5.
  • the discontinuous phase (and preferably the continuous phase also) is preferably water-free or essentially anhydrous, i.e. it does not contain water (i.e. water is not to be added to this phase or the continuous phase).
  • the reason for this is that alpha-hydroxy acids will be charged in an aqueous environment, and charged molecules do not penetrate into the skin readily. If, however, the discontinuous phase contains polar compounds in which alpha- hydroxy acids (e.g. lactic acid) are soluble, then a high penetration of the alpha-hydroxy acids (e.g. lactic acid) may be generated.
  • water-free or “anhydrous” is meant that no water is added to the formulation (unless water is a constituent of the components added to the formulation, e.g. in hydrated form(s) or as in the case of lactic acid containing about 10 % of water). That is, no direct addition of water to a formulation of the present invention.
  • water may be physically and/or chemically absorbed by a formulation and/or by one or more ingredients in a formulation at any time during the preparation, storage, and/or use of a formulation of the present invention (i.e., indirect addition of water to the formulation).
  • the term “anhydrous” means that a formulation has a water content of less than 5% by weight of the formulation or any range therein.
  • formulation of the present invention may have a water content of less than about 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5%, by weight of the composition. Water content may be measured by methods known to those of skill in the art, such as, but not limited to, Karl Fischer titration. Most preferably, the entire topical formulation is water- free, anhydrous or essentially anhydrous.
  • the discontinuous phase comprises an alpha-hydroxy acid.
  • the role of pH for the development of itch in dermatological indications such as atopic dermatitis, ichthyosis and diaper dermatitis has been described in a recent paper. Saba M. Ali and Gil Yosipovitch," Skin pH: From Basic Science to Basic Skin Care” Acta Derm Venereol 2013; 93.
  • occlusive preparations can be useful in the treatment of dermatological diseases involving
  • alpha hydroxyl acids in particular lactic acid
  • alpha hydroxyl acids are excellent for adjustment of pH and have low toxicity, and are also good candidates for restoring and maintaining the pH in the skin.
  • a topical formulation has been generated that can occlude the treated area and at the same time generate an acidic environment.
  • a novel type of formulation comprising, consisting essentially of or consisting of a discontinuous polar phase and a continuous lipid phase, p/o (polar solvent in oil), solves the problem.
  • the topical formulation comprises dissolved alpha hydroxy acids and in particular lactic acid. If lactic acid is not dissolved, the acid will not penetrate the skin. Occlusive substances, lipids, do not dissolve lactic acid and therefore an emulsion is preferred having a lipid continuous phase and a discontinuous phase in which the lactic acid is soluble.
  • the alpha-hydroxy acid has a structure of Formula II:
  • Rl and R2 are independently selected from H, CH 3 , CH 2 (COOH)- and phenyl.
  • R2 is H.
  • acids examples include lactic acid, citric acid, malic acid, glycolic acid and mandelic acid.
  • the alpha-hydroxy acid is lactic acid.
  • the amount of alpha-hydroxy acid in the topical formulation helps to maintain a low pH ( ⁇ pH 6), and/or help maintain an acidic environment in and on the skin.
  • the topical formulation maintains a pH of less than 5.5, more preferably less than 5.2, and most preferably less than 5.0 on the skin. (The pH on the skin should also be maintained above pH 4.0 in order to avoid irritation on the skin, and preferably above 4.5).
  • the concentration or amount of alpha-hydroxy acid in the formulation is preferably a concentration or amount which is capable of maintaining the desired pH on the skin.
  • the amount of alpha-hydroxy acid in the formulation is 0.1% to 5.0% (w/w), more preferably 0.2%- 1.0% (w/w).
  • the amount of lactic acid in the formulation is preferably 0.4-0.8% (w/w), more preferably 0.5- 0.7%) (w/w), and most preferably about 0.59%> (w/w).
  • such increased release of alpha hydroxy acids facilitated by the topical formulation maintains an acidic environment in and on the skin for several hours.
