Upatinib oral solution as well as preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to an upatinib oral solution as well as a preparation method and application thereof. The oral upatinib solution is prepared from the following components in percentage by weight: 0.1%-1.5% of upatinib, 1%-20% of hydroxypropyl beta-cyclodextrin, 0.5%-5% of a flavoring agent and the balance of water, wherein the oral upatinib solution is prepared from the following components in percentage by weight: 0.1%-1.5% of upatinib, 1%-20% of hydroxypropyl beta-cyclodextrin, 0.5%-5% of a flavoring agent and the balance of water; the degree of substitution of the hydroxypropyl beta-cyclodextrin is 4.0 to 5.5. The oral upatinib solution overcomes the problems of overlarge tablet diameter, poor oral compliance, low solubility in water and low bioavailability of upatinib tablets in the prior art, and has the advantages of simplicity in preparation and convenience in use.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an upadacitinib oral solution and a preparation method and application thereof. Background Art

[0002] Upadacitinib is a Janus kinase (JAK) inhibitor. JAK is an intracellular enzyme that transmits signals generated by the interaction of cytokines or growth factor receptors on the cell membrane, thereby affecting the cellular process of hematopoiesis and immune cell function. Its chemical structure is as follows:

[0003]

[0004] Upadacitinib extended-release tablets are in the form of tablets with specifications of 15 mg, 30 mg, and 45 mg. They are clinically used to treat rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and non-radiographic axial spondyloarthritis.

[0005] The recommended dose for rheumatoid arthritis is 15 mg once daily. The recommended dose for psoriatic arthritis is 15 mg once daily. Recommended dose for atopic dermatitis: Initial treatment with 15 mg once daily for pediatric patients 40 years of age and older and adults up to 65 years of age weighing at least 12 kg. If an adequate response is not achieved, consider increasing the dose to 30 mg once daily. If an adequate response is not achieved with the 30 mg dose, discontinue RINVOQ immediately. Use the lowest effective dose required to maintain a response. The recommended dose for adults 65 years of age and older is 15 mg once daily. Recommended dose for ulcerative colitis: Induction therapy in adult patients is 45 mg once daily for 8 weeks. The recommended dose for maintenance therapy in adult patients is 15 mg once daily. For patients with refractory, severe, or extensive disease, consider a dose of 30 mg once daily. If an adequate response is not achieved with the 30 mg dose, discontinue RINVOQ immediately. Use the lowest effective dose required to maintain a response. Recommended Dosages for Crohn's Disease The recommended induction dose for induction therapy in adult patients is 45 mg once daily for 12 weeks. The recommended maintenance dose for adult patients is 15 mg once daily. A dose of 30 mg once daily may be considered for patients with refractory, severe, or extensive disease. If an adequate therapeutic response is not achieved with the 30 mg dose, RINVOQ will be discontinued immediately. Use the lowest effective dose required to maintain a response. The recommended dose for ankylosing spondylitis is 15 mg once daily. The recommended dose for non-radiographic axial spondyloarthritis is 15 mg once daily.

[0006] The first-pass effect of upadacitinib sustained-release tablets is large, thus limiting bioavailability. It is also inconvenient to take, with a tablet diameter of up to 14*8 mm, and poor adaptability to patients with dysphagia and children. At the same time, the tablet preparation process is complex and costly. Therefore, it is urgent to develop an upadacitinib dosage form that is easy to take, has good patient compliance, high bioavailability, low cost, and is suitable for industrial production.

[0007] When converting tablets into oral liquids, solvents, excipients and pH adjusters are usually added. Common solvents include water, ethanol and propanol. Common excipients include sweeteners, preservatives, stabilizers, thickeners, etc. In order to improve the water solubility of poorly soluble drugs, increase drug stability and improve drug bioavailability, hydroxypropyl beta-cyclodextrin is generally added, such as Chinese patents CN 114432252 A and CN 110934834 A.

