A non-fenretinide softgel and a method of making the same

Abstract

The present application provides a non-naliramide soft capsule, which is composed of content and gel shell, wherein the content comprises the following components: non-naliramide, dispersing agent, suspending agent. The non-naliramide soft capsule of the present application uses the dispersing agent as the solvent of non-naliramide, and adds the suspending agent sodium dodecyl sulfate to form the content of the non-naliramide soft capsule, so that the dissolution speed is fast, the bioavailability is high, the therapeutic effect of non-naliramide can be maximized, and the treatment efficiency is improved.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and in particular to a fenelazol soft capsule and its preparation method. Background Technology

[0002] Fennellone is a third-generation, novel, highly selective, nonsteroidal corticosteroid receptor antagonist (MRA) developed by Bayer. It has higher mineralocorticoid receptor specificity and affinity than first- and second-generation MRAs and can selectively bind to mineralocorticoid receptors.

[0003] In July 2021, fenelazol was approved by the FDA for the treatment of adult patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) to reduce the risk of persistent decline in estimated glomerular filtration rate (eGFR), end-stage renal disease (ESKD), cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure. It is marketed under the brand name Kerendia and is available in 10mg and 20mg strengths. Notably, Kerendia was the first nonsteroidal selective mRA to demonstrate positive renal and cardiovascular outcomes in patients with CKD and T2D. Between February and June 2022, the EU, UK, and Japan successively approved Kerendia for marketing, and it was approved for import into China in June 2022.

[0004] As is well known to those skilled in the art, solid dosage forms require disintegration, dissolution, and absorption, which is highly detrimental to the efficacy of poorly soluble drugs. Fennellone active pharmaceutical ingredient (API) has poor solubility, being almost insoluble in water, and is therefore classified as a poorly soluble drug. Thus, developing novel oral formulations of fenelone that can rapidly exert therapeutic effects and improving the in vitro dissolution rate of this drug is a technical challenge for those skilled in the art. Summary of the Invention

[0005] Based on this, the purpose of this invention is to overcome the shortcomings of ordinary oral solid dosage forms of fenelitone tablets and to provide a fenelitone soft capsule with improved in vitro dissolution and its preparation method.

[0006] In a first aspect, the present invention provides a fenelinone soft capsule, the soft capsule being composed of contents and a shell, the contents comprising the following components: fenelinone, a dispersant, and a suspending agent.

[0007] Preferably, the shell comprises the following components: gelatin, plasticizer, and light-blocking agent.

[0008] Preferably, the mass ratio of the contents to the outer shell is 1:1.

[0009] Preferably, the dispersant is one or more of polyethylene glycol PEG300, polyethylene glycol PEG400, glycerin, propylene glycol, simethicone, medium-chain triglycerides, long-chain triglycerides, soybean oil, hydrogenated castor oil, soybean lecithin, and beeswax, and more preferably one or more of polyethylene glycol PEG300, polyethylene glycol PEG400, propylene glycol, and simethicone.

[0010] Preferably, the suspending agent is one or more of sodium dodecyl sulfate, Tween, oleic acid, Span, beeswax, glyceryl oleate, aluminum monostearate, ethyl cellulose, polyethylene glycol PEG 1500, polyethylene glycol PEG 4000, polyethylene glycol PEG 6000, colloidal silica, polyvinylpyrrolidone, and calcium acetate, and is preferably sodium dodecyl sulfate.

[0011] Preferably, the contents comprise the following components by weight: 1 part fenelitonee, 10-30 parts dispersant, and 0.1-0.5 parts suspending agent; more preferably, 1 part fenelitonee, 15-25 parts dispersant, and 0.1-0.3 parts suspending agent.

[0012] Preferably, the contents also include water.

[0013] Preferably, the contents further include the following components by weight: 0.5 to 5.0 parts water, more preferably 0.5 to 2.0 parts water.

[0014] Preferably, the plasticizer is one or more of glycerol, xylitol, sorbitol, and hydrogenated corn steep liquor, with glycerol being the most preferred.

[0015] Preferably, the light-blocking agent is a metal oxide, preferably one or more of iron oxide, titanium dioxide, and zinc oxide, and more preferably red iron oxide and / or titanium dioxide.

[0016] Preferably, the gel shell comprises the following components by weight: 20-50 parts gelatin, 10-40 parts plasticizer, and 0.1-1.0 parts light-blocking agent; more preferably, 30-50 parts gelatin, 20-30 parts plasticizer, and 0.1-0.5 parts light-blocking agent.

