A hydroxysafflor yellow A pharmaceutical composition, a preparation method and application thereof

Abstract

The application discloses a hydroxysafflor yellow A pharmaceutical composition, a preparation method and application thereof. Specifically, the application discloses a hydroxysafflor yellow A pharmaceutical composition which comprises hydroxysafflor yellow A, an absorption promoter and an absorption aid. The application realizes synchronous release of the hydroxysafflor yellow A and the absorption promoter by adding the absorption aid, so that the hydroxysafflor yellow A pharmaceutical composition has higher oral bioavailability. The preparation method of the hydroxysafflor yellow A pharmaceutical composition is simple and easy to operate, has lower production cost, and is beneficial to large-scale production and quality control.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a hydroxysaffron yellow pigment A pharmaceutical composition, its preparation method, and its application. Background Technology

[0002] Hydroxysafflor yellow A (hereinafter referred to as "hydroxyA" or "HSYA"), chemically named 2,5-dihydroxy-6-[(1E,2E)-1-hydroxy-3-(4-hydroxyphenyl)prop-2-enyl]-2-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-3,4,5,6-tetrahydro-2H-pyran-2-yl]-4-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-3,4,5,6-tetrahydro-2H-pyran-2-yl]cyclohex-4-en-1,3-dione, has the chemical formula C1. 27 H 32 O 16 It has a molecular weight of 612.5. Its structural formula is shown in Formula 1. It is a water-soluble compound with a monochalcone glycoside structure extracted and isolated from the traditional Chinese medicine safflower.

[0003] Formula 1

[0004] Hydroxysaffron yellow A is the main active ingredient of safflower, a traditional Chinese medicine. It is the most abundant and most effective monomer among safflower yellow pigments, and one of the few raw materials for Chinese medicine injections used clinically. Clinically, it is used to treat cardiovascular and cerebrovascular diseases such as myocardial ischemia, cerebral ischemia, coronary heart disease, and cerebral thrombosis, all administered intravenously. Safflower yellow for injection is currently the only marketed drug preparation with hydroxysaffron yellow A as the main active ingredient. Each 50 mg vial contains 42.5 mg of hydroxysaffron yellow A and is mainly used for stable exertional angina pectoris of grades I, II, and III caused by blood stasis.

[0005] The administration method for injectable safflower yellow pigment is intravenous infusion, with a single dose taking two hours, causing significant inconvenience to patients. Compared to intravenous infusion, oral administration offers better patient compliance and higher safety. However, due to factors such as poor permeability and easy degradation in the gastrointestinal environment, its oral absorption is extremely poor, with a bioavailability of only about 1%. Oral administration is difficult to apply in clinical practice, and there are currently no oral formulations of hydroxysafflower yellow pigment A on the market.

[0006] To improve the oral absorption of hydroxysaffron yellow A, Zhang Yajun et al. designed and prepared nano-flexible liposomes of hydroxysaffron yellow A, increasing its mucosal cumulative permeability to 1.65 times that of the raw drug. Liu Fuhe et al. combined hydroxysaffron yellow A with phospholipids and used a self-microemulsion drug delivery system to improve the drug's lipid solubility and in vivo absorption; in rats, the area under the drug-time curve (AUC0-t) was 2.93 times higher than that of the pure drug aqueous solution. Li et al. believed that lipid formulations of hydroxysaffron yellow A can significantly reduce its excretion in feces and bile, thereby improving its bioavailability. Furthermore, the addition of 0.02 mg / mL and 0.01 mg / mL of Ligusticum chuanxiong volatile oil was reported to effectively increase the apparent permeability of hydroxysaffron yellow A by 5.34 times and 4.62 times, respectively. The hydroxysaffron yellow A-chitosan complex was reported to have increased relative bioavailability by 4.76 times compared to the pure drug in a rat pharmacokinetic model. Patent (CN113768871A) uses glucose-choline chloride as a co-solvent, increasing the oral bioavailability of hydroxysafflower yellow A by 3.27 times in a rat model. Patent (CN111803651A) uses a composition of the absorption enhancer N-(8-[2-hydroxybenzoyl]-amino)octanoic acid sodium (SNAC) and polymer EPO to increase the oral absorption of the drug by 10.4 times. Patent (CN109044971A) provides a self-microemulsion technology to enhance the oral absorption of the drug. Patent (CN102188470A) uses a physical mixture of safflower phospholipids to enhance the oral absorption of safflower extract. However, the methods reported above have disadvantages such as complex preparation processes, low drug loading, or limited improvement in bioavailability. Patents (CN118178301A) and (CN103127009A) use a composition of an absorption enhancer and a mucosal adhesive for administration via the oral mucosa. However, the absorption rate of drugs through the oral mucosa is extremely rapid, making it impossible to achieve bioequivalence with intravenous infusion. Furthermore, compliance with sublingual administration is slightly lower than with direct oral administration. Patents (CN113995729A, CN102872002A, CN101181282A) utilize semi-solid and oily excipients to promote drug absorption, but this method offers limited improvement in apparent drug permeability, and semi-solid oily excipients are often prone to oxidation and water absorption, leading to stability issues.

[0007] Therefore, there is a significant clinical need and market prospect for an oral formulation of hydroxysaffron yellow pigment A with high bioavailability and sustained-release effect. Summary of the Invention

[0008] To address the deficiencies described in the prior art, this invention provides a hydroxysaffron yellow pigment A pharmaceutical composition, its preparation method, and its applications. The hydroxysaffron yellow pigment A pharmaceutical composition of this invention has high oral bioavailability, meeting clinical medication needs; the preparation method of the hydroxysaffron yellow pigment A pharmaceutical composition of this invention is simple in process and has controllable quality, meeting the requirements for industrial-scale production.

[0009] The present invention solves the above-mentioned technical problems through the following technical solutions:

[0010] This invention discloses a pharmaceutical composition of hydroxysaffron yellow A, comprising hydroxysaffron yellow A, an absorption enhancer, and an absorption aid;

[0011] The absorption enhancer is one or more of the following: sodium caprylate, sodium decanoate, sodium laurylate, glyceryl monocaprylate, glyceryl tricaprylate, glyceryl monocaprylate, glyceryl laurylate, palmitoylcarnitine, lauroylcarnitine chloride, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium taurodeoxycholate, lauroyl maltoside, n-tetradecyl BD-maltoside, dodecyl-β-D-maltoside, sucrose laurate, ethoxylated sugar ester, alkylphenol polyoxyethylene ether, polyoxyethylene oil-based ether, polyoxyethylene castor oil, sodium lauryl sulfate, methyl 5-methoxysalicylate, sodium salicylate, disodium glycerophosphate hydrate, AT-1002, trimethyl chitosan, and sodium 8-(2-hydroxybenzamido)caprylate (SNAC).

[0012] The absorption enhancer is one or more of the following: sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, povidone, carbomer, alginate, deacetylated chitosan, polymethyl methacrylate, ethyl cellulose, polyethylene, polyvinyl chloride, ethylene-vinyl acetate copolymer, and silicone rubber.

[0013] In one embodiment, the absorption promoter is one or more selected from sodium caprylate, dodecyl-β-D-maltose, sodium deoxycholate, sodium decanoate, SNAC, sucrose laurate, sodium lauryl sulfate, sodium cholate, glyceryl laurate, sodium laurate, monocaprylyl glyceryl ester, tricaprylyl glyceryl ester, monodecanoate glyceryl ester, palmitoylcarnitine, lauroylcarnitine chloride, and n-tetradecyl BD-maltose; preferably, the absorption promoter is one or more selected from sodium caprylate, sodium decanoate, dodecyl-β-D-maltose, and sucrose laurate; more preferably, the absorption promoter is sodium decanoate and / or dodecyl-β-D-maltose.

