Enlicarbir for sublingual administration and a method for preparing the same

Abstract

The application discloses a kind of enlicarabine sublingual preparations and preparation method thereof, the enlicarabine sublingual preparation includes the following component raw materials preparation: enlicarabine 2.5~50 parts, dissolving agent 5~20 parts, penetration agent 0.5~25 parts, excipient 17.5~405 parts;Wherein, the dissolving agent is sodium taurocholate, and the penetration agent is 8-(2-hydroxybenzamide) sodium octanoate.This enlicarabine sublingual preparation can be directly absorbed by sublingual mucosa under tongue, and after administration, drug absorption and effect are fast, and it is not necessary to take water, and effectively avoid the first pass effect of oral enlicarabine, wherein when cooperating with dissolving agent sodium taurocholate and penetration agent 8-(2-hydroxybenzamide) sodium octanoate, the solubility of enlicarabine can be obviously increased, and the mucosa absorption effect of enlicarabine can be obviously improved, the bioavailability and curative effect can be greatly improved, and it has good clinical use value and social benefits.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an enrica extract sublingual preparation and its preparation method. Background Technology

[0002] Emricasan is a pancysteine-aspartate proteolytic enzyme (Caspae) inhibitor originally developed by Idun Pharmaceuticals. In April 2005, Pfizer acquired Idun Pharmaceuticals and obtained the compound; in August 2010, Conatus Pharmaceuticals acquired Pfizer's subsidiary Idun Pharmaceuticals, obtaining the rights to continue developing the compound; in December 2016, Novartis and Conatus Pharmaceuticals signed an exclusive licensing, collaboration, and licensing agreement for the drug, under which Conatus will jointly develop and commercialize the drug globally.

[0003] Enricasan, an inhibitor of pancysteine ​​aspartate protease (Caspae), primarily inhibits the activity of Caspase-8 and Caspase-3. Since pancysteine ​​aspartate protease mediates apoptosis and inflammatory pathways, emricasan has significant clinical application potential. Specifically, emricasan has entered Phase I / II clinical trials for the treatment of liver fibrosis (possibly caused by hepatitis B and C virus infection, obesity, and other fibrotic diseases), type 1 diabetes, COVID-19 infection, non-alcoholic fatty liver disease, and portal hypertension. Clinical studies for its use in treating alcoholic hepatitis and liver failure have been suspended, and clinical studies for its use in treating septic shock have been terminated. Furthermore, some domestic research institutions have found that emricasan also has good application potential in the treatment of ischemia-reperfusion-related diseases, such as cerebral ischemia-reperfusion injury and renal ischemia-reperfusion injury.

[0004] Enrickardian has the potential to treat a variety of clinical diseases, but some studies have reported that its oral bioavailability is extremely low (only 2.7%–4%) and it exhibits a significant first-pass effect in the liver (Niel C. Hoglen, et al., 2004). Currently, the dosage forms of enrickardian that have entered clinical trials are primarily oral tablets. Given such low bioavailability, clinical efficacy may be affected, while increasing the dosage may raise safety concerns, and it is also not economical from a drug utilization perspective.

[0005] When enricane is taken orally, the active ingredient undergoes first-pass metabolism and enzymatic degradation in the liver, leading to rapid metabolism under the action of liver enzymes and reduced efficacy. Liver enzymes convert the molecule into inactive metabolites or weaken its activity through biotransformation. Intravenous administration of enricane, compared to oral administration, presents challenges such as poor patient compliance, increased susceptibility to infection and irritation, and requires administration by qualified medical personnel.

[0006] Sublingual preparations are absorbed directly through the sublingual mucosa. The sublingual mucosa has a large surface area and strong permeability, and numerous capillaries converge thereto into the internal jugular vein, from which the drug directly enters the bloodstream via the superior vena cava. This results in rapid drug absorption and onset of action, and the drug can be taken without water, making it convenient and significantly improving bioavailability and efficacy. Therefore, preparing enlicica into sublingual preparations has excellent application value. Summary of the Invention

[0007] The purpose of this invention is to provide a sublingual formulation of enricane that can be rapidly dissolved and absorbed under the tongue.

