Pregabalin Sustained Release Tablets and Their Preparation Methods and Applications

Abstract

The present invention provides a pregabalin sustained-release tablet and its preparation method and application, belonging to the technical field of medical preparations. The pregabalin sustained-release tablet is prepared by uniformly mixing 35-45 parts by weight of pregabalin, 40-48 parts by weight of hydroxypropyl methylcellulose with a viscosity of K4M, 0.1-3 parts by weight of polyvinylpyrrolidone with a viscosity of K16-18, 1-6 parts by weight of polyvinylpyrrolidone with a viscosity of K23-27, and 0.1-9 parts by weight of sodium bicarbonate, screening, granulating, then adding a glidant and mixing evenly, and tabletting. The pregabalin sustained-release tablet is used to relieve the anxiety and fear of animals. The present invention prepares a pregabalin sustained-release tablet with an effective duration of more than 48 hours through a gastric floating sustained-release system, effectively relieving the anxiety and fear of dogs and cats during long-distance transportation and medical treatment, and solving the problem that more and more pet owners carry their pets across provinces or even across countries and it is inconvenient to administer medicine during the journey.

Description

Technical Field

[0001] The present invention relates to the technical field of medical preparations, and in particular to a pregabalin sustained-release tablet and its preparation method and application. Background Art

[0002] Pregabalin is a compound with the chemical name (S)-3-(aminomethyl)-5-methylhexanoic acid, with the molecular formula C8H 17 NO2 and a molecular weight of 159.22600. It is an inhibitor of specific voltage-gated calcium channels and is used in humans for the treatment of epilepsy, neuropathic pain, and generalized anxiety disorder.

[0003] Currently, it has been reported that pregabalin can be used to relieve acute anxiety and fear in dogs and cats during transportation and veterinary visits.

[0004] The U.S. Food and Drug Administration (FDA) has approved a pregabalin oral solution. This is the first animal drug containing pregabalin approved by the FDA and is designed specifically to relieve acute anxiety and fear in cats during transportation and veterinary visits.

[0005] The effective duration of the pregabalin oral solution in relieving feline transportation stress is on average 7 hours. It is usually orally administered to cats 1.5 hours before transportation and can be administered for two consecutive days, but it cannot meet the current needs of more and more pet owners who carry their pets across provinces or even countries (transportation time exceeds 24 hours) and it is inconvenient to administer drugs during the journey. Existing studies have shown that when cats are fed pregabalin at a dose of 2.5 mg / kg, the longest half-life can be 12.0 ± 3.2 h; when cats are fed pregabalin at a dose of 7.5 mg / kg, the longest half-life can be 12.1 ± 2.6 h. It can be seen that it still needs to be administered at least twice a day and still cannot meet the need for animals that are inconvenient to administer drugs during a long transportation time. Therefore, it is necessary to develop a pregabalin preparation that can effectively extend the dosing interval in order to relieve the anxiety and fear of animals during long-distance transportation and medical treatment for a long time. Summary of the Invention

[0006] In view of the above problems, the present invention provides a pregabalin sustained-release tablet and its preparation method and application.

[0007] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0008] A pregabalin sustained-release tablet, in parts by weight, the formula of the pregabalin sustained-release tablet includes:

[0009] Active ingredient: 35 - 45 parts of pregabalin;

[0010] Excipients: 40 - 48 parts of hydroxypropyl methylcellulose with a viscosity of K4M, 0.1 - 3 parts of polyvinylpyrrolidone with a viscosity of K16 - 18, 1 - 6 parts of polyvinylpyrrolidone with a viscosity of K23 - 27, and 0.1 - 9 parts of sodium bicarbonate.

[0011] Furthermore, the excipients also include 0 - 10 parts by weight of a filler.

[0012] Furthermore, the filler is at least one of microcrystalline cellulose, compressible starch, dextrin, and powdered sugar.

[0013] Furthermore, the formula of the pregabalin sustained-release tablets also includes 0.5 - 0.8 parts by weight of a glidant.

[0014] Furthermore, the glidant is at least one of silicon dioxide, talc powder, and magnesium stearate.

