PH-sensitive berberine hydrochloride solid dispersion and preparation method thereof

Abstract

The invention discloses a pH sensitive berberine hydrochloride solid dispersion which comprises berberine hydrochloride, a pH sensitive polymer and a plasticizer, the mass ratio of the berberine hydrochloride to the pH sensitive polymer is 1: (1-9), and the pH sensitive polymer is dissolved in a solution with the pH larger than 5.5. The pH-sensitive polymer is used as a carrier material of berberine hydrochloride, the dissolution of berberine hydrochloride in gastric juice can be inhibited by forming a charge-assisted hydrogen bond between the pH-sensitive polymer and berberine hydrochloride, and the pH-sensitive polymer can be quickly dissolved in a solution with the pH being greater than 5.5, so that quick release in intestinal tracts can be realized; therefore, the absorption of the medicine in the intestinal tract is improved, and the bioavailability is further improved. Meanwhile, the flavoring agent is also added, the bitter taste is mixed through competition between the sour taste of the flavoring agent and a bitter taste receptor, the pH of oral saliva is adjusted, the dissolution of berberine hydrochloride in the oral cavity is further inhibited, and a good taste masking effect is achieved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a pH-sensitive berberine hydrochloride solid dispersion and its preparation method. Background Technology

[0002] Berberine hydrochloride is a natural isoquinoline alkaloid with significant therapeutic potential in treating metabolic disorders, inflammation, infectious diseases, and cancer. Its chemical name is 5,6-dihydro-9,10-dimethoxybenzo(G)1,3-benzodioxomono(5,6-A)quinazine hydrochloride, and its chemical formula is C1. 20 H 18 NO4·HCl, with a molecular weight of 372.822, has the following chemical structure: .

[0003] Oral administration, as the most commonly used route of drug delivery in clinical practice, offers significant advantages such as convenience, cost-effectiveness, and good patient compliance, making it the preferred treatment option in most therapeutic scenarios. However, this method faces a key challenge: for drugs with a noticeably unpleasant taste, the unpleasant flavor and texture can significantly reduce patient adherence and even lead to treatment discontinuation. Berberine hydrochloride is a representative example of a drug whose extremely bitter taste significantly impacts oral acceptability.

[0004] Currently, the main dosage forms of commercially available berberine hydrochloride are coated tablets and capsules. These two forms effectively mask the drug's strong bitter taste through physical isolation. However, while this design achieves taste masking, it introduces new usage barriers: for children and elderly patients with swallowing difficulties, the convenience of taking traditional tablets and capsules is significantly reduced. It is worth noting that although theoretically, orally disintegrating tablets, granules, and dry suspensions are more suitable for patients with swallowing difficulties, the extremely strong bitterness of berberine hydrochloride itself poses a significant challenge to the development of these dosage forms. Furthermore, berberine hydrochloride belongs to BCS Class III drugs, exhibiting high solubility and low permeability. Significant first-pass elimination and P-glycoprotein (P-gp)-mediated efflux contribute to its extremely low bioavailability. These factors not only reduce the patient's medication experience but also limit its clinical application and commercialization potential.

[0005] Reference 1 (Preparation of berberine hydrochloride ion-exchange resin complex by β-cyclodextrin inclusion; Journal of Drug Delivery Science and Technology, 104 (2025)) discloses the use of β-cyclodextrin to improve the solubility of berberine hydrochloride, combined with the addition of acidic anion exchange resin Amberlite IRP69, which binds to berberine hydrochloride through ionic bonds, thus masking its bitter taste. This study provides a method to improve drug loading capacity and efficiency while masking the taste. However, this study has some problems. The concentration of β-cyclodextrin, reaction temperature, and concentration of berberine hydrochloride all affect the reaction rate of the ion exchange resin, making the preparation process relatively complex. Furthermore, the β-cyclodextrin inclusion and drug loading with the ion exchange resin need to be carried out step by step, and the process parameters interfere with each other. This formulation scheme did not undergo in vivo bioavailability studies and lacks systematic validation.

[0006] In recent years, hot-melt extrusion (HME)-based formulations have gained increasing attention in the pharmaceutical industry as a novel taste-masking strategy. It utilizes high temperatures and strong shear forces to transform crystalline drugs into an amorphous form, thereby achieving uniform dispersion within a polymer carrier. This technology not only effectively masks the bitterness of active pharmaceutical ingredients but also significantly improves the bioavailability of poorly water-soluble drugs, enabling controlled and sustained drug release and supporting targeted drug delivery. As a semi-continuous or fully continuous manufacturing process, hot-melt extrusion offers several advantages, including high efficiency, adjustable processing parameters, solvent-free operation, and suitability for large-scale production.

