Guanfacine hydrochloride sustained-release pellet and preparation method thereof

Abstract

The invention discloses guanfacine hydrochloride sustained-release pellets and a preparation method thereof, and belongs to the technical field of biological medicines. The guanfacine hydrochloride sustained-release pellet comprises a drug-containing pellet core and a sustained-release layer, wherein the sustained-release layer is coated on the outer surface of the drug-containing pellet core; the medicine-containing pill core comprises the following components: guanfacine hydrochloride, a filling agent, a sustained-release material and a lubricating agent; and the sustained-release layer comprises the following components: a retardant, a plasticizer and an anti-sticking agent. The preparation method comprises the following steps: firstly, preparing guanfacine hydrochloride and auxiliary materials into a drug-containing pill core through an extrusion-rolling process, wherein the drug-containing pill core contains part of a sustained-release material for preventing sudden release of a drug; and then coating a sustained-release layer outside the drug-containing pellet core through fluidized bed coating to prepare the guanfacine hydrochloride sustained-release pellet. The guanfacine hydrochloride sustained-release pellet is free of burst release after being taken, is not influenced by individual differences of human bodies and pH of intestinal tracts, can tolerate peristalsis and extrusion of gastrointestinal tracts, is continuously released within 24 hours, keeps a proper concentration level in in-vivo blood, and is beneficial to reducing adverse reactions and continuously exerting drug effects.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a guanidine hydrochloride sustained-release microgranule and its preparation method. Background Technology

[0002] In 2009, the U.S. FDA approved Shire's guanifacine hydrochloride extended-release tablets (brand name INTUNIV) for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents aged 6–17 years, available in strengths of 1 mg, 2 mg, 3 mg, and 4 mg, taken once daily. The EMA also approved once-daily guanifacine hydrochloride extended-release tablets for the treatment of ADHD in 2015. Guanifacine hydrochloride is a selective α2α-adrenergic receptor agonist. Preclinical studies have found that guanifacine hydrochloride can directly bind to receptors in the prefrontal cortex, and excitation of postsynaptic α2α-receptors may produce effects such as enhanced working memory, reduced distractibility, improved attention regulation, increased behavioral inhibition, and enhanced impulse control.

[0003] Guanifacin hydrochloride is a white to off-white crystalline powder, slightly soluble in water (approximately 1 mg / mL), ethanol, and acetone, and has relatively high solubility in methanol (>30 mg / mg). Due to its strong central nervous system effects and high plasma protein binding rate, the rapid release rate of conventional immediate-release formulations leads to excessively high peak plasma concentrations, inducing side effects such as drowsiness, dizziness, difficulty falling asleep, nausea, vomiting, and amnesia. Sustained-release formulations effectively reduce peak plasma concentrations and prolong the duration of action, making them effective in treating attention-deficit hyperactivity disorder (ADHD), particularly beneficial for children with both ADHD and behavioral disorders. However, guanifacin hydrochloride solubility is significantly pH-dependent, varying considerably in solutions with different pH levels. It exhibits better solubility in acids, but its solubility decreases significantly with increasing pH. The matrix material used in Shire's guanifacine hydrochloride extended-release tablets contains a pH-sensitive methacrylic acid copolymer, which is easily soluble at pH values ​​greater than 5.5, thus accelerating drug release.

[0004] Patent CN111346067A discloses a controlled-release formulation of guanifacine hydrochloride, which avoids the influence of intestinal pH by using an osmotic pump. Patent CN113648285A discloses a membrane-controlled-release tablet of guanifacine hydrochloride, which, by controlling the ratio of polyvinyl acetate to polyvinyl alcohol-polyethylene glycol copolymer, allows the active ingredient in the prepared tablet to be released steadily and uniformly, unaffected by differences in human body pH.