[0015] A method for preparing pregabalin sustained-release tablets, which is to weigh the main drug and excipients according to the above formula of the pregabalin sustained-release tablets, mix them evenly, granulate after sieving, then add the glidant and mix evenly, and press tablets to prepare the pregabalin sustained-release tablets.

[0016] Furthermore, the aperture of the sieve for sieving is 35 - 50 meshes; the granulation is dry granulation.

[0017] Furthermore, before preparing the pregabalin sustained-release tablets, the main drug, excipients, and glidant are pulverized and sieved.

[0018] An application of pregabalin sustained-release tablets, the above pregabalin sustained-release tablets are used to prepare a drug for relieving anxiety and fear in animals.

[0019] Furthermore, the pregabalin sustained-release tablets are administered once every 48h.

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

[0021] By improving the formula of the pregabalin sustained-release tablets, the present invention prepares a pregabalin sustained-release tablet for sedation and anti-anxiety in dogs and cats, prolongs the half-life of pregabalin, alleviates the stress of animals during medical treatment and transportation, the effective duration is more than 48h, and only one administration is required for transportation of 24 - 48 hours, and it can be administered once every 2 days (i.e., once every 48h), reducing the number of administrations, improving compliance, improving the quality of life of animals, and bringing welfare to animals;

[0022] The present invention provides a new veterinary drug related to pregabalin. A pregabalin sustained-release tablet with an effective duration of more than 48 hours is prepared through a gastric floating sustained-release system, thereby effectively alleviating the anxiety and fear of dogs and cats during long-distance transportation and medical treatment, and solving the problem that an increasing number of pet owners carry their pets across provinces or even across countries and it is inconvenient to administer drugs during the journey;

[0023] The pregabalin sustained-release tablet prepared by the present invention has a small impact on blood pressure. Only the blood pressure drops significantly 2 hours after administration, and there is no significant change in blood pressure at 4 hours, 8 hours, 12 hours, and 24 hours after administration, with high safety. Brief Description of the Drawings

[0024] Figure 1 is the preparation process route diagram of the pregabalin sustained-release tablet of the present invention;

[0025] Figure 2 is the cumulative release percentage of the pregabalin sustained-release tablets with three different viscosities of HPMC in Example 1 of the present invention; Figure 2 Among them, HPMC K4M represents the pregabalin sustained-release tablet made of HPMC with a viscosity of K4M, HPMC K15M represents the pregabalin sustained-release tablet made of HPMC with a viscosity of K15M, and HPMC K100M represents the pregabalin sustained-release tablet made of HPMC with a viscosity of K100M;

[0026] Figure 3 is the cumulative release percentage of the pregabalin sustained-release tablets with three different viscosities of PVP in Example 1 of the present invention; Figure 3 Among them, PVP K16-18 represents the pregabalin sustained-release tablet made of PVP with a viscosity of K16-18, PVP K23-27 represents the pregabalin sustained-release tablet made of PVP with a viscosity of K23-27, and PVP K29-32 represents the pregabalin sustained-release tablet made of PVP with a viscosity of K29-32;

[0027] Figure 4 is the comparison chart of the cumulative release percentage of the pregabalin sustained-release tablet P1 and the pregabalin sustained-release tablets made of other formulations in Example 3 of the present invention; Figure 4 Among them, 38% HPMC K4M represents the pregabalin sustained-release tablet 38% HPMC K4M, 7% PVPK16-18 represents the pregabalin sustained-release tablet 7% PVP K16-18, 7% PVP K23-27 represents the pregabalin sustained-release tablet 7% PVPK23-27, 12% NaHCO3 represents the pregabalin sustained-release tablet 12% NaHCO3, and the optimized formulation represents the pregabalin sustained-release tablet P1;

[0028] Figure 5 is the in vivo drug-time curve of cats after single oral administration of the pregabalin sustained-release tablet P1 in Example 4 of the present invention;

[0029] Figure 6 It is a comparison chart of cat blood pressure measurement before and after the use of pregabalin sustained-release tablet P1 in Example 4 of the present invention. Detailed implementation manners

