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    • 专利摘要:
    METHODS OF REDUCING SKIN SEED PRODUCTION. The present invention relates to methods of using gaseous nitric oxide and / or at least one source of nitric oxide or reducing sebum production in an individual's skin. In some embodiments, the source of nitric oxide includes compounds that release NO from small molecules and / or macromolecules.
    公开号:BR112013014003B1
    申请号:R112013014003-8
    申请日:2011-12-15
    公开日:2020-12-29
    发明作者:Susanne Bauman；Nathan Stasko
    申请人:Novan, Inc；
    IPC主号:
    专利说明:

    REFERENCE TO RELATED PATENT APPLICATIONS
    [0001] This patent application claims the priority of US Provisional Patent Application No. Serial 61 / 423,292, filed on December 15, 2010, and US Provisional Patent Application No.61 / 504,634, filed on July 5, 2011, disclosure of each of which is hereby incorporated by reference in this order in its entirety. FIELD OF THE INVENTION
    [0002] The present invention is directed to methods of treating dermatological diseases. More particularly, the present invention is directed to methods of reducing the production of tallow napele. BACKGROUND OF THE INVENTION
    [0003] Acne vulgaris is the most common skin disease in the United States. It is estimated that 40 to 50 million Americans have acne, including 80% of people between the ages of 11 and 30. The annual direct costs associated with treating acne exceeded $ 2.8 billion in 2007, with most of those costs attributable to prescription medications. In addition, acne causes both physical and psychological effects, including permanent scarring, anxiety, depression and low self-esteem. Even in cases of mild acne, the macula socially associated with the disease often results in significant emotional distress and other psychological issues. Due to its social impacts, the frequency of recurrence or recurrence and necessary maintenance in a prolonged course of therapy, the American Academy of Dermatologists have recommended that acne vulgaris be reclassified and investigated as a chronic disease.
    [0004] Acne vulgaris results from the complex interaction of four main pathogenic factors: 1) sebum overproduction by the sebaceous gland; 2) abnormal keratinization in the follicle; 3) colonization of hair follicles by anaerobic, lipophilic bacteria, Propionibacterium acnes or P. acnes; and 4) release of inflammatory mediators in the skin.
    [0005] The role of sebum production in the pathogenesis of acne has been studied. See, Bellew et al. "Pathogenesis of Acne Vulgaris: What’s new, What’s interesting, and What may be clinically relevant," J. Drugs Dermatol. 2011; 10, 582-585, the disclosure of which is incorporated by reference, as is presented in its entirety in this application. All acne lesions begin when the combination of excessive sebum and abnormal epithelial desquamation fills a follicle, forming a microscopic lesion known as a microcomposite. The anaerobic environment, rich in microcomponent lipids, provides an ideal location for the proliferation of P. acnes. Each microcomponent can progress to form a non-inflammatory open or closed comedo (commonly referred to as a "blackhead" or "pimple", respectively), or an inflammatory lesion that can be further categorized as a wheal, pustule, nodule or cyst.
    [0006] The complexity of the disease may require multiple treatments that may include oral and topical antimicrobials, oral and topical retinoids, oral contraceptives and other prescription skin cleansers. The most effective acne therapies are those that can safely act on more than one of the main causes of the pathogenesis of acne.
    [0007] Antibiotics were the first successful acne treatment due to its antimicrobial and anti-inflammatory properties. Both topical and systemic antibiotics have been very successful, but the lengthy treatment periods required have led to the development of resistance from P. acnes and other non-target (and potentially pathogenic) organisms on a monthly basis. Combining antibiotics with topical retinoids targets three of four major pathogenic factors associated with acne (all except sebum production). The oral retinoid isotretinoin (eg Accu-tane®) is the only drug known to affect the four pathogenic factors associated with acne. However, the severity of its potential side effects (known teratogen and linked to depression, psychosis and suicide) has limited its use and has led to numerous processes.
    [0008] While the problems associated with isotretinoin are the most severe, all current acne medications have some adverse effects. Most current treatments lead to dryness, irritation and peeling of the skin, and oral antibiotics can cause irritation of the gastrointestinal tract, skin photosensitivity, headache, dizziness, anemia, bone and joint pain, nausea and / or depression. As such, new medications for treating acne are desired, and particularly new treatments that target sebum production. SUMMARY OF THE INVENTION
    [0009] In this application, according to the modalities of the invention, methods of reducing the production of sebum in the skin of an individual are provided. Such methods include applying nitric oxide and / or at least one source of nitric oxide to the skin in an amount sufficient to reduce sebum production and / or reduce, eliminate or prevent acne. In some embodiments of the invention, gaseous nitric oxide is applied to the individual's skin. In some embodiments of the invention, at least one source of nitric oxide is applied to the individual's skin.
    [00010] In some embodiments, at least one source of nitric oxide includes a compound that releases nitric oxide (NO), including compounds of small molecules that release NO and macro-molecular compounds that release NO. In some embodiments, compounds that release NO include compounds functionalized with N-diazene-diolate, and in some embodiments, compounds functionalized with N-diazene-diolate include polysiloxane macromolecules co-densified with N-diazene-diolate. In some embodiments, compounds that release NO include compounds functionalized with nitrosothiol. In some embodiments, the NO-releasing compound is present in a pharmaceutically acceptable composition, and in some embodiments, the pharmaceutically acceptable composition includes at least one other therapeutic agent.
    [00011] Also provided in this application, in accordance with the modalities of the invention, methods of reducing the production of sebum in the skin of an individual which systemically include the application of nitric oxide and / or at least one source of nitric oxide to the individual in question. an amount sufficient to reduce sebum production and / or decrease, eliminate or prevent acne on the skin. DETAILED DESCRIPTION OF THE MODALITIES OF THE INVENTION
    [00012] The foregoing and other aspects of the present invention will now be described in more detail with respect to the description and methodologies provided in this application. It must be appreciated that the invention can be personified in different ways and should not be interpreted as limited to the modalities presented in this application. Instead, these modalities are provided so that this disclosure is complete and will fully convey the scope of the invention to those skilled in the art.
