A high bioavailability oral puerarin pharmaceutical composition, a preparation method thereof and application thereof

Abstract

The application discloses a high-bioavailability oral puerarin pharmaceutical composition, a preparation method and application thereof. Specifically, the application discloses a puerarin pharmaceutical composition which comprises puerarin and an absorption promoter; the absorption promoter is sodium caprate. The puerarin pharmaceutical composition has high oral bioavailability, long sustained-release effect and long in-vivo half-life, and can meet the clinical medication requirement; the preparation method of the puerarin pharmaceutical composition is simple in preparation process and controllable in quality, and can meet the industrialized scale production.

Description

Technical Field

[0001] This invention relates to a highly bioavailable puerarin oral pharmaceutical composition, its preparation method, and its application. Background Technology

[0002] Puerarin, also known as puerarin flavonoid, is officially called 8-β-D-glucopyranose-4',7-dihydroxyisoflavone, with the chemical formula C. 21 H 20 O9, with the structural formula shown in Formula 1, is an isoflavone derivative isolated from the traditional Chinese medicine kudzu root.

[0003]

[0004] The main effects of puerarin include vasodilation, improved blood circulation, reduced myocardial oxygen consumption, inhibition of cancer cells, increased coronary blood flow, regulation of microcirculation, treatment of sudden deafness at all ages, and reduction of the risk of cardiovascular and cerebrovascular diseases. Clinically, it is mainly used as an adjunct treatment for coronary heart disease, angina pectoris, myocardial infarction, retinal artery and vein occlusion, and sudden deafness. In addition, researchers have found that puerarin also has pharmacological effects such as weight loss, lowering blood lipids, and lowering blood sugar.

[0005] Currently, the main puerarin preparation on the market is puerarin injection, administered via intravenous drip once daily for 10-20 days as one course of treatment. Typically, 2-3 consecutive courses are required, making the medication very inconvenient. Furthermore, due to technical issues with the purification process of the herbal monomer, puerarin injection contains some sensitizing impurities, causing severe adverse reactions in some patients. The intravenous administration method also affects the safety of puerarin use.

[0006] Compared to intravenous injection, oral administration offers better patient compliance and higher safety. However, puerarin belongs to BCS Class IV drugs, exhibiting poor water and lipid solubility, and is a substrate of P-glycoprotein, resulting in an absolute oral bioavailability of less than 5%, hindering its clinical application. Currently, no oral puerarin formulations are available on the market. Patent CN116036023A discloses a puerarin-loaded microsphere that can be effectively released in the intestinal tract without being digested by gastric juices. However, puerarin is stable under gastric acid conditions, therefore enteric coating is not necessary; this patent does not include in vivo pharmacokinetic studies, and the preparation method is complex with a low drug loading capacity. Patent CN105982877B discloses a puerarin nanocrystalline capsule and its preparation method, which increases the absolute oral bioavailability of puerarin to approximately 20%. However, this preparation process is extremely complex, requiring three steps: mixing, high-pressure cyclic homogenization, and lyophilization / spray drying. Therefore, no related products have yet been marketed.

[0007] Furthermore, the pharmacokinetics of puerarin injection in humans showed that its elimination half-life (t) was short.1 / 2β The half-life of puerarin is relatively short, only 74.0 min. Extending the half-life of puerarin in vivo through sustained-release technology can improve patient compliance. Therefore, an oral formulation of puerarin with high bioavailability and sustained-release effect has significant clinical demand and market potential. Summary of the Invention

[0008] To address the deficiencies described in the prior art, this invention provides a highly bioavailable puerarin oral pharmaceutical composition, its preparation method, and its applications. The puerarin pharmaceutical composition of this invention exhibits high oral bioavailability and a long sustained-release effect, with a long in vivo half-life, meeting clinical medication needs. The preparation method of the puerarin pharmaceutical composition of this invention is simple, with controllable quality, and can meet the requirements for industrial-scale production.

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

[0010] A puerarin pharmaceutical composition comprising puerarin and an absorption enhancer; said absorption enhancer is sodium decanoate.

[0011] In one embodiment, the mass ratio of puerarin to the absorption promoter is 1:(0.5-25), for example, 1:1, 1:3, 1:5, 1:10 and 1:20; preferably, the mass ratio of puerarin to the absorption promoter is 1:(5-20); more preferably, the mass ratio of puerarin to the absorption promoter is 1:(8-12).

