Crocetin preparation with high bioavailability, and use thereof

Abstract

A crocetin preparation with high bioavailability, and the use thereof. Crocetin disodium is used as a main active ingredient, and prepared into an oral enteric coated preparation with high bioavailability and rapid absorption. By means of optimizing the formulation and process of the oral preparation, a lipid material, a solubilizer, and a pH modulator are used as key ingredients in the enteric coated crocetin disodium preparation, which synergistically solves critical technical problems in terms of druggability, such as the aqueous insolubility and poor solution stability of crocetin, and significantly enhances the stability, solubility, and absorption efficiency of the pharmaceutical ingredients in vivo, thereby elevating the oral bioavailability of an insoluble crocetin preparation, and improving the pharmacokinetic parameters and efficacy of the drug. The oral enteric coated preparation can effectively prevent or treat cardiovascular and cerebrovascular diseases and metabolic diseases, greatly expands the clinical value and druggability of crocetin, and has a simple preparation process and low cost.

Description

A high bioavailability crocin preparation and its application Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a crocin preparation with high bioavailability and its application. Background Technology

[0002] Saffron is the dried stigma of *Crocus sativus* L., a plant in the Iridaceae family. It is neutral in nature and sweet in taste, and enters the heart and liver meridians. It has the effects of promoting blood circulation, removing blood stasis, cooling the blood, detoxifying, relieving depression, and calming the mind. Crocin, also known as saffron acid, is one of the active ingredients of saffron and is found in saffron and gardenia plants. It is a natural carotenoid dicarboxylic acid with the molecular formula C2. 20 H 24 O4, with a molecular weight of 328.40 g / mol. Saffron acid is a hydrophobic compound, insoluble in water and most organic solvents. Its anionic form is soluble in water and readily dissolves in diluted sodium hydroxide solution or other alkaline aqueous solutions. Because saffron acid is a polyene compound with conjugated double bonds and isoprene residues, it suffers from poor structural stability, low bioavailability, and is easily degraded, affecting drug safety and efficacy. With ongoing research, saffron acid has been shown to possess various pharmacological effects, including cardioprotection, neuroprotection, liver protection, antidepressant effects, and improvement of Alzheimer's and Parkinson's diseases, indicating significant development potential.

[0003] In modern pharmacology, crocin possesses various therapeutic effects, including improving oxygen diffusion rate, preventing atherosclerosis, lowering blood lipids, lowering blood pressure, and increasing ocular blood flow. This is due to its significant antioxidant properties. Studies have shown that crocin can effectively scavenge free radicals in the body, activate mitogen-activated protein kinase (MAPK) and the PI3K / ATK pathway, reduce the production of reactive oxygen species (ROS) and cardiomyocyte apoptosis, thereby playing a role in preventing and treating heart failure. In clinical trials, crocin has also been shown to inhibit mitochondrial function by scavenging free radicals, activate the AMPK pathway, reduce intracellular lipid oxidation and the expression of cellular immune antigens at lesion sites, promote glucose uptake, accelerate fat consumption, and reverse myocardial damage. Lautenschlager et al. demonstrated that crocin can penetrate the blood-brain barrier, which may be the mechanism by which crocin exerts its pharmacological effects in the central nervous system, giving it the potential to prevent and treat cardiovascular and cerebrovascular diseases.

[0004] However, due to the high price, poor solubility and stability, and extremely low bioavailability of saffron, crocin-related preparations are currently mostly administered intravenously in clinical trials to improve bioavailability, but the drug has a very short half-life. Crocin reaches its maximum plasma concentration approximately 0.5 hours after administration, indicating that its rapid absorption may be due to transport into the bloodstream via the portal vein. In clinical trials on healthy individuals, after a single oral dose of 16 mg crocin, the concentration range of crocin at different sampling intervals was approximately 0.09-0.35 μg / mL. A clinical observation of the pharmacokinetics of crocin in 10 healthy individuals revealed that crocin was detectable in human plasma 1 hour after a single dose of 7.5, 15, and 22.5 mg. max The range is 4.0-0.8h, t 1 / 2 For 6.1-7.5 hours, C max and AUC 0-24h The average bioavailability was 100.9-279.7 ng / mL and 556.5-1720.8 ng / mL, respectively, showing a dose-dependent effect, which is still very low compared to the metabolite of crocin, crocin monoglucuronic acid. When administered orally to rats at a dose of 25 mg / kg, the oral bioavailability of crocin was only 11.25%. Due to the rapid absorption and metabolism of crocin, repeated oral administration does not lead to plasma accumulation and increased blood drug concentration, and the bioavailability of crocin remains very low. Therefore, improving the bioavailability of crocin is an urgent problem to be solved.

[0005] Currently, various novel drug delivery systems have been developed to improve the bioavailability and stability of crocin. In the study by Zhou et al., arabic gum was used as a wall material to prepare crocin microcapsules, which improved the half-life and stability of crocin. However, this method suffers from drawbacks such as the inability to continuously produce microcapsules, resulting in low efficiency and an unstable drug release rate. Furthermore, the drug release rate of microcapsule drugs may be unstable. Langroodi et al. used a W / O / W double emulsion method to prepare crocin PLGA nanoparticles, improving the sustained-release effect and pharmacological activity of crocin. However, this formulation faces challenges such as high production costs and complex preparation. El-Kharrag et al. used FeCl2·4H2O, FeCl3, and dextran-containing NaOH solution as raw materials to prepare magnetic nanoparticles via co-precipitation, followed by in-situ inclusion to prepare crocin magnetic nanoparticles. While this improved the dispersibility and stability of crocin in water, the efficacy of magnetic nanoparticle drugs is affected not only by the strength and direction of the magnetic field, but also by relatively high production and usage costs, which may limit its widespread clinical application. Esposito et al. prepared saffron acid nanostructured lipid dispersions using glyceryl monooleate, sodium cholate, and sodium caseinate as raw materials, which improved the stability and pharmacological activity of saffron acid. However, they also faced problems such as high production costs, and the storage conditions of nanostructured lipid dispersions were more demanding.

[0006] Chinese patent CN109091458A discloses a method for preparing crocin microemulsion and its lyophilized powder. Based on the principle of microemulsification, a surfactant is added during the preparation process, which increases the solubility of crocin in water by 800 times. However, while increasing solubility, it also affects its stability. Furthermore, Chinese patent CN112999162A discloses a crocin solid dispersion and its preparation method. A hydrophilic polymer carrier material is dissolved and mixed with meglumine, causing them to cross-link and form a carrier polymer. This polymer is then mixed and dissolved with crocin, and the solid dispersion is prepared using solvent evaporation or spray drying. This method utilizes the carrier to influence the dissolution and absorption of crocin, but the organic solvents used in the preparation process, such as petroleum ether, acetone, dichloromethane, and chloroform, pose certain safety risks. Foreign patent WO2022 / 025997A1 discloses a trans-saffron acid composition and treatment regimen. The trans-saffron acid drug and administration regimen provided therein significantly increase the solubility and stability of saffron acid. However, the preparation process of trans-liposome formulations is complex and the production cost is high.