[0030] 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 in order to fully understand the present invention, but the present invention can also be implemented in other ways different from those described herein. Those skilled in the art can make similar generalizations without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0031] The present invention protects a pregabalin sustained-release tablet, its preparation method and application. The formula of the pregabalin sustained-release tablet, by weight, includes:

[0032] ① Active ingredient: 35 - 45 parts of pregabalin;

[0033] ② Excipients: 40 - 48 parts of hydroxypropyl methylcellulose with a viscosity of K4M (i.e., HPMC K4M), 0.1 - 3 parts of polyvinylpyrrolidone with a viscosity of K16 - 18 (i.e., PVP K16 - 18), 1 - 6 parts of polyvinylpyrrolidone with a viscosity of K23 - 27 (i.e., PVP K23 - 27), 0.1 - 9 parts of sodium bicarbonate (i.e., NaHCO3), and 0 - 10 parts of filler;

[0034] ③ Glidant: 0.5 - 0.8 parts.

[0035] In the above formula, hydroxypropyl methylcellulose with a viscosity of K4M (i.e., HPMC K4M) is used as a hydrophilic gel matrix, and a mixture of polyvinylpyrrolidone with a viscosity of K16 - 18 (i.e., PVP K16 - 18) and polyvinylpyrrolidone with a viscosity of K23 - 27 (i.e., PVP K23 - 27) is used as a binder;

[0036] The filler is at least one of microcrystalline cellulose (MCC), compressible starch, dextrin, and powdered sugar;

[0037] The glidant is at least one of silica, talc, and magnesium stearate.

[0038] The preparation method of the pregabalin sustained-release tablet is as Figure 1 shown and includes the following steps:

[0039] First, the active ingredient (pregabalin), each excipient, and the glidant are respectively pulverized and sieved (marked as the first sieving) for standby;

[0040] Weigh pregabalin, HPMC K4M, PVP K16-18, PVP K23-27, filler and NaHCO3 according to the formula amount, mix them evenly (marked as premixing), sieve them (marked as the second sieving), granulate by dry granulation method, then add glidant and mix evenly (marked as total mixing), and press them into pregabalin sustained-release tablets on a single punch tablet press.

[0041] The pregabalin sustained-release tablets prepared by the present invention are used to relieve the anxiety and fear of animals (especially dogs, cats, etc.) (especially the acute anxiety and fear that occur during transportation and veterinary visits), and the effective duration is more than 48 hours.

[0042] In the present invention, HPMC K4M all represents hydroxypropyl methylcellulose with a viscosity of K4M;

[0043] HPMC K15M all represents hydroxypropyl methylcellulose with a viscosity of K15M;

[0044] HPMC K100M all represents hydroxypropyl methylcellulose with a viscosity of K100M;

[0045] PVP K16-18 all represents polyvinylpyrrolidone with a viscosity of K16-18;

[0046] PVP K23-27 all represents polyvinylpyrrolidone with a viscosity of K23-27;

[0047] PVP K29-32 all represents polyvinylpyrrolidone with a viscosity of K29-32;

[0048] MCC is all microcrystalline cellulose.

[0049] Example 1 Excipient Screening

[0050] I. Hydrophilic Gel Matrix Screening

[0051] The present invention selects hydroxypropyl methylcellulose (HPMC) as the hydrophilic gel matrix. Through the screening of its viscosity, it is found that HPMC with different viscosities has an impact on the release effect of pregabalin. The specific HPMC viscosity screening experiment is as follows:

[0052] Using HPMC as the hydrophilic gel matrix material, screen three viscosities of HPMC, namely K4M, K15M, and K100M, and prepare pregabalin sustained-release tablets with three different HPMC viscosities according to the formula in Table 1 and the following preparation method. The specific formula is as follows:

[0053] Table 1 Formulation List of Pregabalin Sustained-Release Tablets with Different HPMC Viscosities

[0054]

[0055] The preparation method of pregabalin sustained-release tablets with three different viscosities of HPMC is to first crush and sieve all the raw and auxiliary materials in the formula for standby, and then weigh pregabalin, HPMC, PVP K29-32, MCC and NaHCO3 according to the above formula respectively, mix them evenly, pass through a sieve, granulate by dry granulation, then add silicon dioxide and mix evenly, and press them into pregabalin sustained-release tablets with three different viscosities of HPMC on a single punch tablet press, with each tablet containing 40 mg of pregabalin.

