Gabapentin sustained release tablet as well as preparation method and application thereof

Abstract

The invention provides a gabapentin sustained release tablet as well as a preparation method and application thereof, and belongs to the technical field of medical preparations, the gabapentin sustained release tablet is prepared by uniformly mixing gabapentin, HPMC-K15M, PEO 303, CP, NaHCO3, a filling agent, an adhesive and a flow aid, and tabletting; the gabapentin sustained release tablet is used for relieving animal stress response. According to the gabapentin sustained-release preparation, by optimizing the proportion of the auxiliary materials, first-stage sustained-release kinetics of gabapentin is achieved, the stability of the preparation is improved through the combination of the auxiliary materials, and burst release or incomplete release is avoided.

Description

Technical Field

[0001] This invention relates to the field of medical preparations technology, and in particular to a gabapentin sustained-release tablet, its preparation method, and its application. Background Technology

[0002] Gabapentin (GBP), chemically known as 1-(aminomethyl)cyclohexaneacetic acid, is clinically used to relieve feline neuropathic pain, chronic pain, postoperative analgesia, and preoperative sedation. Transportation and unfamiliar environments can still easily trigger severe stress in cats. Current research has shown that gabapentin can safely and effectively reduce stress during transportation and veterinary visits, reducing aggressive behavior and increasing cooperation in cats.

[0003] Existing studies have shown that a single oral dose of 10 mg / kg of gabapentin in cats reaches peak plasma concentrations within 65–100 minutes, with a clearance rate of 2.7–3 mL / min / kg and an elimination half-life of 2.95–3.53 h. Currently, data on the optimal therapeutic plasma concentration of gabapentin in cats are lacking, but based on effective concentrations in humans or rats, the effective dose for cats may be 8 mg / kg, four times daily. Gabapentin has a short half-life and fluctuates significantly in plasma concentration, leading to frequent dosing and reduced medication adherence. This invention addresses this clinical challenge by providing gabapentin extended-release tablets that regulate release kinetics to prolong the duration of action and stabilize plasma concentrations, thereby reducing dosing frequency and extending the duration of anti-stress effects. Summary of the Invention

[0004] To address the above problems, this invention provides a gabapentin sustained-release tablet, its preparation method, and its application.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A gabapentin extended-release tablet, wherein the formulation of the gabapentin extended-release tablet is as follows, by weight:

[0007] Main drug: Gabapentin 42-47.5 parts;

[0008] Excipients: 20-22.5 parts of hydroxypropyl methylcellulose-K15M, 13.5-15 parts of polyoxyethylene 303, 5-12 parts of carbomer, 3.5-5 parts of sodium bicarbonate, 2.2-2.5 parts of filler, 3.5-4 parts of binder, and 0.45-0.5 parts of flow aid.

[0009] Furthermore, the formulation of the gabapentin extended-release tablets, by weight, is as follows:

[0010] Main drug: Gabapentin 42.05–47.4 parts;

[0011] Excipients: 0.2-22.4 parts of hydroxypropyl methylcellulose-K15M2, 13.5-14.9 parts of polyoxyethylene 303, 5.31-12 parts of carbomer, 3.7-4.8 parts of sodium bicarbonate, 2.2-2.5 parts of filler, 3.55-3.9 parts of binder, and 0.45-0.5 parts of flow aid.

[0012] Furthermore, the adhesive is copolyvinylpyrrolidone, polyvinylpyrrolidone K16-18, or polyvinylpyrrolidone K23-27.

[0013] Furthermore, the filler is at least one of microcrystalline cellulose, compressible starch, dextrin, and powdered sugar.

[0014] Furthermore, the flow aid is at least one of silica, talc, and magnesium stearate.

[0015] A method for preparing gabapentin sustained-release tablets, wherein the preparation method is to weigh the active pharmaceutical ingredient and excipients according to the above-mentioned gabapentin sustained-release tablet formula, mix them evenly, compress them into tablets, and prepare the gabapentin sustained-release tablets.

[0016] Furthermore, the specific process of the preparation method is as follows: polyoxyethylene 303, adhesive and carbomer are premixed, hydroxypropyl methylcellulose-K15M, filler and sodium bicarbonate are added to the resulting powder I and premixed, gabapentin is added to the resulting powder II and mixed, then a gliding agent is added and mixed, and finally the mixture is compressed to obtain gabapentin sustained-release tablets.

[0017] Furthermore, before preparing the gabapentin sustained-release tablets, the active pharmaceutical ingredient and each excipient are pulverized and sieved.

[0018] An application of gabapentin extended-release tablets, wherein the gabapentin extended-release tablets are used to prepare drugs for relieving stress responses in animals.

[0019] Furthermore, the gabapentin extended-release tablets are administered once every 24 hours.

[0020] The beneficial effects of the gabapentin sustained-release tablets of the present invention, their preparation method, and their applications are as follows:

[0021] Since there are currently no new veterinary drugs related to gabapentin in China, and no gabapentin sustained-release formulations are available on the market, this invention achieves first-order sustained-release kinetics of gabapentin by optimizing the ratio of excipients. The excipient combination improves the stability of the formulation and avoids burst release or incomplete release. The gabapentin sustained-release tablets in this invention have a simple process and are suitable for industrial production.

