CN107028949A - Nintedanib is used to treat the purposes in the external preparation medicine of psoriasis - Google Patents
Nintedanib is used to treat the purposes in the external preparation medicine of psoriasis Download PDFInfo
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- CN107028949A CN107028949A CN201710379153.5A CN201710379153A CN107028949A CN 107028949 A CN107028949 A CN 107028949A CN 201710379153 A CN201710379153 A CN 201710379153A CN 107028949 A CN107028949 A CN 107028949A
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- nintedanib
- psoriasis
- preparation
- physiologically acceptable
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- 229960004378 nintedanib Drugs 0.000 title claims abstract description 36
- 201000004681 Psoriasis Diseases 0.000 title claims abstract description 29
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Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
It is used to treat the purposes in the external preparation medicine of psoriasis the present invention relates to Nintedanib or its physiologically acceptable salt.The Nintedanib or its physiologically acceptable salt are when for treating psoriasis by the way of external preparation local application.During local application, Nintedanib or its physiologically acceptable salt can be semisolid or the form of liquid preparation containing Nintedanib or its physiologically acceptable salt and at least one physiologically acceptable excipient and/or adjuvant, and such preparation can be ointment, creme, gel, solution, emulsion, supensoid agent or spray.Experiment shows that Nintedanib has positive effect in terms of psoriasis is treated, and can substantially suppress the mitosis of epithelial cell, promote the formation of rat-tail scale granular layer of epidermis.
Description
Technical field
The present invention relates to the new application of Nintedanib or its physiologically acceptable salts for treating psoriasis.
Background technology
Psoriasis (Psoriasis) is commonly called as psoriasis, is a kind of chronic inflammatory skin, and the course of disease is longer, there is easy recurrence
Tendency, some cases almost cannot be cured all one's life.The disease is fallen ill based on person between twenty and fifty, and the healthy and mental status of patient is influenceed
It is larger.Clinical manifestation is with erythema, and based on the scales of skin that peel off, whole body can fall ill, with scalp, and it is relatively conventional that four limbs stretch side, more in the winter time plus
Weight.Pathological characteristic shows as that epidermal cell proliferation is too fast and parakeratosis.
At present, the class of medications of psoriasis is more, and medicine includes Tretinoin, anthraline, glucocorticoid, vitamine D3
Analog, tar class and neotype immunosuppressant etc., but due to above class of medications each different side effect and work
Still it is not entirely satisfactory with the relative unicity of scoring ring section, its therapeutic effect and with prospect.Because psoriasis acts on machine
System is complicated, and be formed as its histo pathological change with keratinocyte hyperplasia, inflammatory cell infiltration, new vessels three will
Element.New vessels is generated as epidermal hyperplasia and provides support, while inflammatory cell enters lesion by the blood vessel endothelium of high-permeability
Tissue, and the overexpression of papilla endothelial cell is further related in the recurrence of psoriasis and skin damaged.Therefore, to psoriasis blood vessel
The research of generation helps to disclose the pathogenesis of psoriasis, and guides clinical treatment.
At present, about the angiogenesis of psoriasis, some Angiogenesis Stimulators in Human (such as vascular endothelial growth factors are particularly
Sub- VEGF, fibroblast growth factor FGF, platelet derived growth factor PDGF) and apply anti-angiogenic medicaments to control
The research for treating psoriasis is just increasingly subject to pay attention to.
Research discovery, VEGF (VEGF) and monocyte chemotactic factor -1 are respectively provided with the work of angiogenesis
With VEGF is one of most strong, most single-minded direct angiogenic factors of the effect having now been found that.VEGF is specific action in blood
One class glycoprotein of endothelial cell, exists in the form of homodimer, is the Angiogensis for having high biological activity
The factor, has strong rush epithelial cell proliferation effect, can promote the formation of new blood vessel.VEGF increases vasopermeability；Endothelium
Cell propagation, migration, cell ask inter-adhesive；Change extracellular matrix, neovascularization growth environment is built, in angiogenesis
Play induction and Gene regulation.At present, it is endothelial cell-selective mitogen to have proven to VEGF, and decapacitation increase endothelium is thin
Ca in born of the same parents' endochylema2+Concentration and capilary is increased the permeability of macromolecular substances outer, still from number of ways endothelium can be made thin
Born of the same parents' form is in elongate shape and stimulates it to replicate, stimulate glucose transport enter endothelial cell, promote endothelial cell, mouse monocyte and
Tire ox Gegenbaur's cell shift, can change endothelial cell gene activation pattern, up-regulation plasminogen activator and its
Inhibitor PAI-1 expression, induces the expression of other endothelial cell protein enzymes, interstitial collagenase and tissue factor.