[0056] Determine the cumulative release percentage of pregabalin sustained-release tablets with three different viscosities of HPMC at 0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h and 24 h, draw the release curves and compare them. The specific results are shown in Figure 2 Meanwhile, determine the floating-up time and the continuous floating time of pregabalin sustained-release tablets with three different viscosities of HPMC. The specific results are shown in Table 2.

[0057] Among them, the method for determining the cumulative release percentage of pregabalin sustained-release tablets with three different viscosities of HPMC is as follows:

[0058] Referring to the second method (paddle method) of the dissolution determination method in Appendix II of the Chinese Pharmacopoeia 2020 Edition, select 900 mL of 0.1 N HCl aqueous solution as the release medium. The temperature is set at 38.5 ± 0.5 °C and the rotation speed is 50 rpm. Take 5 mL of samples at 0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h and 24 h respectively, and immediately add 5 mL of the release medium at the same temperature to the dissolution system after sampling at each time point. After the extracted solution is filtered through a 0.45 μm filter membrane, take an appropriate amount of the subsequent filtrate, dilute it 100 times with ultrapure water, transfer it to an injection vial, and use a high-resolution liquid chromatography-mass spectrometry instrument for determination. Record the peak area of pregabalin and calculate the corresponding concentration, and then calculate the cumulative release percentage using this concentration.

[0059] The methods for determining the floating-up time and the continuous floating time are as follows:

[0060] The floating-up time is the time from the moment the drug enters the water to the moment the tablet returns to the water surface. The continuous floating time is the time from the drug floating up to the end of the test. Put the prepared pregabalin sustained-release tablets into 900 ml of 0.1 N HCl and observe under the condition of (38.5 ± 0.5) °C.

[0061] Table 2 List of floating-up time and continuous floating time of pregabalin sustained-release tablets with different viscosities of HPMC

[0062] Group Initial floating time Sustained floating time HPMC K4M ＜10s ＞12h HPMC K15M ＜10s ＞12h HPMC K100M ＜10s ＞12h

[0063] From Figure 2As can be seen from Table 2, the cumulative release degrees of pregabalin sustained-release tablets prepared with HPMC of different viscosities can all reach over 90% at 24 h, meeting the requirements of sustained-release preparations. Among them, the release rate of the pregabalin sustained-release tablet prepared with HPMC K4M is the lowest in the first 6 h, but it does not meet the requirement that the release in 2 h of the sustained-release preparation is lower than 40%. The release rates of the pregabalin sustained-release tablets prepared with HPMC of other viscosities are all too fast, and the drug is basically completely released in 12 h, with poor sustained-release effect. Since the shorter the floating-up time, the better the floating performance, the pregabalin sustained-release tablets prepared with HPMC of different viscosities in the present invention can all float up within 1 min, and the continuous floating time is greater than 12 h. Therefore, the present invention selects HPMC K4M as the hydrophilic gel matrix.

[0064] II. Screening of Binder

[0065] The present invention selects polyvinylpyrrolidone (PVP) as the binder. Through the screening of its viscosity, it is found that PVP of different viscosities has an impact on the release effect of pregabalin. The specific PVP viscosity screening experiment is as follows:

[0066] Using PVP as the binder, three viscosities of PVP, namely K16-18, K23-27, and K29-32, are screened respectively. Three pregabalin sustained-release tablets with different PVP viscosities are prepared according to the formula in Table 3 and the following preparation method. The specific formula is as follows:

[0067] Table 3 List of Formulas of Pregabalin Sustained-Release Tablets with Different PVP Viscosities

[0068]

[0069] The preparation method of the three pregabalin sustained-release tablets with different PVP viscosities is to first crush and sieve all the raw and auxiliary materials in the formula for standby, then weigh pregabalin, HPMC K15M, PVP, MCC, and NaHCO3 respectively according to the above formula, mix them evenly, sieve them, granulate by dry granulation, then add silicon dioxide and mix evenly, and press them into three pregabalin sustained-release tablets with different PVP viscosities on a single-punch tablet press, with each tablet containing 40 mg of pregabalin.