[0022] This invention provides a gastric floating, gastric retention sustained-release agent that delays the peak time of gabapentin in the blood, prolongs its half-life, reduces the frequency of administration, alleviates stress in animals during medical treatment and transportation, requires only one dose per day, improves owner compliance, and thus improves animal quality of life and animal welfare.

[0023] The gabapentin sustained-release tablets prepared by this invention have minimal impact on blood pressure and renal function biochemical indicators. Blood pressure showed no significant changes at 4 hours and 8 hours after administration, and renal function indicators remained within the normal range after administration. No serious adverse reactions were observed, demonstrating high safety. Attached Figure Description

[0024] Figure 1 This is a process flow diagram for preparing gabapentin sustained-release tablets of the present invention;

[0025] Figure 2 This represents the cumulative release percentage of gabapentin sustained-release tablets made from three different viscosities of HPMC in Example 1 of this invention; Figure 2 K4M represents gabapentin sustained-release tablets made with HPMC of viscosity K4M, K15M represents gabapentin sustained-release tablets made with HPMC of viscosity K15M, and K100M represents gabapentin sustained-release tablets made with HPMC of viscosity K100M.

[0026] Figure 3 It is the cumulative release percentage of gabapentin sustained-release tablets made from two different types of PEO in Example 1 of this invention; Figure 3 PEO Coagulant represents gabapentin extended-release tablets made using PEO Coagulant, and PEO 303 represents gabapentin extended-release tablets made using PEO 303.

[0027] Figure 4 This represents the cumulative release percentage of gabapentin sustained-release tablets prepared from different proportions of sustained-release matrix in Example 1 of this invention; Figure 4 In the HPMC:PEO ratio, 0.5:1 represents the weight ratio of HPMC-K15 to PEO303, 1:1 represents the weight ratio of HPMC-K15 to PEO303 to 1:1, 1.5:1 represents the weight ratio of HPMC-K15 to PEO303 to 1.5:1, 1:1.5 represents the weight ratio of HPMC-K15 to PEO303 to 0.5:1.5, and 1:0.5 represents the weight ratio of HPMC-K15 to PEO303 to 1:0.5.

[0028] Figure 5 This represents the cumulative release percentage of gabapentin sustained-release tablets prepared with different amounts of carbomer in Example 1 of this invention; Figure 5 0mg carbomer represents gabapentin extended-release tablets made without carbomer, 10mg carbomer represents gabapentin extended-release tablets made with 10mg carbomer, 25mg carbomer represents gabapentin extended-release tablets made with 25mg carbomer, and 40mg carbomer represents gabapentin extended-release tablets made with 40mg carbomer.

[0029] Figure 6 This refers to the cumulative release percentage of gabapentin sustained-release tablets made with different amounts of sodium bicarbonate in Example 1 of this invention; Figure 6 0% NaHCO3 represents gabapentin extended-release tablets made without the addition of NaHCO3, 2% NaHCO3 represents gabapentin extended-release tablets made with the addition of 2% NaHCO3, 4% NaHCO3 represents gabapentin extended-release tablets made with the addition of 4% NaHCO3, and 6% NaHCO3 represents gabapentin extended-release tablets made with the addition of 6% NaHCO3.

[0030] Figure 7 This is a comparison chart of the cumulative release percentage of gabapentin sustained-release tablets prepared with the optimized formula in Example 1 of this invention and formulas ① to ⑥. Figure 7 The optimized formulation represents gabapentin extended-release tablets made with the optimized formulation; HPMC:PEO = 1.5:1 represents gabapentin extended-release tablets made with formulation ②; HPMC:PEO = 1:1 represents gabapentin extended-release tablets made with formulation ①; 7mg NaHCO3 represents gabapentin extended-release tablets made with formulation ④; 10mg carbomer represents gabapentin extended-release tablets made with formulation ③; Box Behnken formulation 12 represents gabapentin extended-release tablets made with formulation ⑤; and Box Behnken formulation 15 represents gabapentin extended-release tablets made with formulation ⑥.

[0031] Figure 8 This is the average drug-time curve of six cats after a single oral administration of gabapentin sustained-release tablet J1 or gabapentin capsules in Example 5 of the present invention; Figure 8 Medium-release tablets represent oral gabapentin sustained-release tablets J1, and immediate-release capsules represent oral gabapentin capsules;

[0032] Figure 9 The results are the systolic blood pressure measurements of cats before and after oral administration of gabapentin sustained-release tablet J1 in Example 5 of this invention; where "ns" indicates that there was no significant difference between the two groups of values ​​(p>0.05);

[0033] Figure 10The figures are the plasma urea (Figure A) and creatinine (Figure B) results of cats before and after oral administration of gabapentin sustained-release tablet J1 in Example 5 of this invention; where "***" indicates that the difference between the two groups is extremely significant (p < 0.01), "**" indicates that the difference between the two groups is significant (p < 0.05), and "ns" indicates that there is no significant difference between the two groups (p > 0.05). Detailed Implementation

[0034] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art can make similar extensions without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0035] This invention protects a gabapentin sustained-release tablet, its preparation method, and its application, wherein the formulation of the gabapentin sustained-release tablet, by weight, comprises:

[0036] ①Main drug: Gabapentin 42.05-47.4 parts;

[0037] ② Excipients: 20.2-22.4 parts of hydroxypropyl methylcellulose-K15M (HPMC-K15M) as the sustained-release matrix material, 13.5-14.9 parts of polyoxyethylene 303 (PEO 303) as the sustained-release matrix material, 5.31-12 parts of carbomer (CP) as the sustained-release matrix material, 3.7-4.8 parts of sodium bicarbonate (NaHCO3) as the foaming agent, 2.2-2.5 parts of microcrystalline cellulose (MCC) as the filler, 3.55-3.9 parts of copovidone (PVP / VA) as the binder, and 0.45-0.5 parts of magnesium stearate (MS) as the flow aid.