[0007] This invention aims to develop an industrially scalable and low-cost formulation. By preparing crocin into its sodium salt and optimizing the formulation and process of oral sodium crocin preparations, the problems of crocin's insolubility in water and the highly unstable solubility of sodium crocin are solved. Ultimately, a highly bioavailable crocin formulation and its applications are provided, effectively prolonging the drug's half-life, improving the solubility and solution stability of crocin, and enhancing the bioavailability of the crocin formulation, thereby improving clinical efficacy in treating cardiovascular and cerebrovascular diseases, metabolic diseases, and other conditions. The preparation process of this invention is highly operable, low-cost, suitable for large-scale industrial production, and has excellent clinical application prospects.

[0008] Summary of the Invention

[0009] To address the problems existing in the prior art, this invention provides a highly bioavailable crocin preparation and its application. Specifically, an enteric-coated formulation is prepared using sodium crocin as the main active ingredient, which significantly improves the stability and solubility of the drug, effectively improves the metabolism of sodium crocin in vivo, thereby increasing the bioavailability and absorption rate of the drug, effectively preventing or treating cardiovascular and cerebrovascular diseases, and greatly expanding the pharmaceutical properties and clinical value of crocin.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0011] On one hand, the present invention provides a highly bioavailable crocin preparation, wherein the preparation is an oral enteric-coated formulation made from the active ingredient of crocin; wherein the active ingredient of crocin is selected from at least one of crocin and sodium crocin.

[0012] Preferably, the saffron acid preparation includes, in addition to the active ingredient of saffron, at least one of a pH adjuster, a solubilizer, and a lipid material.

[0013] More preferably, the saffron acid preparation includes saffron active ingredients, pH adjuster, solubilizer, and lipid material.

[0014] More preferably, the pH adjuster is selected from at least one of sodium bicarbonate, sodium alginate, meglumine, sodium hydroxide, and disodium hydrogen phosphate.

[0015] More preferably, the solubilizer is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl β-cyclodextrin, povidone, copovidone, hydroxypropyl cellulose, polyethylene glycol, polyethylene glycol-15 hydroxystearate, and vitamin E polyethylene glycol succinate.

[0016] More preferably, the lipid material is selected from at least one of mono- and di-stearyl glycerol, behenicol glycerol, and hydrogenated castor oil.

[0017] More preferably, the pH adjuster is sodium bicarbonate.

[0018] More preferably, the solubilizer is selected from at least one of hydroxypropyl methylcellulose and vitamin E polyethylene glycol succinate.

[0019] More preferably, the lipid material is behenicol glyceride.

[0020] More preferably, the saffron acid preparation comprises, by weight, 1 part saffron active ingredient, 1-10 parts pH adjuster, 1-20 parts solubilizer and 1-20 parts lipid material.

[0021] More preferably, the saffron acid preparation comprises, by weight, 1 part saffron active ingredient, 1-8 parts pH adjuster, 1-15 parts solubilizer and 1-15 parts lipid material.

[0022] More preferably, the saffron acid preparation comprises, by weight, 1 part saffron active ingredient, 1-5 parts pH adjuster, 1-10 parts solubilizer and 1-10 parts lipid material.

[0023] Preferably, the saffron acid preparation further includes fillers, flow aids, lubricants, and enteric excipients.

[0024] More preferably, the filler is selected from at least one of lactose, soluble starch, microcrystalline cellulose, dextrin, dicalcium phosphate, mannitol, and pregelatinized starch.

[0025] More preferably, the flow aid is selected from at least one of colloidal silica and talc.

[0026] More preferably, the lubricant is selected from at least one of magnesium stearate, calcium stearate, micronized silica gel, hydrogenated vegetable oil, polyethylene glycol, and sodium dodecyl sulfate.

[0027] More preferably, the weight gain of the enteric excipient after coating is 8%-20%.

[0028] More preferably, the enteric excipient can be a commercially available product, which can be routinely selected by those skilled in the art to ensure that the formulation dissolves in the small intestine rather than in gastric acid.

[0029] Preferably, the dosage form of the saffron acid preparation is selected from any one of enteric-coated tablets, enteric-coated capsules, enteric-coated granules, and enteric-coated microcapsules.

[0030] Furthermore, the present invention also provides a method for preparing the above-mentioned saffron acid preparation, comprising the following steps:

[0031] S1. Pretreatment: Mix the active ingredients of saffron and the filler to form mixture 1, and sieve mixture 1;

[0032] S2. Granulation: Mix mixture 1, slow-release agent, and solubilizer to form mixture 2. Dissolve stabilizer and another solubilizer in water to form a solution. Mix mixture 2 and solution and perform wet granulation to form wet granules. The wet granules are then sieved.

[0033] S3. Drying and granulation: The wet granules are dried and sieved to obtain dry granules;

[0034] S4. Mixture: Mixing gliding agent, lubricant and dry particles to form a mixture;

[0035] S5. Tableting: The total mixture is compressed into tablets to form plain tablets;

[0036] S6. Curing and Coating: The tablets are sequentially cured, isolated, and enteric coated to obtain saffron acid preparation.

[0037] Preferably, in step S1, the mesh size of the sieve is 80 mesh.

[0038] Preferably, in step S2, the sieve mesh size is 40 mesh.

[0039] Preferably, in step S3, the moisture content of the dried wet particles is less than 2.5%.

[0040] Preferably, in step S3, the mesh size of the sieve is 30 mesh.

[0041] Preferably, in step S5, the tableting is performed using a rotary tablet press.

[0042] Preferably, in step S5, the hardness of the raw sheet is 70±20N.

[0043] Preferably, in step S6, the specific conditions for ripening are: temperature of 60-80℃ and time of 1-5h.

[0044] Furthermore, the present invention also provides the application of the crocin preparation in the preparation of drugs for cardiovascular and cerebrovascular diseases and metabolic diseases.

[0045] Preferably, the cardiovascular and cerebrovascular diseases include coronary heart disease, angina pectoris, heart failure, myocardial infarction, hyperlipidemia, and metabolic syndrome.

