WO1998000145A1 - Topical administration of certain azaspiranes to prevent or treat skin conditions associated with hyperproliferation of skin cells and/or immunologically mediated disorders - Google Patents
Topical administration of certain azaspiranes to prevent or treat skin conditions associated with hyperproliferation of skin cells and/or immunologically mediated disorders Download PDFInfo
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- WO1998000145A1 WO1998000145A1 PCT/US1997/011220 US9711220W WO9800145A1 WO 1998000145 A1 WO1998000145 A1 WO 1998000145A1 US 9711220 W US9711220 W US 9711220W WO 9800145 A1 WO9800145 A1 WO 9800145A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/695—Silicon compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- the present invention relates generally to the prevention or treatment of certain types of skin disorders. More particularly, the invention relates to the prevention or treatment of skin conditions associated with hyperproliferation of skin cells and/or immunologically mediated disorders, and involves topical administration of an azaspirane compound such as spirogermanium.
- Spirogermanium was described by L. M. Rice et al.; see, e.g., U.S. Patent No. 3,825,546 to Rice, which discloses the compound as a novel antihypertensive agent, and Rice et al., "Spirans XXII. Synthesis of 4,4-Dialkyl-4-germacyclo- hexanone and 8,8-Dialkyl-8-germaazaspiro-[4.5]decanes," J. Heterocvclic Chem. 11: 1041-1047 (1974), in which the biological properties of the compound are examined in further detail. Syntheses of spirogermanium and related compounds, including silicon-substituted azaspiranes, were also disclosed by Rice, and involve the use of what were apparently novel azaspirodione intermediates.
- Spirogermanium The dimethyl, diethyl, dipropyl and dibutyl derivatives of spirogermanium were later shown to be useful in a variety of contexts, including treatment of hypercholesterolemia (U.S. Patent No. 4,291,030 to Mulinos), arthritis (U.S. Patent No. 4,468,393 to Geschreiber; Badger et al., "Antiarthritic and Suppressor Cell Inducing Activity of Azaspiranes: Structure-Function Relationships of a Novel Class of Immunomodulatory Agents.” J. Med. Che .
- Anticancer activity for spirogermanium itself has also been suggested; see, e.g., Mirabelli et al., "Pharmacological Activities of Spirogermanium and Other Structurally Related Azaspiranes: Effects on Tumor Cell and Macrophage Functions.” Anti-Cancer Drug Design 3:231-242 (1989), Slavik et al., "Spirogermanium: A New Investigational Drug of Novel Structure and Lack of Bone Marrow Toxicity.” Investigational New Drugs 1 :225-234 (1983), and Badger et al., "Generation of Suppressor Cells in Normal Rats by Treatment with
- Spirogermanium is currently available from Unimed, Inc., as the hydrochloride salt, under the trademark SPIRO-32®.
- Spirogermanium HC1 is a white powder that is freely soluble in water and in 95% ethanol, has a molecular weight of 414 and a melting point ranging from 284 °C to 288 °C. Spirogermanium has been administered both by intravenous infusion and orally.
- spirogermanium or related azaspirane compounds topical administration of spirogermanium or related azaspirane compounds is unknown.
- the present invention is premised on the unexpected finding that topical administration of spirogermanium and related azaspiranes is extremely effective in addressing certain skin conditions associated with hyperproliferation of skin cells and/or an immunologically mediated disorder.
- spirogermanium and certain structurally related azaspiranes may be administered in topical formulations to prevent or treat a host of skin conditions, including psoriasis and various forms of dermatitis, including atopical dermatitis, contact dermatitis and seborrhoeic dermatitis.
- topical administration is used in its conventional sense to mean delivery of a topical drug or pharmacologically active agent to the skin or mucosa, as in, for example, the treatment of various skin disorders.
- drug or the term “pharmacologically active agent” as used herein is meant a chemical material or compound suitable for topical administration and which induces the desired effect.
- topical vehicle or “topical carrier” as used herein refers to a vehicle suitable for topical application of a drug, and includes any such materials known in the art, e.g., any liquid or nonliquid carrier, gel, cream, ointment, lotion, paste, emulsifier, solvent, liquid diluent, powder, or the like, which is stable with respect to all components of the topical pharmaceutical formulation.
