WO2012083397A1 - Composé contenant du guanabenz pour le traitement de l'amyloïdose cutanée primaire - Google Patents

Composé contenant du guanabenz pour le traitement de l'amyloïdose cutanée primaire Download PDF

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Publication number
WO2012083397A1
WO2012083397A1 PCT/BR2011/000480 BR2011000480W WO2012083397A1 WO 2012083397 A1 WO2012083397 A1 WO 2012083397A1 BR 2011000480 W BR2011000480 W BR 2011000480W WO 2012083397 A1 WO2012083397 A1 WO 2012083397A1
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weight
fact
pharmaceutical composition
composition according
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PCT/BR2011/000480
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WO2012083397A8 (fr
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Omar da Rosa SANTOS
Luis Eduardo Da Cruz
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Silvestre Labs Químia E Farmaceutica Ltda.
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Priority to PCT/BR2011/000480 priority Critical patent/WO2012083397A1/fr
Priority to BR112013016044A priority patent/BR112013016044A2/pt
Publication of WO2012083397A1 publication Critical patent/WO2012083397A1/fr
Publication of WO2012083397A8 publication Critical patent/WO2012083397A8/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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • 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
    • 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

Definitions

  • This invention refers to a topical compound containing guana- benz as active ingredient and to the use of guanabenz for the preparation of a pharmaceutical compound to treat primary cutaneous amyloidosis.
  • Such pharmaceutical compound for the treatment of primary cutaneous amyloidosis is remarkable because mechanism of action of guanabenz in said therapy is not related to the alpha-2 adrenergic agonist action that is already known for this substance.
  • Amyloidosis comprises several clinical syndromes characterized by the extracellular disposition of a protein substance that, depending on the site where and the amount of which is deposited, causes more or less organ functional impairment.
  • ultramicroscopic studies conducted by Cohen and Calkins invalidated the prior concept about the amyloid homogeneous character, showing that amyloid proteins are fibrous and constituted by rigid and unratified fibers (EICHBAUM, 1979).
  • Amyloidosis are a heterogeneous group of diseases characterized by the building up of insoluble fibrillary protein in tissues and organs. Among them, there are different pathologies, such as Alzheimer's Disease, Parkinson's Disease, type II Diabetes Mellitus, in addition to several other forms of systemic and localized amyloidosis, such as primary cutaneous amyloidosis (BOTELHO & LUPI, 2008).
  • Systemic amyloidosis and primary cutaneous amyloidosis are totally different pathological entities.
  • amorphous proteins and amyloid material preferably in the tunica media of the blood vessels, material that originates from the bone marrow or form the cells of immune system.
  • cutaneous amyloidosis there seems to be a simple degeneration of the cytoplasm of the epidermal kerati- nocyte, cell from the stratified squamous epithelium, maybe after repeated traumas to the skin, or excessive sun exposure, with secondary formation of amyloid material which deposits on the dermal papillae, quite far from the site of deposition of the systemic forms.
  • systemic and cutaneous amyloidoses are two completely distinct diseases as to physiopatholo- gy, condition, diagnosis, therapy and prognosis, that is, everything that cha- racterized a pathological entity.
  • the single link between systemic and cutaneous amyloidoses is the fact that both have deposits of material with staining characteristics similar to that of amyloids, a fact that made ancient pa- thologists to classify diseases that different with a single name.
  • pathologists from the same ages when amyloidosis were described also called as "lupus” different diseases like systemic lupus erythematosus, an autoimmune disease, and lupus vulgaris, which is actually a cutaneous tuberculosis; the fact they share the single name "lupus” does not place these diseases in the same group, just as obvious as the two manifestations of amyloidosis are clearly not similar.
  • the proteins that are involved in each of these diseases included in the group of amyloidosis have no biochemical relation, in addition they have different physiopathological mechanisms, but, as they share some characteristics, such as green birefringence on polarized light after staining with Congo red, and the presentation in beta-pleated sheet noted by x-ray diffraction, they had been arranged in a single group.
