Pharmaceutical composition for treating inflammatory diseases

Abstract

The invention provides a pharmaceutical composition containing a JAK inhibitor and a PDE4 inhibitor, the JAK inhibitor is selected from one or a combination of more of upatinib, digotinib, BMS-986165 or pharmaceutically acceptable salts thereof, and the PDE4 inhibitor is selected from one or a combination of more of apremilast, defamilast or pharmaceutically acceptable salts thereof. The invention finds that the JAK inhibitor and the PDE4 inhibitor are combined to have a synergistic effect and can be used for treating inflammatory diseases.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a compound pharmaceutical composition comprising a JAK inhibitor and a PDE4 inhibitor for treating inflammatory diseases. Background Art

[0002] Inflammation is a protective immune response of the evolutionarily conserved innate immune system to harmful stimuli (such as pathogens, dead cells or irritants). It is strictly regulated by the host. Insufficient inflammatory response can lead to persistent infection of pathogens, while excessive inflammatory response can lead to chronic or systemic inflammatory diseases [Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics [J]. Nat Med, 2015, 21 (7): 677-87]. Inflammatory diseases include a variety of diseases characterized by inflammation, such as atopic dermatitis, urticaria, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, multiple sclerosis, etc.

[0003] Inflammatory diseases involve complex immune responses in their pathogenesis, with both common potential immune pathways and unique immune pathways involved, making the treatment of such diseases a major clinical challenge. Current treatment strategies have evolved from broad-spectrum immunomodulators to highly targeted inhibitors, such as JAK inhibitors, PDE4 inhibitors, antibodies, etc.

[0004] JAK kinase is a family of intracellular non-receptor tyrosine kinases, including four members: JAK1, JAK2, JAK3 and TYK2. JAK-STAT, as an intracellular inflammatory signal transduction pathway, is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. It can mediate more than 60 cytokine signal transductions, such as IL-2, IL-4, IL-7, IL-21, TSLP, GM-CSF, etc., and plays an important role in inflammatory diseases [Xin P, Xu X, Deng C, Liu S, Wang Y, Zhou X, Ma H, Wei D, Sun S. The role of JAK / STAT signaling pathway and its inhibitors in diseases[J]. Int Immunopharmacol. 2020, 80: 106210.]. Upadacitinib is a JAK1 / JAK2 inhibitor, digatinib is a JAK1 / JAK2 / JAK3 inhibitor, BMS-986165 is a TYK2 inhibitor, and tofacitinib is a JAK1 / JAK3 inhibitor. These drugs have been approved for marketing for the treatment of one or more inflammatory diseases, and some drugs even show better therapeutic effects than antibody drugs.

[0005] Phosphodiesterases (PDEs) are a superfamily that can catalyze 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 inflammation and multiple functions of inflammatory cells, and plays an important role in many diseases and conditions. In these cells, cAMP-specific PDE4 is the main form of PDE. PDE4 inhibitors can increase the level of cAMP and can be used to treat a variety of inflammatory diseases, such as atopic dermatitis, psoriasis, asthma, etc. [Parikh N, Chakraborti AK. Phosphodiesterase 4 (PDE4) Inhibitors in the Treatment of COPD: Promising Drug Candidates and Future Directions [J]. Curr Med Chem, 2016, 23 (2): 129-41]. Apremilast, defamister, and crisaborole are all PDE4 inhibitors that have been marketed and are used to treat atopic dermatitis and / or psoriasis.

[0006] The structures of relevant JAK inhibitors and PDE4 inhibitors are as follows:

[0007]

[0008] However, at present, the above-mentioned drugs all have certain defects in clinical use. JAK inhibitors can cause adverse reactions such as infection, thrombosis or lymphoma, and black box warnings have been added to the instructions of many marketed drugs; PDE4 inhibitors have problems such as insufficient efficacy and easy to cause vomiting. At present, the current status of clinical treatment of inflammatory diseases is that some patients can achieve high response rates and relieve symptoms under an acceptable toxicity burden [McInnes IB, Gravallese EM, Immune-mediated inflammatory disease therapeutics: past, present and future. Nat Rev Immunol 2021Oct; 21(10)]. Patent CN 108992454 A discloses a fixed ratio compound pharmaceutical composition of the JAK inhibitor tofacitinib and the PDE4 inhibitor criborole for the treatment of skin inflammatory diseases, but it is limited to external skin treatment. Finding or developing new oral therapeutic drugs with better efficacy still has important application value. Summary of the invention

[0009] The inventors have unexpectedly discovered through extensive research that JAK inhibitors and PDE4 inhibitors have a significant synergistic effect in the oral combined use for the treatment of inflammatory diseases, which makes the drug combination have a stronger therapeutic effect and a lower dosage, can effectively reduce the adverse reactions of JAK inhibitors and PDE4 inhibitors, and has a strong clinical use value.

