Novel salt forms of amiloride and derivatives thereof for pharmaceutical use

Abstract

The present invention relates to the lactate, acetate and phosphate salts of amiloride, and to certain amiloride derivatives. The present invention also relates to the use of such salts in medicine, pharmaceutical and cosmetic compositions comprising the novel salts, and methods of treating psoriasis with the salts.

Description

[Technical field]

[0001] The present invention relates to the field of medical therapy, in particular medical therapy using novel salts of certain amiloride derivatives. [Background technology]

[0002] Amiloride (3,5-diamino-6-chloro-N-(diaminomethylidene)pyrazine-2-carboxamide, CAS reg. no. 2609-46-3) is commonly used as the hydrochloride salt and as a potassium-sparing diuretic in the treatment of edema, often in combination with a thiazide diuretic. Amiloride is known to interact with proteins of the epithelial sodium channel (ENaC) and acid-sensing ion channel, as well as the sodium / hydrogen antiporter (NHE) and sodium / calcium exchanger (NCX). Amiloride as the hydrochloride salt has been approved for marketing in Europe since at least the early 1970s.

[0003] One amiloride derivative is benzamil, i.e. benzyl amiloride (3,5-diamino-N-(N'-benzylcarbamimidoyl)-6-chloropyrazine-2-carboxamide, CAS Registry Number 2898-76-2). WO 2015 / 168574 proposes the use of epithelial ion channel blockers, such as amiloride and its derivative benzamil, for the treatment of psoriasis. WO 2015 / 168574 discusses the use of pharma- ceutically acceptable salts of amiloride and its derivatives, but does not mention specific salts or how to select specific salts. U.S. Patent Application Publication No. 2013 / 109856 discloses a method for preparing the trifluoroacetic acid (TFA) salt of benzamil. Those skilled in the art will appreciate that TFA is not a suitable counterion for the drug.

[0004] Psoriasis is a chronic, recurrent immune-mediated skin disease. According to prevalence estimates, psoriasis affects 1-2% of the world's population, with equal distribution in men and women. Psoriasis can appear at any time during life, usually peaking between 30-39 years of age and between 60-69 years of age. Patients may experience itching, pain, and / or psoriasis-associated nail disease and arthritis. Considerable morbidity has psychosocial effects on individuals. Psoriasis patients are often stigmatized by people who stare at their damaged skin. Patients may experience reduced self-esteem and may face difficulties in relationships and employment. Psoriasis is also associated with an increased risk of cardiovascular disease, stroke, and cancer.

[0005] Histological evaluation of psoriatic plaques shows keratinocyte hyperproliferation with parakeratinization, epithelial elongation or interpapillary ridges, increased angiogenesis, and dermal infiltration of inflammatory cells, including T cells, neutrophils, macrophages, and dendritic cells (DCs).Other histological features frequently observed in psoriatic skin include carp micropustules, Munro microabscesses, thinning or loss of the granular layer, thinning of the papillary plate, and papillary dermis containing dilated superficial blood vessels.

[0006] The pathogenesis of psoriasis is multifactorial. Environmental factors such as trauma, stress, infections, and drugs activate an exaggerated inflammatory response in the skin in susceptible individuals. Psoriasis is a disease caused by dysfunctional proliferation and differentiation of keratinocytes, with a strong contribution of T cells through the release of proinflammatory cytokines that promote further recruitment of immune cells, keratinocyte proliferation, and persistent chronic inflammation. These T cells proliferate in the epidermis of psoriatic plaques.

[0007] The presence of innate immune cells and their products in psoriatic skin plaques indicates a role for innate immunity. Cells of the innate immune system include macrophages, NK and NKT cells, and DCs. The number of plasmacytoid and myeloid DCs is increased in psoriatic skin compared to non-lesional skin. Other cellular elements of innate immunity are also involved in the development of psoriasis, including numerous macrophages that can secrete IL-6, IL-12, IL-23, and TNF, respectively. Keratinocytes are also competent resident antigen-presenting cells (APCs) in the skin. When stimulated, they produce large amounts of cytokines (e.g., TNF, IL-6, and IL-18), chemotactic chemokines (e.g., IL-8 and CCL20), and antimicrobial peptides (e.g., β-defensin and LL37).

[0008] Genome-wide scans have reported that at least nine chromosomal loci have been linked to psoriasis, among which the PSORS1 locus accounts for 35-50% of the heritability of the disease. PSORS1 is located in the major histocomplex (MHC) region of chromosome 6 (6p21), whereby several genes contained in this region, namely HLA-Cw6, CCHCR1 (coiled-coil o helical rod protein), and CDSN (corneodesmosin), have been linked to psoriasis. Other susceptibility loci have also been identified, such as genes expressed in keratinocytes (LCE3B (late keratinocyte 3B) and LCE3C1 (late keratinocyte 3C1)) and immune cells (IL-12B, IL23R, and IL23A). This indicates that both the epidermal barrier and the immune response to pathogens are involved in psoriasis pathogenesis.

[0009] Currently, the first line of treatment for mild to moderate psoriasis is the use of topical agents. When topical treatments fail, the next level of treatment often includes phototherapy, oral systemic agents, and / or injectable biological agents. Corticosteroids, vitamin D analogs, and tazarotene are all used to treat chronic plaque psoriasis. However, prolonged exposure to topical corticosteroids can lead to skin atrophy, persistent striae, and telangiectasia. Although vitamin D analogs (e.g., calcitriol, calcipotriol, and tacalcitol) are effective psoriasis treatments, excessive use can lead to hypercalcemia. The odds of successful treatment are increased when vitamin D analogs are combined with topical corticosteroids compared to vitamin D analog monotherapy. As a result, the first line of treatment often recommended for plaque psoriasis is a combination of vitamin D analogs and topical steroids.

[0010] Other topical agents are commonly combined with topical corticosteroids and vitamin D analogs for the treatment of psoriatic plaques. Salicylic acid is a topical keratolytic agent used adjunctively to remove skin flakes, and it works by reducing the binding between keratinocytes, increasing hydration, and softening the stratum corneum by decreasing skin pH. However, salicylic acid toxicity can occur systemically after prolonged use over large skin areas. Retinoids, another common treatment for psoriasis, act on the skin by mediating or inducing cell differentiation and normalizing proliferation. Systemic retinoids, such as tazarotene, are associated with several adverse effects, including teratogenicity, elevated serum lipids, mucocutaneous toxicity, skeletal changes, and hair loss.

[0011] Ultraviolet (UV) therapy induces T-lymphocyte apoptosis in dermal and epidermal psoriatic lesions. Oral 8-methoxypsoralen-UV-A (PUVA) and narrow-band UVB (NB-UVB) are well-established effective treatments for chronic plaque psoriasis. PUVA has a response rate of about 80% compared to 70% for NB-UVB, but NB-UVB is preferred due to its greater convenience, except when the plaques are very thick. Systemic treatments are often used in combination with topical and phototherapy for patients with severe psoriasis. Oral systemic agents for the treatment of psoriasis include methotrexate, cyclosporine, and acitretin. Injectable biologic agents are an emerging approach to the treatment of psoriasis by targeting molecules in the inflammatory pathway. They are being considered for patients with severe psoriasis who are resistant to oral immunosuppressants and phototherapy. The two major therapeutic classes of injectable biologic agents are anti-cytokine agents and T-cell targeted agents. The first class consists of the injectable immunoglobulins (Igs), infliximab, and adalimumab, and targeted lytic membrane-bound forms of TNF. Other anti-cytokine therapeutics include etanercept and ustekinumab. The second therapeutic class of injectable therapeutics includes agents that bind to T-cells and prevent T-cell activation, such as alefacept and efalizumab.

[0012] Dermatologists and patients would benefit from new treatments for psoriasis, both locally and systemically deliverable. Summary of the Invention [Problem to be solved by the invention]

[0013] The present inventors have discovered that certain salts of the amiloride derivative benzamil have improved properties, at least in terms of improved stability, increased water solubility, and / or reduced polymorphism, compared to the free base compound and known salts of benzamil. [Means for solving the problem]

[0014] Thus, the present invention provides novel salt forms of benzamil, amiloride, and certain amiloride derivatives.

[0015] The free base compounds useful in the present invention are of formula (I):

[0016] [ka]

[0017] wherein R is selected from the following:

[0018] [ka]

[0019] -H; -C(CH3)2CH2C(CH3)3;

[0020] [ka]

[0021] [ka]

[0022] [ka]

[0023] In a first aspect, there is provided a salt of the above free base, ie, the lactate, acetate, or phosphate salt.

[0024] In one embodiment, the salt is a lactate salt.