  • Amyloidosis is a disease caused by the deposition of a type of extracellular protein, the so called amyloid protein (DHODAPKAR ET AL 2000). As a result of different factors, a sequence of changes in protein folding takes place and induces the deposition of insoluble amyloid fibrils, mainly in the extracellular spaces of organs and tissues (SIPE & COHEN, 2006).
  • Figure 1 shows a schematic representation of the two major protein secondary structures: (A) alpha helix, and (B) beta-pleated sheets.
  • the red circles represent the oxygen molecules, the gray ones, carbon mole- cules, the blue ones, nitrogen groups, and the white ones, hydrogen molecules.
  • the green lines and the numbers show the distances between the molecules (Figure copied from internet: http://pharm1 .pharmazie. uni- greifswald.de/bednarski_web/web/data/personen/Lectures/PMC/ Kir- vieren/Alpha-helix.jpg).
  • the dashed lines represent the hydrogen bonds between beta-pleated sheets, and the hydrogen molecules and other lateral groupings were not shown in order to render the scheme more simple (BOTELHO & LUPI, 2008).
  • amyloid fibrils in addition to having identical secondary structures (configuration as beta-pleated sheets), present a peculiar ul- trastructure, containing serum amyloid P component (SAP) and glycosami- noglycans, although protein depositions can also be found (for example, in the brain or in the kidneys), without the classic fibrillary amyloid and SAP morphology (SIPE & COHEN, 2006).
  • SAP serum amyloid P component
  • glycosami- noglycans although protein depositions can also be found (for example, in the brain or in the kidneys), without the classic fibrillary amyloid and SAP morphology (SIPE & COHEN, 2006).
  • Amyloidosis is characterized as a condition whereby insoluble amyloid fibrils deposit in the extracellular spaces of organs and tissues (SIPE & COHEN, 2006). Depending on the biochemical nature of the amyloid protein precursor, the amyloid fibrils can deposit locally or affect virtually all the organic systems of the body, and may have no apparent clinical consequence or be associated to severe physiopathological changes (LOBATO, 2006). Thus, amyloids can be classified by two ways: by the identity of the fibril- forming proteins, as recently preconized, or by clinical manifestation.
  • amyloid deposit and, consequently, the disease symptoms are related to the type of protein precursor, which, in turn depends on the underlying disease. Therefore, there is recently the trend of classifying the disease according to the nature of the protein precursors of amyloid fibrillary proteins (ALVAREZ-RUIZ ET AL 2005), as detailed on Table 1 .
  • Amyloidoses are classically divided according to their clinical status. Thus, if the amyloid deposits occur in several organs, the amyloidosis is systemic, but if the affect one single tissue or organ, the amyloidosis is localized.
  • Primary amyloidosis also called light chain amyloidoses (AL) or multiple myeloma-associated amyloidosis
  • AL light chain amyloidoses
  • multiple myeloma-associated amyloidosis results from the formation of fibrils by fragments of light chains from monoclonal antibodies.
  • the primary structure of the light chain which forms the amyloid is singular, reflecting the characteristics of B cells clone that produced it (DHODAPKAR ET AL 2000; SEL- DIN & SANCHORAWALA, 2006; SIPE & COHEN, 2006).
  • Secondary amyloidosis also called amyloid amyloidosis AA, reactive or acquired amyloidosis
  • AA amyloid amyloidosis
  • AA reactive or acquired amyloidosis
  • Localized amyloidosis occur in isolated organs, without any evidence of systemic involvement and, just like systemic amyloidoses, they form a heterogeneous group of diseases, with very distinct physiopathogenic me- onanisms and clinical manifestations.
  • Some described forms of localized amyloidoses are: (a) Alzheimer's disease, where there is the deposition of ⁇ amyloid protein ( ⁇ ) on the walls of brain vessels and neuritic plaques; (b) Amyloidosis derived from polypeptide hormones, where there are amyloid depositions on polypeptide- producing tissues and tumors; (c) Localized corneal amyloidosis associated to mutations in the BIGH3 gene and deposition of keratoepithelin (AKer) on the stratum corneum, and (d) localized cutaneous amyloidosis, which will be described later on.
  • ⁇ amyloid protein ⁇ amyloid protein
  • AKer keratoepithelin
  • Localized cutaneous amyloidosis is a relatively common disease that can occur primarily, or be secondary to infectious or neoplastic processes, and must not be taken by the systemic form, related to higher morbidity.
  • amyloids depositions associated to other dermatologic diseases are not rare.
  • the amyloid proteins are, in general, seen within the stroma of associated lesions or in the underlying connective tissue.
  • the wall of vessels and dermal appendages are not affected by the depositions, as in the systemic forms.