  • the formulation should preferably contain about 20 to 90% of continuous phase (w/w), more preferably 40 to 75%, and most preferably 50 to 60%> in order to facilitate physical stability and occlusion.
  • the emulsion is preferably formed and stabilized by the use of one or more emulsifiers and/or surfactants.
  • the emulsifier should have a HLB
  • the emulsifiers have saturated fatty acid chains.
  • the emulsion can be formed by a single emulsifyer or surfactant or by the use of a combination of several emulsifiers or surfactants. Examples of preferred emulsifiers and surfactants include polyglycerol stearate and PEG 30
  • dipolyhydroxystearate e.g. CitrolTM DPHS-SO-(MV)
  • the topical formulation of the invention preferably has a semi-solid viscosity.
  • the topical formulation does not comprise a medically active compound intended for the treatment or relief of dermato logical conditions.
  • the topical formulation does not comprise nuclear receptor agonists, nuclear receptor antagonists, non-steroidal anti-inflammatory drugs, kinase inhibitors, phosphatase inhibitors, ion channel blockers, immunomodulators, G-protein coupled receptor antagonists, G-protein coupled receptor agonists, monoamine transporter blockers, enzyme inhibitors, anti-fibrotics or anti-infective substances.
  • the topical formulation does not comprise Mometasone, Diclofenac, Doxepin, Pramoxine, Calcipotriol, Apremilast, Tacrolimus, Tofacitinib, Pirfenidone, Desloratadin, Hydrocortisone, Piroxicam, Clindamycin, Urea or Clobetasol.
  • the topical formulation of the invention does not comprise an aminoguanidine of Formula I:
  • R -R 5 are independently H, Ci_ 5 -alkyl, OH, Ci_ 5 -alkoxy, SMe, SEt, CF 3 , OCF 3 , F, CI, Br, I, CN, S(0)Me, S(0) 2 Me, S(0) 2 NMe 2 , NMe 2 , NHC(0)H, NHC(0)Me, or CONMe 2 , optionally including two adjacent groups, R'-R 2 , R 2 -R 3 , R 3 -R 4 , or R 4 -R 5 , representing OCH 2 0, OCH 2 CH 2 0 or SCH 2 CH 2 S;
  • Y is absent or CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , CH 2 ) 4 or (CH 2 ) 5 ;
  • A is H, Ph or a 5-6 membered hetero-aromatic ring containing 1-3 hetero-atoms independently N, O or S;
  • B is H, Me, Et, Ph, benzyl or OH.
  • the topical formulation does not comprise an aminoguanidine.
  • the topical formulation does not comprise a pharmaceutically active medicinal product.
  • the term 'medicinal product' means any substance or combination of substances presented for treating or preventing disease in human beings or animals and any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in humans or in animals.
  • the term “medicinal product” refers to substance or combination of substances for which marketing authorisation has been granted in Europe or the US.
  • the topical formulation additionally comprises a medically- active compound intended for the treatment or relief of dermato logical conditions.
  • a medically- active compound intended for the treatment or relief of dermato logical conditions.
  • Such compounds can be dissolved in either the lipid phase or in the polar phase.
  • Non-limiting examples of such compounds are nuclear receptor agonists, nuclear receptor antagonists, nonsteroidal anti-inflammatory drugs, kinase inhibitors, phosphatase inhibitors, ion channel blockers, immunomodulators, G-protein coupled receptor antagonists, G-protein coupled receptor agonists, monoamine transporter blockers, enzyme inhibitors, anti-fibrotics or anti- infective substances, exemplified by but not limited to Mometasone, Diclofenac, Doxepin, Pramoxine, Calcipotriol, Apremilast, Tacrolimus, Tofacitinib, Pirfenidone, Desloratadin, Hydrocortisone, Piroxicam, Clindamycin, U
  • the concentration of the active component in the formulation should be selected in such way that the desired pharmacological effect is achieved without causing adverse effects. This concentration is individual for each active component depending on its ability to pass the stratum corneum and its binding properties at the site of action as would be understood by one of ordinary skill in the art. In some embodiments, the concentration of the active components ranges from about 0.01 to about 10%, in some embodiments about 0.1 to about 10 %, in some embodiments about 0.1 to about 5%, in some embodiments about 0.5 to about 5 % by weight of the topical formulation. These concentration levels relate to certain dosage levels of the active components corresponding to a one, two, three or four times daily topical application of the formulation.
