WO2020018032A2 - Formulations pharmaceutiques topiques comprenant du pimecrolimus, du clobétasol et du calcipotriol pour le traitement du psoriasis - Google Patents

Formulations pharmaceutiques topiques comprenant du pimecrolimus, du clobétasol et du calcipotriol pour le traitement du psoriasis Download PDF

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Publication number
WO2020018032A2
WO2020018032A2 PCT/TR2019/050110 TR2019050110W WO2020018032A2 WO 2020018032 A2 WO2020018032 A2 WO 2020018032A2 TR 2019050110 W TR2019050110 W TR 2019050110W WO 2020018032 A2 WO2020018032 A2 WO 2020018032A2
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WIPO (PCT)
Prior art keywords
clobetasol
calcipotriol
pimecrolimus
formulation
psoriasis
Prior art date
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PCT/TR2019/050110
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English (en)
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WO2020018032A3 (fr
Inventor
Tambay TAŞKIN
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Taskin Tambay
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Publication date
Application filed by Taskin Tambay filed Critical Taskin Tambay
Publication of WO2020018032A2 publication Critical patent/WO2020018032A2/fr
Publication of WO2020018032A3 publication Critical patent/WO2020018032A3/fr

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    • 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
    • A61K31/56—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
    • A61K31/59—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics

Definitions

  • the present invention relates to topical pharmaceutical combinations comprising
  • pimecrolimus pimecrolimus, clobetasol or derivative and calcipotriol suitable for dermal use.
  • Psoriasis is a chronic skin disease characterized by fluctuations in the course of the disease.
  • Psoriasis is a common autoimmune skin disease characterized by T-cell mediated hyperproliferation of keratinocytes. The disease has a strong but complex genetic background in monozygotic twins with approximately 60% compliance, indicating that HLA-Cw * 0602 is a major allele for psoriasis.
  • Sources suggest that CD8 + T cells may play an important role as an effector in psoriasis.
  • CD8 + T cells are involved in a complex interaction between CD4 +, CD8 + T cells and cross-presented dendritic cells in the control of Thl polarization observed in psoriasis lesions. It has also been suggested that fluctuations in spontaneous remissions or disease activity can be determined by a balance in effect between the effector and suppressor CD4 + and CD8 + T cells.
  • pimecrolimus which is a macrolactam, a other calcineurin inhibitor
  • the problem of not being able to penetrate the skin with a high molecular weight (about 1200 Da) of a drug such as cyclosporine has disappeared, and this drug is used topically in psoriasis, atopic dermatitis and other dermatoses. It was initiated.
  • Pimecrolimus is a relatively low molecular weight compound (about 800 Da) (USPatent 6423722; TR 03189T2).
  • the mechanism of calcineurin inhibitors is based on the suppression of the synthesis of proinflammatory cytokines.
  • pimecrolimus In the cytoplasm of target cells, pimecrolimus binds to macrophilin-l2, an intracellular protein (also known as FK506-binding protein).
  • the immunosuppressive activity of pimecrolimus is based on calcium and calmodulin (serine- threonine phosphatase). This active substance eliminates gene expression of inflammatory cytokines by inhibiting calcineurin, which leads to dephosphorylation of nuclear factor (NF) in the cell.
  • NF nuclear factor
  • the anti-inflammatory activity of the drug depends on T-helper cell activity by suppressing the synthesis and release of proinflammatory cytokines.
  • Interleukin 2, 3, 4, 5 and 17 IF-2, IF-3, IF-4, IF-5, IF- 17
  • INF-g interferon-,
  • TNF- a tumor necrosis factor-a
  • the mechanism of calcineurin inhibitors is based on the suppression of the synthesis of proinflammatory cytokines.
  • pimecrolimus In the cytoplasm of target cells, pimecrolimus binds to macrophilin-l2, an intracellular protein (also known as FK506-binding protein).
  • the immunosuppressive activity of pimecrolimus is based on calcium and calmodulin (serine- threonine phosphatase). This active substance eliminates gene expression of inflammatory cytokines by inhibiting calcineurin, which leads to dephosphorylation of nuclear factor (NF) in the cell.
  • NF nuclear factor
  • the anti-inflammatory activity of the drug depends on T-helper cell activity by suppressing the synthesis and release of proinflammatory cytokines.
  • IL-2 Interleukin 2, 3, 4, 5 and 17
  • INF-g interferon-,
  • TNF- a tumor necrosis factor-a
  • Topical corticosteroids act on genomic and nongenomic pathways.
  • the genomic pathway points to the glucocorticoid receptor and results in receptor homodimerization with activation and subsequent binding to glucocorticoid-responsive elements.
  • glucocorticoid responder GR
  • HSP90 and HSP70 hot shock proteins
  • glucocorticoid response elements tyrosine amino transferase (TAT), phosphoenolpyruvate carboxime kinase (PEPCK), IL-10, transcription of genes with anti-inflammatory functions such as b-adrenergic receptor, IL-l receptor protein phosphatase 1 (DUSP-l) with an antagonist and dual-selectivity is stimulated (Luis Uva, 2012).
  • TAT tyrosine amino transferase
  • PEPCK phosphoenolpyruvate carboxime kinase
  • IL-10 transcription of genes with anti-inflammatory functions such as b-adrenergic receptor, IL-l receptor protein phosphatase 1 (DUSP-l) with an antagonist and dual-selectivity is stimulated (Luis Uva, 2012).
  • the nongenomic pathway involves membrane -bound receptors and secondary messengers and is responsible for the rapid effects of glucocorticoids. This pathway does not require de novo protein
  • Glucocorticoids have many functions that are anti-inflammatory, antimitotic, apoptotic, vasoconstrictive and immunomodulatory. These features are closely related to the effectiveness of skin diseases.
  • the anti-inflammatory process is characterized by increased transcription of anti inflammatory genes and decreased transcription of inflammatory genes after the activity of glucocorticoids.
  • Glucocorticoids induce the expression of annexin A1 (lipocortin 1; ANXA1 encoded) and ALXR (annexin A1 receptor).
  • Annexin A1 is substantially localized in basal keratinocytes of the basement membrane. In normal skin, the amniotic Al is usually in the cytoplasm. However, there is a translocation of this protein in the skin with psoriatic lesions and it is concentrated in the cell membrane. Thus, it reduces the synthesis of inflammatory prostanoids.
  • Annexin Al blocks the synthesis of prostaglandins, prostacyclins, leukotrienes, and thromboxane, which are eicosanoids derived from arachidonate by blocking phospholipase A2 (PLA2). This effect results in repressions of glucocorticoid linked cyclooxygenase 2 transcription.