  • the amyloid can be associated, such as: actinic keratosis, basal cell carcinoma, and fungoid mycosis (HABERMANN, 976).
  • GCA cutaneous amyloidosis
  • amyloid histogenesis A major point distinguishing localized cutaneous amyloidosis and the systemic forms is the amyloid histogenesis, which is presented in a different way. It is believed that the formation of the amyloid substance in localized cutaneous amyloidosis results from the deep layers of the epidermis, through the degeneration of their keratinocytes ⁇ BLACK, 1971 ).
  • This histological characteristic is not a mere curiosity, it is a disease defining factor, since, as it generates a localized and superficial amyloid deposition, the cutaneous amyloidosis results in a disease that is not that severe, is localized and have a benign and insidious course, totally different from systemic amyloidosis, which has vascular depositions, severe and aggressive course, high morbidity, and poor prognosis.
  • Maculopapular amyloidosis brownish maculae and papulae with linear distribution, pruriginous, normally localized on the interscapular region;
  • Papular amyloidosis or lichen amyloidosus papulae covered by a rough surface with crusts localized on the pretibial region, very pruriginous;
  • Nodular amyloidosis subcutaneous nodular isolated lesion adhered to the superficial layers, not pruriginous nor painful, no preferred location. Considered by some authors as a kind of extramedullary plasmacytoma.
  • Guanabenz is a classical agonist of alpha-2 adrenergic recep- tors, which has been used in human medicine as a vasoactive drug, routinely indicated for the treatment of arterial hypertension.
  • alpha-2 adrenergic receptors when administered intravenously or intramuscularly also have sedative, muscle relaxant and analgesic actions, and its use as a sedative, tranquilizer and analgesic has been proposed for veterinary use.
  • the patent application US 2008/0275129 discloses the use of guanabenz for the preparation of a drug for the treatment of neurological lesions, preferably spinal cord lesions.
  • neurological lesions preferably spinal cord lesions.
  • the document WO 2001/089508 A1 targets the veterinary field and refers to the composition comprising guanidine derivatives, such as guanabenz and guanabenz acetate, for the production of a fast-action and long- lasting analgesic and sedative effect in an animal.
  • the use disclosed in this document is totally different of that proposed herein and, therefore, it is not relevant.
  • Patent US 6413962 grants protection for a method to treat a mammalian putting it under anesthesia, and involves the administration of an amount of guanidine compound.
  • This patent also discloses a composition comprising aromatic compounds which contain the guanidine group used for the induction of anesthesia. Therefore, the objective of this document is totally different of the purpose of this invention, and, hence, is not relevant as well.
  • Cutaneous amyloidosis are benign diseases, that are localized and has no ability to disseminate, while minimal amounts of prion material can be lethal, tend to disseminate and become systematic;
  • Clorpromazine cream 1%, qd
  • This patient had already used topical steroids and compounded drugs containing salicylic acid at 5% with no remarkable result, such as most of the cases of primary cutaneous amyloidosis.
  • this patient began the use of topical formulation of chlorpromazine.
  • the pruritus worsened and the treatment was discontinued.
  • Figures 2 and 3 show, respectively, the initial lesion and the lesion 30 days after the treatment, evidencing that there was no improvement.
  • the inventors of this invention chose to test the guanabenz in one patient with confirmed diagnosis of primary cutaneous amyloidosis of macular subtype for 5 years.
  • the patient had been previously treated with topical steroids (betamethasone dipropionate and clobetasol), topical depigmenting agents (hy- droquinone 5%) and topical retinoic acid at 0.05% without any clinical response.
  • this invention evidenced that guanabenz surprisingly presents excellent results in the treatment of primary cutaneous amy- loidosis.
  • This invention refers to the development of a topical pharmaceutical composition with guanabenz as active ingredient and is indicated for the treatment of primary cutaneous amyloidosis.
  • Guanabenz used as active ingredient in the topical pharmaceutical composition hereunder can be present at a concentration ranging from 0.01% to 10% by weight, preferably from 0.5% to 2%, based on the total weight of the composition.