[0012] In one embodiment, the puerarin pharmaceutical composition further comprises a sustained-release agent, which is one or more selected from hydroxypropyl methylcellulose, ethylcellulose, polyethylene, sodium carboxymethyl cellulose, polyvinyl chloride, povidone, ethylene-vinyl acetate copolymer, carbomer, and sodium alginate; preferably, the sustained-release agent is hydroxypropyl methylcellulose and / or ethylcellulose; for example, a combination of hydroxypropyl methylcellulose and ethylcellulose.

[0013] In one embodiment, when the puerarin pharmaceutical composition contains a sustained-release agent, the puerarin pharmaceutical composition comprises the following components in weight fractions: 3-12% puerarin, 40-85% absorption enhancer, and 10-50% sustained-release agent.

[0014] In this invention, the mass fraction of each component in the puerarin pharmaceutical composition refers to the mass percentage of each component relative to the total mass of the puerarin pharmaceutical composition.

[0015] In one embodiment, the mass fraction of puerarin is 5-10%, preferably 7-10%; more preferably, the mass fraction of puerarin is 7.8-8.5%.

[0016] In one embodiment, the mass fraction of the absorption promoter is 45-80%, preferably 65-80%; more preferably, the mass fraction of the absorption promoter is 78-80%.

[0017] In one embodiment, the mass fraction of the sustained-release agent is 10-45%, preferably 10-25%; more preferably, the mass fraction of the sustained-release agent is 12-14%.

[0018] In one embodiment, when the sustained-release agent is a combination of hydroxypropyl methylcellulose and ethylcellulose, the mass fraction of the hydroxypropyl methylcellulose is 9-40%, preferably 7-20%, and more preferably 9.5-10.5%; the mass fraction of the ethylcellulose is 1-5%, preferably 3-5%, and more preferably 2.5-3.5%.

[0019] In one embodiment, the puerarin pharmaceutical composition comprises 7.8-8.5% puerarin by mass, 78-80% an absorption enhancer by mass, 9.5-10.5% hydroxypropyl methylcellulose by mass, and 2.5-3.5% ethylcellulose by mass.

[0020] In one embodiment, the puerarin pharmaceutical composition also includes other pharmaceutical excipients, such as lubricants.

[0021] In one embodiment, the lubricant is magnesium stearate.

[0022] In one embodiment, the mass fraction of the lubricant is 0.1-1%, for example 0.4-0.6%, or even 0.5%.

[0023] In one embodiment, the puerarin pharmaceutical composition comprises the following components by mass fraction:

[0024] Formula 1: 7.9% puerarin, 78.6% sodium decanoate, 3.0% ethyl cellulose, 10.0% hydroxypropyl methylcellulose and 0.5% magnesium stearate;

[0025] Formula 2: 7.0% puerarin, 69.5% sodium decanoate, 3.0% ethyl cellulose, 20.0% hydroxypropyl methylcellulose and 0.5% magnesium stearate;

[0026] Formula 3: 6.0% puerarin, 60.5% sodium decanoate, 3.0% ethyl cellulose, 30.0% hydroxypropyl methylcellulose and 0.5% magnesium stearate;

[0027] Formula 4: 5.1% puerarin, 51.4% sodium decanoate, 3.0% ethyl cellulose, 40.0% hydroxypropyl methylcellulose and 0.5% magnesium stearate;

[0028] Formula 5: 7.7% puerarin, 76.8% sodium decanoate, 5.0% ethyl cellulose, 10.0% hydroxypropyl methylcellulose and 0.5% magnesium stearate;

[0029] Formula 6: 6.8% puerarin, 67.7% sodium decanoate, 5.0% ethyl cellulose, 20.0% hydroxypropyl methylcellulose and 0.5% magnesium stearate;

[0030] Formula 7: 5.9% puerarin, 58.6% sodium decanoate, 5.0% ethyl cellulose, 30.0% hydroxypropyl methylcellulose and 0.5% magnesium stearate;

[0031] Formula 8: 5.0% puerarin, 49.5% sodium decanoate, 5.0% ethyl cellulose, 40.0% hydroxypropyl methylcellulose and 0.5% magnesium stearate;

[0032] Formula 9: 5.0% puerarin, 49.5% sodium decanoate, 5.0% polyethylene, 40.0% sodium carboxymethyl cellulose and 0.5% magnesium stearate;

[0033] Formula 10: 5.0% puerarin, 49.5% sodium decanoate, 5.0% polyvinyl chloride, 40.0% povidone and 0.5% magnesium stearate.

