WO2012083397A1 - Guanabenz-containing compound for the treatment of primary cutaneous amyloidosis - Google Patents

Abstract

This invention refers to the pharmaceutical composition with guanabenz as active ingredient and is indicated for the treatment of primary cutaneous amyloidosis. The composition of this invention can be supplied as cream, gel, jelly cream, ointment, lotion or any other dosage form intended for topical use.

Description

Title: "GUANABENZ-CONTAINING COMPOUND FOR THE TREATMENT OF PRIMARY CUTANEOUS AMYLOIDOSIS".

Field of the Invention

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.

Theoretical Basis

1. Amyloidoses

1 .1 . History

The first probable clinical description of amyloidosis dates back to the XVII century and took place when Bonet described a patient with hepatic abscess associated to enlarged spleen with several "white stones". In 1846, Rokitansky, when seeing wasting syndrome patients with lardaceous liver and spleen tumors has been the first to identify the pathological entity of such findings.

Then, in 1854, Virchow observed that, by applying the technique used to stain starch, these "homogeneous infiltrates" from the liver and the spleen presented a blue-violet color, and thus they were called "amyloids", that is starchlike, as a reference to the term coined by the German botanist Mathias Schleiden, in 1838, to describe the normal amilaceous component of plants (LOBATO, 2006).

Few years after that, in 1859, the protein nature of the disease was demonstrated by Schmidt, Friedrich and Keckule, and, although improper, the name proposed by Virchow has been preserved.

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. In 1959, 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).

More than 70 years after that, Divry and Florkin stained the amyloid aggregates with Congo red and observed that under polarized light they presented green birefringence, the method that nowadays is still used for the diagnosis of amyloidosis (BOTELHO & LUPI, 2008).

1 .2. Definition

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, for instance, are totally different pathological entities. In the first case, there is a deposition of 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. In case of 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.

Several diseases described on past times still have obsolete names that must be changed. As is the case for systemic and cutaneous amyloidoses. They 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. Also employing this mistaken methods, 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.

1 .3. Etiology and Pathogenesis

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).

The protein aggregation process which takes place in amyloidosis results in the production of ordinated polymers that forms protofilaments and fibrils with beta-pleated structure (SELDIN & SANCHORAWALA, 2006). This structure consists of several laminae of polypeptides placed one above the other that are folded over themselves, being each lamina linked to the next one by hydrogen bonds (Figure 1) (ALBERTS ET AL 1994; BOTELHO & LUPI, 2008).

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. In (A) 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/ Wechsel- wirkungen/Alpha-helix.jpg). In (B) 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).

In general, 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).

It was formerly believed that only the accumulation of fibril in the extracellular space was responsible for the physical disorder and for the consequent dysfunction in the surrounding tissue. However, recent theories sug- gest that the lesions occurring in the tissues are due to multiple mechanisms. It is believed that not only the deposition of fibrils in their terminal form that cause the disease, but also its precursor structures and the way in which they can interact with cells, generating toxicity to them (SELDIN & SANCHORA- WAL-A, 2006). Thus, although the term amyloidosis refers to a group of dis- eases, it is evident that each disease has its particularities and different phy- siopathogenic mechanisms.

1.4. Classification

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.

a) Classification according to the identity of fibril-forming protein

The kind of 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 .

Table 1 : Amyloid fibrillary proteins and their precursors.

AMYLOID_mt-~._m~~_n SYSTEMIC (S) OR SYNDROME OR AF-

PRECURSOR

PROTEIN LOCALIZED (L) FECTED TISSUES

AMYLOID_nn„_{l inenn} SYSTEMIC (S) OR SYNDROME OR AF-

Adapted from SIPE & COHEN, 2006.

b) Classification by clinical manifestation

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.

- Systemic Amyloidoses

In relation to systemic amyloidosis, there are three major categories:

1. Primary amyloidosis (also called light chain amyloidoses (AL) or 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).

2. Secondary amyloidosis (also called amyloid amyloidosis AA, reactive or acquired amyloidosis) - occurs more frequently as a complication of a chronic inflammatory disease. During the inflammation, some inflammatory cytokines stimulate the hepatic synthesis of serum amyloid A, the pre- cursor of AA fibrils. In this case, the effective treatment of the underlying inflammation blocks the stimulation for the synthesis of the precursor (SIPE & COHEN, 2006).