[0017] Preferably, the components of the gel shell also include water.

[0018] Preferably, the gel shell further comprises, by weight, 20-60 parts water, more preferably 30-50 parts water.

[0019] Secondly, the present invention provides a method for preparing fenelazol soft capsules as described above, comprising the following steps:

[0020] (1) Add fenephenone, suspending agent and water to the dispersant and mix to obtain the contents;

[0021] (2) Add the opaque agent to the mixture of plasticizer and water to obtain solution A, dissolve the gelatin in water to obtain solution B, mix solution A and solution B, perform vacuum degassing, keep warm and stand to obtain the gel shell material;

[0022] (3) Put the contents obtained in step (1) and the shell material obtained in step (2) into a soft capsule machine to press into capsules, thus obtaining fenelinedone soft capsules.

[0023] Preferably, in step (1), the mixing includes stirring and / or dissolving.

[0024] Preferably, in step (2), gelatin is dissolved in water at 60-70°C to obtain solution B.

[0025] Preferably, in step (2), the temperature of the heat preservation is 50-60°C.

[0026] Preferably, step (3) further includes drying the pressed capsules.

[0027] Compared to existing technologies, the phenelzine soft capsules of this invention use a dispersant as a solvent for phenelzine and add sodium dodecyl sulfate as a suspending agent to form the contents of the phenelzine soft capsules. This results in rapid dissolution, high bioavailability, and maximizes the therapeutic effect of phenelzine, thereby improving treatment efficiency. Attached Figure Description

[0028] Figure 1 Dissolution curves plotted for the test results of Examples 1-4 and Comparative Examples of the present invention. Detailed Implementation

[0029] To facilitate understanding of the present invention, a more complete description will be given below with reference to the accompanying drawings. Preferred embodiments of the invention are shown in the drawings. However, the invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the invention.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0031] In a first aspect, the present invention provides a fenelinone soft capsule, the soft capsule being composed of contents and a shell, the contents comprising the following components: fenelinone, a dispersant, and a suspending agent.

[0032] In some embodiments, the shell comprises the following components: gelatin, plasticizer, and light-blocking agent.

[0033] In some embodiments, the mass ratio of the contents to the shell is 1:1.

[0034] In some embodiments, the dispersant is one or more of polyethylene glycol PEG300, polyethylene glycol PEG400, glycerin, propylene glycol, simethicone, medium-chain triglycerides, long-chain triglycerides, soybean oil, hydrogenated castor oil, soybean lecithin, and beeswax.

[0035] In some embodiments, the dispersant is one or more of polyethylene glycol PEG300, polyethylene glycol PEG400, propylene glycol, and simethicone.

[0036] In some embodiments, the suspending agent is one or more of sodium dodecyl sulfate, Tween, oleic acid, Span, beeswax, glyceryl oleate, aluminum monostearate, ethyl cellulose, polyethylene glycol PEG 1500, polyethylene glycol PEG 4000, polyethylene glycol PEG 6000, colloidal silica, polyvinylpyrrolidone, and calcium acetate.

[0037] In some embodiments, the suspending agent is sodium dodecyl sulfate.

[0038] In some embodiments, the contents, by weight, include the following components: 1 part feneline, 10 to 30 parts of dispersant, such as 10, 15, 20, 25, 30 parts, etc.; and 0.1 to 0.5 parts of suspending agent, such as 0.1, 0.2, 0.3, 0.4, 0.5 parts, etc.

[0039] In some embodiments, the contents comprise, by weight, the following components: 1 part feneline, 15-25 parts dispersant, and 0.1-0.3 parts suspending agent.

[0040] In some embodiments, the contents may also include water.

[0041] In some embodiments, the contents further include the following components by weight: 0.5 to 5.0 parts of water, for example, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1.0 parts, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts, 1.5 parts, 1.6 parts, 1.7 parts, 1.8 parts, 1.9 parts, 2.0 parts, 2.5 parts, 3.0 parts, 3.5 parts, 4.0 parts, 4.5 parts, 5.0 parts, etc.

[0042] In some embodiments, the contents may further include, by weight, 0.5 to 2.0 parts of water.

[0043] In some embodiments, the contents, by weight, comprise the following components: 1 part feneline, 15-25 parts dispersant, 0.1-0.3 parts suspending agent, and 0.1-2.0 parts water.

[0044] In some embodiments, the plasticizer is one or more of glycerol, xylitol, sorbitol, and hydrogenated corn steep liquor.