[0025] In one embodiment, the free base compound is benzamil.

[0026] In one embodiment, the salt has only one crystalline form.

[0027] In a second aspect, the present invention relates to a pharmaceutical or cosmetic composition comprising a salt of the invention and, optionally, a pharma- ceutically and / or cosmetically acceptable excipient.

[0028] In one embodiment, the pharmaceutical composition is adapted for topical administration.

[0029] In a third aspect, the invention relates to a salt of the first aspect or a pharmaceutical composition of the second aspect for use in medicine.

[0030] In one embodiment, the invention relates to said salt or pharmaceutical composition for use in a method for the treatment of psoriasis.

[0031] In one embodiment, the psoriasis is chronic psoriasis or plaque psoriasis.

[0032] In one embodiment, the salt or composition is administered locally or systemically.

[0033] In a fourth aspect, the invention relates to the use of a salt of the first aspect in the manufacture of a pharmaceutical composition for use in a method for the treatment of psoriasis.

[0034] In one embodiment, the psoriasis is chronic psoriasis or plaque psoriasis.

[0035] In one embodiment, the salt is administered locally or systemically.

[0036] In a fifth aspect, the present invention relates to a method of treating psoriasis comprising administering to an individual in need of such treatment an effective amount of a salt of the first aspect or a pharmaceutical composition of the second aspect.

[0037] In one embodiment, the psoriasis is chronic psoriasis or plaque psoriasis.

[0038] In one embodiment, the salt is administered locally or systemically. [Brief description of the drawings]

[0039] [Figure 1] FIG. 1 shows a high-throughput XRPD diffractogram of the lactate salt of benzamil, form LAC1. [Diagram 2] FIG. 2 shows high-throughput XRPD diffractograms of benzamil lactate form LAC1 after it was prepared and subjected to accelerated degradation conditions (AAC). [Diagram 3] FIG. 3 shows a high-throughput XRPD diffractogram of benzamil acetate form ACA1. [Figure 4] FIG. 4 shows a high-throughput XRPD diffractogram of the acetate salt form of benzamil, ACA2. [Diagram 5] FIG. 5 shows high-throughput XRPD diffractograms of benzamil acetate forms ACA1 and ACA2 after they were prepared and subjected to accelerated degradation conditions (AAC). [Figure 6] FIG. 6 shows a high-throughput XRPD diffractogram of the phosphate form PHO2 of benzamil. [Figure 7] FIG. 7 shows high-throughput XRPD diffractograms of the phosphate form PHO2 of benzamil after it was prepared and subjected to accelerated aging conditions (AAC). [Figure 8] FIG. 8 shows the intrinsic dissolution rate profiles in water of A) benzamil lactate (LAC1) and B) benzamil TFA (TFA2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0041] The terms "sensitivity" and "sensitizing" used in relation to treatment are relative terms that refer to the effectiveness of a therapeutic compound in reducing or alleviating the symptoms of the disease being treated.For example, the term "increased sensitivity" used in relation to the treatment of cells or patients refers to at least a 5% or greater increase in efficacy in reducing or alleviating the symptoms of psoriasis, as measured by any method well-accepted in the art.

[0042] As used herein, and unless otherwise specified, the term "therapeutically effective amount" of a compound refers to an amount sufficient to provide a therapeutic benefit in the treatment or management of psoriasis, or to delay or minimize one or more symptoms associated with psoriasis. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, used alone or in combination with another therapeutic agent, that provides a therapeutic benefit in the treatment or management of psoriasis. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of psoriasis, or enhances the therapeutic effect of another therapeutic agent.

[0043] The term "likelihood" generally refers to an increased probability of an event. When used in relation to the efficacy of a patient response, the term "likelihood" generally takes into account an increased probability that the symptoms of psoriasis will be reduced or alleviated.

[0044] The terms "determining," "measuring," "assessing," "determining," and "assaying," as used herein, generally refer to any form of measurement, including determining the presence or absence of an element. These terms include both quantitative and / or qualitative determinations. Determinations may be relative or absolute. "Determining the presence or absence" includes measuring the amount of something present, not just determining presence or absence.

[0045] As used herein, the term "sample" refers to a material or mixture of materials, typically, but not necessarily, in fluid form, containing one or more components of interest.

[0046] As used herein, a "biological sample" refers to a sample obtained from a biological subject, including, for example, a sample derived from a biological tissue or fluid obtained, taken, or retrieved from in vivo or in situ. Biological samples also include samples derived from an area of ​​a biological subject that contains precancerous or cancerous cells or tissues. Such samples include, but are not limited to, organs, tissues, fragments, and cells isolated from a mammal. Examples of biological samples include, but are not limited to, cell lysates, cell cultures, cell lines, tissues, oral tissues, gastrointestinal tissues, organs, organelles, body fluids, blood samples, urine samples, skin samples, and the like. Suitable examples of biological samples include, but are not limited to, whole blood, partially purified blood, PBMCs, histology samples, and the like.

[0047] The term "combination," as in the phrase "a first agent in combination with a second agent," encompasses, for example, simultaneous administration of the first and second agents, which may be dissolved or mixed in the same pharma- ceutically acceptable carrier, administration of the first agent followed by the second agent, or administration of the second agent followed by the first agent. Thus, the present invention includes combination therapies and combination pharmaceutical compositions.

[0048] The term "concurrent" in the phrase "concurrent therapy" includes administering an agent in the presence of a second agent. Concurrent therapy includes methods in which a first, second, third, or further agent is administered simultaneously. Concurrent therapy also includes, for example, when a first or further agent is administered in the presence of a second or further agent, which may have been administered earlier. Concurrent therapy may be performed stepwise by different practitioners. For example, one practitioner may administer a first agent to a subject, and a second practitioner may administer a second agent to the subject, and the administration steps of both agents may be simultaneous, near simultaneous, or at separate times, as long as the administration of the first agent (and further agent) is in the presence of the second agent (and further agent). The practitioner and the subject may be the same entity (e.g., human).

[0049] As used herein, the term "dose" refers to the amount of a substance administered to a subject, e.g., in milligrams (mg). In one embodiment, the dose is a fixed dose, e.g., independent of the weight of the subject to whom the substance is administered. In another embodiment, the dose is a relative, non-fixed dose, e.g., depending on the weight of the subject to whom the substance is administered, or, in the case of topical treatments, the dose is relative to the surface area to be treated, e.g., the area of ​​the skin. 2 The dose may be per unit.

[0050] As used herein, the term "periodic" as it relates to the administration of a substance refers to the (regular) recurring cycle of administering the substance to a subject.

[0051] "Cycle duration" refers to the time during which repeated cycles of administration occur.

[0052] As used herein, the terms "treat", "treating" and "treatment", unless otherwise specified, refer to an effect occurring during a patient's illness with psoriasis, which effect reduces the severity of psoriasis, prevents or slows the progression of psoriasis, or achieves or maintains a therapeutic objective. An "effective patient response" refers to an increase in therapeutic benefit to the patient. An "effective patient psoriasis response" can be, for example, a 5%, 10%, 25%, 50%, or 100% reduction in the physical symptoms of psoriasis.

[0053] The term "kit" as used herein refers to a packaged product comprising ingredients to be administered together with the novel salt forms of the invention for the treatment of psoriasis. Preferably, the kit comprises a box or container holding the components of the kit. The box or container may be accompanied by a label or instructions approved by the Food and Drug Administration. The box or container holds the components of the invention, preferably in a plastic, polyethylene, polypropylene, ethylene, or propylene container. The container may be a tube or bottle with a lid. The kit may also include instructions for use.

[0054] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of a subject without causing toxicity, irritation, allergic reaction, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable compounds, materials, compositions, and / or dosage forms are also considered to be cosmetically acceptable.

[0055] As used herein, the phrase "pharmaceutical acceptable excipient" refers to an acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, manufacturing aid (e.g., lubricants, talc, magnesium, calcium or zinc stearates, or steric acids), solvent, or encapsulating material, that is involved in carrying or transporting any therapeutic compound for administration to a subject. Each excipient is "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the subject. Some examples of materials that can be used as pharmaceutical excipients include: ethanol; sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; gelatin; talc; wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as ethylene glycol and propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers; water; isotonic saline; pH buffers; and other non-toxic compatible substances used in pharmaceutical formulations. If necessary, certain sweeteners and / or flavors and / or colorants may be added. Pharmaceutically acceptable excipients are also considered to be cosmetically acceptable excipients.

[0056] As used herein, the term "compound" includes the free base form of a compound as well as the salt form of the compound.