[0038] The preparation method of gabapentin sustained-release tablets is as follows: Figure 1 As shown, it includes the following steps:

[0039] Take gabapentin and each excipient and pass them through a 50-70 mesh sieve for later use;

[0040] PEO 303, PVP / VA and CP were premixed. HPMC-K15M, MCC and NaHCO3 were added to the resulting powder mixture I and premixed. Gabapentin was added to the resulting powder mixture II and mixed. MS was then added and mixed. Finally, the mixture was compressed into round tablets using a single-punch tablet press, which is the gabapentin sustained-release tablet.

[0041] The gabapentin sustained-release tablets produced by this invention are used to relieve stress reactions in animals (especially dogs, cats, etc.), particularly stress reactions that occur during transportation, in unfamiliar environments, and during veterinary visits, with an effective duration of more than 24 hours.

[0042] Example 1: Screening of excipients

[0043] I. Hydrophilic Gel Backbone: Screening of Hydroxypropyl Methylcellulose (HPMC) Types

[0044] This invention uses hydroxypropyl methylcellulose (HPMC) as the hydrophilic gel framework. Screening revealed that HPMC with different viscosities affects the release effect of gabapentin. Specific HPMC viscosity screening experiments are as follows:

[0045] HPMC was used as the hydrophilic gel matrix material. HPMC with three viscosities—HPMC-K4M (molecular weight 400,000, viscosity 2700–5040 mPa*s), HPMC-K15M (molecular weight 575,000, viscosity 13,500–25,200 mPa*s), and HPMC-K100M (molecular weight 1,000,000, viscosity 75,000–140,000 mPa*s)—was screened. Gabapentin sustained-release tablets with three different HPMC viscosities were prepared according to the formulations in Table 1 and the following preparation methods. The specific formulations are as follows:

[0046] Table 1. A list of formulations for gabapentin sustained-release tablets with different HPMC viscosities.

[0047]

[0048]

[0049] The preparation methods for gabapentin sustained-release tablets with three different HPMC viscosities are as follows:

[0050] Take gabapentin and each excipient and pass them through a 60-mesh sieve separately, then set aside.

[0051] PEO and PVP / VA were premixed. HPMC and MCC were added to the resulting powder mixture I and premixed. Gabapentin was added to the resulting powder mixture II and mixed. MS was then added for final mixing. Finally, the mixture was compressed into 7mm round tablets using a single-punch tablet press, which is the gabapentin sustained-release tablet.

[0052] The cumulative release rates of gabapentin sustained-release tablets with three different HPMC viscosities were determined at 1h, 2h, 4h, 8h, 12h, and 24h, and release curves were plotted and compared. Specific results are shown in Table 2 and [Table data missing]. Figure 2 The method for determining the cumulative release of gabapentin sustained-release tablets with three different HPMC viscosities is as follows:

[0053] Referring to the Dissolution Determination Method II (Slurry Method) in Appendix II of the 2020 Edition of the Chinese Pharmacopoeia, 500 mL of HCl aqueous solution with a pH of 1.2 was selected as the release medium. The temperature was set at 38.5 ± 0.5℃, and the rotation speed was 50 rpm. 2 mL samples were taken at 0h, 1h, 2h, 4h, 8h, 12h, and 24h, and immediately after each sampling, 2 mL of the same temperature release medium was added to the dissolution system. The extracted solution was filtered through a 0.45 μm polyethersulfone membrane, and an appropriate amount of the filtrate was transferred to a sample vial. The solution was analyzed using liquid chromatography, and the peak area of ​​gabapentin was recorded and the corresponding concentration was calculated. The cumulative release percentage was then calculated using this concentration.

[0054] Table 2. Cumulative release rate of gabapentin (%) of different HPMC viscosity sustained-release tablet formulations.

[0055]

[0056] From Table 2 and Figure 2 It can be seen that the cumulative release rates of HPMC-K4M and HPMC-K15M both reached over 90% after 24 hours, meeting the requirements for sustained-release formulations. Meanwhile, HPMC-K15M had the lowest release rate in the first 4 hours, but did not meet the requirement of less than 40% release after 2 hours for sustained-release formulations. Therefore, this invention selected HPMC-K15M as a partial sustained-release matrix material.

[0057] II. Hydrophilic Gel Framework: Screening of Polyoxyethylene (PEO) Types

[0058] PEO has a wide molecular weight range (100,000–7,000,000), with the 303 model (7,000,000 molecular weight) or the Coagulant model (5,000,000 molecular weight) generally used as the matrix material for sustained-release tablets. Following the preparation process in the hydroxypropyl methylcellulose (HPMC) screening process, two different formulations of gabapentin sustained-release tablets were prepared using different PEO types. Specific formulations are shown in Table 3. The cumulative release percentage of the different formulations of gabapentin sustained-release tablets was determined at 1h, 2h, 4h, 8h, 12h, and 24h according to the determination methods used in the HPMC screening process. Release curves were plotted and compared. The results are shown in Table 3. Figure 3 And Table 4.