  • said composition can comprise some pharmaceuti- cally acceptable adjuvants, such as, but not limited to, thickeners (for example, xanthan gum, guar gum, acrylate polymers, cellulosic polymers, cetyl alcohol, cetostearyl alcohol), self emulsifying waxes (for example, cetostearyl alcohol, ethoxylated cetostearyl alcohol, mixed fatty alcohols e polyethox- ylated sorbitan fatty acid ester, self emulsifying glyceryl monoestearate), non- ionic emulsifying agents (for example, ethoxylated cetostearyl alcohol, ethoxylated oleyl alcohol, glyceryl monostearate, propoxylated stearyl alcohol) emollients and occlusive emollients (for example, capric/caprylic acid triglycerides, isopropyl myristate,
  • the thickener or the self emulsifying wax can be used in an amount ranging from 1% to 20% by weight, preferably 15% by weight, based on the total weight of the composition.
  • the non-ionic emulsifying agent can be used in an amount ranging from 0.1 % to 8% by weight, preferably 1 % to 5% by weight, based on the total weight of the composition.
  • the occlusive emollient can be used in an amount ranging from 1% to 15% by weight, preferably 5% by weight, based on the total weight of the composition.
  • the humectant can be used in an amount ranging from 1 % to 50% by weight, preferably 5% to 30% by weight, based on the total weight of the composition.
  • the preferable conditioning agents / emollients are selected among propylene glycol, lanolin and mineral oil, and can be used in an amount ranging from 0,01% to 50% by weight, based on the total weight of the composition.
  • the preferable viscosity regulator is the carbomer, which can be used in an amount ranging from 0.1 % to 10% by weight, preferably 0.4% to 0.6% by weight, based on the total weight of the composition.
  • the pH adjuster can be used in an amount ranging from 0.0001 % to1 % by weight, preferably 0.0003% to 0,05% by weight, based on the total weight of the composition.
  • the preservative can be used in an amount ranging from 0.01% to 2% by weight, preferably 0.5% by weight, based on the total weight of the composition.
  • composition of this invention can be presented as cream, gel, gel-cream, ointment, lotion or any other pharmaceutical form intended for topical use.
  • composition of this invention can also contain substances that, if associated to guanabenz in any of the previously described pharmaceutical forms may bring benefits.
  • substances that can be associated to guanabenz worth noting are included in any of the previously described pharmaceutical forms.
  • Keratolytic agents such as, retinoic acid (in an amount ranging from 0.01% to 0.1 % by weight of composition) and/or glycolic acid (in an amount ranging from 10% to 30% by weight of composition) and/or salicylic acid (in an amount ranging from 5% to 10% by weight of composition).
  • retinoic acid in an amount ranging from 0.01% to 0.1 % by weight of composition
  • glycolic acid in an amount ranging from 10% to 30% by weight of composition
  • salicylic acid in an amount ranging from 5% to 10% by weight of composition
  • - Skin depigmenting agents such as, hydroquinone, in an amount ranging from 2% to 5% by weight of composition, which helps to re- store skin normal color;
  • High potency steroids such as, clobetasol propionate, desonide and betamethasone dipropionate / valerate in an amount ranging from 0.05% to 0.1 % by weight of composition.
  • These drugs are toxic for melanocytes, and therefore have the ability to depigment the skin, and may be useful for the control of maculae (hyperpigmented lesions) observed in cutaneous amyloidosis.
  • the steroid has anti-inflammatory action and, when combined with keratolytic agents, they can reduce the irritation and the inflamma- tion provoked by them.
  • This invention further refers to the use of guanabenz in the preparation of a topical pharmaceutical composition for the treatment of primary cutaneous amyloidosis.
  • this invention also described a method for treating primary cutaneous amyloidosis through the administration of a topical pharmaceutical composition to a patient with symptoms of said disease.
  • the formulations containing guanabenz must be applied directly on the site of the lesion(s), one to three times a day, until the symptoms re- solve, or according to medical instructions.
  • Example 1 - Cream A is the preferred variations and illustrate the composition of this invention, but must not be construed as limitation to it. In light of this, the scope of this invention must be construed to comprise other possible variations, being exclusively limited by the content of the claims attached hereto, there including potential equivalents.
  • Example 1 - Cream A is the preferred variation and illustrate the composition of this invention, but must not be construed as limitation to it. In light of this, the scope of this invention must be construed to comprise other possible variations, being exclusively limited by the content of the claims attached hereto, there including potential equivalents.
  • Preservatives phenox- yethanol and/or methy- lisothiazolinone and/or 0.01% to 2% 0.5%