[0070] The cumulative release percentages of the three pregabalin sustained-release tablets with different PVP viscosities at 0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h are measured by the same measurement method as in the screening process of the hydrophilic gel matrix, and the release curves are plotted and compared. The specific results are shown in Figure 3 . At the same time, the floating-up time and continuous floating time of the pregabalin sustained-release tablets with different HPMC viscosities are measured by the same measurement method as in the screening process of the hydrophilic gel matrix. The specific results are shown in Table 4.

[0071] Table 4 List of floating start time and continuous floating time of pregabalin sustained-release tablets with different PVP viscosities

[0072] Group Initial floating time Sustained floating time PVP K16 - 18 ＜10s ＞12h PVP K23 - 27 ＜10s ＞12h PVP K29 - 32 ＜10s ＞12h

[0073] From Figure 3 and Table 4, it can be seen that the cumulative release degrees of pregabalin sustained-release tablets prepared with PVP of different viscosities can all reach more than 90% at 24 h, meeting the requirements of sustained-release preparations. Among them, the pregabalin sustained-release tablets prepared with PVP K23-27 have a slower release in the first 2 h, and the pregabalin sustained-release tablets prepared with PVP K16-18 have a slower release from the 2nd to the 10th h. The release rates of pregabalin sustained-release tablets prepared with PVP of different viscosities are all faster than expected, and the drug is basically completely released in 12 h, with poor sustained-release effect. Moreover, the pregabalin sustained-release tablets prepared with PVP of different viscosities all start to float within 1 min, and the continuous floating time is greater than 12 h.

[0074] Therefore, the present invention selects the mixed use of PVP K16-18 and PVP K23-27 as the binder.

[0075] III. Formulation optimization (full factor analysis)

[0076] Orthogonal experimental design selects some representative points from the comprehensive experiment according to orthogonality to conduct experiments, replacing the comprehensive experiment with a small number of experiments, which has the advantages of high efficiency, rapidity, and economy.

[0077] Preliminary experiments have proved that the preparation of pregabalin sustained-release tablets with HPMC of different viscosities and PVP of different viscosities all has an impact on the drug release rate. After confirming the selection of HPMC K4M as the hydrophilic gel matrix through the screening experiment of the hydrophilic gel matrix and confirming the selection of the mixed use of PVP K16-18 and PVP K23-27 as the binder through the screening experiment of the binder, the amounts of HPMC K4M, PVP K16-18, and PVP K23-27 are used as the three factors of the orthogonal experiment again to investigate their influence on the sustained-release effect of the prepared pregabalin sustained-release tablets. During the orthogonal experiment, 2 levels are selected for each factor, and the drug release rate is used as the evaluation index (the target of the specific evaluation index is shown in Table 5), and an orthogonal experiment is designed to obtain the optimized formulation. Pregabalin accounts for 40%, NaHCO3 accounts for 8%, and the balance is MCC in each formulation. The specific formulations are shown in Table 6.

[0078] Table 5 List of target levels of evaluation indexes for orthogonal experiments

[0079] Index Target level Drug dissolution at 2h 20％-40％ Drug dissolution at 4h 40％-60％ Drug dissolution at 6h 50％-70％ Drug dissolution at 8h 60％-80％ Drug dissolution at 12h 70％-90％ Drug dissolution at 24h 80％-100％

[0080] Table 6 List of formulations for each group of orthogonal experiments

[0081]

[0082] The raw and auxiliary materials in Table 6 were separately crushed and sieved for standby. Then, pregabalin, HPMC K4M, PVP K16 - 18, PVP K23 - 27, MCC, and NaHCO3 were weighed according to the formula in Table 6 respectively, mixed evenly, sieved, granulated by dry granulation method, and then silicon dioxide was added and mixed evenly. Pregabalin sustained - release tablets with different formula numbers were pressed on a single - punch tablet machine, and each tablet contained 40 mg of pregabalin.