[0059] Table 3. List of prescriptions for different PEO groups

[0060]

[0061] Table 4. Cumulative release rates (%) of gabapentin extended-release tablets of different PEO formulations.

[0062]

[0063] From Table 4 and Figure 3 It can be seen that the cumulative release rate of PEO 303 reached over 90% after 24 hours, meeting the requirements for sustained-release formulations. The release rate of PEO 303 was slower than that of PEO Coagulant in the first 8 hours; therefore, PEO 303 was chosen as a partial sustained-release matrix material in this invention. However, both formulations showed almost complete drug release after 12 hours of dissolution, resulting in unsatisfactory sustained-release effects, requiring further optimization.

[0064] III. Dosage Assessment of the Sustained-Release Matrix

[0065] To preliminarily determine the scope and trend of its influence on drug release and to provide a reasonable range of variables and experimental design basis for subsequent response surface methodology, the effect of the dosage of the sustained-release matrix on the dissolution curve of the sustained-release tablets was investigated. Gabapentin sustained-release tablets with different formulation contents of HPMC-K15 and PEO 303 sustained-release matrices were prepared according to the preparation process used in the HPMC screening process. The specific formulations are shown in Table 5. The cumulative release percentage of gabapentin sustained-release tablets with different formulations was determined at 0h, 1h, 2h, 4h, 8h, 12h, and 24h according to the determination method used in the HPMC screening process. Release curves were plotted and compared. The results are shown in Table 5. Figure 4 See Table 6.

[0066] Table 5. Summary of dosage formulations for different ratios of sustained-release matrix.

[0067]

[0068] Table 6. Cumulative release rates (%) of gabapentin extended-release tablets with different formulations of the extended-release matrix.

[0069]

[0070] from Figure 4 As shown in Table 6, increasing the concentration of both HPMC-K15M and PEO 303 increases gel viscosity, slows down the dissolution rate of the skeleton, and delays the drug release rate. Therefore, in formulations with low concentrations of the two polymers, the initial release of the active drug component is relatively large. Considering the release data of each formulation, the HPMC-K15M / PEO 303 (1.5:1) blend has better sustained-release characteristics. The ratio of this polymer blend is selected as the key formulation factor for optimizing the process.

[0071] IV. Hydrophilic Gel Skeleton Materials: Screening of Carbomer (CP) Dosage

[0072] The formulation containing only HPMC-K15M and PEO 303 showed poor sustained-release and floating effects. The effect of adding carbomer (CP) on the dissolution curve was investigated. Gabapentin sustained-release tablets with different carbomer contents were prepared according to the following preparation process (see Table 7). The cumulative release percentage of gabapentin sustained-release tablets with different carbomer contents was determined at 0h, 1h, 2h, 4h, 8h, 12h, and 24h according to the determination method used in the screening process of hydroxypropyl methylcellulose (HPMC). Release curves were plotted and compared. The results are shown in Table 7. Figure 5 And Table 8.

[0073] Preparation process: Gabapentin and each excipient are passed through a 60-mesh sieve and set aside;

[0074] PEO 303, PVP / VA and CP were premixed. HPMC-K15M and NaHCO3 were added to the resulting powder mixture I and premixed. Gabapentin was added to the resulting powder mixture II and mixed. MS was then added for total mixing. Finally, the mixture was compressed into 7mm round tablets using a single-punch tablet press, which is the gabapentin sustained-release tablet.

[0075] Table 7. List of different carbomer dosage prescriptions

[0076]

[0077] Table 8. Cumulative release (%) of gabapentin extended-release tablets with different carbomer contents

[0078]

[0079] from Figure 5 As shown in Table 8, the release rate of the formulation with added carbomer was lower at all time points within 24 hours than that without carbomer, indicating that the addition of carbomer slowed down the drug dissolution and release rate, and different contents of carbomer had a significant impact on dissolution. Therefore, in the optimization experiment, the carbomer content was listed as a key independent variable for investigation.

[0080] V. Foaming Agent: Screening of Sodium Bicarbonate (NaHCO3) Dosage

[0081] To rationally adjust the flotation ability and porosity of tablets, the effect of foaming agent dosage on drug flotation and release was investigated. Sustained-release tablets with different foaming agent contents were prepared according to the preparation process used in the carbomer (CP) dosage screening process (see Table 9). The cumulative release percentage of gabapentin sustained-release tablets with different formulations was determined at 0h, 1h, 2h, 4h, 8h, 12h, and 24h according to the assay method used in the hydroxypropyl methylcellulose (HPMC) screening process. Release curves were plotted and compared. The release results are shown in Table 9. Figure 6And Table 10. The flocculation properties of gabapentin sustained-release tablets with different formulations were also determined, and the results are shown in Table 11. The flocculation property determination method is as follows:

[0082] Each gabapentin sustained-release tablet was placed in 500 mL of hydrochloric acid aqueous solution with pH 1.2 and kept at 38.5 ± 0.5 °C. The following data were recorded: (1) Floating Lag Time (FLT): the time required for the tablet to float from the surface of the liquid; (2) Total Floating Duration (TFD): the duration for which the tablet remained floating.

[0083] Table 9. Formulation composition with different foaming agent dosages.

[0084]

[0085] Table 10. Cumulative release (%) of gabapentin in sustained-release tablets with different foaming agent contents

[0086]

[0087]

[0088] Table 11. Flotation performance of sustained-release tablets with different foaming agent contents.