[0007] Chinese patent document CN115025043A discloses a solid dispersion of Coptis chinensis extract, prepared by hot-melt extrusion process using Coptis chinensis extract as the active ingredient, a gastric-soluble polymeric carrier, and a plasticizer. The solid dispersion of Coptis chinensis extract prepared by the method of this invention achieves an inclusion rate of 91%, dissolving only 10% in oral solution after 90 minutes, and reaching over 80% in gastric solution after 2 minutes. However, the gastric-soluble polymeric carrier used in this patent is E100 with a pH < 5, primarily intended to increase the dissolution of berberine hydrochloride in gastric juice. Rapid dissolution may lead to a sudden increase in local drug concentration, directly irritating the gastric mucosa, causing vomiting and nausea, and increasing the probability of common side effects of berberine hydrochloride. Furthermore, the main absorption site of berberine hydrochloride is in the small intestine; premature dissolution in the stomach increases the risk of degradation and increases the proportion of berberine rapidly entering the portal vein circulation after gastric absorption, thereby to some extent aggravating first-pass metabolism in the liver and reducing bioavailability.

[0008] Therefore, there is an urgent need to find a method that can mask the taste while improving the bioavailability of berberine hydrochloride. Summary of the Invention

[0009] To address the aforementioned technical problems, this invention provides a pH-sensitive berberine hydrochloride solid dispersion that can inhibit the dissolution of berberine hydrochloride in gastric juice and simulated oral saliva, achieving rapid release in the intestine. This avoids discomfort caused to patients by excessive release in the stomach, while maintaining a supersaturated state of the amorphous drug in the intestine, increasing the instantaneous concentration, promoting intestinal absorption, and thus improving bioavailability.

[0010] A pH-sensitive berberine hydrochloride solid dispersion comprises berberine hydrochloride, a pH-sensitive polymer, and a plasticizer, wherein the mass ratio of berberine hydrochloride to the pH-sensitive polymer is 1:1 to 9, and the pH-sensitive polymer is soluble in a solution with pH > 5.5.

[0011] In this invention, a pH-sensitive polymer is used as a carrier material for berberine hydrochloride. By forming charge-assisted hydrogen bonds between the pH-sensitive polymer and berberine hydrochloride, the dissolution of berberine hydrochloride in gastric juice can be inhibited. Since the pH-sensitive polymer can dissolve rapidly in solutions with pH > 5.5, it can achieve rapid release in the intestine, thereby improving drug absorption in the intestine and thus improving bioavailability.

[0012] Preferably, the pH-sensitive polymer has carboxyl groups on its main chain, and the polymer chain has an amorphous, coiled, three-dimensional flexible chain structure.

[0013] In this invention, the main chain of the pH-sensitive polymer has carboxyl groups and a pKa of about 6. The polymer chain has an amorphous, coiled, three-dimensional flexible chain structure. In a solution with pH > 5.5, the polymer chain segments will change from a tightly contracted state to an extended state through ionization and dissolve rapidly, thereby achieving the rapid release of berberine hydrochloride in the intestine.

[0014] Preferably, the pH-sensitive polymer is at least one of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylate-ethyl acrylate copolymer, cellulose acetate phthalate, polyvinyl alcohol phthalate, hyaluronic acid, sodium hyaluronate, alginate, sodium alginate, sodium acrylate, sodium methacrylate, and carboxymethyl cellulose.

[0015] More preferably, the pH-sensitive polymer is a methacrylic acid-ethyl acrylate copolymer, wherein the average molecular weight (Mw) of the methacrylic acid and ethyl acrylate copolymer is 10,000~1,000,000 g / mol, and it has anionic properties, and its structure is shown below: .

[0016] In this invention, berberine hydrochloride and the methacrylic acid-ethyl acrylate copolymer form charge-assisted hydrogen bonds. In the low pH environment of gastric juice (pH < 5.5), the carboxyl groups in the methacrylic acid-ethyl acrylate copolymer remain protonated (-COOH), causing the polymer chain to become insoluble in water and contract, forming a protective barrier and preventing the release of berberine hydrochloride. When it enters the higher pH environment of the small intestine (pH > 5.5), the carboxyl groups deprotonate to form negatively charged carboxylate ions (-COO₂). - The polymer chains swell and dissolve due to electrostatic repulsion, thereby releasing berberine hydrochloride for precise enteric-coated targeted delivery.

[0017] More preferably, the average molecular weight of the methacrylic acid and ethyl acrylate copolymer is 200,000 to 300,000 g / mol.

[0018] Preferably, the plasticizer is at least one of triethyl citrate, glycerin, polyethylene glycol, erythritol, and methylparaben.

[0019] Preferably, the mass ratio of the plasticizer to the pH-sensitive polymer is 1:1 to 9.

[0020] The plasticizer molecules in this invention have flexible main chains or side chains that are easy to insert into the polymer chains, increasing the degree of freedom of chain segment movement. They also have good compatibility with pH-sensitive polymers and can be uniformly dispersed in the polymer matrix.