[0010] To this end, on the one hand, the present invention provides a pharmaceutical composition comprising a JAK inhibitor and a PDE4 inhibitor, and a pharmaceutically acceptable carrier, wherein the JAK inhibitor is selected from a combination of one or more of digaotinib, upadacitinib, BMS-986165 or pharmaceutically acceptable salts thereof, and the PDE4 inhibitor is selected from a combination of one or more of apremilast, defamikast or pharmaceutically acceptable salts thereof, and the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:8.

[0011] In one embodiment, the present invention provides a pharmaceutical composition comprising a JAK inhibitor and a PDE4 inhibitor, and a pharmaceutically acceptable carrier, wherein the JAK inhibitor is selected from a combination of one or more of diastatinib, upadacitinib, BMS-986165 or pharmaceutically acceptable salts thereof, and the PDE4 inhibitor is selected from a combination of one or more of apremilast, defamilastat or pharmaceutically acceptable salts thereof, and the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:4; preferably, the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:2; more preferably Preferably, the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:1; preferably, the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 4:1 to 1:2; more preferably, the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 4:1 to 1:1; preferably, the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 2:1 to 1:2; more preferably, the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 2:1 to 1:1; most preferably, the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 1:1.

[0012] In one embodiment, the present invention provides a pharmaceutical composition comprising a JAK inhibitor and a PDE4 inhibitor, and a pharmaceutically acceptable carrier, wherein the JAK inhibitor is selected from digotinib or a pharmaceutically acceptable salt thereof, the PDE4 inhibitor is selected from apremilast or a pharmaceutically acceptable salt thereof, and the weight ratio of digotinib or a pharmaceutically acceptable salt thereof to apremilast or a pharmaceutically acceptable salt thereof is 8:1 to 1:4; preferably, the weight ratio of digotinib or a pharmaceutically acceptable salt thereof to apremilast or a pharmaceutically acceptable salt thereof is 8:1 to 1:2; more preferably, the weight ratio of digotinib or a pharmaceutically acceptable salt thereof to apremilast or a pharmaceutically acceptable salt thereof is 8:1 to 1:1; most preferably, the weight ratio of digotinib or a pharmaceutically acceptable salt thereof to apremilast or a pharmaceutically acceptable salt thereof is 1:1.

[0013] In one embodiment, the present invention provides a pharmaceutical composition comprising a JAK inhibitor and a PDE4 inhibitor, and a pharmaceutically acceptable carrier, wherein the JAK inhibitor is selected from upadacitinib or a pharmaceutically acceptable salt thereof, the PDE4 inhibitor is selected from apremilast or a pharmaceutically acceptable salt thereof, and the weight ratio of upadacitinib or a pharmaceutically acceptable salt thereof to apremilast or a pharmaceutically acceptable salt thereof is 8:1 to 1:8; preferably, the weight ratio of upadacitinib or a pharmaceutically acceptable salt thereof to apremilast or a pharmaceutically acceptable salt thereof is 8:1 to 1:1; more preferably, the weight ratio of upadacitinib or a pharmaceutically acceptable salt thereof to apremilast or a pharmaceutically acceptable salt thereof is 4:1 to 1:1; most preferably, the weight ratio of upadacitinib or a pharmaceutically acceptable salt thereof to apremilast or a pharmaceutically acceptable salt thereof is 1:1.

