pharmaceutical formulation for topical application on skin and its use

专利摘要:
PHARMACEUTICAL FORMULATION FOR TOPICAL SKIN APPLICATION. This invention relates to pharmaceutical formulations for topical skin application comprising (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1 -il] propanonitrile, or a pharmaceutically acceptable salt thereof, and use in the treatment of skin disorders.
公开号:BR112012029653B1
申请号:R112012029653-1
申请日:2011-05-20
公开日:2021-01-12
发明作者:Bhavnish Parikh；Bhavesh Shah；Krishnaswamy Yeleswaram
申请人:Incyte Holdings Corporation；
IPC主号:

专利说明:

[0001] [001] This application claims the priority benefit of provisional application US 61 / 347,132, filed on May 21, 2010, which is incorporated herein by reference in its entirety. TECHNICAL FIELD
[0002] [002] This invention relates to pharmaceutical formulations for topical application to skin comprising (R) -3-cyclopentyl-3- [4- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H- pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof and used in the treatment of skin diseases. BACKGROUND
[0003] [003] Protein kinases (PKs) regulate several biological processes, including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer. Cytokines, low molecular weight polypeptides or glycoproteins, regulate many pathways involved in the host inflammatory response to sepsis. Cytokines influence cell activation, proliferation and differentiation and can modulate proinflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. Signaling a wide range of cytokines involves the Janus kinase family (JAKs) of protein tyrosine kinase and Signal Transducers and Transcription Activators (STATs). There are four known mammalian JAKs: JAK1 (Janus kinase-1), JAK2, JAK3 (also known as Janus kinase, leukocytes; JAKL, and L-JAK), and TYK2 (protein tyrosine kinase 2).
[0004] [004] Cytokine-stimulated inflammatory and immune responses contribute to the pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from suppression of the immune system, while the overactive or inappropriate immune / inflammatory response contributes to the pathology of autoimmune diseases ( for example, asthma, systemic lupus erythematosus, thyroiditis, myocarditis), and diseases such as scleroderma and osteoartitis (Ortmann, RA, T. Cheng, et al. (2000) Arthritis Res 2 (1): 16-32).
[0005] [005] Deficiencies in the expression of JAKs are associated with many disease states. For example, JAK1 - / - mice are runted at birth, fail to nourish themselves, and die in the perinatal period (Rodig, S.J., M.A. Meraz et al. (1998) Cell 93 (3): 373-83). Jak2 - / - mouse embryos are anemic and die close to day 12.5 postcoitum due to the absence of definitive erythropoiesis.
[0006] [006] The JAK / STAT pathway, and in particular all four JAKs, are believed to play a role in the pathogenesis of asthmatic response, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. Several cytokines that signal through JAKS have been associated with inflammatory diseases / conditions of the upper respiratory tract, such as those affecting the nose and sinuses (for example, rhinitis and sinusitis) whether classically allergic reactions or not. The JAK / STAT pathway has also been implicated in inflammatory diseases / eye conditions and chronic allergic responses.
[0007] [007] Activation of JAK / STAT in cancers can occur by stimulation of cytokines (for example, IL-6 or GM-CSF), or by a reduction in endogenous JAK signaling suppressors, such as SOCS (cytokine suppressors or signaling) or PIAS (inhibitor of activated STAT protein) (Boudny, V., and Kovarik, J., Neoplasm. 49: 349-355, 2002). Activation of STAT signaling, as well as other pathways downstream of JAKs (eg Akt), has been correlated with poor prognosis in many types of cancer (Bowman, T., et al. Oncogene 19: 2474-2488, 2000 ). The elevated levels of circulating cytokines that signal through JAK / STAT play a causal role in cachexia and / or chronic fatigue. As such, inhibition of JAK may be beneficial for cancer patients, for reasons that extend beyond the potential antitumor activity.
[0008] [008] The inhibition of JAK kinases is also designed to have therapeutic benefits in patients suffering from disorders of the skin's immune system such as psoriasis, and skin sensitization. In psoriasis vulgaris, the most common form of psoriasis, it has been generally accepted that activated T lymphocytes are important for the maintenance of the disease and its associated psoriatic plaques (Gottlieb, AB, et al, Nat Rev Drug Disc., 4:19 -34). Psoriatic plaques contain a significant immune infiltrate, including leukocytes and monocytes, as well as several epidermal layers with increased keratinocyte proliferation. While the initial activation of immune cells in psoriasis occurs by an ill-defined mechanism, maintenance is believed to be dependent on a number of inflammatory cytokines, in addition to various chemokines and growth factors (JCI, 113: 1664-1675). Many of these, including interleukins -2, -4, -6, -7, -12, -15, -18, and -23, as well as GM-CSF and IFNg, signal through Janus kinases (JAK) (Adv. Pharmacol. 2000; 47: 113-74). As such, blocking signal transduction at the level of JAK kinases can result in therapeutic benefits in patients suffering from psoriasis and other immune skin diseases.
[0009] [009] Given the usefulness of JAK inhibitors in the treatment of skin diseases, there is a need for improved topical formulations of JAK inhibitors. In particular, there is a need for stable formulations that are easily applied to JAK inhibitors with good skin permeation characteristics. The formulations of the present invention, as well as the methods described herein, are directed to this need and other purposes. SUMMARY
[0010] [0010] A potent JAK1 / JAK2 inhibitor, (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile, and their pharmaceutically acceptable salts, previously described in US patent 7,598,257, US patent publication 2009/0181959, and US patent publication 2008/0312259, each of which is incorporated herein by reference in its entirety. The present invention describes an oil in water formulation of (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) - 1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile suitable for topical administration and treatment of skin disorders.
[0011] [0011] Thus, the present invention provides, among others, a pharmaceutical formulation for topical application of skin, comprising:
[0012] [0012] an oil-in-water emulsion; and
[0013] [0013] a therapeutically effective amount of a therapeutic agent which is (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) - 1H-pyrazol-1- il] propanonitrile or a pharmaceutically acceptable salt thereof.
[0014] [0014] The present invention also provides a method of treating a skin disease, including applying a pharmaceutical formulation described herein to an area of the patient's skin.
[0015] [0015] The present invention also provides a pharmaceutical formulation described herein for use in the treatment of a skin disease in a patient in need of it.
[0016] [0016] The present invention also provides a pharmaceutical formulation described herein for the preparation of a medicament for use in the treatment of a skin disease in a patient in need of it.
[0017] [0017] The details of one or more modalities of the invention are set out in the accompanying drawings and description below. Other features, objects and advantages of the invention will be apparent from the description and drawings and from claims. DESCRIPTION OF THE DRAWINGS
[0018] [0018] Figure 1 describes a flow chart describing the manufacturing process for an oil in water formulation of (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H -pyrazol-1-yl) -3-cyclopentylpropanonitrile phosphoric acid salt.
[0019] [0019] Figure 2 describes the change in the injury score for subjects with chronic plaque psoriasis treated with 0.5%, 1.0%, and 1.5% w / w of an oil in water formulation (R ) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile phosphoric acid salt (on a free base basis) compared to placebo treatment for a period of 12 weeks (the dotted line is the baseline).
[0020] [0020] Figure 3 shows photographs of subjects with chronic plaque psoriasis before (figure 3 (a)) and after 84 days (figure 3 (b)) of treatment with 1.0% w / w of an oil formulation in (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile water phosphoric acid salt (on a base of free base).
[0021] [0021] Figure 4 shows photographs of subjects with chronic plaque psoriasis before (figure 4 (a)) and after 84 days (figure 4 (b)) of treatment with 1.0% w / w of an oil formulation in (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- cyclopentylpropanonitrile phosphoric acid salt (on a base of free base).
[0022] [0022] Figure 5 shows photographs of subjects with chronic plaque psoriasis before (figure 5 (a)) and after 84 days (figure 5 (b)) of treatment with 1.5% w / w of an oil formulation in (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- cyclopentylpropanonitrile phosphoric acid salt (on a base of free base).
[0023] [0023] Figure 6 shows photographs of subjects with chronic plaque psoriasis before (figure 6 (a)) and after 84 days (figure 6 (b)) of treatment with 0.5% w / w of an oil formulation in (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- cyclopentylpropanonitrile phosphoric acid salt (on a base of free base).
[0024] [0024] Figure 7 shows photographs of subjects with chronic plaque psoriasis before (figure 7 (a)) and after 84 days (figure 7 (b)) of treatment with 1.0% w / w of an oil formulation in (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- cyclopentylpropanonitrile phosphoric acid salt (on a base of free base). DETAILED DESCRIPTION
[0025] [0025] Thus, the present invention provides, among others, a pharmaceutical formulation for topical application, comprising a therapeutically effective amount of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof.
[0026] [0026] In some modalities, the pharmaceutical formulation comprises:
[0027] [0027] an oil-in-water emulsion; and
[0028] [0028] a therapeutically effective amount of a therapeutic agent which is (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) - 1H-pyrazol-1- il] propanonitrile, or a pharmaceutically acceptable salt thereof.
[0029] [0029] In some embodiments, the emulsion comprises water, an oil component, and an emulsifying component.
[0030] [0030] As used here, the term "emulsifying component" refers, in one aspect, to a substance, or mixtures of substances that keep an element or particle in suspension within a fluid medium. In some embodiments, the emulsifying component allows an oily phase to form an emulsion when combined with water. In some embodiments, the emulsifying component refers to one or more nonionic surfactants.