    [00013] The terminology used in describing the invention in this application is for the purpose of describing particular modalities only and is not intended to limit the invention. As used in describing the modalities of the invention and the added claims, the singular forms "a", "o" "an" and "an" are understood to include plural forms as well, unless the context clearly indicate otherwise. Also, as used in this order, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items. In addition, the term "approximately", as used in this application, when referring to a measurable value such as a quantity of a compound, dose, time, temperature, and the like, is intended to encompass variations of 20%, 10 %, 5%, 1%, 0.5%, or up to 0.1% of the specified quantity. It will also be understood that the terms "understand" and / or "comprising", when used in this specification, specify the presence of certain attributes, integers, steps, operations, elements and / or components, but do not prevent the presence or addition of one or more other attributes, integers, steps, operations, elements, components and / or groups thereof. Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
    [00014] All patents, patent applications and publications referred to in this application are incorporated by reference in their entirety. In case of contrary terminology, this specification will control.
    [00015] The modalities described in one aspect of the present invention are not limited to the aspect described. The modalities can also be applied to a different aspect of the invention as long as the modalities do not prevent these aspects of the invention from operating with their desired objective. Chemical definitions
    [00016] As used in this application, the term "alkyl" refers to C1-20 inclusive, linear hydrocarbon chains (i.e., "straight chain"), branched, or cyclic, saturated or at least partially and in some cases totally unsaturated (ie alkenyl and alkynyl), including for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, ethylene, propenyl, butenyl, pentenyl, hexenyl groups octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptinyl, and alenyl. "Branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. Exemplary branched alkyl groups include, but are not limited to, isopropyl, isobutyl, tert-butyl. "Lesser alkyl" refers to an alkyl group having 1 to approximately 8 carbon atoms (i.e., C1-8 alkyl), for example, 1, 2, 3, 4, 5, 6, 7 , or 8 carbon atoms. "Major alkyl" refers to an alkyl group having approximately 10 to approximately 20 carbon atoms, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, "alkyl" refers, in particular, to C1-5 straight chain alkyls. In other modalities, "alkyl" refers especially to branched C1-5 alkyls.
    [00017] Alkyl groups can be optionally substituted (a "substituted alkyl") by one or more alkyl group substituents, which can be the same or different. The term "alkyl group substituent" includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxy, alkoxyl, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxyl, alkoxycarbonyl, oxo and cycloalkyl. One or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms may be optionally inserted along the alkyl chain, where the nitrogen substituent is hydrogen, lower alkyl (also referred to in this application as "alkylaminoalkyl"), or aryl.
    [00018] Thus, as used in this application, the term "substituted alkyl" includes alkyl groups, as defined in this application, in which one or more atoms or functional groups of the alkyl group are replaced by another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate and mercapto.
    [00019] The term "aryl" is used in this application to refer to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings that are fused together, covalently linked, or linked to a common group , such as, but not limited to, a methylene or ethylene moiety. The common bonding group can also be a carbonyl, as in benzophenone or oxygen, as in diphenylether or nitrogen, as in diphenylamine. The term "aryl" specifically encompasses aromatic heterocyclic compounds. The aromatic ring (s) can comprise phenyl, naphthyl, biphenyl, diphenylether, diphenylamine and benzophenone, among others. In particular embodiments, the term "aryl" means a cyclic aromatic comprising approximately 5 to approximately 10 carbon atoms, for example, 5, 6, 7, 8, 9, or 10 carbon atoms, and including hydrocarbons and aromatic rings 5- and 6-membered heterocyclics.
    [00020] The aryl group can be optionally substituted ("substituted aryl") with one or more substituents from the aryl group, which may be the same or different, in which "aryl group substituent" includes alkyl, substituted alkyl, aryl , substituted aryl, aralkyl, hydroxyl, alkoxy, aryloxyl, aralkyloxy, carboxyl, acyl, halo, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxy, acylamino, arylamino, carbamoyl, alkylcarbamoyl, alkylcarbamoyl, aralkyl, aryl, aryl, diall -NR1R2, where R1 and R2 can each be independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and aralkyl.
    [00021] Thus, as used in this application, the term "substituted aryl" includes aryl groups, as defined in this application, in which one or more atoms or functional groups of the aryl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxy, nitro, amino, alkylamino, dialkylamino, sulfate and mercapto. Specific examples of aryl groups include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline , indole, carbazole and the like.
    [00022] "Cyclic" and "cycloalkyl" refer to a mono or multicyclic non-aromatic ring system of approximately 3 to approximately 10 carbon atoms, for example 3, 4, 5, 6, 7, 8, 9 , or 10 carbon atoms. The cycloalkyl group can optionally be partially unsaturated. The cycloalkyl group can also be optionally substituted with an alkyl group substituent as defined in this application, oxo and / or alkylene. One or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms can be optionally inserted along the cyclic alkyl chain, where the nitrogen substituent is hydrogen, alkyl, substituted alkyl, aryl, or aryl substituted, thereby providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl and cycloheptyl. Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphene and noradamanthyl.
    [00023] "Alkoxyl" refers to an alkyl-O- group in which the alkyl is as previously described. The term "alkoxy", as used in this application, can refer to, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, f-butoxy, and pentoxyl. The term "oxyalkyl" can be used interchangeably with "alkoxy". In some modalities, alkoxy has 1, 2, 3, 4, or 5 carbons.
    [00024] "Aralkyl" refers to an aryl-alkyl group in which aryl and alkyl are as previously described, and include substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl and naphthylmethyl.