[0083] The floating - up time, continuous floating - up time, and cumulative release percentage (cumulative release percentage at 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h) of pregabalin sustained - release tablets with different formula numbers were measured respectively by the same measurement method as in the screening process of hydrophilic gel matrix. The specific results are shown in Tables 7 - 8.

[0084] Table 7 List of floating - up time and continuous floating time of pregabalin sustained - release tablets with different formula numbers

[0085]

[0086] It can be seen from Table 7 that pregabalin sustained - release tablets with different formula numbers all floated up from 0.1 N HCl aqueous solution in a short time, and the continuous floating time was greater than 12 h, which could better meet the principle of sustained release of pregabalin sustained - release tablets through floating.

[0087] Table 8 List of cumulative release percentage of pregabalin sustained - release tablets with different formula numbers

[0088]

[0089] Since the burst release phenomenon at 2 h affected the drug release effect, and in actual clinical applications, the release efficiency at 24 h was closely related to the drug efficacy, the importance of improving the release efficiency at 2 h and 24 h was increased in the formula optimization experiment. The importance scores of cumulative release percentage are shown in the following table:

[0090] Table 9 List of importance scores of cumulative release percentage

[0091] Index Importance score Cumulative drug release percentage at 2h 5 Cumulative drug release percentage at 4h 3 Cumulative drug release percentage at 6h 3 Cumulative drug release percentage at 8h 3 Cumulative drug release percentage at 12h 3 Cumulative drug release percentage at 24h 4

[0092] Optimization was carried out according to the importance scores of cumulative release percentage in Table 9. The optimization formula was given by using the experimental design software Design expert. Finally, the optimized formula was determined as 40 g of pregabalin, 44.638 g of HPMC K4M, 1.662 g of PVP K16 - 18, 3.436 g of PVP K23 - 27, 8 g of NaHCO3, 2.264 g of MCC, and 0.6 g of silicon dioxide.

[0093] Example 2 A Pregabalin Sustained Release Tablet and Its Preparation Method and Application

[0094] In this example, a pregabalin sustained release tablet was prepared using an optimized formula. Among them, the formula for preparing the pregabalin sustained release tablet is: 40 g of pregabalin, 44.638 g of HPMC K4M, 1.662 g of PVP K16 - 18, 3.436 g of PVP K23 - 27, 8 g of NaHCO3, 2.264 g of MCC, and 0.6 g of silicon dioxide.

[0095] The specific preparation method of the pregabalin sustained release tablet is as follows: Respectively take pregabalin, HPMC K4M, PVP K16 - 18, PVP K23 - 27, NaHCO3, MCC, and silicon dioxide (i.e., all the raw and auxiliary materials in the formula), crush them and pass through a 60 - mesh sieve (marked as the first sieving) for standby. Then, according to the optimized formula, weigh pregabalin, HPMC K4M, PVP K16 - 18, PVP K23 - 27, NaHCO3, and MCC and mix them evenly (marked as premixing). After passing through a 40 - mesh sieve (marked as the second sieving), granulate by dry granulation, and then add silicon dioxide and mix evenly (marked as total mixing). Press them into pregabalin sustained release tablets with a diameter of 6 mm and a tablet weight of about 100 mg on a single - punch tablet machine, marked as P1 (i.e., the optimized formula), and each tablet contains 40 mg of pregabalin.

[0096] The pregabalin sustained release tablet P1 prepared by the present invention is used to relieve acute anxiety and fear in animals.