[0046] Compared with existing technologies, this invention solves the technical problem of poor drug-likeness of crocin, achieving unexpected technical effects and significantly improving bioavailability and in vivo pharmacological activity after oral administration. Specifically, it has the following significant beneficial effects:

[0047] (1) This invention is the first to propose the preparation of enteric-coated formulations using crocin as the main active ingredient. By optimizing the formulation process, lipid materials, solubilizers, and pH adjusters are used as key components of the crocin enteric-coated formulation. Both lipid materials and solubilizers can improve the solubility of crocin. With the synergistic effect of the three, including the pH adjuster, not only can the solubility of crocin be significantly improved, but the solution stability can also be enhanced. This invention solves the key technical problems of drug-grade crocin, such as its insolubility in water and poor solution stability.

[0048] (2) This invention is the first to discover that preparing sodium crocin into a highly water-soluble sample and administering it via the duodenum can significantly improve the bioavailability of crocin, which is 9.56 times that of the oral gavage group. Furthermore, oral administration of the enteric-coated formulation of this invention can increase the bioavailability to more than 30 times that of oral administration of crocin, and it is also absorbed quickly and has a long half-life.

[0049] (3) The pH adjuster, lipid material, and solubilizer in the enteric-coated formulation prepared in this invention not only synergistically promote the dissolution of crocin, but also, as confirmed by accelerated experiments, show no degradation under accelerated conditions for six months, significantly increasing the stability of crocin. A comparative pharmacodynamic study of a rat model of heart failure induced by myocardial infarction was conducted using conventional enteric-coated formulations of crocin and the full-formula enteric-coated formulation of crocin from this invention. The results showed that the pharmacokinetics and efficacy of the full-formula enteric-coated formulation of crocin from this invention were significantly superior to both conventional enteric-coated formulations and crocin. The full-formula enteric-coated formulation of crocin from this invention can significantly improve the progression of heart failure, improve various cardiac indicators, and effectively treat or prevent cardiovascular and cerebrovascular diseases, greatly expanding the clinical value and pharmaceutical properties of crocin.

[0050] (4) Through extensive literature review and analysis, combined with the inventors' years of research experience and continuous experimental exploration, this invention improves the solubility and solution stability of crocin, ultimately solving the drug-likeness problem of crocin, overcoming the technical difficulties of existing complex formulations such as nano-formulations and liposomes, breaking through the limitation that crocin preparations can only be administered by injection, and reducing costs. This invention discloses a novel, low-cost, fully-formulated enteric-coated crocin preparation suitable for industrial production, significantly improving the bioavailability, therapeutic effect, and clinical application value of crocin. Attached Figure Description

[0051] Figure 1 shows the results of the experiment simulating the cumulative dissolution rate of intestinal fluid.

[0052] Figure 2 shows the effect of each administration group on NT-proBNP in rats during the pharmacodynamic comparison experiment of saffron acid enteric-coated preparation.

[0053] Figure 3 shows the effects of each administration group on the cardiac index of rats in the pharmacodynamic comparison experiment of the crocetin enteric preparation. Detailed implementation mode

[0054] The following non-limiting examples can enable those of ordinary skill in the art to more comprehensively understand the present invention, but do not limit the present invention in any way. The following content is only an exemplary illustration of the scope claimed by the present invention. Those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and it should also fall within the scope claimed in this application.

[0055] The present invention will be further described below by way of specific examples. All chemical reagents used in the embodiments of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all mass contents. Unless otherwise specified, it is understood that the operations are carried out at room temperature.

[0056] Crocetin (CRA) and sodium crocetin (CRAT) were prepared and provided by Xinglin Traditional Chinese Medicine Technology (Guangzhou) Co., Ltd.

[0057] Example 1 (Pharmacokinetic comparison experiment of different administration routes of sodium crocetin)

[0058] 1. Preparation of test substances

[0059] Preparation of the intravenous administration test solution of CRAT: Prepare a dosing solution with a CRAT concentration of 1.5 mg / mL using 5% glucose, and filter and sterilize it before administration;

[0060] Preparation of the intragastric administration and intestinal intubation administration test solutions of CRAT: Dilute and prepare a CRAT suspension with a concentration of 1.5 mg / mL using 0.5% sodium carboxymethylcellulose (CMC-Na);

[0061] Preparation of the intragastric administration test solution of CRA: Dilute and prepare a CRA suspension with a concentration of 1.5 mg / mL using 0.5% CMC-Na.

[0062] 2. Experimental animals

[0063] Twenty-four SD rats, SPF grade, weighing 223.3 - 244.9 g, 6 - 7 weeks old, with half males and half females. They were provided by Hunan Slack Jingda Experimental Animal Co., Ltd. The quality certificate number of the experimental animals was: No430727201101012371, and the production license number of the experimental animals was: SCXK(Xiang)2019 - 0004. Feeding conditions: temperature 20 - 26°C, humidity 40 - 70%, 12 h / 12 h for day and night light and dark alternation, and the rats had free access to food and water. After one week of adaptive feeding, the rats were subjected to the experiment.

[0064] 3. Grouping and administration

[0065] Twenty-four qualified SFP-grade SD rats were randomly divided into four groups according to sex and weight, with three males and three females in each group. The following groups were used for comparative studies: intravenous administration of sodium crocin (IV), intragastric administration of crocin (CRA), intragastric administration of sodium crocin (CRAT), and intraduodenal administration of sodium crocin (DI) (administered via the duodenum). The experimental animals were fasted for 12 hours before administration but had free access to water. The following day, the corresponding test substance was administered according to the administration regimen in Table 1. Water was withheld for 2 hours after administration, and food was withheld for 4 hours.

[0066] Table 1. Test substance grouping and dosing regimen

[0067] Note: The above dosage refers to the dosage of crocin.

[0068] 4. Sample Collection

[0069] At the corresponding time points, approximately 0.25 mL of whole blood was collected from the orbital venous plexus (under isoflurane inhalation anesthesia) or jugular vein into pre-labeled heparinized blood collection tubes. Blood samples were collected from each group of animals before administration and at 5 min, 10 min, 20 min, 45 min, 1.5 h, 3 h, 6 h, 12 h, and 24 h after administration. The blood samples were temporarily stored in an ice box, then centrifuged at 4500 rpm for 10 min to separate the plasma. The separated plasma was placed in labeled centrifuge tubes and temporarily stored in an ultra-low temperature freezer for later analysis.

[0070] 5. High-performance liquid chromatography (HPLC) was used to detect the blood drug concentrations in each group.

[0071] The pharmacokinetic parameters of rats in each group were statistically analyzed. The main pharmacokinetic parameters of CRA in plasma after administration are shown in Table 2.