[0031] [0031] Oil-in-water formulations have been shown to have appearance, spreadability and stability as compared to other formulations. The formulations have a thick, creamy appearance that allows good spreadability of the formulation on the skin. Good spreadability leads to better skin permeation than comparable anhydrous formulations. For example, oil-in-water formulations demonstrate greater cumulative amounts in transport studies through human cadaver skin for 24 hours when compared to an anhydrous ointment. While it is not desired to attach to any particular theory, it is believed that the larger cumulative amounts are due to the better spreadability of the oil-in-water formulation compared to anhydrous ointment, resulting in increased surface area for transport. Higher viscosity for oil-in-water formulations still appeared to be preferable with respect to skin permeation as cream formulations of higher viscosity had better transport through cadaver skin compared to oil-in-water lotions of lower viscosity.
[0032] [0032] The oil-in-water formulations described here have demonstrated good stability over a period of three months when stored at 25 ° C / 60% RH and 40 ° C / 75% RH in aluminum tubes and maintain reasonable viscosity over the time. In comparison, water-in-oil formulations showed syneresis when stored at 40 ° C (syneresis means liquid separation from the emulsion).
[0033] [0033] The water-in-oil formulation was even less desirable than the formulations of the invention, because API dissolved in the base over time, leading to highly variable skin permeation in in vitro studies as well as lack of an increase in permeability with increasing strength of the formulation.
[0034] [0034] In transport studies with freshly extracted mouse skin, oil-in-water formulations still showed a general tendency for increased permeability when the strength of the solubilized cream was increased by 0.5% w / w 1.5% w / p, while the said trend was not observed with water-in-oil formulations. Thus, it appears that water-in-oil emulsions will have no advantage in terms of providing improved permeation with increasing forces.
[0035] [0035] Still, the formulations described here are relatively simple to produce with a repeatable formulation process. The resulting product is easily packaged. The formulations appear to have good stability and relatively consistent permeation profiles.
[0036] [0036] In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the formulation.
[0037] [0037] In some embodiments, the oil component is present in an amount of about 17% to about 27% by weight of the formulation.
[0038] [0038] In some embodiments, the oil component is present in an amount of about 20% to about 27% by weight of the formulation.
[0039] [0039] In some embodiments, the oil component comprises one or more substances independently selected from petrolatums, fatty alcohols, mineral oils, triglycerides, and silicone oils.
[0040] [0040] In some embodiments, the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides and dimethicone.
[0041] [0041] In some embodiments, the oil component comprises an occlusive agent component.
[0042] [0042] In some embodiments, the occlusive agent component is present in an amount of about 2% to about 15% by weight of the formulation.
[0043] [0043] In some embodiments, the occlusive agent component is present in an amount of about 5% to about 10% by weight of the formulation.
[0044] [0044] As used here, the term "occlusive agent component" refers to a hydrophobic agent or mixtures of hydrophobic agents that form an occlusive film on the skin that reduces transepidermal water loss (TEWL) preventing water evaporation from the stratum corneum.
[0045] [0045] In some embodiments, the occlusive agent component comprises one or more substances selected from fatty acids (eg lanolin acid), fatty alcohols (eg lanolin alcohol), hydrocarbon oils and waxes (eg petrolatum), polyhydric alcohols (eg propylene glycol), silicones (eg dimethicone), sterols (eg cholesterol), vegetable or animal fat (eg cocoa butter), vegetable wax (eg carnauba wax), and wax ester (for example, beeswax).
[0046] [0046] In some embodiments, the occlusive agent component comprises one or more substances selected from lanolin fatty acid alcohols, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, carnauba wax, and beeswax.
[0047] [0047] In some embodiments, the occlusive agent component comprises petrolatum.
[0048] [0048] In some embodiments, the occlusive agent component comprises white petrolatum.
[0049] [0049] In some embodiments, the oil component comprises a stiffening agent component.
[0050] [0050] In some embodiments, the stiffening agent component is present in an amount of about 2% to about 8% by weight of the formulation.
[0051] [0051] In some embodiments, the stiffening agent component is present in an amount of about 3% to about 6% by weight of the formulation.
[0052] [0052] In some embodiments, the stiffening agent component is present in an amount of about 4% to about 7% by weight of the formulation.
[0053] [0053] As used herein, the term "stiffening agent component" refers to a substance or mixture of substances that increase the viscosity and / or consistency of the formulation or improve the rheology of the formulation.
[0054] [0054] In some embodiments, the stiffening agent component comprises one or more substances independently selected from fatty alcohols.
[0055] [0055] In some embodiments, the stiffening agent component comprises one or more substances independently selected from C12-20 fatty alcohols.
[0056] [0056] In some embodiments, the stiffening agent component comprises one or more substances independently selected from C16-18 fatty alcohols.
[0057] [0057] In some embodiments, the stiffening agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.
[0058] [0058] In some embodiments, the oil component comprises an emollient component.
[0059] [0059] In some embodiments, the emollient component is present in an amount of about 5% to about 15% by weight of the formulation.
[0060] [0060] In some embodiments, the emollient component is present in an amount of about 7% to about 13% by weight of the formulation.
[0061] [0061] As used herein, the term "emollient component" refers to an agent that softens or softens the skin or softens an irradiated inner surface.
[0062] [0062] In some embodiments, the emollient component comprises one or more substances independently selected from mineral oils and triglycerides.
[0063] [0063] In some embodiments, the emollient component comprises one or more substances independently selected from light mineral oil and medium chain triglycerides.
[0064] [0064] In some embodiments, the emollient component comprises one or more substances independently selected from light mineral oil and medium chain triglycerides.
[0065] [0065] In some embodiments, water is present in an amount of about 35% to about 65% by weight of the formulation.
[0066] [0066] In some embodiments, water is present in an amount of about 40% to about 60% by weight of the formulation.
[0067] [0067] In some embodiments, water is present in an amount of about 45% to about 55% by weight of the formulation.
[0068] [0068] In some embodiments, the emulsifying component is present in an amount of about 1% to about 9% by weight of the formulation.
[0069] [0069] In some embodiments, the emulsifying component is present in an amount of about 2% to about 6% by weight of the formulation.
[0070] [0070] In some embodiments, the emulsifying component is present in an amount of about 3% to about 5% by weight of the formulation.
[0071] [0071] In some embodiments, the emulsifying component is present in an amount of about 4% to about 7% by weight of the formulation.
[0072] [0072] In some embodiments, the pharmaceutical formulation comprises an emulsifying component and a stiffening agent component, wherein the combined amount of emulsifying component and stiffening agent component is at least about 8% by weight of the formulation.
[0073] [0073] In some embodiments, the emulsifying component comprises one or more substances independently selected from fatty esters of glyceryl and fatty esters of sorbitan.
[0074] [0074] In some embodiments, the emulsifying component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.
[0075] [0075] In some embodiments, the pharmaceutical formulation still comprises a component of stabilizing agent.
[0076] [0076] In some embodiments, the stabilizing agent component is present in an amount of about 0.05% to about 5% by weight of the formulation.
[0077] [0077] In some embodiments, the stabilizing agent component is present in an amount of about 0.1% to about 2% by weight of the formulation.
[0078] [0078] In some embodiments, the stabilizing agent component is present in an amount of about 0.3 to about 0.5% by weight of the formulation.
[0079] [0079] As used herein, the term "stabilizing agent component" refers to a substance or mixture of substances that improve the stability of the pharmaceutical formulation and / or the compatibility of the components in the formulation. In some embodiments, the stabilizing agent component prevents the emulsion from agglomerating and stabilizes the droplets in the oil-in-water emulsion.
[0080] [0080] In some embodiments, the stabilizing agent component comprises one or more substances independently selected from polysaccharides.
[0081] [0081] In some embodiments, the stabilizing agent component comprises xanthan gum.
[0082] [0082] In some embodiments, the pharmaceutical formulation still comprises a solvent component.
[0083] [0083] In some embodiments, the solvent component is present in an amount of about 10% to about 35% by weight of the formulation.
[0084] [0084] In some embodiments, the solvent component is present in an amount of about 15% to about 30% by weight of the formulation.
[0085] [0085] In some embodiments, the solvent component is present in an amount of about 20% to about 25% by weight of the formulation.
[0086] [0086] As used herein, the term "solvent component" is a liquid substance or mixture of liquid substances capable of dissolving (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4- il) -1H-pyrazol-1-yl) -3- cyclopentylpropanonitrile or other substances in the formulation. In some embodiments, the solvent component is a liquid substance or mixture of liquid substances in which (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazole- 1-yl) -3-cyclopentylpropanonitrile, or its pharmaceutically acceptable salt, has reasonable solubility. For example, solubilities of (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile (free base) or its phosphate salts are reported in Table 21. In some embodiments, a solvent is a substance or mixture thereof, where (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile, or its pharmaceutically acceptable salt (whichever is used), has a solubility of at least about 10 mg / ml or greater, at least about 15 mg / ml or greater, or at least about 20 mg / ml or greater, when measured as described in Example 4.
[0087] [0087] In some embodiments, the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.
[0088] [0088] In some embodiments, the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.