[0008] In the current existing technology, a company has launched an oral solution of upadacitinib (Rinvoq), named Rinvoq LQ. The concentration of Rinvoq LQ is 1 mg / mL. Each 1 mL of Rinvoq LQ contains 1 mg of upadacitinib free base (equivalent to 1.02 mg of upadacitinib hemihydrate). The excipients of the oral solution are: anhydrous citric acid, purified water, sodium benzoate, sodium citrate dihydrate, and sucralose. This new dosage form provides a new treatment option for patients with psoriatic arthritis aged 2-18 years and patients with polyarticular juvenile idiopathic arthritis. However, the excipient ingredients do not provide more selectivity, and the drug stability and drug bioavailability are not mentioned, and the concentration of each component is also relatively single.

[0009] In summary, there is an urgent need for an oral solution of upadacitinib that has high bioavailability, is easy to take, has low cost, is suitable for industrial production, and has a wide range of ingredients to choose from. Summary of the invention

[0010] Based on the deficiencies of the prior art, the present invention provides an oral solution of upadacitinib with high bioavailability, low cost, suitable for industrial production and with multiple ingredients to choose from, and a preparation method and application thereof. The oral solution of upadacitinib of the present invention has high drug stability and drug bioavailability, is easy to take, and has multiple ingredients to choose from.

[0011] In order to achieve the above object, the present invention adopts the following technical solutions:

[0012] On the one hand, the present invention provides an oral solution of upadacitinib, comprising the following components by weight concentration: 0.1%-1.5% of upadacitinib, 1%-20% of hydroxypropyl-beta-cyclodextrin, 0.5%-5% of flavoring agent and the remainder of water; the degree of substitution of the hydroxypropyl-beta-cyclodextrin is 4.0-5.5.

[0013] Preferably, the degree of substitution of the hydroxypropyl-beta-cyclodextrin is 5.0.

[0014] Preferably, the upadacitinib oral solution comprises the following components by weight concentration: 0.45%-1% upadacitinib, 8%-10% hydroxypropyl-beta-cyclodextrin, 0.7%-2% flavoring agent and the balance water.

[0015] Most preferably, the upadacitinib oral solution comprises the following components by weight concentration: 0.45% upadacitinib, 8% hydroxypropyl-beta-cyclodextrin, 0.7% flavoring agent and the balance water.

[0016] Preferably, the upadacitinib oral solution further comprises a pH adjuster; and the pH range of the upadacitinib oral solution is 3-8.

[0017] Preferably, the flavoring agent is selected from one or more of alitame, glycoside, sodium cyclamate, sucralose, acesulfame potassium, stevioside, aspartame, thaumatin, glycyrrhizin, aspartame, chlortetracycline potassium, sodium cyclamate, saccharin, saccharin sodium or saccharin calcium, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel and honey.

[0018] More preferably, the flavoring agents are aspartame and sorbitol.

[0019] The mass ratio of aspartame to sorbitol is 2-9:12.

[0020] More preferably, the mass ratio of aspartame to sorbitol is 2:5.

[0021] Preferably, the pH adjuster is selected from one or more of tartaric acid, citric acid, citric acid, sodium hydroxide and sodium carbonate.

[0022] More preferably, the pH adjuster is tartaric acid.

[0023] On the other hand, the present invention also provides a method for preparing the above-mentioned upadacitinib oral solution, comprising the following steps:

[0024] 1) dissolving hydroxypropyl-beta-cyclodextrin in water, then adding upadacitinib, stirring to dissolve, to obtain a mixed solution;

[0025] 2) adding a flavoring agent and a pH adjuster to the mixed solution in 1) to adjust the pH;

[0026] 3) Add water to make up to the required volume.

[0027] Preferably, the stirring in step 1) is stirring while heating, and the heating temperature is 50-95°C.

[0028] More preferably, the stirring in step 1) is stirring while heating, and the heating temperature is 65-90°C.