[0057] PSM001, benzylamiloride, and benzamil are used interchangeably and are all intended to refer to 3,5-diamino-N-(N'-benzylcarbamimidoyl)-6-chloropyrazine-2-carboxamide (CAS Registry Number 2898-76-2).

[0058] Detailed Description of the Invention The present invention provides novel salts of amiloride and novel salts of amiloride derivatives that have improved properties in terms of at least improved stability, increased water solubility, and / or reduced polymorphism.

[0059] In a first aspect, the present invention relates to salts of the free base compounds of formula (I).

[0060] [ka]

[0061] The salts are selected from lactate, acetate and phosphate salts.

[0062] The salts of the present invention may have improved water solubility compared to prior art salts. A skilled formulator will appreciate that improved water solubility is advantageous when preparing active pharmaceutical ingredient (API) formulations. For example, higher concentrations of API may be used, which may provide higher dosages in the formulation. Such formulations may be topical or systemic delivery formulations.

[0063] In one embodiment, R is benzyl, i.e., the free base compound is benzamil.

[0064] In one embodiment, the salt is lactate. The advantage of lactate as counterion in pharmaceutical salt is that it is endogenous, e.g., present in human skin. This is particularly advantageous in topical formulations. Another advantage of lactic acid is that it is a keratolytic agent. Thus, in the embodiment where the salt is lactate, both the free base and the counterion can have therapeutic effects. Thus, a formulation comprising a free base compound of formula (I) in combination with lactate can provide a formulation with combined effects suitable for combination therapy.

[0065] In one embodiment, the salt is an acetate salt.

[0066] In one embodiment, the salt is a phosphate salt.

[0067] In one embodiment, the salt has only one crystalline form. A skilled formulator will understand that the presence of a single polymorph may be advantageous in the formulation of an API. For example, APIs with different polymorphs may have different release rates. Furthermore, the ratio of different polymorphs in a formulation may change over time. This may cause the release rate to change over time in a formulation of a salt with more than one polymorph.

[0068] In one embodiment, the free base compound is benzamil, the salt is the lactate salt, and an X-ray powder diffractogram of the salt comprises the characteristic peaks as shown in Figure 1. In one embodiment, the free base compound is benzamil, the salt is the acetate salt, and an X-ray powder diffractogram of the salt comprises the characteristic peaks as shown in Figure 3. In one embodiment, the free base compound is benzamil, the salt is the acetate salt, and an X-ray powder diffractogram of the salt comprises the characteristic peaks as shown in Figure 4. In one embodiment, the free base compound is benzamil, the salt is the phosphate salt, and an X-ray powder diffractogram of the salt comprises the characteristic peaks as shown in Figure 6.

[0069] In one embodiment, R is hydrogen, i.e., the free base compound is amiloride. In one embodiment, the salt is the lactate salt. In one embodiment, the salt is the acetate salt. In one embodiment, the salt is the phosphate salt. In one embodiment, the salt has only one crystalline form.

[0070] In one embodiment, R is -C(CH3)2CH2C(CH3)3. In one embodiment, the salt is the lactate salt. In one embodiment, the salt is the acetate salt. In one embodiment, the salt is the phosphate salt. In one embodiment, the salt has only one crystalline form.

[0071] In one embodiment, R is:

[0072] [ka]

[0073] In one embodiment, the salt is the lactate salt. In one embodiment, the salt is the acetate salt. In one embodiment, the salt is the phosphate salt. In one embodiment, the salt has only one crystalline form.

[0074] In one embodiment, R is phenyl, i.e., the free base compound is phenamil. In one embodiment, the salt is the lactate salt. In one embodiment, the salt is the acetate salt. In one embodiment, the salt is the phosphate salt. In one embodiment, the salt has only one crystalline form.

[0075] In one embodiment, R is:

[0076] [ka]

[0077] In one embodiment, the salt is the lactate salt. In one embodiment, the salt is the acetate salt. In one embodiment, the salt is the phosphate salt. In one embodiment, the salt has only one crystalline form.

[0078] Medicinal uses of the new salt The therapeutic effect of amiloride as a potassium-sparing diuretic is well established. The therapeutic effect of benzamil on psoriasis is plausibly shown in the examples of published PCT application WO2015168574, which is incorporated herein by reference.

[0079] WO2015168574 further discloses that benzamil targets the epithelial sodium channel (ENaC) and the sodium / calcium exchanger (NCX1) in human psoriatic keratinocytes. The inventors have demonstrated that benzamil targets ENaC, NCX1, and also the Na + / H + It has been recognized that related compounds with similar potency to benzamil on the exchange transporter NHE may provide similar beneficial effects as benzamil. Such compounds are disclosed in the prior art (Kleyman et al (1988), J Membrane Biol, 105:1-21) and include the free base compounds used in the present invention. Therapeutic effects have been plausibly established using the experimental protocols provided in WO2015168574.

[0080] Thus, the present invention in certain aspects relates to novel salts of benzamil, amiloride, and certain other amiloride derivatives for use in medicine.

[0081] In certain aspects, the present invention relates to novel salts of benzamil, amiloride, and other certain amiloride derivatives for use in the treatment of psoriasis. In embodiments, the form of psoriasis being treated is any of the forms discussed further below.

[0082] Chronic plaque psoriasis (also called psoriasis vulgaris) is the most common form of psoriasis. Chronic plaque psoriasis is characterized by red, raised areas of skin that can be coin-sized or larger. In chronic plaque psoriasis, the plaques can be single or multiple and can vary in size from a few millimeters to several centimeters. The plaques are usually scaly and red on the surface, and when gently scratched, they reflect light with a "silver" effect. Lesions from chronic plaque psoriasis, which are often symmetrical, occur all over the body, but most commonly on extensor surfaces, including the knees, elbows, lumbosacral region, scalp, and nails. Chronic plaque psoriasis sometimes occurs on the penis, vulva, and flexures, but is usually not scaly. The diagnosis of patients with chronic plaque psoriasis is usually based on the clinical features described above. In particular, the distribution, color, and typical silvery scales of chronic plaque psoriasis lesions are characteristic of chronic plaque psoriasis.

[0083] Guttate psoriasis is a form of psoriasis with characteristic droplet-shaped, scaly plaques. Flares of guttate psoriasis are typically followed by infections, most notably streptococcal throat infections. The diagnosis of guttate psoriasis is usually based on the appearance of the skin and the fact that there is often a recent history of sore throat.

[0084] Inverse psoriasis is a form of psoriasis in which patients have red, inflamed, smooth and usually moist areas of skin that differ from the scaly skin associated with plaque psoriasis. Inverse psoriasis is also called intertriginous psoriasis or intertriginous psoriasis. Inverse psoriasis occurs primarily in the armpits, groin, under the breasts, and in skin folds around the pubic area and buttocks, where friction and sweating irritate the affected areas.

[0085] Pustular psoriasis, also called palmoplantar psoriasis, is a form of psoriasis that causes pustules of various sizes in various locations, but most often on the hands and feet. The pustules may be localized or spread over a wide area of ​​the body. Pustular psoriasis may be tender and painful and may cause fever.

[0086] Erythrodermic psoriasis is a particularly inflammatory form of psoriasis that often affects most of the body surface. It may occur in association with von Zunbusch pustular psoriasis. It is a rare form of psoriasis, occurring at least once in the lifetime of 3 percent of people with psoriasis. It typically appears in people with unstable plaque psoriasis. Widespread redness and peeling of the skin characterizes this form. This condition is often accompanied by severe itching and pain. Erythrodermic psoriasis causes protein and fluid loss that can lead to severe disease. Edema (swelling due to fluid retention), especially around the ankles, can develop with infection. Erythrodermic psoriasis can also cause pneumonia and congestive heart failure. People with severe disease often require hospitalization. Erythrodermic psoriasis can develop suddenly, at the same time as the first signs of psoriasis are visible, or it can develop gradually in people with plaque psoriasis. Combination therapy, for example, a topical drug and one or two systemic drugs, is often required.

[0087] Thus, the present invention also relates to and utilizes a pharma- ceutical acceptable composition comprising at least one salt of the present invention in a therapeutically effective amount, optionally combined with one or more additional agents for the treatment of psoriasis, and formulated with one or more pharma- ceutical acceptable excipients.The active ingredient and one or more excipients may be formulated into a composition or dosage form according to methods known in the art.The pharmaceutical composition of the present invention may be formulated for administration by topical application, for example, as a lotion, cream, ointment, spray, salve, or microneedle array applied to the skin, or may be formulated for oral administration in a solid, liquid, or semi-liquid form, for example, as a tablet, capsule, powder, granule, tongue paste, aqueous or non-aqueous solution or suspension, drench, or syrup.