[0089] [0089] In some embodiments, the therapeutic agent is present in an amount of about 0.5% to about 1.5% by weight of the formulation on a free base basis.
[0090] [0090] In some embodiments, the therapeutic agent is present in an amount of about 0.5% by weight of the formulation on a free base basis.
[0091] [0091] In some embodiments, the therapeutic agent is present in an amount of about 1% by weight of the formulation on a free base basis.
[0092] [0092] In some embodiments, the therapeutic agent is present in an amount of about 1.5% by weight of the formulation on a free base basis.
[0093] [0093] In some embodiments, the therapeutic agent is (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile phosphate.
[0094] [0094] In some embodiments, the pharmaceutical formulation comprises:
[0095] [0095] from about 35% to about 65% water by weight of the formulation;
[0096] [0096] from about 10% to about 40% of an oil component by weight of the formulation;
[0097] [0097] from about 1% to about 9% of an emulsifying component by weight of the formulation;
[0098] [0098] from about 10% to about 35% of a solvent component by weight of the formulation;
[0099] [0099] from about 0.05% to about 5% of a stabilizing agent component by weight of the formulation; and
[0100] [00100] from about 0.5% to about 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H -pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0101] [00101] In some modalities, the pharmaceutical formulation comprises:
[0102] [00102] from about 40% to about 60% water by weight of the formulation;
[0103] [00103] from about 15% to about 30% of an oil component by weight of the formulation;
[0104] [00104] from about 2% to about 6% of an emulsifying component by weight of the formulation;
[0105] [00105] from about 15% to about 30% of a solvent component by weight of the formulation;
[0106] [00106] from about 0.1% to about 2% of a stabilizing agent component by weight of the formulation; and
[0107] [00107] from about 0.5% to about 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H -pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0108] [00108] In some modalities, the pharmaceutical formulation comprises:
[0109] [00109] from about 45% to about 55% water by weight of the formulation;
[0110] [00110] from about 17% to about 27% of an oil component by weight of the formulation;
[0111] [00111] from about 3% to about 5% of an emulsifying component by weight of the formulation;
[0112] [00112] from about 20% to about 25% of a solvent component by weight of the formulation;
[0113] [00113] from about 0.3% to about 0.5% of a stabilizing agent component by weight of the formulation; and
[0114] [00114] from about 0.5% to about 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H -pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0115] [00115] In some modalities, the pharmaceutical formulation comprises:
[0116] [00116] from about 45% to about 55% water by weight of the formulation;
[0117] [00117] from about 17% to about 27% of an oil component by weight of the formulation;
[0118] [00118] from about 4% to about 7% of an emulsifying component by weight of the formulation;
[0119] [00119] from about 20% to about 25% of a solvent component by weight of the formulation;
[0120] [00120] from about 0.3% to about 0.5% of a stabilizing agent component by weight of the formulation; and
[0121] [00121] from about 0.5% to about 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H -pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0122] [00122] In some ways:
[0123] [00123] the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides and dimethicone;
[0124] [00124] the emulsifying component comprises one or more substances independently selected from fatty esters of glyceryl and fatty esters of sorbitan;
[0125] [00125] the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols; and
[0126] [00126] the stabilizing agent component comprises one or more substances independently selected from polysaccharides.
[0127] [00127] In some ways:
[0128] [00128] the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and dimethicone;
[0129] [00129] the emulsifying component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;
[0130] [00130] the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol; and
[0131] [00131] the stabilizing agent component comprises xanthan gum.
[0132] [00132] In some embodiments, the pharmaceutical formulation comprises:
[0133] [00133] from about 35% to about 65% water by weight of the formulation;
[0134] [00134] from about 2% to about 15% of an occlusive agent component by weight of the formulation;
[0135] [00135] from about 2% to about 8% of a stiffening agent component by weight of the formulation;
[0136] [00136] from about 5% to about 15% of an emollient component by weight of the formulation;
[0137] [00137] from about 1% to about 9% of an emulsifying component by weight of the formulation;
[0138] [00138] from about 0.05% to about 5% of a stabilizing agent component by weight of the formulation;
[0139] [00139] from about 10% to about 35% of a solvent component by weight of the formulation; and
[0140] [00140] from about 0.5% to about 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H -pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0141] [00141] In some embodiments, the pharmaceutical formulation comprises:
[0142] [00142] from about 40% to about 60% water by weight of the formulation;
[0143] [00143] from about 5% to about 10% of an occlusive agent component by weight of the formulation;
[0144] [00144] from about 2% to about 8% of a stiffening agent component by weight of the formulation;
[0145] [00145] from about 7% to about 12% of an emollient component by weight of the formulation;
[0146] [00146] from about 2% to about 6% of an emulsifying component by weight of the formulation;
[0147] [00147] from about 0.1% to about 2% of a stabilizing agent by weight of the formulation;
[0148] [00148] from about 15% to about 30% of a solvent component by weight of the formulation; and
[0149] [00149] from about 0.5% to about 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H -pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0150] [00150] In some modalities, the pharmaceutical formulation comprises:
[0151] [00151] from about 45% to about 55% water by weight of the formulation;
[0152] [00152] from about 5% to about 10% of an occlusive agent component by weight of the formulation;
[0153] [00153] from about 3% to about 6% of a stiffening agent component by weight of the formulation;
[0154] [00154] from about 7% to about 13% of an emollient component by weight of the formulation;
[0155] [00155] from about 3% to about 5% of an emulsifying component by weight of the formulation;
[0156] [00156] from about 0.3% to about 0.5% of a stabilizing agent component by weight of the formulation;
[0157] [00157] from about 20% to about 25% of a solvent component by weight of the formulation; and
[0158] [00158] from about 0.5% to about 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H -pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0159] [00159] In some embodiments, the pharmaceutical formulation comprises:
[0160] [00160] from about 45% to about 55% water by weight of the formulation;
[0161] [00161] from about 5% to about 10% of an occlusive agent component by weight of the formulation;
[0162] [00162] from about 4% to about 7% of a stiffening agent component by weight of the formulation;
[0163] [00163] from about 7% to about 13% of an emollient component by weight of the formulation;
[0164] [00164] from about 4% to about 7% of an emulsifying component by weight of the formulation;
[0165] [00165] from about 0.3% to about 0.5% of a stabilizing agent component by weight of the formulation;
[0166] [00166] from about 20% to about 25% of a solvent component by weight of the formulation; and
[0167] [00167] from about 0.5% to about 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H -pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0168] [00168] In some embodiments, the pharmaceutical formulation comprises:
[0169] [00169] from about 45% to about 55% water by weight of the formulation;
[0170] [00170] about 7% of an occlusive agent component by weight of the formulation;
[0171] [00171] from about 4.5% to about 5% of a stiffening agent component by weight of the formulation;
[0172] [00172] about 10% of an emollient component by weight of the formulation;
[0173] [00173] from about 4% to about 4.5% of an emulsifying component by weight of the formulation;
[0174] [00174] about 0.4% of a stabilizing agent component by weight of the formulation;
[0175] [00175] about 22% of a solvent component by weight of the formulation; and
[0176] [00176] from about 0.5% to about 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H -pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0177] [00177] In some embodiments, the combined amount of the stiffening agent and emulsifying component is at least about 8% by weight of the formulation.
[0178] [00178] In some ways:
[0179] [00179] the occlusive agent component comprises a petrolatum;
[0180] [00180] the stiffening agent component comprises one or more substances independently selected from one or more fatty alcohols;
[0181] [00181] the emollient component comprises one or more substances independently selected from mineral oils and triglycerides;
[0182] [00182] the emulsifying component comprises one or more substances independently selected from fatty esters of glyceryl and fatty esters of sorbitan;
[0183] [00183] the stabilizing agent component comprises one or more substances independently selected from polysaccharides; and
[0184] [00184] the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.
[0185] [00185] In some ways:
[0186] [00186] the occlusive agent component comprises white petrolatum;
[0187] [00187] the stiffening agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol;
[0188] [00188] the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides, and dimethicone;
[0189] [00189] the emulsifying component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;
[0190] [00190] the stabilizing agent component comprises xanthan gum; and
[0191] [00191] the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.
[0192] [00192] In some embodiments, the pharmaceutical formulation still comprises an antimicrobial preservative component.
[0193] [00193] In some embodiments, the antimicrobial preservative component is present in an amount of about 0.05% to about 3% by weight of the formulation.
[0194] [00194] In some embodiments, the antimicrobial preservative component is present in an amount of about 0.1% to about 1% by weight of the formulation.
[0195] [00195] As used here, the phrase "antimicrobial preservative component" is a substance or mixtures of substances that inhibits microbial growth in the formulation.
[0196] [00196] In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from alkyl parabens and phenoxyethanol.
[0197] [00197] In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from methyl paraben, propyl paraben, and phenoxyethanol.
[0198] [00198] In some embodiments, the pharmaceutical formulation still comprises a chelating agent component.
[0199] [00199] As used herein, the phrase "chelating agent component" refers to a compound or mixture of compounds that has the ability to bind strongly with metal ions.
[0200] [00200] In some embodiments, the chelating agent component comprises disodium edetate.
[0201] [00201] (R) -3- (4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile can be prepared as described in the US patent 7,598,257 and US patent publication 2009/0181959, each of which is incorporated herein by reference in its entirety. The (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile 1: 1 phosphate salt can be prepared as described in US patent publication 2008/0312259, which is incorporated herein by reference in its entirety.