[0005] Patent CN102579381A discloses a guanifacine hydrochloride sustained-release formulation, which is mainly composed of guanifacine hydrochloride, filler, sustained-release material, and pH-sensitive material, prepared by a wet granulation process. The guanifacine hydrochloride, filler, sustained-release material, and pH-sensitive material are mixed uniformly at high speed. The uniformly mixed powder is then wet-granulated, dried at high temperature, and finally, a glidant, lubricant, and binder are added, followed by tableting to prepare guanifacine hydrochloride sustained-release tablets. Patent CN114533684A discloses a guanifacine hydrochloride sustained-release tablet using a dry granulation process, which, in addition to the sustained-release material (methylcellulose and acrylic acid copolymer), also includes a pH adjuster.

[0006] Patent CN103705480A discloses a solid oral dosage form of guanifacin pharmaceutical composition (guanifacin hydrochloride sustained-release tablets), which is prepared using a direct compression method.

[0007] Although various sustained-release formulations and preparation methods of guanifacine hydrochloride are disclosed in the prior art, the existing products or technologies of guanifacine hydrochloride still have the following defects: ① Due to the large individual differences in the acid-base balance in the human body, unstable pH values ​​can lead to unstable drug release; ② Different patients have different intestinal pH values, and the use of pH-sensitive materials in guanifacine hydrochloride sustained-release formulations can affect drug release due to individual differences in the intestinal pH values ​​of patients, resulting in poor drug release stability; ③ Guanifacine hydrochloride sustained-release formulations, especially gel matrix sustained-release tablets, may be deformed, ruptured, or accelerated erosion due to the mechanical forces generated by gastrointestinal peristalsis, and may not be tolerant to the peristaltic compression of the gastrointestinal tract, causing changes in the drug release rate.

[0008] Microgranules, as multi-unit formulations, are dispersed throughout the gastrointestinal tract, resulting in lower local drug concentrations and effectively reducing gastrointestinal irritation. Furthermore, defects in individual unit formulations do not lead to burst drug release, having a minimal impact on the overall formulation. Compared to single-unit formulations (such as sustained-release tablets and capsules), the incidence of adverse reactions is lower.

[0009] Based on this, the present invention provides guanethidine hydrochloride sustained-release microgranules and a method for preparing the same. Summary of the Invention

[0010] One objective of this invention is to provide a guanethidine hydrochloride sustained-release microsphere, comprising a drug-containing pellet core and a sustained-release layer, wherein the sustained-release layer coats the outer surface of the drug-containing pellet core, and the mass ratio of the drug-containing pellet core to the sustained-release layer is (130-160):(28-36).

[0011] The components of the pill core include guanethidine hydrochloride, filler, sustained-release material, and lubricant;

[0012] The sustained-release layer comprises a barrier agent, a plasticizer, and an anti-adhesion agent.

[0013] Furthermore, in the drug-containing pellet core, the mass ratio of guanethidine hydrochloride, filler, sustained-release material and lubricant is (1-5):(100-130):(7-24):(0-4);

[0014] The filler is selected from microcrystalline cellulose, mannitol, sorbitol, dextrin, corn starch, sucrose, lactose, and sodium lauryl sulfate;

[0015] The sustained-release material is selected from glyceryl behenate, xanthan gum, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and sodium carboxymethyl cellulose;

[0016] The lubricant is selected from talc, silica, magnesium stearate, glyceryl monostearate, and polyethylene glycol.

[0017] In one specific embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and lactose, with a mass ratio of (90-120):(10-30). Microcrystalline cellulose, lactose, starch, and dextrin are commonly used as fillers in the extrusion and spheroidization process for preparing microspheres. Microcrystalline cellulose exhibits good spheroidization and is known as a spheroidizing agent. However, using microcrystalline cellulose alone results in a low spheroidization rate because cellulose compounds are highly hygroscopic, requiring the addition of large amounts of solvent when preparing soft materials. The resulting soft materials are relatively hard and easily clog the extrusion die after entering the extruder. Lactose, starch, and dextrin are all carbohydrate compounds. When preparing soft materials, these excipients exhibit a certain viscosity. However, extrudates formed using these excipients alone are too soft and lack plasticity, resulting in low hardness and low microsphere yield. Therefore, a mixture of microcrystalline cellulose, lactose, starch, and dextrin is generally used to ensure smoother extrusion, providing the extrudate with plasticity and moisture, thus improving the spheroidization rate during spheroidization.