[0014] In one embodiment, the present invention provides a pharmaceutical composition comprising a JAK inhibitor and a PDE4 inhibitor, and a pharmaceutically acceptable carrier, wherein the JAK inhibitor is selected from upadacitinib or a pharmaceutically acceptable salt thereof, the PDE4 inhibitor is selected from defamilastat or a pharmaceutically acceptable salt thereof, and the weight ratio of upadacitinib or a pharmaceutically acceptable salt thereof to defamilastat or a pharmaceutically acceptable salt thereof is 8:1 to 1:4; preferably, the weight ratio of upadacitinib or a pharmaceutically acceptable salt thereof to defamilastat or a pharmaceutically acceptable salt thereof is 2:1 to 1:2; more preferably, the weight ratio of upadacitinib or a pharmaceutically acceptable salt thereof to defamilastat or a pharmaceutically acceptable salt thereof is 2:1 to 1:1; most preferably, the weight ratio of upadacitinib or a pharmaceutically acceptable salt thereof to defamilastat or a pharmaceutically acceptable salt thereof is 1:1.

[0015] In one embodiment, the present invention provides a pharmaceutical composition comprising a JAK inhibitor and a PDE4 inhibitor, and a pharmaceutically acceptable carrier, wherein the JAK inhibitor is selected from digaotinib or a pharmaceutically acceptable salt thereof, and the PDE4 inhibitor is selected from defamilastat or a pharmaceutically acceptable salt thereof, and the weight ratio of the digaotinib or a pharmaceutically acceptable salt thereof to the defamilastat or a pharmaceutically acceptable salt thereof is 8:1 to 1:8; preferably, the weight ratio of the digaotinib or a pharmaceutically acceptable salt thereof to the defamilastat or a pharmaceutically acceptable salt thereof is 8:1 to 1:4; more preferably, the weight ratio of the digaotinib or a pharmaceutically acceptable salt thereof to the defamilastat or a pharmaceutically acceptable salt thereof is 2:1 to 1:2; most preferably, the weight ratio of the digaotinib or a pharmaceutically acceptable salt thereof to the defamilastat or a pharmaceutically acceptable salt thereof is 1:1.

[0016] In one embodiment, the present invention provides a pharmaceutical composition comprising a JAK inhibitor and a PDE4 inhibitor, and a pharmaceutically acceptable carrier, wherein the JAK inhibitor is selected from BMS-986165 or a pharmaceutically acceptable salt thereof, the PDE4 inhibitor is selected from Apremilast or a pharmaceutically acceptable salt thereof, and the weight ratio of BMS-986165 or a pharmaceutically acceptable salt thereof to Apremilast or a pharmaceutically acceptable salt thereof is 8:1 to 1:2; preferably, the weight ratio of BMS-986165 or a pharmaceutically acceptable salt thereof to Apremilast or a pharmaceutically acceptable salt thereof is 4:1 to 1:2; more preferably, the weight ratio of BMS-986165 or a pharmaceutically acceptable salt thereof to Apremilast or a pharmaceutically acceptable salt thereof is 2:1 to 1:1; most preferably, the weight ratio of BMS-986165 or a pharmaceutically acceptable salt thereof to Apremilast or a pharmaceutically acceptable salt thereof is 1:1.

[0017] In one embodiment, the pharmaceutical composition provided by the present invention comprises one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers can be solid or liquid. Among them, solid carriers can be one or more substances used as excipients, diluents, sweeteners, solubilizers, lubricants, adhesives, tablet disintegrating agents, stabilizers, preservatives or encapsulating materials. Liquid carriers can be solvents or liquid dispersion media. Suitable solid carriers include, but are not limited to, for example, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, saccharin sodium, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth gum, gum arabic, sodium alginate, parabens, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc. Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycerides, agar, pyrogen-free water, isotonic saline, Ringer's solution and mixtures thereof.

[0018] In one embodiment, the pharmaceutical composition according to the present invention can be any form suitable for the intended method of administration, preferably, the pharmaceutical composition according to the present invention can be an oral formulation. For example, when used for oral use, it can be prepared into tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, hard or soft capsules, oral liquids, syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for making pharmaceutical compositions.

[0019] In one embodiment, the effective dose of the pharmaceutical composition according to the present invention depends at least on the nature, toxicity, delivery method and pharmaceutical formulation of the treated condition, and will be determined by a clinician using a conventional dose escalation study. It can be expected that about 0.0001 to about 100 mg per kilogram of body weight per day; generally about 0.01 to about 10 mg per kilogram of body weight per day; more typically, about 0.01 to about 5 mg per kilogram of body weight per day; most typically about 0.05 to about 0.5 mg per kilogram of body weight per day. For example, the daily candidate dose for an adult of about 70 kg body weight will be in the range of 1 mg to 1000 mg, preferably in the range of 5 mg to 500 mg, and can be in the form of a single dose or multiple doses.