[0021] Preferably, the berberine hydrochloride solid dispersion further includes a flavoring agent, which is at least one selected from citric acid, mannitol, maltitol, aspartame, acesulfame potassium, sucralose, steviol glycosides, and fruit flavoring.

[0022] The flavoring agent of the present invention has polar / acidic groups, sweet hydroxyl groups, polyhydroxy sugars, aromatic hydrophobic rings, and encapsulated cyclic or polymeric structures that can interact with bitter taste receptors or bitter taste molecules (i.e., berberine hydrochloride).

[0023] Preferably, the mass ratio of the flavoring agent to berberine hydrochloride is 1:1 to 20.

[0024] More preferably, the plasticizer is polyethylene glycol and the flavoring agent is citric acid.

[0025] In this invention, the plasticizer primarily addresses the poor processability caused by the high melt viscosity of some polymers. When high molecular weight polyethylene glycol is chosen, this hydrophilic carrier not only maintains the enteric coating function of the polymer but also helps form a more stable amorphous solid dispersion matrix, promoting drug dispersion and controlled release. When citric acid is chosen as the flavoring agent, its synergistic effect of confusing taste and adjusting pH further enhances the taste-masking ability of the pH-sensitive berberine hydrochloride solid dispersion. It can compete with bitter taste receptors through its own acidity, thus confusing bitterness. Simultaneously, since the pH-sensitive polymer used is poorly soluble below pH 5.5, the addition of citric acid can adjust the pH of oral saliva, further inhibiting the dissolution of berberine hydrochloride in the oral cavity, achieving a good taste-masking effect.

[0026] This invention also provides a method for preparing the above-mentioned pH-sensitive berberine hydrochloride solid dispersion, which is obtained by hot melt extrusion or solvent evaporation. The specific steps of the hot melt extrusion method are as follows: A1. Weigh out berberine hydrochloride, pH-sensitive polymer, flavoring agent and plasticizer separately, mix them evenly to obtain a physical mixture; A2. The physical mixture obtained in step A1 is passed through a hot melt extruder and then sieved to obtain berberine hydrochloride solid dispersion; The specific steps of the solvent evaporation method are as follows: B1. Dissolve berberine hydrochloride, pH-sensitive polymer, flavoring agent, and plasticizer in methanol to obtain a mixed solution; B2. The mixed solution obtained in step B1 is subjected to rotary evaporation under reduced pressure to obtain berberine hydrochloride solid dispersion.

[0027] In this invention, berberine hydrochloride solid dispersions can be prepared by both hot-melt extrusion and solvent evaporation. The resulting solid dispersions transform berberine hydrochloride from a crystalline state to an amorphous state with short-range order and long-range disorder, highly dispersed within a pH-sensitive polymer matrix. Specifically, the high temperature and strong shear force of the hot-melt extruder convert berberine hydrochloride into an amorphous form, thereby achieving uniform dispersion within the pH-sensitive polymer carrier. This not only effectively masks the bitterness of berberine hydrochloride but also significantly improves the bioavailability of the poorly water-soluble berberine hydrochloride, enabling controlled and continuous release of berberine hydrochloride.

[0028] Preferably, the extrusion temperature of the hot melt extruder is 100~150 ℃.

[0029] Preferably, the extrusion speed of the hot melt extruder is 10~200 r / min.

[0030] Preferably, the hot melt extruder is a twin-screw hot melt extruder.

[0031] The pH-sensitive berberine hydrochloride solid dispersion particles prepared by this invention can also be applied to the development of dosage forms such as granules and suspensions.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The berberine hydrochloride solid dispersion provided by the present invention forms charge-assisted hydrogen bonds between pH-sensitive polymer and berberine hydrochloride, thereby inhibiting the dissolution of berberine hydrochloride in gastric juice, which helps to slow down the rapid release and absorption of berberine hydrochloride in the stomach, thereby reducing the risk of berberine hydrochloride directly entering the portal vein circulation and being metabolized by the liver first pass, and maintaining a supersaturated state in intestinal juice, promoting release and absorption in the intestine, and ultimately improving oral bioavailability.

[0033] (2) The flavoring agent citric acid added to the solid dispersion of the present invention can further improve the bitterness of berberine hydrochloride by adjusting the pH value and by using the sour taste to confuse the bitter taste.

[0034] (3) The preparation process in this invention is simple, energy-efficient, and leaves no solvent residue; and can be further prepared into granules, dry suspensions, orally disintegrating tablets and other dosage forms suitable for children and the elderly to meet clinical and market demands. Attached Figure Description

[0035] Figure 1 The images show the XRD patterns of the berberine hydrochloride solid dispersions prepared in Examples 1-6 and 16.

[0036] Figure 2 The images show the XRD patterns of the raw materials citric acid, berberine hydrochloride, PEG 8000, Kollicoat MAE 100-55, the physical mixture prepared in Example 7, and the solid dispersion of berberine hydrochloride prepared in Example 7.