Fibroblast growth factor (FGF) is the huge of the peptide matters composition that a class has extensive biological activity
, there is very strong rush cells of vascular wall hyperplasia in protein Duo Fu families, can promote endothelial cell mitogen and strengthen it
Differentiation.At present, it has been found that there are 24 members in FGF families.FGF-1 (also known as acid fibroblast growth factor, aFGF),
FGF-2 (also known as basic fibroblast growth factor, bFGF), belongs to the FGF family for possessing and widely promoting cell division effect
A member of race.It, which participates in a series of physiology course, includes embryonic development, hyperplasia, tissue repair, tumour growth and infiltration.
FGF-2 has the effect of nuclear fission, angiogenic growth and the neurotrophic factor of wide spectrum.The biological activity scope phase of two kinds of structures
Together, and by acting on same cell surface receptor group play a role.Result of study shows that FGF-1 is in psoriasis vulgaris
High expression in skin damaged, compared with compareing skin, FGF-1 albumen and mRNA expression substantially up-regulation in psoriasis vulgaris,
Speculate that FGF-1 may take part in the abnormality proliferation and papillary layer of corium aberrant angiogenesis new life of psoriatic lesions
Process.
Platelet derived growth factor (PDGF) is a kind of cell factor secreted by various kinds of cell, and it is with autocrine or side
The mode of secretion acts on histocyte and played an important role in tissue repair, embryonic development, immune and a variety of common diseases.
PDGF plays its biological effect by acting on the single-minded acceptor of cell membrane.Pdgf receptor is that molecular weight is 180-190KD
Glycoprotein, experiment finds that vascular smooth alum cell, fibroblast and chamber cell plastid have pdgf receptor.PDGF is into fiber
Cell has important regulating and controlling effect, and research recently thinks that fibroblast abnormal in corium is probably the initiating of onset of psoriasis
One of factor.Research finds that PDGF and its receptor system high expression in psoriatic lesion point out PDGF by regulating and controlling into fiber
The function of cell is played a role in psoriatic pathogenesis.
Nintedanib (Nintedanib), chemical name (3Z) -2,3- dihydros -3- [[[4- [methyl [2- (4- methyl isophthalic acids-piperazine
Piperazine base) acetyl] amino] phenyl] amino] benzylidene] -2- oxo -1H- methyl indole-6-carboxylate esilates are a kind of small
Molecular chemistry synthetic drug, is VEGF, FGF, pdgf receptor selective antagonist.In October, 2014, U.S. FDA approval listing was used for
The treatment of idiopathic pulmonary fibrosis, in November, 2014, Europe listed the treatment for non-small cell lung cancer.But have no Nintedanib
Activity and the report of purposes for curing psoriasis.
The content of the invention
The purpose of the present invention is Nintedanib or its physiologically acceptable salt in the external application system for treating psoriasis
Purposes in agent medicine.
Nintedanib or its physiologically acceptable salt described in such use are used when for treating psoriasis
The mode of external preparation local application.
During local application, Nintedanib or its physiologically acceptable salt can be to contain Nintedanib or its physiology
The semisolid or the shape of liquid preparation of upper acceptable salt and at least one physiologically acceptable excipient and/or adjuvant
Formula, such preparation can be ointment, creme, gel, solution, emulsion, supensoid agent or spray.
This kind of semi-solid or liquid preparation is particularly suitable for treating all clinical manifestations of psoriasis, including homeliness type silver bits
Disease, psoriasis pustulosa and erythrodermic psoriasis.
Will this kind of semi-solid or liquid preparation of local application can have mass concentration to be 0.1% to 20%, it is more excellent
Select 0.5% to 15%, most preferably 1% to 9% Nintedanib concentration.They are particularly suitable for by being directly applied to skin disease
Skin psoriasis is treated in change.
Pharmaceutical composition can be prepared according to routine techniques, described pharmaceutical composition can be assigned containing pharmaceutically acceptable
Shape agent, adjuvant and/or carrier, and can also be comprising (joint) one or more active components, the active component, which has, to be mended
It is filling or be useful activity anyway.