[0089]

[0090] From Table 10 and Figure 6 It can be seen that in the initial dissolution stage (0–4h), the release rate of the 6% NaHCO3 formulation was significantly lower than that of the 2% NaHCO3 formulation. However, as the dissolution process progressed (8–24h), the release rates of the three groups tended to be the same. Table 11 shows that the addition of a foaming agent helps the tablets float. As the foaming agent content increases, the floating lag time shortens. Therefore, the floating performance of the tablets needs to be considered in the optimization design, with the foaming agent content as one of the independent variables for optimization.

[0091] VI. Formula Optimization

[0092] 1) Box Behnken response surface analysis

[0093] Previous experiments have shown that the sustained-release matrix material HPMC / PEO (1.5:1), CP, and foaming agent NaHCO3 all affect the drug release rate. A three-factor, three-level response surface methodology was performed. The factors for formulation optimization are shown in Table 12. Other excipients were maintained at gabapentin 90.00 mg, MCC 4.63 mg, PVP / VA 7.40 mg, and MS 0.93 mg. The specific components of each formulation are shown in Table 13.

[0094] Table 12 Coding Table for Formula Optimization Factors

[0095]

[0096] Table 13 Optimization Design Table for Box-Behnken Method Formulation

[0097]

[0098] Based on the 17 formulation components in Table 13, gabapentin sustained-release tablets were prepared according to the following method, and the initial floating time, sustained floating time, and cumulative release at 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after in vitro dissolution were determined. The optimization targets for the cumulative release rate and floating lag time of gabapentin sustained-release tablets are shown in Table 14, and the cumulative release results for each formulation are shown in Table 15.

[0099] Preparation process: Gabapentin and each excipient are passed through a 60-mesh sieve and set aside;

[0100] PEO, PVP / VA and CP were premixed. HPMC-K15M, MCC and NaHCO3 were added to the resulting powder mixture I and premixed. Gabapentin was added to the resulting powder mixture II and mixed. MS was then added and mixed. Finally, the mixture was compressed into 7mm round tablets using a single-punch tablet press, which is the gabapentin sustained-release tablet.

[0101] Table 14 Target Levels of Response Surface Optimization Experiment

[0102]

[0103]

[0104] Table 15. Cumulative Release Rate Results for Each Prescription (Mean ± Standard Deviation) (n = 3)

[0105]

[0106] The optimization was performed using Design Expert software with the targets in Table 14 as the criteria. The resulting formulation consisted of 47.9 mg of HPMC-K15M, 31.9 mg of PEO-303, 19.9 mg of CP, and 9.9 mg of NaHCO3. The expected and measured values ​​of the dissolution of the optimized formulation are shown in Table 16.

[0107] Table 16 Expected and Measured Values ​​of Dissolution of Optimized Formulations (Mean ± Standard Deviation) (n = 3)

[0108]

[0109]

[0110] The measured dissolution rate of the optimized formulation was close to the predicted value, and the dissolution curve similarity factor f2 was 88.9. The cumulative release rate at 24 h was >95%, which meets the needs of veterinary clinical use. Therefore, the optimized formulation (90.0 mg GBP, 47.9 mg HPMC-K15M, 31.9 mg PEO 303, 19.9 mg CP, 9.9 mg NaHCO3, 5.35 mg MCC, 8.0 mg PVP / VA, and 1.1 mg MS) was selected.

[0111] VII. Advantages of Prescription

[0112] This invention compares the optimized formulation (90.0 mg GBP, 47.9 mg HPMC-K15M, 31.9 mg PEO 303, 19.9 mg CP, 9.9 mg NaHCO3, 5.35 mg MCC, 8.0 mg PVP / VA, and 1.1 mg MS) with formulation ① (90.0 mg GBP, 31.23 mg HPMC-K15M, 31.23 mg PEO 303, 6.16 mg PVP / VA, 4.11 mg MCC, and 1.64 mg MS) prepared with HPMC-K15M / PEO 303 (1:1) and formulation ② (90.0 mg GBP, 31.23 mg HPMC-K15M, 31.23 mg PEO 303, 6.16 mg PVP / VA, 4.11 mg MCC, and 1.64 mg MS) prepared with HPMC-K15M / PEO 303 (1:1). Gabapentin extended-release tablets made with 303 (1.5:1) contain 90.0 mg GBP, 46.85 mg HPMC-K15M, 31.23 mg PEO 303, 6.16 mg PVP / VA, and 1.64 mg MS; Formulation ③ contains gabapentin extended-release tablets made with 10 mg carbomer added (90.0 mg GBP, 10 mg CP, 31.23 mg HPMC-K15M, 31.23 mg PEO 303, 7.0 mg NaHCO3, 6.16 mg PVP / VA, and 1.64 mg MS); Formulation ④ contains gabapentin extended-release tablets made with 7 mg NaHCO3 added (90.0 mg GBP, 7 mg NaHCO3, 31.23 mg HPMC-K15M, 31.23 mg PEO 303, 7.0 mg NaHCO3, 6.16 mg PVP / VA, and 1.64 mg MS). 303, 6.16 mg PVP / VA and 1.64 mg MS). Experimental results are shown in […]. Figure 7 As shown in Table 17, the sustained-release effect of the optimized formulation is significantly better than that of the other four formulations.