[0072] Table 2. Summary of major pharmacokinetic parameters for each treatment group (n=6)

[0073] As shown in Table 2, the AUC of the CRAT intestinal intubation administration group was... (0-t) The AUC of the CRAT gavage administration group was 77305.3±23733.1 μg / L*h. (0-t) The bioavailability was 8086.2 ± 1872.5 μg / L*h. The bioavailability of the intestinal intubation group was 9.56 times that of the gavage group and 32.86 times that of the equal-dose CRA gavage group. The intravenous administration dose was t... 1 / 2 The duration of administration was 0.67 ± 0.17 h, and the t was 0.67 ± 0.17 h after gavage. 1 / 2 The t-day duration of administration via the duodenum was 9.64 ± 13.09 h. 1 / 2The mean time to peak concentration (CPR) was 4.65 ± 2.62 h, indicating that CPR is rapidly metabolized after entering the bloodstream, with a short half-life and rapid time to peak concentration, resulting in a lower CPR rate in the intravenously administered group. max Higher than the intestinal intubation administration group.

[0074] Furthermore, the water solubility of crocin increases after salt formation, and its bioavailability is approximately four times higher than that of crocin alone. However, the absolute bioavailability of the CRA and CRAT gavage groups was only 1.62% and 5.58%, respectively, both extremely low. In contrast, the absolute bioavailability of the CRAT duodenal administration group was 53.39%, significantly higher than that of the gavage group. This indicates that although CRAT has improved water solubility, conventional gastric-coated formulations still suffer from insufficient drug-likeness. In summary, sodium crocin is more suitable for clinical use as an enteric-coated formulation; therefore, this invention further investigates enteric-coated formulations.

[0075] Example 2 (Investigation of the effect of saffron acid enteric-coated formulation on pH adjuster)

[0076] Extensive formulation studies and dissolution testing revealed that neither sodium crocin nor crocin, prepared using conventional formulation processes, met the pharmacopoeia's dissolution requirements for qualified formulations, exhibiting extremely low dissolution rates in conventional neutral or slightly acidic media. Crocin has extremely low solubility in neutral and acidic environments, rendering it insoluble. Furthermore, sodium crocin readily hydrolyzes into crocin on the particle surface in neutral to slightly acidic environments, resulting in the inability of either sodium crocin or crocin samples to dissolve smoothly in conventional media. Therefore, in addition to minimizing the particle size and increasing the dispersion of the active pharmaceutical ingredient (API), alkaline excipients were introduced into the formulation to increase the pH value of the API particle microenvironment, thereby increasing API dissolution. The effect of pH adjusters on enteric-coated formulations was first investigated; the formulations are shown in Table 3.

[0077] Table 3. Formulas for Saffron Acid Enteric-Coated Preparations

[0078] Note: " / " indicates that it has not been added, and the same applies below.

[0079] The preparation processes for prescriptions 1-5 are as follows:

[0080] S1. Pretreatment: Cranberry acid and lactose are pulverized together in a high-shear pulverizer for 30 seconds, and the pulverized mixture is then passed through an 80-mesh sieve.

[0081] S2. Granulation: Place the above mixture, microcrystalline cellulose, and crospovidone in a 5L wet granulation tank, stir at 300 rpm, cut at 2000 rpm, and mix for 5 minutes. Dissolve the pH adjuster in purified water, pour the solution into the wet granulation tank, stir at 300 rpm, cut at 2000 rpm, and granulate for 3 minutes. Pass the resulting soft material through a 40-mesh sieve.

[0082] S3. Drying and granulation: Place the wet granules in a 60℃ forced-air drying oven for 2 hours to dry them. The moisture content of the granules should be controlled within 2.5%. The resulting dry granules are then granulated using a 30-mesh sieve.

[0083] S4. Total Mixing: Add colloidal silica, magnesium stearate and the above dry granules into a 5L cone-shaped mixer hopper and mix for 5 minutes to obtain the total mixture.

[0084] S5. Tableting: The above mixture is compressed into tablets using a rotary tablet press, with the hardness controlled at 100±20N, to obtain unprocessed tablets.

[0085] The in vitro dissolution rates of formulations 1-5 were determined (using high-performance liquid chromatography), and the results are as follows;

[0086] In vitro dissolution method: pH 6.0 phosphate buffer was used as the dissolution medium, with a volume of 900 mL and a rotation speed of 50 rpm. The dissolution rate was tested using the slurry method, with 10 mL of sample taken and replenished each time. The dissolution results were determined by high performance liquid chromatography, and the cumulative dissolution rate was calculated. The results are shown in Table 4.

[0087] Table 4. Cumulative Dissolution Rate

[0088] Comparing formulations 1-5, it is evident that crocin is virtually non-dissolved in a medium with a pH of 6.0. The surface of the active pharmaceutical ingredient (API) particles is easily acidified and hydrolyzed into crocin, resulting in almost no dissolution of the API, with a final solubility of only about 2%. Adding commonly used alkaline pH adjusters (glucamine, sodium bicarbonate, sodium alginate, and sodium hydroxide) to the formulations improved the solubility to varying degrees. The results indicate that sodium bicarbonate, as an alkaline excipient, has the most significant solubilizing effect, while glucamine has a slightly weaker effect, and sodium hydroxide and sodium alginate have almost no effect.

[0089] Example 3 (Investigation of the effect of saffron acid enteric-coated formulation on solubilizer)

[0090] Simply adding pH adjusters can only slightly alter the dissolution rate in the intestinal pH environment. Further improvements in the dissolution rate of sodium crocin are needed. Considering that crocin has long hydrophobic conjugated double bonds and two hydrophilic terminal carboxyl groups, exhibiting surfactant-like properties, this invention considers introducing solubilizers into the formulation. Different solubilizers were screened, and by analyzing the characteristics of this component and the experimental results, and comparing available solubilizers, 10 formulations were proposed for research, as shown in Table 5.

[0091] Table 5. Formulas for Saffron Acid Enteric-Coated Preparations

[0092] The preparation process of prescription 6-11 is as follows:

[0093] S1. Pretreatment: Sodium crocinate and lactose are pulverized together in a high-shear pulverizer for 30 seconds, and the pulverized mixture is then passed through an 80-mesh sieve.

[0094] S2. Granulation: Place the above mixture, microcrystalline cellulose, cross-linked povidone, and solubilizer (hydroxypropyl methylcellulose, hydroxypropyl β-cyclodextrin, povidone VA064, copovidone, hydroxypropyl cellulose, polyethylene glycol 6000) into a 5L wet granulation tank. Stir at 300 rpm and cut at 2000 rpm for 5 minutes. Pour purified water into the wet granulation tank for wet granulation. Stir at 300 rpm and cut at 2000 rpm for 3 minutes. Pass the resulting soft material through a 40-mesh sieve.