[0202] [00202] The compounds of the present invention further include pharmaceutically acceptable salts of the compounds disclosed herein. As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the addition of a pharmaceutically acceptable acid or base to a compound disclosed herein. As used herein, the phrase "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Pharmaceutically acceptable salts, including mono- and bi-salts, include, but are not limited to, those derived from organic and inorganic acids such as, but not limited to, acetic, lactic, cinnamic, tartaric, succinic, fumaric, maleic, mandelic, malic, oxalic, propionic , hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
[0203] [00203] It will also be understood that compounds described herein can exist in solvated, for example, hydrated, as well as unsolvated forms. It will be further understood that the present invention includes all solvated forms of the compounds.
[0204] [00204] As used here, "% by weight of the formulation" means the percentage concentration of the component in the formulation is on a weight / weight basis. For example, 1% w / w component A = [(mass of component A) / (total mass of the formulation)] x 100.
[0205] [00205] As used herein, (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H- "wt. Formulation on a free base base" pyrazol-1-yl) -3-cyclopentylpropanonitrile, or pharmaceutically acceptable salt thereof "means that the% w / w is calculated based on the weight of (R) -3- (4- (7H-pyrrole [2,3- d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile in the total formulation. For example, "0.5% w / w in a free base base" of (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) - 1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile phosphate means that for 100 grams of total formulation, there is 0.66 grams of ( R) -3- (4- (7H-pyrrolo [2,3- d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile phosphate in the formulation (which is equivalent to 0.5 gram of free base, (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile).
[0206] [00206] In some modalities, the components are present in exactly the specified ranges (for example, the term "about" is not present). In some modalities, "about" means about 10% of the value.
[0207] [00207] As will be appreciated, some components of the pharmaceutical formulations described here can have several functions. For example, a certain substance can act as both an emulsifying agent and a stabilizing agent. In some cases, the function of a certain component can be considered singular, even though its properties can allow for several functionalities. In some embodiments, each component of the formulation comprises a different substance or mixture of substances.
[0208] [00208] As used here, the term "component" can mean a substance or a mixture of substances.
[0209] [00209] As used here, the term "fatty acid" refers to an aliphatic acid that is saturated or unsaturated. In some embodiments, the fatty acid is in a mixture of different fatty acids. In some embodiments, the fatty acid has between about eight to about thirty carbons on average. In some embodiments, the fatty acid has about 12 to 20, 14-20, or 16-18 carbons on average. Suitable fatty acids include, but are not limited to, cetyl acid, stearic acid, lauric acid, myristic acid, erucic acid, palmitic acid, palmitoleic acid, capric acid, caprylic acid, oleic acid, linoleic acid, linolenic acid, hydroxystearic acid, 12- hydroxystearic, keto-stearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, behenic acid, isobenic acid, and arachidonic acid, or mixtures thereof.
[0210] [00210] As used here, the term "fatty alcohol" refers to an aliphatic alcohol that is saturated or unsaturated. In some embodiments, fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, fatty alcohol has between about 12 to about 20, about 14 to about 20, or about 16 to about 18 carbons on average. Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmitil alcohol, cetyl alcohol, capryl alcohol, capryl alcohol, oleyl alcohol, linolenyl alcohol, arachidonic alcohol, behenyl alcohol, isobehenyl alcohol, saddle alcohol, chemil alcohol, and alcohol linoleil, or mixtures thereof.
[0211] [00211] As used herein, the term "polyalkylene glycol", used alone or in combination with other terms, refers to a polymer containing units of oxyalkylene monomer, or copolymer of different units of oxyalkylene monomer, in which the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term "oxyalkylene", used alone or in combination with other terms, refers to a group of formula-O-alkylene-. In some embodiments, polyalkylene glycol is polyethylene glycol.
[0212] [00212] As used herein, the term "sorbitan fatty ester" includes products derived from sorbitan or sorbitol and fatty acids and, optionally, poly (ethylene glycol) units, including sorbitan esters and sorbitan polyethoxyl esters. In some embodiments, the sorbitan fatty ester is a polyethoxylated sorbitan ester.
[0213] [00213] As used herein, the term "sorbitan ester" refers to a compound, or mixture of compounds, derived from esterification of sorbitol and at least one fatty acid. Fatty acids useful for derivating sorbitan esters include, but are not limited to, derivatives here. Suitable sorbitan esters include, but are not limited to, the Span ™ series (available from Uniqema), which includes Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan mono- oleate), and 85 (sorbitan trioleate). Other suitable sorbitan esters include those listed in R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., Which is incorporated herein by reference in its entirety.
[0214] [00214] As used herein, the term "polyethoxylated sorbitan ester" refers to a compound, or mixture thereof, derived from the ethoxylation of a sorbitan ester. The polyoxyethylene portion of the compound can be between the fatty ester and the sorbitan fraction. As used herein, the term "sorbitan ester" refers to a compound, or mixture of compounds, derived from esterification of sorbitol and at least one fatty acid. Fatty acids useful to derive esters of polyethoxylated sorbitan include, among others, those described herein. In some embodiments, the polyoxyethylene fraction of the compound or mixture has about 2 to about 200 units of oxyethylene. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 2 to about 100 units of oxyethylene. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 80 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 40 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 20 oxyethylene units. Suitable polybutylated sorbitan esters include, among others, the Tween ™ series (available from Uniqema), which includes Tween 20 (POE (20) sorbitan monolaurate), 21 (POE (4) sorbitan monolaurate), 40 (POE (20) sorbitan monopalmitate), 60 (POE (20) monostearate sorbitan), 60K (POE (20) monostearate sorbitan), 61 (POE (4) monostearate sorbitan), 65 (POE (20) tristearate sorbitan), 80 (POE (20) sorbitan mono-oleate), 80K (POE (20) monooleate sorbitan), 81 (POE (5) mono-oleate sorbitan), and 85 (POE (20) trioleate sorbitan). As used here, the acronym "POE" refers to polyoxyethylene. The number following the acronym POE refers to the number of repeated units of oxyethylene in the compound. Other suitable polyethoxylated sorbitan esters include the polyoxyethylene sorbitan fatty acid esters listed in R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., Which is incorporated herein by reference in its entirety. In some embodiments, the polyethoxylated ester sorbitan is a polysorbate. In some embodiments, the sorbitan polyethoxylated ester is polysorbate 20.
[0215] [00215] As used herein, the term "glyceryl fatty esters" refers to mono-, di- or triglycerides of fatty acids. Glyceryl fatty esters can be optionally substituted with groups of sulfonic acid, or pharmaceutically acceptable salts thereof. Fatty acids suitable for derivating glycerides from fatty acids include, but are not limited to, those described here. In some embodiments, the glycerol fatty ester is a mono-glyceride of a fatty acid containing 12 to 18 carbon atoms. In some embodiments, the glyceryl fatty ester is glyceryl stearate.
[0216] [00216] As used here, the term "triglycerides" refers to a fatty acid triglyceride. In some embodiments, triglyceride is medium chain triglyceride.
[0217] [00217] As used herein, the term "alkylene glycol" refers to a group of the formula -O-alkylene-, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkylene glycol is propylene glycol (1,2-propanediol).
[0218] [00218] As used herein, the term "polyethylene glycol" refers to a polymer containing ethylene glycol monomer units of the formula -O-CH2-CH2-. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or it may have one or more hydroxyl groups etherified with a lower alkyl, for example, a methyl group. Still suitable are derivatives of polyethylene glycols containing esterifiable carboxyl groups. Polyethylene glycols useful in the present invention can be polymers of any chain length or molecular weight, and can include branching. In some embodiments, the average molecular weight of polyethylene glycol is about 200 to about 9000. In some embodiments, the average molecular weight of polyethylene glycol is about 200 to about 5000. In some embodiments, the average molecular weight polyethylene glycol is about 200 to about 900. In some embodiments, the average molecular weight of polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to, polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol- 400, polyethylene glycol-600, and polyethylene glycol-900. The number after the line in the name refers to the average molecular weight of the polymer.
[0219] [00219] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate modalities, can still be provided in combination in a single modality. Conversely, several features of the invention that are, for brevity, described in the context of a single embodiment, can still be provided separately or in any appropriate subcombination. Methods
[0220] [00220] The pharmaceutical formulations of the invention are useful in the treatment of skin diseases. In some modalities, skin disease is an autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous pemphigus (BP). In some embodiments, the skin disease is psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitivity (for example, contact dermatitis or allergic contact dermatitis). For example, certain substances including some pharmaceuticals when topically applied can cause skin sensitization. In some embodiments, co-administration or sequential administration of the topical formulations of the invention together with the agent that causes unwanted sensitization may be useful in the treatment as unwanted sensitization or dermatitis.