[0045] In some embodiments, the plasticizer is glycerin.

[0046] In some embodiments, the light-blocking agent is a metal oxide.

[0047] In some embodiments, the light-blocking agent is one or more of iron oxide, titanium dioxide, and zinc oxide.

[0048] In some embodiments, the light-blocking agent is red iron oxide and / or titanium dioxide.

[0049] In some embodiments, the light-blocking agent is red iron oxide and titanium dioxide.

[0050] In some embodiments, the mass ratio of the red iron oxide to the titanium dioxide is 1:(1-2).

[0051] In some embodiments, the mass ratio of the red iron oxide to the titanium dioxide is 1:1.

[0052] In some embodiments, the gel shell comprises, by weight, the following components: 20 to 50 parts of gelatin, for example, 20, 25, 30, 35, 40, 45, 50 parts; 10 to 40 parts of plasticizer, for example, 10, 15, 20, 25, 30, 35, 40 parts; and 0.1 to 1.0 parts of light-blocking agent, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 parts.

[0053] In some embodiments, the shell comprises, by weight, the following components: 30-50 parts gelatin, 20-30 parts plasticizer, and 0.1-0.5 parts opacifier.

[0054] In some embodiments, the composition of the gel shell also includes water.

[0055] In some embodiments, the gel shell further includes the following components by weight: 20 to 60 parts of water, for example, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, etc.

[0056] In some embodiments, the gel shell further includes, by weight, 30 to 50 parts of water.

[0057] In some embodiments, the gel shell comprises, by weight, the following components: 30-50 parts gelatin, 20-30 parts plasticizer, 0.1-0.5 parts opacifier, and 30-50 parts water.

[0058] In some embodiments, the soft capsule, by weight, comprises contents and a shell; the contents are composed of the following components: 1 part feneline, 20 parts dispersant, 0.2 parts suspending agent, and 1 part water; the shell is composed of the following components: 40 parts gelatin, 20 parts plasticizer, 0.4 parts opacifier, and 30-50 parts water.

[0059] In some embodiments, the soft capsule, by weight, comprises contents and a shell; the contents are composed of the following components: 1 part feneline, 20 parts dispersant, 0.2 parts suspending agent, and 1 part water; the shell is composed of the following components: 40 parts gelatin, 20 parts plasticizer, 0.4 parts opacifier, and 48 parts water.

[0060] Secondly, the present invention provides a method for preparing fenelazol soft capsules as described above, comprising the following steps:

[0061] (1) Add fenephenone, suspending agent and water to the dispersant and mix to obtain the contents;

[0062] (2) Add the opaque agent to the mixture of plasticizer and water to obtain solution A, dissolve the gelatin in water to obtain solution B, mix solution A and solution B, perform vacuum degassing, keep warm and stand to obtain the gel shell material;

[0063] (3) Put the contents obtained in step (1) and the shell material obtained in step (2) into a soft capsule machine to press into capsules, thus obtaining fenelinedone soft capsules.

[0064] In some embodiments, the mixing in step (1) includes stirring and / or dissolving.

[0065] In some embodiments, in step (2), gelatin is dissolved in water at 60-70°C to obtain solution B.

[0066] In some embodiments, the temperature of the heat preservation in step (2) is 50-60°C.

[0067] In some embodiments, step (3) further includes drying the pressed capsules.

[0068] The sample information involved in the examples and comparative examples is shown in the table below.

[0069] Table 1 Sample Information

[0070] name source Specification batch number Finazine soft capsules self made 10mg / Fennedone tablets self made 10mg /

[0071] Where specific experimental steps or conditions are not specified in the embodiments, they can be performed according to the conventional experimental steps or conditions described in the literature in this field. All materials, consumables, and equipment used are commercially available conventional products, including but not limited to the materials, consumables, and equipment used in the embodiments of this application.

[0072] Example 1: Fennellone soft capsules

[0073] Step 1, Preparation of contents: Weigh out the contents according to the following mass ratio: 1 part fenelitonee, 20 parts propylene glycol, 0.2 parts sodium dodecyl sulfate, and 1 part water; slowly add fenelitonee, sodium dodecyl sulfate, and water to propylene glycol, stir to dissolve, and obtain the contents.

[0074] Step 2, Preparation of the gel shell: Weigh out the following components according to the mass ratio of gel shell: 40 parts gelatin, 20 parts glycerin, 0.2 parts red iron oxide, 0.2 parts titanium dioxide, and 48 parts water; add red iron oxide and titanium dioxide to the mixture of glycerin and water to make a suspension; then add gelatin to water at 60-70℃ and stir until completely dissolved; finally, mix the two solutions evenly, degas under vacuum, and keep warm at 50-60℃ to obtain the gel shell material.