[0037] Figure 3 The charts show the DSC diagrams of the raw materials PEG 8000, berberine hydrochloride, citric acid, Kollicoat MAE 100-55, the physical mixture prepared in Example 7, and the solid dispersions of berberine hydrochloride prepared in Examples 3 and 7.

[0038] Figure 4 Infrared spectra of raw materials PEG 8000, berberine hydrochloride, citric acid, Kollicoat MAE 100-55, the physical mixture prepared in Example 7, and the solid dispersion of berberine hydrochloride prepared in Example 7.

[0039] Figure 5 The dissolution diagrams are shown for the berberine hydrochloride solid dispersions prepared in Examples 3-7 in simulated oral saliva.

[0040] Figure 6Dissolution diagrams of berberine hydrochloride, the physical mixture prepared in Example 7, and the berberine hydrochloride solid dispersion prepared in Example 7 in simulated oral saliva.

[0041] Figure 7 and Figure 8 The figures show the dissolution of berberine hydrochloride, the physical mixture prepared in Example 7, and the solid dispersion of berberine hydrochloride prepared in Example 7 in simulated gastric and intestinal fluids, respectively.

[0042] Figure 9 The bitterness evaluation results are shown in the figure for berberine hydrochloride, the physical mixture prepared in Example 7, and the berberine hydrochloride solid dispersions prepared in Examples 3 and 7.

[0043] Figure 10 Blood drug concentration-time distribution in rats of berberine hydrochloride, the physical mixture prepared in Example 7, and the solid dispersion of berberine hydrochloride prepared in Example 7. Detailed Implementation

[0044] The present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited to the following embodiments.

[0045] All raw materials used in this invention are commercially available.

[0046] Example 1 (1) Weigh 10 g of berberine hydrochloride, 33.2 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and 6.8 g of PEG 8000 and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 130 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0047] Example 2 (1) Weigh 10 g of berberine hydrochloride, 33.2 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and 6.8 g of PEG 8000 and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 140 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0048] Example 3 (1) Weigh 10 g of berberine hydrochloride, 33.2 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and 6.8 g of PEG 8000 and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0049] Example 4 (1) Weigh 5 g of berberine hydrochloride, 37.5 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and 7.5 g of PEG 8000 and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0050] Example 5 (1) Weigh 15 g of berberine hydrochloride, 29.2 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and 5.8 g of PEG 8000 and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0051] Example 6 (1) Weigh 10 g of berberine hydrochloride, 31 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and 9 g of PEG 8000 and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0052] Example 7 (1) Weigh 10 g of berberine hydrochloride, 32 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol), 6.3 g of PEG 8000 and 1.7 g of citric acid and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0053] Example 8 (1) Weigh 10 g of berberine hydrochloride, 33 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol), 6.5 g of PEG 8000 and 0.5 g of citric acid and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0054] Example 9 (1) Weigh 10 g of berberine hydrochloride, 32 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol), 6.3 g of PEG 8000 and 1.7 g of aspartame and put them into a resealable bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0055] Example 10 (1) Weigh 10 g of berberine hydrochloride, 32 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol), 6.3 g of PEG 8000 and 1.7 g of erythritol and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0056] Example 11 (1) Weigh 10 g of berberine hydrochloride, 33.2 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and 6.8 g of glycerol and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0057] Example 12 (1) Weigh 10 g of berberine hydrochloride, 33.2 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and 6.8 g of triethyl citrate, put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0058] Example 13 (1) Weigh 10 g of berberine hydrochloride, 33.2 g of Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and 6.8 g of PEG 400 and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0059] Example 14 (1) Weigh 10 g of berberine hydrochloride, 33.2 g of HPMCAS and 6.8 g of PEG 8000 and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0060] Example 15 (1) Weigh 10 g of berberine hydrochloride, 33.2 g of hydroxypropyl methylcellulose phthalate, and 6.8 g of PEG8000 and put them into a self-sealing bag and mix them thoroughly to make a physical mixture; (2) Set the temperature of the twin-screw hot melt extruder to 145 ℃. After the temperature rises to the set value, adjust the speed to 60 r / min. Quickly cool the extrudate to room temperature, crush it, and pass it through a 60-mesh sieve to obtain berberine hydrochloride solid dispersion.

[0061] Example 16 (1) Weigh 900 mg of polymer Kollicoat MAE 100-55 (i.e., methacrylic acid-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and add it to 100 mL of methanol solution. Stir at 500 rpm for 30 min to dissolve completely. (2) After the polymer Kollicoat MAE 100-55 was completely dissolved in methanol, 100 mg of berberine hydrochloride was added, and the mixture was stirred in a water bath at 50 °C for 1 h to fully dissolve it. (3) Set the vacuum rotary evaporation conditions: temperature 40~60 ℃, rotation speed: 100 rpm / min, and perform vacuum rotary evaporation for 30 min; (4) Remove the product from the rotary evaporator and encapsulate it to obtain a solid dispersion powder.