- azaspirane “azaspirane compound” and “azaspirane derivative” are used interchangeably herein to refer to compounds encompassed by structural formula (I)
- R 1 and R 2 may be the same or different and are each selected from the group consisting of hydrogen and lower alkyl;
- X is selected from the group consisting of Ge, Si, C and Sn;
- R 3 is alkylene or alkenylene
- n is an integer in the range of 2 to 6 inclusive when R 3 is alkylene and 3 to 6 inclusive when R 3 is alkenylene
- R 4 and R 5 are independently selected from the group consisting of lower alkyl or lower alkenyl, or are linked together to form a heterocyclic group selected from morpholino, pyrrolidino, piperidino and lower alkyl substituted piperazino in which the lower alkyl group is attached to a terminal nitrogen atom.
- lower alkyl as used herein in the description of chemical structures is intended to encompass alkyl groups having 1 through 6, preferably 1 through 4, carbon atoms.
- a locally administrable topical pharmaceutical composition for the prevention or treatment of skin conditions associated with hyperproliferation of skin cells and/or an immunologically mediated disorder.
- skin conditions are exemplified by, but not limited to: psoriasis; atopical dermatitis; contact dermatitis and further eczematous dermatitises; seborrhoeic dermatitis; Lichen planus; Pemphigus; bullous Pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides; erythemas; cutaneous eospinphilias; Lupus erythematoses; and Alopecia areata.
- the topical pharmaceutical formulation of the invention may also be useful in the treatment of actinic keratosis and skin cancer.
- Skin conditions of particular interest herein are psoriasis, atopical dermatitis, contact dermatitis, seborrhoeic dermatitis and lupus, most particularly psoriasis itself.
- the inventor herein believes that the present invention is effective against such conditions and disorders by virtue of inhibiting the underlying disease process rather than by treating the inflammation and other symptoms.
- the invention appears to act both to inhibit underlying autoimmune responses and to directly inhibit hyperproliferation of skin cells.
- the locally administrate topical pharmaceutical composition includes a topical carrier and either spirogermanium or a related azaspirane, i.e., a compound having the structure of formula (I)
- R 1 , R 2 , R 3 , R", R 5 , Y 1 , Y 2 , Z, m and n are as defined above.
- Examples of particular compounds of interest are wherein "X" is germanium, such as in spirogermanium itself, and wherein "X" is carbon or silicon.
- the compounds may be administered as the free base or present in the form of an acid addition salt.
- Acid addition salts may be prepared from the free base using conventional means, which generally involve reaction of the free base with a suitable acid.
- the free base is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added at a temperature of about 0°C to about 100°C, preferably at ambient temperature.
- Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, and inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- organic acids e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
- the topical carrier is one which is generally suited to topical drug administration and includes any such materials known in the art.
- the topical carrier is selected so as to provide the composition in the desired form, e.g., as a liquid, lotion, cream, paste, gel, powder, or ointment, and may comprise a material of either naturally occurring or synthetic origin. It is essential, clearly, that the selected carrier not adversely affect the active agent or other components of the topical formulation.
- suitable topical carriers for use herein include water, alcohols and other nontoxic organic solvents, glycerin, mineral oil, silicone, petroleum jelly, lanolin, fatty acids, vegetable oils, parabens, waxes, and the like.
- composition of the invention may also be administered in the form of a shampoo, in which case conventional components of such a formulation are included as well, e.g., surfactants, conditioners, viscosity modifying agents, humectants, and the like.
- Particularly preferred formulations herein are colorless, odorless ointments, lotions, creams and gels.
- Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives.
- the specific ointment base to be used is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like.
- an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy. 19th Ed.
- ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
- Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
- Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
- Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil- in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.
- W/O water-in-oil
- O/W oil- in-water
- Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, reference may be had to Remington: The Science and Practice of Pharmacy for further information.
- Lotions are preparations to be applied to the skin surface without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base.
- Lotions are usually suspensions of solids, and preferably, for the present purpose, comprise a liquid oily emulsion of the oil-in-water type.
- Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition. It is generally necessary that the insoluble matter in a lotion be finely divided.
- Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethyl-cellulose, or the like.
- a particularly preferred lotion formulation for use in conjunction with the present invention contains propylene glycol mixed with a hydrophilic petrolatum such as that which may be obtained under the trademark Aquaphor® from Beiersdorf, Inc. (Norwalk, CT).
- Creams containing the selected azaspirane derivative are, as known in the art, viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil.
- Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
- the oil phase also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
- the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
- Gel formulations are preferred for application to the scalp.
- gels are semisolid, suspension-type systems.
- Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil.
- Shampoos for treating psoriasis and other skin conditions associated with hyperproliferation and/or an immunologically mediated disorder may be formulated with the selected azaspirane derivative and standard shampoo components, i.e., cleansing agents, thickening agents, preservatives, and the like, with the cleansing agent representing the primary ingredient, typically an anionic surfactant or a mixture of an anionic surfactant and an amphoteric surfactant.
- the cleansing agent representing the primary ingredient, typically an anionic surfactant or a mixture of an anionic surfactant and an amphoteric surfactant.
- Various additives known to those skilled in the art, may be included in the topical formulations of the invention. For example, solvents may be used to solubilize certain drug substances.
- additives include skin permeation enhancers, opacifiers, anti-oxidants, gelling agents, thickening agents, stabilizers, and the like.
- agents may also be added, such as antimicrobial agents, antifungal agents, antibiotics and anti-inflammatory agents such as steroids.
- the active azaspirane agent is present in an amount which is generally less than 10% by weight of the total composition, preferably less than about 1% by weight, and most preferably less than about 0.1% by weight.
- the topical compositions of the invention may also be delivered to the skin using conventional "transdermal"-type patches, wherein the drug composition is contained within a laminated structure that serves as a drug delivery device to be affixed to the skin. In such a structure, the drug composition is contained in a layer, or "reservoir,” underlying an upper backing layer.
- the laminated structure may contain a single reservoir, or it may contain multiple reservoirs.
- the reservoir comprises a polymeric matrix of a pharmaceutically acceptable adhesive material that serves to affix the system to the skin during drug delivery.
- suitable adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
- the adhesive selected will depend on the particular drug, vehicle, etc., i.e., the adhesive must be compatible with all components of the drug-containing composition.
- the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form.
- the backing layer in these laminates serves as the upper surface of the device.
- the material selected for the backing material should be substantially impermeable to the drug and any other components of the drug-containing composition, thus preventing loss of any components through the upper surface of the device.
- the backing layer may be either occlusive or nonocclusive, depending on whether it is desired that the skin become hydrated during drug delivery.
- the backing is preferably made of flexible elastomeric material, e.g., polyethylene, polypropylene, polyesters, or the like.
- the laminated structure includes a release liner. Immediately prior to use, this layer is removed from the device so that the system may be affixed to the skin.
- the release liner should be made from a drug/vehicle impermeable material.
- Such devices may be fabricated using conventional techniques known in the art, for example by casting a fluid admixture of adhesive, drug and vehicle onto the backing layer, followed by lamination of the release liner.
- the adhesive mixture may be cast onto the release liner, followed by lamination of the backing layer.
- the drug reservoir may be prepared in the absence of drug or excipient, and then loaded by "soaking" in a drug/vehicle mixture.
- the drug composition contained within the drug reservoirs of these laminated system may contain a number of components.
- the drug may be delivered "neat," i.e., in the absence of additional liquid.
- the drug will be dissolved, dispersed or suspended in a suitable pharmaceutically acceptable vehicle, typically a solvent or gel.
- suitable pharmaceutically acceptable vehicle typically a solvent or gel.
- Other components which may be present include preservatives, stabilizers, surfactants, and the like.
- Both the topical formulations and the laminated drug delivery systems may in addition contain a skin permeation enhancer.
- Suitable enhancers include, for example, dimethylsulfoxide (DMSO), dimethyl formamide (DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C 10 MSO), C 2 -C 6 alkanediols, and the 1 -substituted azacycloheptan-2-ones, particularly l-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone® from Whitby Research Incorporated, Richmond, V A), alcohols, and the like.
- DMSO dimethylsulfoxide
- DMF dimethyl formamide
- DMA N,N-dimethylacetamide
- C 10 MSO decylmethylsulfoxide
- C 10 MSO C 2 -C 6 alkanediols
- 1 -substituted azacycloheptan-2-ones particularly l-n-dodecylcyclazacycloheptan-2-
- the topical compositions and drug delivery systems of the invention can be used in the prevention or treatment of the skin conditions identified above.
- susceptible skin is treated prior to any visible lesions on areas known to be susceptible to such lesions in a particular individual.
- an immunologically mediated disorder it will be recognized by those skilled in the art that the optimal quantity and spacing of individual dosages of compounds of Formula (I) will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular individual undergoing treatment, and that such optimums can be determined by conventional techniques.
