WO2008015539A2 - Topical preparation containing sirolimus for treating inflammatory skin deseases - Google Patents
Topical preparation containing sirolimus for treating inflammatory skin deseases Download PDFInfo
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- WO2008015539A2 WO2008015539A2 PCT/IB2007/002197 IB2007002197W WO2008015539A2 WO 2008015539 A2 WO2008015539 A2 WO 2008015539A2 IB 2007002197 W IB2007002197 W IB 2007002197W WO 2008015539 A2 WO2008015539 A2 WO 2008015539A2
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- Prior art keywords
- inflammatory skin
- treating inflammatory
- dermatitis
- skin
- topical preparation
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
Definitions
- the present invention relates to a topical preparation for treating inflammatory skin diseases (dermatitis, including psoriasis and lichen ruber planus), in an ointment pharmaceutical form containing: sirolimus as active ingredient and a carrier formulated with all or some of the following components: ultra white petrolatum, mineral oil, glyceryl monostearate, anhydrous lanoline, white wax, N- methyl-2-pyrrolidone and antioxidant.
- inflammatory skin diseases is given as a generic name to skin diseases which are manifested by scars, stains, grains or eruptions. Inflammatory skin diseases affect men, women, children and elders of all races.
- Dermatitis and eczema are frequently used as synonyms for referring to a skin inflammation, which often represents an allergic response to various agents.
- Inflammation can have an acute, subacute or chronic clinical course.
- Primary lesions are maculae, papules and vesicles; secondary ones are exudation, scalls, fissures, lichenification and scars.
- Pruritus is a common sign of all the dermatitis in this group.
- Seborrheic dermatitis Contact dermatitis is caused by the skin contact with an agent acting as specific allergic sensitizer or as primary irritant (delayed hypersensitivity IV). Atopic dermatitis shows type I hypersensitivity.
- Every kind of typical dermatitis has epidermal and dermal alterations.
- acute phases there are spongiotical vesicles and in chronic phases acanthosis and hyperkeratosis; a combination of both lesions is observed in the subacute forms.
- Spongiosis is intraepidermal edema.
- spongiosis is observed only as a separation of epidermal cells, specially of those of the Malpighi stratum.
- intercellular bridges are elongated by liquid accumulation, eventually forming a intraepidermal vesicle and, if the size thereof increases, it is clinically visible.
- lymphocytes There is epidermal infiltration of lymphocytes, few eosinophils and rarely neutrophils.
- the edema In the corneal layer, the edema is mixed with parakeratositic cells and constitutes the so called crusty scales. If inflammation persists, a psoriasiform epidermal hyperplasia develops with fibrosis in the papular dermis, but with minimal spongiosis.
- the exact pathogeny of dermatitis is unknown, it has been associated to diverse immune and physiological alterations.
- the immune alterations are an elevated IgE production, the presence of cellular immunity alterations with higher frequency of viral and bacterial skin infections, alterations in lymphocyte T populations and in Langerhans cells and eosinophilia.
- Generalized pustular psoriasis a. von Zumbuch generalized pustular psoriasis b. Hallopeau generalized continuous dermatitis c. Herpetiform impetigo
- Psoriasis is a common, chronic inflammatory disease which has multiple clinical expressions. It is characterized by keratinopoiesis defects leading to an exaggerated epidermal growth, with alteration in the cellular maduration, plus vascular and inflammatory changes. Its cause is unknown, but it has been considered multifactorial.
- One of the hypothesis proposes that there exists a genetic predisposition triggered by an environmental stimulus, also there has been found an association to other inflammatory diseases such as arthritis, inflammatory bowel disease and HIV infection. It has been suggested that psoriasis must be considered as a chronic inflammatory condition, which results from the persistent stimulation of T cells by epidermal origin immunogens in a process that in turn needs three steps:
- T cell LFA-1 and CD2 bind to ICAM-1 and CPA LFA-3) they suffer an independent antigen costimulation called signal 2, which is necessary for maintaining immune activation.
- T cell Migration of T cell to the skin, this process is mediated by the interaction with the endothelium through adhesion molecules.