    [00025] "Alkylene" refers to a straight or branched bivalent aliphatic hydrocarbon group having from 1 to approximately 20 carbon atoms, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group can also be optionally unsaturated and / or substituted by one or more "alkyl group substitutes". One or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms (also referred to in this application as "alkylaminoalkyl") can be optionally inserted along the alkylene group, where the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (- (CH2) 3-); cyclohexylene (- C6H10-); -CH = CH-CH = CH -; - CH = CH-CH2-; where each q and q is independently an integer from 0 to approximately 20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and R is hydrogen or lower alkyl; methylenedioxy (-O- CH2-O-); and ethylenedioxy (-O- (CH2) 2-O-). An alkylene group can have approximately 2 to approximately 3 carbon atoms and may also have 6 to 20 carbons.
    [00026] "Arylene" refers to a divalent aryl group. An exemplary arylene is phenylene, which may have ring carbon atoms available for bonding in the ortho, meta, or to each other positions, that is, respectively. The arylene group can also be naphthylene. The arylene group can be optionally substituted (a "substituted arylene") with one or more "aryl group substituents" as defined in this application, which can be the same or different.
    [00027] "Aralkylene" refers to a divalent group that contains both alkyl and aryl groups. For example, aralkylene groups may have two alkyl groups and an aryl group (ie, - alkyl-aryl-alkyl-), an alkyl group and an aryl group (ie, aryl-alkyl) or two aryl groups and an alkyl group (i.e., "aryl-alkyl-aryl").
    [00028] The term "amino" and "amine" refers to groups containing nitrogen such as NR3, NH3, NHR2, and NH2R, where R can be alkyl, branched alkyl, cycloalkyl, aryl, alkylene, arylene, aralkylene . Thus, "amino", as used in this application, can refer to a primary amine, a secondary amine or a tertiary amine. In some embodiments, an R of an amino group can be a stabilized diazene-diolate cation (ie, NONO-X +).
    [00029] The terms "cationic amine" and "quaternary amine" refer to an amino group that has an additional group (i.e., a quarter), for example, a hydrogen or an nitrogen-bonded alkyl group. Thus, cationic and quarternary amines carry a positive charge.
    [00030] The term "alkylamine" refers to the alkyl-NH2 group.
    [00031] The term "carbonyl" refers to the group - (C = O) -.
    [00032] The term "carboxyl" refers to the group -COOH and the term "carboxylate" refers to an anion formed from a carboxyl group, that is, -COO-.
    [00033] The terms "halo", "halide" or "halogen", as used in this application, refer to fluorine, chlorine, bromine and iodine groups.
    [00034] The term "hydroxyl" and "hydroxy" refers to the -OH group.
    [00035] The term "hydroxyalkyl" refers to an alkyl group substituted by an -OH group.
    [00036] The term "mercapto" or "uncle" refers to the group -SH. The term "silyl" refers to groups comprising silicon atoms (Si).
    [00037] As used in this application, the term "alkoxysilane" refers to a compound comprising one, two, three, or four alkoxy groups attached to a silicon atom. For example, tetra-alkoxysilane refers to Si (OR) 4, where R is alkyl. Each alkyl group can be the same or different. An "alkylsilane" refers to an alkoxysilane in which one or more of the alkoxy groups has been replaced by an alkyl group. Thus, an alkylsilane comprises at least one alkyl-Si bond. The term "fluorinated silane" refers to an alkylsilane in which one of the alkyl groups is replaced by one or more fluorine atoms. The term "cationic or anionic silane" refers to an alkylsilane in which one of the alkyl groups is further substituted with an alkyl substituent that has a positive (ie, cationic) or negative (ie, anionic) charge , or it can be charged (that is, it is ionizable) in a particular environment (that is, in vivo).
    [00038] The term "silanol" refers to a group of Si-OH. Methods of reducing sebum production in the skin
    [00039] Methods of reducing sebum production which include the application of nitric oxide and / or at least one source of nitric oxide to an individual's skin to reduce sebum production in the skin are provided according to some embodiments of the invention. Not being limited to any particular theory, it is postulated that sebum production can be reduced by nitric oxide through one or more reduction in the size or number of sebum production sites (ie, reducing the size of sebaceous glands or impact direct sebocyte toxicity) or by biochemical regulation of lipogenesis. In some cases, nitric oxide may be preferentially toxic to sebum production sites over keratinocyte sites such that the size or amount of sebum production site can be reduced without substantially reducing the viability of keratinocytes or other cells viable in the dermis or epidermis. For example, at some dose levels, nitric oxide toxicity may be preferentially toxic to sebum production sites over keratinization sites at a ratio of 2: 1, 3: 1 or even 4: 1.
    [00040] Separately, nitric oxide can also modulate the regulatory mechanism of sebum production. The levels of nitric oxide needed to modulate lipogenesis may be lower than those that are toxic to sebum production sites. In addition, on some levels, sebum production can be affected both by modulating lipogenesis and by reducing the size or number of sebum production sites. Consequently, some embodiments of the present invention can provide nitric oxide levels that are non-toxic to sebocytes but which are effective in down regulating lipogenesis, which are toxic to sebum production sites or both. Gaseous nitric oxide
    [00041] In some modalities, methods of reducing sebum production include the application of gaseous nitric oxide directly or indirectly to an individual's skin. Applying nitric oxide "directly" refers to the application of gaseous nitric oxide to the skin surface, without any barrier between the gas flow and the skin. Applying gaseous nitric oxide "indirectly" refers to the application of gaseous nitric oxide by a substrate, such as a fabric, ornament, membrane, medicine, powder, ointment and the like, before reaching the skin.