[0014] In one embodiment, the absorption enhancer is one or more of hydroxypropyl methylcellulose, ethylcellulose, polyethylene, sodium carboxymethyl cellulose, polyvinyl chloride, povidone, ethylene-vinyl acetate copolymer, carbomer, and sodium alginate; preferably, the absorption enhancer is hydroxypropyl methylcellulose and / or ethylcellulose, for example, hydroxypropyl methylcellulose or a combination of hydroxypropyl methylcellulose and ethylcellulose; when the absorption enhancer is hydroxypropyl methylcellulose and ethylcellulose, the mass ratio of hydroxypropyl methylcellulose to ethylcellulose is preferably (2-20):1, for example, 3.3:1, 6.7:1, 10:1, 13.3:1, 2:1, 4:1, 6:1, 8:1, or 5.9:1.

[0015] In one embodiment, the mass ratio of hydroxysaffron yellow A to the absorption promoter is 1:(0.05-15), for example 1:(0.1-10), or even 1:0.1, 1:1, 1:2, 1:3, 1:9 and 1:10; preferably, the mass ratio of hydroxysaffron yellow A to the absorption promoter is 1:(1-10).

[0016] In one embodiment, the hydroxysaffron yellow A pharmaceutical composition comprises the following components in weight fractions: 3-50% hydroxysaffron yellow A, 35-85% an absorption enhancer, and 5-50% an absorption aid.

[0017] In this invention, the mass fraction of each component in the hydroxysaffron yellow pigment A pharmaceutical composition refers to the mass percentage of each component relative to the total mass of the hydroxysaffron yellow pigment A pharmaceutical composition.

[0018] In one embodiment, the mass fraction of hydroxysaffron yellow pigment A is 8-45%; more preferably, the mass fraction of hydroxysaffron yellow pigment A is 8-22%.

[0019] In one embodiment, the mass fraction of the absorption promoter is 40-79%; more preferably, the mass fraction of the absorption promoter is 64-79%.

[0020] In one embodiment, the mass fraction of the absorption aid is preferably 13-33%; more preferably, the mass fraction of the absorption aid is 12-14%.

[0021] In one embodiment, the hydroxysaffron yellow A pharmaceutical composition comprises the following components by mass fraction: 8-45% hydroxysaffron yellow A, 40-79% an absorption enhancer, and 13-33% an absorption aid; wherein the absorption enhancer is one or more of sodium caprylate, sodium decanoate, dodecyl-β-D-maltodextrin, and sucrose laurate; and the absorption aid is hydroxypropyl methylcellulose and / or ethylcellulose.

[0022] In one embodiment, the hydroxysaffron yellow A pharmaceutical composition comprises the following components by mass fraction: 8-22% hydroxysaffron yellow A, 64-79% an absorption enhancer, and 12-14% an absorption aid; wherein the absorption enhancer is sodium decanoate and / or dodecyl-β-D-maltodextrin; and the absorption aid is hydroxypropyl methylcellulose and / or ethylcellulose.

[0023] In one embodiment, the hydroxysaffron yellow A pharmaceutical composition further comprises other pharmaceutical excipients, such as lubricants.

[0024] In one embodiment, the lubricant is magnesium stearate.

[0025] In one embodiment, the mass fraction of the lubricant is 0.1-1%, for example 0.4-0.6%, or even 0.5%.

[0026] In one embodiment, the hydroxysaffron yellow A pharmaceutical composition comprises hydroxysaffron yellow A, an absorption enhancer, an absorption aid, and a lubricant, or comprises hydroxysaffron yellow A, an absorption enhancer, an absorption aid, a lubricant, and an enteric-coated material.

[0027] In one embodiment, the hydroxysaffron yellow A pharmaceutical composition further comprises an enteric-coated material.

[0028] In one embodiment, the enteric material is one or more of acrylic resin polymers, hydroxypropyl methylcellulose succinate (HPMCAS), hydroxypropyl methylcellulose titanate (HPMCP), and cellulose acetate ester (CAP).

[0029] In one embodiment, the hydroxysaffron yellow A pharmaceutical composition comprises the following components by mass fraction:

[0030] Formula 1: 21.6% hydroxysaffron yellow pigment A, 61.9% sodium decanoate, 3.0% ethyl cellulose, 10.0% hydroxypropyl methylcellulose, 0.5% magnesium stearate;

[0031] Formula 2: 19.1% hydroxysaffron yellow pigment A, 57.4% sodium decanoate, 3.0% ethyl cellulose, 20.0% hydroxypropyl methylcellulose, 0.5% magnesium stearate;

[0032] Formula 3: 6.0% hydroxysaffron yellow pigment A, 60.5% sodium decanoate, 3.0% ethyl cellulose, 30.0% hydroxypropyl methylcellulose, 0.5% magnesium stearate;

[0033] Formula 4: 5.1% hydroxysaffron yellow pigment A, 51.4% sodium decanoate, 3.0% ethyl cellulose, 40.0% hydroxypropyl methylcellulose, 0.5% magnesium stearate;

[0034] Formula 5: 7.7% hydroxysaffron yellow pigment A, 76.8% sodium decanoate, 5.0% ethyl cellulose, 10.0% hydroxypropyl methylcellulose, 0.5% magnesium stearate;

[0035] Formula 6: 6.8% hydroxysaffron yellow pigment A, 67.7% sodium decanoate, 5.0% ethyl cellulose, 20.0% hydroxypropyl methylcellulose, 0.5% magnesium stearate;

[0036] Formula 7: 5.9% hydroxysaffron yellow pigment A, 58.6% sodium decanoate, 5.0% ethyl cellulose, 30.0% hydroxypropyl methylcellulose, 0.5% magnesium stearate;

[0037] Formula 8: 5.0% hydroxysaffron yellow pigment A, 49.5% sodium decanoate, 5.0% ethyl cellulose, 40.0% hydroxypropyl methylcellulose, 0.5% magnesium stearate;

[0038] Formula 9: 5.0% hydroxysaffron yellow pigment A, 49.5% sodium decanoate, 5.0% polyethylene, 40.0% sodium carboxymethyl cellulose, 0.5% magnesium stearate;

[0039] Formula 10: 5.0% hydroxysaffron yellow pigment A, 49.5% sodium decanoate, 5.0% polyvinyl chloride, 40.0% povidone, 0.5% magnesium stearate;

[0040] Formula 11: 5.0% hydroxysaffron yellow pigment A, 49.5% sodium decanoate, 5.0% ethylene-vinyl acetate copolymer, 20.0% carbomer, 20.0% sodium alginate, 0.5% magnesium stearate;

[0041] Formula 12: 8.0% hydroxysaffron yellow pigment A, 79.0% sodium decanoate, 3.0% ethyl cellulose, 10.0% hydroxypropyl methylcellulose;

[0042] Formula 13: 9.6% hydroxysaffron yellow pigment A, 76.9% sodium decanoate, 3.0% ethyl cellulose, 10.0% hydroxypropyl methylcellulose, 0.5% magnesium stearate;

[0043] Formula 14: 22.4% hydroxysaffron yellow pigment A, 67.1% sodium decanoate, 10.0% hydroxypropyl methylcellulose, 0.5% magnesium stearate;

[0044] Formula 15: 19.1% hydroxysaffron yellow pigment A, 57.4% sodium decanoate, 20.0% hydroxypropyl methylcellulose, 3.0% ethylcellulose, 0.5% magnesium stearate;

[0045] Formula 16: 16.6% hydroxysaffron yellow pigment A, 49.9% sodium decanoate, 30.0% hydroxypropyl methylcellulose, 3.0% ethylcellulose, 0.5% magnesium stearate;

[0046] Formula 17: 21.1% hydroxysaffron yellow pigment A, 63.4% sodium decanoate, 10.0% hydroxypropyl methylcellulose, 5.0% ethylcellulose, 0.5% magnesium stearate;

[0047] Formula 18: 16.1% hydroxysaffron yellow pigment A, 48.4% sodium decanoate, 30.0% hydroxypropyl methylcellulose, 5.0% ethylcellulose, 0.5% magnesium stearate;

[0048] Formula 19: 21.75% hydroxysaffron yellow pigment A, 65.25% dodecyl-β-D-maltodextrin, 10.0% hydroxypropyl methylcellulose, 3.0% ethylcellulose;

[0049] Formula 20: 21.75% hydroxysaffron yellow pigment A, 65.25% sodium decanoate, 10.0% hydroxypropyl methylcellulose, 3.0% ethylcellulose;

[0050] Formula 21: 21.75% hydroxysaffron yellow pigment A, 65.25% sucrose laurate, 10.0% hydroxypropyl methylcellulose, 3.0% ethylcellulose;

[0051] Formula 22: 43.5% hydroxysaffron yellow pigment A, 43.5% dodecyl-β-D-maltodextrin, 10.0% hydroxypropyl methylcellulose, 3.0% ethylcellulose;

[0052] Formula 23: 29.0% hydroxysaffron yellow pigment A, 58.0% dodecyl-β-D-maltodextrin, 10.0% hydroxypropyl methylcellulose, 3.0% ethylcellulose;

[0053] Formula 24: 8.7% hydroxysaffron yellow pigment A, 78.3% dodecyl-β-D-maltodextrin, 10.0% hydroxypropyl methylcellulose, and 3.0% ethylcellulose.