- the lesions are well delimited, usually covered by fine plated scales which leave a bed having fine bleeding spots (Auspitz sign).
- the plaques are usually located on scalp, sacral region and extensor surfaces of the limbs. In some cases there can also be located in flexion zones and creases. A ungeal commitment is frequent. Psoriatic arthritis characteristically compromises the interphalangial joints and not rarely large joints.
- Psoriatic epidermis In psoriatic skin, the transit time of a basal cell from the basal stratum to the corneal layer is of 5 days (normally 13 days) and the germinal reproduction cycle is of 100 hours (normally 200 hours). Psoriatic epidermis lacks intercellular contact growth control and a cyclic AMP system defect has been disclosed - adenyl cyclase.. There has been investigations for a immune base, but there is no clear and definitive information in this respect.
- Sirolimus also known as rapamycin, is a lipophilic macrolide from Streptomices hygroscopicus which produces immunosupression by different mechanisms. Its intracellular receptor is the same as that of tacrolimus, i.e., the FKBP enzyme family. When rapamycin binds to its receptor, it retains its three- dimensional structure in an almost identical way to its free crystalline state; contrary to what occurs with tacrolimus. Rapamycin has two domains, a binding one which mediates FKBP interaction and another which interacts with TOR enzyme. Tacrolimus has calcium-dependent signals and rapamycin calcium-dependent and independent signals.
- the rapamycin-FKBP complex acts on TOR protein which intervenes in the transduction signal coordinating the necessary nutrient elements of the cell in order for its division to progress from G1 phase to S phase. Rapamycin treatment or deprivation of these cell nutrients produces an acute reduction in the transduction initiation, a glucogen accumulation and an increase in vacuole size.
- Rapamycin activity affects biochemical processes in the medium and final periods of G1 , the following effects been known:
- Blocks BcI- 1 transcription which is a protein that protects cells from apoptosis.
- Topical administration of sirolimus allows lesser systemic exposure to the drug and therefore less adverse effects, compared to glucocorticoids which cause skin atrophy due to the blockade of collagen and other macrolide synthesis which when used by a long period of time have adverse effects particularly nephrotoxicity, fibrosis and kidney function impairment by inhibiting activated T cell nuclear factor and blocking calcineurin production, aspects from which sirolimus is exempt.
- Therapeutic applications of the present product taking into consideration the active ingredient and skin inflammatory diseases pathogenies, are the following: a).- Psoriasis (varieties) b).- Dermatitis (varieties) c).- Lichen ruber planus
- the present stable formulation contains sirolimus in a pharmaceutically useful ointment, thus providing the patient with a quality, effective and safe product as the carrier containing it is completely inert and innocuous, the excipients of said carrier being of high quality and used within the allowed normative limits.
- the excipients used in the formula are inert and innocuous.
- the mineral oil present in the formulation is used as emollient for removing skin dead cells and facilitating cleansing thereof.
- Glyceryl monostearate used in the formulation provides emolliency apart from being a non toxic and safe material.
- N-Methyl-2-pyrrolidone GMP grade is used as solvent, it augments bioavailability in topical formulations and even transdermal ones by increasing skin penetration.
- Anhydrous USP lanoline provides long lasting emolliency, moisturizes and works as skin repairing barrier, promoting absorption.
- White beeswax is an emulsifying agent which augments the ointment consistency.
- the antioxidant used butyl hydroxy toluene helps to prevent the oxidation of fats and oils present in the formulation.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a topical preparation for treating inflammatory skin diseases (dermatitis, including psoriasis and lichen ruber planus), in an ointment form containing sirolimus as active ingredient and a carrier formulated with all or some of the following components: ultra white petrolatum, mineral oil, glyceryl monostearate, anhydrous lanoline, white wax, N-methyl-2-pyrrolidone and antioxidant. The advantages of the present invention with respect to the state of the art compositions are based on the fact that the present composition contains an immunosupressing macrolide which acts specifically binding to a family of cytosolic immunophylins known as FKBP thus offering fewer adverse effects, compared to other agents used for treating inflammatory skin diseases which cause skin atrophy, nephrotoxicity, fibrosis and kidney function impairment.