[0008] The following technical solutions are used to achieve the above objectives.

[0009] The first aspect of this invention provides a sublingual preparation of Enrica, which, by weight, is prepared from raw materials comprising the following components:

[0010]

[0011] The solvent is sodium taurocholate, and the penetration enhancer is sodium 8-(2-hydroxybenzamido)octanoate.

[0012] In some embodiments, the following components of the Enrica sublingual formulation are, by weight:

[0013]

[0014] In some embodiments, the following components of the Enrica sublingual formulation are, by weight:

[0015]

[0016] In some embodiments, each unit weight of the enlical sublingual preparation is 25-500 mg; preferably, each unit weight of the enlical sublingual preparation is 25-400 mg; more preferably, each unit weight of the enlical sublingual preparation is 25-200 mg.

[0017] In some embodiments, the excipient includes:

[0018]

[0019] In some embodiments, the enlical sublingual formulation is prepared from raw materials comprising the following components:

[0020]

[0021] In some embodiments, the filler is one or a combination of mannitol, sorbitol, polyethylene glycol 6000, lactose, microcrystalline cellulose, xylitol, cyclodextrin, glucose, and modified starch; preferably, the filler is one or a combination of mannitol, sorbitol, polyethylene glycol 6000, lactose, and microcrystalline cellulose.

[0022] In some embodiments, the disintegrant is one or a combination of sodium carboxymethyl starch, crospovidone, crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; preferably, the disintegrant is one or a combination of sodium carboxymethyl starch and crospovidone.

[0023] In some embodiments, the flavoring agent is one or a combination of cyclamate, menthol, glycyrrhizin, steviol glycoside, fumaric acid, citric acid, tartaric acid, lactic acid, malic acid, succinic acid, and their alkali metal salts; preferably, the flavoring agent is one or a combination of cyclamate, citric acid, and lactic acid.

[0024] In some embodiments, the flow aid is one or a combination of magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, and sodium dodecyl sulfate, preferably magnesium stearate.

[0025] A second aspect of the present invention provides a method for preparing a sublingual formulation based on enricane as described above, comprising the following steps:

[0026] S1. Dissolve enrikacin, sodium taurocholate, and sodium 8-(2-hydroxybenzamido)octanoate in water to obtain an aqueous solution;

[0027] S2. Add filler and disintegrant to the aqueous solution to prepare soft material, sieve to make granules, and dry to obtain whole granules;

[0028] S3. Add flavoring agent and flow aid to the granules, mix well, and compress into tablets to obtain the Enrica sublingual preparation.

[0029] In this invention, the inventors discovered that a sublingual enlicin preparation made by using enlicaxin as the main drug, combined with a solubilizer, a penetration enhancer, and excipients, can be directly absorbed by the sublingual mucosa. This results in rapid drug absorption and onset of action after administration, requires no water, is convenient to use, improves patient compliance, and effectively avoids the first-pass effect of oral enlicaxin. The types of solubilizers and penetration enhancers have a significant impact on the solubility and absorption of this sublingual enlicin preparation. When combined with the solubilizer sodium taurocholate and the penetration enhancer sodium 8-(2-hydroxybenzamido)octanoate, the solubility of enlicaxin is significantly increased, and the mucosal absorption effect of enlicaxin is significantly improved, greatly enhancing bioavailability and efficacy, thus possessing significant clinical value and social benefits. Detailed Implementation

[0030] To facilitate understanding of the present invention, a more complete description will be provided below. The present 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 present invention.

[0031] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. All commonly used chemical reagents used in the examples are commercially available products.

[0032] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used in this invention includes any and all combinations of one or more of the associated listed items.

[0033] Example 1

[0034] The enrica extract sublingual preparation provided in this embodiment, by weight, has the following raw material composition:

[0035] Sodium taurocholate 10g Sodium 8-(2-hydroxybenzamido)octanoate 15g Sorbitol 324g Sodium carboxymethyl starch 25g Citric acid 0.5g magnesium stearate 5.5g

[0036] The preparation method of the sublingual formulation of Enrica in this embodiment specifically includes the following steps:

[0037] Sodium taurocholate and sodium 8-(2-hydroxybenzamido)octanoate were dissolved in 80 mL of water to obtain solution A. Enricasan was then dissolved in solution A to obtain an aqueous solution.