[0062] Example 17 (1) Weigh 640 mg of polymer Kollicoat MAE 100-55 (i.e., methacrylate-ethyl acrylate copolymer with a molecular weight of 250,000 g / mol) and 160 mg of PEG 8000 and add them to 100 mL of methanol solution. Stir at 500 rpm for 30 min to dissolve completely. (2) After the polymers Kollicoat MAE 100-55 and PEG 8000 were completely dissolved in methanol, 200 mg of berberine hydrochloride was added, and the mixture was stirred in a water bath at 50 °C for 1 h to fully dissolve the polymers. (3) Set the vacuum rotary evaporation conditions: temperature 40~60 ℃, rotation speed: 100 rpm / min, and perform vacuum rotary evaporation for 30 min; (4) Remove the product from the rotary evaporator and encapsulate it to obtain a solid dispersion powder.

[0063] Sample Analysis I. Characterization of berberine hydrochloride solid dispersion (1) XRD characterization The berberine hydrochloride solid dispersions prepared in Examples 1-6 and Example 16 were characterized by XRD. The instrument used was a Bruker D8 Advance X-ray diffractometer; the target was a Cu Kα target; the wavelength was 1.5406 Å; the tube voltage was 40 kV; the tube current was 40 mA; the compensation was 0.02 °; and the scan rate was 4 ° / min. The results are as follows: Figure 1 As shown.

[0064] Figure 1 The figures show the XRD patterns of the berberine hydrochloride solid dispersions obtained in Examples 1-6 and 16. As shown, Examples 1 and 2 show weak characteristic peaks because the system did not completely melt or form a uniform amorphous dispersion. Examples 3-6 and 16 exhibit a broad and diffuse morphology with no obvious diffraction peaks, confirming the successful formation of a completely amorphous solid dispersion.

[0065] The raw materials citric acid, berberine hydrochloride, PEG 8000, Kollicoat MAE 100-55, the physical mixture obtained in step (1), and the berberine hydrochloride solid dispersion obtained in Example 7 were characterized by XRD, and the results are as follows: Figure 2 As shown.

[0066] Figure 2 The figure shows the XRD patterns of the raw materials citric acid, berberine hydrochloride, PEG 8000, Kollicoat MAE 100-55, the physical mixture obtained in step (1), and the solid dispersion of berberine hydrochloride obtained in Example 7. As shown in the figure, the characteristic crystal diffraction peaks of the raw materials citric acid, berberine hydrochloride, PEG 8000, and Kollicoat MAE 100-55 disappear in the solid dispersion of berberine hydrochloride obtained after hot melt extrusion, indicating that berberine hydrochloride is dispersed in an amorphous form in a pH-sensitive polymer carrier.

[0067] (2) Differential scanning calorimetry (DSC) detection The raw materials PEG 8000, berberine hydrochloride, citric acid, Kollicoat MAE 100-55, the physical mixture prepared in Example 7, and the berberine hydrochloride solid dispersions prepared in Examples 3 and 7 were analyzed by DSC. The instrument was a TA 2500 differential scanning calorimeter, with a heating rate of 10 °C / min and a temperature range of 30–145 °C. The results are as follows: Figure 3 As shown.

[0068] Figure 3The figure shows the DSC diagrams of the raw materials PEG 8000, berberine hydrochloride, citric acid, Kollicoat MAE 100-55, the physical mixture prepared in Example 7, and the solid dispersions of berberine hydrochloride prepared in Examples 3 and 7. As shown in the figure, the crystallization melting peaks of the raw materials berberine hydrochloride and PEG 8000 disappear in the solid dispersions of berberine hydrochloride obtained after hot melt extrusion, indicating that berberine hydrochloride is dispersed in an amorphous form in a pH-sensitive polymer carrier.

[0069] (3) Fourier transform infrared spectroscopy (FT-IR) detection The raw materials PEG 8000, berberine hydrochloride, citric acid, Kollicoat MAE 100-55, the physical mixture prepared in Example 7, and the berberine hydrochloride solid dispersion prepared in Example 7 were subjected to infrared spectroscopy. The instrument used was a Nicolet IS50 infrared spectrometer, in attenuated total reflectance (ATR) mode, with a wavelength of 400–4000 cm⁻¹. -1 Resolution: 4 cm -1 The result is as follows Figure 4 As shown.

[0070] Figure 4 The figure shows the infrared spectra of the raw materials PEG 8000, berberine hydrochloride, citric acid, Kollicoat MAE 100-55, the physical mixture prepared in Example 7, and the berberine hydrochloride solid dispersion prepared in Example 7. As shown in the figure, compared to the active pharmaceutical ingredient, the intensity of the C=O peak on the carboxyl group in the berberine hydrochloride solid dispersion obtained after hot melt extrusion is significantly reduced and becomes weaker than the C=O peak on the ester group. Furthermore, C−N... + The stretching vibration became wider and shifted to 1340 cm. -1 These findings suggest an intermolecular interaction between the quaternary ammonium group of berberine hydrochloride and the carboxyl group of the methacrylate-ethyl acrylate copolymer, possibly forming OH···N + Charge-assisted hydrogen bonds.