[0095] S3. Drying and granulation: Place the wet granules in a 60℃ forced-air drying oven for 2 hours to dry them. The moisture content of the granules should be controlled within 2.5%. The resulting dry granules are then granulated using a 30-mesh sieve.

[0096] S4. Total Mixing: Add colloidal silica, magnesium stearate and the above dry granules into a 5L cone-shaped mixer hopper and mix for 5 minutes to obtain the total mixture.

[0097] S5. Tableting: The above mixture is compressed into tablets using a rotary tablet press, with the hardness controlled at 100±20N, to obtain unprocessed tablets.

[0098] The preparation processes for formulations 12-15 are consistent with those for formulations 6-11, except for the granulation process. The granulation process is as follows:

[0099] The granulation parameters used were consistent with those of Formulation 6-11, but the solubilizers (sodium dodecyl sulfate, Tween 80, polyethylene glycol-15 hydroxystearate, and vitamin E polyethylene glycol succinate) were first dissolved in purified water before wet granulation.

[0100] The in vitro dissolution rate of formulation 6-15 was determined, and the results are as follows;

[0101] In vitro dissolution method: pH 6.0 phosphate buffer was used as the dissolution medium, with a volume of 900 mL and a rotation speed of 50 rpm. The dissolution rate was tested using the slurry method, with 10 mL of sample taken and replenished each time. The dissolution results were determined by high performance liquid chromatography, and the cumulative dissolution rate was calculated. The results are shown in Table 6.

[0102] Table 6. Cumulative Dissolution Rate

[0103] Comparing formulations 6-15, it is evident that hydroxypropyl methylcellulose, hydroxypropyl β-cyclodextrin, polyethylene glycol-15-hydroxystearate, and vitamin E polyethylene glycol succinate, as solubilizers, exhibit significant solubilizing effects on sodium crocin. Other excipients show slight solubilizing effects. Sodium dodecyl sulfate and Tween 80 not only fail to increase solubility but also accelerate the precipitation of the active pharmaceutical ingredient (API). Hydroxypropyl β-cyclodextrin significantly increases the dissolution rate of the API in a short time; excessively high concentrations induce vigorous hydrolysis of the API, resulting in a low final solution concentration. Furthermore, the samples prepared with vitamin E polyethylene glycol succinate and polyethylene glycol-15-hydroxystearate did not show a significant decrease in API concentration during dissolution. Both can form deep red droplets with dissolved crocin, suggesting the formation of crocin micelles. High molecular weight compounds, due to the presence of multiple hydrophilic hydroxyl groups, can reduce the activity of API molecules, thus exhibiting some solubilizing effect, with hydroxypropyl methylcellulose showing the most significant effect.

[0104] Example 4 (Investigation of the effect of saffron acid enteric-coated formulation on lipid materials)

[0105] Adding pH adjusters or solubilizers to the formulation can improve the dissolution rate of sodium crocin in slightly acidic media, but the result is still low, with the cumulative dissolution rate failing to exceed 30%. Even with adjustments to the preparation process and formulation, the cumulative dissolution rate of the samples still failed to reach 50%. Comparing the dissolution results of all samples in Examples 2 and 3 revealed that all samples reached the dissolution endpoint within 30 minutes and underwent partial hydrolysis, a phenomenon detrimental to drug absorption in vivo. Therefore, this invention, through exploratory research, discovered that lipid materials, being insoluble in the dissolution medium, can provide a small space for the dissolution of sodium crocin. It was considered whether this characteristic could be used to improve the dissolution rate and solution stability of sodium crocin. Therefore, to further improve the dissolution rate and solution stability of crocin, the characteristics of various lipid materials were analyzed. Through preliminary testing, lipid materials that could potentially achieve the desired results were selected, and further research on the formulation process was conducted. The specific design is shown in Table 7.

[0106] Table 7. Formulas for Saffron Acid Enteric-Coated Preparations

[0107] The preparation process of prescriptions 16-23 is as follows:

[0108] S1. Pretreatment: Sodium crocinate and lactose are pulverized together in a high-shear pulverizer for 30 seconds, and the pulverized mixture is then passed through an 80-mesh sieve.

[0109] S2. Granulation: Place the above mixture, lipid materials (glyceryl monostearate and distearate, glyceryl behenate, hydrogenated castor oil), and hydroxypropyl methylcellulose in a 5L wet granulation tank. Stir at 300 rpm and cut at 2000 rpm for 5 minutes. Dissolve sodium bicarbonate and vitamin E polyethylene glycol succinate in purified water. Pour the solution into the wet granulation tank for wet granulation. Stir at 300 rpm and cut at 2000 rpm for 3 minutes. Pass the resulting soft material through a 40-mesh sieve.

[0110] S3. Drying and granulation: Place the wet granules in a 60℃ forced-air drying oven for 2 hours to dry them. The moisture content of the granules should be controlled within 2.5%. The resulting dry granules are then granulated using a 30-mesh sieve.

[0111] S4. Total Mixing: Add colloidal silica, magnesium stearate and the above dry granules into a 5L cone-shaped mixer hopper and mix for 5 minutes to obtain the total mixture.

[0112] S5. Tableting: The above mixture is compressed into tablets using a rotary tablet press, with the hardness controlled at 70±20N, to obtain plain tablets.

[0113] The in vitro dissolution rate and content of formulation 16-23 were determined (by high performance liquid chromatography), and the results are as follows;

[0114] In vitro dissolution method: pH 6.0 phosphate buffer was used as the dissolution medium, with a volume of 900 mL and a rotation speed of 50 rpm. The dissolution rate was tested using the slurry method, with 10 mL of sample taken and replenished each time. The dissolution results were determined by high performance liquid chromatography, and the cumulative dissolution rate was calculated. The results are shown in Table 8.

[0115] Table 8. Cumulative Dissolution Rate

[0116] Table 8 shows the dissolution test results. A comparison of formulations 18, 20, 22, and 16 indicates that lipid materials can improve the dissolution rate of crocin, but adding lipid materials alone cannot solve the problem of low dissolution. As shown in the previous examples, adding only pH adjusters and solubilizers is insufficient to meet the dissolution requirements. The dissolution results of formulations 19, 21, and 23 meet the pharmacopoeia requirements and are significantly higher than all other formulations, indicating that the lipid materials, pH adjusters, and solubilizers in the formulations have a synergistic effect, significantly improving the solubility and solution stability of sodium crocin. Whether bioavailability and efficacy can also be significantly improved requires further investigation.