[0038] Sorbitol and sodium carboxymethyl starch powder were mixed evenly to obtain a powder. The powder was added to an aqueous solution to prepare a soft material. The material was granulated by passing it through an 18-mesh sieve. After drying at 40°C, the granules were sized by passing them through a 16-mesh sieve. Citric acid and magnesium stearate were added to the dry granules, and the mixture was mixed and then compressed into tablets with a tablet weight of 400 mg.

[0039] Example 2

[0040] The enrica extract sublingual preparation provided in this embodiment, by weight, has the following raw material composition:

[0041] Sodium taurocholate 5g Sodium 8-(2-hydroxybenzamido)octanoate 6g microcrystalline cellulose 160g Cross-linked polyvinylpyrrolidone 15g cyclamate 0.5g magnesium stearate 3.5g

[0042] The preparation method of the sublingual formulation of Enrica in this embodiment specifically includes the following steps:

[0043] Sodium taurocholate and sodium 8-(2-hydroxybenzamido)octanoate were dissolved in 50 mL of water to obtain solution B. Enricasan was then dissolved in solution B to obtain an aqueous solution.

[0044] Microcrystalline cellulose and crospovidone are mixed evenly to obtain a powder. The powder is added to an aqueous solution to prepare a soft material. The material is then passed through a 20-mesh sieve to form granules. After drying at 40°C, the granules are sieved through an 18-mesh sieve. Aspartame and magnesium stearate are added to the dry granules, mixed well, and then compressed into tablets with a tablet weight of 200mg.

[0045] Example 3

[0046] The enrica extract sublingual preparation provided in this embodiment, by weight, has the following raw material composition:

[0047] Sodium taurocholate 5g Sodium 8-(2-hydroxybenzamido)octanoate 5g lactose 66g Polyethylene glycol 6000 50g Cross-linked polyvinylpyrrolidone 15g Menthol 1g magnesium stearate 5g

[0048] The preparation method of the sublingual formulation of Enrica in this embodiment specifically includes the following steps:

[0049] Sodium taurocholate and sodium 8-(2-hydroxybenzamido)octanoate were dissolved in 40 mL of water to obtain solution C. Enricasan was then dissolved in solution C to obtain an aqueous solution.

[0050] Lactose, polyethylene glycol 6000, and crospovidone were mixed evenly to obtain a powder. The powder was added to an aqueous solution to prepare a soft material. The material was then passed through a 20-mesh sieve to form granules. After drying at 40°C, the granules were sieved through a 16-mesh sieve. Menthol and magnesium stearate were added to the dry granules, mixed well, and then compressed into tablets with a tablet weight of 150 mg.

[0051] Example 4

[0052] The enrica extract sublingual preparation provided in this embodiment, by weight, has the following raw material composition:

[0053] Sodium taurocholate 3g Sodium 8-(2-hydroxybenzamido)octanoate 0.2g lactose 74.8g Polyethylene glycol 6000 50g Cross-linked polyvinylpyrrolidone 15g Menthol 1g magnesium stearate 5g

[0054] The preparation method of the sublingual formulation of Enrica in this embodiment specifically includes the following steps:

[0055] Sodium taurocholate and sodium 8-(2-hydroxybenzamido)octanoate were dissolved in 40 mL of water to obtain solution C. Enricasan was then dissolved in solution C to obtain an aqueous solution.

[0056] Lactose, polyethylene glycol 6000, and crospovidone were mixed evenly to obtain a powder. The powder was added to an aqueous solution to prepare a soft material. The material was then passed through a 20-mesh sieve to form granules. After drying at 40°C, the granules were sieved through a 16-mesh sieve. Menthol and magnesium stearate were added to the dry granules, mixed well, and then compressed into tablets with a tablet weight of 150 mg.