Description
TOPICAL PREPARATION CONTAINING SIROLIMUS FOR TREATING INFLAMMATORY SKIN DISEASES
FIELD OF THE INVENTION The present invention relates to a topical preparation for treating inflammatory skin diseases (dermatitis, including psoriasis and lichen ruber planus), in an ointment pharmaceutical form containing: sirolimus as active ingredient and a carrier formulated with all or some of the following components: ultra white petrolatum, mineral oil, glyceryl monostearate, anhydrous lanoline, white wax, N- methyl-2-pyrrolidone and antioxidant.
BACKGROUND OF THE INVENTION
The term "inflammatory skin diseases" is given as a generic name to skin diseases which are manifested by scars, stains, grains or eruptions. Inflammatory skin diseases affect men, women, children and elders of all races.
There is a huge number of skin inflammations that can be grouped under the denomination of dermatitis (or dermitis). The following describes the most frequent forms. A. Dermatitis
Dermatitis and eczema are frequently used as synonyms for referring to a skin inflammation, which often represents an allergic response to various agents.
Inflammation can have an acute, subacute or chronic clinical course. Primary lesions are maculae, papules and vesicles; secondary ones are exudation, scalls, fissures, lichenification and scars. Pruritus is a common sign of all the dermatitis in this group.
Among the main dermatitis forms we can find:
• Contact dermatitis
• Numular dermatitis
• Atopic dermatitis • Chronic simple lichen
• Seborrheic dermatitis.
Contact dermatitis is caused by the skin contact with an agent acting as specific allergic sensitizer or as primary irritant (delayed hypersensitivity IV). Atopic dermatitis shows type I hypersensitivity.
Histologically, every kind of typical dermatitis has epidermal and dermal alterations. In acute phases there are spongiotical vesicles and in chronic phases acanthosis and hyperkeratosis; a combination of both lesions is observed in the subacute forms. Spongiosis is intraepidermal edema. As it appears as gaps in usual dyeings, spongiosis is observed only as a separation of epidermal cells, specially of those of the Malpighi stratum. At the beginning, intercellular bridges are elongated by liquid accumulation, eventually forming a intraepidermal vesicle and, if the size thereof increases, it is clinically visible. There is epidermal infiltration of lymphocytes, few eosinophils and rarely neutrophils. In the corneal layer, the edema is mixed with parakeratositic cells and constitutes the so called crusty scales. If inflammation persists, a psoriasiform epidermal hyperplasia develops with fibrosis in the papular dermis, but with minimal spongiosis.
In the acute phase there is surface perivascular lymphohistiocytal infiltration with a varying number of eosinophils, papular dermis edema and vacuolar degeneration or epidermal cell cytolysis.
The exact pathogeny of dermatitis is unknown, it has been associated to diverse immune and physiological alterations. Among the immune alterations the are an elevated IgE production, the presence of cellular immunity alterations with higher frequency of viral and bacterial skin infections, alterations in lymphocyte T populations and in Langerhans cells and eosinophilia.
B. Psoriasis According to Lever, the following varieties are known:
Psoriasis vulgaris
Localized pustular psoriasis a. Pustule psoriasis (Schuppener) b. Hallopeau localized continuous achrodermatitis c. Pustular palm and sole psoriasis
Generalized pustular psoriasis a. von Zumbuch generalized pustular psoriasis
b. Hallopeau generalized continuous dermatitis c. Herpetiform impetigo
Psoriasis is a common, chronic inflammatory disease which has multiple clinical expressions. It is characterized by keratinopoiesis defects leading to an exaggerated epidermal growth, with alteration in the cellular maduration, plus vascular and inflammatory changes. Its cause is unknown, but it has been considered multifactorial. One of the hypothesis proposes that there exists a genetic predisposition triggered by an environmental stimulus, also there has been found an association to other inflammatory diseases such as arthritis, inflammatory bowel disease and HIV infection. It has been suggested that psoriasis must be considered as a chronic inflammatory condition, which results from the persistent stimulation of T cells by epidermal origin immunogens in a process that in turn needs three steps:
I. Initial activation of T cells: Where T cell binds to antigen presenting cell (CPA) through adhesion molecules (T cell LFA-1 and CD2 bind to ICAM-1 and CPA LFA-3) they suffer an independent antigen costimulation called signal 2, which is necessary for maintaining immune activation.