3. Hereditary Amyloidosis - associated to mutations that intensify the improper folding of proteins and the formation of insoluble fibrils. Involves different precursors and, consequently, different clinical forms (SIPE & COHEN, 2006). - Localized amyloidoses

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 β amyloid protein (Αβ) 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.

Localized Cutaneous Amyloidosis

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.

a) Secondary cutaneous amyloidosis:

The observation of amyloids depositions associated to other dermatologic diseases is not rare. In such cases, 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. In several dermatosis the amyloid can be associated, such as: actinic keratosis, basal cell carcinoma, and fungoid mycosis (HABERMANN, 976).

b) Primary cutaneous amyloidosis, idiopatic or genuine:

The notion of genuine cutaneous amyloidosis (GCA) has been created in 1955 (Amyloidosis cutis propria), when the theory of exclusively cutaneous forms was first formulated (RABELLO, 1981 ).

Brownstein & Helwig (1970), in Archives of Dermatology, as to the lichen amyloidosus and the macular variant, now called GCA, adverted that there is no need to seek visceral amyloidosis, among other reasons, because the autopsies that were performed were shown to be totally negative for the presence of extracutaneous amyloid depositions.

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.

Primary cutaneous amyloidosis affects around 1-2% of the population and can be presented in four different clinical forms:

a. Macular amyloidosis, brownish maculae tending to confluence, pruriginous, normally located on the interscapular region;

b. Maculopapular amyloidosis: brownish maculae and papulae with linear distribution, pruriginous, normally localized on the interscapular region;

c. Papular amyloidosis or lichen amyloidosus: papulae covered by a rough surface with crusts localized on the pretibial region, very pruriginous;

d. 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.

Despite the multiple therapeutic attempts throughout the years, such as topical steroids, immunomodulating agents (tacrolimus, pimecroli- mus), keratolytic agents (salicylic acid) at several concentration and formulations, and other local irritative agents (glycolic and retinoic acid), the disease remains a therapeutical challenge, and there is no evidenced description of regression of disease with any of these therapies.

2. Guanabenz

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.

Based on its actions on the adrenergic receptors, its use has also been proposed for the treatment of other pathologies, such as lesions in the central nervous system resulting from trauma or disease.

The agonists of 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.

For the last years, the interest in drugs with antiprion action has grown a lot. In this setting, several drugs have been tested systematically, among those guanabenz.

Guanabenz in vivo action against prion proteins has been shown recently (TRIBOUILLARD-TANVIER ET AL.2008 a). The mechanism of action through which the drug promotes the remotion of prion proteins seems to be related to a potential interaction of the drug with the ribosomes, organelles responsible for the production of proteins and their structuring, through a RNA-dependent mechanism (TRIBOUILLARD-TANVIER ET AL 2008 b).

Although there are several points to be clarified, it is clear that the effect of guanabenz on proteins with improper conformation is not related to the action of this drug as alpha-2 adrenergic agonist, what is ratified by the fact that other agonists of alpha-2 adrenergic receptors has no action against prions (TRIBOUILLARD-TANVIER ET AL 2008 a).

State of the art

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. However, there is no word on primary cutaneous amyloidosis, neither is the mechanism of action described. 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. As we could note, 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.

The European patent EP 1 908 465 B1 , titled "Use of chlorine guanabenz derivatives for treating prion-based diseases", reports the indication of guanabenz and its derivatives for the treatment of prion diseases, but does not describe its mechanism of action in such cases.

Document WO/2009/065116, in turn, describes a method to treat purpura through the administration of a therapeutically effective amount of an alpha-adrenergic agonist. Guanabenz is among the potential agonists of al- pha-adrenergic receptor. However, as we previously mentioned, the mechanism of action of guanabenz in the treatment of primary cutaneous amyloidosis is not made through the activation of the alpha-adrenergic receptor.

Finally, the North-American patent application US 2006/264515 A describes a method to improve the telangiectasia through the topical application of a composition comprising at least one alpha-adrenergic receptor agonist. Despite such document mentions guanabenz as potential component, it is not impeditive for this invention, since guanabenz there acts as alpha-adrenergic agonist for the treatment of telangiectasia. Said document does not disclose nor suggest in any moment an alternate mechanism of action for guanabenz through which it would be possible to treat primary cutaneous amyloidosis. Thus, such document does not anticipate this invention. According to the literature, there is no report of drugs with anti- prion action being effective for the treatment of primary cutaneous amyloidosis. In fact, prion diseases and amyloidoses have only a discrete relation, that is the prevalence of amyloid deposit. However, the deposition of amyloid ma- terial is considered a primary ethiopathogenic factor in amyloidosis, and a completely peripheral and secondary finding in case of diseases caused by prions. It is easier to list the lack of similarity between both mentioned groups than their similarity, limited to the amyloid deposition. Listed below are some of the several differences between said groups that can clearly show that their origin, manifestation and outcome are very different:

a. 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;

b. All the known sterilization methods, probably except incinera- tion, are ineffective for prion material, while amyloid material is easily dissociated by the proteases;

c. There is no description of infection with material from cutaneous amyloidosis, despite lots of years of skin biopsies; in the same way a patient with cutaneous amyloidosis does not transmit his/her disease through the contact with his/her spouse or relatives, while prions are proved to be highly infective and can be transmitted orally, through contaminated surgical and biological material and, perhaps, through ectoparasites that infest the skin (larval flies, acari, etc);

d. Histologically, they are very different diseases. In prion infec- tions, cellular spongiosis and apoptosis predominates, while in amyloidoses, there is a single amyloid deposition without detectable inflammatory process; the apoptosis is not observed, as is not observed any type of cellular change like spongiosis;

e. In case of prion diseases, there is already a broad mapping of the sequencing of genetic defects related to the predisposal to develop the disease among homozygous subjects at the position 122 of the prion gene for the metionine amino acid. Nothing similar has been ever described in case of any amyloidosis, whether systemic or cutaneous.

Description of the Invention

Despite the large differences between both groups, the total lack of therapeutic perspectives for amyloidosis nowadays has lead the inventors of this invention to test the effectivity of drugs with antiprion action in the topical treatment of primary cutaneous amyloidosis.

Initially, Clorpromazine (cream 1%, qd) has been applied on a patient with diagnosis of primary cutaneous amyloidosis of macular subtype, who had a pruriginous hyperchromic macula in the dorsum that had been progressing for two years with a slow centrifuge growing. 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. In May 2010, this patient began the use of topical formulation of chlorpromazine. After eight days, 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.

Despite the poor therapeutic response achieved with this drug, 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. As clinical manifestation of the disease, patient presented a brow- nish macula measuring 10 cm on the interscapular region, and intense local pruritus, which did not improve despite the use of oral antihistamines, such as 25 mg hydroxyzine and 180 mg fexofenadine (Figure 4). When using the formulation containing guanabenz (cream, 0.5% qd), the patient surprisingly achieved the control of the pruritus, which was observed within 2 weeks of daily use of guanabenz, and decreased lesion area; in first place the brownish macula was observed to progressively brighten, followed by the reduction of lesion dimensions, earlier over peripheral areas. Thirty-three days af- ter the treatment had been started, patient already presented major lesion improvements (Figure 5).

As we first said, this invention evidenced that guanabenz surprisingly presents excellent results in the treatment of primary cutaneous amy- loidosis.

The result achieved with guanabenz has been satisfactory and completely unexpected, and such fact confirmed the prior knowledge about the physiopathogenic difference between prion disease and primary cutaneous amyloidosis, reinforcing the hypothesis that antiprion treatments are not effective for cutaneous amyloidosis.

Despite the multiple therapeutic attempts throughout the years, such as topical steroids, immunomodulating agents (tacrolimus, pimecroli- mus), keratolytic agents (salicylic acid) at several concentrations and formulations, and other local irritative agents (glycolic and retinoic acid), the treat- ment of primary cutaneous amyloidosis remains a therapeutical challenge, and there is no evidenced description of regression of disease with any of the current therapies. In such a setting, the development of a pharmaceutical composition for the effective treatment of primary cutaneous amyloidosis represents a big therapeutic advance and this invention brings the exciting possibility of topically using guanabenz for the treatment of this pathology. Detailed Description of the Invention

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.

Furthermore, 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, white beeswax, 2-octyldodecanol, sweet almond oil, grape seed oil, solid vaseline, mineral oil, dimethicone, simethicone, cyc- lomethicone), humectants (for example, propylene glycol, glycerine, polyethylene glycol, solid vaseline, sorbitol), conditioning agents (for example, vitamin E, silicones, macadamia nut oil, aloe vera oil, mineral oil, propylene glycol, lanolin) viscosity regulators and pH adjusters (for example, aminomethyl pro- panol, sodium hydroxide, citric acid, lactic acid) and preservatives (for example, methylparaben, propylparaben, ethylparaben, butylparaben, isobutylpa- raben, phenoxyethanol, imidazolidinyl urea, methylisothiazolinone).