[0029] More preferably, the stirring in step 1) is stirring while heating, and the heating temperature is 80°C.

[0030] Preferably, the mass volume ratio of the cyclodextrin to water in step 1) is 1-20 g:80 mL.

[0031] Preferably, the water is water for injection.

[0032] Preferably, the mass volume ratio of the cyclodextrin to water is 8 g:80 mL

[0033] Preferably, the preparation method further comprises filtering and filling.

[0034] Preferably, the filtering step is filtering through 0.45 μm and 0.22 μm PES filter elements in sequence.

[0035] Preferably, the pH value for adjusting the pH is in the range of 3-8; more preferably, the pH is 4-7; further preferably, the pH is 5.5.

[0036] In yet another aspect, the present invention further provides use of the upadacitinib oral solution and the upadacitinib oral solution obtained by the above-mentioned preparation method in the preparation of a drug for treating rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis or non-radiographic axial spondyloarthritis.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] 1) The present invention is an oral liquid preparation, which overcomes the problems in the prior art that upadacitinib tablets have a large tablet diameter, poor oral compliance, low solubility in water and obvious first-pass effect, thereby limiting their bioavailability.

[0039] 2) The upadacitinib oral solution of the present invention adopts inclusion technology to increase the solubility of upadacitinib and thus improve the bioavailability, and the inclusion technology is implemented by using hydroxypropyl-beta-cyclodextrin with a specific degree of substitution range; the upadacitinib oral solution of the present invention has the advantages of simple preparation and convenient use, and solves the problem of poor compliance of patients taking the drug, and is particularly suitable for patients with dysphagia and children. DETAILED DESCRIPTION

[0040] The present invention is further described in detail below with reference to specific embodiments.

[0041] Example 1 An oral solution of upadacitinib

[0042] The components and dosages of upadacitinib oral solution are shown in Table 1 below.

[0043] Table 1

[0044] Element Dosage Upadacitinib 45g H-β-CD 800g Sucralose 10g Sorbitol 60g tartaric acid Add tartaric acid to adjust pH to 5.0 Water for injection Up to 10000ml

[0045] The preparation method of upadacitinib oral solution comprises the following steps:

[0046] Hydroxypropyl beta-cyclodextrin (degree of substitution 4.0) was dissolved in 80% of the prescribed amount of water for injection, and upadacitinib was added under heating at 80°C in a water bath while stirring until dissolved; sucralose and sorbitol were continued to be added until dissolved, tartaric acid was used to adjust the pH to 5.0, and the volume of water for injection was fixed to 10000 ml. The above solution was filtered through 0.45μm and 0.22μm PES filter cartridges to obtain the final solution.

[0047] Example 2 An oral solution of upadacitinib

[0048] The components and dosages of upadacitinib oral solution are shown in Table 2 below.

[0049] Table 2

[0050] Element Dosage Upadacitinib 45g H-β-CD 800g Aspartame 20g Sorbitol 50g tartaric acid Add tartaric acid to adjust pH to 5.5 Water for injection Up to 10000ml

[0051] The preparation method of upadacitinib oral solution comprises the following steps:

[0052] Hydroxypropyl beta-cyclodextrin (degree of substitution 5.0) was dissolved in 80% of the prescribed amount of water for injection, and upadacitinib was added under heating at 80°C in a water bath while stirring until dissolved; aspartame and sorbitol were continued to be added until dissolved, tartaric acid was used to adjust the pH to 5.5, and the volume of water for injection was fixed to 10000 ml. The above solution was filtered through 0.45μm and 0.22μm PES filter cartridges to obtain the final solution.

[0053] Example 3 An oral solution of upadacitinib

[0054] The components and dosages of upadacitinib oral solution are shown in Table 3 below.