[0034] Formula 11: 5.0% puerarin, 49.5% sodium decanoate, 5.0% ethylene-vinyl acetate copolymer, 20.0% carbomer, 20% sodium alginate and 0.5% magnesium stearate;

[0035] Formula 12: 8.0% puerarin, 79.0% sodium decanoate, 3.0% ethyl cellulose and 10.0% hydroxypropyl methylcellulose;

[0036] Formula 13: 9.6% puerarin, 76.9% sodium decanoate, 3.0% ethyl cellulose, 10.0% hydroxypropyl methylcellulose and 0.5% magnesium stearate.

[0037] In one embodiment, the puerarin pharmaceutical composition comprises puerarin as described above and an absorption enhancer as described above.

[0038] In one embodiment, the puerarin pharmaceutical composition comprises puerarin as described above, an absorption enhancer as described above, and a sustained-release agent as described above.

[0039] In one embodiment, the puerarin pharmaceutical composition comprises puerarin as described above, an absorption enhancer as described above, a sustained-release agent as described above, and a lubricant as described above.

[0040] In one embodiment, the dosage form of the puerarin pharmaceutical composition is a tablet, capsule, or droplet, more preferably a tablet or capsule.

[0041] In this invention, the capsule shell of the capsule is a pharmaceutically acceptable capsule shell, such as a gelatin capsule shell or a hydroxypropyl methylcellulose capsule shell.

[0042] This invention also provides a method for preparing a puerarin pharmaceutical composition, comprising the following steps:

[0043] The puerarin and the absorption enhancer are mixed, granulated, and then compressed into tablets or filled into capsules.

[0044] In one embodiment, when the puerarin pharmaceutical composition further comprises a sustained-release agent, the preparation method includes the following steps: mixing the puerarin, the absorption enhancer, and the sustained-release agent, granulating, and then compressing into tablets or filling capsules.

[0045] In one embodiment, when the puerarin pharmaceutical composition contains a sustained-release agent and a lubricant, the preparation method includes the following steps: mixing the puerarin, the absorption promoter, and the sustained-release agent, granulating, then mixing with the lubricant, and finally compressing into tablets or filling capsules.

[0046] In one embodiment, when the puerarin pharmaceutical composition further comprises a sustained-release agent, the granulation is either wet granulation or dry granulation, preferably wet granulation.

[0047] In one embodiment, when the sustained-release agent is hydroxypropyl methylcellulose and ethylcellulose, the ethylcellulose exists in the form of a solution; the solution is, for example, an alcohol solution, preferably an ethanol solution, and more preferably an 80% ethanol solution; the mass fraction of ethylcellulose in the ethylcellulose solution is 2-5%, for example, 3%; the mass fraction is the percentage of the mass of ethylcellulose to the total mass of the ethylcellulose solution.

[0048] The present invention also provides a pharmaceutical formulation comprising the puerarin pharmaceutical composition as described above.

[0049] In one embodiment, the pharmaceutical preparation is a tablet, capsule, or droplet, more preferably a tablet or capsule.

[0050] In this invention, the capsule shell of the capsule is a pharmaceutically acceptable capsule shell, such as a gelatin capsule shell or a hydroxypropyl methylcellulose capsule shell.

[0051] The present invention also provides the use of the puerarin pharmaceutical composition or the pharmaceutical preparation described above in the preparation of a drug for the treatment and / or prevention of sudden deafness and cardiovascular and cerebrovascular diseases; the cardiovascular and cerebrovascular diseases may be one or more of coronary heart disease, angina pectoris, myocardial infarction, and retinal arterial and venous occlusion.

[0052] 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.

[0053] 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.

[0054] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0055] 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.

[0056] The reagents and raw materials used in this invention are all commercially available.

[0057] The positive and progressive effects of this invention are as follows:

[0058] (1) By employing a technology that promotes the intestinal penetration of puerarin, this invention significantly improves the transmembrane transport capacity of puerarin in the small intestine. This improvement significantly increases the oral bioavailability of puerarin from 2% to 48% in animal experiments;

[0059] (2) This invention utilizes sustained-release technology to effectively slow down the dissolution rate of puerarin in the pharmaceutical composition. This technology reduces the half-life (t) of orally administered puerarin. 1 / 2 In animal studies, the duration of action of puerarin was extended from 0.94 h to 4.21 h, thus prolonging its effect in vivo.

[0060] (3) Beagle dog experiments showed that, compared with intravenous infusion of 1 mg / kg puerarin injection, the present invention has a higher area under the drug-time curve (AUC) at an oral dose of 8 mg / kg, indicating that the present invention has the potential to replace puerarin injection.

