(19)
(11)EP 3 685 840 A1

(12)EUROPEAN PATENT APPLICATION
published in accordance with Art. 153(4) EPC

(43)Date of publication:
29.07.2020 Bulletin 2020/31

(21)Application number: 19822182.2

(22)Date of filing:  09.05.2019
(51)International Patent Classification (IPC): 
A61K 31/69(2006.01)
A61P 29/00(2006.01)
A61P 17/06(2006.01)
A61K 31/519(2006.01)
A61P 17/00(2006.01)
A61P 17/08(2006.01)
(86)International application number:
PCT/CN2019/086094
(87)International publication number:
WO 2019/242422 (26.12.2019 Gazette  2019/52)
(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
Designated Extension States:
BA ME
Designated Validation States:
KH MA MD TN

(30)Priority: 20.06.2018 CN 201810637196

(71)Applicants:
  • HEFEI INDUSTRIAL PHARMACEUTICAL INSTITUTE CO., LTD.
    Hefei, Anhui Province 230601 (CN)
  • HEFEI AMVITE PHARMACEUTICAL CO., LTD
    Hefei, Anhui Province 230601 (CN)

(72)Inventors:
  • HE, Guangwei
    Hefei, Anhui 230601 (CN)
  • CHU, Zhaoxing
    Hefei, Anhui 230601 (CN)
  • XU, Qinlong
    Hefei, Anhui 230601 (CN)
  • MO, Jiajia
    Hefei, Anhui 230601 (CN)
  • ZHAO, Yan
    Hefei, Anhui 230601 (CN)
  • BIAN, Lincui
    Hefei, Anhui 230601 (CN)
  • GU, Yuanfeng
    Hefei, Anhui 230601 (CN)
  • SHAO, Li
    Hefei, Anhui 230601 (CN)

(74)Representative: Hanna Moore + Curley 
Garryard House 25/26 Earlsfort Terrace
Dublin 2, D02 PX51
Dublin 2, D02 PX51 (IE)

  


(54)COMPOUND PHARMACEUTICAL COMPOSITION FOR TREATING INFLAMMATORY SKIN DISEASES


(57) The disclosure relates to the field of pharmaceutical technology, in particular, to a compound pharmaceutical composition for treating skin inflammatory diseases, which is characterized in that an active ingredient of the compound pharmaceutical of the disclosure is composed of tofacitinib and crisaborole, and the composition has a stronger therapeutic effect and a lower dosage with a significant synergistic therapeutic effect. The pharmaceutical composition of the disclosure can be used to treat skin inflammatory diseases.


Description

Technical Field



[0001] The disclosure relates to the field of pharmaceutical technology, in particular, to a compound pharmaceutical composition for treating skin inflammatory diseases. The pharmaceutical composition of the disclosure can be used to treat skin inflammatory diseases.

Background



[0002] Inflammation is a common and important basic pathological process. Body trauma infections and most common and multiple diseases of various organs are inflammatory diseases. [Cruz-Migoni S, Caamaño J. Fat-Associated Lymphoid Clusters in Inflammation and Immunity [J]. Front Immunol. 2016, 7: 612]. Skin inflammatory diseases include a variety of diseases characterized by skin inflammation and itching, such as atopic dermatitis, eczema, psoriasis, contact dermatitis, allergic dermatitis, seborrheic dermatitis, contact dermatitis, systemic lupus erythematosus, etc.

[0003] Inflammation and itching of the skin are two important characteristics of skin inflammatory diseases. JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines, involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. The JAK-STAT pathway is closely related to the occurrence and development of various inflammations. Recent studies have found that the JAK-STAT pathway is also closely related to skin itching , and many cytokines and growth factors conduct signals through the JAK-STAT signaling pathway, including TSLP, interleukins 2∼7 (IL-2-7), GM-CSF (granulocyte/macrophage colony-stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PDGF (platelet-derived factor), and IFN (interferon) and so on. And, TSLP is considered to be the main cause of skin itching. Tofacitinib is a JAK1/JAK3 inhibitor developed by Pfizer for the treatment of rheumatoid arthritis. Recent clinical phase II studies have found that topical 2% tofacitinib has a certain therapeutic effect on atopic dermatitis and can improve itching symptoms in patients.