[0071] II. Dissolution Test (1) Dissolution test of simulated oral saliva Approximately 100 mg of berberine hydrochloride solid dispersions prepared in Examples 3-7 (equivalent to 20 mg of berberine hydrochloride) were taken from each sample and passed through a 60-mesh sieve. The dissolution test method was the second method (paddle method) of General Chapter 0931 of the 2015 edition of the Chinese Pharmacopoeia. The dissolution medium was simulated oral saliva (containing CaCl2, MgCl2, NaCl, K2CO3, Na2HPO4, and NaH2PO4), the medium volume was 200 mL, the temperature was 37±0.5 ℃, and the rotation speed was 50 rpm. Sampling times were 0.5, 1, 2, 3, and 5 min, with a sampling volume of 1 mL. Samples were filtered through a 0.22 μm aqueous membrane. The concentration of berberine hydrochloride was determined using an Agilent (1260) high-performance liquid chromatography system under the following conditions: Chromatographic conditions: detection wavelength UV-260 nm, Agilent ZORBAX SB C18 column (4.6 mm × 250 mm, 5 μm), mobile phase acetonitrile:water (0.05 M disodium hydrogen phosphate and 0.05 mL sodium heptanesulfonate, pH adjusted to 3.5), flow rate 1.0 mL / min, injection volume 10 μL, and run time 10 min.

[0072] Figure 5 The figures show the dissolution of berberine hydrochloride solid dispersions prepared in Examples 3-7 in simulated oral saliva. As shown in the figures, Example 7 exhibits the best ability to inhibit drug dissolution in simulated saliva. Compared to Example 8, Example 7 has a better dissolution inhibition effect because it contains more citric acid, which can better adjust the pH value.

[0073] Using pure berberine hydrochloride and a physical mixture as controls, the powder dissolution of pure berberine hydrochloride and the physical mixture in simulated oral saliva was tested under the same operation (i.e., the samples in the above method were replaced with 20 mg of pure berberine hydrochloride and 100 mg of the physical mixture).

[0074] Figure 6 The figures show the dissolution rates of berberine hydrochloride, the physical mixture prepared in Example 7, and the berberine hydrochloride solid dispersion prepared in Example 7 in simulated oral saliva. As shown, in the simulated oral saliva environment, the berberine hydrochloride solid dispersion exhibited the lowest dissolution rate, with only 2.52% dissolution at 30 seconds, compared to 8.03% for berberine hydrochloride and 11.20% for the physical mixture. At 5 minutes, the dissolution rate of the berberine hydrochloride solid dispersion was 6.50%, while the rates for berberine hydrochloride and the physical mixture were 21.97% and 25.84%, respectively. These results indicate that the berberine hydrochloride solid dispersion has a good ability to inhibit release in simulated oral saliva.

[0075] (2) Dissolution test in simulated gastric and intestinal fluids Approximately 500 mg of berberine hydrochloride masking solid dispersion (equivalent to 100 mg of berberine hydrochloride) prepared in Example 7 and passed through a 60-mesh sieve was used. The dissolution test method was Method II (paddle method) of General Chapter 0931 in the 2015 edition of the Chinese Pharmacopoeia. The dissolution media were simulated gastric juice (pH 1.2 hydrochloric acid solution) and simulated intestinal juice (pH 6.8 PBS solution). The media volume was 900 mL, the temperature was 37 ± 0.5 ℃, and the rotation speed was 50 rpm. Sampling times were 5, 10, 20, 40, 60, 90, 120, and 150 min, with a sampling volume of 5 mL. Samples were filtered through a 0.22 μm aqueous membrane. The concentration of berberine hydrochloride was determined using an Agilent (1260) high-performance liquid chromatography system under the following conditions: Chromatographic conditions: detection wavelength UV-260 nm, Agilent ZORBAX SBC18 column (4.6 mm × 250 mm, 5 μm), mobile phase acetonitrile:water (0.05 M disodium hydrogen phosphate and 0.05 mL sodium heptanesulfonate, pH adjusted to 3.5), flow rate 1.0 mL / min, injection volume 10 μL, and run time 10 min.

[0076] Meanwhile, using pure berberine hydrochloride and the physical mixture as controls, the powder dissolution of pure berberine hydrochloride and the physical mixture in simulated gastric and intestinal fluids was tested under the same operation (i.e., the samples in the above method were simply replaced with 100 mg of pure berberine hydrochloride and 500 mg of the physical mixture).