[0088] Thus, the present invention also relates to and utilizes a cosmetically acceptable composition comprising an amount of at least one salt of the present invention, optionally in combination with one or more additional agents and formulated with one or more acceptable excipients. The cosmetic composition may be useful for improving the appearance or feel of the skin of a subject, but does not have an effect on the skin that is considered to be therapeutic. The salt and one or more excipients may be formulated into a composition or dosage form according to methods known in the art. The cosmetic composition of the present invention may be formulated for administration by topical application, for example, as a lotion, cream, ointment, spray, salve, or microneedle array applied to the skin, or may be formulated to be suitable for oral administration, for example, as a solid, liquid, or semi-liquid, such as a tablet, capsule, powder, granule, tongue paste, aqueous or non-aqueous solution or suspension, drench, or syrup.

[0089] The medicaments, pharmaceutical compositions, or therapeutic combinations of the invention may be in any form suitable for administration to humans and / or animals, preferably humans, including infants, children, and adults, and may be prepared by standard procedures known to those skilled in the art. Medicaments, (pharmaceutical) compositions or combinations of therapeutic agents can be prepared according to standard procedures known to those skilled in the art, for example according to the tables of contents of "Pharmaceutics: The Science of Dosage Forms", Second Edition, Aulton, ME (ED. Churchill Livingstone, Edinburgh (2002); "Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, J. and Boylan JC (Eds.), Marcel Dekker, Inc. New York (2002); "Modern Pharmaceutics", Fourth Edition, Banker GS and Rhodes CT (Eds.) Marcel Dekker, Inc. New York 2002 y "The Theory and Practice of Industrial Pharmacy", Lachman L., Lieberman H. And Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986), each of which is incorporated herein by reference and forms part of the present disclosure.

[0090] An effective dose of the salt of the present invention may include a "therapeutically effective dose or amount" or a "prophylactically effective dose or amount" as defined above. The therapeutically effective amount may vary depending on factors such as the individual's medical condition, age, sex, and weight, and whether the individual is capable of eliciting a desired response. A therapeutically effective dose / amount is also one whereby any toxic or detrimental effects are outweighed by the therapeutically beneficial effects. A "prophylactically effective dose / amount" refers to an amount effective to be administered at a frequency and for a period of time necessary to achieve the desired prophylactic result. Typically, a prophylactic dose is used in subjects prior to or at an early stage of disease, such that the prophylactically effective amount will be less than the therapeutically effective amount.

[0091] Treating psoriasis can involve achieving or maintaining a PGA score of 0 / 1 or a PASI50, PASI75, PASI90, or PASI100 response score during or after treatment (e.g., for at least 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 52, 54, 56, 58, or 60 weeks, or longer). Treating psoriasis can also involve achieving or maintaining health-related quality of life (HRQOL) outcomes. HRQOL outcomes included the Dermatology Life Quality Index (DLQI), visual analogue scales for Ps-related (VAS-Ps) and psoriatic arthritis-related (VAS-PsA) pain, mental (MCS) and physical (PCS) summary scores from the Short-Form 36 Health Survey, and Activities of Daily Living (TAI) scores.

[0092] Treatment of psoriasis can also involve achieving or maintaining a minimum clinically important difference (MCID) in any one or combination of the HRQOL outcomes provided herein, such as the DLQI, VAS-Ps, VAS-PsA, MCS, PCS, and TAI.

[0093] Treatment of psoriasis may also involve achieving or maintaining a minimal clinically important change (MCID) response rate in any one or a combination of any of the HRQOL outcomes provided herein, such as DLQI, VAS-Ps, VAS-PsA, MCS, PCS, and TAI. "Treatment" or "treating" of psoriasis may also mean achieving or maintaining a clinically meaningful reduction in any one or a combination of any of the HRQOL outcomes provided herein, such as DLQI, VAS-Ps, VAS-PsA, MCS, PCS, and TAI. "Treatment" or "treating" psoriasis can also mean achieving or maintaining a Nail Psoriasis Severity Index (NAPSI) score during or after treatment (e.g., for at least 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 52, 54, 56, 58, or 60 weeks, or longer).

[0094] Treating psoriasis can also involve achieving or maintaining any of the results provided herein in a certain percentage of the subject population (e.g., at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% of the subject population).

[0095] Dosage regimen may be adjusted to provide the optimum desired response (e.g., therapeutic or prophylactic response). For example, a single dose may be administered, or several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Dosage may be administered to a subject at the time of skin disease symptoms or prior to the onset of symptoms.

[0096] It should be noted that dosage values ​​may vary depending on the type and severity of the condition to be alleviated. It should further be understood that for any particular subject, specific dosage regimens will need to be adjusted over time according to the individual needs and professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or application of the claimed compositions.

[0097] In one embodiment, the dose is a fixed dose, e.g., not dependent on the weight of the subject to which the substance is administered. In another embodiment, the dose is not a fixed dose, e.g., dependent on the weight of the subject to which the substance is administered, or, in the case of topical treatment, the dose is related to the surface area to be treated, e.g., the area of ​​the skin. 2 The dose may be per unit.

[0098] Suitable examples of doses, e.g., fixed doses for use in treating adult humans, include about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 50 mg, about 100 mg, about 500 mg, or more.

[0099] A suitable example of a dose, e.g., for topical use to treat an adult human with the method of the present invention, is about 0.01 mg / m 2 Surface area, approximately 0.05mg / m 2 Surface area, approximately 0.1mg / m 2 Surface area, approximately 0.5mg / m 2 Surface area, approximately 1mg / m 2 Surface area, approximately 5mg / m 2 Surface area, approximately 10mg / m 2 Surface area, approximately 50mg / m 2 Surface area, approximately 100mg / m 2 Surface area, approximately 500mg / m 2 surface area, or even more.

[0100] Intermediate ranges between the ranges recited above are also contemplated, e.g., ranges having any of these values ​​as upper or lower limits, such as about 0.01 mg to about 100 mg, about 1 mg to about 10 mg, etc., are also contemplated as part of the invention.

[0101] The administration of the composition can comprise a repeated cycle of administering the composition to the subject.The periodicity of administration of the composition can be about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, about once every eleven weeks, about once every twelve weeks, about once every thirteen weeks, about once every fourteen weeks, about once every fifteen weeks, about once every sixteen weeks, about once every seventeen weeks, about once every eighteen weeks, about once every nineteen weeks, about once every twenty weeks, about once every twenty-one weeks, about once every twenty-two weeks, about once every twenty-three weeks, about once every twenty-four ... The period may be once every 5-10 days, once every about 10-20 days, once every about 10-50 days, once every about 10-100 days, once every about 10-200 days, once every about 25-35 days, once every about 20-50 days, once every about 20-100 days, once every about 20-200 days, once every about 30-50 days, once every about 30-90 days, once every about 30-100 days, once every about 30-200 days, once every about 50-150 days, once every about 50-200 days, once every about 60-180 days, or once every about 80-100 days. The present invention also contemplates periods intermediate between the periods recited above. The present invention also contemplates ranges intermediate between the ranges recited above. For example, ranges having any of these values ​​as upper or lower limits, such as about 110 days to about 170 days, about 160 days to about 220 days, etc., are also considered to be part of the present invention.

[0102] The periodic duration of the substance administration may be up to about 4 weeks, up to about 8 weeks, up to about 12 weeks, up to about 16 weeks or more, up to about 20 weeks, up to about 24 weeks, up to about 28 weeks, up to about 32 weeks or more, during which the periodicity of administration may be about once per week. For example, the periodic duration may be about 6 weeks, during which the periodicity of administration may be about once per 4 weeks, for example, the substance is administered at week 0 and week 4. EXAMPLES

[0103] The abbreviations in Table 1 are used throughout this disclosure.

[0104] [Table 1]

[0105] Example 1: Preparation of novel salts The thermal stability of benzamil was evaluated in three solvent systems: acetonitrile:water=1:1, ethanol, and 0.1 M HCl. Solutions of benzamil (approximately 0.5 mg / mL) were prepared in the selected solvents above and dispensed into three vials. The solutions were stirred at room temperature, 50°C, and 80°C for 1 h and then analyzed by UPLC MS. The chemical purity of benzamil measured in the solutions incubated at 50°C and 80°C for 1 h was compared to that measured in the starting solution. Benzamil appeared to be stable when incubated in ethanol at 50°C for 1 h, but some chemical decomposition was observed in the solution incubated at 80°C. Based on these results, the highest application temperature for further studies was set at 50°C.