[0018] In one specific embodiment of the present invention, the sustained-release material is xanthan gum and / or glyceryl behenate. Xanthan gum dissolves rapidly upon contact with gastric juice, forming a high-viscosity, weak gel structure. Even at low concentrations, it exhibits significant viscosity, effectively inhibiting the burst release of guanifacin hydrochloride, reducing peak blood drug concentration, and prolonging the duration of drug action. Xanthan gum possesses excellent adhesive properties and can be formulated with various excipients to prepare sustained-release microspheres with different hardness and dissolution rates, controlling the drug release rate in vivo, allowing for slow release over a longer period, maintaining stable blood drug concentrations, and reducing drug toxicity. Simultaneously, glyceryl behenate, as a non-ionic glyceride, does not react with the active pharmaceutical ingredient or other excipients and can be used as an insoluble sustained-release material suitable for various granulation processes. It releases the drug through a diffusion mechanism and is unaffected by pH.

[0019] Furthermore, in the sustained-release layer, the mass ratio of the inhibitor, plasticizer, and anti-adhesion agent is (15-25):(2-6):(6-10);

[0020] The inhibitor is selected from Eutectic RL, Eutectic RS, Eutectic NE30D, ethyl cellulose, and Aidoxiu. TM Sulis, Kollicoat SR30D, polymethyl methacrylate, cellulose acetate phthalate, hydroxypropyl cellulose acrylate copolymer;

[0021] The plasticizer is selected from triethyl citrate, polyethylene glycol, tributyl citrate, and dibutyl sebacate;

[0022] The anti-adhesion agent is selected from talc, silicon dioxide, magnesium stearate, and glyceryl monostearate.

[0023] In one specific embodiment of the invention, the inhibitor is a mixture of Eutrapeptide RL and Eutrapeptide RS in a mass ratio of (12-15):(5-8). The Eutrapeptide RL / RS used is insoluble in water but swells, forming pores in the coating film. The pore diameter of Eutrapeptide RL is 1-5 μm, and that of Eutrapeptide RS is 0.1-0.6 μm, through which the drug inside the coating is released. The release rate can be adjusted by regulating the ratio and coating amount of these two materials. Within the physiological pH range (pH 1-8), the hydrophilicity of Eutrapeptide RL / RS is independent of pH, therefore the release rate of its sustained-release formulation is independent of pH differences in the gastrointestinal tract of different individuals.

[0024] The second objective of this invention is to provide a method for preparing the above-mentioned guanidine hydrochloride sustained-release microspheres, comprising the following steps:

[0025] Step 1: Mix guanethidine hydrochloride, filler, sustained-release material and lubricant, add wetting agent to prepare soft material, make pellet core by extrusion-spheronization method, dry to moisture content below 2%, and obtain the drug-containing pellet core after sieving.

[0026] The size of the medicated pill core is 0.4mm-1.0mm;

[0027] The rolling speed is 1000-1500 rpm, and the time is 1-5 minutes;

[0028] Step 2: Add plasticizer and anti-adhesion agent to organic solvent, then add retardant, homogenize to obtain sustained-release coating solution; place the drug-containing pellet core from Step 1 in a fluidized bed, preheat, coat with sustained-release coating solution, and dry until the water content is below 1% to obtain the sustained-release microparticles;

[0029] The preheating temperature is 25-40℃;

[0030] The conditions for fluidized bed coating are: spray rate of 0.5-2 mL / min, air volume of 10-20 cubic meters / hour, and air temperature of 25-40℃.

[0031] A third objective of this invention is to provide a pharmaceutical composition comprising the aforementioned guanifacine hydrochloride sustained-release microcapsules. These sustained-release microcapsules can be packaged in pharmaceutically acceptable packaging, allowing patients to swallow them directly after removing the packaging; alternatively, the sustained-release microcapsules can be encapsulated alone or mixed with suitable excipients, allowing patients to take them in capsule form; furthermore, the sustained-release microcapsules can be combined with suitable excipients such as suspending agents, pH adjusters, and flavoring agents to form a dry suspension, which patients then mix with an appropriate amount of water before taking.