[0054] In one embodiment, the dosage form of the hydroxysaffron yellow A pharmaceutical composition is tablets, capsules, or pellets, preferably tablets or capsules; more preferably capsules; the capsules are preferably enteric-coated capsules.

[0055] In this invention, the capsule shell of the capsule is a pharmaceutically acceptable capsule shell, such as a gelatin capsule shell or an enteric-coated capsule shell.

[0056] The present invention also provides a method for preparing the hydroxysaffron yellow pigment A pharmaceutical composition as described above, which includes the following steps: mixing the hydroxysaffron yellow pigment A, the absorption promoter and the absorption aid, granulating, and compressing into tablets or filling capsules.

[0057] In one embodiment, the capsule is an enteric-coated capsule.

[0058] In one embodiment, when the hydroxysaffron yellow pigment A pharmaceutical composition contains a lubricant, the preparation method includes the following steps: mixing the hydroxysaffron yellow pigment A, the absorption promoter, and the absorption aid, granulating, then mixing with the lubricant, and finally tableting or filling capsules.

[0059] In one embodiment, the granulation is either wet granulation or dry granulation, preferably wet granulation.

[0060] In one embodiment, when the absorption enhancer contains ethyl cellulose, the ethyl cellulose is present in the form of a solution. The solution is, for example, an alcohol solution, preferably an ethanol solution, more preferably an 80% ethanol solution; the mass fraction of ethyl cellulose in the ethyl cellulose solution is, for example, 2-5%, or, for example, 3%; the mass fraction is the percentage of the mass of ethyl cellulose relative to the total mass of the ethyl cellulose solution.

[0061] The present invention also provides a pharmaceutical formulation comprising the hydroxysaffron yellow pigment A pharmaceutical composition as described above.

[0062] In one embodiment, the dosage form of the pharmaceutical preparation is a tablet, capsule, or droplet, preferably a tablet or capsule; more preferably a capsule; the capsule is preferably an enteric-coated capsule.

[0063] In this invention, the capsule shell of the capsule is a pharmaceutically acceptable capsule shell, such as a gelatin capsule shell or an enteric-coated capsule shell.

[0064] The present invention also provides the use of the aforementioned hydroxysaffron yellow A pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of cardiovascular and cerebrovascular diseases; wherein the cardiovascular and cerebrovascular diseases may be one or more of myocardial ischemia, cerebral ischemia, coronary heart disease, ischemic stroke, stroke and cerebral thrombosis.

[0065] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. They are all substances contained in pharmaceutical preparations, excluding the active ingredient.

[0066] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0067] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0068] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0069] The reagents and raw materials used in this invention are all commercially available.

[0070] The positive and progressive effects of this invention are as follows:

[0071] (1) By employing a technology that promotes the intestinal permeation of hydroxysaffron yellow A and by adding an absorption enhancer, this invention significantly improves the transmembrane transport capacity of hydroxysaffron yellow A in the small intestine. This improvement significantly enhances the absolute oral bioavailability of hydroxysaffron yellow A;

[0072] (2) The present invention uses absorption-enhancing materials, which can promote the simultaneous release of drugs and absorption enhancers, thereby further improving the oral absorption of hydroxysaffron yellow A and significantly improving the absolute oral bioavailability of hydroxysaffron yellow A.

[0073] (3) The hydroxysaffron yellow pigment A pharmaceutical composition provided by the present invention, after increasing the dosage, can achieve bioequivalence of a single dose in the pharmacokinetic curve compared with the intravenous drip administration method;

[0074] (4) The preparation process of the present invention is simple and easy to implement, with low production cost, and is conducive to large-scale production and quality control. Attached Figure Description

[0075] Figure 1 The apparent permeability coefficients of the drug in samples 4, 5, 6, 7, 8, 9, 10, and 11 were determined for hydroxysaffron yellow A and ranitidine hydrochloride (hypotonic positive control). Value graph.

[0076] Figure 2The figures represent in vitro release behavior curves, where: A is the in vitro release behavior curve of hydroxysaffron yellow A and the absorption promoter in Example 6; B is the in vitro release behavior curve of hydroxysaffron yellow A and the absorption promoter in Example 43; C is the in vitro release behavior curve of hydroxysaffron yellow A and the absorption promoter in Example 44; D is the in vitro release behavior curve of hydroxysaffron yellow A and the absorption promoter in Example 45; E is the in vitro release behavior curve of hydroxysaffron yellow A and the absorption promoter in Example 46; F is the in vitro release behavior curve of hydroxysaffron yellow A and the absorption promoter in Example 47; and G is the superposition of the cumulative drug release curves of the above examples.

[0077] Figure 3 The drug-time curves for rats after oral administration of hydroxysaffron yellow A aqueous solution via gavage, and in Examples 6 and 44.

[0078] Figure 4 In the figure, 'a' represents the change in concentration of hydroxysaffron yellow A in the gastrointestinal tract relative to pH over time; 'b' represents the change in concentration in simulated gastrointestinal fluid over time.

[0079] Figure 5 Drug-time curves after intravenous injection of hydroxysaffron yellow A, oral administration of hydroxysaffron yellow A, and oral administration of Examples 20 and 30.

[0080] Figure 6 The drug-time curves for rats after oral administration of hydroxysaffron yellow A aqueous solution and in Examples 48, 49, 50, and 51.

[0081] Figure 7 The drug-time curves for oral administration of hydroxysaffron yellow A aqueous solution to rats and for oral administration in Examples 52, 53, and 54.

[0082] Figure 8 Drug-time curves after intravenous infusion of hydroxysaffron yellow A and oral administration of Example 31 to beagle dogs. Detailed Implementation

[0083] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0084] In this embodiment of the invention, the capsules used are enteric-coated empty capsules, size 0, Aoquanjian®, produced by Shanxi Guangsheng Capsule Co., Ltd.

[0085] Preparation Examples 1-54

[0086] Example 1

[0087] The ratio of hydroxysaffron yellow A to sodium caprylate in the hydroxysaffron yellow A pharmaceutical composition is 1:10.

[0088] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: Weigh 100.0 mg of hydroxysaffron yellow A and 1000.0 mg of sodium caprylate, mix them simply, and then granulate and compress them into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0089] Example 2

[0090] The ratio of hydroxysaffron yellow A to dodecyl-β-D-maltodextrin in the hydroxysaffron yellow A pharmaceutical composition is 1:1.

[0091] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 1000.0 mg of hydroxysaffron yellow A and 1000.0 mg of dodecyl-β-D-maltodextrin are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0092] Example 3

[0093] The ratio of hydroxysaffron yellow A to dodecyl-β-D-maltodextrin in the hydroxysaffron yellow A pharmaceutical composition is 1:2.

[0094] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 500.0 mg of hydroxysaffron yellow A and 1000.0 mg of dodecyl-β-D-maltodextrin are weighed, simply mixed, granulated, and tableted to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0095] Example 4

[0096] The ratio of hydroxysaffron yellow pigment A to sodium deoxycholate in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:3.

[0097] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 250.0 mg of hydroxysaffron yellow A and 750.0 mg of sodium deoxycholate are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0098] Example 5

[0099] The ratio of hydroxysaffron yellow A to dodecyl-β-D-maltodextrin in the hydroxysaffron yellow A pharmaceutical composition is 1:3.