[0061] (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

[0062] Figure 1 Release curves of pure puerarin and the drug in Examples 1, 2, 9, 28, 29, 30, 31, and 32.

[0063] Figure 2 Drug-time curves after intravenous injection of puerarin, gavage administration of puerarin, and gavage administration in Examples 1 and 2 are shown in rats.

[0064] Figure 3 Drug-time curves after oral administration to rats in Examples 3, 4, and 5;

[0065] Figure 4 Drug-time curves after oral administration of puerarin suspension to rats in Examples 9, 28, 29, 30, 31, and 32;

[0066] Figure 5 Dissolution curves for Examples 2, 15, 16, 17, 18, 19, 20, 21, and 22;

[0067] Figure 6 Drug-time curves after oral administration to rats in Examples 15, 19, 20, and 21;

[0068] Figure 7 Drug-time curves after intravenous infusion of puerarin and oral administration of Examples 26 and 27 to beagle dogs. Detailed Implementation

[0069] 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.

[0070] Preparation Examples 1-32: Preparation Examples of Puerarin Pharmaceutical Compositions

[0071] Example 1

[0072] The ratio of puerarin to sodium caprylate in the puerarin pharmaceutical composition is 1:10.

[0073] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of sodium caprylate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0074] Example 2

[0075] The ratio of puerarin to sodium decanoate in the puerarin pharmaceutical composition is 1:10.

[0076] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of sodium decanoate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0077] Example 3

[0078] The ratio of puerarin to sodium decanoate in the puerarin pharmaceutical composition is 1:1.

[0079] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 100.0 mg of sodium decanoate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0080] Example 4

[0081] The ratio of puerarin to sodium decanoate in the puerarin pharmaceutical composition is 1:3.

[0082] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 300.0 mg of sodium decanoate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0083] Example 5

[0084] The ratio of puerarin to sodium decanoate in the puerarin pharmaceutical composition is 1:5.

[0085] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 500.0 mg of sodium decanoate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0086] Example 6

[0087] The ratio of puerarin to sodium decanoate in the puerarin pharmaceutical composition is 1:20.

[0088] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 2000.0 mg of sodium decanoate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0089] Example 7

[0090] The ratio of puerarin to sodium lauryl lactone in the puerarin pharmaceutical composition is 1:10.

[0091] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of sodium laurate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0092] Example 8

[0093] The ratio of puerarin to glyceryl monocaprylate in the puerarin pharmaceutical composition is 1:10.

[0094] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of caprylic acid glyceride, mix them simply, and fill them into capsules to obtain the puerarin drug composition.

[0095] Example 9

[0096] The ratio of puerarin to trioctyl glycerol in the puerarin pharmaceutical composition is 1:10.

[0097] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of tricaprylic acid glyceride, mix them simply, and fill them into capsules to obtain the puerarin drug composition.

[0098] Example 10

[0099] The ratio of puerarin to monodecanoic acid glyceride in the puerarin pharmaceutical composition is 1:10.

[0100] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of monodecanoic acid glyceride, mix them simply, and then fill them into capsules to obtain the puerarin drug composition.

[0101] Example 11

[0102] The ratio of puerarin to glyceryl laurate in the puerarin pharmaceutical composition is 1:10.

[0103] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of glyceryl laurate, mix them simply, and then fill them into capsules to obtain the puerarin drug composition.

[0104] Example 12

[0105] The ratio of puerarin to palmitoylcarnitine in the puerarin drug composition is 1:10.

[0106] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of palmitoylcarnitine, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0107] Example 13

[0108] The ratio of puerarin to lauroylcarnitine chloride in the puerarin pharmaceutical composition is 1:10.

[0109] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of lauroylcarnitine chloride, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0110] Example 14

[0111] The ratio of puerarin to sodium cholate in the puerarin pharmaceutical composition is 1:10.

[0112] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of sodium cholate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0113] Example 15

[0114] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 7.9%, sodium decanoate 78.6%, ethyl cellulose 3.0%, hydroxypropyl methylcellulose 10.0%, and magnesium stearate 0.5%.

[0115] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 237.0 mg of puerarin, 300.0 mg of hydroxypropyl methylcellulose, and 2358.0 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 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0116] Example 16

[0117] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 7.0%, sodium decanoate 69.5%, ethyl cellulose 3.0%, hydroxypropyl methylcellulose 20.0%, and magnesium stearate 0.5%.