  • additional compounds which are often used in skin products but which are not included to treat dermatological conditions (i.e. they merely improve the properties of the formulation) may also be included.
  • examples of such compounds include, but are not limited to, chemical stabilisers, penetration enhancers, compounds giving texture to the formulation, pH modifiers, physical or chemical sun-blocking agents, antimicrobial agents, antioxidants, etc.
  • the invention also provides a topical formulation as defined herein for use in therapy or for use as a medicament.
  • Another embodiment of the invention is a formulation as defined herein for the treatment of dermatological conditions.
  • Another embodiment of the invention is a formulation as defined herein including a medical agent suitable for the treatment of dermatological conditions.
  • Another embodiment of the invention is a formulation including a medical agent suitable for the treatment of dermatological conditions involving inflammation.
  • the dermatological conditions which may be treated by the invention include dermatitis, psoriasis, skin fibrosis, pruritus/itch and pain.
  • the dermatological condition may be one which is caused by a viral, bacterial or fungal infection (e.g. infective dermatitis).
  • the viral infection to be treated is chickenpox, shingles or cold sores.
  • the bacterial infection to be treated is impetigo, erysipelas, folliculitis or cellulitis.
  • the bacterial infection is one caused by Staphylococci, Streptococci and/or Pseudomonas aeruginosa.
  • the fungal infection to be treated is dermatophyte) sis or tinea nigra.
  • any portion of a subject's skin may be treated.
  • the subject's head, neck, face, trunk, upper extremities and/or lower extremities is treated.
  • the skin may be detached from a subject or may be a sample of skin, a skin graft or artificial skin.
  • Skin is intended to include, but is not be limited to, the epidermal and/or dermal layers, and may also include the underlying subcutaneous tissue. Mucosa (e.g., mouth, nasal, vaginal, etc.) and/or a surface of a subject's eye may also be treated.
  • Mucosa e.g., mouth, nasal, vaginal, etc.
  • a surface of a subject's eye may also be treated.
  • Subjects suitable to be treated with formulations of the present invention include, but are not limited to, avian and mammalian subjects.
  • Mammals according to the present invention include, but are not limited to, canines, felines, bovines, caprines, equines, ovines, porcines, rodents (e.g. rats and mice), lagomorphs, primates, humans, and the like, and mammals in utero.
  • Any mammalian subject in need of being treated or desiring treatment according to the present invention is suitable.
  • Human subjects of any gender for example, male, female or transgender
  • at any stage of development i.e., neonate, infant, juvenile, adolescent, adult, elderly
  • the topical formulation is for paediatric use, e. g. for use on subjects aged between 0 and 18 years.
  • the invention may also be carried out on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, livestock and horses for veterinary purposes, and for drug screening and drug development purposes.
  • animal subjects particularly mammalian subjects such as mice, rats, dogs, cats, livestock and horses for veterinary purposes, and for drug screening and drug development purposes.
  • Illustrative avians according to the present invention include chickens, ducks, turkeys, geese, quail, pheasant, ratites (e.g., ostrich) and domesticated birds (e.g., parrots and canaries), and birds in ovo.
  • Subjects may be afflicted with or at risk of developing a dermato logical condition, including a dermatological inflammatory condition.
  • the invention also relates to a process for producing an essentially-anhydrous topical formulation, the process comprising the step of combining:
  • an emulsion comprising: (a) a lipid continuous phase;
  • the alpha-hydroxy acids, polar compounds, non-polar solvents, lipids and/or emulsifiers are as defined in herein.