[0100] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 250.0 mg of hydroxysaffron yellow A and 750.0 mg of dodecyl-β-D-maltodextrin are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0101] Example 6

[0102] The ratio of hydroxysaffron yellow pigment A to sodium decanoate in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:3.

[0103] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 250.0 mg of hydroxysaffron yellow A and 750.0 mg of sodium decanoate are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0104] Example 7

[0105] The ratio of hydroxysaffron yellow pigment A to SNAC in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:3.

[0106] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: Weigh 250.0 mg of hydroxysaffron yellow A and 750.0 mg of SNAC, mix them simply, and then granulate and compress them into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0107] Example 8

[0108] The ratio of hydroxysaffron yellow pigment A to sucrose laurate in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:3.

[0109] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 250.0 mg of hydroxysaffron yellow A and 750.0 mg of sucrose laurate are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0110] Example 9

[0111] The ratio of hydroxysaffron yellow A to sodium caprylate in the hydroxysaffron yellow A pharmaceutical composition is 1:3.

[0112] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: Weigh 250.0 mg of hydroxysaffron yellow A and 750.0 mg of sodium caprylate, mix them simply, and then granulate and compress them into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0113] Example 10

[0114] The ratio of hydroxysaffron yellow pigment A to sodium dodecyl sulfate in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:3.

[0115] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: Weigh 250.0 mg of hydroxysaffron yellow A and 750.0 mg of sodium dodecyl sulfate, mix them simply, and then granulate and compress them into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0116] Example 11

[0117] The ratio of hydroxysaffron yellow pigment A to sodium cholate in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:3.

[0118] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: Weigh 250.0 mg of hydroxysaffron yellow A and 750.0 mg of sodium cholate, mix them simply, and then granulate and compress them into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0119] Example 12

[0120] The ratio of hydroxysaffron yellow pigment A to glyceryl laurate in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:3.

[0121] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: Weigh 250.0 mg of hydroxysaffron yellow A and 750.0 mg of glyceryl laurate, mix them simply, and then granulate and compress them into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0122] Example 13

[0123] The ratio of hydroxysaffron yellow A to dodecyl-β-D-maltodextrin in the hydroxysaffron yellow A pharmaceutical composition is 1:9.

[0124] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 100.0 mg of hydroxysaffron yellow A and 900.0 mg of dodecyl-β-D-maltodextrin are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0125] Example 14

[0126] The ratio of hydroxysaffron yellow pigment A to sodium deoxycholate in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:3.

[0127] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 250.0 mg of hydroxysaffron yellow A and 750.0 mg of sodium deoxycholate are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0128] Example 15

[0129] The ratio of hydroxysaffron yellow pigment A to sodium decanoate in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:1.

[0130] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 1000.0 mg of hydroxysaffron yellow A and 1000.0 mg of sodium decanoate are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0131] Example 16

[0132] The ratio of hydroxysaffron yellow A to sodium decanoate in the hydroxysaffron yellow A pharmaceutical composition is 1:2.

[0133] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 500.0 mg of hydroxysaffron yellow A and 1000.0 mg of sodium decanoate are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0134] Example 17

[0135] The ratio of hydroxysaffron yellow A to sodium decanoate in the hydroxysaffron yellow A pharmaceutical composition is 1:9.

[0136] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: Weigh 100.0 mg of hydroxysaffron yellow A and 900.0 mg of sodium decanoate, mix them simply, and then granulate and compress them into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0137] Example 18

[0138] The ratio of hydroxysaffron yellow A to sodium decanoate in the hydroxysaffron yellow A pharmaceutical composition is 10:1.

[0139] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 1000.0 mg of hydroxysaffron yellow A and 100.0 mg of sodium decanoate are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0140] Example 19

[0141] The ratio of hydroxysaffron yellow A to sodium lauryl ester in the hydroxysaffron yellow A pharmaceutical composition is 10:1.

[0142] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 1000.0 mg of hydroxysaffron yellow A and 100.0 mg of sodium laurylate are weighed, simply mixed, granulated and compressed into tablets to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0143] Example 20

[0144] The ratio of hydroxysaffron yellow pigment A to sodium decanoate in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:3.

[0145] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 250.0 mg of hydroxysaffron yellow A and 750.0 mg of sodium decanoate are weighed, simply mixed, and then filled into enteric-coated empty capsules.

[0146] Example 21

[0147] The ratio of hydroxysaffron yellow pigment A to glyceryl monocaprylate in the pharmaceutical composition is 1:10.

[0148] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 100.0 mg of hydroxysaffron yellow A and 1000.0 mg of caprylic acid glyceride are weighed, simply mixed, granulated, and filled into enteric-coated empty capsules to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0149] Example 22

[0150] The ratio of hydroxysaffron yellow pigment A to trioctanoic acid glyceride in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:10.

[0151] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 100.0 mg of hydroxysaffron yellow A and 1000.0 mg of tricaprylic acid glyceride are weighed, simply mixed, granulated, and filled into enteric-coated empty capsules to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0152] Example 23

[0153] The ratio of hydroxysaffron yellow pigment A to monodecanoic acid glyceride in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:10.

[0154] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 100.0 mg of hydroxysaffron yellow A and 1000.0 mg of sodium decanoate are weighed, simply mixed, granulated, and filled into enteric-coated empty capsules to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0155] Example 24

[0156] The ratio of hydroxysaffron yellow pigment A to glyceryl laurate in the pharmaceutical composition is 1:10.

[0157] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 100.0 mg of hydroxysaffron yellow A and 1000.0 mg of glyceryl laurate are weighed, simply mixed, granulated, and filled into enteric-coated empty capsules to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0158] Example 25

[0159] The ratio of hydroxysaffron yellow pigment A to palmitoylcarnitine in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:10.

[0160] In this embodiment, the preparation process of the hydroxysaffron yellow A drug composition is as follows: 100.0 mg of hydroxysaffron yellow A and 1000.0 mg of palmitoylcarnitine are weighed, simply mixed, granulated, and filled into enteric-coated empty capsules to obtain the hydroxysaffron yellow A drug composition.

[0161] Example 26

[0162] The ratio of hydroxysaffron yellow pigment A to lauroyl carnitine chloride in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:10.

[0163] In this embodiment, the preparation process of the hydroxysaffron yellow pigment A pharmaceutical composition is as follows: 100.0 mg of hydroxysaffron yellow pigment A and 1000.0 mg of lauroyl carnitine chloride are weighed, simply mixed, granulated, and filled into No. 0 capsules to obtain the hydroxysaffron yellow pigment A pharmaceutical composition.

[0164] Example 27

[0165] The ratio of hydroxysaffron yellow pigment A to sodium cholate in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:10.

[0166] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 100.0 mg of hydroxysaffron yellow A and 1000.0 mg of sodium cholate are weighed, simply mixed, granulated, and filled into enteric-coated empty capsules to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0167] Example 28

[0168] The ratio of hydroxysaffron yellow pigment A to SNAC in the hydroxysaffron yellow pigment A pharmaceutical composition is 1:10.

[0169] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 100.0 mg of hydroxysaffron yellow A and 1000.0 mg of SNAC are weighed, simply mixed, granulated, and filled into enteric-coated empty capsules to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0170] Example 29

[0171] The ratio of hydroxysaffron yellow A to tetradecyl BD-maltodextrin in the hydroxysaffron yellow A pharmaceutical composition is 1:10.

[0172] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: 100.0 mg of hydroxysaffron yellow A and 1000.0 mg of n-tetradecyl BD-maltodextrin are weighed, simply mixed, granulated, and filled into enteric-coated empty capsules to obtain the hydroxysaffron yellow A pharmaceutical composition.

[0173] Example 30

[0174] The hydroxysaffron yellow A pharmaceutical composition contains 21.6% hydroxysaffron yellow A by mass, 61.9% sodium decanoate, 3.0% ethyl cellulose, 10.0% hydroxypropyl methylcellulose, and 0.5% magnesium stearate.