[0118] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 210.0 mg of puerarin, 600.0 mg of hydroxypropyl methylcellulose, and 2085.0 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 mass. Pass the soft mass through a sieve to make uniformly sized particles and dry them in a 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0119] Example 17

[0120] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 6.0%, sodium decanoate 60.5%, ethyl cellulose 3.0%, hydroxypropyl methylcellulose 30.0%, and magnesium stearate 0.5%.

[0121] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 180.0 mg of puerarin, 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 mass. Pass the soft mass through a sieve to make uniformly sized particles and dry them in a 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0122] Example 18

[0123] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 5.1%, sodium decanoate 51.4%, ethyl cellulose 3.0%, hydroxypropyl methylcellulose 40.0%, and magnesium stearate 0.5%.

[0124] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 153.0 mg of puerarin, 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 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0125] Example 19

[0126] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 7.7%, sodium decanoate 76.8%, ethyl cellulose 5.0%, hydroxypropyl methylcellulose 10.0%, and magnesium stearate 0.5%.

[0127] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 231.0 mg of puerarin, 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 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0128] Example 20

[0129] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 6.8%, sodium decanoate 67.7%, ethyl cellulose 5.0%, hydroxypropyl methylcellulose 20.0%, and magnesium stearate 0.5%.

[0130] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 204.0 mg of puerarin, 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 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0131] Example 21

[0132] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 5.9%, sodium decanoate 58.6%, ethyl cellulose 5.0%, hydroxypropyl methylcellulose 30.0%, and magnesium stearate 0.5%.

[0133] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 177.0 mg of puerarin, 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 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0134] Example 22

[0135] The formulation components and their weight percentages of puerarin sustained-release preparations are as follows:

[0136] Puerarin 5.0%, sodium decanoate 49.5%, ethyl cellulose 5.0%, hydroxypropyl methylcellulose 40.0%, magnesium stearate 0.5%.

[0137] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 150.0 mg of puerarin, 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 make a soft material. Pass the soft material through a sieve to make uniformly sized particles and dry them in a 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0138] Example 23

[0139] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 5.0%, sodium decanoate 49.5%, polyethylene 5.0%, sodium carboxymethyl cellulose 40.0%, and magnesium stearate 0.5%.

[0140] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 150.0 mg of puerarin, 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 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0141] Example 24

[0142] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 5.0%, sodium decanoate 49.5%, polyvinyl chloride 5.0%, povidone 40.0%, and magnesium stearate 0.5%.

[0143] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 150.0 mg of puerarin, 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 form a soft material. Pass the soft material through a sieve to form particles of uniform size and dry them in a 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0144] Example 25

[0145] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 5.0%, sodium decanoate 49.5%, ethylene-vinyl acetate copolymer 5.0%, carbomer 20.0%, sodium alginate 20%, and magnesium stearate 0.5%.

[0146] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 150.0 mg of puerarin, 600.0 mg of carbomer, 600.0 mg of sodium alginate, and 1485.0 mg of sodium decanoate. Mix the three together and add 5.0 mL of ethylene-vinyl acetate copolymer solution (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 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0147] Example 26

[0148] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 8.0%, sodium decanoate 79.0%, ethyl cellulose 3.0%, and hydroxypropyl methylcellulose 10.0%.

[0149] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 240.0 mg of puerarin, 300.0 mg of hydroxypropyl methylcellulose, and 2370.0 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 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0150] Finally, 300 mg was weighed and filled into a No. 0 capsule, which is a regular empty capsule, No. 0, Aoquanjian®, produced by Shanxi Guangsheng Capsule Co., Ltd.

[0151] Example 27

[0152] The formulation components and their weight percentages of the puerarin sustained-release preparation are as follows: puerarin 9.6%, sodium decanoate 76.9%, ethyl cellulose 3.0%, hydroxypropyl methylcellulose 10.0%, and magnesium stearate 0.5%.

[0153] In this embodiment, the preparation process of the puerarin sustained-release formulation is as follows: Weigh 288.3 mg of puerarin, 300.0 mg of hydroxypropyl methylcellulose, and 2306.7 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 60°C oven for 2 hours. Finally, add 15.0 mg of magnesium stearate and compress into tablets to obtain the puerarin sustained-release formulation.

[0154] Example 28

[0155] The ratio of puerarin to sodium deoxycholate in the puerarin pharmaceutical composition is 1:10.

[0156] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of sodium deoxycholate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0157] Example 29

[0158] The ratio of puerarin to dodecyl-β-D-maltodextrin in the puerarin pharmaceutical composition is 1:10.

[0159] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of dodecyl-β-D-maltodextrin, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0160] Example 30

[0161] The ratio of puerarin to sucrose laurate in the puerarin pharmaceutical composition is 1:10.