[0057] Example 5

[0058] Animal experiments: Bioavailability study of Enrica sublingual formulation

[0059] Drug used: Enricacin (batch number: 20626) was purchased from Shanghai Haoyuan Biomedical Technology Co., Ltd.

[0060] Enricasan was prepared into intravenous and oral administration solutions using 100mM phosphate buffer (pH 7.4) as the solvent. For sublingual administration of enricasan, samples from Examples 1-4 were used, and absolute bioavailability was calculated with the mean area under the curve of the intravenous injection group as 100%.

[0061] Laboratory animals and their grouping:

[0062] Twenty-seven male SD rats, weighing 250-300g, were housed in a barrier system. The environmental conditions in the animal room were controlled at a room temperature of 20℃-26℃ and a humidity of 40%-70%. The keepers recorded the data twice a day, once in the morning and once in the afternoon. The air in the room was exchanged 10 to 20 times per hour. The lighting in the animal room was alternated between light and dark for 12 / 12 hours (except for necessary interruptions during the experimental activities). Any interruptions were recorded.

[0063] After fasting overnight, the animals were randomly divided into 9 groups of 3 animals each according to their body weight. These groups were: Enricacin intravenous injection group, Enricacin oral gavage group, Enricacin Example 1 sublingual formulation group, Enricacin Example 2 sublingual formulation group, Enricacin Example 3 complete sublingual formulation group, Enricacin Example 3 incomplete sublingual formulation group A (prescription without sodium taurocholate), Enricacin Example 3 incomplete sublingual formulation group B (prescription without sodium 8-(2-hydroxybenzamide)octanoate), Enricacin Example 3 incomplete sublingual formulation group C (prescription without sodium taurocholate and sodium 8-(2-hydroxybenzamide)octanoate), and Enricacin Example 4 sublingual formulation group. Each group consisted of 3 animals. See Table 1 below.

[0064] Table 1 Dosing design for each prescription group

[0065]

[0066]

[0067]

[0068] The analytical methods for detecting enricane in plasma are shown in Table 2 below:

[0069] Table 2. Analytical and detection methods for enricazone in plasma.

[0070]

[0071]

[0072] Table 3. PK parameters of SD rats administered 10 mg / kg enricane via tail vein injection.

[0073] <![CDATA[t 1 / 2 ]]> h 0.621 0.194 31.3 Kel 1 / h 1.21 0.452 37.4 Vdss L / kg 1.43 0.409 28.7 <![CDATA[MRT inf ]]> h 0.714 0.284 39.8 Cl mL / min / kg 36.2 12.9 35.7 <![CDATA[AUC 0-t ]]> h*ng / mL 4917 1857 37.8 <![CDATA[AUC 0-inf ]]> h*ng / mL 5013 1750 34.9 <![CDATA[AUC 0-t / AUC 0-inf ]]> / 0.973 0.0376 3.86

[0074] Table 4. PK parameters of SD rats administered 10 mg / kg enricane by gavage

[0075] <![CDATA[t 1 / 2 ]]> h 0.890 0.307 34.5 <![CDATA[T max ]]> h 0.0833 NA NA <![CDATA[C max ]]> ng / mL 62.8 50.7 80.8 <![CDATA[AUC 0-t ]]> h*ng / mL 47.1 25.2 53.5 <![CDATA[AUC 0-inf ]]> h*ng / mL 50.0 26.3 52.6 F(％) / 0.997 0.525 52.7 <![CDATA[AUC 0-t / AUC 0-inf ]]> / 0.935 0.0299 3.20

[0076] Table 5. PK parameters of SD rats administered 10 mg / kg enlicacin sublingual formulation (Example 3 complete prescription group)

[0077] <![CDATA[t 1 / 2 ]]> h 0.563 0.100 17.8 <![CDATA[T max ]]> h 0.0833 NA NA <![CDATA[C max ]]> ng / mL 3053 1064 34.9 <![CDATA[AUC 0-t ]]> h*ng / mL 2702 597 22.1 <![CDATA[AUC 0-inf ]]> h*ng / mL 2726 608 22.3 F(％) / 54.4 12.0 22.1 <![CDATA[AUC 0-t / AUC 0-inf ]]> / 0.991 0.00541 0.546