    [00042] Gaseous nitric oxide can be applied to the skin in any suitable pressure, flow rate and / or concentration, and can be applied for any suitable duration. It can be applied in a sealed system (for example, a mask or chamber affixed to the affected area) or it can be freely poured over the surface of the skin. Gaseous nitric oxide can also be present in a gas mixture or can be applied by itself. In addition, the nitric oxide gas can be used in combination (before, concurrently and / or after) with any other treatment, including any other method described in this application and any known anti-acne or treatment regimen. Nitric oxide source
    [00043] In some embodiments of the invention, methods of reducing sebum production include applying at least one source of nitric oxide directly or indirectly to the skin. Applying a source of nitric oxide "directly" refers to the application of a source of nitric oxide directly on the surface of the skin, without any barrier between the source of nitric oxide and the skin. Applying gaseous nitric oxide "indirectly" refers to the application of a source of nitric oxide by a substrate, such as a fabric, coating, membrane, or above other medication, powder, ointment and the like. The term "nitric oxide source" refers to a compound, or other composition or device that provides nitric oxide to the skin, but it is not gaseous nitric oxide. In some embodiments, the nitric oxide source includes a compound that releases nitric oxide, hereinafter referred to as a "NO-releasing compound." A compound that releases NO includes at least one NO donor, which is a functional group that can release nitric oxide under certain conditions.
    [00044] Any compound that releases suitable NO can be used. In some embodiments, the NO-releasing compound includes the small molecule compound that does not include a NO donor group. Small molecule compounds are defined in this application as compounds having a molecular weight of less than 500 daltons and included in small organic and / or inorganic molecules. In some modalities, the compound that releases NO includes a macromolecule that does not include a NO donor group. A macromolecule is defined in this application as any compound having a molecular weight of 500 daltons or greater. Any suitable macromolecule can be used, including cross-linked or non-cross-linked polymers, dendrimers, metal compounds, organometallic compounds, inorganic compounds and other macromolecular frameworks. In some embodiments, the macromolecule has a nominal diameter ranging from 0.1 nm - 100 μm and can comprise the aggregation of two or more macromolecules, whereby the macromolecular structure is no longer modified with a NO donor group.
    [00045] In some embodiments of the invention, NO donor of the compound that releases NO releases nitric oxide after exposure to an external condition, such as light, heat, water, acid, base and the like. For example, in some embodiments, the NO-releasing compound includes a diazenium-diolate functional group as a NO donor. The diazenium-diolate functional group can produce nitric oxide under certain conditions, such as after exposure to water. As another example, in some embodiments, the NO-releasing compound includes a nitrosothiol functional group as a NO donor. The NO donor can produce nitric oxide under certain conditions, such as after exposure to light. Examples of another NO donor group include nitrosamine, hydroxyl nitrosamine, hydroxylamine and hydroxyurea. Any suitable combination of NO donor and / or NO releasing compounds can also be used in the methods described in this application. In addition, the NO donor can be incorporated into or over the small molecule or macromolecule by covalent and / or non-covalent interactions.
    [00046] In some embodiments of the invention, the NO-releasing macromolecules may be in the form of NO-releasing particles, such as those described in U.S. Publication No. 2009/0214618, the disclosure of which is incorporated by reference in this application in its entirety. Such particles can be prepared by methods described herein.
    [00047] As an example, in some embodiments of the invention, NO-releasing particles include precipitated NO-charged silica. The NO-charged precipitated silica can be formed from modified silane monomers with nitric oxide donors in a co-condensed siloxane network. In embodiments of the invention, the nitric oxide donor is an N-diazene-diolate.
    [00048] In some embodiments, the nitric oxide donor can be formed from an aminoalkoxysilane by a preload method, and the co-condensed siloxane network can be synthesized from the condensation of a silane mixture that includes an alkoxysilane and the aminoalcoxysilane to form a cocondensed siloxane network modified with a nitric oxide donor. As used in this application, the "preload method" means that aminoalkoxysilane is "pre-treated" or "preloaded" with nitric oxide prior to co-condensation with alkoxysilane. In some embodiments, nitric oxide preload can be performed by chemical methods. In another embodiment, the "preload" method can be used to create co-condensed siloxane networks and more densely functionalized materials with NO donors.
    [00049] The co-condensed siloxane network can be uniformly sized silica particles, a collection of silica particles with a variety of sizes, amorphous silica, sublimated silica, nanocrystalline silica, ceramic silica, colloidal silica, a coating silica, silica film, organically modified silica, mesoporous silica, silica gel, bioactive glass or any suitable form or state of the silica.
    [00050] In some embodiments, alkoxysilane is a tetra-alkoxysilane having the formula Si (OR) 4, where R is an alkyl group. The R groups can be the same or different. In some modalities, tetraalkoxysilane is selected as tetramethyl orthosilicate (TMOS) or tetraethyl orthosilicate (TEOS). In some embodiments, the aminoalkoxysilane has the formula: R "- (NH-R ') n-Si (OR) 3, where R is alkyl, R' is alkylene, branched alkylene or aralkylene, n is 1 or 2, and R "is selected from the group consisting of alkyl, cycloalkyl, aryl and alkylamine.
    [00051] In some embodiments, the aminoalkoxysilane can be selected from N- (6-aminohexyl) aminopropyltrimethoxysilane (AHAP3); N-3- (2-aminoethyl) aminopropyltrimethoxysilane (AEAP3); (3-trimethoxysilylpropyl) di-ethylene triamine (DET3); (aminoethylaminomethyl) phenylyltrimethoxysilane (AEMP3); [3- (methylamino) propyl] trimethoxysilane (MAP3); N-butylamino-propyltrimethoxysilane (n-BAP3); N-butylaminopropyltrimethoxysilane (t-BAP3); N-ethylaminoisobutyltrimethoxysilane (EAiB3); N-phenylamino-propyltrimethoxysilane (PAP3); and N-cyclohexylaminopropyltrimethoxysilane (cHAP3).
    [00052] In some embodiments, the aminoalkoxysilane has the formula: NH [R'-Si (OR) 3] 2, where R is alkyl and R 'is alkylene. In some embodiments, the aminoalkoxysilane can be selected from bis (3-triethoxysilylpropyl) amine, bis- [3- (trimethoxysilyl) propyl] amine and bis- [(3-trimethoxysilyl) propyl] ethylenediamine.