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.

The composition of this invention can be presented as cream, gel, gel-cream, ointment, lotion or any other pharmaceutical form intended for topical use.

The composition of this invention can also contain substances that, if associated to guanabenz in any of the previously described pharmaceutical forms may bring benefits. Among the substances that can be associated to guanabenz worth noting:

- 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). The keratolytic action of these substances provokes a reduction in the stratum corneum of the epidermis and increases the dermal absorption of topical compounds applied over the skin, thus increasing the potential action of guanabenz;

- 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. In addition, 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.

Finally, 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.

A proof of principle has been conducted in one patient with confirmed diagnosis of primary cutaneous amyloidosis of macular subtype for five 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. As clinical manifestation of the disease, patient presented a brownish macula measuring 10 cm on the interscapular region, and intense local pruritus, which did not improve despite the use of oral antihistamines, such as 25 mg hydroxyzine and 180 mg fexofenadine (Figure 4). When using the formulation containing guanabenz (cream, 0.5% qd), patient initially achieved the control of the pruritus, which was observed within 2 weeks of daily use of guanabenz, and decreased lesion area; in first place the brownish macula was observed to progressively brighten, followed by the reduction of lesion dimensions, earlier over peripheral areas. Thirty-three days after the treat- ment had been started, patient already presented major lesion improvements (Figure 5).

Examples of formulations

The following examples are 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:

Example 2 - Cream B:

Preferred ConcenSpecial Concen¬

Raw material

tration (%w/w) tration (%w/w) Properties

Guanabenz 0.01 % to 10% 1 % Active ingredient

Cetostearyl alcohol 1 % to 20% 15% Thickener

Ethoxylated cetostearyl Non-ionic emulsi¬

0.1% to 8% 5%

alcohol fying agent

Occlusive emol¬

Solid vaseline 1% to 15% 5%

lient

Conditioning agent

Propylene glycol 0.01% to 50% 10%

/ emollient Preferred ConcenSpecial Concen¬

Raw material

tration (%w/w) tration (%w/w) Properties

Preservatives (phenox- yethanol and/or methy- lisothiazolinone and/or 0.01% to 2% 0.5% Preservative methylparaben and/or

propylparaben)

Water q.s.p. 100% q.s.p. 100% Carrier

Example 3 - Cream C:

Preferred ConcenSpecial Concen¬

Raw material

tration (%w/w) tration (%w/w) Properties

Guanabenz 0.01% to 10% 2% Active ingredient

Cetostearyl alcohol 1 % to 20% 15% Thickener

Ethoxylated cetosNon-ionic emulsify¬

0.1 % to 8% 5%

tearyl alcohol ing agent

Occlusive emol¬

Solid vaseline 1% to 15% 5%

lient

Conditioning agent

Propylene glycol 0.01% to 50% 10%

/ emollient

Preservatives (phe- noxyethanol and/or

methylisothiazolinone 0.01 % to 2% 0.5% Preservative and/or methylparaben

and/or propylparaben)

Water q.s.p. 100% q.s.p. 100% Carrier

Example 4 - Ointment:

Preferred ConcentraSpecial Concen¬

Raw material

tion (%w/w) tration (%w/w) Properties

Guanabenz 0.01 % to 10% 1 % Active ingredient

Conditioning agent

Lanolin 0.01% to 50% 20%

/ emollient Preferred ConcentraSpecial Concen¬

Raw material

tion (%w/w) tration (%w/w) Properties

Conditioning agent

Mineral oil 0.01% to 50% 50%

/ emollient

Conditioning agent

Polyethylene glycol 0.01 % to 50% 29%

/ emollient

Example 5 - Gel-Cream:

Example 6 - Gel:

Preferred ConcentraSpecial Concen¬

Raw material

tion (%w/w) tration (%w/w) Properties

Guanabenz 0.01% to 10% 1 % Active ingredient

Viscosity regula¬

Carbomer 0.1% to 10% 0.6%

tor

Sodium hydroxide 0.0001% to 1 % 0.0004% pH adjuster

Propylene glycol 0.01 % to 50% 5% Humectant Preferred ConcentraSpecial Concen¬

Raw material

tion (%w/w) tration (%w/w) Properties

Preservatives (phe- noxyet anol and/or

methylisothiazolinone

0.01 % to 2% 0.5% Preservative and/or methylparaben

and/or propylparaben)

Water q.s.p. 100% q.s.p. 100% Carrier

Example 7 - Lotion:

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Claims

1. Pharmaceutical composition for the treatment of primary cutaneous amyloidosis, characterized by the fact of comprising guanabenz as active ingredient.