The united activating agent of Nintedanib that can be used with the present invention includes but is not limited to：Immunodepressant, sugared skin
Matter steroids, vitamins, Antibiotics, immunomodulator, tar preparation, Dithranol, biological agent class；It is such activity into
Dividing can apply together with Nintedanib, or they can be with the close mode of Nintedanib separate administration or time directly in skin
Applied in skin or nail lesion.The example of immunodepressant include methotrexate (MTX), ethyleneimine, hydroxycarbamide, sandimmun neoral Ke Mosi,
Pimecrolimus.Vitamins includes vitamin Calcipotriol, Tacalcitol, etretinate, Acitretin, fragrant Tretinoin ethyl ester.Antibacterial
Class medicine includes penicillin, cephalosporins, chloramphenicol, erythromycin, metronidazole, Thiamphenicol.Immunomodulator includes thymus gland
Factor D, levamisol.Biological agent includes Etanercept, infliximab, A Dalimu monoclonal antibodies, in accordance with the law Ah method's Saite, sharp pearl
Monoclonal antibody.
The example of composition prepared in accordance with the present invention includes：For the creme of local application, gel, ointment, molten
Liquor, emulsion, supensoid agent, spray.
Experiment shows that Nintedanib has positive effect in terms of psoriasis is treated, and can substantially suppress epithelial cell
Mitosis, the formation for promoting rat-tail scale granular layer of epidermis.
The pharmaceutical composition and purposes of the present invention are now more fully described by following examples.However, should note
These embodiments of anticipating are to provide by way of illustration and unrestricted.
Embodiment
The present invention is described further with reference to embodiments.
Embodiment 1
Paste externally-applied soft ointment is made in Nintedanib and suitable matrix：Nintedanib 1g, albolene 83g, sapn
6g, propane diols 10g, obtain the medicinal external emulsifiable paste that Nintedanib mass content is 1% after mixing.Its character and texture be uniform,
Outward appearance is fine and smooth, steady quality, be applied on skin without obvious acute toxic reaction, it is nonirritant, do not produce partial and systemic hypersensitivity
Reaction.
Embodiment 2
Nintedanib 3g, albolene 81g, sapn 6g, propane diols 10g, Nintedanib mass content is obtained after mixing is
3% medicinal external emulsifiable paste.Its character and texture are uniform, outward appearance is fine and smooth, steady quality, are applied on skin without obvious acute toxicity
Reaction, it is nonirritant, do not produce partial and systemic hypersensitivity reaction.
Embodiment 3
Nintedanib 9g, albolene 75g, sapn 6g, propane diols 10g, Nintedanib mass content is obtained after mixing is
9% medicinal external emulsifiable paste.Its character and texture are uniform, outward appearance is fine and smooth, steady quality, are applied on skin without obvious acute toxicity
Reaction, it is nonirritant, do not produce partial and systemic hypersensitivity reaction.
Embodiment 4
Take female KM kind mouse 60,20 ± 2g of body weight.Give mouse peritoneal injection stilbestrol, 0.2mg/ only, daily
Once, for three days on end, it is at estrogen physiological period.Mouse was randomly divided into 6 groups in 4th day, every group 10, made a living respectively
Manage salt solution group, ointment bases group, 1 group of embodiment, 2 groups of embodiment, 3 groups of embodiment and scaly tetter ointment group (the raw doctor of Nanyang Ji
Medicine health products Co., Ltd, authentication code：(Henan) defends the card word (2013) the 0024th that disappears).One time a day, applies pharmaceutical quantities
70mg/, continuous coating 7 days.Colchicin is injected intraperitoneally to terminate cell division, every 2mg/kg within 1 hour after last dose.
Mouse is killed after 6 hours.Mouse vagina tissue is cut, is fixed with 10% formalin, FFPE, HE dyeing.It is aobvious in optics
The mitotic cell number appeared in 400 mouse vagina basal cells is counted under micro mirror, is converted in every 100 basal cells
Mitosis number (mitotic index).Experimental result is shown in Table 1, and it shows that the Nintedanib of different content has obvious suppression
The mitotic effect of mouse vagina epithelial cell.