[0004] Phosphodiesterases (PDEs) are a super-family capable of catalyzing the hydrolysis of cAMP and/or cGMP. [Murthy VS, Mangot AG. Psychiatric aspects of phosphodiesterases: An overview [J]. Indian J Pharmacol, 2015, 47(6): 594-599]. Cyclic adenosine monophosphate (cAMP) can inhibit multiple functions of inflammation and inflammatory cells, and plays an important role in many diseases and conditions. In these cells, cAMP-specific PDE4 is the main form of PDE, and the PDE4 inhibitor can increase cAMP levels, so as to be used for, but not limited to, inflammation, asthma, and other conditions. [Parikh N, Chakraborti AK. Phosphodiesterase4 (PDE4) Inhibitors in the Treatment of COPD: Promising Drug Candidates and Future Directions [J]. Curr Med Chem, 2016, 23(2): 129-41]. Crisaborole is a topical PDE-4 inhibitor approved in 2016 for the treatment of atopic dermatitis.

[0005] The structural formulas for tofacitinib and crisaborole are as follows:



[0006] However, at present, the above drugs have certain defects in clinical use, so it is still important to find or develop new therapeutic drugs with better efficacy.

Summary



[0007] By combining tofacitinib and crisaborole in a fixed dose ratio, the disclosure unexpectedly finds that the composition has a stronger therapeutic effect and a lower dosage with a significant synergistic therapeutic effect, while having strong clinical use value.

[0008] The disclosure discloses a compound pharmaceutical composition of tofacitinib and crisaborole. Pharmacodynamic test proves that the compound pharmaceutical composition of the disclosure has significant synergistic therapeutic effect in treating skin diseases caused by itching and inflammation, with a stronger therapeutic effect and a lower dosage.

[0009] Among them, preferably, a weight ratio of tofacitinib and crisaborole has a range of1: 8 to 8: 1. Preferably, the compound pharmaceutical composition of the disclosure is a dosage form for topical administration, which is preferably cream, ointment, gel, foam, powder, tincture, lotion, spray or patch. The composition of the disclosure is used for the treatment of skin inflammatory diseases, including, but not limited to allergic dermatitis, urticaria, atopic dermatitis, seborrheic dermatitis, or contact dermatitis, and inflammatory skin reactions caused by immune diseases such as psoriasis and systemic lupus erythematosus.

[0010] The following are some of the pharmacodynamic tests and results of the compound pharmaceutical composition of the disclosure:

1. Therapeutic effects of the compound pharmaceutical composition of the disclosure on a phorbol ester-induced mouse ear swelling model



[0011] SPF ICR mice, male, 18-22g, randomly divided into compound groups with different compound ratios and a model group according to body weight, 10 mice for each group. The test drug is dissolved in a 20 µL solvent of DMSO. The specific group numbers are as follows:
  1. (1) Compound groups with different compound ratios
    Tofacitinib: crisaborole = 2mg: 2mg/20µL (dose ratio = 1: 1; group a); tofacitinib: crisaborole = 2mg : 1mg/20µL (dose ratio = 2: 1; group b); tofacitinib: crisaborole = 2mg : 0.5mg/20µL (dose ratio = 4: 1; group c); tofacitinib: crisaborole = 2mg : 0.25mg/20µL (dose ratio = 8: 1; group d); tofacitinib: crisaborole = 2mg : 0.2mg/20µL (dose ratio = 10: 1; group e); tofacitinib: crisaborole = 2mg: 0.125mg/20µL (dose ratio = 16: 1; group f); tofacitinib: crisaborole = 1mg: 2mg/20µL (dose ratio = 1: 2; group g); tofacitinib: crisaborole = 0.5mg : 2mg/20µL (dose ratio = 1: 4; group h); tofacitinib: crisaborole = 0.25mg : 2mg/20µL (dose ratio = 1: 8; group i); tofacitinib: crisaborole = 0.2mg : 2mg/20µL (dose ratio = 1: 10; group j); tofacitinib: crisaborole = 0.125mg : 2mg/20µL (dose ratio = 1: 16; group k).
  2. (2) Model Group
  3. (3) Crisaborole (4mg/20ul)
  4. (4) Tofacitinib (4mg/20 ul)
  5. (5) Blank group: applying with 20 µL DMOS as a solvent for comparison.

Experimental method:



[0012] For the mice of each group, 20 ul (5 µg/20 ul/ear) of phorbol ester is applied to the front and back of the right ear for modeling, and 20µl solvent medium (acetone) is applied to the left ear; except for the model group, the right ears of the mice in each administration group are applied with corresponding drugs 20 µl/ear 30 minutes before and 15 minutes after modeling, respectively. 6h after modeling, the ear swelling is measured with a thickness gauge as an indicator of inflammation; then, the animals are sacrificed, the ears are cut and punched with a 6mm punch, the ear pieces are weighed, and the swelling degree (weight) is calculated.