[0078] Table 6. PK parameters of SD rats administered 10 mg / kg enlical preparation (Example 3 Incomplete prescription group A)

[0079] <![CDATA[t 1 / 2 ]]> h 0.669 0.150 22.4 <![CDATA[T max ]]> h 0.0833 NA NA <![CDATA[C max ]]> ng / mL 2002 998 49.9 <![CDATA[AUC 0-t ]]> h*ng / mL 1586 368 23.2 <![CDATA[AUC 0-inf ]]> h*ng / mL 1658 376 22.7 F(％) / 33.1 8.5 25.7 <![CDATA[AUC 0-t / AUC 0-inf ]]> / 0.957 0.00682 0.713

[0080] Table 7. PK parameters of SD rats administered 10 mg / kg enlical preparation (Example 3 Incomplete prescription group B).

[0081] <![CDATA[t 1 / 2 ]]> h 0.643 0.201 31.3 <![CDATA[T max ]]> h 0.0833 NA NA <![CDATA[C max ]]> ng / mL 1458 526 36.1 <![CDATA[AUC 0-t ]]> h*ng / mL 879 202 23.0 <![CDATA[AUC 0-inf ]]> h*ng / mL 901 218 24.2 F(％) / 18.0 5.1 28.3 <![CDATA[AUC 0-t / AUC 0-inf ]]> / 0.976 0.00789 0.808

[0082] Table 8. PK parameters of SD rats administered 10 mg / kg enlical preparation (Example 3 incomplete prescription group C)

[0083] <![CDATA[t 1 / 2 ]]> h 0.811 0.292 36.0 <![CDATA[T max ]]> h 0.0833 NA NA <![CDATA[C max ]]> ng / mL 103 38.9 37.8 <![CDATA[AUC 0-t ]]> h*ng / mL 68.5 21.1 30.8 <![CDATA[AUC 0-inf ]]> h*ng / mL 72.3 19.8 27.4 F(％) / 1.44 0.337 23.4 <![CDATA[AUC 0-t / AUC 0-inf ]]> / 0.947 0.0318 3.36

[0084] Table 9. PK parameters of SD rats administered 10 mg / kg enlicacin sublingual formulation (Formulation group of Example 1).

[0085]

[0086]

[0087] Table 10 PK parameters of SD rats administered 10 mg / kg enlicacin sublingual formulation (Formulation group of Example 2)

[0088] <![CDATA[t 1 / 2 ]]> h 0.645 0.247 38.3 <![CDATA[T max ]]> h 0.0833 NA NA <![CDATA[C max ]]> ng / mL 2906 901 31.0 <![CDATA[AUC 0-t ]]> h*ng / mL 2562 826 32.2 <![CDATA[AUC 0-inf ]]> h*ng / mL 2594 795 30.6 F(％) / 51.7 13.8 26.7 <![CDATA[AUC 0-t / AUC 0-inf ]]> / 0.988 0.00913 0.924

[0089] Table 11 PK parameters of SD rats administered 10 mg / kg enlical preparation (Formulation group of Example 4)

[0090] <![CDATA[t 1 / 2 ]]> h 0.686 0.235 34.3 <![CDATA[T max ]]> h 0.0833 NA NA <![CDATA[C max ]]> ng / mL 1028 411 40.0 <![CDATA[AUC 0-t ]]> h*ng / mL 678 256 37.8 <![CDATA[AUC 0-inf ]]> h*ng / mL 712 268 37.6 F(％) / 14.2 4.5 31.7 <![CDATA[AUC 0-t / AUC 0-inf ]]> / 0.952 0.0894 9.4

[0091] Experimental results:

[0092] Absolute bioavailability was calculated using the mean area under the curve for the intravenous injection group as 100%. The bioavailability of enricacin in the oral gavage group was approximately 1%, which is close to the 2.7%–4% reported in the literature (Niel C. Hoglen, et al., 2004). This confirms that enricacin has low oral bioavailability and a severe first-pass effect in the liver.