- a dosing regimen i.e., the number of doses of spirogermanium or an analog thereof encompassed by the generic structure of Formula (I), can be ascertained using conventional course of treatment determination tests.
- a dosing regimen involves administration of the selected topical formulation at least once daily, and preferably one to four times daily, until the psoriatic or other symptoms have subsided.
- the mitotic activity of epidermal keratinocytes is one of the most obvious histological features of the psoriatic lesion. Many cytotoxic drugs used to treat the disease are believed to function by direct inhibition of keratinocyte replication.
- Spirogermanium affects this aspect of epidermal metabolism, in view of its demonstrated effects on tumor cells.
- Human foreskin keratinocytes were cultured in GM. When the dishes were approximately 50% covered by cells, SG was added to give final concentrations of 5 x 10 -5 to 5 x 10' 9 M. After three days, the cells were pulsed with 3 H-TdR for four hours, and incorporation into DNA assayed by conventional means. The inhibition of incorporation in two experiments was as follows:
- SG inhibited DNA synthesis at concentrations as low as 10 * M.
- concentrations as low as 10 * M indicate that spirogermanium is a very potent inhibitor of DNA synthesis in keratinocytes, and thus a very potent inhibitor of keratinocyte proliferation, suggesting that spirogermanium is a highly effective agent in treating psoriasis and other such skin disorders.
- Example 3 Compounds encompassed by structural formula (I) are evaluated in vivo for their efficacy in treating psoriasis.
- the methods of the following references are used in the evaluation: Berardesca et al., "Non-invasive Evaluation of Topical Calcipofriol versus Clobetasol in the Treatment of Psoriasis," Acta Derm Venereol (Stokh. 74:302-304 (1994); Elias et al., "A Controlled Trial of Topical Propylthiouracil in the Treatment of Patients with Psoriasis," J. Amer. Acad. Dermatol.
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Abstract
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE69732108T DE69732108T2 (en) | 1996-06-28 | 1997-06-26 | TOPICAL ADMINISTRATION OF CERTAIN AZAPRIRANES FOR PREVENTING OR TREATING SKIN CONDITIONS ASSOCIATED WITH SKIN CELL HYPERPROLIFERATION AND / OR IMMUNOLOGICALLY DISORDED DISEASES |
AT97930236T ATE285778T1 (en) | 1996-06-28 | 1997-06-26 | TOPICAL ADMINISTRATION OF CERTAIN AZAPRIRANES FOR THE PREVENTION OR TREATMENT OF SKIN CONDITIONS ASSOCIATED WITH SKIN CELL HYPERPROLIFERATION AND/OR IMMUNOLOGY-MEDIATED DISEASES |
AU34119/97A AU734702B2 (en) | 1996-06-28 | 1997-06-26 | Topical administration of certain azaspiranes to prevent or treat skin conditions associated with hyperproliferation of skin cells and/or immunologically mediated disorders |
CA002257875A CA2257875C (en) | 1996-06-28 | 1997-06-26 | Topical administration of certain azaspiranes to prevent or treat skin conditions associated with hyperproliferation of skin cells and/or immunologically mediated disorders |
JP10504321A JP2000514798A (en) | 1996-06-28 | 1997-06-26 | Topical administration of certain azaspiranes to prevent or treat skin conditions associated with skin cell hyperproliferation and / or immune-mediated disorders |
EP97930236A EP0909173B1 (en) | 1996-06-28 | 1997-06-26 | Topical administration of certain azaspiranes to prevent or treat skin conditions associated with hyperproliferation of skin cells and/or immunologically mediated disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US08/672,728 | 1996-06-28 | ||
US08/672,728 US5843936A (en) | 1996-06-28 | 1996-06-28 | Topical administration of azaspiranes to prevent or treat skin conditions associated with hyperproliferation of keratinocytes |
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WO1998000145A1 true WO1998000145A1 (en) | 1998-01-08 |
WO1998000145B1 WO1998000145B1 (en) | 1998-02-12 |