[0175] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: 648.0 mg of hydroxysaffron yellow A, 300.0 mg of hydroxypropyl methylcellulose, and 1857.0 mg of sodium decanoate were weighed, mixed, and then 3.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) was added to form a soft material. The soft material was then passed through a sieve to form uniformly sized particles, and then dried in a 50°C oven for 2 hours. Finally, 15.0 mg of magnesium stearate was added, and the mixture was filled into enteric-coated empty capsules to obtain the final product.

[0176] Example 31

[0177] The hydroxysaffron yellow A pharmaceutical composition contains 19.1% by weight of hydroxysaffron yellow A, 57.4% sodium decanoate, 3.0% ethyl cellulose, 20.0% hydroxypropyl methylcellulose, and 0.5% magnesium stearate.

[0178] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 573.8 mg of hydroxysaffron yellow A, 600.0 mg of hydroxypropyl methylcellulose, and 1721.3 mg of sodium decanoate. Mix the three ingredients and add 3.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to form a soft material. Pass the soft material through a sieve to form uniformly sized particles and dry them in a 50°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0179] Example 32

[0180] The hydroxysaffron yellow A pharmaceutical composition contains 6.0% by weight of hydroxysaffron yellow A, 60.5% sodium decanoate, 3.0% ethyl cellulose, 30.0% hydroxypropyl methylcellulose, and 0.5% magnesium stearate.

[0181] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 180.0 mg of hydroxysaffron yellow A, 900.0 mg of hydroxypropyl methylcellulose, and 1815.0 mg of sodium decanoate. Mix the three together and add 3.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50℃ oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0182] Example 33

[0183] The hydroxysaffron yellow A pharmaceutical composition contains 5.1% by weight of hydroxysaffron yellow A, 51.4% sodium decanoate, 3.0% ethyl cellulose, 40.0% hydroxypropyl methylcellulose, and 0.5% magnesium stearate.

[0184] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 153.0 mg of hydroxysaffron yellow A, 1200.0 mg of hydroxypropyl methylcellulose, and 1542.0 mg of sodium decanoate. Mix the three together and add 3.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50℃ oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0185] Example 34

[0186] The hydroxysaffron yellow A pharmaceutical composition contains 7.7% hydroxysaffron yellow A by mass, 76.8% sodium decanoate, 5.0% ethyl cellulose, 10.0% hydroxypropyl methylcellulose, and 0.5% magnesium stearate.

[0187] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 231.0 mg of hydroxysaffron yellow A, 300.0 mg of hydroxypropyl methylcellulose, and 2304.0 mg of sodium decanoate. Mix the three together and add 5.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50℃ oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0188] Example 35

[0189] The hydroxysaffron yellow A pharmaceutical composition contains 6.8% hydroxysaffron yellow A by mass, 67.7% sodium decanoate, 5.0% ethyl cellulose, 20.0% hydroxypropyl methylcellulose, and 0.5% magnesium stearate.

[0190] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 204.0 mg of hydroxysaffron yellow A, 600.0 mg of hydroxypropyl methylcellulose, and 2031.0 mg of sodium decanoate. Mix the three together and add 5.0 mL of ethyl cellulose solution (3.0% (w / w), solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50℃ oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0191] Example 36

[0192] The hydroxysaffron yellow A pharmaceutical composition contains 5.9% hydroxysaffron yellow A by weight, 58.6% sodium decanoate, 5.0% ethyl cellulose, 30.0% hydroxypropyl methylcellulose, and 0.5% magnesium stearate.

[0193] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 177.0 mg of hydroxysaffron yellow A, 900.0 mg of hydroxypropyl methylcellulose, and 1758.0 mg of sodium decanoate. Mix the three together and add 5.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50℃ oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0194] Example 37

[0195] The hydroxysaffron yellow A pharmaceutical composition contains 5.0% by weight of hydroxysaffron yellow A, 49.5% sodium decanoate, 5.0% ethyl cellulose, 40.0% hydroxypropyl methylcellulose, and 0.5% magnesium stearate.

[0196] In this embodiment, the preparation process of the hydroxysaffron yellow A pharmaceutical composition is as follows: Weigh 150.0 mg of hydroxysaffron yellow A, 1200.0 mg of hydroxypropyl methylcellulose, and 1485.0 mg of sodium decanoate. Mix the three together and add 5.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to form a soft material. Pass the soft material through a sieve to form uniformly sized particles and dry them in a 50℃ oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the sustained-release formulation of hydroxysaffron yellow A.

[0197] Example 38

[0198] The hydroxysaffron yellow A pharmaceutical composition contains 5.0% by weight of hydroxysaffron yellow A, 49.5% sodium decanoate, 5.0% polyethylene, 40.0% sodium carboxymethyl cellulose, and 0.5% magnesium stearate.

[0199] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 150.0 mg of hydroxysaffron yellow A, 1200.0 mg of sodium carboxymethyl cellulose, and 1485.0 mg of sodium decanoate. Mix the three together and add 5.0 mL of polyethylene solution (solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0200] Example 39

[0201] The hydroxysaffron yellow A pharmaceutical composition contains 5.0% by weight of hydroxysaffron yellow A, 49.5% sodium decanoate, 5.0% polyvinyl chloride, 40.0% povidone, and 0.5% magnesium stearate.

[0202] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 150.0 mg of hydroxysaffron yellow A, 1200.0 mg of povidone, and 1485.0 mg of sodium decanoate. Mix the three together and add 5.0 mL of polyvinyl chloride solution (solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0203] Example 40

[0204] The hydroxysaffron yellow A pharmaceutical composition contains 5.0% by weight of hydroxysaffron yellow A, 49.5% sodium decanoate, 5.0% ethylene-vinyl acetate copolymer, 20.0% carbomer, 20% sodium alginate, and 0.5% magnesium stearate.

[0205] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 150.0 mg of hydroxysaffron yellow A, 600.0 mg of carbomer, 600.0 mg of sodium alginate, and 1485.0 mg of sodium decanoate. Mix the four ingredients thoroughly and add 5.0 mL of ethylene-vinyl acetate copolymer solution (solvent is 80.0% ethanol solution) to form a soft mass. Pass the soft mass through a sieve to form uniformly sized particles, then dry it in a 50°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0206] Example 41

[0207] The hydroxysaffron yellow A pharmaceutical composition contains 8.0% by weight of hydroxysaffron yellow A, 79.0% by weight of sodium decanoate, 3.0% by weight of ethyl cellulose, and 10.0% by weight of hydroxypropyl methylcellulose.

[0208] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 240.0 mg of hydroxysaffron yellow A, 2370.0 mg of sodium decanoate, and 300.0 mg of hydroxypropyl methylcellulose. Mix the three ingredients and add 3.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50°C oven for 2 hours. Finally, weigh 300 mg and fill it into enteric-coated empty capsules to obtain the final product.

[0209] Example 42

[0210] The hydroxysaffron yellow A pharmaceutical composition contains 9.6% hydroxysaffron yellow A by mass, 76.9% sodium decanoate, 3.0% ethyl cellulose, 10.0% hydroxypropyl methylcellulose, and 0.5% magnesium stearate.

[0211] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 288.0 mg of hydroxysaffron yellow A, 2307.0 mg of sodium decanoate, and 300.0 mg of hydroxypropyl methylcellulose. Mix the three ingredients and add 3.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50℃ oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0212] Example 43

[0213] The hydroxysaffron yellow A pharmaceutical composition contains 22.4% hydroxysaffron yellow A by mass, 67.1% sodium decanoate, 10.0% hydroxypropyl methylcellulose, and 0.5% magnesium stearate.

[0214] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 224.0 mg of hydroxysaffron yellow A, 671.0 mg of sodium decanoate, and 100.0 mg of hydroxypropyl methylcellulose. Mix the three together and add 1.0 mL of 80% ethanol solution to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50°C oven for 2 hours. Finally, add 5.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0215] Example 44

[0216] The hydroxysaffron yellow A pharmaceutical composition contains 19.1% hydroxysaffron yellow A by mass, 57.4% sodium decanoate, 20.0% hydroxypropyl methylcellulose, 3.0% ethylcellulose, and 0.5% magnesium stearate.