[0093] Enricacin sublingual formulation (Example 3 complete prescription group) is rapidly absorbed, reaching peak plasma concentration within 5 minutes, with a bioavailability of 54.4%, which is more than 50 times higher than that of oral gavage. Literature reports (Niel C. Hoglen, et al., 2004) that the bioavailability of enricacin via intraperitoneal injection is 49%, indicating that the bioavailability of the sublingual formulation is comparable to that of intraperitoneal injection.

[0094] Compared to the sublingual formulation of Enrica (Example 3 Complete Prescription Group):

[0095] The Cmax value of the incomplete formulation A (containing only the absence of the solubilizing sodium taurocholate) of Enricacin in Example 3 was reduced, and the bioavailability was 33.1%, which is about half that of the complete formulation. This indicates that the solubilizing sodium taurocholate plays an important role in improving the absorption of the Enricacin sublingual formulation.

[0096] In Example 3, the Cmax value of the incomplete formulation group B of the sublingual enricacin preparation (which only did not contain the penetration enhancer sodium 8-(2-hydroxybenzamido)octanoate) was significantly reduced, and the bioavailability was 18.0%, which was about one-third of that of the complete formulation group. This indicates that the penetration enhancer sodium 8-(2-hydroxybenzamido)octanoate plays an important role in improving the absorption of the sublingual enricacin preparation, and its effect is greater than that of the solubilizer sodium taurocholate.

[0097] The pharmacokinetic characteristics of the incomplete formulation group C of the sublingual enricacin preparation of Example 3 (which only did not contain the solubilizer sodium taurocholate and the penetration enhancer sodium 8-(2-hydroxybenzamido)octanoate) were similar to those of the oral gavage preparation. However, the Cmax was low, and the bioavailability was 1.44%, which was comparable to that of the oral gavage preparation. This was nearly 40 times less than the bioavailability of the sublingual enricacin preparation (the complete formulation group of Example 3), indicating that the solubilizer sodium taurocholate and the penetration enhancer sodium 8-(2-hydroxybenzamido)octanoate play a key role in improving the absorption of the sublingual enricacin preparation.

[0098] The sublingual formulations of enricavirin in Examples 1 and 2 were rapidly absorbed, reaching peak plasma concentration within 5 minutes, with bioavailability exceeding 50%, specifically 50.8% and 51.7%, respectively. This represents an approximately 50-fold increase in bioavailability compared to oral gavage. Literature reports (Niel C. Hoglen, et al., 2004) that the bioavailability of enricavirin administered intraperitoneally is 49%, while the bioavailability of the sublingual formulations in Examples 1 and 2 is comparable to that of intraperitoneal injection.

[0099] In the sublingual formulation of enricasan in Example 4, the amounts of enricasan, sodium taurocholate, and sodium 8-(2-hydroxybenzamido)octanoate were lower, resulting in a significantly reduced Cmax value and a bioavailability of 14.2%, approximately one-third of the formulations in Examples 1 and 2. This indicates that the formulation ratio of enricasan, sodium taurocholate, and sodium 8-(2-hydroxybenzamido)octanoate also has a significant impact on bioavailability.

[0100] The bioavailability of the endocardine sublingual formulation in Example 3 (complete prescription group) reached 54.4%, comparable to the reported intraperitoneal injection bioavailability and significantly higher than that of the incomplete prescription groups A (excluding sodium taurocholate, the solubilizer), B (excluding sodium 8-(2-hydroxybenzamido)octanoate, and C. Furthermore, the bioavailability and Cmax value of Example 3 were slightly higher than those of Examples 1-2, indicating the best efficacy. Therefore, sodium taurocholate and sodium 8-(2-hydroxybenzamido)octanoate play a crucial role in improving the absorption of endocardine sublingual formulations. When used in combination, they significantly increase the solubility of endocardine and improve its mucosal absorption.

[0101] Example 6

[0102] Comparative study on the bioavailability of different types of solubilizers and penetration enhancers in pharmaceutical formulations:

[0103] In Example 3, the types of solubilizers and penetration enhancers in the formulation were replaced, while other components remained unchanged. Bioavailability studies were conducted according to the method in Example 5. The bioavailability results of sublingual formulations containing different types of solubilizers and penetration enhancers are shown in Table 9 below:

[0104] Table 9. Bioavailability results of sublingual formulations containing different types of solubilizers and penetration enhancers.