[0075] Step 3, Preparation of fenelazol soft capsules: The contents and shell material are placed into a soft capsule machine and pressed into capsules at a mass ratio of 1:1. After drying, fenelazol soft capsules are obtained.

[0076] Example 2: Fennellone soft capsules

[0077] Step 1, Preparation of contents: Weigh out the contents according to the following mass ratio: 1 part fenelitonee, 20 parts PEG300, 0.2 parts sodium dodecyl sulfate, and 1 part water; slowly add fenelitonee, sodium dodecyl sulfate, and water to PEG300, stir to dissolve, and obtain the contents.

[0078] Step 2, Preparation of the gel shell: Weigh out the following components according to the mass ratio of gel shell: 40 parts gelatin, 30 parts glycerin, 0.2 parts red iron oxide, 0.2 parts titanium dioxide, and 30 parts water; add red iron oxide and titanium dioxide to the mixture of glycerin and water to make a suspension; then add gelatin to water at 60-70℃ and stir until completely dissolved; finally, mix the two solutions evenly, degas under vacuum, and keep warm at 50-60℃ to obtain the gel shell material.

[0079] Step 3, Preparation of fenelazol soft capsules: The contents and shell material are placed into a soft capsule machine and pressed into capsules at a mass ratio of 1:1. After drying, fenelazol soft capsules are obtained.

[0080] Example 3: Fennellone soft capsules

[0081] Step 1, Preparation of contents: Weigh out the contents according to the following mass ratio: 1 part fenelitonee, 20 parts PEG400, 0.2 parts sodium dodecyl sulfate, and 1 part water; slowly add fenelitonee, sodium dodecyl sulfate, and water to PEG400, stir to dissolve, and obtain the contents.

[0082] Step 2, Preparation of the gel shell: Weigh out the following components according to the mass ratio of gel shell: 40 parts gelatin, 30 parts glycerin, 0.2 parts red iron oxide, 0.2 parts titanium dioxide, and 30 parts water; add red iron oxide and titanium dioxide to the mixture of glycerin and water to make a suspension; then add gelatin to water at 60-70℃ and stir until completely dissolved; finally, mix the two solutions evenly, degas under vacuum, and keep warm at 50-60℃ to obtain the gel shell material.

[0083] Step 3, Preparation of fenelazol soft capsules: The contents and shell material are placed into a soft capsule machine and pressed into capsules at a mass ratio of 1:1. After drying, fenelazol soft capsules are obtained.

[0084] Example 4: Fennellone soft capsules

[0085] Step 1, Preparation of contents: Weigh out the contents according to the following mass ratio: 1 part fenelitonee, 20 parts simethicone, 0.2 parts sodium lauryl sulfate, and 1 part water; slowly add fenelitonee, sodium lauryl sulfate, and water to the simethicone, stir and suspend to obtain the contents.

[0086] Step 2, Preparation of the gel shell: Weigh out the following components according to the mass ratio of gel shell: 40 parts gelatin, 20 parts glycerin, 0.2 parts red iron oxide, 0.2 parts titanium dioxide, and 40 parts water; add the red iron oxide and titanium dioxide to the mixture of glycerin and water to make a suspension; then add the gelatin to water at 60-70℃ and stir until completely dissolved; finally, mix the two solutions evenly, degas under vacuum, and keep warm at 50-60℃ to obtain the gel shell material.

[0087] Step 3, Preparation of fenelazol soft capsules: The contents and shell material are placed into a soft capsule machine and pressed into capsules at a mass ratio of 1:1. After drying, fenelazol soft capsules are obtained.

[0088] Comparative example: Fennellone tablets

[0089] 1. Add 1 part phenelzine, 6 parts microcrystalline cellulose, 5 parts lactose, 0.5 parts hydroxypropyl methylcellulose, and 0.5 parts croscarmellose sodium to a wet granulation mixer, and stir and shear to mix evenly.

[0090] 2. Preparation of granulation solution: Dissolve 0.05 parts sodium dodecyl sulfate in 10 parts water completely.

[0091] 3. Add the granulation solution to the well-mixed material, perform wet granulation, and granulate through an 18-mesh sieve; after boiling and drying, granulate through an 18-mesh sieve; add 0.1 parts of magnesium stearate, mix well, and then compress and coat into tablets.