[0162] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of sucrose laurate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0163] Example 31

[0164] The ratio of puerarin to sodium dodecyl sulfate in the puerarin pharmaceutical composition is 1:10.

[0165] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of sodium dodecyl sulfate, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0166] Example 32

[0167] The ratio of puerarin to SNAC in the puerarin pharmaceutical composition is 1:10.

[0168] In this embodiment, the preparation process of the puerarin drug composition is as follows: weigh 100.0 mg of puerarin and 1000.0 mg of SNAC, mix them simply, and then granulate and compress them into tablets to obtain the puerarin drug composition.

[0169] Examples of efficacy of puerarin drug compositions (Examples 1-7)

[0170] Example 1

[0171] Evaluation of the effects of puerarin and absorption enhancers on drug release behavior.

[0172] Take appropriate amounts of pure puerarin and those from Examples 1, 2, 9, 28, 29, 30, 31, and 32 into glass bottles, and add pure water to achieve a target drug concentration of 10 mg / mL. Place the samples at 37°C and 100 rpm and stir to ensure complete drug release. After 48 hours, remove the samples, centrifuge at 14,000 rpm, collect the supernatant, dilute it, and determine the drug concentration to calculate the drug release amount. Results are shown below. Figure 1 Table 1.

[0173] Table 1. Drug release (%) in pure puerarin and in Examples 1, 2, 9, 28, 29, 30, 31, and 32

[0174]

[0175] The experimental results showed that under these conditions, only 36.16 ± 0.55% of the pure puerarin was released. After adding absorption enhancers, the solubility and release of the drugs, except for glyceryl tricaprylate, were significantly improved. In Examples 1, 2, 28, 31, and 32, the drugs were almost completely released. These results indicate that some absorption enhancers can significantly improve the solubility of puerarin and optimize its in vitro release behavior, which will be beneficial for drug absorption.

[0176] Example 2

[0177] Absolute oral bioavailability of puerarin in rats and relative oral bioavailability in rats in Examples 1 and 2:

[0178] Twelve healthy male Wistar rats, weighing 250 ± 20 g, were randomly divided into four groups and fasted for 12 h. One group was intravenously injected with 10 mg / kg of puerarin saline solution (0.5 mg / mL), and blood was collected from the orbital venous plexus at 5, 15, 30, 60, and 120 min after anesthesia. The other three groups were administered 100 mg / kg of puerarin suspension, Example 1, and Example 2 by gavage, respectively, and blood was collected from the orbital venous plexus at 0.5, 1, 2, and 4 h after anesthesia. Plasma samples were processed, and the blood drug concentrations at different time points were determined by HPLC, and the pharmacokinetic parameters were calculated.

[0179] The results are as follows Figure 2 As shown, compared to puerarin suspension, the oral bioavailability of puerarin in Examples 1 and 2 was significantly improved. Specific pharmacokinetic parameters are shown in Table 1. Absolute oral bioavailability of puerarin suspension in rats (F... abs The oral bioavailability (F) of puerarin in rats in Examples 1 and 2 of the present invention was only 2.09%, which was 6.99 times and 22.61 times that of puerarin suspension, respectively. That is, the absolute oral bioavailability of puerarin in Examples 1 and 2 was 14.10% and 48.00%, respectively. The specific pharmacokinetic parameters are shown in Table 2.

[0180] Table 2. Pharmacokinetic parameters of puerarin in rats after intravenous injection of physiological saline solution and gavage administration of puerarin suspension, as well as in Examples 1 and 2.

[0181]

[0182] Example 3

[0183] Pharmacokinetic assays of rats after oral administration in Examples 3, 4, and 5

[0184] Nine healthy male Wistar rats, weighing 250 ± 20 g, were randomly divided into three groups and fasted for 12 h. They were administered drugs (Examples 3, 4, and 5) by gavage at 100 mg / kg. Blood samples were collected from the orbital venous plexus at 0.5, 1, 2, and 4 h after anesthesia. Plasma samples were processed, and plasma drug concentrations at different time points were determined by HPLC to calculate pharmacokinetic parameters.

[0185] The results are as follows Figure 3 As shown, the absolute oral bioavailability of puerarin in Examples 3, 4 and 5 of the present invention is 3.74%, 9.81% and 48.00%, respectively, which improves the oral absorption of puerarin. The specific pharmacokinetic parameters are shown in Table 3.