[0106] The solubility of benzamil free base was qualitatively evaluated in ethanol, water, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile, tert-butyl methyl ether, heptane, ethyl acetate, THF, and methanol. Aliquots of solvent were added to approximately 5 mg of benzamil free base until dissolution occurred. If benzamil did not dissolve at a concentration of approximately 3 mg / mL, the suspension was incubated at 50° C. for 30 minutes to investigate the effect of temperature on solubility. Benzamil was insoluble in most of the solvents tested, except that it was slightly soluble in methanol and 1,2-dimethoxyethane. The suspension in THF appeared to thin when incubated at 50° C. for 30 minutes, indicating that higher temperatures slightly improved solubility.

[0107] Based on the results of the thermal stability and qualitative solubility tests, salt formation experiments were carried out by slurry conversion in methanol (MeOH), 1,2-dimethoxyethane (DME), and THF.

[0108] Suspensions of benzamil free base were prepared in three selected solvents and counterions were added in aqueous solutions at 1:0.5, 1:1, and 1:2 (pK a The mixture was first heated at 50°C for 1 h and then cooled to 5°C.

[0109] The precipitated solids were analyzed by high-throughput X-ray powder diffraction (HTXRPD). The liquid phase (both the solution and the mother liquor) was evaporated under ambient conditions and the residual solids were analyzed by HTXRPD.

[0110] 23 novel crystalline phases were identified (presumably monophasic). At least one crystalline form was identified by reaction of benzamil with each counterion tested except gluconic acid. Salt formation with lactic acid in DME and THF produced the same crystalline phase (designated "LAC1"), whereas in MeOH, amorphous material was recovered. Salt formation with acetic acid, benzoic acid, tartaric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and sulfuric acid often identified different XRPD patterns in solids isolated from different solvents, suggesting that the salts are polymorphic. Reaction of benzamil with benzoic acid, nitric acid, and p-toluenesulfonic acid also produced a mixture of crystalline phases in some cases.

[0111] The physical stability of the newly identified phases was tested by exposing the solids to 40° C. / 75% relative humidity (RH) for 2 days (accelerated aging conditions, AAC).

[0112] The results are shown in Table 2. In the table, benzamil is sometimes referred to as "API."

[0113] [Table 2] JPEG2024538621000012.jpg238152JPEG2024538621000013.jpg244156

[0114] The XRPD patterns for salts ACA1, ACA2, BNZ1, BNZ2, BNZ3, DiHCl1, DiHCl2, LAC1, NIT1, NIT2, PHO2, PHO3, TOS1, TOS2a, TOS3, TOS4, TOS5, SUL1, SUL3 showed good crystallinity, whereas the XRPD patterns for TAR1, TAR2, NIT4, PHO1, SUL2, SUL4, SUL5, SUL6 showed poor crystallinity. Figure 1 shows the HR-XRPD pattern of the lactate salt form LAC1 of benzamil. Figure 2 shows the HR-XRPD patterns of the acetate salt forms ACA1 and ACA2 of benzamil. Figure 3 shows the HR-XRPD pattern of the phosphate salt form PHO2 of benzamil.

[0115] Physical stability studies carried out at 40 °C / 75% RH for 2 days showed that ACA1, ACA2, BNZ1, BNZ2, BNZ3, LAC1, TAR1, TAR2, PHO2, TOS1, TOS3, and SUL1 were physically stable salts, whereas diHCl1, diHCl2, NIT1, NIT2, NIT4, PHO1, PHO3, TOS2a, SUL2, SUL3, SUL4, SUL5, and SUL6 were physically unstable salts.

[0116] New XRPD patterns were identified for the salt forms obtained for HCl in methanol and DME. The new forms were designated "DiHCl1" and "DiHCl2". Both phases exposed to AAC (40°C / 75% RH) for 2 days were partially or totally converted to a mixture of mono-HCl salts A+B (denoted "SM1"). Thus, both DiHCl1 and DiHCl2 were physically unstable.

[0117] The water solubility of the salts was qualitatively evaluated by the solvent aliquot addition method. Aliquots of water were added to approximately 5 mg of salt up to 500-600 μL. The solubility of the free base was also evaluated. The results of the solubility tests are shown in Table 3. LAC1 showed a solubility of 26-51 mg / mL; ACA1 and ACA2 showed solubilities of 15-19 and 12-16 mg / mL, respectively; PHO2 showed a solubility of 12-16 mg / mL.

[0118] The remainder of the experiment remained as suspensions (concentration of approximately 10 mg / mL). The suspensions were allowed to equilibrate at room temperature for 24 hours. The solid was then separated from the liquid phase. The liquid phase was filtered and analyzed by HPLC to determine solubility. The pH of the solutions / mother liquors was also measured. BNZ1, BNZ2, BNZ3, SUL1, TAR1pc, TOS1, and NIT5 showed solubilities below 2 mg / mL. Benzamil free base was practically insoluble in water.

[0119] [Table 3]

[0120] Although it was physically unstable after 2 days of AAC (40°C / 75% RH), the water solubility of the di-HCl salt was also evaluated for comparison with the solubility value of 2-3 mg / mL previously evaluated for the mono-HCl salt (Sigma-Aldrich, product no. B2417). Suspensions of the two salts were prepared in water at concentrations of 9-10 mg / mL. The mixtures were allowed to equilibrate at room temperature for 24 hours. The solids were then separated from the liquid phase. The liquid phase was filtered and analyzed by HPLC to determine solubility. The pH of the mother liquors was also measured. The solubility of both salts appeared to be around 3 mg / mL, and thus similar to that of the mono-HCl salt.

[0121] The hygroscopic behavior of the salts was evaluated by dynamic water vapor sorption (DVS) measurements with RH profiles of 40–95 and 0–40%, at 25 °C, and dm / dt of 0.002. The classification of hygroscopic behavior is based on water vapor uptake at 25 °C / 80% RH in the first adsorption cycle of the sorption isotherm. ACA1 and BNZ1 were non-hygroscopic since they adsorbed 0.1% water vapor. BNZ2, LAC1, PHO2, TOS1, and NIT5 were slightly hygroscopic since they adsorbed 0.2 to 0.9% water vapor. The analyzed salts were physically stable when exposed to varying RH levels, since their XRPD patterns remained unchanged after DVS measurements.

[0122] Only one polymorph of the lactate salt was observed.

[0123] In summary, the lactate, phosphate, and acetate salts of benzamil exhibited improved stability and increased water solubility, little or no hygroscopicity, and reduced polymorphism.

[0124] Example 2: Preparation of further novel salts Salt formation experiments were further carried out to test additional salts in association with 35 pharma- ceutically acceptable counterions to test crystallinity, stability and solubility.

[0125] Analysis method The following analytical methods were used in Examples 2 and 3.

[0126] High-Throughput X-Ray Powder Diffraction (HT-XRPD) XRPD patterns were obtained using an Ardena T2 high-throughput XRPD setup. The plates were mounted on a Bruker General Area Detector Diffraction System (GADDS) equipped with a VANTEC-500 gas area detector corrected for intensity and geometric variations. Calibration of measurement accuracy (peak positions) was performed using NIST SRM1976 standards (corundum).

[0127] Data collection was performed at room temperature using monochromatic Cu Kα radiation in the 2θ region between 1.5° and 41.5°, which is the most distinct part of the XRPD pattern. Diffraction patterns for each well were collected in two 2θ ranges (first window 1.5°≦2θ≦21.5°, second window 19.5°≦2θ≦41.5°) with an exposure time of 90 seconds for each window. No background subtraction or curve smoothing was applied to the XRPD patterns.

[0128] thermal analysis TGA / SDTA and TGMS analysis: Mass loss due to solvent or water loss from the crystals was measured by TGA / DSC. The weight of the sample was monitored during heating in a TGA / DSC 3+ STARe system (Mettler Toledo GmbH, Switzerland) resulting in weight vs. temperature curves and heat flow signal measurement points. The TGA / DSC 3+ was temperature calibrated with indium and aluminum samples. Samples (approximately 2 mg) were weighed into 100 μL aluminum crucibles and sealed. A pinhole was drilled in the seal and the crucibles were heated in the TGA from 25 to 300 °C at a heating rate of 10 °C min-1. Dry N2 gas was used for purging.

[0129] The gases coming from the TGA samples were analyzed with a mass spectrometer Omnistar GSD301T2 (Pfeiffer Vacuum GmbH, Germany), which is a quadrupole mass spectrometer that analyzes mass in the temperature range of 0–200 amu.