[0032] The fourth objective of this invention is to provide the use of the above-mentioned guanifacine hydrochloride sustained-release microgranules or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating attention deficit hyperactivity disorder.

[0033] This invention first prepares guanifacine hydrochloride and excipients into a drug-containing pellet core using an extrusion and spheronization process. This pellet core contains a sustained-release material that partially prevents sudden drug release. Then, a sustained-release layer is coated onto the pellet core using a fluidized bed coating process to obtain guanifacine hydrochloride sustained-release microspheres. These guanifacine hydrochloride sustained-release microspheres do not exhibit sudden release after administration, are unaffected by individual differences or intestinal pH, and can withstand gastrointestinal peristalsis and compression, maintaining a continuous release over 24 hours and a suitable concentration level in the bloodstream. This helps reduce adverse reactions and ensures sustained efficacy.

[0034] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

[0035] 1. The hydrophilic gel matrix material in sustained-release tablets (such as hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, etc.) rapidly expands upon contact with water or gastrointestinal fluids, forming a gel barrier. The thickness and strength of the gel layer depend on factors such as the molecular weight, degree of substitution, particle size of the matrix material, and tablet hardness. The mechanical forces generated by gastrointestinal peristalsis may cause deformation, rupture, or accelerated dissolution of the gel matrix tablets. For example, when taken with food, the friction and compression between the food in the stomach and the tablet may cause localized damage to the gel layer, affecting the uniformity of drug release. Studies have shown that tablets with lower hardness have weaker gel strength and are more susceptible to peristalsis. Moderate peristaltic compression helps the drug release slowly from the gel layer, but excessive compression may lead to excessively rapid or irregular drug release. Gel matrix tablets achieve sustained release by controlling the diffusion and dissolution of the drug in the gel layer. Gastrointestinal peristalsis can alter the pore structure of the gel layer and the drug diffusion pathway, thereby affecting the release rate.

[0036] 2. To avoid the influence of gastrointestinal motility on the release rate, this invention disperses guanifacin hydrochloride into tens to hundreds of sustained-release microspheres (coated with a diffuse controlled-release membrane), with a diameter of approximately 0.4-1.2 mm. Upon entering the gastrointestinal tract, gastric or intestinal fluid permeates into the microspheres, causing them to swell and gradually reveal membrane pores. The gastrointestinal fluid enters the microspheres through these pores, dissolving the active ingredient. The dissolved drug is then slowly released through the membrane pores. The release amount and rate are controlled by the size and number of pores, maintaining the therapeutic effect for 24 hours. The small size of the microspheres prevents them from being affected by gastrointestinal motility, resulting in a stable drug release rate.

[0037] 3. This invention employs a sustained-release microparticle process. To avoid the impact of individual differences in intestinal pH on the release of pH-sensitive materials (e.g., methacrylic acid copolymer, etc.) or pH-sensitive sustained-release coatings in the sustained-release tablets, the Eutrapeptide RL / RS used is insoluble in water but swells to form pores in the coating film. The pore diameter of Eutrapeptide RL is 1-5 μm, and that of Eutrapeptide RS is 0.1-0.6 μm. The drug inside the coating is released through these pores. The release rate can be adjusted by regulating the ratio and coating amount of these two materials. Within the physiological pH range (pH 1-8), the hydrophilicity of Eutrapeptide RL / RS is independent of pH, therefore the release rate of its sustained-release formulation is independent of pH differences in the gastrointestinal tract of different individuals.

[0038] 4. Guanifaxine hydrochloride has a water solubility of approximately 1 mg / mL, but its solubility is significantly pH-dependent, varying considerably in solutions with different pH values. It solubles better in acidic environments, but its solubility decreases significantly with increasing pH. Therefore, in the acidic environment of the stomach, guanifaxine hydrochloride is released rapidly, resulting in higher blood concentrations. Because guanifaxine hydrochloride has strong central nervous system effects and a high plasma protein binding rate, its rapid release rate leads to higher peak blood concentrations, inducing side effects such as drowsiness, dizziness, difficulty falling asleep, nausea, vomiting, and amnesia.