[0186] Table 3. Pharmacokinetic parameters of rats administered via gavage in Examples 3, 4 and 5

[0187]

[0188] Example 4

[0189] Oral pharmacokinetic assays in rats in Examples 9, 28, 29, 30, 31, and 32

[0190] Twenty-one healthy male Wistar rats, weighing 250 ± 20 g, were randomly divided into 7 groups and fasted for 12 h. Each group was administered 100 mg / kg of puerarin suspension by gavage (used as a control) in Examples 9, 28, 29, 30, 31, and 32. Blood samples were collected from the orbital venous plexus at 0, 0.83, 1.33, 2, and 4 h after anesthesia. Plasma samples were processed, and the blood drug concentration at different time points was determined by HPLC. The relative bioavailability (%) was calculated. Results are shown below. Figure 4 Table 4.

[0191] Examples 28, 29, 30, 31, and 32 of the present invention can significantly improve the absorption of the drug in rats, with relative bioavailability of 578.69%, 274.34%, 752.73%, 651.24%, and 630.43%, respectively.

[0192] Table 4. Relative bioavailability (%) of puerarin in rats after gavage administration of puerarin suspension and in Examples 9, 28, 29, 30, 31, and 32

[0193]

[0194] Example 5

[0195] Dissolution determination in Examples 2, 15, 16, 17, 18, 19, 20, 21, and 22

[0196] Examples 2, 15, 16, 17, 18, 19, 20, 21, and 22 were placed in brown vials equipped with rotors and 30 mL of PBS solution was added. The vials were placed in a water bath at 37 ± 0.5 °C and magnetically stirred. 0.5 mL samples were taken at 0.5, 1, 2, 4, 6, and 8 h, and 0.5 mL of PBS was added to make up the volume. After sampling, the samples at each time point were centrifuged, the supernatant was collected, diluted, and then analyzed by HPLC.

[0197] The results are as follows Figure 5 As shown in Table 5, the dissolution rates of Examples 15, 16, 17, 18, 19, 20, 21, and 22, after the addition of the skeleton-type sustained-release material, were all slower, and all were completely released after more than 4 hours.

[0198] Table 5. Dissolution determination of Examples 2, 15, 16, 17, 18, 19, 20, 21, and 22

[0199]

[0200] Example 6

[0201] Oral pharmacokinetic assays in rats in Examples 15, 19, 20, and 21

[0202] Twelve healthy male Wistar rats, weighing 250 ± 20 g, were randomly divided into four groups and fasted for 12 h. They were administered drugs (Examples 15, 19, 20, and 21) by gavage at 100 mg / kg. Blood samples were collected from the orbital venous plexus at 0.5, 1, 2, and 4 h after anesthesia. Plasma samples were processed, and plasma drug concentrations at different time points were determined by HPLC to calculate pharmacokinetic parameters.

[0203] The results are as follows Figure 6 As shown, the absolute oral bioavailability of puerarin in Examples 15, 19, 20, and 21 of the present invention were 49.25%, 26.50%, 11.87%, and 12.71%, respectively. Compared with puerarin suspension, the oral absorption of the present invention was significantly improved. The t... 1 / 2 The in vivo half-lives of puerarin were 2.58±0.98 h, 7.95±7.47 h, 1.36±0.10 h, and 3.09±1.41 h, respectively. Compared with Example 2 without the addition of a matrix-type sustained-release material, the in vivo half-life of puerarin was significantly increased. The specific pharmacokinetic parameters are shown in Table 6.

[0204] Table 6. Pharmacokinetic parameters of rats administered via gavage in Examples 15, 19, 20 and 21.

[0205]

[0206] Example 7

[0207] Pharmacokinetic assays of beagle dogs after intravenous infusion and oral administration of puerarin, as described in Examples 26 and 27.

[0208] Six male beagle dogs, weighing 20 kg ± 2 kg, were divided into three groups. Before the experiment, the beagle dogs were fasted but allowed free access to water for 12 hours. One group received an intravenous infusion of 1 mg / kg puerarin injection (solvent containing 0.16% DMSO and 5% glucose), another group was given 3 tablets of Example 26 (dose 4 mg / kg), and the third group was given 6 tablets of Example 27 (dose 8 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 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 HPLC analysis.