[0130] DSC analysis: Thermal events were visualized from DSC thermograms and recorded on a heat flux DSC 3+ STARe system (Mettler Toledo GmbH, Switzerland). The DSC 3+ was calibrated for temperature and enthalpy with small pieces of indium (mp=156.6 °C; δHf=28.45 J / g) and zinc (mp=419.6 °C; δHf=107.5 J / g). Samples (approximately 2 mg) were sealed in standard 40 μL aluminum pans, pinhole drilled, and heated in the DSC from 25 °C to 300 °C at a heating rate of 10 °C / min. During the measurements, the DSC instrument was purged with dry N2 gas at a flow rate of 50 mL / min.

[0131] 1H-NMR spectroscopy 1 Compound integrity was characterized by H-NMR spectroscopy in DMSO-d6 and salt and co-crystal stoichiometries were determined where appropriate. Spectra were recorded at room temperature (RT) using standard pulse sequences on a 500 MHz instrument (Bruker Biospin GmbH). Data were processed with ACD Labs software Spectrus Processor 2016.2.2 (Advanced Chemistry Development Inc., Canada).

[0132] UPLC analysis UPLC system: UPLC: Agilent 1290 Detector 1: Diode array UV detector (set to 286 nm) Detector 2: MSD XT single quadrupole in positive scan mode UPLC conditions: Autosampler temperature: Room temperature Column: Agilent Eclipse Plus C18 HD (50 x 2.1 mm; 1.8 μm) Column temperature: 40℃ Flow cell: 10 mm flow path Mobile phase A: 10 mM ammonium acetate in water Mobile phase B: Acetonitrile Flow rate: 0.6ml / min Gradient: Time [min]: Eluent A: Eluent B: 0.00 95% 5% 0.10 95% 5% 2.50 10% 90% 2.55 10% 90% 2.56 95% 5% 3.50 95% 5% Implementation time: 3.5 minutes sample: Concentration: Approximately 1.0mg / mL Solvent: MeCN Injection volume: 1μL Holding time: 1.22 minutes MS: m / z 320

[0133] Compound completeness was expressed as a percentage of the peak area calculated from the area of ​​each peak other than the "injection peak" in the chromatogram, with the total peak area being:

[0134]

number

[0135] The peak area percentage of the compound of interest was used as an indication of purity of the component in the sample.

[0136] Experimental Method material Approximately 3 g of benzamil lactate salt (batch SBO-84-44) was supplied by Ardena AB, Södertälje, Sweden. All chemicals were obtained from Fisher Scientific or Sigma-Aldrich. Chemicals used were of research grade and had a purity of at least 99%.

[0137] Preparation of the free base: Approximately 5 g of benzyl lactate was dissolved in 320 mL of water. The pH of the solution was 5.8. A 1 M aqueous solution of NaOH was added stepwise (total of 14 mL of 1 M NaOH added) until the pH stabilized at 10.5, forming a white precipitate. The suspension was stirred for 30 min and the precipitate was aged. The precipitate was filtered in a Büchner funnel and washed twice with 200 mL of water. The resulting solid was dried overnight at 50 °C and 5 mbar. Yield = 3.6 g (92%). Previously, the eluate was characterized by HT-XRPD, UPLC-MS, TGMS (thermogravimetric analysis coupled with mass spectrometry), and 1 The solid was characterized by H-NMR and used as starting material for salt screening.

[0138] method Salt sieving experiments were carried out in methanol (MeOH), 1,2-dimethoxyethane (DME), and tetrahydrofuran (THF). Suspensions of benzamil free base prepared in these three solvents and counterion solutions were added to give benzamil free base:counterion molar ratios of 1:0.55, 1:1.1, and 1:2.2. The experimental counterions are listed in Table 4.

[0139] [Table 4]

[0140] The suspension was heated to 50°C for 1 h, then cooled at 1°C / h to 5°C and aged at this temperature for 3 days. The solids were separated from the liquid phase by centrifugation, dried in vacuum at 50°C overnight and analysed by HT-XRPD. The solvent was evaporated from the remaining mother liquors and solutions at ambient conditions (evaporative crystallization experiments) and the residual solids analysed by HT-XRPD. All solids were exposed to accelerated aging conditions (AAC, 40°C / 75%RH) for 2 days and re-analysed by HT-XRPD.

[0141] The counterions, applied benzamil:counterion (API:CI) ratios, and isolation conditions (crystallization method and solvent) are reported for each salt form identified, along with an indication of crystallinity and physical stability, in Table 5.

[0142] result

[0143] [Table 5] JPEG2024538621000018.jpg235161JPEG2024538621000019.jpg221158

[0144] Salts with ethane, L-ascorbic acid, L-aspartic acid, and galactaric acid were not observed. However, for the same counterion, different XRPD patterns were often identified in solids isolated from different crystallization solvents, suggesting that the salts in question are polymorphs.

[0145] In the case of 1,5-naphthalenedisulfonic acid (NDS1), L-glutamic acid (GLT1), nicotinic acid (NIC), oxalic acid (OXA1), pivalic acid (PIV1), succinic acid (SUC1), and trifluoroacetic acid (TFA1), only one salt polymorph was observed from all three crystallization solvents, and all of these forms were physically stable when exposed to ACC.

[0146] Two crystalline salt forms were observed in the isolated solids for cinnamic acid (CIN1-2), citric acid (CIT1-2), fumaric acid (FUM1-2), glutaric acid (GLU1-2), hippuric acid (HIP1-2), L-malic acid (MAL1-2), stearic acid (STE1 and STE3), adipic acid (ADI1 and ADI3), and valeric acid (VAL1-2). Three crystalline salt forms were identified for gentisic acid (GEN1-3), benzenesulfonic acid (BES1-3), butyric acid (BUT1-3), maleic acid (MAE1-3), methanesulfonic acid (MES1-3), orotic acid (ORO1-3), and salicylic acid (SAL1-3). However, further analytical characterization revealed that ADI2 and STE3 were physical mixtures of API and CI.

[0147] Several forms were identified by salt formation with 1,2-ethanedisulfonic acid (EDY1–6), 2-furoic acid (FUR1–5), ethanesulfonic acid (ESY1–4), formic acid (FOR1–5), hydrobromic acid (HBR1–10), malonic acid (MAO1–4), naphthalene-2-sulfonic acid (NSA1–4), pamoic acid (PAM1–4), and propionic acid (PRO1–6).

[0148] The salt forms EDY1, EDY2, EDY3, EDY4, EDY6, NDS1, FUR1, FUR2, FUR3, ADI1, ADI3, BES1, BES2, BES3, BUT1, CIN2, CIT2, ESY1, FOR1, FOR3, FOR4, FOR5, FUM1, FUM2, HIP1, HBR6, HBR7, HBR8, MAL1, MAE1, MAE2, MAO1, MAO4, MES1, NSA1, NIC1, ORO1, ORO2, PIV1, PRO1, SAL1, SUC1, TFA1, and VAL1 showed good crystallinity. The other salt forms showed moderate or poor crystalline phases or were isolated only as mixtures and not as pure forms, and therefore crystallinity was not assessed.

[0149] After 2 days of exposure to AAC (40 °C / 75% RH), only the following solid phases were physically stable salts: EDY2, EDY3, NSD1, GEN1, GEN2, FUR1, BUT1, CIN1, CIN2, ESY1, FUM2, GLU1, GLU2, HBR1, GLT1, MAL1, MAE2, MAE3, MAO1, MES1, NSA2, NSA4, NIC1, ORO1, ORO2, OXA1, PAM1, PAM2, PIV1, SAL1, STE1, STE2, SUC1, TFA1, and VAL1.

[0150] In conclusion, benzamil showed a tendency to form physically stable salts.

[0151] Solid-state characterization of salts The physicochemical characterization of the salts in physically stable, phase pure form with good crystallinity was performed by UPLC, TGA, DSC, and 1The analysis was performed by H-NMR. The salts obtained after one week exposure to 40°C / 75%RH were also analyzed by TGMS. Analysis by TGMS determined the amount and nature of the solvent that evaporated when the samples were heated.

[0152] result The chemical purity of benzamil in the identified novel salts ranged from 98.7 to 99.9% (area %). Some of the salts exhibited more than one crystalline phase, including anhydrous polymorphs as well as hydrates, hemihydrates, dihydrates, solvates, and combinations of water and solvent in the crystal lattice.

[0153] [Table 6]

[0154] Usually, the DSC curves show for the anhydrous salts one event that may correspond to melting and / or the onset of decomposition. In the case of hydrated / solvated forms, a broad endothermic event assigned to the evaporation of water and / or solvent from the crystal lattice was recorded before the final melting / onset of decomposition.