[0039] 5. To avoid the situation where conventional sustained-release microcapsules rely on a sustained-release coating material to control drug release, resulting in rapid release in acidic environments with high solubility, this invention incorporates sustained-release materials, such as xanthan gum and behenicol glycerides, into the core formulation. Xanthan gum dissolves rapidly upon contact with gastric juice, forming a high-viscosity, weak gel structure. Even at low concentrations, it exhibits significant viscosity, effectively inhibiting the burst release of guanifacin hydrochloride, reducing peak blood drug concentration, and prolonging the duration of drug action. Xanthan gum possesses excellent adhesive properties and can be formulated with various excipients to prepare sustained-release microcapsules with different hardness and dissolution rates, controlling the drug release rate in vivo, allowing for slow release over a longer period, maintaining stable blood drug concentrations, and reducing drug toxicity. Furthermore, behenicol glycerides, as a non-ionic glyceride, do not react with the active pharmaceutical ingredient or other excipients. As an insoluble sustained-release material, it is suitable for various granulation processes, releasing the drug through a diffusion mechanism unaffected by pH. Attached Figure Description

[0040] Figure 1 The dissolution curves of guanidine hydrochloride sustained-release microparticles in Examples 1-5 in hydrochloric acid solution at pH 2.2 are shown.

[0041] Figure 2 The dissolution curves of comparative examples 1-2 guanidine hydrochloride sustained-release microspheres in hydrochloric acid solution at pH 2.2 are shown.

[0042] Figure 3 The dissolution curves of guanidine hydrochloride sustained-release microspheres in Examples 1-5 in phosphate buffer solution at pH 6.8 are shown.

[0043] Figure 4 The dissolution curves of comparative examples 1-2, guanidine hydrochloride sustained-release microspheres, in phosphate buffer solution at pH 6.8 are shown. Detailed Implementation

[0044] The preferred embodiments of the present invention will now be described in detail with reference to specific examples. It should be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art can make various modifications and substitutions to the present invention without departing from its spirit and essence.

[0045] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0046] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0047] Example 1

[0048] The formulation of guanifacine hydrochloride sustained-release microgranules in this embodiment is as follows:

[0049]

[0050] The preparation method includes the following steps:

[0051] a. Weigh each component of the drug-containing pill core according to the prescription amount and mix for 15 minutes. Add an appropriate amount of isopropanol as a wetting agent to prepare a soft material. Extrude the soft material through a sieve plate (0.6 mm aperture). Place the resulting strip-shaped material in a spherical rolling pan and roll it into pill cores. Dry at 40°C until the moisture content is below 2%. Then sieve to obtain target pill cores containing guanethidine hydrochloride with a diameter of 0.4 mm-1.0 mm. The spherical rolling speed is 1200 rpm and the spherical rolling time is 2 minutes.

[0052] b. Preparation of Guanifacine Hydrochloride Sustained-Release Microspheres: Triethyl citrate and talc were added to 95% ethanol and homogenized. Eudragit RS100 and Eudragit RL100 were then slowly added to the 95% ethanol and homogenized. After dissolution, the mixture was passed through a 50-mesh sieve. The Guanifacine Hydrochloride pellet cores were placed in a fluidized bed and preheated to 30°C. The spray rate was adjusted to approximately 0.8 mL / min, the air volume to approximately 15 m³ / h, and the air temperature to approximately 35°C to ensure continuous coating operation. The material temperature was maintained at 20-30°C, and the material flowed smoothly. The microspheres were then dried to a moisture content below 1%.

[0053] Example 2

[0054] The formulation of guanifacine hydrochloride sustained-release microgranules in this embodiment is as follows:

[0055]

[0056] The preparation method includes the following steps:

[0057] a. Weigh each component of the drug-containing pill core according to the prescription amount and mix for 15 minutes. Add an appropriate amount of isopropanol as a wetting agent to prepare a soft material. Extrude the soft material through a sieve plate (0.6 mm aperture). Place the resulting strip-shaped material in a spherical rolling pan and roll it into pill cores. Dry at 40°C until the moisture content is below 2%. Then sieve to obtain target pill cores containing guanethidine hydrochloride with a diameter of 0.4 mm-1.0 mm. The spherical rolling speed is 1400 rpm and the spherical rolling time is 2 minutes.