    [00053] In some embodiments, as described in this application above, the aminoalkoxysilane is preloaded to release NO and the amino group is replaced by a diazene diolate. Therefore, in some embodiments, the aminoalkoxysilane has the formula: R "-N (NONO-X +) - R'-Si (OR) 3, where R is alkyl, R 'is alkylene or aralkylene, R" is alkyl or alkylamine, and X + is a cation selected from the group consisting of Na +, K + and Li +.
    [00054] The composition of the siloxane network, (for example, amount or chemical composition of the aminoalkoxysilane) and the nitric oxide loading conditions (for example, the solvent and the base) can be varied to optimize the amount and the duration of nitric oxide release. Thus, in some embodiments, the composition of the silica particles can be modified to regulate the NO release half-life of the silica particles.
    [00055] In another embodiment, the amino group of aminoalkoxysilane is replaced by a diazene-diolate and the aminoalkoxysilane having a formula R "-N (NONO-X +) - R'-Si (OR) 3, where: R is alkyl , R 'is alkylene or aralkylene, R "is alkyl or alkylamine, and X + is a cation selected from the group consisting of Na + and K +.
    [00056] In some embodiments of the invention, the particle size of the particles that release NO is in the range of 20 nm and 10 μm. The particle size can be adapted to minimize or prevent toxicity and penetration through the epidermis (or compromised dermis) and into blood vessels.
    [00057] In another modality, the composition that releases NO is S-nitroglutiona (GNSO). Pharmaceutically acceptable compositions
    [00058] In some embodiments, at least one compound that releases NO is applied to the skin in a pharmaceutically acceptable composition. As such, at least one source of nitric oxide is present in the pharmaceutically acceptable compositions. A pharmaceutically acceptable composition, as defined in this application, refers to a composition that is suitable for application to an individual, such as a human being, without excessive side effects such as toxicity or skin irritation. Excessive side effects are those that make the composition unsuitable for application to an individual because the damage from the side effects outweighs the benefits of the composition. In some embodiments, pharmaceutically acceptable compositions include at least one NO-releasing compound; optionally, at least one additional therapeutic agent; and at least one pharmaceutically acceptable excipient.
    [00059] NO-releasing compounds can be present in pharmaceutically acceptable compositions according to the modalities of the invention at any suitable concentration, but in some embodiments, NO-releasing compounds are present in the compositions in a concentration sufficient to reduce, eliminate or prevent acne and / or reduce sebum production. In some embodiments, the concentration of compounds that release NO ranges from 0.1% to 20% w / w in the composition.
    [00060] As described above, in some embodiments, pharmaceutically acceptable compositions include at least one additional therapeutic agent, such as those that have antimicrobial, anti-inflammatory, pain-relieving, immunosuppressive or vasodilatory properties. Other anti-acne therapeutic agents such as retinoids can also be included in compositions according to an embodiment of the invention.
    [00061] Pharmaceutically acceptable compositions can be present in any physical form, such as ointments, creams, milks, ointments, powders, impregnated pads, solutions, gels, sprayers, lotions or suspensions. They can also be in the form of suspensions of microspheres or nanospheres or lipid or polymeric vesicles, or polymeric adhesives and controlled-release hydrogels. These compositions for topical application may be in anhydrous form, in aqueous form or in the form of an emulsion (for example, oil in water or water in oil emulsions).
    [00062] The term excipient refers to "inert" constituents of pharmaceutically acceptable compositions. The term "inert" indicates that such constituents are not therapeutic agents like compounds that release NO or other antimicrobial compounds, anti-inflammatory agents, pain relievers, immunosuppressants and vasodilators. However, as one of ordinary skill in the art will understand, excipients can provide beneficial or therapeutic action to the skin (for example, moisturize) that can directly affect acne. Excipients can also indirectly affect the treatment of acne by affecting the activity of compounds that release NO or other therapeutic agents within the compositions.
    [00063] Excipients for use in topical formulations are well known in the art and examples can be found in the Handbook of Pharmaceutical Excipients (Rowe, R.C. et al., APhA Publications; 5th ed., 2005). Exemplary excipients can include talc, calcium carbonate, calcium phosphate, magnesium stearate, waxes, various sugars and types of starch, polymers, gels, emollients, thickening agents, rheology modifiers, humectants, glycerol, composites organic bases, cellulose derivatives, gelatine, vegetable oils, polyethylene glycols and solvents. Examples of rheology modifiers include Carbopol, C26-28 alkyl dimethicone, C26-28 alkyl methicone, polyphenylsisquioxane, trimethylsiloxysilicate, cross-linked cyclopentasiloxane polymers and dimethicone / vinyltrimethylsiloxysilicate and mixtures thereof. Examples of emollients include glycerin, pentylene glycol, sodium carboxylic acid pyrrolidone, lanolin, saccharide isomerate, dimethicone stearoxide, stearyl dimethicone, and mixtures thereof. Emollients can be useful to prevent dehydration of the horny layer that appears due to the use of anhydrous solvents in the formulation. Examples of organic bases include methanolamines, triethanolamines, Trisamino, AMP-95, AmP-Ultra PC 2000, triisopropanolamine, diisopropanolamine, Neutrol TE, Ethomeen and mixtures thereof. The organic base can make the pH of the medicine basic or neutral, and can directly affect the NO release of NO-releasing compounds that include the diazonium diolate NO donor group, reducing donor decomposition with increasing alkalinity.
    [00064] Other exemplary excipients include water-soluble porogens. A water-soluble porogen is an additive that can facilitate the entry of water and diffusion into the pharmaceutically acceptable composition. Any suitable porogen can be used, but in some embodiments, the porogen can include sodium chloride, sucrose, glucose, lactose, sorbitol, xylitol, polyethylene glycol, polyvinylpyrrollidone, polyvinyl alcohol or mixtures thereof. Electrolytes, such as NaCl, can also be added as excipients.