[0113] Further comparisons were made between the optimized formulation (90.0 mg GBP, 47.9 mg HPMC-K15M, 31.9 mg PEO3O3, 19.9 mg CP, 9.9 mg NaHCO3, 5.35 mg MCC, 8.0 mg PVP / VA, and 1.1 mg MS) and formulation ⑤ [Box Behnken response surface methodology formulation 12 (90.0 mg GBP, 10 mg CP, 42 mg HPMC-K15M, 28 mg PEO3O3, 7.0 mg NaHCO3, 7.40 mg PVP / VA, 4.63 mg MCC, and 0.93 mg MS)]. Formula 15 [BoxBehnken response surface methodology optimization formula 15 (90.0 mg GBP, 25 mg CP, 42 mg HPMC-K15M, 28 mg PEO3O3, 10.0 mg NaHCO3, 7.40 mg PVP / VA, 4.63 mg MCC, and 0.93 mg MS)] shows similarity factors f2 between formula 5 and the optimized formula (80.38 > 50), and between formula 6 and the optimized formula (79.95 > 50). Therefore, both dissolution curves are considered similar to the dissolution curve of the optimized formula.

[0114] Table 17 Cumulative dissolution rate (%) for each formulation

[0115]

[0116] Example 2: A gabapentin sustained-release tablet, its preparation method, and its application.

[0117] In this embodiment, gabapentin sustained-release tablets were prepared using an optimized formulation. The formulation for preparing gabapentin sustained-release tablets, by weight percentage, is as follows: 42.05% GBP, 22.4% HPMC-K15M, 14.9% PEO 3O3, 9.3% CP, 4.6% NaHCO3, 2.5% MCC, 3.75% PVP / VA, and 0.5% MS.

[0118] The specific preparation method for gabapentin sustained-release tablets is as follows: take gabapentin and each excipient and pass them through a 50-70 mesh sieve for later use;

[0119] PEO 303, PVP / VA and CP were premixed. HPMC-K15M, MCC and NaHCO3 were added to the resulting powder mixture I and premixed. Gabapentin was added to the resulting powder mixture II and mixed. MS was then added and mixed. Finally, the mixture was compressed into 7mm round tablets using a single-punch tablet press. These tablets are gabapentin sustained-release tablets, labeled J1. The cumulative dissolution rate results are shown in the optimized formulation in Table 18.

[0120] The gabapentin sustained-release tablets produced by this invention are used to relieve stress responses in animals (especially dogs, cats, etc.), particularly stress responses that occur during transportation, in unfamiliar environments, and during veterinary visits.

[0121] Example 3: A gabapentin sustained-release tablet, its preparation method, and its application.

[0122] In this embodiment, gabapentin sustained-release tablets were prepared using formulation ⑥ from Example 1. The formulation for preparing gabapentin sustained-release tablets, by weight percentage, is: 43.3% GBP, 20.2% HPMC-K15M, 13.5% PEO 3O3, 12% CP, 4.8% NaHCO3, 2.2% MCC, 3.55% PVP / VA, and 0.45% MS.

[0123] The specific preparation method for gabapentin sustained-release tablets is as follows: take gabapentin and each excipient and pass them through a 50-mesh sieve, and set aside.

[0124] PEO 303, PVP / VA and CP were premixed. HPMC-K15M, MCC and NaHCO3 were added to the resulting powder I and premixed. Gabapentin was added to the resulting powder II and mixed. MS was then added and mixed. Finally, the mixture was compressed into 7mm round tablets using a single-punch tablet press. This is the gabapentin sustained-release tablet, labeled J2. The cumulative dissolution rate results are shown in Formulation ⑥ in Table 18.

[0125] The gabapentin sustained-release tablets produced by this invention are used to relieve stress responses in animals (especially dogs, cats, etc.), particularly stress responses that occur during transportation, in unfamiliar environments, and during veterinary visits.

[0126] Example 4: A gabapentin sustained-release tablet, its preparation method, and its application.

[0127] In this embodiment, gabapentin sustained-release tablets were prepared using formulation ⑤ from Example 1. The formulation for preparing gabapentin sustained-release tablets, by weight percentage, is as follows: 47.4% GBP, 22.1% HPMC-K15M, 14.7% PEO 303, 5.31% CP, 3.7% NaHCO3, 2.4% MCC, 3.9% PVP / VA, and 0.49% MS.

[0128] The specific preparation method for gabapentin sustained-release tablets is as follows: take gabapentin and each excipient and pass them through a 70-mesh sieve, and set them aside;

[0129] PEO 303, PVP / VA and CP were premixed. HPMC-K15M, MCC and NaHCO3 were added to the resulting powder I and premixed. Gabapentin was added to the resulting powder II and mixed. MS was then added and mixed. Finally, the mixture was compressed into 7mm round tablets using a single-punch tablet press. These tablets are gabapentin sustained-release tablets, labeled J3. The cumulative dissolution rate results are shown in formulation ⑤ in Table 18.

[0130] The gabapentin sustained-release tablets produced by this invention are used to relieve stress responses in animals (especially dogs, cats, etc.), particularly stress responses that occur during transportation, in unfamiliar environments, and during veterinary visits.

[0131] Example 5: Validation of the advantages of gabapentin sustained-release tablet formulation

[0132] I. In vitro dissolution

[0133] The cumulative release rates of gabapentin sustained-release tablets J1-J3 prepared in Examples 2-4 were determined according to the determination method in the screening process of hydroxypropyl methylcellulose (HPMC). The results are shown in Table 18. It can be seen that the gabapentin sustained-release tablets prepared in this invention have a good sustained-release effect, avoiding burst release or incomplete release, and can ensure that only one dose is needed per day.