[0117] Furthermore, given that behenyl glycerol, as a lipid-soluble material, can provide a stable microenvironment for the dissolution of the active pharmaceutical ingredient, the uneven distribution of lipid-soluble materials in freshly compressed tablets leads to an uneven or unstable microenvironment structure. Considering that the melting point of behenyl glycerol is 65-70℃, the tablets were aged at 70℃ for 2 hours to achieve a more uniform distribution and create a smaller, more uniform, and more stable microenvironment. The in vitro dissolution results (using the same method as above) of the sample prepared according to formulation 21 after aging are shown in Table 9.

[0118] Table 9. Cumulative in vitro dissolution rate of the sample prepared from Formula 21 after maturation.

[0119] Example 5

[0120] Conventional enteric-coated tablets were prepared according to Formulation 1 of Example 2. This enteric-coated tablet formulation does not contain pH adjusters, solubilizers, or lipid materials.

[0121] The uncoated tablets of Formula 1 in Example 2 were first isolated and coated with Opadry 88A180040-CN, increasing the weight by about 3%, and then enteric coated with Opadry 93O65142-CN, increasing the weight by about 10%, thus obtaining enteric-coated tablets.

[0122] Example 6

[0123] Enteric-coated tablets (containing pH adjuster) were prepared according to Formulation 3 of Example 2. This enteric-coated tablet formulation does not contain solubilizers or lipid materials.

[0124] The uncoated tablets of Formula 3 in Example 2 were first isolated and coated with Opadry 88A180040-CN, increasing the weight by about 3%, and then enteredic coated with Opadry 93O65142-CN, increasing the weight by about 10%, thus obtaining enteric-coated tablets.

[0125] Example 7

[0126] Enteric-coated tablets (containing pH adjuster and solubilizer) were prepared according to Formulation 15 of Example 4. This enteric-coated tablet formulation does not contain lipid materials.

[0127] The uncoated tablets of Formula 15 in Example 4 were first isolated and coated with Opadry 88A180040-CN, increasing the weight by about 3%, and then enteric coated with Opadry 93O65142-CN, increasing the weight by about 10%, thus obtaining enteric-coated tablets.

[0128] Example 8

[0129] Enteric-coated tablets (complete formula) were prepared according to formulation 21 of Example 4. The formulation of the enteric-coated tablets contains a pH adjuster, a solubilizer, and lipid materials.

[0130] The uncoated tablets of Formula 21 in Example 4 were aged at 70°C for 2 hours. The aged tablets were first coated with Opadry 88A180040-CN for isolation, resulting in a weight gain of about 3%. Then, they were coated with Opadry 93O65142-CN for enteric coating, resulting in a weight gain of about 10%, thus obtaining enteric-coated tablets.

[0131] Example 9

[0132] According to the formulation (complete formula) of Formula 21 in Example 4, crocin acid was used as a raw material to replace sodium crocin to prepare crocin enteric-coated tablets containing pH adjuster, solubilizer and lipid material.

[0133] S1. Pretreatment: Sodium crocinate and lactose are pulverized together in a high-shear pulverizer for 30 seconds, and the pulverized mixture is then passed through an 80-mesh sieve.

[0134] S2. Granulation: Place the above mixture, glyceryl behenate, and hydroxypropyl methylcellulose in a 5L wet granulation tank. Stir at 300 rpm and cut at 2000 rpm for 5 minutes. Dissolve vitamin E polyethylene glycol succinate in purified water. Pour the solution into the wet granulation tank for wet granulation. Stir at 300 rpm and cut at 2000 rpm for 3 minutes. Pass the resulting soft material through a 40-mesh sieve.

[0135] S3. Drying and granulation: Place the wet granules in a 60℃ forced-air drying oven for 2 hours to dry them. The moisture content of the granules should be controlled within 2.5%. The resulting dry granules are then granulated using a 30-mesh sieve.

[0136] S4. Total Mixing: Add colloidal silica, magnesium stearate and the above dry granules into a 5L cone-shaped mixer hopper and mix for 5 minutes to obtain the total mixture.

[0137] S5. Tableting: The above mixture is compressed into tablets using a rotary tablet press, with the hardness controlled at 70±20N, to obtain plain tablets.

[0138] S6. Drying the slices: Place the above-mentioned raw slices at 70°C and dry for 2 hours to obtain matured raw slices.

[0139] S7. The above-mentioned matured slices are first coated with Opadry 88A180040-CN for isolation, increasing the weight by about 3%, and then coated with Opadry 93O65142-CN for enteric coating, increasing the weight by about 10%.

[0140] Example 10

[0141] Enteric-coated microcapsules were prepared according to Formula 21 (complete formula) in Example 4.

[0142] S1. Pretreatment: Sodium crocinate and lactose are pulverized together in a high-shear pulverizer for 30 seconds, and the pulverized mixture is then passed through an 80-mesh sieve.

[0143] S2. Granulation: Place the above mixture, glyceryl behenate, and hydroxypropyl methylcellulose in a 5L wet granulation tank, stir at 300 rpm, cut at 2000 rpm, and mix for 5 minutes. Pour the sodium bicarbonate and vitamin E polyethylene glycol succinate solution into the wet granulation tank for wet granulation, stir at 300 rpm, cut at 2000 rpm, and granulate for 3 minutes to obtain a soft material;

[0144] S3. Pelletizing: Pour the soft material prepared above into an extrusion rounding machine, install a 0.8mm extrusion screen, turn on the extrusion rounding machine, and prepare micro pellets;

[0145] S4. Drying and granulation: Transfer the above micro-pellets to a fluidized bed, set the inlet air temperature to 60℃ for drying, and after the material is dried, put it into a 10-mesh sieve for sorting, and remove the fine powder with a 40-mesh sieve to obtain dried micro-pellets.

[0146] S5. Coating: The above microparticles are transferred to a fluidized bed and sprayed with Opadry 88A180040-CN for isolation coating, resulting in a weight gain of about 3%. Then, Opadry 93O65142-CN is used for enteric coating, resulting in a weight gain of about 10%.

[0147] Example 11

[0148] Enteric-coated granules were prepared according to Formula 21 (complete formula) in Example 4.

[0149] S1. Pretreatment: Sodium crocinate and lactose are pulverized together in a high-shear pulverizer for 30 seconds, and the pulverized mixture is then passed through an 80-mesh sieve.