[0055] Table 3

[0056] Element Dosage Upadacitinib 45g H-β-CD 800g Sucralose 30g Sorbitol 40g tartaric acid Add tartaric acid to adjust pH to 7.0 Water for injection Up to 10000ml

[0057] The preparation method of upadacitinib oral solution comprises the following steps:

[0058] Hydroxypropyl beta-cyclodextrin (degree of substitution 5.0) was dissolved in 80% of the prescribed amount of water for injection, and upadacitinib was added under heating at 60°C in a water bath while stirring until dissolved; sucralose and sorbitol were continued to be added until dissolved, tartaric acid was used to adjust the pH to 7.0, and the volume of water for injection was fixed to 10000 ml. The above solution was filtered through 0.45μm and 0.22μm PES filter cartridges to obtain the final solution.

[0059] Example 4 An oral solution of upadacitinib

[0060] The components and dosages of upadacitinib oral solution are shown in Table 4 below.

[0061] Table 4

[0062] Element Dosage(g) Pharmaceutically acceptable salt of upadacitinib 10 H-β-CD 100 Cyclamate 25 Acesulfame K 25 Citric Acid Add citric acid to adjust pH to 3.0 Water for injection Up to 10000ml

[0063] The preparation method of upadacitinib oral solution comprises the following steps:

[0064] Dissolve hydroxypropyl beta-cyclodextrin (degree of substitution 5.5) in 80% of the prescribed amount of water for injection, add upadacitinib while stirring under heating at 65°C water bath, and stir until dissolved; continue to add sodium cyclamate and acesulfame potassium until dissolved, adjust pH to 3.0 with citric acid, and dilute to 10000 ml with water for injection. Filter the above solution through 0.45μm and 0.22μm PES filter cartridges to obtain the final solution.

[0065] Example 5 An oral solution of upadacitinib

[0066] The components and dosages of upadacitinib oral solution are shown in Table 5 below.

[0067] Table 5

[0068] Element Dosage(g) Upadacitinib 100 H-β-CD 1000 sucrose 120 maltose 80 Sodium hydroxide Add sodium hydroxide to adjust pH to 8.0 Water for injection Up to 10000ml

[0069] The preparation method of upadacitinib oral solution comprises the following steps:

[0070] Hydroxypropyl beta-cyclodextrin (degree of substitution 5.5) was dissolved in 80% of the prescribed amount of water for injection, and upadacitinib was added under heating at 95°C in a water bath while stirring until dissolved; sucrose and maltose were continued to be added until dissolved, and the pH was adjusted to 8.0 with sodium hydroxide, and the volume of water for injection was fixed to 10000 ml. The above solution was filtered through 0.45μm and 0.22μm PES filter cartridges to obtain the final solution.

[0071] Example 6 An oral solution of upadacitinib

[0072] The components and dosages of upadacitinib oral solution are shown in Table 6 below.

[0073] Table 6

[0074]

[0075] The preparation method of upadacitinib oral solution comprises the following steps:

[0076] Hydroxypropyl beta-cyclodextrin (degree of substitution 5.5) was dissolved in 80% of the prescribed amount of water for injection, and upadacitinib was added under heating at 90°C in a water bath while stirring until dissolved; aspartame, glycyrrhizin, and mannitol were added until dissolved, tartaric acid and sodium carbonate were used to adjust the pH to 3.0, and the volume of water for injection was adjusted to 10000 ml. The above solution was filtered through 0.45μm and 0.22μm PES filter cartridges to obtain the final solution.

[0077] Comparative Example 1: Upadacitinib oral solution

[0078] The only difference from Example 1 is that the degree of substitution of hydroxypropyl-beta-cyclodextrin is different, specifically, the degree of substitution of hydroxypropyl-beta-cyclodextrin is 3.0, and the other components and contents are the same.

[0079] Hydroxypropyl beta-cyclodextrin (degree of substitution 3.0) was dissolved in 80% of the prescribed amount of water for injection, and upadacitinib was added under heating at 90°C in a water bath while stirring until dissolved; aspartame, glycyrrhizin, and mannitol were added until dissolved, tartaric acid was used to adjust the pH to 3.0, and the volume of water for injection was adjusted to 10000 ml. The above solution was filtered through 0.45μm and 0.22μm PES filter cartridges to obtain the final solution.