[0020] On the other hand, the pharmaceutical composition according to the present invention can be used for preventing and / or treating inflammatory diseases. In one embodiment, the pharmaceutical composition according to the present invention can be used for preventing and / or treating inflammatory diseases, and the inflammatory diseases include but are not limited to atopic dermatitis, urticaria, allergic rhinitis, seborrheic dermatitis, contact dermatitis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ulcerative colitis, vitiligo, immune diseases such as multiple sclerosis.

[0021] In another aspect, the present invention also provides the use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating an inflammatory disease. In one embodiment, the present invention provides the use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating an inflammatory disease, wherein the inflammatory disease includes but is not limited to atopic dermatitis, urticaria, allergic rhinitis, seborrheic dermatitis, contact dermatitis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ulcerative colitis, vitiligo, multiple sclerosis and other immune diseases. DETAILED DESCRIPTION

[0022] Example 1: Therapeutic effect of the compound pharmaceutical composition on the phorbol ester-induced mouse ear swelling model

[0023] SPF ICR mice, male, 18-22g, were randomly divided into different dose compound groups, different single drug groups, blank group, and model group according to body weight, with 8 mice in each group. The drugs to be tested were suspended with 0.5% CMC-Na, and the specific groups were as follows:

[0024] (1) Compound groups with different dosage ratios

[0025] Digatinib: Apremilast = 4 mg / kg: 4 mg / kg (dose ratio = 1:1)

[0026] Digatinib: Apremilast = 4mg / kg: 2mg / kg (dose ratio = 2:1)

[0027] Digatinib: Apremilast = 4mg / kg: 1mg / kg (dose ratio = 4:1)

[0028] Digatinib: Apremilast = 4 mg / kg: 0.5 mg / kg (dose ratio = 8:1)

[0029] Digatinib: Apremilast = 2mg / kg: 4mg / kg (dose ratio = 1:2)

[0030] Digatinib: Apremilast = 1mg / kg: 4mg / kg (dose ratio = 1:4)

[0031] Digatinib: Apremilast = 0.5 mg / kg: 4 mg / kg (dose ratio = 1:8)

[0032] Upadacitinib: Apremilast = 4 mg / kg: 4 mg / kg (dose ratio = 1:1)

[0033] Upadacitinib: Apremilast = 4 mg / kg: 2 mg / kg (dose ratio = 2:1)

[0034] Upadacitinib: Apremilast = 4 mg / kg: 1 mg / kg (dose ratio = 4:1)

[0035] Upadacitinib: Apremilast = 4 mg / kg: 0.5 mg / kg (dose ratio = 8:1)

[0036] Upadacitinib: Apremilast = 2 mg / kg: 4 mg / kg (dose ratio = 1:2)

[0037] Upadacitinib: Apremilast = 1 mg / kg: 4 mg / kg (dose ratio = 1:4)

[0038] Upadacitinib: Apremilast = 0.5 mg / kg: 4 mg / kg (dose ratio = 1:8)

[0039] Upadacitinib: defamilast = 4 mg / kg: 4 mg / kg (dose ratio = 1:1)

[0040] Upadacitinib: defamilast = 4 mg / kg: 2 mg / kg (dose ratio = 2:1)

[0041] Upadacitinib: defamilast = 4 mg / kg: 1 mg / kg (dose ratio = 4:1)

[0042] Upadacitinib: defamilast = 4 mg / kg: 0.5 mg / kg (dose ratio = 8:1)

[0043] Upadacitinib: defamilast = 2 mg / kg: 4 mg / kg (dose ratio = 1:2)

[0044] Upadacitinib: defamilast = 1 mg / kg: 4 mg / kg (dose ratio = 1:4)