  • Figure 1 Release of lactic acid in relation to the composition of the polar phase (x-axis (hours), y-axis (%)).
  • Figure 2 Efficacy of formulation for treatment of pruritus over initial 12 hours. Median results are shown.
  • Cool phase A to 75°C.
  • the cream is cooled to ambient temperature with moderate stirring.
  • lactic acid is a naturally occurring substance and enzymes in the skin can be active long after slaughter of the animal.
  • the experiment is performed in a Franz diffusion cell using Ultracel ® 100 KDa cellulose membrane as barrier.
  • the receptor fluid is water and we have samples after 3 and 6 hours.
  • EXAMPLE 3 SOLUBILITY OF MEDICALLY ACTIVE AGENTS IN THE LIPID AND POLAR PHASE
  • the solubility was studied by dissolving an excess amount of active to the respective phases at ambient temperature, 25 C, in 500 ⁇ of the respective phases, stir and store the sample for >24 hours.
  • the samples were centrifuged and analysed by HPLC.
  • the membrane used was porcine ear skin the skin samples were dermatomed to about 0.5-1 mm. All membranes were taken from one individual and randomised before start.
  • Porcine ear skin was retrieved from a local slaughterhouse.
  • each formulation was charged in each cell using a plastic pasteur pipette and the exact weight added was recorded.
  • the receptor fluid was sampled at 3, 6 and 24 hours After the termination of the in vitro experiment, each cell was washed, dismounted and prepared according the following procedure:
  • the cell was washed by adding 0.5 ml of receptor solution with a pipette into the cell.
  • the solution was drawn and dispensed several times to clean the surface. The procedure was repeated 6 times and the fractions were collected in a test tube (total volume 3 ml). 2. The cell was dismounted.
  • the stratum corneum was gently separated from dermis with a scalpel and cut into thin strips. The material was collected in separate Eppendorf tubes.
  • the receptor solution samples were analysed according to method suitable for analysing the particular active by HPLC.
  • the analysis of the skin samples was performed by adding 1.5 ml of acetonitrile to the samples to extract the active from the cut membranes. 3.0 ml of acetonitrile was added to the skin wash samples to dissolve the active substance. The samples were sonicated for 30 minutes in an Ultra bath before short vortex mixing. The samples were then centrifuged at 14500 rpm and transferred to HPLC vials for analysis. The samples were analysed directly after the in vitro run.
  • Cool phase A to 75°C.
  • the cream is cooled to ambient temperature with moderate stirring.
  • the water solubility of Calcipotriol is 13.5 ⁇ g/ml and the substance is lipid in character. Therefore we have selected phosphate buffered saline, pH 7.4+ 2% PEG-20 oleyl ether as receptor fluid.
  • porcine ear skin to be used in the study was dermatomed to about 0.5-1 mm. All membranes were taken from one individual and randomised before start.
  • Porcine ear skin was retrieved from a local slaughterhouse.
  • Emulsifyer poly glycerol stearate 3.01
  • the water solubility of desloratadin is very low, 4 ⁇ g/ml and the receptor phase selected was phosphate buffered saline, pH 7.4+ 2% PEG-20 oleyl ether.
  • Desloratidine was found in dermis, in vitro tests, at levels above 300 ng/ml while very little penetration through the skin was detected.
  • Desloratidine decreases the magnitude of effect of inflammatory reactions in cell suspension experiments above 1 ng/ml (Mullol J 1 , Roca-Ferrer J, Alobid I, Pujols L, Valero A, Xaubet A, Bernal-Sprekelsen M, Picado C "Effect of desloratadine on epithelial cell granulocyte-macrophage colony- stimulating factor secretion and eosinophil survival.” Clin Exp Allergy. 2006 Jan;36(l):52-8.). Compound 1 was not included in the penetration experiment performed; however it should not affect the data significantly.