[0134] Table 18. Cumulative in vitro dissolution release rates (%) of Examples 2-4

[0135]

[0136] Since the in vitro release effects of Examples 2-4 are almost identical, this example only conducts in vivo release tests, blood pressure measurements, and renal function biochemical index detection on the gabapentin sustained-release tablet J1 prepared in Example 2, as follows:

[0137] II. In vivo release experiment

[0138] This invention, referring to the guidelines for animal pharmacokinetic studies of oral sustained-release formulations, established an LC-MS / MS method for determining gabapentin plasma concentrations. A two-phase, two-treatment, fasting design was used for animal pharmacokinetic evaluation. Domestic cats were administered gabapentin sustained-release tablets J1 and commercially available gabapentin capsules, with a two-week washout period between the two phases. Cats were weighed before each phase, fasted for 12 hours prior to administration, and allowed free access to food after administration. Six cats were randomly divided into two groups. One group (n=3) received a first-phase administration of gabapentin extended-release tablets, with 1 mL blood samples collected from the medial saphenous vein of the hind limb or the cephalic vein of the forelimb before administration and at 2, 4, 6, 8, 10, 12, 24, 48, and 72 hours after administration. The second phase received a single dose of commercially available gabapentin capsules (batch number: 241121MF), with 1 mL blood samples collected from the medial saphenous vein of the hind limb or the cephalic vein of the forelimb before administration and at 1, 2, 4, 6, 8, 12, 24, and 48 hours after administration. The other group (n=3) received the reverse administration and blood collection protocol.

[0139] Sample preparation: Take 100 μL of plasma and add 400 μL of methanol (containing 100 μL of pregabalin internal standard). Vortex for 1 min and place at -20℃ to precipitate proteins for about 2 h. Centrifuge at 12000 rpm / min and 4℃ for 10 min. Filter the supernatant through a 0.22 μm nylon filter membrane and transfer it to a sample vial for LC-MS / MS analysis.

[0140] The chromatographic conditions for LC-MS / MS analysis were as follows: separation was performed on an ACQUITY UPLC HSS T3 reversed-phase column (2.1 mm × 50 mm, 1.8 μm). The mobile phase consisted of ultrapure water (A) containing 0.1% formic acid and methanol (B) containing 0.1% formic acid. The flow rate was 0.3 mL / min, the injection volume was 1 μL, the column temperature was 40 °C, and the following elution gradient was used: 0–0.6 min, A:B = 75:25; 1.6 min, A:B = 60:40; 1.7–2.2 min, A:B = 10:90; 2.3–3.5 min, A:B = 75:25.

[0141] The mass spectrometry conditions for LC-MS / MS analysis are as follows:

[0142] Ion source: Electrospray ionization (ESI)

[0143] Scan mode: Parallel Reaction Monitoring (PRM)

[0144] Sheath gas: 30 arb; Auxiliary gas: 10 arb

[0145] Spray voltage: 4500V

[0146] Capillary temperature: 320℃

[0147] Auxiliary gas heating temperature: 220℃

[0148] Resolution: 60000

[0149] AGC target: 2e5

[0150] Maximum injection time: 100ms

[0151] Isolation window: 4.0m / z

[0152] Collision voltage: 35eV

[0153] Polarity: Cation Detection

[0154] Ions for quantitative analysis: Gabapentin m / z 172.13→154.12; Pregabalin m / z 160.13→142.12;

[0155] The pharmacokinetic parameters of the gabapentin sustained-release tablet J1 prepared in this invention in cats are shown in Table 19, and the average drug-time curves of the 6 tested cats are shown in Table 19. Figure 8 .

[0156] Table 19 Mean pharmacokinetic parameters of gabapentin in cats

[0157]

[0158] Note: t 1 / 2λZ To eliminate the half-life, T max For the time to peak drug concentration, C max To achieve peak drug concentration, AUC last The area under the drug-time curve (AUC) is the distance between the time point before drug administration and the last observable drug concentration. INF_obs Vz_F_obs represents the area under the curve from before drug administration to infinity, where Vz_F_obs is the apparent volume of distribution, Cl_F is the clearance rate, and MRT is the mean square root of the drug. last This represents the average dwell time.

[0159] By 19 and Figure 8 It can be seen that the average half-life of the gabapentin sustained-release tablets prepared in this invention in cats was extended from 3.66 h to 7.24 h, the time to peak plasma concentration was delayed from 1.50 h to 4.67 h, and the average peak plasma concentration (C) was [not specified]. maxThe concentration of gabapentin decreased from 25736.51 ng / mL to 20033.59 ng / mL, confirming the sustained-release effect of gabapentin extended-release tablets in cats. Furthermore, compared to conventional capsules, the relative bioavailability of the extended-release tablets was 103.17 ± 18.86%, indicating that the two formulations are bioequivalent under fasting conditions.