[0092] Test Example 1: Dissolution Test

[0093] The fenelazol soft capsules and fenelazol tablets (10 mg) prepared in Examples 1-4 and the comparative examples above were tested using the Chinese Pharmacopoeia 2020 edition, method for determination of solubility and release (General Rule 0931, Method II). The paddle method at 75 rpm was selected, and 900 mL of pH 4.5 acetate buffer was used as the dissolution medium. The dissolution rate of the samples was measured at 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min. The in vitro release was investigated, and the test results are shown in Table 2 below.

[0094] Table 2 Dissolution test results

[0095]

[0096] As can be seen from Table 2 above, the felinerone soft capsules prepared in Examples 1 to 4 have a faster dissolution rate and higher bioavailability than the felinerone tablets prepared in the comparative examples, which can maximize the therapeutic effect of felinerone and improve the treatment efficiency.

[0097] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A fenelazol soft capsule, characterized in that, The soft capsule consists of contents and a shell, the contents of which include the following components: phenelzine, dispersant, and suspending agent.

2. The fenelazol soft capsule as described in claim 1, characterized in that, The gel shell comprises the following components: gelatin, plasticizer, and light-blocking agent; Preferably, the mass ratio of the contents to the outer shell is 1:

1.

3. The fenelazol soft capsule as described in claim 1, characterized in that, The dispersant is one or more of polyethylene glycol PEG300, polyethylene glycol PEG400, glycerin, propylene glycol, simethicone, medium-chain triglycerides, long-chain triglycerides, soybean oil, hydrogenated castor oil, soybean lecithin, and beeswax, preferably one or more of polyethylene glycol PEG300, polyethylene glycol PEG400, propylene glycol, and simethicone. Preferably, the suspending agent is one or more of sodium dodecyl sulfate, Tween, oleic acid, Span, beeswax, glyceryl oleate, aluminum monostearate, ethyl cellulose, polyethylene glycol PEG 1500, polyethylene glycol PEG 4000, polyethylene glycol PEG 6000, colloidal silica, polyvinylpyrrolidone, and calcium acetate, and is preferably sodium dodecyl sulfate.

4. The fenelazol soft capsule as described in claim 1, characterized in that, The contents, by weight, comprise the following components: 1 part fenelitonee, 10-30 parts dispersant, and 0.1-0.5 parts suspending agent, preferably 1 part fenelitonee, 15-25 parts dispersant, and 0.1-0.3 parts suspending agent.

5. The fenelazol soft capsule as described in claim 1, characterized in that, The contents also include water; Preferably, the contents further include the following components by weight: 0.5 to 5.0 parts water, more preferably 0.5 to 2.0 parts water.

6. The fenelazol soft capsule as described in claim 2, characterized in that, The plasticizer is one or more of glycerol, xylitol, sorbitol, and hydrogenated corn steep liquor, preferably glycerol; Preferably, the light-blocking agent is a metal oxide, preferably one or more of iron oxide, titanium dioxide, and zinc oxide, and more preferably red iron oxide and / or titanium dioxide.

7. The fenelazol soft capsule as described in claim 2, characterized in that, The gel shell comprises the following components by weight: 20-50 parts gelatin, 10-40 parts plasticizer, and 0.1-1.0 parts light-blocking agent, preferably 30-50 parts gelatin, 20-30 parts plasticizer, and 0.1-0.5 parts light-blocking agent.

8. The fenelazol soft capsule as described in claim 2, characterized in that, The components of the gel shell also include water; Preferably, the gel shell further comprises, by weight, 20-60 parts water, more preferably 30-50 parts water.

9. A method for preparing fenelazol soft capsules as described in any one of claims 1 to 8, characterized in that, Includes the following steps: (1) Add fenephenone, suspending agent and water to the dispersant and mix to obtain the contents; (2) Add the opaque agent to the mixture of plasticizer and water to obtain solution A, dissolve the gelatin in water to obtain solution B, mix solution A and solution B, perform vacuum degassing, keep warm and stand to obtain the gel shell material; (3) Put the contents obtained in step (1) and the shell material obtained in step (2) into a soft capsule machine to press into capsules, thus obtaining fenelinedone soft capsules.

10. The preparation method according to claim 9, characterized in that, In step (1), the mixing includes stirring and / or dissolving; Preferably, in step (2), gelatin is dissolved in water at 60-70°C to obtain solution B; Preferably, in step (2), the temperature for heat preservation is 50-60°C; Preferably, step (3) further includes drying the pressed capsules.

Images