  • the next two examples will demonstrate the positive effect of the formulation on skin penetration of steroids. Since the aqueous solubility of steroids is low the receptor phase must contain organic solvents. This an accepted technique and the membrane used is silicon sheets. The membrane used was silastic sheeting NRV 0.005. The integrity test of the membrane was done visually and by testing leakage of receptor solution in the Franz equipment when mounted in the cells.
  • the receptor phase consists of the components in table below.
  • the experiment is performed in a Franz cell equipment where the receptor fluid is static. Sampling is performed at termination of the experiment, at 6 hours. Raw materials used in receptor fluids for steroid experiments
  • Table 6 Set up of 6 cells of the Franz equipment for silicon sheeting penetration.
  • Mometasone and hydrocortisone were analyzed by HPLC/UV according to current European pharmacopoeia, 7.0.
  • composition of topical formulation Composition of topical formulation
  • Figure 2 shows the fast onset of the formulation for the treatment of pruritus: relief from pruritus starts within 1 hour of application of the formulation to the skin.
  • Figure 3 shows that relief from pruritus was sustained over the 15 day trial period.
  • composition of the formulation is given below:
  • composition of topical formulation Composition of topical formulation

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Abstract

La présente invention concerne de manière générale des formulations topiques d'émulsions anhydres permettant la pénétration d'acides alpha-hydroxylés, en particulier de l'acide lactique.
PCT/EP2016/063065 2015-06-09 2016-06-08 Pénétration d'acides alpha-hydroxylés à partir d'émulsions anhydres WO2016198469A1 (fr)

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WO2017216738A1 (fr) 2016-06-15 2017-12-21 Torrent Pharmaceuticals Limited Compositions topiques d'apremilast
US20190046505A1 (en) * 2016-03-30 2019-02-14 Sarudbhava Formulations Private Limited Apremilast pharmaceutical compositions
JP2020505469A (ja) * 2017-01-27 2020-02-20 サルドバーヴァ フォーミュレーションズ プライベート リミテッドＳａｒｕｄｂｈａｖａ Ｆｏｒｍｕｌａｔｉｏｎｓ Ｐｒｉｖａｔｅ Ｌｉｍｉｔｅｄ 治療用アプレミラスト局所組成物
CN113616590A (zh) * 2021-07-27 2021-11-09 北京鑫开元医药科技有限公司 一种枸橼酸托法替布口服溶液及其制备方法
CN113712918A (zh) * 2021-10-28 2021-11-30 济南纽华医药科技有限公司 一种阿普斯特微乳及其制备方法
US11807453B2 (en) 2015-06-08 2023-11-07 Ocado Innovation Limited Object storage, handling, and retrieving system and method

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11807453B2 (en) 2015-06-08 2023-11-07 Ocado Innovation Limited Object storage, handling, and retrieving system and method
US20190046505A1 (en) * 2016-03-30 2019-02-14 Sarudbhava Formulations Private Limited Apremilast pharmaceutical compositions
US11110077B2 (en) * 2016-03-30 2021-09-07 Sarudbhava Formulations Private Limited Apremilast pharmaceutical compositions
WO2017216738A1 (fr) 2016-06-15 2017-12-21 Torrent Pharmaceuticals Limited Compositions topiques d'apremilast
JP2020505469A (ja) * 2017-01-27 2020-02-20 サルドバーヴァ フォーミュレーションズ プライベート リミテッドＳａｒｕｄｂｈａｖａ Ｆｏｒｍｕｌａｔｉｏｎｓ Ｐｒｉｖａｔｅ Ｌｉｍｉｔｅｄ 治療用アプレミラスト局所組成物
EP3573599A4 (fr) * 2017-01-27 2020-12-09 Sarudbhava Formulations Private Limited Compositions thérapeutiques topiques d'aprémilast
CN113616590A (zh) * 2021-07-27 2021-11-09 北京鑫开元医药科技有限公司 一种枸橼酸托法替布口服溶液及其制备方法
CN113712918A (zh) * 2021-10-28 2021-11-30 济南纽华医药科技有限公司 一种阿普斯特微乳及其制备方法

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