[0080] Comparative Example 2: An oral solution of upadacitinib

[0081] The only difference from Example 1 is that the degree of substitution of hydroxypropyl-beta-cyclodextrin is different, specifically, the degree of substitution of hydroxypropyl-beta-cyclodextrin is 6.5, and the other components and contents are the same.

[0082] The preparation method of upadacitinib oral solution comprises the following steps:

[0083] Hydroxypropyl beta-cyclodextrin (substitution degree 6.5) was dissolved in 80% of the prescribed amount of water for injection, and upadacitinib was added under heating at 90°C in a water bath while stirring until dissolved; aspartame, glycyrrhizin, and mannitol were added until dissolved, tartaric acid was used to adjust the pH to 3.0, and the volume of water for injection was adjusted to 10000 ml. The above solution was filtered through 0.45μm and 0.22μm PES filter cartridges to obtain the final solution.

[0084] Comparative Example 3: An oral solution of upadacitinib

[0085] The only difference from Example 1 is that the degree of substitution of hydroxypropyl-beta-cyclodextrin is different, specifically, the degree of substitution of hydroxypropyl-beta-cyclodextrin is 7.0, and the other components and contents are the same.

[0086] The preparation method of upadacitinib oral solution comprises the following steps:

[0087] Hydroxypropyl beta-cyclodextrin (substitution degree 7.0) was dissolved in 80% of the prescribed amount of water for injection, and upadacitinib was added under heating at 90°C in a water bath while stirring until dissolved; aspartame, glycyrrhizin, and mannitol were added until dissolved, tartaric acid was used to adjust the pH to 3.0, and the volume of water for injection was adjusted to 10000 ml. The above solution was filtered through 0.45μm and 0.22μm PES filter cartridges to obtain the final solution.

[0088] Effect experiment

[0089] Experiment 1

[0090] The products prepared by the prescription processes of the technical solutions of Examples 1-6 and Comparative Examples 1-3 of the present invention have all met the requirements for key quality attributes. The detailed test results of upadacitinib oral solution are shown in Table 7 below:

[0091] Table 7

[0092]

[0093]

[0094] According to Appendix 9001 "Guidelines for Stability Testing of Raw Materials and Preparations" of Part IV of the 2020 Edition of the Chinese Pharmacopoeia, the samples obtained from Example 2 of the optimal combination were subjected to stability testing: Accelerated test: The samples were placed in a constant temperature and humidity chamber at a temperature of 40°C and a relative humidity of 75% for 6 months, and samples were taken at the 1st, 3rd, and 6th months, respectively, and tested according to the stability test items, and compared with the data of October. Long-term test: The samples were placed in a constant temperature and humidity chamber at a temperature of 25°C and a relative humidity of 60% for 12 months, and samples were taken at the 6th and 12th months, respectively, and tested according to the inspection items, and compared with the data of October. The results of the stability test are shown in Table 8.

[0095] Table 8

[0096]

[0097] The stability test results show that the upadacitinib oral solution prepared by the present invention has stable quality.

[0098] Experiment 2

[0099] Experimental methods

[0100] This experiment compares the relative bioavailability of upadacitinib oral solution and commercially available upadacitinib tablets (trade name Rinvoq) in Beagle dogs. Test animals: 40 Beagle dogs, test drugs: upadacitinib oral solutions prepared in Examples 1-6 and Comparative Examples 1-3 were used as test samples, and the test samples were diluted with water to 3 mg / mL. Upadacitinib tablets (trade name: Rinvoq, specification: 15 mg) were used as control samples, and the control samples used the original preparation without preparation. The experiment was divided into 9 test groups and 1 control group, with 4 dogs in each group. The animals in the test groups were given 5 mL (15 mg upadacitinib) of diluted upadacitinib oral solutions of Examples 1-6 and Comparative Examples 1-3, respectively, and the animals in the control group were given one tablet of the control sample (15 mg upadacitinib) and fed with 5 ml of water. The administration method was oral, and the experiment was a single-cycle design. Blood samples were collected before administration and 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration to test the peak plasma concentration Cmax and peak time Tmax of upadacitinib. AUC0-∞ represents the area enclosed by the plasma concentration and time during the entire process from the start of drug administration to the complete elimination of the drug from the body. This value can reflect the total exposure of the drug in the body and is an important indicator for evaluating the degree of drug absorption.