[0097] Example 3 Verification of the Formulation Advantage of Pregabalin Sustained Release Tablets

[0098] In this example, the formulation advantage of the pregabalin sustained release tablet P1 prepared in Example 2 was verified as follows:

[0099] The cumulative release percentage of the pregabalin sustained release tablet P1 (the cumulative release percentage at 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h, i.e., the dissolution rate) was measured using the same measurement method as in the screening process of the hydrophilic gel matrix, and compared with the expected value given by Design Expert. The specific results are shown in the following table:

[0100] Table 10 Comparison Results List of Expected and Measured Values of Pregabalin Sustained Release Tablet P1 Prepared with the Optimized Formula

[0101] Time Expected value (%) Measured value (%) 2h 35.511 34.352 4h 55.350 55.081 6h 67.362 69.567 8h 72.925 74.469 12h 80.953 81.517 24h 90.005 94.997

[0102] As can be seen from Table 10, the measured value of the dissolution rate (i.e., the cumulative release percentage) of the pregabalin sustained release tablet P1 prepared with the optimized formula is close to the expected value. The phenomenon of rapid drug release in the early stage has been significantly improved, and the cumulative release percentage of the drug at 24 h is large, which can meet the needs of animal clinical practice.

[0103] The cumulative release percentages of pregabalin sustained-release tablets P1 and those prepared with other formulations were further determined using the same measurement method as in the hydrophilic gel matrix screening process. The specific results are shown in Table 11 and Figure 4 .

[0104] Among them, the methods for preparing pregabalin sustained-release tablets with other formulations (Formulations ① - ④) are as follows:

[0105] Formulation ①: All the raw and auxiliary materials were separately pulverized and screened for standby. Then, 40 g of pregabalin, 38 g of HPMC K4M, 7 g of PVP K29 - 32, 11 g of MCC, and 4 g of NaHCO3 were weighed and mixed evenly. After screening, dry granulation was carried out, and then 0.6 g of silicon dioxide was added and mixed evenly. The mixture was pressed into pregabalin sustained-release tablets (labeled as 38% HPMC K4M) on a single punch tablet press, with each tablet containing 40 mg of pregabalin.

[0106] Formulation ②: All the raw and auxiliary materials were separately pulverized and screened for standby. Then, 40 g of pregabalin, 38 g of HPMCK15M, 7 g of PVP K16 - 18, 11 g of MCC, and 4 g of NaHCO3 were weighed and mixed evenly. After screening, dry granulation was carried out, and then 0.6 g of silicon dioxide was added and mixed evenly. The mixture was pressed into pregabalin sustained-release tablets (labeled as 7% PVP K16 - 18) on a single punch tablet press, with each tablet containing 40 mg of pregabalin.

[0107] Formulation ③: All the raw and auxiliary materials were separately pulverized and screened for standby. Then, 40 g of pregabalin, 38 g of HPMCK15M, 7 g of PVP K23 - 27, 11 g of MCC, and 4 g of NaHCO3 were weighed and mixed evenly. After screening, dry granulation was carried out, and then 0.6 g of silicon dioxide was added and mixed evenly. The mixture was pressed into pregabalin sustained-release tablets (labeled as 7% PVP K23 - 27) on a single punch tablet press, with each tablet containing 40 mg of pregabalin.

[0108] Formulation ④: All the raw and auxiliary materials were separately pulverized and screened for standby. Then, 40 g of pregabalin, 38 g of HPMCK15M, 7 g of PVP K29 - 32, 3 g of MCC, and 12 g of NaHCO3 were weighed and mixed evenly. After screening, dry granulation was carried out, and then 0.6 g of silicon dioxide was added and mixed evenly. The mixture was pressed into pregabalin sustained-release tablets (labeled as 12% NaHCO3) on a single punch tablet press, with each tablet containing 40 mg of pregabalin.

[0109] Table 11 List of cumulative release percentages of pregabalin sustained-release tablets P1 and those prepared with other formulations

[0110]

[0111] From Table 11 and Figure 4It can be seen that the sustained-release effect of the pregabalin sustained-release tablet P1 (i.e., the optimized formulation) prepared by the present invention is significantly better than that of the pregabalin sustained-release tablets prepared from the other four formulations.