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PCT/US1997/011220 WO1998000145A1 (en) | 1996-06-28 | 1997-06-26 | Topical administration of certain azaspiranes to prevent or treat skin conditions associated with hyperproliferation of skin cells and/or immunologically mediated disorders |
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US (2) | US5843936A (en) |
EP (1) | EP0909173B1 (en) |
JP (1) | JP2000514798A (en) |
AT (1) | ATE285778T1 (en) |
AU (1) | AU734702B2 (en) |
CA (1) | CA2257875C (en) |
DE (1) | DE69732108T2 (en) |
ES (1) | ES2234021T3 (en) |
WO (1) | WO1998000145A1 (en) |
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CN101484178A (en) | 2005-11-01 | 2009-07-15 | 赛德罗米克斯有限责任公司 | Growth control of oral and superficial microorganisms using gallium compounds |
JP2009541301A (en) * | 2006-07-14 | 2009-11-26 | ザ プロクター アンド ギャンブル カンパニー | Treatment article capable of delivering intensive care and overall treatment simultaneously |
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JP6670244B2 (en) | 2014-01-07 | 2020-03-18 | バビタ アグラワル | Immunomodulatory compositions and uses thereof |
Citations (6)
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- 1996-06-28 US US08/672,728 patent/US5843936A/en not_active Expired - Fee Related
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1997
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- 1997-06-26 JP JP10504321A patent/JP2000514798A/en not_active Ceased
- 1997-06-26 AT AT97930236T patent/ATE285778T1/en not_active IP Right Cessation
- 1997-06-26 AU AU34119/97A patent/AU734702B2/en not_active Ceased
- 1997-06-26 CA CA002257875A patent/CA2257875C/en not_active Expired - Fee Related
- 1997-06-26 ES ES97930236T patent/ES2234021T3/en not_active Expired - Lifetime
- 1997-06-26 DE DE69732108T patent/DE69732108T2/en not_active Expired - Fee Related
- 1997-06-26 WO PCT/US1997/011220 patent/WO1998000145A1/en active IP Right Grant
- 1997-07-29 US US08/902,503 patent/US5916885A/en not_active Expired - Fee Related
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US4468393A (en) * | 1982-12-06 | 1984-08-28 | Unimed, Inc. | Treatment of arthritis |
EP0201804A1 (en) * | 1985-04-30 | 1986-11-20 | Sloan-Kettering Institute For Cancer Research | Composition to treating bone disorders |
EP0310321A2 (en) * | 1987-09-28 | 1989-04-05 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
WO1992002229A1 (en) * | 1990-08-10 | 1992-02-20 | Smithkline Beecham Corporation | Immunosuppressive compositions |
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B.T. HILL ET AL.: "CYTOTOXIC EFFECTS AND BIOLOGICAL ACTIVITY OF 2-AZA-8-GERMANSPIRO(4,5)-DECANE-2-PROPANAMINE-8,8-DIETHYL-N,N-DIMETHYL DICHLORIDE (NSC 192965; SPIROGERMANIUM) IN VITRO", CANCER RESEARCH, vol. 42, no. 7, 1982, pages 2852 - 2856, XP002043548 * |
BADGER A M ET AL: "ANTIARTHRITIC AND SUPPRESSOR CELL INDUCING ACTIVITY OF AZASPIRANES: STRUCTURE-FUNCTION RELATIONSHIPS OF A NOVEL CLASS OF IMMUNOMODULATORY AGENTS", JOURNAL OF MEDICINAL CHEMISTRY, vol. 33, no. 11, pages 2963 - 2970, XP000605424 * |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100540630B1 (en) * | 2002-12-12 | 2006-01-11 | 정장수 | Drill tool with assembled cutting blade that has prominence and depression shape |
US8449913B2 (en) | 2003-02-07 | 2013-05-28 | Teikoku Pharma Usa, Inc. | Methods of administering a dermatological agent to a subject |
Also Published As
Publication number | Publication date |
---|---|
DE69732108T2 (en) | 2005-12-22 |
US5843936A (en) | 1998-12-01 |
CA2257875A1 (en) | 1998-01-08 |
ES2234021T3 (en) | 2005-06-16 |
EP0909173B1 (en) | 2004-12-29 |
JP2000514798A (en) | 2000-11-07 |
DE69732108D1 (en) | 2005-02-03 |
AU734702B2 (en) | 2001-06-21 |
US5916885A (en) | 1999-06-29 |
ATE285778T1 (en) | 2005-01-15 |
EP0909173A1 (en) | 1999-04-21 |
CA2257875C (en) | 2007-08-28 |
AU3411997A (en) | 1998-01-21 |
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