[0101] Experimental results and analysis

[0102] The results are shown in Table 9:

[0103] Table 9

[0104]

[0105] According to the results of Examples 1, 2 and 3 and Rinvoq, upadacitinib oral solution as a whole has better oral bioavailability than tablets, and when the degree of substitution of hydroxypropyl-beta-cyclodextrin is 4.0-5.5, there is no significant difference in bioavailability;

[0106] According to the data results of Comparative Examples 1-3 and Example 2, when the degree of substitution of hydroxypropyl-beta-cyclodextrin is less than 4.0 or greater than 5.5, the bioavailability is reduced.

[0107] Therefore, the oral solution according to the present invention has a simple preparation process, a low first-pass effect, and a high bioavailability, and is more suitable for patients with dysphagia and children.

[0108] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An oral solution of upadacitinib, characterized in that: The upadacitinib oral solution comprises the following components by weight concentration: 0.1%-1.5% upadacitinib, 1%-20% hydroxypropyl beta-cyclodextrin, 0.5%-5% flavoring agent and the remainder water; the degree of substitution of the hydroxypropyl beta-cyclodextrin is 4.0-5.

5.

2. The oral solution of upadacitinib according to claim 1, characterized in that: The upadacitinib oral solution comprises the following components by weight concentration: 0.45%-1% upadacitinib, 8%-10% hydroxypropyl beta-cyclodextrin, 0.7%-2% flavoring agent and the balance water.

3. The oral solution of upadacitinib according to claim 1, characterized in that: The upadacitinib oral solution also includes a pH regulator; the pH range of the upadacitinib oral solution is 3-8.

4. The oral solution of upadacitinib according to claim 1, characterized in that: The flavoring agent is selected from one or more of alitame, glycoside, sodium cyclamate, sucralose, acesulfame potassium, stevioside, aspartame, thaumatin, glycyrrhizin, aspartame, chlortetracycline potassium, sodium cyclamate, saccharin, saccharin sodium or saccharin calcium, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel and honey.

5. The oral solution of upadacitinib according to claim 3, characterized in that: The pH regulator is selected from one or more of tartaric acid, citric acid, citric acid, sodium hydroxide and sodium carbonate.

6. The oral solution of upadacitinib according to claim 4, characterized in that: The flavoring agent is a mixture of aspartame and sorbitol, and the mass ratio of aspartame to sorbitol is 1-4.5:

6.

7. The method for preparing upadacitinib oral solution according to any one of claims 1 to 6, characterized in that: The steps include: 1) dissolving hydroxypropyl-beta-cyclodextrin in water, then adding upadacitinib, stirring to dissolve, to obtain a mixed solution; 2) adding a flavoring agent and a pH adjuster to the mixed solution in 1) to adjust the pH; 3) Add water to make up to the required volume.

8. The preparation method according to claim 7, characterized in that: The stirring in step 1) is stirring while heating, and the heating temperature is 50-95°C.

9. The preparation method according to claim 7, characterized in that: The mass volume ratio of hydroxypropyl-beta-cyclodextrin to water in step 1) is 1-20 g:80 mL; the water is water for injection.

10. Use of the upadacitinib oral solution according to any one of claims 1 to 6 or the upadacitinib oral solution obtained by the preparation method according to any one of claims 7 to 9 in the preparation of a medicament for treating rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis or non-radiographic axial spondyloarthritis.

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