[0045] Upadatinib: Defamist = 0.5 mg / kg: 4 mg / kg (dose ratio = 1:8) Digatinib: Defamist = 4 mg / kg: 4 mg / kg (dose ratio = 1:1) Digatinib: Defamist = 4 mg / kg: 2 mg / kg (dose ratio = 2:1) Digatinib: Defamist = 4 mg / kg: 1 mg / kg (dose ratio = 4:1) Digatinib: Defamist = 4 mg / kg: 0.5 mg / kg (dose ratio = 8:1) Digatinib: Defamist = 2 mg / kg: 4 mg / kg (dose ratio = 1:2) Digatinib: Defamist = 1 mg / kg: 4 mg / kg (dose ratio = 1:4) Digatinib: Defamist = 0.5 mg / kg: 4 mg / kg (dose ratio = 1:8) BMS -986165: Apremilast = 4 mg / kg: 4 mg / kg (dose ratio = 1:1) BMS-986165: Apremilast = 4 mg / kg: 2 mg / kg (dose ratio = 2:1) BMS-986165: Apremilast = 4 mg / kg: 1 mg / kg (dose ratio = 4:1) BMS-986165: Apremilast = 4 mg / kg: 0.5 mg / kg (dose ratio = 8:1) BMS-986165: Apremilast = 2 mg / kg: 4 mg / kg (dose ratio = 1:2) BMS-986165: Apremilast = 1 mg / kg: 4 mg / kg (dose ratio = 1:4) BMS-986165: Apremilast = 0.5 mg / kg: 4 mg / kg (dose ratio = 1:8) (2) Single drug group

[0046] Apremilast: 2 mg / kg

[0047] Apremilast: 4 mg / kg

[0048] Apremilast: 8 mg / kg

[0049] Apremilast: 16 mg / kg

[0050] Digatinib: 2 mg / kg

[0051] Digatinib: 4 mg / kg

[0052] Digatinib: 8 mg / kg

[0053] Digatinib: 16 mg / kg

[0054] Upadacitinib: 2 mg / kg

[0055] Upadacitinib: 4 mg / kg

[0056] Upadacitinib: 8 mg / kg

[0057] Upadacitinib: 16 mg / kg

[0058] Defamilastat: 2 mg / kg

[0059] Defamilastat: 4 mg / kg

[0060] Defamilastat: 8 mg / kg

[0061] Defamilastat: 16 mg / kg

[0062] BMS-986165: 2 mg / kg

[0063] BMS-986165: 4 mg / kg

[0064] BMS-986165: 8 mg / kg

[0065] BMS-986165: 16 mg / kg

[0066] (3) Model group: 10 ml / kg 0.5% CMC-Na solvent

[0067] (4) Blank group: 10 ml / kg 0.5% CMC-Na solvent

[0068] Experimental methods

[0069] The mice in each group were smeared with phorbol ester (5μg / 20μl / ear) on the front and back of the right ear for modeling, and 20μl of solvent (acetone) was smeared on the left ear. The blank group was not treated; the mice in each group were given the corresponding drugs by oral gavage 30 minutes before modeling, and the administration volume was 10ml / kg. The blank group and the model group were given the corresponding volume of 0.5% CMC-Na solvent. 6 hours after modeling, the ear thickness was measured by a thickness gauge as an index of swelling, and the swelling and inhibitor calculation formulas are as follows:

[0070] Swelling degree = average thickness of right ear - average thickness of left ear

[0071] Inhibition rate = (average swelling degree of model group - average swelling degree of drug administration group) / average swelling degree of model group * 100% Experimental results

[0072] Table 1. Phorbol ester-induced ear swelling and swelling inhibition rate in mice (mean ± SD, n = 8)

[0073]

[0074]

[0075]

[0076] Note: #P<0.05, ##P<0.01 vs blank group; *P<0.05, **P<0.01 vs model group; aP<0.05, aaP<0.01 vs apremilast 8 mg / kg; bP<0.05, bbP<0.01 vs digaotinib 8 mg / kg; cP<0.05, ccP<0.01 vs upadacitinib 8 mg / kg; dP<0.05, ddP<0.01 vs defamilastat 8 mg / kg; eP<0.05, eeP<0.01 vs BMS-9861658 mg / kg

[0077] The Choμ-Talalay combination index method was used as the evaluation basis, and the Calcμsyn2 statistical software was used for dose-effect analysis. According to the experimental drug effect, namely the inhibition rate (fa), the software calculated the median dose Dm of the two single drugs, namely the drug dose at 50% effect, as well as the drug dose required for various effects when the two drugs were used alone or in combination. Finally, the combination index CI of the two drugs in various effects could be calculated.