[0058] b. Preparation of Guanifacine Hydrochloride Sustained-Release Microspheres: Triethyl citrate and talc were added to ethanol and homogenized. Eudragit RS100 and Eudragit RL100 were then slowly added to the above 95% ethanol and homogenized. After dissolution, the mixture was passed through a 50-mesh sieve. The Guanifacine Hydrochloride pellet cores were placed in a fluidized bed and preheated to 30°C. The spray rate was adjusted to approximately 0.8 mL / min, the air volume to approximately 15 m³ / h, and the air temperature to approximately 35°C to ensure continuous coating operation. The material temperature was maintained at 20-30°C, and the material flowed smoothly. The microspheres were then dried to a moisture content below 1%.

[0059] Example 3

[0060] The formulation of guanifacine hydrochloride sustained-release microgranules in this embodiment is as follows:

[0061]

[0062] The preparation method includes the following steps:

[0063] a. Weigh each component of the drug-containing pill core according to the prescription amount and mix for 15 minutes. Add an appropriate amount of isopropanol as a wetting agent to prepare a soft material. Extrude the soft material through a sieve plate (0.6 mm aperture). Place the resulting strip-shaped material in a spherical rolling pan and roll it into pill cores. Dry at 40°C until the moisture content is below 2%. Then sieve to obtain target pill cores containing guanethidine hydrochloride with a diameter of 0.4 mm-1.0 mm. The spherical rolling speed is 1400 rpm and the spherical rolling time is 2 minutes.

[0064] b. Preparation of Guanifacine Hydrochloride Sustained-Release Microspheres: Triethyl citrate and talc were added to 95% ethanol and homogenized. Eudragit RS100 and Eudragit RL100 were then slowly added to the 95% ethanol and homogenized. After dissolution, the mixture was passed through a 50-mesh sieve. The Guanifacine Hydrochloride pellet cores were placed in a fluidized bed and preheated to 30°C. The spray rate was adjusted to approximately 0.8 mL / min, the air volume to approximately 15 m³ / h, and the air temperature to approximately 35°C to ensure continuous coating operation. The material temperature was maintained at 20-30°C, and the material flowed smoothly. The microspheres were then dried to a moisture content below 1%.

[0065] Example 4

[0066] The formulation of guanifacine hydrochloride sustained-release microgranules in this embodiment is as follows:

[0067]

[0068] The preparation method includes the following steps:

[0069] a. Weigh each component of the drug-containing pill core according to the prescription amount and mix for 15 minutes. Add an appropriate amount of isopropanol as a wetting agent to prepare a soft material. Extrude the soft material through a sieve plate (0.6 mm aperture). Place the resulting strip-shaped material in a spherical rolling pan and roll it into pill cores. Dry at 40°C until the moisture content is below 2%. Then sieve to obtain target pill cores containing guanethidine hydrochloride with a diameter of 0.4 mm-1.0 mm. The spherical rolling speed is 1400 rpm and the spherical rolling time is 2 minutes.

[0070] b. Preparation of Guanifacine Hydrochloride Sustained-Release Microspheres: Triethyl citrate and talc were added to 95% ethanol and homogenized. Eudragit RS100 and Eudragit RL100 were then slowly added to the 95% ethanol and homogenized. After dissolution, the mixture was passed through a 50-mesh sieve. The Guanifacine Hydrochloride Microsphere cores were placed in a fluidized bed and preheated to 30°C. The spray rate was adjusted to approximately 0.8 mL / min, the air volume to approximately 15 m³ / h, and the air temperature to approximately 35°C to ensure continuous coating. The material temperature was maintained at 20-30°C, and the material flowed smoothly. The microspheres were then dried to a moisture content below 1%.