[0217] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 191.0 mg of hydroxysaffron yellow A, 574.0 mg of sodium decanoate, and 200.0 mg of hydroxypropyl methylcellulose. Mix the three together and add 1.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50℃ oven for 2 hours. Finally, add 5.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0218] Example 45

[0219] The hydroxysaffron yellow A pharmaceutical composition contains 16.6% hydroxysaffron yellow A by mass, 49.9% sodium decanoate, 30.0% hydroxypropyl methylcellulose, 3.0% ethylcellulose, and 0.5% magnesium stearate.

[0220] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 166.0 mg of hydroxysaffron yellow A, 499.0 mg of sodium decanoate, and 300.0 mg of hydroxypropyl methylcellulose. Mix the three together and add 1.0 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50℃ oven for 2 hours. Finally, add 5.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0221] Example 46

[0222] The hydroxysaffron yellow A pharmaceutical composition contains 21.1% hydroxysaffron yellow A by mass, 63.4% sodium decanoate, 10.0% hydroxypropyl methylcellulose, 5.0% ethylcellulose, and 0.5% magnesium stearate.

[0223] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 211.0 mg of hydroxysaffron yellow A, 634.0 mg of sodium decanoate, and 100.0 mg of hydroxypropyl methylcellulose. Mix the three together and add 1.7 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50℃ oven for 2 hours. Finally, add 5.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0224] Example 47

[0225] The hydroxysaffron yellow A pharmaceutical composition contains 16.1% hydroxysaffron yellow A by mass, 48.4% sodium decanoate, 30.0% hydroxypropyl methylcellulose, 5.0% ethylcellulose, and 0.5% magnesium stearate.

[0226] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 161.0 mg of hydroxysaffron yellow A, 484.0 mg of sodium decanoate, and 300.0 mg of hydroxypropyl methylcellulose. Mix the three together and add 1.7 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50°C oven for 2 hours. Finally, add 5.0 mg of magnesium stearate and compress into tablets to obtain the final product.

[0227] Example 48

[0228] The hydroxysaffron yellow A pharmaceutical composition contains 21.75% hydroxysaffron yellow A by mass, 65.25% dodecyl-β-D-maltodextrin, 10.0% hydroxypropyl methylcellulose, and 3.0% ethylcellulose.

[0229] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 217.5 mg of hydroxysaffron yellow A, 652.5 mg of dodecyl-β-D-maltodextrin, and 100.0 mg of hydroxypropyl methylcellulose. Mix the three ingredients and add 1 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles, and then dry it in a 50°C oven for 2 hours. Compress the particles into tablets to obtain the final product.

[0230] Example 49

[0231] The hydroxysaffron yellow A pharmaceutical composition contains 21.75% hydroxysaffron yellow A by mass, 65.25% sodium decanoate, 10.0% hydroxypropyl methylcellulose, and 3.0% ethylcellulose.

[0232] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 217.5 mg of hydroxysaffron yellow A, 652.5 mg of sodium decanoate, and 100.0 mg of hydroxypropyl methylcellulose. Mix the three ingredients and add 1 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles, and then dry it in a 50℃ oven for 2 hours. Compress the particles into tablets to obtain the final product.

[0233] Example 50

[0234] The hydroxysaffron yellow A pharmaceutical composition contains 21.75% hydroxysaffron yellow A by mass, 65.25% sucrose laurate, 10.0% hydroxypropyl methylcellulose, and 3.0% ethylcellulose.

[0235] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 217.5 mg of hydroxysaffron yellow A, 652.5 mg of sucrose laurate, and 100.0 mg of hydroxypropyl methylcellulose. Mix the three together and add 1 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles, and then dry it in a 50℃ oven for 2 hours. Compress the particles into tablets to obtain the final product.

[0236] Example 51

[0237] The hydroxysaffron yellow A pharmaceutical composition contains 21.75% hydroxysaffron yellow A by mass, 65.25% sodium caprylate, 10.0% hydroxypropyl methylcellulose, and 3.0% ethylcellulose.

[0238] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 217.5 mg of hydroxysaffron yellow A, 652.5 mg of sodium caprylate, and 100.0 mg of hydroxypropyl methylcellulose. Mix the three ingredients and add 1 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles, and then dry it in a 50°C oven for 2 hours. Compress the particles into tablets to obtain the final product.

[0239] Example 52

[0240] The hydroxysaffron yellow A pharmaceutical composition contains 43.5% by weight of hydroxysaffron yellow A, 43.5% by weight of dodecyl-β-D-maltodextrin, 10.0% by weight of hydroxypropyl methylcellulose, and 3.0% by weight of ethylcellulose.

[0241] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 435.0 mg of hydroxysaffron yellow A, 435.0 mg of dodecyl-β-D-maltodextrin, and 100.0 mg of hydroxypropyl methylcellulose. Mix the three ingredients and add 1 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles, and then dry it in a 50°C oven for 2 hours. Compress the particles into tablets to obtain the final product.

[0242] Example 53

[0243] The hydroxysaffron yellow A pharmaceutical composition contains 29.0% by weight of hydroxysaffron yellow A, 58.0% by weight of dodecyl-β-D-maltodextrin, 10.0% by weight of hydroxypropyl methylcellulose, and 3.0% by weight of ethylcellulose.

[0244] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 290.0 mg of hydroxysaffron yellow A, 580.0 mg of dodecyl-β-D-maltodextrin, and 100.0 mg of hydroxypropyl methylcellulose. Mix the three ingredients and add 1 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50°C oven for 2 hours. Then compress the particles into tablets to obtain the final product.

[0245] Example 54

[0246] The hydroxysaffron yellow A pharmaceutical composition contains 8.7% hydroxysaffron yellow A by mass, 78.3% dodecyl-β-D-maltodextrin, 10.0% hydroxypropyl methylcellulose, and 3.0% ethylcellulose.

[0247] The preparation process of the hydroxysaffron yellow A pharmaceutical composition in this embodiment is as follows: Weigh 87.0 mg of hydroxysaffron yellow A, 783.0 mg of dodecyl-β-D-maltodextrin, and 100.0 mg of hydroxypropyl methylcellulose. Mix the three ingredients and add 1 mL of ethyl cellulose solution (3.0%, w / w, solvent is 80.0% ethanol solution) to make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 50°C oven for 2 hours. Then compress the particles into tablets to obtain the final product.

[0248] Effect Examples 1-8

[0249] Example 1

[0250] This study used the Caco-2 model to determine the transport and permeability of HSYA at the cellular level. Caco-2 cell suspensions were seeded into the Apical (AP) ends of Transwell plates (Corning, Pole size 0.4 μm, membrane area 0.33 cm²) at a cell density of 1 × 10⁵ cells / cm². The medium was changed every two days post-seeding, and daily thereafter after two weeks. Monolayers of cells differentiated approximately 21 days post-seeding. Electroelectric resistance (TEER) was measured at three wells for each concentration on days 3, 6, 9, 12, 15, 18, and 21 post-seeding to observe the dynamic formation of tight junctions in the cell monolayer.

[0251] After 21 days of cell culture, the culture medium was discarded, and HBSS was added and the cells were incubated at 37 °C. Cell wells with a TEER value greater than 700 Ω·cm² and good cell growth were selected. Cells were washed three times with HBSS to remove impurities from the cell monolayer surface. 200 μL of the test solution was added to the AP end, and 700 μL of blank HBSS was added to the Basolateral end (BL end) as the receiving pool. At 1, 2, 3, and 4 h, 150 μL of solution was aspirated from the receiving pool, and an equal volume of blank HBSS was immediately added. The samples were centrifuged at 20, 200 g for 10 minutes, and the supernatant was used to determine the drug concentration.

[0252] The apparent permeability coefficient is calculated according to the following formula (1). value:

[0253]

[0254] Formula (1)

[0255] in, This is the initial concentration on the side where the drug is located (AP side). It is the rate of increase in drug concentration on the receiver side (BL side). For the volume of the BL side, This represents the area of ​​the Transwell membrane. The higher the value, the higher the drug penetration rate and the stronger the drug transport capacity.

[0256] The apparent permeability coefficients of the drugs in samples 4, 5, 6, 7, 8, 9, 10, and 11 were determined according to the above method. Values, results are shown below Figure 1 .