[0078]

[0079] Notes: (D)1, (D)2 are the doses of drug 1 and drug 2, respectively; (Dm)1, (Dm)2 are the median effect doses of drug 1 and drug 2, respectively; m1, m2 are the coefficients of the dose-effect relationship of drug 1 or drug 2, respectively, where m=1, >1, <1 represent hyperbolic, S-shaped and flat S-shaped dose-effect curves, respectively; fa is the drug action inhibition rate; CI is the combination index.

[0080] After software analysis, the compound drug composition has good synergistic effect. The specific effects are shown in Tables 2 to 5 below. According to the principle of Median-effect Principle for evaluating the effect, when the CI index is <0.1, it has very strong synergism; when the CI index is 0.1-0.3, it has strong synergism; when the CI index is 0.3-0.7, it has synergism; when the CI index is 0.7-0.85, it has moderate synergism; when the CI index is 0.85-0.9, it has weak synergism; when the CI index is 0.9-1.1, it has a near additive effect; when the CI index is >1.1, it has an antagonistic effect.

[0081] Table 2 Comparison of the combined index CI of different dose combinations of diastatinib and apremilast

[0082]

[0083] Note: Digatinib Dm = 13.79 mg / kg, Apremilast Dm = 12.10 mg / kg.

[0084] As can be seen from Table 2, the combination of digotinib and apremilast has a synergistic effect within the dose ratio range of 8:1 to 1:4, among which it has a strong synergistic effect (Strong synergism) when the dose ratio is 1:1, a synergistic effect (Synergism) when the dose ratio is 8:1 to 1:2, a moderate synergistic effect (Moderate synergism) when the dose ratio is 1:4, and a nearly additive effect (Nearly additive) when the dose ratio is 1:8.

[0085] Table 3 Comparison of the combined index CI of different dose combinations of upadacitinib and apremilast

[0086]

[0087] Note: Upadacitinib Dm = 9.44 mg / kg, Apremilast Dm = 12.10 mg / kg.

[0088] As shown in Table 3, the combination of upadacitinib and apremilast has a synergistic effect within the dose ratio range of 8:1 to 1:8, wherein a strong synergism is observed at a dose ratio of 1:1, a synergistic effect is observed at a dose ratio of 2:1 to 8:1, and a moderate synergism is observed at a dose ratio of 1:2 to 1:8.

[0089] Table 4 Comparison of the combined index CI of different dose combinations of upadacitinib and defamilastat

[0090]

[0091] Note: Upadacitinib Dm = 9.44 mg / kg, Defamikast Dm = 13.85 mg / kg.

[0092] As shown in Table 4, the combination of upadacitinib and defamikast has a synergistic effect in the dosage ratio range of 8:1 to 1:4, and has a nearly additive effect when the dosage ratio is 1:8.

[0093] Table 5 Comparison of the combined index CI of different dose combinations of digaotinib and defamilastat

[0094]

[0095] Note: Digaotinib Dm = 13.79 mg / kg, Defamikast Dm = 13.85 mg / kg.

[0096] As can be seen from Table 5, the combination of digaotinib and defamilastat has a synergistic effect within the dosage ratio range of 8:1 to 1:8, wherein a synergistic effect (Synergism) is present within the dosage ratio range of 8:1 to 1:4, and a moderate synergistic effect (Moderate synergism) is present at a dosage ratio of 1:8.

[0097] Table 6 Comparison of the combined index CI of different dose combinations of BMS-986165 and Apremilast

[0098]

[0099]

[0100] Note: BMS-986165 Dm = 9.91 mg / kg, Apremilast Dm = 12.10 mg / kg.

[0101] As can be seen from Table 6, the combination of BMS-986165 and Apremilast has a synergistic effect within the dose ratio range of 8:1 to 1:2, wherein a strong synergistic effect is observed at a dose ratio of 1:1, a synergistic effect is observed at a dose ratio of 2:1, a moderate synergistic effect is observed at dose ratios of 4:1 and 1:2, a weak synergistic effect is observed at a dose ratio of 8:1, and a nearly additive effect is observed at dose ratios of 1:4 to 1:8.