[0155] Among the anhydrous salts, 1,5-napadisylate NDS1 showed the highest melting point (280 °C), followed by the esylate ESY1 (260 °C), the fumarate FUM1 (253 °C), the succinate SUC1 (241 °C), and the TFA salt TFA1 (239 °C).

[0156] In most cases, salt formation 1 This was confirmed by H-NMR analysis. The signals of benzamil (especially the CH2 group) were shifted in the spectrum of the salt, suggesting that proton transfer had occurred from the acidic counterion to the basic benzamil free base. The stoichiometry of the salt was calculated by proton signal integration.

[0157] Most of the salt forms had a stoichiometry of 1:1 (API:CI) except for MAL1, FUM1, and EDY3, which had a stoichiometry of 1:0.5 between API and counter ion. Furthermore, in the cases of CIT1, HBR1, OXA1, and TFA1, the counter ion was 1 The stoichiometry could not be determined because they did not appear in the 1 H-NMR spectrum or their signals overlapped with those of water.

[0158] Some salts did not show any signal transition (BUT1, CIN1, CIN2, GLU1, PIV1, and VAL1). As can be seen in Table 7, most of the salt forms showed a single event in the DSC patterns that most likely corresponds to the melting of the salt. 1 They can be classified as salts even if H-NMR analysis fails to confirm salt formation: the lack of movement in the NMR signal can be explained by the small difference in their pKa values.

[0159] [Table 7]

[0160] To further classify the salts, the water solubility was measured for the anhydrous and hydrated salt forms as well as the salts found after stability studies. Given the presence of organic solvents in the solid phase of GEN1, CIT1, FOR1, HIP1, ORO2, and SAL1, these salts were not investigated further. Also, the solids of FUR3, ESY1, MAE2, and PAM2 were not sufficiently recovered by sieving, so these salts could not be investigated further. A summary of the physicochemical characterization results collected for the tested salts and the crystalline phases found by sieving is shown in Table 8.

[0161] [Table 8] JPEG2024538621000023.jpg72157

[0162] water soluble Water solubility was measured for the anhydrous and hydrated salt forms as well as for the salts found after stability studies. Aliquots of water were added to the solid salts until dissolution occurred or until 1600 μL of water was added. The lactate salt was used as a reference in the solubility studies. MES1, GLT1, and BUT1 were completely dissolved. All other salt forms were not fully dissolved and remained in suspension even after the addition of 1600 μL of water. To promote full dissolution, the suspensions were heated at 50° C. for 15 min. HBR1, MAO1, FOR3, and PRO2 were dissolved under these conditions. The results of the solubility measurements performed in water (in mg / mL of dissolved free base to facilitate comparison between salt forms) are reported in Table 9.

[0163] When the solubility measurements were completed, the remaining solids were separated from the liquid phase and allowed to air dry. The dried solids were analyzed by HT-XRPD.

[0164] [Table 9]

[0165] Only MES1 showed better solubility values ​​than the starting material (LAC1). However, precipitation was observed after full dissolution. The water solubility measurements were repeated, this time targeting a concentration of 50 mg / ml. The salt dissolved quickly at room temperature and emerged again as a white solid after 15 minutes.

[0166] Example 3: Comparative study of benzamil lactate and trifluoroacetate salts In this example, the lactate and TFA salts of benzamil were compared in terms of physicochemical parameters, polymorphism, solubility, and dissolution rate.

[0167] material Chemicals were obtained from Fisher Scientific or Sigma-Aldrich. Chemicals used were of research grade and had a purity of at least 99%. Five grams of lactate salt PSM001 (benzamil lactate, batch SB084-44) were supplied by Psomri. Benzamil lactate (anhydrous form LAC1) was 1 This was confirmed by H-NMR. The lactate counter ion 1 H-NMR visualized the salt stoichiometry as 1:1, and UPLC analysis confirmed the chemical purity to be 99.4% (area %).

[0168] Experimental Method Preparation of the free base: Approximately 2 g of benzamil lactate was dissolved in 128 mL of water. The pH of the solution was 5.8. A 1 M aqueous solution of NaOH was added stepwise (a total of 7 mL of 1 M NaOH was added) until the pH stabilized at 10.5, forming a white precipitate. The suspension was stirred for 30 min and the precipitate was aged. The precipitate was filtered in a Büchner funnel and washed twice with 200 mL of water at room temperature. The resulting solid was dried overnight at 50° C. and 5 mbar. The yield was 1.4 g (72%) of benzamil free base. The solid was analyzed by HT-XRPD and 1 Analysis by 1 H-NMR compared with starting material confirmed the formation of the free base.

[0169] Preparation of TFA salt: A suspension of the free base (1.2 grams) was prepared in THF (14.75 ml) at room temperature. Counterion solution (1M TFA in water) was added until an API:CI ratio of 1:1.1 was reached. The suspension was heated to 50° C. and held at this temperature for 1 hour, then cooled to 5° C. and held at this temperature for 3 days. After completion of the aging period, the solid was separated from the liquid phase by centrifugation and analyzed by HR-XRPD, TGA, DSC, UPLC, and HPLC as a vacuum dried solid (Sample ID: GEN8). 1 Analysis by 1 H-NMR confirmed that the product was the benzamil TFA salt.

[0170] Preparation of amorphous benzamil lactate salt: Approximately 10 mg of API was dissolved in a mixture of organic solvent and water (listed in Table 10). The solution was frozen in liquid nitrogen and dried overnight in a freeze dryer (Christ Alpha 2-4LD). The recovered solid was analyzed by HT-XRPD.

[0171] Amorphous solids were obtained from tert-butanol / water (50 / 50), 1,4-dioxane / water (50 / 50), tetrahydrofuran / water (50 / 50), acetonitrile / water (50 / 50), and 2,2,2-trifluoroethanol / water (50 / 50). The amorphous solids were analyzed by TGMS to determine the residual solvent / water content. The experimental details and results are reported in Table 10.

[0172] Considering that the concentration of API can be very high in solution and that the final preparation will have a low content of residual solvents, a larger batch of amorphous material was prepared following the experimental conditions applied in experiment ID GEN3 (from 1,4-dioxane / water (50 / 50)). The resulting amorphous solid (experiment ID GEN9) was used for thermal cycling experiments.

[0173] [Table 10]

[0174] Generation of amorphous benzamil TFA salt: Approximately 10 mg of TFA salt (from experiment ID GEN8) was dissolved in a mixture of organic solvent and water (listed in Table 11). The solution was frozen in liquid nitrogen and dried overnight in a freeze-dryer (Christ Alpha 2-4LD). The recovered solid was analyzed by HT-XRPD. Amorphous solids were obtained from 1,4-dioxane / water (70 / 30), tetrahydrofuran / water (50 / 50), and acetonitrile / water (70 / 30). The amorphous solids were analyzed by TGMS to determine the residual solvent / water content. Experimental details and results are reported in Table 11.

[0175] Considering that the API concentration would be highest in solution and that the final preparation would have a lower content of residual solvents, a larger batch of amorphous material was prepared according to the experimental conditions applied in experiment ID GEN11. The resulting amorphous solid (experiment ID GEN16) was used for the thermal cycling experiments (from 1,4-dioxane / water (70 / 30)).

[0176] [Table 11]

[0177] Polymorphic state The polymorphic state of both benzamil lactate and TFA salts was assessed by thermal cycling. Slurries of amorphous solids (GEN9 and GEN16, respectively) were prepared in 15 solvents at room temperature. The suspensions were subjected to a temperature profile that included three heating and cooling cycles. At the end of the temperature profile, the solids were isolated by centrifugation and dried at ambient conditions and under vacuum at 50°C. Upon completion of all crystallization experiments, all solids were analyzed by HT-XRPD. Subsequently, all solids were exposed to accelerated aging conditions (AAC, 40°C / 75% RH) for 48 days and then reanalyzed by HT-XRPD.

[0178] result The results are shown below in Tables 12 and 13. Only one polymorph of the lactate salt was found (LAC1), while two forms of the TFA salt were found (TFA1 and TFA2).

[0179] [Table 12]

[0180] [Table 13]

[0181] For the lactate salt, LAC1 was the only polymorph found in all solvent systems used in the screening. LAC1 was also the crystalline phase provided as the starting material. Based on the results, the benzamil lactate salt did not appear to be polymorphic. LAC1 was physically stable when exposed to stress conditions.

[0182] Next to TFA1 (see Example 2, Table 7), polymorph screening starting with the amorphous TFA salts recovered TFA2. TFA2 and mixtures of TFA1+TFA2 were only seen from water and MeOH, respectively. All other solvents occurred in TFA1. Both TFA salts (TFA1 and TFA2) were physically stable when exposed to AAC (no solid form transformation was observed when exposed to stress conditions at 40° C. and 75% RH for 2 days). Benzamil TFA salt appeared to be polymorphic.