[0150] S2. Place the above mixture, glyceryl behenate, and hydroxypropyl methylcellulose in a 5L wet granulation tank, stir at 300 rpm, cut at 2000 rpm, and mix for 5 minutes. Pour the sodium bicarbonate and vitamin E polyethylene glycol succinate solution into the wet granulation tank for wet granulation, stir at 300 rpm, cut at 2000 rpm, and granulate for 3 minutes to obtain a soft material;

[0151] S3. Granulation: Pour the prepared soft material into a rotary granulator and granulate it using a 0.8mm mesh screen at a speed of 20rpm.

[0152] S4. Drying and granulation: Transfer the above particles to a fluidized bed, set the inlet air temperature to 60℃ for drying, and after the material is dried, put it into a 10-mesh sieve for sorting, and remove the fine powder with a 40-mesh sieve to obtain dried particles.

[0153] S5. Coating: The above particles are transferred to a fluidized bed and sprayed with Opadry 88A180040-CN for isolation coating, resulting in a weight gain of about 3%. Then, Opadry 93O65142-CN is used for enteric coating, resulting in a weight gain of about 10%.

[0154] Results and Discussion

[0155] 1. Simulated intestinal fluid cumulative dissolution rate experiment

[0156] In vitro dissolution was determined according to Method 1 of Dissolution and Release Determination for Enteric-coated Preparations in the Pharmacopoeia of the People's Republic of China 2020 Edition, 0931. 750 mL of 0.1 mol / L hydrochloric acid solution was used as the dissolution medium, and the rotation speed was 50 rpm. After 120 minutes, 250 mL of 0.2 mol / L sodium phosphate solution preheated to 37℃±0.5℃ was immediately added, and the rotation speed was 50 rpm. 10 mL of sample was taken each time for replenishment. The dissolution results were determined by high-performance liquid chromatography (HPLC). Formal sampling began before the addition of sodium phosphate solution, and the cumulative dissolution rate was calculated. The results are shown in Table 10.

[0157] Table 10. Cumulative Dissolution Rate

[0158] The above experimental results show that the formulations of Formula 1, Formula 21, and the samples prepared in Examples 5-7 did not simultaneously incorporate the key component combination of the present invention, resulting in excessively low dissolution rates. The enteric-coated tablets, enteric-coated microcapsules, and enteric-coated granules of Examples 8-11, tested for acid resistance and dissolution, all met the high dissolution requirements of the General Rules for Enteric-coated Preparations in the Chinese Pharmacopoeia. The prepared enteric-coated preparations achieved the expected drug release effect, namely, maintaining their intact form for 2 hours in a specified acidic medium (gastric acid), with little or no drug release, while achieving almost 100% dissolution in intestinal fluid. This achieves the sustained-release purpose of the drug not being released in the stomach but rapidly dissolving upon reaching the intestines, significantly improving the bioavailability of crocin administered orally and the concentration of crocin in the intestines.

[0159] 2. Accelerated stability test

[0160] The enteric-coated tablets prepared in Examples 8 and 9 were placed in a stabilizing chamber at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at 0, 1, 3 and 6 months to detect the content and 60-minute dissolution rate of the three batches of samples. The test results are shown in Table 11.

[0161] Table 11. Accelerated Stability Test Results

[0162] Accelerated stability test results show that the sodium crocin enteric-coated preparation and the crocin enteric-coated preparation prepared by this invention have good stability under accelerated conditions. Through content determination, related substances and 60-minute dissolution test, no degradation was observed under accelerated conditions for six months, and there were no significant changes in dissolution and content. All test indicators meet the requirements.

[0163] 3. Comparative pharmacokinetic experiments of enteric-coated saffron acid preparations

[0164] To observe the dissolution and absorption behavior of different formulations in vivo, pharmacokinetic experiments in animals were conducted during the formulation screening process for verification.

[0165] 3.1 Test Sample

[0166] Example 2: Ordinary sodium crocin tablets prepared according to Formula 1; Saffron acid enteric-coated tablets prepared according to Examples 5, 7, 8, and 9; and Sodium crocin enteric-coated microspheres prepared according to Example 10.

[0167] 3.2 Laboratory Animals

[0168] Ordinary grade Beagle dogs, weighing 11.84-13.56 kg, 16-24 months old, half male and half female, laboratory animal quality certificate numbers: No.110334210100040471, No.370825220100019471. Environmental temperature: 16-26℃, humidity: 40%-70%. Day / night cycle: 12h / 12h. These animals underwent at least 14 days of quarantine and observation in the designated breeding area of ​​this center, observed once daily, and no obvious abnormalities were observed before the experiment began.

[0169] 3.3 Grouping and Dosage Design

[0170] The dogs were divided into 6 groups according to Table 12, with 4-6 dogs in each group, half male and half female. The dosage was 100 mg / dog, administered orally.

[0171] Table 12. Grouping and Dosing Design

[0172] 3.4 Animal drug administration and sample collection

[0173] Before administration, the dog's mouth and esophagus were moistened with 15 mL of purified water. The drug was then placed at the base of the dog's tongue, and after swallowing, it was administered with 25 mL of purified water. Approximately 2 mL of whole blood was collected from the saphenous veins of the dog's limbs at corresponding time points before and after administration and placed into pre-marked heparinized blood collection tubes. Blood samples were collected from each group of animals before administration and at 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 16 h, and 20 h after administration.

[0174] 3.5 Test Results

[0175] The pharmacokinetic parameters of each group were calculated. The specific pharmacokinetic parameters of CRA in plasma after administration of each group are shown in Tables 13 and 14.

[0176] Table 13. Results of the comparative study of pharmacokinetic parameters in group A animals of Example 5

[0177] Table 14. Comparative Study Results of Pharmacokinetic Parameters in Group B Animals of Formula 1 in Example 2

[0178] As shown in Tables 13 and 14, the bioavailability of the enteric-coated tablets of Example 5, with the same formulation and process, is three times that of the uncoated ordinary tablets of Formulation 1 in Example 2. Therefore, to further verify the inventiveness and clinical value of the present invention, a pharmacokinetic comparative study was conducted in Beagle dogs using samples from Examples 7, 8, 9, 10, and 5 in Table 12, combined with in vitro dissolution experiments.