[0221] [00221] The present invention further provides a method of treating dermatological side effects of other pharmaceutical products by administering the compound of the invention. For example, several pharmaceutical agents result in unwanted allergic reactions that can manifest as acneiform rash or related dermatitis. Exemplary pharmaceutical agents that have said undesirable side effects include anti-cancer drugs such as gefitinib, cetuximab, erlotinib, and the like. The formulations of the invention can be administered systemically or topically (for example, located in the vicinity of dermatitis) in combination with (for example, simultaneously or sequentially) the pharmaceutical agent containing the undesirable dermatological side effect. In some embodiments, the formulation of the invention can be administered topically along with one or more pharmaceutical products, where pharmaceutical products when topically applied in the absence of a formulation of the invention cause contact dermatitis, allergic contact sensitization, or similar skin disease. Thus, formulations of the invention include topical formulations still comprising an international pharmaceutical agent that can cause dermatitis, skin diseases, or related side effects.
[0222] [00222] As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, pigs, cattle, sheep, horses, or primates, and more preferably human.
[0223] [00223] As used here, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that induces the biological or medicinal response being searched for in a tissue, system, animal, individual or human by a researcher , veterinarian, doctor or other.
[0224] [00224] As used herein, the term "treat" or "treatment" refers to one or more of (1) preventing the disease, for example, preventing a disease, condition, or disorder in an individual that may be predisposed to disease, condition or disorder, but does not yet experience or present the pathology or symptoms of the disease; (2) inhibit the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or presenting the pathology or symptomatology of the disease, condition or disorder (ie, interrupting other development of the pathology and / or symptomatology); and (3) alleviating the disease, for example, alleviating a disease, condition or disorder in an individual who experiences or presents the pathology or symptomatology of the disease, condition or disorder (ie reversing the pathology and / or symptomatology) how to reduce severity of the disease. Combination therapies
[0225] [00225] One or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors, such as those described in WO 2006 / 056399, or other agents can be used in combination with the formulations of the present invention for the treatment of diseases, disorders or conditions associated with JAK. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
[0226] Exemplary chemotherapeutics include proteasome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.
[0227] [00227] Exemplary steroids include corticosteroids such as dexamethasone or prednisone.
[0228] [00228] Examples of Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in US patent 5,521,184, WO 04/005281, and US 60 / 578,491.
[0229] [00229] Suitable examples of Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.
[0230] [00230] Suitable examples of RAF inhibitors include the compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444.
[0231] [00231] Suitable examples of FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01 / 014402.
[0232] [00232] In some embodiments, the formulations of the invention can be used in combination with one or more other kinase inhibitors including imatinib, particularly to treat patients resistant to imatinib or other kinase inhibitors.
[0233] [00233] In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the compound of the invention where dexamethasone is administered intermittently as opposed to continuously. Marked compounds and test methods
[0234] [00234] Another aspect of the present invention relates to formulations comprising an active labeled compound (radiolabeled, fluorescent-labeled, etc.) that could be useful not only in imaging techniques, but also in tests, both in vitro and in vivo , to locate and quantify JAK in tissue samples, including human, and to identify JAK ligands by inhibiting a labeled compound. Thus, the present invention includes JAK assays that contain said labeled compounds.
[0235] [00235] The present invention further includes formulations of an isotopically labeled compound. An "isotopically" or "radiolabeled" compound is a compound where one or more atoms are replaced or replaced by an atom containing an atomic mass or mass number other than the atomic mass or mass number typically found in nature (ie, occurring nature). Suitable radionuclides that can be incorporated into compounds of the present invention include, but are not limited to, 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated into the present radiolabeled compounds will depend on the specific application of that radiolabeled compound. For example, for in vitro JAK labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 125I, 131I, 35S or will generally be more useful. For 11C, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br or 77Br radio imaging applications will generally be more useful.
[0236] [00236] It is understood that a "radiolabeled" or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of 3H, 14C, 125I, 35S and 82Br. Kits
[0237] [00237] The present invention further includes pharmaceutical kits useful, for example, in the treatment or prevention of disorders or diseases associated with JAK, such as cancer, which includes one or more containers containing a pharmaceutical formulation of the invention. Said kits may further include, if desired, one or more components of conventional pharmaceutical kits, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, such as package inserts or labels, indicating quantities of components to be administered, instructions for administration, and / or instructions for mixing the components, may also be included in the kit.
[0238] [00238] The invention will be described in more detail by means of specific examples. The following examples are provided for purposes of illustration, and are not intended to limit the invention in any way. Those skilled in the art will recognize a variety of non-critical parameters that can be altered or modified to generate essentially the same results. In some embodiments, the present invention provides pharmaceutical formulations comprising the components specified in the exemplary formulations (for example, Example 3), wherein the components are present in about amounts in Tables 2-5. Examples Example 1: (3R) - e (3S) -3-Cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile
[0239] [00239] To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) at 0ºC was added under a drip a solution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in THF (300 mL). The cold bath was removed and the reaction was warmed to room temperature followed by cooling to 0ºC, during which time a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 ml) was added under a drip. The bath was removed and the reaction warmed to room temperature and stirred for 64 hours. The mixture was partitioned between diethyl ether and water, the aqueous layer was extracted with the three portions of ether, followed by two portions of ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to generate a mixture containing 24.4 g of olefin isomers which was used without further purification (89%).
[0240] [00240] 1H NMR (400 MHz, CDCl3): δ 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5 , 20 (d, 1H, cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product), 1.98-1.26 (m, 16H). Step 2. (3R) - e (3S) -3-Cyclopentyl-3- [4- (7- [2- (trimethylsilyl) ethoxy] methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile
[0241] [00241] To a solution of 4- (1H-pyrazol-4-yl) -7- [2- (trimethylsilyl) ethoxy] methyl-7H-pyrrolo [2,3-d] pyrimidine (15.0 g, 0, 0476 mol) in ACN (300 ml) 3-cyclopentylacrylonitrile (15 g, 0.12 mol) (as a mixture of cis and trans isomers) was added, followed by DBU (15 ml, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0N HCl. The aqueous layer was extracted back with the three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate / hexanes gradient) to generate a clear viscous syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to generate 19.4 g of adduct. racemic (93%). The enantiomers were separated by preparative HPLC, (OD-H, 15% ethanol / hexanes) and used separately in the next step to generate their corresponding final products. The final products (see step 3) resulting from each of the separate enantiomers have been shown to be active JAK inhibitors; however, the final product resulting from the second peak to elute from preparative HPLC was more active than its enantiomer.
[0242] [00242] 1H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5 , 68 (s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2, 50 (m, 1H), 2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), -0.06 (s, 9H); MS (ES): 437 (M + 1). Step 3. (3R) - e (3S) -3-Cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) - 1H-pyrazol-1-yl] propanonitrile
[0243] [00243] To a solution of 3-cyclopentyl-3- [4- (7- [2- (trimethylsilyl) ethoxy] methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazole- 1-yl] propanonitrile (6.5 g, 0.015 mol, R or S enantiomer as isolated above) in DCM (40 ml) TFA (16 ml) was added and this was stirred for 6 hours. The solvent and TFA were removed in vacuo. The residue was dissolved in DCM and concentrated using a rotary evaporator twice more to remove as much of the TFA as possible. After that, the residue was stirred with ethylenediamine (4 ml, 0.06 mol) in methanol (30 ml) overnight. The solvent was removed in vacuo, water was added and the product was extracted into three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to generate the crude product which was purified by flash column chromatography (eluting with a methanol / DCM gradient). The resulting mixture was further purified by preparative HPLC / MS (C18 eluting with an ACN / H2O gradient containing 0.15% NH4OH) to generate the product (2.68 g, 58%).
[0244] [00244] 1H NMR (400 MHz, D6-dmso): δ 12.11 (br s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H ), 7.60 (d, 1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48 -2.36 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H); MS (ES): 307 (M + 1). Example 2: (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol1-yl) -3-cyclopentylpropanonitrile salt
[0245] [00245] To a test tube was added (R) -3- (4- (7H-pyrrolo [2,3- d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile ( 153.5 mg) and phosphoric acid (56.6 mg) followed by isopropyl alcohol (IPA) (5.75 ml). The resulting mixture was heated to clear, cooled to room temperature, and then stirred for an additional 2 hours. The precipitate was collected by filtration and the cake was washed with 0.6 ml of cold IPA. The cake was vacuum dried to constant weight to generate the final salt product (171.7 mg).
[0246] [00246] The phosphoric acid salt was shown to be a 1: 1 salt by 1H NMR and crystallinity was confirmed by X-ray powder diffraction (XRPD). Differential scanning calorimetry (DSC) generated an acute melting peak at about 198.66 ° C. The product showed little weight loss up to 200 ° C by TGA. Example 3: Preparation of oil cream formulations in water of (R) -3- acid salt (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- phosphoric cyclopentylpropanonitrile
[0247] [00247] A cream oil-in-water formulation was prepared for (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl salt ) -3- phosphoric cyclopentylpropanonitrile (Example 2) at 0.5, 1.0 and 1.5% by weight of the formulation (equivalent of free base). Compositions for a 15 gram tube are provided in Table 2 below. The formulation for three intensities was identical, except for adjustments to the amount of purified water based on the amount of active ingredient. All excipients used in the formulation were of a compendial grade (ie USP / NF or BP) or are approved for use in topical products.
[0248] [00248] Quantitative formulas for 400 kg lots representative of the cream formulation for Example 2 at 0.5, 1.0 and 1.5% are further provided in Tables 3, 4, and 5, respectively.