    [00065] Polymers can also act as excipients. Exemplary polymers include hydrophilic polyurethane, hydrophilic polyacrylates, copolymers of carboxymethylcellulose and acrylic acid, Nvinylpyrrolidone, poly (hydroxy acids), polyanhydrides, polyiorthesters, polyamide, polycarbonates, polyalkylenes (for example, polyethylene (polyethylene) and polyethylene (polyethylene), ), polyalkylene oxides (eg polyethylene oxide), polyalkylene terephthalates (eg polyethylene terephthalate), polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides (eg poly (polyvinyl chloride)), , polysiloxanes, poly (vinyl acetate), polystyrene, polyurethane copolymers, cellulose, derived celluloses, alginates, poly (acrylic acid), poly (acrylic acid) derivatives, acrylic acid copolymers, methacrylic acid, methacrylic acid derivatives, copolymers of methacrylic acid, poly (butyric acid), poly (valeric acid), poly (lactide-co-c aprolactone), copolymers thereof and mixtures thereof.
    [00066] In some embodiments of the invention, the polymers can be superabsorbent polymers (SAPs). A polymer is considered superabsorbent, as defined by IUPAC, as a polymer that can absorb and conserve extremely large amounts of water in relation to its own mass. SAPs can absorb water up to 500 times its own weight and can swell to 1000 times its original volume. Particular SAPs of interest include sodium polyacrylate, Tecophilic TG-2000 polyurethane and polymers prepared by using the polyacrylamide copolymer, ethylene maleic anhydride copolymer, cross-linked carboxymethylcellulose, polyvinyl alcohol copolymers, polyvinylpyrrolidone and reticulated polyethylene oxide. In some embodiments, SAP can absorb water from the skin, thereby inducing NO to be released from compounds that release NO.
    [00067] In some embodiments of the invention, polymers that are relatively hydrophobic can be used. Any suitable hydrophobic polymer can be used. However, exemplary polymers that are relatively hydrophobic include aromatic polyurethane, silicone rubber, polysiloxanes, polycaprolactone, polycarbonate, polyvinyl chloride, polyethylene, poly-L-lactide, poly-DL-glycolide, polyetheretherketone (PEEK), polyamide , polyimide and polyvinyl acetate. In addition, a hydrophobic gel-base and / or rheology modifier can be used.
    [00068] In some embodiments of the invention, notably in gels, polymers can act as thickening agents in medicines. Specifically, the polymeric portion of the gel can act as a viscoelastic substance and can preserve the gel at the application site, along with compounds that release NO dispersed therein.
    [00069] In some other modalities, notably in gels and ointments, a drug that includes a polymer may have dispersibility such that it forms a thin film when applied to the surface of the skin. This film can allow the application of NO-releasing compounds contained over a wide area and can serve to maintain NO-releasing compounds in the affected area of the skin.
    [00070] Other excipients can include various ionic or non-ionic compounds to maintain the stability of the formulation, which thereby protects against emulsification, liquidation, agglomeration or degradation of the formulation constituents that can reduce its therapeutic or aesthetic value.
    [00071] Examples of ionic compounds can include salts such as sodium chloride, potassium chloride; cationic, anionic or zwitterionic surfactants such as sodium dodecyl sulfate (SDS), perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), ammonium lauryl sulfate (ALS), sodium lauryl sulfate ether (SLES), benzene alkyl sulfonate , cetyl trimethylammonium bromide (CTAB), cetylpyridinium chloride (CPC), tallow polyethoxylated amine (POEA), benzalkonium chloride (BAC), benzethonium chloride, dodecyl betaine, cocamidopropyl betaine and cocoanfoglycinate.
    [00072] Examples of non-ionic compounds that can act as excipients include non-ionic surfactants such as Pluronic, Tween, AMP and the Brij family of surfactants; and surfactants derived from biological sources, for example, natural or semi-synthetic surfactants, such as oleic acid, sorbitan trioleate, sorbitan mono-oleate, lecithin, cocamide MEA, cocamide DEA and cocamidopropyl betaine. Surfactants (both ionic and non-ionic) can reduce the interfacial surface energy and can facilitate the dispersion of the ointment or liquid over a wider area.
    [00073] In some embodiments of the invention, the soluble excipients can be used as a carrier vehicle for compounds that release NO and other excipients. The polymer chains can interact with the solvent and undergo swelling to form a network that can transmit viscoelastic properties to the medication. In some types of medicine, the solvent can evaporate according to the application, leaving a residual film of the polymer together with the compounds that release captured NO.
    [00074] Examples of solvent excipients include dimethyl isosorbed, propylene glycol, glycerol, isopropanol, ethanol, ethylene glycol, polyethylene glycol, ethoxydiglycol or mixtures thereof. Exemplary solvent excipients that may be useful in hydrophobic formulations may include isododecane, isodecyl neopentanoate, butylene glycol, pentylene glycol, hexylene glycol, methoxy polyethylene glycol, cyclopentasiloxane, cyclotetrasiloxane, dimethicone, caprylil methicone or mixtures thereof.
    [00075] In addition to molecules that release NO, excipients and other therapeutic agents, pharmaceutically acceptable compositions can also include other compounds that improve the organoleptic properties of the composition. Examples of such compounds include perfumes, dyes and dyes; chelating agents including but not limited to EDTA, EGTA, CP94, citric acid; preservatives including but not limited to quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, de-qualium chloride and cetylpyridinium chloride; mercury agents, such as phenylmercury nitrate, phenylmercury acetate and thimerosal; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol and benzyl alcohol; antibacterial esters, for example, parahydroxybenzoic acid esters; and other antimicrobial agents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin. Treatment methods
    [00076] As discussed above, provided in accordance with some embodiments of the invention are methods of reducing sebum production on the skin of an individual by applying gaseous nitric oxide and / or at least one source of nitric oxide to the skin. Acne reduction can be detected by a visual reduction in the amount or severity of acne and / or by a reduction in pain or discomfort associated with acne, as identified by the individual. Methods of reducing sebum production on an individual's skin by applying gaseous nitric oxide and / or at least one source of nitric oxide to the skin can be used in those individuals who have overproduction of sebum in the skin. In some cases, reducing the production of sebum in the skin, particularly in those individuals who have overproduction of sebum, can reduce, eliminate or prevent acne.