[0257] Apparent permeability coefficient of ranitidine hydrochloride positive control group 1.5×10 -7 The speed of cm / s indicates that the Caco-2 monolayer cell model was successfully established. The HSYA in the control group... 6.5×10 -8 cm / s. Examples 4, 5, 6, 7, 8, 9, 10, and 11 all effectively improved the apparent permeability coefficient of drug HSYA, increasing it by 1.7-83.1 times. Among them, Examples 4, 5, 6, 10, and 11 significantly improved the apparent permeability coefficient of HSYA. Increased to 5.3×10 -6 2.3×10 -6 5.4×10 -6 3.8×10 -6 5.0×10 -6 cm / s. The drugs in Examples 7, 8, and 9. The measured value was 0.11 × 10⁻⁶. -6 1.1×10 -6 1.4×10 -6 cm / s.

[0258] Example 2

[0259] In vitro release behavior determination of hydroxysaffron yellow A and absorption promoter in Examples 6, 43, 44, 45, 46, and 47.

[0260] Take appropriate amounts of samples from Examples 6, 43, 44, 45, 46, and 47, and add them to 500 mL of pure water. Conduct the release experiment under leaky conditions. Control the release conditions at 37°C and 50 rpm. Take 1 mL samples at 1 h, 2 h, 3 h, 4 h, 5 h, and 6 h to determine the content of the drug and absorption enhancer. Replenish the dissolution medium after each sampling.

[0261] The cumulative release curve is shown below. Figure 2 The specific details are shown in Table 1. Experiments revealed that the in vitro release behavior of both the drug and the absorption enhancer was controlled after the addition of the absorption enhancer, and the drugs in the above embodiments were essentially released within 6 hours. The drugs and absorption enhancers can be released simultaneously in the dissolution medium.

[0262] Table 1

[0263]

[0264] Example 3

[0265] Six healthy male Wistar rats, weighing 250 ± 20 g, were randomly divided into two groups and fasted for 12 h. The two groups were administered the drug orally via gavage according to Examples 6 and 44, respectively, at a dose of 30 mg / kg. Blood samples were collected from the orbital venous plexus after anesthesia at 0, 30, 60, 120, 240, 360, and 480 min after drug administration. The plasma samples were processed, and the relative bioavailability was calculated by determining the blood drug concentration at different time points. The results are shown in […]. Figure 3 Table 2.

[0266] Table 2. Relative oral bioavailability of rats after oral gavage in Examples 6 and 44.

[0267]

[0268] Experimental results show that absorption enhancers can improve the bioavailability of hydroxysaffron yellow A. Furthermore, selecting appropriate absorption aids can further promote the absorption of hydroxysaffron yellow A in vivo. Absorption enhancers and absorption aids can exert a synergistic effect.

[0269] Example 4

[0270] A series of buffer solutions with pH values ​​of 1.3, 6.8, and 8.0 were prepared using a dilute hydrochloric acid and phosphate buffer system to simulate the slightly alkaline pH environment of gastric juice, intestinal juice, and intestinal juice, respectively. An appropriate amount of hydroxysaffron yellow A was dissolved in pure water to prepare a 10 mg / mL solution. 50 μL of this solution was added to 9.95 mL of each of the different pH buffer solutions and mixed thoroughly (50 μg / mL). The solutions were incubated at 37°C, and samples were taken at 0 h, 4 h, and 8 h. The pH of the samples was then adjusted to approximately 6.8 using either phosphoric acid or sodium hydroxide solution, and the drug concentration change over time was measured. The results are shown below. Figure 4 a, Table 3.

[0271] Besides pH, the abundant enzymes in the gastrointestinal tract may affect drug stability, thus limiting drug absorption into the bloodstream. Therefore, this invention further evaluated the effects of different digestive fluids on drug stability. The simulated gastric juice (pH=1.2) contained pepsin. The simulated intestinal juice (pH=6.8) was prepared by dissolving 6.8 g of potassium dihydrogen phosphate in 500 mL of water and then using 0.1 mol·L⁻¹... -1 Adjust the pH of the sodium hydroxide solution to 6.8; separately dissolve 10 g of pancreatic enzyme in an appropriate amount of water; mix the two solutions and dilute with water to 1 L for later use.

[0272] A suitable amount of hydroxysaffron yellow A was dissolved in water to prepare a 10 mg / mL solution. 50 μL of this solution was then dissolved in 9.95 mL of different simulated digestive fluids, with a target initial drug concentration of 50 μg / mL. Samples were taken at 37 ℃ at different time points (simulated gastric fluid: 0h, 2h, 4h; simulated intestinal fluid: 0h, 3h, 6h). The pH of the solutions was adjusted with hydrochloric acid or sodium hydroxide solution to inactivate the enzymes in the gastric or intestinal fluids. After 5 min, the pH of the samples was adjusted to approximately 6.8, and the change in drug concentration over time was measured. Results are shown below. Figure 4 b, Table 3.

[0273] Table 3. Retention rate of hydroxysaffron yellow A in different media (%)

[0274]

[0275] In stability experiments in physiologically similar environments, it was found that HSYA was relatively stable in buffer solutions with intestinal-associated pH values ​​of 6.8 and 8.0, but unstable in an acidic environment with pH of 1.2, with a concentration decrease of about 18%. This indicates that the intestinal pH environment has little effect on hydroxyl A, while the acidic environment of the stomach will affect the stability of hydroxyl A.

[0276] Pepsin and trypsin were added to the above buffer solution to form simulated gastric and intestinal fluids, further investigating the effect of proteases on drug stability. Experimental results showed that HSYA was relatively stable in simulated intestinal fluid but less stable in simulated gastric fluid. In simulated gastric fluid, the drug concentration decreased by approximately 24% after 4 hours. In contrast, the concentration of HSYA decreased by approximately 13% after incubation at pH 1.2 for 4 hours. This indicates that pepsin in simulated gastric fluid can further degrade HSYA and affect its stability during oral administration, which is worthy of attention in the development of oral drug formulations. Therefore, in some embodiments and experimental examples of this invention, enteric-coated capsules are used to increase the stability of the drug in the gastrointestinal tract.

[0277] Example 5

[0278] Hydroxysaffron Yellow A was administered orally and intravenously to beagle dogs. Drug-time curve determination was performed in Examples 20 and 30.

[0279] Eight healthy male beagles, weighing 10 kg each, were randomly divided into four groups. Before the experiment, the beagles were fasted for 12 hours but allowed free access to water. Hydroxysaffron yellow A was administered intravenously or orally via gavage, as described in Examples 1-20 and 1-30. The intravenous injection group received 3 mg / kg, while the oral group received 15 mg / kg. Approximately 1 mL of blood was collected from the forelimb vein before administration and at 0.25, 0.5, 1, 2, 4, 6, and 8 hours after administration, and placed in anticoagulant tubes. The tubes were centrifuged at 2,000 g (4°C) for 10 min, and the supernatant was stored at -70°C for subsequent analysis. One week later, a crossover was performed to ensure n=4. The absolute bioavailability of hydroxysaffron yellow A in the examples is shown in [examples omitted]. Figure 5 Table 4.

[0280] Experimental results showed that the absolute oral bioavailability of Examples 20 and 30 of the present invention in beagles reached 15.2% and 18.7%, respectively. Compared with direct oral administration of hydroxysaffron yellow A, the relative bioavailability of Examples 1-20 was 537.1%, and the peak plasma concentration C0 was [missing value]. max The concentration increased from 0.8 ± 0.2 ug / mL to 5.2 ± 1.6 ug / mL, indicating that the absorption enhancer effectively improved drug absorption in beagle dogs. The relative bioavailability of Example 30 was further improved to 662.9%, C max The concentration increased to 6.2±0.7ug / mL, indicating that in the beagle dog model, the absorption enhancer and enteric-coated capsules can also work synergistically with the absorption enhancer to further improve drug absorption in vivo.

[0281] Table 4. Pharmacokinetic parameters of oral administration of hydroxysaffron yellow A in Beagle dogs: oral administration in Examples 20 and 30, and intravenous injection of hydroxysaffron yellow A.