[0249] 1. Uma fase de parabeno foi preparada misturando metil e propil parabenos com uma porção do propileno glicol (ver % nas Tabelas 2 a 5). 2. Em seguida, uma fase de goma xantana foi preparada misturando goma xantana com propileno glicol (ver % nas Tabelas 2 a 5). 3. Uma fase oleosa foi, então, preparada misturando óleo mineral leve, estearato de glicerila, polissorbato 20, petrolato branco, álcool cetílico, álcool estearílico, dimeticona e triglicerídeos de cadeia média. A fase é aquecida a 70-80°C para fundir e formar uma mistura uniforme. 4. A fase aquosa foi em seguida preparada misturando água purificada, polietileno glicol, e EDTA dissódico. A fase é aquecida a 70-80°C. 5. A fase aquosa da etapa 4, fase de parabeno da etapa 1, e Exemplo 2 (sal de fosfato de API) foram combinadas para formar uma mistura. 6. A fase de goma xantana da etapa 2 foi, então, adicionada à mistura da etapa 5. 7. A fase oleosa da etapa 3 foi, então, combinada sob mistura de alto cisalhamento com a mistura da etapa 6 para formar uma emulsão. 8. Fenoxietanol foi, então, adicionado à emulsão da etapa 7. A mistura foi continuada e, então, o produto foi resfriado sob mistura de baixo cisalhamento. [00249] Cream-in-water formulations were synthesized according to the following procedure on a 3.5 kg or 400 kg scale (when prepared in a 3.5 kg lot size, the quantities in Tables 3 to 5 were scaled appropriately). Some batches have undergone minor changes associated with scaling up, such as the size of mixing vessels and mixers. Generally, the overhead mixer with high and low shear mixing blades is suitable for the process. Figure 1 shows a flow diagram of the process for producing the oil in water formulation. (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile is referred to as the "API" throughout this order. Procedure 1. A paraben phase was prepared by mixing methyl and propyl parabens with a portion of propylene glycol (see% in Tables 2 to 5). 2. Then, a xanthan gum phase was prepared by mixing xanthan gum with propylene glycol (see% in Tables 2 to 5). 3. An oily phase was then prepared by mixing light mineral oil, glyceryl stearate, polysorbate 20, white petrolatum, cetyl alcohol, stearyl alcohol, dimethicone and medium chain triglycerides. The phase is heated to 70-80 ° C to melt and form a uniform mixture. 4. The aqueous phase was then prepared by mixing purified water, polyethylene glycol, and disodium EDTA. The phase is heated to 70-80 ° C. 5. The aqueous phase of step 4, paraben phase of step 1, and Example 2 (API phosphate salt) were combined to form a mixture. 6. The xanthan gum phase from step 2 was then added to the mixture from step 5. 7. The oil phase from step 3 was then combined under high shear mixing with the mixture from step 6 to form an emulsion. 8. Phenoxyethanol was then added to the emulsion from step 7. The mixing was continued and then the product was cooled under a low shear mixture.
[0250] [00250] More consistent batches on larger scales (eg 140 kg) could be obtained by adding Example 2 gradually to the aqueous phase and then combining with other phases. Similarly, more consistent batches could be obtained by slower cooling (for example, using water at room temperature in the outer jacket of the reactor, instead of water at a lower temperature). Analytical results for cream formulations and stability studies A. Methods
[0251] [00251] The appearance of the cream was visually inspected. Viscosity was measured using a Brookfield viscometer at 25ºC. The pH was measured in the final cream formulation. The microbial limit test is performed as per USP. The fill weight is analyzed as a test in process during the filling of the cream in the tubes.
[0252] [00252] Assay, related substances, identity and uniformity of content were determined in the formulation by a reverse phase gradient HPLC with UV detection at 294 nm. A Waters HPLC was used with a Zorbax SB-C18 column (3.5 µm, 4.6 X 150 mm) at a flow rate of 1.0 mL / minute, temperature 40 ° C using 2 mL TFA Mobile Phase A in 4 L of water (0.05% TFA), or Mobile Phase B of 2 mL of TFA in 4 L of methanol (0.05% TFA). B. Results
[0253] [00253] The results are shown below for 3.5 kg batches at 0.5%, 1% and 1.5% intensity of Example 2 (on a free base (API) basis) (Table 6).
[0254] [00254] The stability data of the batches of the cream formulation at 0.5, 1.0 and 1.5% w / w of intensity stored in aluminum tubes of 15 grams are provided in Tables 7 to 10 and 19 to 20 In addition, the batch stability data of the cream formulation at 0.5, 1.0 and 1.5% w / w intensity packed in amber glass containers (0.06L (2 oz.) With teflon lid ) are provided in Tables 13-17, while longer stability data for the 1.0% w / w formulation packaged in amber glass containers of 0.47L (16 oz.) are provided in Tables 11-12. Preliminary stability data for the drug product did not show chemical instability after 3 months of storage at 25 ° C / 60% RH and 40 ° C / 75% RH in the packaging configuration. A change in viscosity is observed after 3 months at 40 ° C / 75% RH for the formulation stored in amber glass containers. However, physical inspection of the product does not indicate any phase separation.
[0255] [00255] Acceptance criteria are shown below.
[0256] [00256] To determine the solubility of (R) -3- (4- (7H-pyrrolo [2,3- d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile (free base ) or its phosphate salt, approximately 5 ml of a potential solvent was added to approximately 50 mg of API or its salt at room temperature. The mixtures were suspended and spun on a wheel. If the mixtures become clear solutions, more solid material was added. The suspensions were then suspended for 24 hours. The samples were filtered through 0.2 micron filters. The liquid portions were collected and diluted with 50/50 methanol / water. The concentrations of the diluted samples were analyzed by HPLC. When the free base or salt base was very insoluble, the results are only approximate.
[0257] [00257] Three different topical formulations incorporating the phosphate salt of (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- cyclopentylpropanonitrile were also prepared. The compositions of a dispersed cream 1% w / w (water in oil formulation), 1% w / w anhydrous ointment, and 1% w / w lotion are summarized in Table 22 (percentages are on a free base basis). Each of the formulations with 1% w / w of the phosphate salt of API were lower in viscosity compared to placebo (in placebo, the balance is [water). Not wishing to be bound by any particular theory, it is believed that the lower viscosity due to the electrolytic nature of the phosphate salt. Viscosities of the formulations and placebo over time are shown in table 23. The dispersed cream at 1% (water in oil formulation) showed syneresis after two and four weeks of aging at 40 ° C, while formulations at 1% lotion and cream solubilized at 1% (oil in water formulations) did not show syneresis. The 1% solubilized cream formulation was generally higher in viscosity than the 1% lotion.
[0258] [00258] The three different topical formulations in Example 5 (Table 20) and the cream formulation in Example 3 (Table 4) were evaluated for transport through human cadaver skin. The skin permeation data are summarized in table 24. Significant variability was observed in the transport between the three replicates for each formulation. Transport variability may be due in part to differences in skin samples (donor, body region, thickness, etc.). In general, the two cream formulations showed greater flow compared to lotion or ointment. The cumulative amount of API transported to the ointment formulation was particularly low compared to the other three formulations and this, at least in part, could be due to the low spreadability of the ointment leading to the reduced surface area for transport. As a result, cream formulations were selected for further development, one as an oil in water (see Example 3 above) and the other as a water-in-oil emulsion base. Based on the solubility of the drug substance, intensities containing 1.0, 1.5, and 2.0% w / w (R) -3- phosphate salt (4- (7H-pyrrole [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile were developed for oil-in-water cream (solubilized cream) and 1.0, 2.0, and 3.0% w / w were developed for water based oil in oil (dispersed cream). Procedures for skin permeation studies are described below. Studies of skin transport in human cadavers
[0259] [00259] The permeability of API in topical formulations was studied using samples of human cadaver skin and Franz diffusion cells. Dermatomated human cadaver skin was obtained from tissue banks, while Franz diffusion cells were prepared. Human cadaver skin samples, sized to fit between the donor and recipient compartments, were placed on Franz's diffusion cells. The topical formulations were weighed (20 mg) on glassine paper, placed the formulation aside on the skin and pressed into place. The dosing chamber was covered with parafilm. Next to the reservoir it was filled using saline with 4% albumin. The reservoir was agitated and maintained at 37 ° C using a dry block heater (Aungst B. Fatty Acid Skin Penetration Enhancers. Pharm. Res. 1989; 6 (3): 244-247). In 4 hours, a 1 ml sample was removed and placed with 1 ml of saline + 4% albumin. In 24 hours, the reservoir was collected. The fabric was visually examined for any holes or tears. The lateral samples of the reservoir were analyzed for API concentrations by an LC / MS assay. Transport studies in mouse skin
[0260] [00260] The permeability of API in topical formulations was studied using freshly extracted mouse skin samples mounted on Franz diffusion cells. Balb / c mice were shaved using a hair removal technique, four days before the experiment. On the morning of the experiment, the mice were sacrificed and as much of the shaved skin as possible was removed, washed and kept moist with 37 ° C saline until use. The mouse skin samples, sized to fit between the donor and recipient compartments, were positioned between the donor and recipient compartments of Franz's diffusion cells. The opening of the Franz cell was 1 cm2. The topical formulations were weighed (20 mg) on glassine paper, placed the formulation aside on the skin and pressed into place. The dosing chamber was covered with parafilm. The reservoir side was filled using saline with 4% albumin. The reservoir was stirred and maintained at 37 ° C using a dry block heater (Aungst 1989 (above)). In 4 hours, a 1 mL sample was removed and replaced with 1 mL of saline + 4% albumin. In 24 hours, the reservoir was collected. The fabric was visually examined for any holes or tears. The lateral samples of the reservoir were analyzed for API concentrations by an LC / MS assay.