[0077] Figure 7 and Figure 8 The figures show the dissolution rates of berberine hydrochloride, the physical mixture prepared in Example 7, and the solid dispersion of berberine hydrochloride prepared in Example 7 in simulated gastric and intestinal fluids, respectively. In the simulated gastric fluid environment, the dissolution rate of berberine hydrochloride in the solid dispersion was significantly reduced, with only 15.2% dissolving at 150 minutes, compared to 80.4% for pure berberine hydrochloride. This indicates that the solid dispersion of berberine hydrochloride inhibits the release of berberine hydrochloride in the simulated gastric fluid. Figure 7 In a simulated intestinal fluid environment, the dissolution rates of berberine hydrochloride solid dispersion and berberine hydrochloride were roughly the same. After 1 hour, the cumulative dissolution rate of berberine hydrochloride masking solid dispersion reached 100.7%, while that of berberine hydrochloride was 97.2%, indicating that berberine hydrochloride solid dispersion had a faster dissolution rate. Figure 8 ).

[0078] III. Evaluation of Odor Masking Effect The bitterness masking efficacy of pH-sensitive solid dispersions was evaluated by comparing the bitterness intensity of pure berberine hydrochloride, the physical mixture of Example 7, and the solid dispersions prepared in Examples 3 and 7. Sensory evaluation was performed using a classic group tasting method, and the results were analyzed using an Integrated Scoring Evaluation Method (ISEM). Eight healthy adult volunteers participated in this study. A single-blind, randomized design was used, with each participant receiving approximately 3 mg of pure berberine hydrochloride and corresponding amounts of the physical mixture and solid dispersion. Subjects were instructed to place each sample in their mouth for 10 seconds, then cough and rinse with purified water. Immediately afterwards, they rated the bitterness intensity using a standardized five-point scale. Additional rinsing was allowed after the evaluation. Each sample was tasted at least 10 minutes apart to minimize residual effects. Bitterness was rated from 0 (no bitterness) to 5 (extremely bitter).

[0079] Sensory evaluations were performed on eight healthy adult volunteers. The results were as follows: Figure 9 As shown. The average bitterness score of pure berberine hydrochloride was 4.5, and some participants were unable to keep the berberine hydrochloride sample in their mouths for a full 10 seconds, choosing to spit it out prematurely. The average score of the physical mixture of Example 7 was 3.875, which was not significantly different from that of pure berberine hydrochloride (p>0.05). Participants reported a noticeable sour taste when tasting the physical mixture (PM), attributed to the presence of citric acid; however, this was insufficient to effectively mask the strong bitterness of berberine hydrochloride (BH). Compared to berberine hydrochloride and the physical mixture, the solid dispersion prepared in Example 3 exhibited a stronger masking ability, with an average bitterness score of 2.0, significantly lower than that of berberine hydrochloride (p≤0.001). Example 7, containing citric acid, showed the best masking effect, with an average score of 1.125. This superior performance is attributed to the synergistic effect between the amorphous polymer matrix and citric acid, which effectively modulates the pH of the local microenvironment and further limits the release of BH. In addition, citric acid exhibits a distinct sour taste and can effectively inhibit the competitive perception of bitterness by regulating the activation of taste receptors.

[0080] IV. Evaluation of the in vivo absorption of berberine hydrochloride Eighteen male Sprague Dawley (SD) rats (180-220 g) were fasted for 12 hours before the experiment, but were allowed to drink water normally. They were then randomly divided into three groups (n=6).

[0081] The berberine hydrochloride solid dispersion prepared in Example 7, pure berberine hydrochloride, and the physical mixture prepared in Example 7 were administered orally by gavage as a suspension containing 200 mg / kg of berberine hydrochloride, with a suspension dose of 10 ml / kg.

[0082] Blood samples (0.5 mL at each time point) were collected in heparinized tubes at 0.33, 0.66, 1, 2, 3, 4, 6, 8, 12, and 24 hours after the jugular vein dose. 200 μL of plasma sample was added to 800 μL of methanol, vortexed at 2000 rpm for 5 minutes, centrifuged at 12000 rpm for 10 minutes, concentrated by nitrogen blowing, reconstituted with 100 μL of methanol, centrifuged at 12000 rpm for 5 minutes, and the supernatant was collected for HPLC analysis. Specific chromatographic conditions were as follows: detection wavelength UV-345 nm, Agilent ZORBAX SB C18 column (4.6 mm × 250 mm, 5 μm), mobile phase acetonitrile:water (33 mmol / L potassium dihydrogen phosphate) = 33:67, flow rate 1.0 mL / min, injection volume 20 μL, and run time 20 min.

[0083] Calculation of pharmacokinetic parameters: The main pharmacokinetic parameter is the area under the drug concentration-time curve (AUC) from time 0 to the last sample collection time t where the concentration can be accurately determined. 0-t The area under the drug concentration-time curve (AUC) from time 0 to infinity (∞). 0-∞ Peak drug concentration (C) max Other indicators include: elimination half-life (t) 1 / 2β ), peak time of drug action (T) max The calculation of pharmacokinetic (PK) parameters will be performed by collecting and measuring blood sample data at predetermined time points, using a non-compartmental PK model.