II. Migration of T cell to the skin, this process is mediated by the interaction with the endothelium through adhesion molecules.
III. Cell action on the skin mediated by cytokine release and immune cascade amplification. The last step in psoriasis immune process is the induction of keratinocyte changes by T cells and other inflammatory cells, which lead to the formation of a psoriasis plaque.
Psoriasis vulgaris
This is a chronic disease of unknown cause, characterized by brownish red papules and descaling plaques. The lesions are well delimited, usually covered by fine plated scales which leave a bed having fine bleeding spots (Auspitz sign).
The plaques are usually located on scalp, sacral region and extensor surfaces of the limbs. In some cases there can also be located in flexion zones and creases. A ungeal commitment is frequent. Psoriatic arthritis characteristically compromises the interphalangial joints and not rarely large joints.
Histologically, there is interpapillar crest elongation with thickening of the lower portion thereof (psoriasiform hyperplasia), papillae elongation and edema,
suprapapillar epidermal atrophy with spongiform intracorneal pustules (Kogoj), absence of granular stratum or hypogranulosis, parakeratosis, intraepidermal microabscesses (Munro), dilated and tortuous papilar capillae, perivascular lymphohistiocytal infiltration and a few eosinophils and plasmocytes. In the active lesions an increased epidermal multiplication is found. In psoriatic skin, the transit time of a basal cell from the basal stratum to the corneal layer is of 5 days (normally 13 days) and the germinal reproduction cycle is of 100 hours (normally 200 hours). Psoriatic epidermis lacks intercellular contact growth control and a cyclic AMP system defect has been disclosed - adenyl cyclase.. There has been investigations for a immune base, but there is no clear and definitive information in this respect.
C. Lichen ruber planus
This is a subacute-chronic dermatosis characterized by small, polygonal violet red papules which can coalescence in plaques. There is exacerbated pruritus. It generally compromises flexing surfaces of the legs, arms, penis and oral mucosa. Pillar or follicular lichen planus mainly affects the scalp.
Histologically, hyperkeratosis, hypergranulosis, irregular acanthosis, vacuolar type dermatitis in the dermo-epidermal juncture, band dermal lymphohistiocytal infiltration and numerous eosinophil or Civatte bodies (homogeneous eosinophil globules of 10 μm diameter, PAS +, which in direct immunofluorescence contain IgM, IgG, IgA, complement, fibrin and cytokeratin) are observed. In the infiltrate there are predominantly lymphocytes, histiocytes and occasional mastocytes. Rarely there are eosinophils and characteristically there are no plasma cells. In pillar lichen planus the lesions mainly compromise hair follicles. The main damage from this disease seems to be that of the basal keratinocytes, apparently mediated by delayed hypersensitivity (T lymphocytes and Langerhans cells).
Sirolimus
Sirolimus, also known as rapamycin, is a lipophilic macrolide from Streptomices hygroscopicus which produces immunosupression by different mechanisms. Its intracellular receptor is the same as that of tacrolimus, i.e., the FKBP enzyme family. When rapamycin binds to its receptor, it retains its three-
dimensional structure in an almost identical way to its free crystalline state; contrary to what occurs with tacrolimus. Rapamycin has two domains, a binding one which mediates FKBP interaction and another which interacts with TOR enzyme. Tacrolimus has calcium-dependent signals and rapamycin calcium-dependent and independent signals.
The rapamycin-FKBP complex acts on TOR protein which intervenes in the transduction signal coordinating the necessary nutrient elements of the cell in order for its division to progress from G1 phase to S phase. Rapamycin treatment or deprivation of these cell nutrients produces an acute reduction in the transduction initiation, a glucogen accumulation and an increase in vacuole size.