    [00077] In some embodiments, nitric oxide gas, at least one source of nitric oxide and / or a pharmaceutically acceptable composition according to the modalities of the invention, is currently applied to the individual's skin. Any portion of the individual's skin can be treated. However, in some embodiments, the individual's face is treated by a method described in this application. In addition, in some modalities, the individual's torso is treated by a method described in this application.
    [00078] Additionally, in some embodiments, the nitric oxide gas, at least one source of nitric oxide and / or a pharmaceutically acceptable composition according to the modalities of the invention are applied in another way, as a systemic application.
    [00079] As used in this application, systemic application refers to the application that introduces nitric oxide, at least one source of nitric oxide and / or pharmaceutically acceptable composition throughout the body. In addition, in some embodiments, nitric oxide gas, at least one source of nitric oxide and / or pharmaceutically acceptable composition can be applied to the individual parenterally, orally, orally, subcutaneously, via inhalation, intratracheally, surgically, transdermally, or by any other method known in the art for introducing a drug into the body.
    [00080] Individuals suitable to be treated with a method of the invention include, but are not limited to, avian individuals and mammals. Mammals of the present invention include, but are not limited to, canines, felines, cattle, goats, horses, sheep, porcines, rodents (e.g., rats and mice), lagomorphs, primates, humans, and the like , and mammals in uterus. Any mammalian individual in need of treatment according to the present invention is suitable. Human beings of both genders and at any stage of development (that is, newborn, child, youth, adolescent, adult) can be treated in accordance with the present invention.
    [00081] Illustrative birds according to the present invention include chickens, ducks, turkeys, geese, quail, pheasant, ratites (for example, ostrich) and domesticated birds (for example, parrots and canaries), and birds in egg.
    [00082] The invention can also be carried out on animal individuals, particularly mammalian individuals such as mice, rats, dogs, cats, cattle and horses for veterinary purposes, and for drug development and drug tracking purposes.
    [00083] In some embodiments, methods of reducing sebum production may include using a method described in this application in combination with another therapeutic regimen and / or in combination with other drugs, such as those that have antimicrobial properties , anti-inflammatory, pain relief, immunosuppressants, vasodilators and / or anti-acne properties. For example, other anti-acne agents, such as retinoids, can be used in conjunction (prior, concurrently or after) with the application of nitric oxide gas and / or at least one source of nitric oxide. As such, in some embodiments of the invention, a patient can be treated with gaseous nitric oxide, at least one source of NO and / or a composition described in this application in combination with an additional therapeutic agent when the additional therapeutic agent does not. is in the same composition. For example, in some embodiments, an additional therapeutic agent may be administered (for example, topically, systemically, parenterally, orally, orally, subcutaneously, via inhalation, intratracheally, surgically, transdermally, etc.) concurrently. and / or sequentially with the application of nitric oxide, at least one source of nitric oxide and / or a pharmaceutically acceptable composition that includes at least one source of nitric oxide.
    [00084] In some embodiments of the invention, a pharmaceutically acceptable composition can be administered to the skin via spray delivery. A non-aqueous delivery propellant can be used for compounds that release water-sensitive NO as compounds modified with diazene diolate. In addition, in some modalities, the particular components of the medication may be separated at some point before the medication is applied. For example, a compound that releases reactive NO in water can be stored separately from an aqueous or propellant component until application (for example, by spraying or applying a gel). In some embodiments, compounds that release NO can be combined with an aqueous constituent prior to application or compounds that release NO and an aqueous constituent can be applied to the skin sequentially.
    [00085] In some modalities, an ointment containing compounds modified with nitrosothiol can be kept at a low temperature (for example, <0 ° C) to minimize thermal decomposition and NO release. The cold ointment can then be applied to the skin and the high temperature of the skin can allow the release of NO. In some embodiments, nitrosothiol may be present in a medication (for example, a hydrophilic formulation that can limit the diffusion of NO) such that it is stable at room temperature due to cage effects, and then releases NO upon application to the skin. The light can also be applied to a medicine that includes compounds modified with nitrosothiol. The application of light in streams can be applied to create NO streams.
    [00086] Many modifications and other modalities of the inventions presented in this application will come to the memory of one skilled in the art to which these inventions belong, taking advantage of the teachings presented in the preceding descriptions and associated drawings. Therefore, it should be understood that inventions should not be limited to the specific modalities described and that modifications and other modalities are intended to be included within the scope of the added claims. Although specific terms are used in this order, they are used in a generic and descriptive sense only and not for the purpose of limitation.
    [00087] The present invention will be further illustrated by the following non-limiting examples. EXAMPLES
    [00088] It is known that the increase in dermal lipogenesis is associated with increased sebum production and increased acne severity. Thus, an experiment was designed to determine whether applying a source of nitric oxide would reduce insulin-stimulated lipogenesis 1 μg / mL in SEB-1 sebocytes. Example 1
    [00089] The cytotoxicity of Nitricil ™ -NJ0109 available from Novan, Inc., Durham, North Carolina has been determined. Nitricil ™ -NJ0109 is a co-condensed silica that releases NO. Cytotoxicity was determined in normal human keratinocytes (NHEK, Lonza) using the Cell Titer-Blue® cell viability assay (Promega). The cells were grown close to confluence in 96-well plates. Before treatment, the growth media were removed and replaced with serum-free media containing insulin in order to mimic the conditions used in lipogenesis assays. Nitricil ™ - NJ0109 particles (1, 0.5, 0.1 mg / mL) were added to wells and cell viability was assessed after 24, 48, and 72 hours (n = 3 per treatment per time point) . The results are shown in Table 1. Table 1

    [00090] Nitricil ™ -NJ0109 particles were more toxic to sebocytes than keratinocytes at all concentrations and time points.