2. Pharmaceutical composition according to claim 1 , characterized by the fact that guanabenz is present in an amount ranging from 0.01 % to 10% by weight, preferably from 0.5% to 2% by weight, based on the total weight of the composition.

3. Pharmaceutical composition according to claim 1 or 2, charac- terized by the fact of comprising at least one adjuvant and/or dermatologically acceptable carrier.

4. Pharmaceutical composition according to claim 3, characterized by the fact that at least one dermatologically acceptable adjuvant is selected among thickeners, self emulsifying waxes, non-ionic emulsifying agents, emollients / occlusive emollients, humectants, conditioning agents / emollients, viscosity regulators, pH correctors and preservatives.

5. Pharmaceutical composition according to claim 4, characterized by the fact that the thickener or self emulsifying wax is cetostearyl alcohol present in an amount ranging from 1 % to 20% by weight, preferably 15% by weight, based on the total weight of the composition.

6. Pharmaceutical composition according to claim 4, characterized by the fact that the non-ionic emulsifying agent is ethoxylated cetostearyl alcohol present 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.

7. Pharmaceutical composition according to claim 4, characterized by the fact that the occlusive emollient is solid vaseline present in an amount ranging from 1 % to 15% by weight, preferably 5% by weight, based on the total weight of the composition.

8. Pharmaceutical composition according to claim 4, characte- rized by the fact that the humectant is selected among solid vaseline and po- lyethilene glycol and is present in an amount ranging from 1 % to 50% by weight, preferably 5% to 30% by weight, based on the total weight of the composition.

9. Pharmaceutical composition according to claim 4, characterized by the fact that the conditioning agent / emollient is selected among propylene glycol, lanoline and mineral oil and is present in an amount ranging from 0.01 % to 50% by weight of composition.

10. Pharmaceutical composition according to claim 4, characterized by the fact that the viscosity regulator is carbomer present 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.

11. Pharmaceutical composition according to claim 4, characterized by the fact that the pH adjuster is sodium hydroxide present in an amount ranging from 0.0001 % to 1 % by weight, preferably 0.0003-0.05% by weight, based on the total weight of the composition.

12. Pharmaceutical composition according to claim 4, characte- rized by the fact that the preservative is selected among phenoxiethanol, me- thylisothiazolinone, methylparaben and propylparaben and is present in an amount ranging from 0.01 % to 2% by weight, preferably 0.5% by weight, based on the total weight of the composition.

13. Pharmaceutical composition according to claim 3, characte- rized by the fact that at least one dermatologically acceptable carrier is water.

14. Pharmaceutical composition according to any of the claims 1-13 characterized for further comprising other substances associated to gu- anabenz.

5. Pharmaceutical composition according to claim 14 characte- rized by the fact that said substances combined with guanabenz are selected among keratolytic agents, cutaneous depigmenting agents, and high-potency steroids.

16. Pharmaceutical composition according to claim 5, characterized by the fact that keratolytic agents are selected among retinoic acid, present in an amount ranging from 0.01 % to 0.1 % by weight, glycolic acid, present in an amount ranging from 10% to 30% by weight, and salicylic acid, present in an amount ranging from 5% to 10% by weight, based on the total weight of the composition.

17. Pharmaceutical composition according to claim 15, characterized by the fact that the skin depigmenting agent is hydroquinone present in an amount ranging from 2% to 5% by weight of composition.

18. Pharmaceutical composition according to claim 5, characterized by the fact that high-potency steroids are selected among clobetasol, desonide and betamethasone dipropionate / valerate and is present in an amount ranging from 0.05% to 0.1% by weight of composition.

19. Pharmaceutical composition according to any of the claims 1-18, characterized by the fact of being supplied as cream, gel, gel-cream, ointment or lotion.

20. Use of guanabenz, characterized by the fact of being for the preparation of a pharmaceutical composition as defined in any of the claims 1-19.

21. Method to test primary cutaneous amyloidosis, characterized by the fact that comprises the administration of a therapeutically effective dose of a pharmaceutical composition, as defined in any of the claims 1-19 to a patient with symptoms of the disease.