[0282]

[0283] Example 6

[0284] Oral administration time curve of hydroxysaffron yellow pigment A in rats and determination of oral administration time curve in Examples 48, 49, 50, and 51.

[0285] Fifteen healthy male Wistar rats, weighing 250 ± 20 g, were randomly divided into 6 groups and fasted for 12 h. One group was orally administered hydroxysaffron A aqueous solution, while the other groups were orally administered as described in Examples 48, 49, 50, and 51, respectively, at a dose of 30 mg / kg. Blood samples were collected from the orbital venous plexus after anesthesia at 0, 30, 60, 120, 240, 360, and 480 min after administration. The relative bioavailability was calculated by measuring the blood drug concentration at different time points after plasma sample processing.

[0286] The results are as follows Figure 6As shown, compared with the pure aqueous solution of hydroxysaffron yellow A, Examples 48, 49, 50, and 51 all significantly improved the relative oral bioavailability of the drug (results are shown in Table 5).

[0287] Table 5. Relative oral bioavailability of pure aqueous solution of hydroxysaffron yellow A administered orally to rats, Examples 48, 49, 50, and 51.

[0288]

[0289] Example 7

[0290] Oral administration time curve of hydroxysaffron yellow pigment A in rats and Examples 52, 53, and 54: determination of oral administration time curve.

[0291] Nine healthy male Wistar rats, weighing 250 ± 20 g, were randomly divided into three groups and fasted for 12 h. They were orally administered drugs according to Examples 52, 53, and 54, at a dose of 30 mg / kg. Blood samples were collected from the orbital venous plexus at 0, 30, 60, 120, 240, 360, and 480 min after anesthesia. Plasma samples were processed, and blood drug concentrations were determined at different time points.

[0292] The experimental results are shown in Figure 7 Compared to the oral pure aqueous solution of hydroxysaffron yellow A, oral examples 52, 53, and 54 all significantly improved the relative oral bioavailability of the drug, and the blood drug concentration increased with the increase of the proportion of absorption enhancer in the prescription.

[0293] Table 6. Relative oral bioavailability of rats in oral gavage examples 52, 53, and 54.

[0294]

[0295] Example 8

[0296] Hydroxysafflower yellow pigment A was administered intravenously to beagle dogs, and the drug-time curve was determined in Example 31 (orally).

[0297] Four healthy male beagles, each weighing 10 kg, were randomly divided into two groups. Before the experiment, the beagles were fasted for 12 hours but allowed free access to water. Hydroxysaffron dye A was administered intravenously, while the oral administration (Example 31) was administered orally. The intravenous infusion group received 3 mg / kg of the drug, and the oral administration group received 15 mg / kg. The intravenous infusion volume was 150 mL, and the infusion time was 2 hours. Approximately 1 mL of blood was collected from the forelimb vein before and at 0.25, 0.5, 1, 2, 4, 6, and 8 hours after drug administration and placed in anticoagulant tubes. The blood was centrifuged at 2,000 g (4°C) for 10 minutes, and the supernatant was stored at -70°C for subsequent analysis. One week later, a crossover was performed to make n=4. The experimental results are shown below. Figure 8 Table 7.

[0298] The results showed that the drug-time curves of intravenous infusion of hydroxysaffron yellow A and oral administration in Example 31 were similar, with T0 being the most significant difference. max Same, and C max T 1 / 2 AUC 0-t The pharmacokinetic parameters were similar, with confidence intervals less than 90%. This result suggests that, in a beagle dog model, the currently developed oral HSYA formulation and intravenous infusion are bioequivalent to a single dose in terms of pharmacokinetic curves. Based on the pharmacokinetic curves of the two administration methods, it is speculated that increasing the dosage by 5 times would result in oral administration achieving non-inferiority to intravenous infusion in terms of efficacy. The oral hydroxysaffron yellow A formulation of this invention has the potential to clinically replace hydroxysaffron yellow A injection.

[0299] Table 7. Pharmacokinetic parameters of intravenous infusion of hydroxysaffron yellow A and oral administration in beagle dogs, Example 31.

[0300]

[0301] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A pharmaceutical composition of hydroxysaffron yellow pigment A, characterized in that, It comprises the following components by mass fraction: 3-50% hydroxysaffron yellow A, 35-85% absorption enhancer, and 5-50% absorption aid; the mass fraction of each component in the hydroxysaffron yellow A pharmaceutical composition refers to the mass percentage of each component relative to the total mass of the hydroxysaffron yellow A pharmaceutical composition. The absorption enhancer is sodium decanoate; The absorption enhancer is hydroxypropyl methylcellulose or a combination of hydroxypropyl methylcellulose and ethylcellulose.

2. The pharmaceutical composition of hydroxysaffron yellow A as described in claim 1, characterized in that, The mass ratio of hydroxypropyl methylcellulose to ethylcellulose is (2-20):

1.

3. The pharmaceutical composition of hydroxysaffron yellow A as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) The mass fraction of the hydroxysaffron yellow pigment A is 8-45%; (2) The mass fraction of the absorption promoter is 40-79%; (3) The mass fraction of the absorption enhancer is 13-33%; (4) The mass ratio of the hydroxysaffron yellow pigment A to the absorption promoter is 1:(0.05-15); (5) The hydroxysaffron yellow pigment A pharmaceutical composition further comprises a lubricant; (6) The hydroxysaffron yellow A pharmaceutical composition further comprises a lubricant; the mass fraction of the lubricant is 0.1-1%; (7) The hydroxysaffron yellow A pharmaceutical composition further comprises an enteric-coated material; The dosage form of the hydroxysaffron yellow pigment A pharmaceutical composition described in (8) is tablets, capsules or drops.

4. The pharmaceutical composition of hydroxysaffron yellow A as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) The mass fraction of the hydroxysaffron yellow pigment A is 8-22%; (2) The mass fraction of the absorption promoter is 64-79%; (3) The mass fraction of the absorption enhancer is 12-14%; (4) The mass ratio of the hydroxysaffron yellow pigment A to the absorption promoter is 1:(0.1-10); (5) The hydroxysaffron yellow A pharmaceutical composition further comprises a lubricant, wherein the lubricant is magnesium stearate; (6) The hydroxysaffron yellow A pharmaceutical composition further comprises a lubricant, wherein the mass fraction of the lubricant is 0.4-0.6%; (7) The hydroxysaffron yellow A pharmaceutical composition further comprises an enteric material; the enteric material is one or more of acrylic resin polymers, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose titanate, and cellulose acetate ester; The dosage form of the hydroxysaffron yellow A pharmaceutical composition described in (8) is tablets or capsules; the capsules are enteric-coated capsules.

5. The pharmaceutical composition of hydroxysaffron yellow A as described in claim 1, characterized in that, The mass ratio of the hydroxysaffron yellow pigment A to the absorption promoter is 1:(1-10).

6. A method for preparing a pharmaceutical composition of hydroxysaffron yellow A as described in any one of claims 1-5, characterized in that, It includes the following steps: Hydroxysaffron yellow pigment A, absorption promoter, and absorption aid are mixed, granulated, and then compressed into tablets or filled into capsules.

7. The method for preparing the hydroxysaffron yellow pigment A pharmaceutical composition according to claim 6, characterized in that, It meets one or more of the following conditions: (1) When the hydroxysaffron yellow pigment A pharmaceutical composition contains a lubricant, the preparation method includes the following steps: mixing the hydroxysaffron yellow pigment A, the absorption promoter and the absorption aid, granulating, mixing with the lubricant, and finally compressing into tablets or filling capsules; (2) The granulation is wet granulation or dry granulation; (3) The capsule is an enteric-coated capsule; The ethyl cellulose in (4) is present in the form of a solution; the solution is an alcohol solution; the mass fraction of ethyl cellulose in the ethyl cellulose solution is 2-5%; the mass fraction is the mass percentage of ethyl cellulose in the total mass of the ethyl cellulose solution.

8. A pharmaceutical formulation comprising the hydroxysaffron yellow A pharmaceutical composition as described in any one of claims 1-5.

9. The pharmaceutical preparation according to claim 8, characterized in that, The dosage form of the pharmaceutical preparation is tablets, capsules, or pellets.

Images