[0209] The results are as follows Figure 7 As shown, the absolute oral bioavailability of the puerarin in Examples 26 and 27 of the present invention reached 11.95% and 13.02%, respectively, in beagle dogs. The AUC of puerarin after intravenous infusion of 1 mg / kg of puerarin in physiological saline in beagle dogs was 5.21 ± 1.55 μg / mL*h, and the AUC of puerarin in Example 27 after administration of 8 mg / kg was 12.13 ± 7.15 μg / mL*h. The AUC of 8 mg / kg of puerarin in Example 27 after oral administration in beagle dogs was much higher than that of 1 mg / kg of intravenous injection, indicating that the oral puerarin preparation of Example 27 has the potential to be a clinical substitute for puerarin injection.

[0210] Table 7. Pharmacokinetic parameters of intravenous infusion and oral gavage of puerarin in beagle dogs in Examples 26 and 27.

[0211]

[0212] 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 puerarin pharmaceutical composition, characterized in that, The puerarin pharmaceutical composition comprises the following components in the following mass fractions: 3-12% puerarin, 40-85% absorption enhancer and 10-50% sustained-release agent; the absorption enhancer is sodium decanoate; the mass ratio of puerarin to the absorption enhancer is 1:(5-10).

2. The puerarin pharmaceutical composition according to claim 1, characterized in that, The mass ratio of puerarin to the absorption promoter is 1:(8-10).

3. The puerarin pharmaceutical composition according to claim 1, characterized in that, The sustained-release agent is one or more of hydroxypropyl methylcellulose, ethylcellulose, polyethylene, sodium carboxymethyl cellulose, polyvinyl chloride, povidone, ethylene-vinyl acetate copolymer, carbomer, and sodium alginate.

4. The puerarin pharmaceutical composition according to claim 3, characterized in that, It meets one or more of the following conditions: (1) The sustained-release agent is hydroxypropyl methylcellulose and / or ethylcellulose; (2) The mass fraction of the puerarin is 5-10%; (3) The mass fraction of the absorption promoter is 45-80%; (4) The mass fraction of the sustained-release agent is 10-45%; (5) When the sustained-release agent is a combination of hydroxypropyl methylcellulose and ethylcellulose, the mass fraction of the hydroxypropyl methylcellulose is 9-40%; and the mass fraction of the ethylcellulose is 1-5%. (6) The puerarin pharmaceutical composition further comprises a lubricant; The dosage form of the puerarin pharmaceutical composition described in (7) is tablets, capsules or pills.

5. The puerarin pharmaceutical composition according to claim 3, characterized in that, When the sustained-release agent is a combination of hydroxypropyl methylcellulose and ethylcellulose, the mass fraction of the hydroxypropyl methylcellulose is 7-20% and the mass fraction of the ethylcellulose is 3-5%.

6. The puerarin pharmaceutical composition according to claim 4, characterized in that, It meets one or more of the following conditions: (1) The sustained-release agent is a combination of hydroxypropyl methylcellulose and ethylcellulose; (2) The mass fraction of the puerarin is 7-10%; (3) The mass fraction of the absorption promoter is 65-80%; (4) The mass fraction of the sustained-release agent is 10-25%; (5) The lubricant is magnesium stearate; (6) The mass fraction of the lubricant is 0.1-1%; The dosage form of the puerarin pharmaceutical composition described in (7) is tablets or capsules.

7. The puerarin pharmaceutical composition according to claim 6, characterized in that, It meets one or more of the following conditions: (1) The mass fraction of the puerarin is 7.8-8.5%; (2) The mass fraction of the absorption promoter is 78-80%; (3) The mass fraction of the sustained-release agent is 12-14%; (4) When the sustained-release agent is a combination of hydroxypropyl methylcellulose and ethylcellulose, the mass fraction of the hydroxypropyl methylcellulose is 9.5-10.5%; and the mass fraction of the ethylcellulose is 2.5-3.5%. The mass fraction of the lubricant mentioned in (5) is 0.4-0.6%.

8. A method for preparing a puerarin pharmaceutical composition according to any one of claims 1-7, characterized in that, It includes the following steps: The puerarin, the absorption promoter, and the sustained-release agent are mixed, granulated, and then compressed into tablets or filled into capsules.

9. The method for preparing the puerarin pharmaceutical composition according to claim 8, characterized in that, When the puerarin pharmaceutical composition contains a sustained-release agent and a lubricant, the preparation method includes the following steps: mixing the puerarin, the absorption promoter and the sustained-release agent, granulating, then mixing with the lubricant, and finally compressing into tablets or filling capsules.

10. A pharmaceutical preparation, characterized in that, It comprises the puerarin pharmaceutical composition as described in any one of claims 1-7.

11. The pharmaceutical formulation as described in claim 10, characterized in that, The pharmaceutical preparation is in the form of tablets, capsules, or pellets.

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