[0179] Table 15. Summary of pharmacokinetic parameters comparison study results of Beagle dogs in various examples (n=6)

[0180] Based on the above results, the AUC of the conventional CRAT tablets in Example 2, Prescription 1 (0-t) t 1 / 2 and C max Compared to the enteric-coated sodium crocin formulations of Examples 7-10, the low levels indicate that the enteric-coated formulation of the present invention significantly improves the bioavailability of crocin. Furthermore, the enteric-coated sodium crocin tablets of Example 5 (without pH adjusters, solubilizers, or lipid materials) and the enteric-coated sodium crocin tablets of Example 7 (without lipid materials) both improved the bioavailability and half-life of the drug, consistent with the conclusions of Example 1. The enteric-coated sodium crocin tablets of Example 8, the enteric-coated crocin tablets of Example 9, and the enteric-coated sodium crocin microgranules of Example 10, all containing the complete formulation, significantly improved the AUC. (0-t) and t max The experimental results show that the bioavailability of the enteric-coated sodium crocin preparation prepared in this invention is approximately 3-4 times that of Formulation 1 in Example 2. At the same dosage, compared with the gastric-coated preparation, the enteric-coated preparation prepared in this invention significantly accelerates absorption, effectively prolongs drug half-life, and improves in vivo bioavailability. Compared with conventional enteric-coated preparations, this invention can significantly improve the oral bioavailability of poorly soluble crocin preparations.

[0181] 4. Comparative Pharmacodynamic Experiment of Saffron Acid Enteric-Coated Preparations

[0182] 4.1 Experimental Samples

[0183] Group A: Sodium crocin raw material, provided by Xinglin Traditional Chinese Medicine Technology (Guangzhou) Co., Ltd.;

[0184] Group B: Samples prepared in Example 5;

[0185] Group C: The enteric-coated microspheres prepared in Example 10.

[0186] 4.2 Experimental Animals and Methods

[0187] SPF-grade male SD rats, weighing 170.6-258.1g, were used to establish a chronic heart failure (HFrEF) model induced by coronary artery ligation (excluding 6 rats in the sham-operated group). The remaining rats were routinely fed for 8 weeks post-operation. At week 8, echocardiography was performed, and animals with an ejection fraction (EF) <50% were randomly divided into four groups: a model control group, group A (sodium crocin raw material), group B (ordinary sodium crocin enteric-coated tablets), and group C (all-purpose sodium crocin enteric-coated microgranules), with 6 rats in each group. Each group was administered the medication by gavage once daily for 5 consecutive weeks.

[0188] 4.3 Grouping and Dosage Design

[0189] According to Table 16, the animals were divided into 5 groups, with 6 animals in each group. The dosage is shown in Table 16. All animals were administered the medication by gavage at a dose of 10 mL / kg body weight.

[0190] Table 16. Grouping and Dosing Design

[0191] 4.4 Animal Sample Collection and Testing

[0192] Ejection fraction (EF) was measured in echocardiography at week 0 and week 6 after drug administration. After week 5, 0.5 mL of blood was collected from the sublingual vein of HFrEF rats after anesthesia, allowed to stand at room temperature for about 1 h, centrifuged at 4000 rpm for 10 min, and the serum was separated to detect N-terminal pro-brain natriuretic peptide (NT-proBNP).

[0193] Take the animal heart, rinse it with pre-cooled physiological saline, blot it dry with filter paper, weigh it quickly, and then calculate the cardiac index (CI).

[0194] 4.5 The test results are as follows:

[0195] NT-proBNP is a marker of myocardial injury, and the NT-proBNP level is directly proportional to the degree of myocardial injury. EF, also known as ejection fraction, can assess the systolic and diastolic function of the human heart and the effective ejection volume per minute. The detection results of NT-proBNP, cardiac index and EF of each group are shown in Table 17 and Figures 2 and 3.

[0196] Table 17. Cardiac function test results of each treatment group

[0197] Note: vs. sham surgery group: ## p<0.01; vs. model control group: ** p<0.01;

[0198] Table 17 shows that at week 5 of administration, compared with the sham-operated group, the serum NT-proBNP level and cardiac index in the model control group were significantly increased (p<0.01), while the serum NT-proBNP and cardiac index in groups A, B, and C showed a decreasing trend (p<0.01). This indicates that crocin can improve heart failure to a certain extent, protect cardiomyocytes, reduce myocardial oxidative stress damage, and improve the degree of myocardial fibrosis. Furthermore, compared with the model control group, the ejection fraction (EF%) in groups A, B, and C increased after 5 weeks of administration (p<0.01), indicating that crocin can improve cardiac ejection function in heart failure rats, and the enteric-coated microcapsules in group C showed a significant effect in improving ejection function. These results suggest that crocin can be used to treat heart failure. The full-formula crocin enteric-coated microcapsules in group C, containing pH adjusters, solubilizers, and lipid materials, showed significantly stronger effects than the ordinary sodium crocin enteric-coated tablets in group B and the raw material in group A, exhibiting the best therapeutic effect on HFrEF. The enteric-coated preparation of crocin prepared by this invention can effectively prevent and treat cardiovascular and cerebrovascular diseases, greatly expanding the clinical value and pharmaceutical properties of crocin.

[0199] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A highly bioavailable crocin preparation, characterized in that, The saffron acid preparation is an oral enteric-coated formulation made from the active ingredients of saffron. The active ingredient in saffron is selected from at least one of saffron acid and sodium saffronate.

2. The saffron acid preparation according to claim 1, characterized in that, The saffron acid preparation includes, in addition to the active ingredient of saffron, at least one of a pH adjuster, a solubilizer, and a lipid material.

3. The saffron acid preparation according to claim 2, characterized in that, The saffron acid preparation includes saffron active ingredients, pH adjusters, solubilizers, and lipid materials.

4. The saffron acid preparation according to claim 3, characterized in that, The pH adjuster is selected from at least one of sodium bicarbonate, sodium alginate, meglumine, sodium hydroxide, and disodium hydrogen phosphate.

5. The saffron acid preparation according to claim 3, characterized in that, The solubilizer is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl β-cyclodextrin, povidone, copovidone, hydroxypropyl cellulose, polyethylene glycol, polyethylene glycol-15 hydroxystearate, and vitamin E polyethylene glycol succinate.

6. The saffron acid preparation according to claim 3, characterized in that, The lipid material is selected from at least one of mono- and di-stearyl glycerol, behenicol glycerol, and hydrogenated castor oil.

7. The saffron acid preparation according to any one of claims 3-6, characterized in that, The saffron acid preparation comprises, by weight, 1 part saffron active ingredient, 1-10 parts pH adjuster, 1-20 parts solubilizer and 1-20 parts lipid material.

8. The saffron acid preparation according to any one of claims 1-7, characterized in that, The saffron acid preparation also includes fillers, flow aids, lubricants, and enteric excipients.

9. The saffron acid preparation according to any one of claims 1-8, characterized in that, The dosage form of the crocin preparation is selected from any one of enteric-coated tablets, enteric-coated capsules, enteric-coated granules, and enteric-coated microcapsules.

10. The use of the crocin preparation according to any one of claims 1-9 in the preparation of drugs for treating cardiovascular and cerebrovascular diseases and metabolic diseases.

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