[0084] Figure 10 The figure shows the plasma concentration-time distribution of berberine hydrochloride, the physical mixture prepared in Example 7, and the solid dispersion of berberine hydrochloride prepared in Example 7 in rats. The time T for peak plasma concentration of the taste-masked solid dispersion of berberine hydrochloride administered by gavage to rats is also shown. max On average, it takes 1.67 hours to reach peak concentration C. max The average concentration was 158.43 ng / mL, with an AUC of 0-∞ The average concentration was 394.42 ng·h / mL; while the time to peak plasma concentration of berberine hydrochloride raw material administered by gavage to rats was T0. max On average, the peak concentration C is reached in 1 hour. max The average concentration was 75.63 ng / mL, with an AUC of 0-∞ The average was 178.84 ng·h / mL. The time to peak plasma concentration (T0) for the physical mixture was... max On average, it takes 0.94 hours to reach peak concentration C. max The average value was 70.9 ng / mL, with an AUC of 0-∞The average value was 250.86 ng·h / mL. In Example 7, the area under the curve (AUC) of the berberine hydrochloride solid dispersion was the highest, which was 2.21 times that of the berberine hydrochloride raw material. This indicates that the berberine hydrochloride solid dispersion prepared by hot melt extrusion improves the bioavailability of berberine hydrochloride by inhibiting dissolution in the stomach, releasing it locally in the intestine, and maintaining a supersaturated state.

[0085] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. 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 pH-sensitive berberine hydrochloride solid dispersion, characterized in that, It includes berberine hydrochloride, a pH-sensitive polymer, and a plasticizer, wherein the mass ratio of berberine hydrochloride to the pH-sensitive polymer is 1:1 to 9, and the pH-sensitive polymer is soluble in a solution with pH > 5.

5.

2. The pH-sensitive berberine hydrochloride solid dispersion according to claim 1, characterized in that, The pH-sensitive polymer is at least one of the following: hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylate-ethyl acrylate copolymer, cellulose acetate phthalate, polyvinyl alcohol phthalate, hyaluronic acid, sodium hyaluronate, alginate, sodium alginate, sodium acrylate, sodium methacrylate, and carboxymethyl cellulose.

3. The pH-sensitive berberine hydrochloride solid dispersion according to claim 2, characterized in that, The pH-sensitive polymer is a methacrylic acid-ethyl acrylate copolymer, and the average molecular weight of the methacrylic acid and ethyl acrylate copolymer is 10,000~1,000,000 g / mol.

4. The pH-sensitive berberine hydrochloride solid dispersion according to claim 1, characterized in that, The mass ratio of the plasticizer to the pH-sensitive polymer is 1:1~9.

5. The pH-sensitive berberine hydrochloride solid dispersion according to claim 1, characterized in that, The plasticizer is at least one of triethyl citrate, glycerin, polyethylene glycol, erythritol, and methylparaben.

6. The pH-sensitive berberine hydrochloride solid dispersion according to claim 1, characterized in that, The berberine hydrochloride solid dispersion further includes a flavoring agent, which is at least one of citric acid, mannitol, maltitol, aspartame, acesulfame potassium, sucralose, steviol glycosides, and fruit flavoring.

7. The pH-sensitive berberine hydrochloride solid dispersion according to claim 1, characterized in that, The mass ratio of the flavoring agent to berberine hydrochloride is 1:1~20.

8. The pH-sensitive berberine hydrochloride solid dispersion according to claim 5 or 6, characterized in that, The plasticizer is polyethylene glycol, and the flavoring agent is citric acid.

9. The method for preparing the pH-sensitive berberine hydrochloride solid dispersion according to any one of claims 1 to 10, characterized in that, It is prepared by hot melt extrusion or solvent evaporation. The specific steps of the hot melt extrusion method are as follows: A1. Weigh out berberine hydrochloride, pH-sensitive polymer, flavoring agent and plasticizer separately, mix them evenly to obtain a physical mixture; A2. The physical mixture obtained in step A1 is passed through a hot melt extruder and then sieved to obtain berberine hydrochloride solid dispersion; The specific steps of the solvent evaporation method are as follows: B1. Dissolve berberine hydrochloride, pH-sensitive polymer, flavoring agent, and plasticizer in methanol to obtain a mixed solution; B2. The mixed solution obtained in step B1 is subjected to rotary evaporation under reduced pressure to obtain berberine hydrochloride solid dispersion.

10. The method for preparing pH-sensitive berberine hydrochloride solid dispersion according to claim 9, characterized in that, In step A2, the extrusion temperature of the hot melt extruder is 100~150 ℃, and the extrusion speed of the hot melt extruder is 10~200 r / min.

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