Experimental results



[0013] 
Table 1 Effects of phorbol ester on the swelling degree of the auricle and inhibition rate of the swelling for the mice (ear thickness of 10-2mm)
GroupDose (mg/20µL)Left ear (mm) (%)Right ear (mm)Swelling degree (mm)Inhibition rate
blank   30.1±2.0 30.3±2.3 0.2±0.1 -
model   29.4±1.8 48.4±3.5 19.0±4.4 -
Tofacitinib 4 29.3:f:1.7 41.6±3.4 12.4±3.2△△ 34.7
Crisaborole 4 29.8±1.7 43.0±3.7 13.3±3.4△ 30.0
a 2/2 29.3±1.6 36.9±2.4 7.6±1.3△△**## 60.0
b 2/1 28.9±1.2 37.0±2.5 8.1±3.1△△*## 57.4
c 2/0.5 29.0±1.1 37.4±2.7 8.4±3.3△△## 55.8
d 2/0.25 29.1±1.5 38.0±3.1 8.9±3.0△△*# 53.2
e 2/0.2 29.4±1.2 39.4±3.7 10.0±3.0△△ 47.4
f 2/0.125 29.5±1.4 41.3±1.8 11.8±2.1△△ 37.9
g 1/2 29.1±1.5 37.6±2.0 8.5±2.4△△*## 55.3
h 0.5/2 29.1±1.2 37.9±3.0 8.8±3.1△△*# 53.7
i 0.25/2 29.3±1.7 38.4±2.8 9.1±2.0△△*# 52.1
j 0.2/2 29.4±1.4 40.3±3.1 10.9±3.3△△ 42.6
k 0.125/2 29.3±1.6 42.0±3.2 12.8±3.2△△ 32.6
Note: △P<0.05, △△P<0.01 vs. model; *P<0.05, **P<0.01 vs. tofacitinib 4mg/20µL single use; #P<0.05,
##P<0.01 vs. gram; crisaborole 4mg/20µL single use


[0014] From above results, it can be known that a range of 16:1 to 1:16 for tofacitinib: crisaborole has a significant inhibition effect on the ear swelling of phorbol ester-induced mice, wherein when tofacitinib: crisaborole = 1:8 to 8:1, the anti-inflammatory effect is better than when tofacitinib (4mg/20µL) and crisaborole (4mg/20µL) are used alone, thereby displaying significant anti-inflammatory synergy.

Description of embodiments


Embodiment1



[0015] For ointment, the prescription is as follows:
 ComponentConcentration (%W/W)
 Crisaborole 1.0%
 Tofacitinib 1.0%
 Albolene 60%
Glycerin monostearate 10%
 Propylene glycol 19.98%
 Glycerinum 8%
Dibutyl hydroxytoluene 0.02%


[0016] A prescribed amount of crisaborole and Tofacitinib is taken, and dissolved or dispersed in a mixed solution of 27.98% propylene glycol and glycerin, then after they are evenly dispersed, an appropriate amount of antioxidant is added for mixing uniformly before use; another 70% white petrolatum and glycerin monostearate are taken in a stainless steel tank and heated, melted at 65°C±5°C, then the temperature is remained, followed by slowly adding the above mixed solution into the melted matrix through mixing with a blender/homogenizer; after mixing for a period of time, the heat source is removed, and mixing is continued after cooling until completely homogeneous, so as to obtain the ointment.


Claims

1. A compound pharmaceutical composition, comprising a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, wherein the pharmaceutically active ingredient is composed of tofacitinib and crisaborole.
 
2. The compound pharmaceutical composition according to claim 1, wherein a weight ratio of tofacitinib and crisaborole is 1: 8 to 8: 1.
 
3. A use of the compound pharmaceutical composition according to claim 1 or 2 for preparing a drug for treating skin inflammatory diseases.
 
4. The use according to claim 3, wherein the skin inflammatory diseases are allergic dermatitis, urticaria, atopic dermatitis, seborrheic dermatitis, or contact dermatitis.
 
5. The use according to claim 3, wherein the skin inflammatory diseases are inflammatory skin reactions caused by psoriasis or systemic lupus erythematosus.
 
6. The compound pharmaceutical composition according to claim 1 or 2, having a dosage form of an external preparation.
 
7. The compound pharmaceutical composition according to claim 6, wherein the dosage form of the external preparation is cream, gel, foam, powder, tincture, lotion, spray or patch.
 





Search report













Cited references

REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Non-patent literature cited in the description