The different content Nintedanib of table 1 is on the mitotic influence of mouse vagina epithelial cell
| Group | Dosage (mg/ is only) | Number of animals (only) | Mitotic index |
| Physiological saline group | 10 | 17.28±2.25 | |
| Ointment bases group | 70 | 10 | 15.87±2.08 |
| 1 group of embodiment | 70 | 10 | 6.99±2.17 |
| 2 groups of embodiment | 70 | 10 | 5.89±2.15 |
| 3 groups of embodiment | 70 | 10 | 5.18±2.01 |
| Scaly tetter ointment group | 70 | 10 | 6.07±2.13 |
By table 1, it can be seen that Nintedanib, which has, substantially suppresses the mitotic effect of mouse vagina epithelial cell, Ni Da
The content of Buddhist nun's cloth is higher, and inhibitory action is further obvious.
Embodiment 5
Mouse 60 is taken, 20 ± 2g of body weight, male and female half and half are randomly divided into 6 groups, respectively physiological saline group, ointment bases
(Ji raw Medicines and Health Product Limited Liability in Nanyang is public for group, 1 group of embodiment, 2 groups of embodiment, 3 groups of embodiment and scaly tetter ointment group
Department, authentication code：(Henan) defends the card word (2013) the 0024th that disappears), every group 10.Respectively by ointment bases, 1 group of embodiment, reality
Apply 2 groups of example, 3 groups of embodiment and be directly applied to mouse tail with scaly tetter ointment, 3 times a day, each 45mg is put to death after even applying 15 days
Mouse.About 1.5cm tail skins are cut from the 2cm of rat-tail root, are fixed with 10% formalin solution, FFPE,
HE is dyed.The scale of mouse tail skin is observed under an optical microscope, counts the scale for having stratum granulosum in every 100 scales
Number.Experimental result is shown in Table 2.
Influence of the Nintedanib of table 2 to rat-tail scale stratum granulosum
| Group | Dosage (mg/ is only) | Number of animals (only) | There is particle scale number/100 scale |
| Physiological saline group | 10 | 7.12±1.88 | |
| Ointment bases group | 45 | 10 | 7.75±2.01 |
| 1 group of embodiment | 45 | 10 | 13.58±3.48 |
| 2 groups of embodiment | 45 | 10 | 14.72±3.14 |
| 3 groups of embodiment | 45 | 10 | 15.56±3.37 |
| Scaly tetter ointment group | 45 | 10 | 14.99±3.31 |
By table 2, it can be seen that Nintedanib can be obviously promoted being formed for rat-tail scale granular layer of epidermis, and with Nintedanib
The increase of content, facilitation is further obvious.
Claims (10)
1. the purposes of Nintedanib or its physiologically acceptable salt in the external preparation medicine for treating psoriasis.
2. purposes according to claim 1, it is characterised in that：The psoriasis is psoriasis vulgaris, pustule type silver bits
Disease or erythrodermic psoriasis.
3. purposes according to claim 1, it is characterised in that：Nintedanib or its physiologically acceptable salt for
Affected part is locally applied to by the way of external preparation during treatment psoriasis.
4. purposes according to claim 1, it is characterised in that：The external preparation is ointment, creme, gel, molten
Liquor, emulsion, supensoid agent or spray.
5. purposes according to claim 4, it is characterised in that：In terms of w/w, the preparation has 0.1%~20% Buddhist nun
Da Nibu or its salinity.
6. purposes according to claim 4, it is characterised in that：In terms of w/w, the preparation has 0.5%~15% Buddhist nun
Da Nibu or its salinity.
7. purposes according to claim 4, it is characterised in that：In terms of w/w, the preparation has 1%~9% Ni Dani
Cloth or its salinity.
8. according to any described purposes of claim 1-7, it is characterised in that：Nintedanib or its physiologically acceptable salt
Applied with least one other active ingredient combination or the time closely applies, wherein, at least one other work
Property composition be selected from immunodepressant, glucocorticoids compound, vitamin compound, Antibiotics compound, immune adjust
Save agent, tar preparation, Dithranol, biological agent.
9. purposes according to claim 8, it is characterised in that：Immunodepressant is selected from methotrexate (MTX), ethyleneimine, hydroxyl
Urea, sandimmun neoral Ke Mosi, pimecrolimus；Vitamin compound be selected from vitamin Calcipotriol, Tacalcitol, etretinate,
Acitretin, fragrant Tretinoin ethyl ester；Antibiotics compound be selected from penicillin, cephalosporins, chloramphenicol, erythromycin, metronidazole,
Thiamphenicol.
10. purposes according to claim 8, it is characterised in that：Immunomodulator is selected from thymic factor D, levamisol；It is raw
Thing preparation is selected from Etanercept, infliximab, A Dalimu monoclonal antibodies, Ah method's Saite, efalizumab.
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