Rapamycin activity affects biochemical processes in the medium and final periods of G1 , the following effects been known:
• Inhibits the 70 kDa enzyme called S6 kinase (p70S6k) which is involved in important cell division cycle processes. • Inhibits cdk4-cyclin D kinase activity and that of cdk2-cyclin E complexes.
• Blocks BcI- 1 transcription, which is a protein that protects cells from apoptosis.
• Prevents CD28 inhibitory effect (second signal) on IkB-oc transcription thus producing c-rel transcription factor translocation inhibition which stimulates in a sustained way IL-2 gene expression.
Safety: Topical administration of sirolimus allows lesser systemic exposure to the drug and therefore less adverse effects, compared to glucocorticoids which cause skin atrophy due to the blockade of collagen and other macrolide synthesis which when used by a long period of time have adverse effects particularly nephrotoxicity, fibrosis and kidney function impairment by inhibiting activated T cell nuclear factor and blocking calcineurin production, aspects from which sirolimus is exempt.
Therapeutic applications of the present product, taking into consideration the active ingredient and skin inflammatory diseases pathogenies, are the following: a).- Psoriasis (varieties)
b).- Dermatitis (varieties) c).- Lichen ruber planus
OBJECTS OF THE INVENTION 1. To provide society with a medicament having a therapeutic action for treating skin inflammatory diseases (dermatitis including psoriasis and lichen ruber planus), with higher efficiency and safety.
2. Make a contribution to the dermatological field by presenting a medicament having a novel active ingredient, topically used for treating dermatitis, psoriasis and lichen ruber planus.
BRIEF DISCLOSURE OF THE INVENTION
Currently there are in the market potent immunosuppresant topical use agents which have shown to be effective for treating skin inflammatory diseases. Although their long term use in dermatological conditions is limited by their profile regarding toxic effects, above all nephrotoxicity.
The present stable formulation contains sirolimus in a pharmaceutically useful ointment, thus providing the patient with a quality, effective and safe product as the carrier containing it is completely inert and innocuous, the excipients of said carrier being of high quality and used within the allowed normative limits.
Contains 70-85% of ultra white petrolatum as ointment base, this material is considered as non irritant and not toxic, which during its manufacture is subject to a refining process for eliminating polycyclic aromatic hydrocarbon residues which might cause negative effects such as skin irritation, thus proving the safeness of the material.
The excipients used in the formula are inert and innocuous. The mineral oil present in the formulation is used as emollient for removing skin dead cells and facilitating cleansing thereof.
Glyceryl monostearate used in the formulation provides emolliency apart from being a non toxic and safe material.
N-Methyl-2-pyrrolidone GMP grade is used as solvent, it augments bioavailability in topical formulations and even transdermal ones by increasing skin penetration.
Anhydrous USP lanoline provides long lasting emolliency, moisturizes and works as skin repairing barrier, promoting absorption.
White beeswax is an emulsifying agent which augments the ointment consistency.
The antioxidant used butyl hydroxy toluene helps to prevent the oxidation of fats and oils present in the formulation.