[0160] III. Blood Pressure Measurement

[0161] During the in vivo release experiment, Doppler flowmeters were used to monitor the arterial systolic blood pressure of six cats before and after drug administration. Measurements were repeated three times at each time point, with intervals of 3–5 minutes. Paired t-tests were performed on the systolic blood pressure measurements before and after drug administration. The results are shown below. Figure 9 Statistical analysis of baseline blood pressure before administration and systolic blood pressure at 4 and 8 hours after administration revealed no significant difference (p = 0.7931, p = 0.2886). The systolic blood pressure of the six cats measured at the three time points ranged from 108 to 145 mmHg, indicating that the gabapentin sustained-release tablets prepared in this invention had no significant effect on blood pressure in cats.

[0162] IV. Detection of Renal Function Biochemical Indicators

[0163] Furthermore, the concentrations of non-protein nitrogenous compounds in animal plasma were investigated. During the in vivo release experiment, the concentrations of creatinine and urea in the plasma of cats were measured using a fully automated biochemical analyzer before administration and at 4 and 24 hours after administration. Changes in renal function biochemical indicators were observed, and the results are shown below. Figure 10 .

[0164] Plasma Crea concentrations in all six cats were within the normal range (reference range: 0.8–2.1 mg / dL) before and after administration of gabapentin extended-release tablets. Plasma Urea concentrations in four of these cats were within the normal range (reference range: 36.4–74.9 mg / dL) before and after administration, while plasma Urea concentrations in two cats were below the reference range at 24 hours post-administration. A paired-samples t-test revealed that plasma Urea levels were significantly elevated at 4 hours post-administration compared to pre-administration levels (p = 0.0076), but returned to baseline levels at 24 hours (p = 0.6387). Simultaneously, Crea concentrations significantly decreased at 4 hours post-administration (p = 0.0047), and this downward trend continued until 24 hours (p = 0.0499 compared to 4 hours).

[0165] In summary, the gabapentin sustained-release tablets prepared by this invention have minimal impact on blood pressure and renal function biochemical indicators. Blood pressure showed no significant changes at 4 hours and 8 hours after administration, and renal function indicators remained within the normal range after administration. No serious adverse reactions were observed, demonstrating high safety.

[0166] Examples 6-9: Gabapentin sustained-release tablets, their preparation methods, and applications

[0167] Examples 6-9 describe a gabapentin sustained-release tablet, its preparation method, and its application. The preparation process of the gabapentin sustained-release tablets in Examples 6-9 is basically the same as that in Example 2, with the only difference being the formulation. See Table 20 for details.

[0168] Table 20: Summary of the formulations in Examples 6-9

[0169]

[0170] The contents of other parts of Examples 6 to 9 are the same as those of Example 2, and will not be repeated here.

[0171] Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A gabapentin sustained-release tablet, characterized in that, The formulation of the gabapentin extended-release tablets, by weight, is as follows: Main drug: Gabapentin 42-47.5 parts; Excipients: 20-22.5 parts of hydroxypropyl methylcellulose-K15M, 13.5-15 parts of polyoxyethylene 303, 5-12 parts of carbomer, 3.5-5 parts of sodium bicarbonate, 2.2-2.5 parts of filler, 3.5-4 parts of binder, and 0.45-0.5 parts of flow aid.

2. The gabapentin sustained-release tablet according to claim 1, characterized in that, The formulation of the gabapentin extended-release tablets, by weight, is as follows: Main drug: Gabapentin 42.05–47.4 parts; Excipients: 20.2-22.4 parts of hydroxypropyl methylcellulose-K15M, 13.5-14.9 parts of polyoxyethylene 303, 5.31-12 parts of carbomer, 3.7-4.8 parts of sodium bicarbonate, 2.2-2.5 parts of filler, 3.55-3.9 parts of binder, and 0.45-0.5 parts of flow aid.

3. The gabapentin sustained-release tablet according to claim 1 or 2, characterized in that, The adhesive is copolyvinylpyrrolidone, polyvinylpyrrolidone K16-18 or polyvinylpyrrolidone K23-27.

4. The gabapentin sustained-release tablet according to claim 1 or 2, characterized in that, The filler is at least one of microcrystalline cellulose, compressible starch, dextrin, and powdered sugar.

5. The gabapentin sustained-release tablet according to claim 1 or 2, characterized in that, The flow aid is at least one of silica, talc, and magnesium stearate.

6. A method for preparing gabapentin sustained-release tablets, characterized in that, The preparation method is to weigh the active pharmaceutical ingredient and excipients according to the formulation of gabapentin sustained-release tablets according to any one of claims 1-5, mix them evenly, compress them into tablets, and prepare the gabapentin sustained-release tablets.

7. The method for preparing gabapentin sustained-release tablets according to claim 6, characterized in that, The specific process of the preparation method is as follows: Polyoxyethylene 303, adhesive and carbomer are premixed, hydroxypropyl methylcellulose-K15M, filler and sodium bicarbonate are added to the resulting powder I and premixed, gabapentin is added to the resulting powder II and mixed, then a gliding agent is added and mixed, and finally the mixture is compressed to obtain gabapentin sustained-release tablets.

8. The method for preparing gabapentin sustained-release tablets according to claim 6 or 7, characterized in that, Before preparing the gabapentin sustained-release tablets, the active pharmaceutical ingredient and each excipient are pulverized and sieved.

9. An application of gabapentin sustained-release tablets, characterized in that, The gabapentin sustained-release tablets according to any one of claims 1-5 are used to prepare a drug for relieving stress response in animals.

10. The application of the gabapentin sustained-release tablet according to claim 9, characterized in that, The gabapentin extended-release tablets are administered once every 24 hours.

Images