[0102] The above results show that the combination of JAK inhibitors and PDE4 inhibitors in the dose ratio range of 1:8 to 8:1 has a significant inhibitory effect on phorbol ester-induced ear swelling in mice, among which the combination of digotinib and apremilast has a synergistic effect in the dose ratio range of 8:1 to 1:4, the combination of upadatinib and apremilast has a synergistic effect in the dose ratio range of 8:1 to 1:8, the combination of upadatinib and defamister has a synergistic effect in the dose ratio range of 8:1 to 1:4, the combination of digotinib and defamister has a synergistic effect in the dose ratio range of 8:1 to 1:8, and the combination of BMS-986165 and apremilast has a synergistic effect in the dose ratio range of 8:1 to 1:2. The effects of each combination at a ratio of 1:1 are significantly better than those of the 8 mg / kg dose group of each single therapeutic drug, showing significant synergistic enhancement and dose reduction effects.

[0103] Example 2 Compound Pharmaceutical Composition Preparation

[0104] (1) Digatinib (10 mg) + Apremilast (10 mg) capsules

[0105] The prescription is as follows (1000 tablets):

[0106] Raw material name Dosage(g) Digatinib 10 Apremilast 10 Low substituted hydroxypropyl cellulose 37.5 Sodium carboxymethyl starch 12.5 lactose 43.8 Magnesium Stearate 1.3 30% ethanol Moderate

[0107] Preparation method: Take the prescribed amount of digaotinib, apremilast, and magnesium stearate and pass them through a 120-mesh sieve, and pass low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and lactose through an 80-mesh sieve for later use; weigh the prescribed amount of digaotinib, apremilast, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and lactose, pass through an 80-mesh sieve in equal increments and mix evenly, use 30% ethanol solution as a wetting agent to prepare a soft material, granulate through a 30-mesh sieve, dry at 50-60°C for 3-4 hours, sieve through a 30-mesh sieve, add the prescribed amount of magnesium stearate, mix evenly, and fill into capsules.

[0108] (2) Upadacitinib (7.5 mg) + Defamikast (7.5 mg) tablets

[0109] The prescription is as follows (1000 tablets):

[0110] Raw material name Dosage(g) Upadacitinib 7.5 Defamister 7.5 Microcrystalline Cellulose 40 Sodium carboxymethyl starch 10 lactose 45 Magnesium Stearate 1 30% ethanol Moderate

[0111] Preparation method: take the prescribed amount of upadacitinib, defamilastat, and magnesium stearate through a 120-mesh sieve, and pass microcrystalline cellulose, sodium carboxymethyl starch, and lactose through an 80-mesh sieve for later use; weigh the prescribed amount of upadacitinib, defamilastat, microcrystalline cellulose, sodium carboxymethyl starch, and lactose, pass through an 80-mesh sieve in equal increments and mix evenly, use 30% ethanol solution as a wetting agent to prepare a soft material, granulate through a 30-mesh sieve, dry at 50-60° C. for 3-4 hours, sieve through a 30-mesh sieve, add the prescribed amount of magnesium stearate, mix evenly, and press into tablets.

[0112] (3) Digaotinib (10 mg) + Defamist (10 mg) Granules

[0113] The prescription is as follows (1000 packs):

[0114] Raw material name Dosage(g) Digatinib 10 Defamister 10 Sucrose powder 850 Microcrystalline Cellulose 135 Sodium carboxymethyl starch 150 lactose 130 Aspartame 75 Sodium Lauryl Sulfate 5.5 3% povidone in 30% ethanol Moderate

[0115] Preparation method: Take the prescribed amount of digaotinib, difamilastat, sucrose powder, microcrystalline cellulose, sodium carboxymethyl starch, lactose, and aspartame and pass them through a 100-mesh sieve, and pass sodium lauryl sulfate through an 80-mesh sieve for later use; weigh the prescribed amount of digaotinib, difamilastat, sucrose powder, microcrystalline cellulose, sodium carboxymethyl starch, lactose, and aspartame and mix them in equal amounts in increasing amounts, prepare a soft material with a 30% ethanol solution of 3% povidone, granulate with a 20-mesh sieve, dry at 50-60°C for 3-4 hours, sieve through an 18-mesh sieve, add the prescribed amount of sodium lauryl sulfate, mix well, and seal the bag to obtain the product.