  • Topical corticosteroids from vasodilated veins of psoriatic skin can easily reach systemic circulation and show systemic effects. This may lead to increased systemic side effects due to the dose of the drug used, the width of the applied surface and occlusion. Systemic side effects after chronic topical administration constitute a major risk for corticosteroids with high potency (Luis Uva, 2012). Corticosteroids, one of the most important and indispensable components in combination therapies, still remain important for side effects.
  • the treatment of psoriasis can be summarized as the general approach, which may require the combination of two, three or more pharmacological agents, and the side effects and toxicity profile after prolonged contact with optimum components, so as not to impair patient compliance.
  • the first patent for the use of calcipotriol with topical corticosteroids is US 5,565,462.
  • Calcipotriol is a synthetic derivative of l,25-dihydroxy vitamin D3.
  • betamethasone which is calcipotriol and a corticosteroid (Patent No. EP 2 455 083 Bl; priority date April 23, 1999). Until then, no information is available on the use of this component with topical corticosteroids.
  • Topical corticosteroids and vitamin D derivatives can be combined with other topical therapies, systemic therapies and biologic agents in a simple and reliable manner. It is also effective as an immunomodulator (Atif Shahzad, Bengal Shahzad, Khawar Khurshid, 2006).
  • Topical calcipotriol, hyperkeratosis, acanthosis, parakeratosis and epidermal hyperproliferation characterize the skin differentiation of the epidermalkeratinocytes without touching keratin gene expression helps to improve the terminal differentiation (Atif Shahzad, Bengal Shahzad, Khawar Khurshid, 2006) (Gniadecki R., 1998).
  • calcineurin is a particularly critical calmodulin-like cytosolic protein in the differentiation of T-lymphocytes. This protein activates very specific gene expression mechanisms by dephosphorylation instead of phosphorylation.
  • T-lymphocytes This is a process that results from the degenerating of T-lymphocytes pre-conditioned by dendritic cells from the Dendritic cells and by the introduction of NF into the nucleus of the cell as a result of dephosphorylation and by the expression of gene expression in the production of inflammatory cytokines.
  • Differentiation of T-lymphocytes initiates a pathological condition in favor of the psoriatic inflammatory process in the dermis.
  • the proliferation of keratinocytes, increased transformation of corneocytes, vasodilatation, increased dermal inflammation against increased chemotactic stimuli, etc. psoriatic plaques are formed and the disease becomes chronic.
  • Calcipotriol acts by suppressing the proliferation frequently seen in psoriatic tissue.
  • this triple composition synergistically influenced each other in addition to its pharmacological activities and demonstrated therapeutic effects well below the usual doses used.
  • the present Application includes ointment, cream, lotion, gel, spray, foam, shampoo, solution, liniment or other sprayable liquid and semi-solid dermatological pharmaceutical preparations prepared for use in the treatment of psoriasis, seborrhiasis or seborrheic dermatitis in humans and other mammals at least one calcineurin inhibitor, including, but not limited to, tacrolimus or pimecrolimus, or cyclosporin, for example, but not limited to the examples as active ingredient; topical corticosteroids of class III and class IV according to the Niedner classification, for example: Clobetasol propionate, betamethasone dipropionate, diflucortolone valerate, mometasone furoate, fluticasone propionate, betamethasone valerate, halometasone monohydrate, halcinonide, fluocortolone) and at least one vitamin D derivative (eg calcipotriol), at least one contains a solvent, solvent or
  • compositions for the treatment of psoriasis, sebopsoriasis or seborrheic dermatitis in humans and other mammals are provided.
  • the preferred topical pharmaceutical formulation in the present invention is generally an ointment, cream, lotion, liniment, suspension, transdermal patch, preferably hair lotion, or other sprayable liquid or semi-solid pulps.
  • Another preferred embodiment is a anhydrous mono-phasic formulation (e.g., a single solvent system such as ointments).
  • anhydrous pharmaceutical composition for dermal use comprising at least one solvent component selected from the following to prepare said composition:
  • Isopropyl esters of straight or branched C 10-08 alkanoic or alkenoic acids such as myristate, isopropyl palmitate, isopropyl iso-stearate, isopropyl linoleate and isopropyl mono oleate;
  • Miglyol® 840 (caprylic and caprylic acid propylene glycol diester);
  • composition according to the invention provides the following therapeutic advantages in the treatment of skin diseases caused by psoriasis, sebopsoriasis disease and related disorders, as compared to single compound therapy of the prior art or dual combination therapy:
  • composition of the invention which combines a calcineurin inhibitor, a vitamin D analogue and a topical corticosteroid, has provided additional benefit to the patient since it provides a direct synergistic effect of the active ingredients as well as the therapeutic effect of the active ingredients.
  • the use of a combined product provided with three types of active compounds includes the use of therapeutic agents, such as less skin irritation and the advantage of the adverse effect provided by low-dose use and the ease of administration;
  • therapeutic agents such as less skin irritation and the advantage of the adverse effect provided by low-dose use and the ease of administration;
  • the treatment regimen faced by most psoriasis patients would eliminate the problem of failure in treatment and failure to provide benefit due to non- compliance.
  • a lower dose of active ingredients is used in the composition prepared according to the invention, resulting in a shorter period of time with reduced skin atrophy and corticosteroid side effects.
  • the patient will have a simpler application in terms of providing a single treatment, which will enable the patient to be given advanced treatment and an effective treatment of a much larger population of psoriasis patients.
  • the composition of the invention relates to the treatment of psoriasis and related skin diseases in a mammal; and administering an effective amount of a composition according to the present invention to a patient in need thereof for psoriasis treatment.
  • Said method preferably comprises one or two topical administration of a medically sufficient dosage of said composition.
  • the composition according to the invention preferably comprises a calcineurin inhibitor, preferably pimecrolimus at a dosage range of from 1.5 mg/g to 5.5 mg/g, preferably at a dose of 3.5 mg/g, preferably a corticosteroid, at a dose range of from 0.085 mg/g to 0.255 mg/g.
  • the calcipotriol at a dose of 0.17 mg/g and a vitamin D analogue, preferably at a dose of from 0.0085 mg/g to 0.0255 mg/g, preferably at 0.017 mg/g.
  • the pharmaceutical formulation comprises pimecrolimus in the range of from 1.5 mg/g to 5.5 mg/g; in the range of 0.085 mg/g to 0.255 mg/g, clobetasol or ester thereof and calcipotriol in the range of of from 0.0085 mg/g to 0.0255 mg/g in the formulation.
  • the pharmaceutical formulation comprises pimecrolimus in the range of 3-4 mg/g; Clobetasol or ester of 0.15-0.20 mg/g and calcipotriol of 0.015-0.20 mg/g in the formulation.
  • the pharmaceutical formulation comprises pimecrolimus at a dose of 3-4 mg/g; Clobetasol or ester of 0.15 mg/g and calcipotriol of 0.015 mg/g in the formulation.
  • the pharmaceutical formulation comprises pimecrolimus in the range of 3-4 mg/g; 0.20 mg/gclobetasol or ester and 0.20 mg/g of calcipotriol in the formulation.
  • the pharmaceutical formulation comprises pimecrolimus of 3.5 mg/g; Clobetasol or its ester of 0.17 mg/g and calcipotriol of 0.017 mg/g in the formulation..
  • the disclosed combined topical pharmaceutical formulation at much lower doses has surprisingly yielded a much more efficacious result than the individual doses used in the aforementioned diseases.
  • the systemic adverse effects that may occur during the use of these substances in local treatment have been reduced to a negligible level.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La Présente invention concerne une formulation pharmaceutique topique comprenant du pimecrolimus qu'inhibiteur de la calcineurine, du clobétasol en tant que corticostéroïde et du calcipotriol en tant que dérivé de la vitamine D, en tant qu'inhibiteur de la calcineurine pour le traitement du psoriasis, du sébopsoriasis ou de la dermatite séborrhéique chez l'humain et chez d'autres mammifères.
PCT/TR2019/050110 2018-03-06 2019-02-18 Formulations pharmaceutiques topiques comprenant du pimecrolimus, du clobétasol et du calcipotriol pour le traitement du psoriasis WO2020018032A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
TR2018/03213A TR201803213A2 (tr) 2018-03-06 2018-03-06 Psori̇asi̇s tedavi̇si̇ i̇çi̇n pi̇mekroli̇mus, klobetazol ve kalsi̇potri̇ol i̇çeren topi̇kal farmasöti̇k formülasyonlar
TR2018/03213 2018-03-06
TRTR2018/03213 2018-03-06

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WO2020018032A2 true WO2020018032A2 (fr) 2020-01-23
WO2020018032A3 WO2020018032A3 (fr) 2020-03-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022015960A3 (fr) * 2020-07-17 2022-02-24 Icahn School Of Medicine At Mount Sinai Biomarqueurs et classificateur du psoriasis et méthodes de traitement

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200740441A (en) * 2005-06-17 2007-11-01 Combinatorx Inc Methods and reagents for the treatment of inflammatory disorders
AU2014241396A1 (en) * 2013-03-14 2015-09-17 Hallux, Inc. Method of treating infections, diseases or disorders of nail unit
WO2016025686A1 (fr) * 2014-08-15 2016-02-18 Celgene Corporation Dosage d'aprémilast pour le traitement de maladies améliorées par l'inhibition de pde4

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022015960A3 (fr) * 2020-07-17 2022-02-24 Icahn School Of Medicine At Mount Sinai Biomarqueurs et classificateur du psoriasis et méthodes de traitement

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TR201803213A2 (tr) 2018-04-24
WO2020018032A3 (fr) 2020-03-19

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