[0071] Example 5

[0072] The formulation of guanifacine hydrochloride sustained-release microgranules in this embodiment is as follows:

[0073]

[0074] The preparation method includes the following steps:

[0075] a. Weigh each component of the medicated pellet core according to the prescription amount and mix for 15 minutes. Add an appropriate amount of water as a wetting agent to prepare a soft material. Extrude the soft material through a sieve plate (0.6 mm aperture). Place the resulting strip-shaped material in a spherical rolling pan and roll it into pellet cores. Dry at 40°C until the moisture content is below 2%. Then sieve to obtain target pellet cores containing guanethidine hydrochloride with a diameter of 0.4 mm-1.0 mm. The spherical rolling speed is 1200 rpm and the rolling time is 2 minutes.

[0076] b. Preparation of Guanifacine Hydrochloride Sustained-Release Microspheres: Triethyl citrate and talc were added to 95% ethanol and homogenized. Eudragit RS100 and Eudragit RL100 were then slowly added to the 95% ethanol and homogenized. After dissolution, the mixture was passed through a 50-mesh sieve. The Guanifacine Hydrochloride Microsphere cores were placed in a fluidized bed and preheated to 30°C. The spray rate was adjusted to approximately 0.8 mL / min, the air volume to approximately 15 m³ / h, and the air temperature to approximately 35°C to ensure continuous coating. The material temperature was maintained at 20-30°C, and the material flowed smoothly. The microspheres were then dried to a moisture content below 1%.

[0077] Comparative Example 1

[0078] The difference between this embodiment and embodiment 3 is that the core of the medicated pill does not contain xanthan gum, a sustained-release material, while the other processes, materials, and proportions are the same as in embodiment 3.

[0079] Comparative Example 2

[0080] The formulation of guanifacine hydrochloride sustained-release microgranules in this embodiment is as follows:

[0081]

[0082] a. By thorough stirring, guanifacine hydrochloride, hydroxypropyl methylcellulose, and silica are fully dissolved or dispersed in water to form a drug-coated solution. A fluidized bed is used to apply the drug to blank sucrose pellet cores, adjusting the spray rate to approximately 0.7 ml / min, the air volume to approximately 12 cubic meters / hour, and the air temperature to approximately 38°C, to obtain guanifacine hydrochloride microgranules / cores.

[0083] b. Preparation of Guanifacine Hydrochloride Sustained-Release Microspheres: Triethyl citrate and talc were added to 95% ethanol and homogenized. Eudragit RS100 and Eudragit RL100 were then slowly added to the 95% ethanol and homogenized. After dissolution, the mixture was passed through a 50-mesh sieve. The Guanifacine Hydrochloride Microsphere cores were placed in a fluidized bed and preheated to 30°C. The spray rate was adjusted to approximately 0.8 mL / min, the air volume to approximately 15 m³ / h, and the air temperature to approximately 35°C to ensure continuous coating. The material temperature was maintained at 20-30°C, and the material flowed smoothly. The microspheres were then dried to a moisture content below 1%.

[0084] Example 6

[0085] Release curve of guanidine hydrochloride sustained-release microspheres

[0086] The dissolution rate of guanidin hydrochloride sustained-release microspheres in Examples 1-5 and Comparative Examples 1-2 was studied at different pH values. Using a paddle apparatus (Chinese Pharmacopoeia 2020 edition), at 50 rpm and 37°C, the dissolution medium was 500 mL of pH 2.2 hydrochloric acid solution and pH 6.8 phosphate buffer solution. Samples were taken and analyzed at 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours.

[0087] Dissolution rates are provided in Tables 1 and 2, and in Figure 1 , Figure 2 , Figure 3 , Figure 4 Displayed as a curve.