[0116] (4) Upadacitinib (7.5 mg) + Apremilast (7.5 mg) oral solution

[0117] The prescription is as follows (1000 bottles)

[0118] Raw material name Dosage(g) Upadacitinib 7.5 Apremilast 7.5 Aspartame 30 Sodium citric acid 2.5 Sodium Citrate 7.5 Water for injection 5000mL

[0119] Preparation method: Take the prescribed amount of aspartame, orange flavor, and citric acid and dissolve them in the specified water for injection, filter, add the prescribed amount of upadacitinib and apremilast at room temperature, dissolve, filter, and fill.

[0120] (5) BMS-986165 (3 mg) + Apremilast (3 mg) syrup

[0121] The prescription is as follows:

[0122] Raw material name Dosage(g) BMS-986165 3 Apremilast 3 sucrose 875 Aspartame 25 Orange flavor 2 Sodium Citrate 7.5 Water for injection 1000mL

[0123] Preparation method: Add the prescribed amount of sucrose to 900 mL of water for injection, heat to boil, dissolve, filter while hot, cool to room temperature for use (syrup); dissolve the prescribed amount of BMS-986165, apremilast, aspartame, orange flavor, and sodium citrate in 60 mL of water for injection, filter, add to the above syrup, add water for injection to 1000 mL, mix well, and fill to obtain the product.

Claims

1. A pharmaceutical composition for treating an inflammatory disease, comprising a JAK inhibitor, a PDE4 inhibitor and a pharmaceutically acceptable carrier, wherein the JAK inhibitor is selected from a combination of one or more of upadacitinib, diafatinib, BMS-986165 or pharmaceutically acceptable salts thereof, and the PDE4 inhibitor is selected from a combination of one or more of apremilast, defamilastat or pharmaceutically acceptable salts thereof, wherein the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:

8.

2. The pharmaceutical composition according to claim 1, wherein the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:4; preferably, the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:

2.

3. The pharmaceutical composition according to claim 1 or 2, wherein the JAK inhibitor is selected from diatinib or a pharmaceutically acceptable salt thereof, the PDE4 inhibitor is selected from apremilast or a pharmaceutically acceptable salt thereof, and the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:4, preferably 8:1 to 1:2; more preferably 8:1 to 1:1; most preferably 1:

1.

4. The pharmaceutical composition according to claim 1 or 2, wherein the JAK inhibitor is selected from upadacitinib or a pharmaceutically acceptable salt thereof, the PDE4 inhibitor is selected from apremilast or a pharmaceutically acceptable salt thereof, and the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:8; preferably 8:1 to 1:1; more preferably 4:1 to 1:1; most preferably 1:

1.

5. The pharmaceutical composition according to claim 1 or 2, wherein the JAK inhibitor is selected from upadacitinib or a pharmaceutically acceptable salt thereof, the PDE4 inhibitor is selected from defamilastat or a pharmaceutically acceptable salt thereof, and the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:4; preferably 2:1 to 1:2; more preferably 2:1 to 1:1; most preferably 1:

1.

6. The pharmaceutical composition according to claim 1 or 2, wherein the JAK inhibitor is selected from digaotinib or a pharmaceutically acceptable salt thereof, the PDE4 inhibitor is selected from defamilastat or a pharmaceutically acceptable salt thereof, and the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:8; preferably 8:1 to 1:4; more preferably 2:1 to 1:2; most preferably 1:

1.

7. The pharmaceutical composition according to claim 1 or 2, wherein the JAK inhibitor is selected from BMS-986165 or a pharmaceutically acceptable salt thereof, the PDE4 inhibitor is selected from Apremilast or a pharmaceutically acceptable salt thereof, and the weight ratio of the JAK inhibitor to the PDE4 inhibitor is 8:1 to 1:2; preferably 4:1 to 1:2; more preferably 2:1 to 1:1; most preferably 1:

1.

8. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a medicament for treating inflammatory diseases.

9. The method according to claim 9, wherein the inflammatory disease is selected from atopic dermatitis, urticaria, allergic rhinitis, seborrheic dermatitis, contact dermatitis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ulcerative colitis, vitiligo, multiple sclerosis.

10. The pharmaceutical composition according to any one of claims 1 to 7, which is an oral administration preparation.

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