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Abstract

La présente invention concerne une composition pharmaceutique avec du guanabenz en tant que substance active et qui est indiquée pour le traitement de l'amyloïdose cutanée primaire. La composition de cette invention peut être fournie sous forme de crème, de gel, de crème gélifiée, de pommade, de lotion ou d'une autre forme pharmaceutique quelconque destinée à une utilisation topique.
PCT/BR2011/000480 2010-12-22 2011-12-20 Composé contenant du guanabenz pour le traitement de l'amyloïdose cutanée primaire WO2012083397A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/BR2011/000480 WO2012083397A1 (fr) 2010-12-22 2011-12-20 Composé contenant du guanabenz pour le traitement de l'amyloïdose cutanée primaire
BR112013016044A BR112013016044A2 (pt) 2010-12-22 2011-12-20 composto contendo guanabenzeno para tratamento de amiloidose cutânea primária.

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BR020100119505 2010-12-22
BRPI10155082-8 2010-12-22
PCT/BR2011/000480 WO2012083397A1 (fr) 2010-12-22 2011-12-20 Composé contenant du guanabenz pour le traitement de l'amyloïdose cutanée primaire

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WO2012083397A1 true WO2012083397A1 (fr) 2012-06-28
WO2012083397A8 WO2012083397A8 (fr) 2013-07-18

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020222188A1 (fr) * 2019-05-01 2020-11-05 Clexio Biosciences Ltd. Méthodes de traitement du prurit
WO2020222192A1 (fr) 2019-05-01 2020-11-05 Clexio Biosciences Ltd. Méthodes de traitement du prurit

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WO2003063880A1 (fr) * 2002-01-29 2003-08-07 Protemix Corporation Limited Dislocation de l'amyloide insulaire par des composes polycycliques
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US6413962B1 (en) 1988-05-02 2002-07-02 N. Eric Naftchi Guanidino compounds effective as anesthetics
WO2001089508A1 (fr) 2000-05-24 2001-11-29 University Of Kentucky Research Foundation Nouveaux sedatifs et analgesiques veterinaires reversibles a action prolongee et leur methode d'utilisation
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EP1908465B1 (fr) 2006-10-04 2009-04-29 Centre National De La Recherche Scientifique (Cnrs) Utilisation de dérivées chlores du guanabenz dans le traitement des maladies à prions
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WO2020222188A1 (fr) * 2019-05-01 2020-11-05 Clexio Biosciences Ltd. Méthodes de traitement du prurit
WO2020222192A1 (fr) 2019-05-01 2020-11-05 Clexio Biosciences Ltd. Méthodes de traitement du prurit
US11185532B2 (en) 2019-05-01 2021-11-30 Clexio Biosciences Ltd. Methods of treating pruritus
US11903928B2 (en) 2019-05-01 2024-02-20 Clexio Biosciences Ltd. Methods of treating pruritus

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