[0261] [00261] The intensity effect of solubilized or dispersed cream formulation on the transpore of (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) - 1H-pyrazol-1-yl ) -3-cyclopentylpropanonitrile through human cadaver skin was further evaluated and the data are summarized in table 25. Increases in intensity of 1% w / w 3% w / w of the dispersed cream formulation (water-in-oil) and 1% w / w 2% w / w of the solubilized cream formulation (oil-in-water) did not result in any significant change in (R) -3- (4- (7H-pyrrole [2,3-d] transport) pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile, suggesting that the flow of (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl ) -1H-pyrazol-1-yl) - 3-cyclopentylpropanonitrile is not limited by the release rate of each of these formulations.
[0262] [00262] The transportation of (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1Hpyrazol-1-yl) -3-cyclopentylpropanonitrile through newly mouse skin extracted was evaluated using formulations that were used in rodent pharmacology studies (table 26). There was a general tendency for increased permeability when the intensity of the solubilized cream was increased from 0.5 to 1.5%, while this trend was not seen with the dispersed formulation. For the solubilized cream, the average cumulative amount of (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile through the skin of the mouse for 24 h it was about twenty times greater than that seen in human cadaver skin studies (cumulative average of all experiments).
[0263] [00263] Based on the solubility of (R phosphate) -3- (4- (7Hpyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanonitrile, a loading maximum 1.5% drug use was possible with the formulation of oil in water (solubilized cream). Of the two formulated creams, the product oil in water (solubilized cream) showed better physical stability (see table 21 above). It should be noted that intensities greater than 3% in the dispersed cream formulation and 2% in the solubilized cream formulation were not physically stable, in addition to several days of storage in a controlled temperature environment, as the drug substance crystallized out of the solution. Based on these findings, together with skin permeability results, industrialization data and physical and chemical characterization obtained for the initial stage formulations, a solubilized cream with an oil-in-water emulsion base (with a maximum intensity of 1.5% p / p) were chosen for development.
[0264] [00264] Approximately 200 subjects with chronic plaque psoriasis were included in a double-blind placebo-controlled study. There were four dose groups, three active and vehicle treatment groups. The active treatment groups were treated with 0.5%, 1.0% and 1.5% w / w oil in water formulations (See Example 3 above). Approximately 50 subjects were randomized into each treatment group. A thin layer of cream was applied once daily to 20% body surface area of plaque psoriasis. The treatment was applied for 84 days and effectiveness was measured by the change in the total lesion score, a measurement scale that assesses the amount of erythema, scaling and plaque thickness (figure 2). 25% of patents randomized to 1% w / w or 1.5% w / w of the API had lesions that were clear or almost clear at week 12, against 6% in the vehicle.
[0265] [00265] In a subset of sites, photos were obtained from subjects who signed an informed consent for the photos. The images were obtained at baseline (before the first application of the study treatment) and on day 84 (the last day of application for the study treatment) (see figures 3-7). These photos are representative of a subset of the subjects who were treated with the oil in water formulations. Example 8: Test of delayed contact hypersensitivity response on murine skin
[0266] [00266] The formulations described here can also be tested for their efficacy (of inhibiting JAK targets) in the T cell targeted delayed hypersensitivity test model. The delayed contact type hypersensitivity (DTH) response with murine skin is considered as a valid clinical model of contact dermatitis and other immune disorders of the skin mediated by T lymphocytes, such as psoriasis (Immunol Today. 1998 Jan; 19 (1): 37-44). Murine DTH shares characteristics with psoriasis, including immune infiltrate, the accompanying increase in inflammatory cytokines and keratinocyte hyperproliferation. In addition, many classes of agents that are effective in treating psoriasis in the clinic are also effective inhibitors of the DTH response in mice (Agents Actions. 1993 Jan; 38 (1-2): 116-21).
[0267] [00267] On days 0 and 1, Balb / c mice are sensitized with a topical application, to their abdomen scraped with antigen 2,4, dinitro-fluorobenzene (DNFB). On day 5, ears are measured for thickness using the engineer’s micrometer. This measurement is recorded and used as a baseline. Both animals' ears are then challenged by a topical application of DNFB in a total of 20 μL (10 μL on the internal pinna and 10 μL on the external ear) at a concentration of 0.2%. Twenty-four to seventy-two hours after the challenge, the ears are measured again. Treatment with test formulations is administered throughout the sensitization and challenge phases (day -1 to day 7) or before and during the challenge phase (usually in the afternoon from day 4 to day 7). The treatment of the test compounds (in different concentrations) is administered topically (topical application of the treatment to the ears). The effectiveness of the test formulations is indicated by a reduction in ear swelling compared to the situation without treatment. The compounds, causing a reduction of 20% or more are considered effective. In some experiments, the mice are challenged, but not sensitized (negative control).
[0268] [00268] The inhibitory effect (inhibition of the activation of the JAK-STAT pathways) of the test formulations can be confirmed by immunohistochemical analysis. The activation of the JAK-STAT pathways results in the formation and translocation of functional transcription factors. In addition, the influx of immune cells and the increasing proliferation of keratinocytes should also provide unique changes in the expression profile in the ear that can be investigated and quantified. Sections of ear fixed in formalin and embedded in paraffin (collected after the challenge phase in the DTH model) are subjected to immunohistochemical analysis using an antibody that specifically interacts with phosphorylated STAT3 (clone 58E12, Cell Signaling Technologies). The mouse ears are treated with test, vehicle or dexamethasone formulations (a clinically effective treatment for psoriasis), or without any treatment, in the DTH model for comparisons. Test formulations and dexamethasone can produce similar transcriptional changes both qualitatively and quantitatively, and test and dexamethasone formulations can reduce the number of cell infiltrations. Topical administration of the test compounds can produce inhibitory effects, that is, reduction of the number of cell infiltration and inhibition of transcriptional changes.
[0269] [00269] Various modifications of the invention, in addition to those described here, will be apparent to those skilled in the art from the above description. Such modifications are also intended to fall within the scope of the attached claims. Each reference cited in this application is hereby incorporated by reference in its entirety.

权利要求:
Claims (47)
[0001]
Pharmaceutical formulation in oil-in-water emulsion cream for topical application to the skin, characterized by the fact that it comprises: an oil-in-water emulsion, comprising water, an oil component, an emulsifying component, a solvent component; and a therapeutic agent that is (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically salt acceptable of the same, wherein the oil-in-water emulsion forms a cream, where the therapeutic agent is present in an amount of 0.5% to 1.5% by weight of the formulation on a free base basis; wherein the solvent component comprises one or more substances selected independently from alkylene glycols, polyalkylene glycols, glycerin, transcutol and trolamine; wherein the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides, silicone oils, fatty acids, hydrocarbon oils, hydrocarbon waxes, polyhydric alcohols, silicones, sterols, vegetable fat , animal fat, vegetable wax, and wax ester; and wherein the emulsifying component comprises one or more non-ionic surfactants.
[0002]
Pharmaceutical formulation, according to claim 1, characterized by the fact that the oil component is present in an amount of 20% to 27% by weight of the formulation.
[0003]
Pharmaceutical formulation according to claim 1 or 2, characterized by the fact that the oil component comprises one or more substances selected independently from petrolatums, fatty alcohols, triglycerides, mineral oils and silicones.
[0004]
Pharmaceutical formulation according to any one of claims 1 to 3, characterized in that the petrolatum is white petrolatum.
[0005]
Pharmaceutical formulation according to any one of claims 1 to 3, characterized by the fact that the fatty alcohol is cetyl alcohol or stearyl alcohol.
[0006]
Pharmaceutical formulation according to any one of claims 1 to 3, characterized in that the mineral oil is light mineral oil.
[0007]
Pharmaceutical formulation according to any one of claims 1 to 3, characterized by the fact that the triglyceride is medium-chain triglycerides.
[0008]
Pharmaceutical formulation according to any one of claims 1 to 3, characterized in that the silicone is dimethicone.
[0009]
Pharmaceutical formulation according to any one of claims 1 to 3, characterized in that the oil component comprises an occlusive agent component present in an amount of 5% to 10% by weight of the formulation, wherein the agent component The occlusive comprises one or more substances independently selected from fatty acids, fatty alcohols, hydrocarbon oils, hydrocarbon waxes, polyhydric alcohols, silicones, sterols, vegetable fat, animal fat, vegetable wax and wax ester.
[0010]
Pharmaceutical formulation according to claim 9, characterized by the fact that the occlusive agent component comprises one or more substances independently selected from hydrocarbon oils and hydrocarbon waxes.
[0011]
Pharmaceutical formulation according to claim 10, characterized in that the hydrocarbon oil or hydrocarbon wax is white petrolatum.
[0012]
Pharmaceutical formulation according to any one of claims 1 to 11, characterized in that the oil component comprises a curing agent component in an amount of 4% to 7% by weight of the formulation, wherein the curing agent component comprises one of more substances independently selected from fatty alcohols.