    [00091] Then, the ability of non-toxic concentrates of Nitricil ™ -NJ0109 particles to affect lipogenesis in insulin-activated SEB-1 cells was studied. The cells were induced with 1 μg / mL insulin to ensure that levels of lipogenesis, which are very low in SEB-1 under standard culture conditions, were sufficiently stimulated to detect a treatment-induced reduction. Total lipid production was analyzed by measuring the amount of 14C-acetate incorporation in neutral lipids. As shown in Table 2, in concentrations that are not cytotoxic to SEB-1 cells, Nitricil ™ -NJ0109 reduced lipogenesis by up to 17% within 24 hours.
    t Each treatment was carried out in triplicate. Values represent mean counts per minute / 106 cells / hour ± SEM from three independent experiments. * Against vehicle treatment (double-tailed Student t test) Example 2
    [00092] Example 1 was duplicated except the NO-releasing composition was S-nitroglutiona (GSNO) and replaced the Nitricil ™ particles. GSNO is available from Cayman Chemical, Ann Arbor, Michigan. The results are shown in Tables 3 and 4.Table 3
    Table 4The effect of GSNO on total lipid production in SEB-1 sebocytes stimulated by insulin.
    t Each treatment was carried out in triplicate. Values represent average counts per minute / 106 cells / hour ± SEM from three independent experiments. * Against vehicle treatment (Student t-test with two tails).
    [00093] Many modifications and other modalities of the inventions presented in this application will come to the memory of one skilled in the art to which these inventions belong, taking advantage of the teachings presented in the preceding descriptions and the associated drawings. Therefore, it should be understood that inventions should not be limited to the specific modalities described and that the modifications and other modalities are intended to be included within the scope of the added claims. Although specific terms are used in this application, they are used in a generic and descriptive sense only and do not serve purposes of limitation.
    权利要求:
    Claims (13)
    [0001]
    1. Non-therapeutic method for reducing the production of sebum in the skin of an individual, characterized by the fact that it comprises the administration to said individual of a compound that releases nitric oxide, in which the compound that releases NO comprises a diazene-diolate functional group or a nitrosothiol functional group as a NO donor.
    [0002]
    2. Non-therapeutic method according to claim 1, characterized by the fact that the NO-releasing compound has a molecular weight of less than 500 daltons.
    [0003]
    3. Non-therapeutic method according to claim 1, characterized by the fact that the NO-releasing compound has a molecular weight of 500 daltons or more.
    [0004]
    4. Non-therapeutic method according to claim 3, characterized by the fact that the NO-releasing compound comprises a diazene-diolate functional group as a NO donor.
    [0005]
    5. Non-therapeutic method according to claim 4, characterized in that the compound that releases NO comprises polysiloxane macromolecules co-condensed with N-diazene-diolate.
    [0006]
    6. Non-therapeutic method according to claim 3, characterized in that the compound that releases NO comprises macromolecules functionalized with nitrosothiol.
    [0007]
    7. Non-therapeutic method according to claim 1, characterized by the fact that the NO-releasing compound is present in a pharmaceutically acceptable composition.
    [0008]
    Non-therapeutic method according to claim 7, characterized in that the pharmaceutically acceptable composition comprises at least one other therapeutic agent.
    [0009]
    9. Non-therapeutic method according to claim 1, characterized by the fact that the compound that releases NO is applied in a concentration that is toxic to the sebum production sites.
    [0010]
    10. Non-therapeutic method according to claim 1, characterized by the fact that the NO-releasing compound is applied in a concentration that is not toxic to the sebum production sites.
    [0011]
    11. Non-therapeutic method according to claim 1, characterized by the fact that the compound that releases NO is applied in a concentration that is preferably toxic to the sebum production sites on keratinocytes.
    [0012]
    12. Non-therapeutic method for reducing the production of sebum on the skin of an individual, characterized by the fact that it comprises the systemic application of a compound that releases nitric oxide to that individual, in an amount sufficient to reduce the production of sebum in the skin, where the NO-releasing compound comprises a diazenium-diolate functional group or a nitrosothiol functional group as a NO donor.
    [0013]
    13. Non-therapeutic method according to any of claims 1 to 12, characterized in that the production of sebum in the skin is associated with a dermatological disease.
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    公开号 | 公开日
    EP2651381A1|2013-10-23|
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    WO2012082976A1|2012-06-21|
    JP2013545813A|2013-12-26|
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    CA2821962A1|2012-06-21|
    US8591876B2|2013-11-26|
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    US20140057001A1|2014-02-27|
    ES2589682T3|2016-11-15|
    MX348078B|2017-05-25|
    MX2013006871A|2013-07-05|
    CN103379892A|2013-10-30|
    EP3085354B1|2018-02-14|
    JP5980804B2|2016-08-31|
    EP2651381A4|2014-05-28|
    BR112013014003A2|2020-06-16|
    KR101874141B1|2018-07-03|
    CA2821962C|2020-10-27|
    EP2651381B1|2016-06-08|
    US20120156163A1|2012-06-21|
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    法律状态:
    2020-06-23| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-10-06| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-12-29| 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 15/12/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US42329210P| true| 2010-12-15|2010-12-15|
    US61/423,292|2010-12-15|
    US201161504634P| true| 2011-07-05|2011-07-05|
    US61/504,634|2011-07-05|
    US13/325,826|US8591876B2|2010-12-15|2011-12-14|Methods of decreasing sebum production in the skin|
    US13/325,826|2011-12-14|
    PCT/US2011/065043|WO2012082976A1|2010-12-15|2011-12-15|Methods of decreasing sebum production in the skin|
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