Quali-Quantitative Formula
Claims
1. A topical preparation related to inflammatory skin diseases therapy containing sirolimus, characterized by comprising:
N-methyl-pyrrolidone or any derivative or combination including N- methyl pyrrolidone as solvent or as skin penetrating agent; mineral oil and glyceryl monostearate as emollients; anhydrous lanoline as moisturizer and skin repair agent; ultra white petrolatum, white wax and butyl hydroxy toluene.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MXPA/A/2006/008797 | 2006-08-03 | ||
| MXPA06008797 MXPA06008797A (en) | 2006-08-03 | 2006-08-03 | Sirolimus-containing topic preparation for treating skin inflammatory diseases. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2008015539A2 true WO2008015539A2 (en) | 2008-02-07 |
| WO2008015539A3 WO2008015539A3 (en) | 2008-12-04 |
Family
ID=38997521
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2007/002197 Ceased WO2008015539A2 (en) | 2006-08-03 | 2007-07-25 | Topical preparation containing sirolimus for treating inflammatory skin deseases |
Country Status (2)
| Country | Link |
|---|---|
| MX (1) | MXPA06008797A (en) |
| WO (1) | WO2008015539A2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011160170A1 (en) * | 2010-06-21 | 2011-12-29 | Peter Maccallum Cancer Institute | Stimulating immune response |
| US20180280362A1 (en) * | 2015-09-24 | 2018-10-04 | Drexel University | Novel Compositions and Methods for Treating or Preventing Dermal Disorders |
| US10172789B2 (en) | 2013-01-24 | 2019-01-08 | Palvella Therapeutics Llc | Compositions for transdermal delivery of mTOR inhibitors |
| CN109431977A (en) * | 2018-12-20 | 2019-03-08 | 武汉科福新药有限责任公司 | A kind of rapamycin ointment and preparation method thereof for treating vascular malformation |
| US10722499B2 (en) | 2017-01-06 | 2020-07-28 | Palvella Therapeutics, Inc. | Anyhydrous compositions of mTOR inhibitors and methods of use |
| US11000513B2 (en) | 2018-07-02 | 2021-05-11 | Palvella Therapeutics, Inc. | Anhydrous compositions of mTOR inhibitors and methods of use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050250805A1 (en) * | 2004-05-06 | 2005-11-10 | Glenmark Pharmaceuticals Limited | Pharmaceutical ointment formulations |
-
2006
- 2006-08-03 MX MXPA06008797 patent/MXPA06008797A/en active IP Right Grant
-
2007
- 2007-07-25 WO PCT/IB2007/002197 patent/WO2008015539A2/en not_active Ceased
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011160170A1 (en) * | 2010-06-21 | 2011-12-29 | Peter Maccallum Cancer Institute | Stimulating immune response |
| US9724329B2 (en) | 2010-06-21 | 2017-08-08 | Peter Maccallum Cancer Institute | Stimulating immune response |
| US10172789B2 (en) | 2013-01-24 | 2019-01-08 | Palvella Therapeutics Llc | Compositions for transdermal delivery of mTOR inhibitors |
| US20180280362A1 (en) * | 2015-09-24 | 2018-10-04 | Drexel University | Novel Compositions and Methods for Treating or Preventing Dermal Disorders |
| US11179374B2 (en) | 2015-09-24 | 2021-11-23 | Drexel University | Compositions and methods for treating or preventing dermal disorders |
| US10695326B2 (en) * | 2015-09-24 | 2020-06-30 | Drexel University | Compositions and methods for treating or preventing dermal disorders |
| US10722499B2 (en) | 2017-01-06 | 2020-07-28 | Palvella Therapeutics, Inc. | Anyhydrous compositions of mTOR inhibitors and methods of use |
| EP3565520A4 (en) * | 2017-01-06 | 2020-08-19 | Palvella Therapeutics, Inc. | Anhydrous compositions of MTOR inhibitors and method of use |
| US11135204B2 (en) | 2017-01-06 | 2021-10-05 | Palvella Therapeutics, Inc. | Anhydrous compositions of mTOR inhibitors and methods of use |
| US12268673B2 (en) | 2017-01-06 | 2025-04-08 | Palvella Therapeutics, Inc. | Anhydrous compositions of mTOR inhibitors and methods of use |
| US11000513B2 (en) | 2018-07-02 | 2021-05-11 | Palvella Therapeutics, Inc. | Anhydrous compositions of mTOR inhibitors and methods of use |
| EP3817743A4 (en) * | 2018-07-02 | 2022-07-06 | Palvella Therapeutics, Inc. | Anhydrous compositions of mtor inhibitors and methods of use |
| US11679101B2 (en) | 2018-07-02 | 2023-06-20 | Palvella Therapeutics, Inc. | Anhydrous compositions of mTOR inhibitors and methods of use |
| US12329748B2 (en) | 2018-07-02 | 2025-06-17 | Palvella Therapeutics, Inc. | Anhydrous compositions of mTOR inhibitors and methods of use |
| CN109431977A (en) * | 2018-12-20 | 2019-03-08 | 武汉科福新药有限责任公司 | A kind of rapamycin ointment and preparation method thereof for treating vascular malformation |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008015539A3 (en) | 2008-12-04 |
| MXPA06008797A (en) | 2008-02-04 |
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