[0013]
Pharmaceutical formulation, according to claim 12, characterized by the fact that fatty alcohol is selected from cetyl alcohol and stearyl alcohol.
[0014]
Pharmaceutical formulation according to any one of claims 1 to 13, characterized in that the oil component comprises an emollient component in an amount of 7% to 13% by weight of the formulation, wherein the emollient component comprises one or more independently selected substances from mineral oils, triglycerides and silicones.
[0015]
Pharmaceutical formulation according to claim 14, characterized by the fact that mineral oil is light mineral oil.
[0016]
Pharmaceutical formulation according to claim 14, characterized by the fact that the triglyceride is medium chain triglycerides.
[0017]
Pharmaceutical formulation according to claim 14, characterized by the fact that silicone is dimethicone.
[0018]
Pharmaceutical formulation according to any one of claims 1 to 17, characterized in that the water is present in an amount of 45% to 55% by weight of the formulation.
[0019]
Pharmaceutical formulation according to any one of claims 1 to 18, characterized in that the emulsifying component is present in an amount of 4% to 7% by weight of the formulation.
[0020]
Pharmaceutical formulation according to any one of claims 1 to 19, characterized in that the emulsifying component comprises one or more substances selected independently from glyceryl stearate and polysorbate 20.
[0021]
Pharmaceutical formulation according to any one of claims 12 to 20, characterized in that the combined amount of emulsifying component and hardening agent component is 8% by weight of the formulation.
[0022]
Pharmaceutical formulation according to any one of claims 1 to 21, characterized in that said pharmaceutical formulation further comprises a component of stabilizing agent in an amount of 0.3% to 0.5% by weight of the formulation.
[0023]
Pharmaceutical formulation according to claim 22, characterized in that the stabilizing agent component comprises xanthan gum.
[0024]
Pharmaceutical formulation according to any one of claims 1 to 23, characterized in that the solvent component is present in an amount of 20% to 25% by weight of the formulation.
[0025]
Pharmaceutical formulation according to any one of claims 1 to 24, characterized in that the solvent component comprises one or more substances selected independently from propylene glycol and polyethylene glycol.
[0026]
Pharmaceutical formulation according to any one of claims 1 to 25, characterized in that said therapeutic agent is (R) -3-cyclopentyl-3- [4- (7H-pyrrole [2,3-d] acid salt pyrimidin-4-yl) -1H-pyrazol-1-yl] phosphoric propanonitrile.
[0027]
Pharmaceutical formulation according to claim 1, characterized by the fact that it comprises: 35% to 65% water by weight of the formulation; from 10% to 40% of an oil component by weight of the formulation; from 1% to 9% of an emulsifying component by weight of the formulation; from 10% to 35% of a solvent component by weight of the formulation; from 0.05% to 5% of a stabilizing agent component by weight of the formulation; and from 0.5% to 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0028]
Pharmaceutical formulation according to claim 1, characterized by the fact that it comprises: 40% to 60% water by weight of the formulation; from 15% to 30% of an oil component by weight of the formulation; from 2% to 6% of an emulsifying component by weight of the formulation; from 15% to 30% of a solvent component by weight of the formulation; from 0.1% to 2% of a stabilizing agent component by weight of the formulation; and from 0.5% to 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0029]
Pharmaceutical formulation according to claim 1, characterized by the fact that it comprises: 45% to 55% water by weight of the formulation; from 17% to 27% of an oil component by weight of the formulation; from 3% to 5% of an emulsifying component by weight of the formulation; from 20% to 25% of a solvent component by weight of the formulation; from 0.3% to 0.5% of a stabilizing agent component by weight of the formulation; and from 0.5% to 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0030]
Pharmaceutical formulation according to claim 1, characterized by the fact that it comprises: 45% to 55% water by weight of the formulation; from 17% to 27% of an oil component by weight of the formulation; from 4% to 7% of an emulsifying component by weight of the formulation; from 20% to 25% of a solvent component by weight of the formulation; from 0.3% to 0.5% of a stabilizing agent component by weight of the formulation; and from 0.5% to 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0031]
Pharmaceutical formulation according to any of claims 27 to 30, characterized by the fact that: the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides and dimethicone; the emulsifying component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20; the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol; and the stabilizing agent component comprises xanthan gum.
[0032]
Pharmaceutical formulation according to claim 1, characterized by the fact that it comprises: 35% to 65% water by weight of the formulation; from 2% to 15% of an occlusive agent component by weight of the formulation; from 2% to 8% of a curing agent component by weight of said formulation; from 5% to 15% of an emollient component by weight of the formulation; from 1% to 9% of an emulsifying component by weight of the formulation; from 0.05% to 5% of a stabilizing agent component by weight of the formulation; from 10% to 35% of a solvent component by weight of the formulation; and from 0.5% to 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0033]
Pharmaceutical formulation according to claim 1, characterized by the fact that it comprises: 40% to 60% water by weight of the formulation; from 5% to 10% of an occlusive agent component by weight of the formulation; from 2% to 8% of a curing agent component by weight of said formulation; from 7% to 12% of an emollient component by weight of the formulation; from 2% to 6% of an emulsifying component by weight of the formulation; from 0.1% to 2% of a stabilizing agent by weight of the formulation; from 15% to 30% of a solvent component by weight of the formulation; and from 0.5% to 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0034]
Pharmaceutical formulation according to claim 1, characterized by the fact that it comprises: 45% to 55% water by weight of the formulation; from 5% to 10% of an occlusive agent component by weight of the formulation; from 3% to 6% of a curing agent component by weight of said formulation; from 7% to 13% of an emollient component by weight of the formulation; from 3% to 5% of an emulsifying component by weight of the formulation; from 0.3% to 0.5% of a stabilizing agent component by weight of the formulation; from 20% to 25% of a solvent component by weight of the formulation; and from 0.5% to 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0035]
Pharmaceutical formulation according to claim 1, characterized by the fact that it comprises: 45% to 55% water by weight of the formulation; from 5% to 10% of an occlusive agent component by weight of the formulation; from 4% to 7% of a curing agent component by weight of said formulation; from 7% to 13% of an emollient component by weight of the formulation; from 4% to 7% of an emulsifying component by weight of the formulation; from 0.3% to 0.5% of a stabilizing agent component by weight of the formulation; from 20% to 25% of a solvent component by weight of the formulation; and from 0.5% to 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0036]
Pharmaceutical formulation according to claim 1, characterized by the fact that it comprises: 45% to 55% water by weight of the formulation; 7% of an occlusive agent component by weight of the formulation; from 4.5% to 5% of a curing agent component by weight of said formulation; 10% of an emollient component by weight of the formulation; from 4% to 4.5% of an emulsifying component by weight of the formulation; 0.4% of a stabilizing agent component by weight of the formulation; 22% of a solvent component by weight of the formulation; and from 0.5% to 1.5% of (R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.
[0037]
Pharmaceutical formulation according to any one of claims 32 to 36, characterized in that the combined amount of the curing agent component and the emulsifying component is 8% by weight of the formulation.
[0038]
Pharmaceutical formulation according to any of claims 32 to 37, characterized in that: the occlusive agent component comprises white petrolatum; the curing agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol; the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides and dimethicone; the emulsifying component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20; the stabilizing agent component comprises xanthan gum; and the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.
[0039]
Use of a pharmaceutical formulation, as defined in any of claims 1 to 38, characterized by the fact that it is for the preparation of a medicament for the treatment of a skin disease.
[0040]
Use according to claim 39, characterized by the fact that the skin disorder is atopic dermatitis or psoriasis.
[0041]
Use according to claim 40, characterized by the fact that the skin disorder is psoriasis.
[0042]
Use according to claim 40, characterized by the fact that said skin disorder is skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.
[0043]
Use according to claim 40, characterized by the fact that the skin disorder is bullous skin disorder.
[0044]
Use according to claim 43, characterized by the fact that said bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP).
[0045]
Use, according to claim 40, characterized by the fact that the skin disorder is atopic dermatitis.
[0046]
Pharmaceutical formulation according to claim 1, characterized by the fact that the oil-in-water emulsion has a pH of no more than 3.6.
[0047]
Pharmaceutical formulation according to claim 1, characterized by the fact that the oil-in-water emulsion has a pH of 2.9 to 3.6.

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法律状态:
2017-07-11| B25G| Requested change of headquarter approved|Owner name: INCYTE CORPORATION (US) |

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2017-07-25| B25A| Requested transfer of rights approved|Owner name: INCYTE HOLDINGS CORPORATION (US) |

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-04-24| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-10-15| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2019-10-22| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-04-07| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-08-25| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-12-01| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 20/05/2011, OBSERVADAS AS CONDICOES LEGAIS. |

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2020-12-29| B16D| Grant of patent or certificate of addition of invention cancelled|Free format text: ANULADA A PUBLICACAO CODIGO 16.1 NA RPI NO 2604 DE 01/12/2020 POR TER SIDO INDEVIDA. |

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2021-01-05| B09X| Republication of the decision to grant [chapter 9.1.3 patent gazette]|

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2021-01-12| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 20/05/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US34713210P| true| 2010-05-21|2010-05-21|

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US61/347,132|2010-05-21|

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PCT/US2011/037291|WO2011146808A2|2010-05-21|2011-05-20|Topical formulation for a jak inhibitor|

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