[0183] The three powder patterns (LAC1, TFA1, and TFA2) were further analyzed by UPLC, 1 The properties were evaluated by H-NMR, DSC, and TGMS analytical methods.

[0184] Solid-state characterization LAC1 (from experiment ID TCP2), TFA1 (from experiment ID TCP16), and TFA2 (from experiment ID TCP25) were characterized by TGMS, DSC, UPLC, and 1 The structure was evaluated by H-NMR.

[0185] Similar to the 1:1 stoichiometry in the case of LAC1, 1 Salt formation was confirmed by H-NMR analysis (TFA was 1 (Not seen by H-NMR). Thermal analysis indicated that LAC1 (residual solvent content 0.5%) is anhydrous and nonsolvated in nature, and that both TFA1 and TFA2 are in nonsolvated, anhydrous form. The melting temperatures and chemical purities of LAC1, TFA1, and TFA2 are shown in Table 14.

[0186] [Table 14]

[0187] Further attempts were made to prepare TFA1 so that further characterization could be performed. However, all attempts resulted in TFA2. Therefore, the TFA1 salt obtained by sieving was used for further studies of solubility, physical and chemical stability, as well as intrinsic dissolution rate. TFA2 (Experiment ID GEN8), prepared on a larger scale, was used for further studies (the anhydrous form with the highest melting temperature).

[0188] Solubility study The kinetic and thermodynamic solubility of lactate (LAC1) and TFA salts (TFA1 and TFA2) was measured in water by incubation at 37° C. for 1 and 18 h under continuous magnetic stirring.

[0189] Two sets of 30 mg / ml suspensions of the LAC1, TFA1 and TFA2 salts were prepared in the selected media. The first set of suspensions was equilibrated for 1 h at 37 °C under continuous stirring, the second set was equilibrated for 18 h at 37 °C under continuous stirring. After 10 min of incubation, the pH was measured and again at the end of the equilibration time. The pH value did not change during the incubation. After the end of the equilibration time, the liquid phase was separated from the solid phase, filtered and analyzed by UPLC to measure the solubility. In water, a solubility of about 0.7 mg / mL was measured for both incubation times (1 h and 18 h), indicating that the solubility reaches a maximum already after 1 h at 37 °C. Comparing the solubility results of both TFA salts, it becomes clear that the solubility of the TFA1 salt is lower than that measured for the TFA2 salt.

[0190] The residual solids were collected and analyzed by HT-XRPD, both as air and vacuum dried (5 mbar / 25° C.) solids. The solubility measurements are shown in Table 15 below.

[0191] [Table 15]

[0192] Intrinsic dissolution rate study The intrinsic dissolution rates of LAC1 (batch SB084-44), TFA2 (experiment ID GEN8), and TFA1 (experiment ID TCP17) were determined in water and FaSSIF (fasted simulated intestinal fluid).

[0193] Materials and Methods Rotating disk intrinsic dissolution measurements were carried out using a μDiss instrument (Pion, USA) equipped with six independent glass fiber probes, each connected to a diode region. The probes were calibrated using the spectrum of a 362 nm mercury pen lamp before the start of the experiment. Disks were made in a passivated aluminum die using a mini-IDR press (Heath Scientific, UK).

[0194] Six dilutions of benzamil lactate, ranging from 0 to 0.5 mg / mL, were prepared in dissolution medium and the solutions were stirred with a cross-shaped magnetic stirrer. These dilutions were used for a calibration curve, which was then used to calculate the amount of benzamil in solution. Additionally, the solution was used to select the wavelength at which the samples were measured and to select the correct path length.

[0195] Approximately 6–10 mg of the different salts (LAC1, TFA1, TFA2) were immersed in water at 40 tons of pressure for 1 min on a passivated aluminum die (with a normalized surface area of ​​0.071 cm 2 ). The dies were placed in their Teflon holders on magnetic stirrers and placed in 20 mL glass vials. Before sample measurement, material of each medium was taken in the respective channel. The experiment was started by gentle addition of pre-heated dissolution medium. The vials were incubated at 37°C under continuous stirring at 100 rpm for up to 4 hours. UV absorption was measured with an in-line probe at regular intervals. After the experiment was completed, the pH of the solution was determined. The API concentration in the solution was calculated using a calibration curve and plotted against time. The dissolution rate was calculated for the linear portion of the curve. All dissolution rate experiments were performed in triplicate, except TFA1, which was performed in duplicate due to lack of material.

[0196] result The results are shown in Figure 8 and Table 16 below. As can be seen from Table 16 below, the dissolution rate of LAC1 was much faster than TFA2 and TFA1. For LAC1, the entire tablet dissolves in about 50 minutes, and the curve becomes flat (Figure 8A). The IDR of benzamil LAC1 in water was calculated to be 1.87 ± 0.06 mg / cm over the range of 1 to 36 minutes. 2 / min.

[0197] Dissolution of TFA2 and TFA1 was slower. After about 4 hours, the tablets were still not completely dissolved (TFA2: FIG. 8B; TFA1: not shown). The IDRs of benzamil for TFA2 and TFA1 were 0.13±0.01 and 0.09±0.01 mg / cm, respectively. 2 / min (calculated between 10 and 100 min).

[0198] [Table 16]

[0199] conclusion The intrinsic dissolution rate of LAC1 in water was almost 5-fold faster than that in FaSSIF. For TFA1 and TFA2, the intrinsic dissolution rates in water were 15-20-fold lower than that of LAC1, whereas in FaSSIF the difference was about 4-fold.

[0200] Physiochemical stability study The stability of benzamil salts LAC1 (SM, batch SB084-44), TFA2 (from experiment ID GEN8), and TFA1 (from experiment ID TCP16) was investigated under two stress conditions. 1. At 25°C and 60% RH, in an open container 2. At 40°C and 75% RH, in an open container

[0201] Materials and Methods For LAC1 and TFA2, the solids were analyzed by UPLC, TGMS, and HT-XRPD after 3 days, 1 week, and 3 weeks of incubation under stress conditions. For TFA1, the solids were analyzed after 3 days and 1 week.

[0202] result Analytical data are shown in Table 17. After 3 weeks of incubation at both conditions, no solid form transformation was observed for either salt, suggesting that both salts were physically stable under the conditions tested.

[0203] The chemical purity measured by UPLC for solids incubated for 3 days, 1 week, and 3 weeks in both conditions was similar to the purity of the solids at the start (t0), suggesting that no chemical degradation occurred for either salt under the conditions tested.

[0204] Thermal analysis (TGMS) showed small deviations when comparing t0 and 3 days of incubation with 1 week and 3 weeks of incubation (approximately 1% to 0.1%). This observation was made for both LAC1 and TFA2. These results can be explained by the presence of slight residual process solvents in the first two samples (t0 and t3 days), which are released or replaced by water only after 1 week of incubation at 25 °C / 60% RH and 40 °C / 75% RH.

[0205] [Table 17]

[0206] conclusion It was concluded that the salts LAC1, TFA1, and TFA2 were physically and chemically stable when incubated at 25°C / 60% RH and 40°C / 75% RH for 3 weeks.

[0207] Overall conclusions from Example 3 Overall, it can be concluded that the lactate salt of benzamil has a significantly higher solubility than the TFA salt.

Claims

1. A salt of the free base compound of formula (I); 【Chemical 1】 In the formula, R is 【Chemistry 2】 -H; -C(CH ３ ) ２ CH ２ C(CH ３ ) ３ ; 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 wherein the salt is selected from lactate, acetate, and phosphate.

2. The salt of claim 1 , wherein the salt is a lactate salt.

3. The salt of claim 1 wherein the free base compound is benzamil.

4. The salt of claim 1, wherein the free base compound is benzamil and the salt is a lactate salt.

5. 10. The salt of claim 1 having only one crystalline form.

6. A pharmaceutical or cosmetic composition comprising the salt of claim 1 and, optionally, a pharmaceutically and / or cosmetically acceptable excipient.

7. The composition of claim 6 , wherein the composition is adapted for topical administration.

8. 10. A salt according to claim 1 or a pharmaceutical composition according to claim 6 for use in medicine.

9. 9. The salt or composition for use according to claim 8, wherein the use in medicine is use in a method for treating psoriasis.

10. 10. The salt or composition for use according to claim 9, wherein the psoriasis is chronic psoriasis or plaque psoriasis.

11. 9. The salt or composition for use according to claim 8, wherein the salt or composition is administered locally or systemically.

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