[0105] 1 Sodium taurocholate, sodium 8-(2-hydroxybenzamido)octanoate 54.4％ 2 Polyvinylpyrrolidone K30, Sodium 8-(2-hydroxybenzamido)octanoate 42.1％ 3 Polyvinylpyrrolidone K30, Caprylic / Capric Acid / Capric Acid Polyethylene Glyceryl Ester 32.8％ 4 Sodium taurocholate, ethanol 23.5％ 5 Soybean oil, sodium lauryl sulfate 21.8％ 6 Cyclodextrin, peppermint oil 23.1％

[0106] As shown in Table 9, different types of solubilizers and penetration enhancers have different bioavailability for sublingual enlical formulations. Among them, the highest bioavailability (54.4%) was achieved when sodium taurocholate, a solubilizer, and sodium 8-(2-hydroxybenzamido)octanoate, a penetration enhancer, were used together.

[0107] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0108] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A sublingual preparation of enlicacin, characterized in that, The Enrica sublingual formulation, by weight, is prepared from raw materials comprising the following components: Enriched with 2.5-4 servings 5-7 parts of co-solvent 4-7 parts of penetration enhancer 100-120 parts of filler 12-17 parts disintegrant Flavoring agent 0.8~1.2 parts 4-6 parts of glidin; The solvent is sodium taurocholate, and the penetration enhancer is sodium 8-(2-hydroxybenzamido)octanoate.

2. The sublingual preparation of Enrica as described in claim 1, characterized in that, Each unit weight of the enricane sublingual preparation is 25-500 mg.

3. The sublingual preparation of Enrica as described in claim 2, characterized in that, Each unit weight of the enricane sublingual preparation is 25-400 mg.

4. The sublingual preparation of Enrica as described in claim 3, characterized in that, Each unit weight of the enricane sublingual preparation is 25-200 mg.

5. The sublingual preparation of Enrica as described in claim 1, characterized in that, The filler is one or a combination of mannitol, sorbitol, polyethylene glycol 6000, lactose, microcrystalline cellulose, xylitol, cyclodextrin, glucose, and modified starch.

6. The sublingual preparation of Enrica as described in claim 5, characterized in that, The filler is one or a combination of mannitol, sorbitol, polyethylene glycol 6000, lactose, and microcrystalline cellulose.

7. The sublingual preparation of Enrica as described in claim 1, characterized in that, The disintegrant is one or a combination of sodium carboxymethyl starch, crospovidone, crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

8. The sublingual preparation of Enrica as described in claim 7, characterized in that, The disintegrant is one or a combination of sodium carboxymethyl starch and crospovidone.

9. The sublingual preparation of Enrica as described in claim 1, characterized in that, The flavoring agent is one or a combination of cyclamate, menthol, glycyrrhizin, steviol glycoside, fumaric acid, citric acid, tartaric acid, lactic acid, malic acid, and succinic acid.

10. The sublingual preparation of Enrica as described in claim 9, characterized in that, The flavoring agent is one or a combination of cyclamate, citric acid, and lactic acid.

11. The sublingual preparation of Enrica as described in claim 1, characterized in that, The gliding agent is one or a combination of magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, and sodium dodecyl sulfate.

12. The sublingual formulation of Enrica as described in claim 11, characterized in that, The gliding agent is magnesium stearate.

13. A method for preparing a sublingual formulation of enricavirin according to any one of claims 1 to 12, characterized in that, Includes the following steps: S1. Dissolve enrikacin, sodium taurocholate, and sodium 8-(2-hydroxybenzamido)octanoate in water to obtain an aqueous solution; S2. Add filler and disintegrant to the aqueous solution to prepare soft material, sieve to make granules, and dry to obtain whole granules; S3. Add flavoring agent and flow aid to the granules, mix well, and compress into tablets to obtain the Enrica sublingual preparation.

Images