[0088] Table 1

[0089]

[0090] Table 2

[0091]

[0092] According to dissolution data and curves, under pH 2.2 and pH 6.8 conditions, Comparative Examples 1-2, which contain drug-eluting pellets without sustained-release materials, exhibited rapid release, achieving complete release within 8-10 hours; while Examples 1-5 showed sustained release of guanifacine hydrochloride for 24 hours. This ensures that guanifacine hydrochloride is not rapidly and completely released and absorbed after administration, but rather gradually begins to be released and continues for 24 hours, maintaining a suitable concentration level in the bloodstream for an extended period, which is beneficial for maintaining a relatively stable blood drug concentration. Furthermore, the sustained-release microgranules of guanifacine hydrochloride can maintain sustained release for 24 hours in buffer solutions with different pH values, such as pH 2.2 and pH 6.8, unaffected by the pH of the gastrointestinal tract.

Claims

1. A guanidine hydrochloride sustained-release microgranule, characterized in that, It includes a drug-containing pill core and a sustained-release layer, wherein the sustained-release layer covers the outer surface of the drug-containing pill core, and the mass ratio of the drug-containing pill core to the sustained-release layer is (130-160):(28-36); The components of the pill core include guanethidine hydrochloride, filler, sustained-release material, and lubricant; The sustained-release layer comprises a barrier agent, a plasticizer, and an anti-adhesion agent.

2. The guanidine hydrochloride sustained-release microgranules according to claim 1, characterized in that, In the drug-containing pellet core, the mass ratio of guanethidine hydrochloride, filler, sustained-release material and lubricant is (1-5):(100-130):(7-24):(0-4); The filler is selected from microcrystalline cellulose, mannitol, sorbitol, dextrin, corn starch, sucrose, lactose, and sodium lauryl sulfate; The sustained-release material is selected from glyceryl behenate, xanthan gum, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and sodium carboxymethyl cellulose; The lubricant is selected from talc, silica, magnesium stearate, glyceryl monostearate, and polyethylene glycol.

3. The guanidine hydrochloride sustained-release microgranules according to claim 1, characterized in that, In the sustained-release layer, the mass ratio of the inhibitor, plasticizer, and anti-adhesion agent is (15-25):(2-6):(6-10); The inhibitor is selected from Eutectic RL, Eutectic RS, Eutectic NE30D, ethyl cellulose, and Aidoxiu. TM Sulis, Kollicoat SR30D, polymethyl methacrylate, cellulose acetate phthalate, hydroxypropyl cellulose acrylate copolymer; The plasticizer is selected from triethyl citrate, polyethylene glycol, tributyl citrate, and dibutyl sebacate; The anti-adhesion agent is selected from talc, silicon dioxide, magnesium stearate, and glyceryl monostearate.

4. The method for preparing guanidine hydrochloride sustained-release microspheres according to any one of claims 1-3, characterized in that, Includes the following steps: Step 1: Mix guanethidine hydrochloride, filler, sustained-release material and lubricant, add wetting agent to prepare soft material, make the soft material into pellet core by extrusion-spheronization method, dry to the moisture content below 2%, and obtain the drug-containing pellet core after sieving. The size of the drug-containing pellet core is 0.4mm-1.0mm. Step 2: Add plasticizer and anti-adhesion agent to organic solvent, then add retardant, homogenize to obtain sustained-release coating solution; place the drug-containing pellet core from Step 1 in a fluidized bed, preheat, coat with sustained-release coating solution, and dry until the water content is below 1% to obtain the sustained-release microparticles.

5. The preparation method according to claim 4, characterized in that, In step 1, the rolling speed is 1000-1500 rpm and the time is 1-5 minutes.

6. The preparation method according to claim 4, characterized in that, In step 2, the preheating temperature is 25-40℃; the fluidized bed coating conditions are a spray rate of 0.5-2 mL / min, an air volume of 10-20 cubic meters / hour, and an air temperature of 25-40℃.

7. A pharmaceutical composition, characterized in that, Includes the guanifacine hydrochloride sustained-release microgranules as described in any one of claims 1-3.

8. The pharmaceutical composition according to claim 7, characterized in that, It also includes pharmaceutically acceptable excipients.

9. The use of the guanifacine hydrochloride sustained-release microgranules according to any one of claims 1-3 or the pharmaceutical composition according to any one of claims 7-8 in the preparation of a medicament for treating attention deficit and hyperactivity disorder.

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