[0112] Application of Pregabalin Sustained-Release Tablets in Example 4

[0113] I. In-Vivo Release Experiment

[0114] Referring to the guiding principles for the pharmacokinetic study of orally administered sustained- and controlled-release preparations in animals, a method for determining the in-vivo blood drug concentration of pregabalin sustained-release tablets was established. The in-vivo drug-time curves of cats after single oral administration of pregabalin sustained-release tablet P1 at 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, and 120 h in the state of free eating were measured. The results are shown in Figure 5 .

[0115] Among them, the method for determining the in-vivo blood drug concentration of pregabalin sustained-release tablets is as follows:

[0116] I. Design of Animal Dosing Scheme

[0117] Arrangement before dosing: Six experimental cats were selected. Taking 8 am as 0 h, the blood pressure of all test cats was measured at 0, 2, 4, 8, 12, and 24 h. Each time point was measured 3 times, and the recorded blood pressure value at each time point was the average of the 3 measurements.

[0118] Dosing arrangement: Six of the above cats were selected. Each cat was orally administered 1 tablet (100 mg per tablet) of pregabalin sustained-release tablet P1 at 8 am. During the dosing process, the preparation should not be damaged, and the washout period was set to one week.

[0119] Dosing arrangement in the first cycle: Each cat was given 1 tablet of pregabalin sustained-release tablet P1, followed by oral administration of 5 mL of drinking water. Venous blood (1 mL) was collected at 0, 2, 4, 8, 12, 24, 48, 72, and 120 h after the first dose. The blood sample was placed in a clean EP tube, centrifuged at 12000 rpm for 5 minutes to separate the plasma, and stored in a -20°C refrigerator for later measurement.

[0120] Dosing arrangement in the second cycle: Each cat was given 1 tablet of pregabalin sustained-release tablet P1, followed by oral administration of 5 mL of drinking water. The blood pressure of the cats in the resting state was measured at 0, 2, 4, 8, 12, and 24 h after the first dose. Each time point was measured 3 times, and the recorded blood pressure value at each time point was the average of the 3 measurements. The status of the cats was observed and recorded at 0, 2, 4, 8, 12, 24, 48, 72, and 120 h after dosing.

[0121] II. Plasma Sample Processing

[0122] Collect the obtained blood in a 1.5 mL EP tube, centrifuge at 12,000 r / min for 5 min, and take the supernatant plasma. Pipette 100 μL of the plasma into a clean 1.5 mL EP tube, add 400 μL of methanol, vortex for 5 min, then place at -20 °C to precipitate proteins for about 2 h, centrifuge at 12,000 r / min for 5 min while frozen, transfer the supernatant and centrifuge again at 12,000 r / min for 5 min, transfer the supernatant to an injection vial, and perform LC-MS / MS analysis.

[0123] III. LC-MS / MS Analysis

[0124] Chromatographic Conditions

[0125] Select the ACQUITY UPLC HSS T3 Column (2.1×50 mm) as the analytical column. The mobile phase is ultrapure water with 0.1% formic acid (A) and acetonitrile (B), the flow rate is 0.3 mL / min, and the column temperature is 40 °C. Gradient elution is adopted, and the specific settings are shown in Table 2-3. The injection volume is 1 μL. Under the above conditions, the retention time of pregabalin is 0.85 min.

[0126] Table 12 Gradient Elution Table

[0127]

[0128] Mass Spectrometry Conditions

[0129] Select the electrospray ionization source (ESI), and set the source parameters as follows: Spray Voltage 4500 V, Capillary Temperature 320 °C, Sheath Gas 30 L / min, Aux Gas 10 L / min, Probe Heater Temperature 220 °C, z-Lens 3 Voltage 330 V. Select multiple reaction monitoring (MRM) in the positive ion mode (Positive). The MRM parameters of pregabalin are: the parent ion (Q1 Mass) is 160.13285 Da, m / z is 142.12267, and the collision voltage (Collusion Energy / CE) is hcd20.

[0130] The pharmacokinetic parameters of the pregabalin sustained-release tablets P1 prepared by the present invention measured by the above method in cats are shown in the following table:

[0131] Table 13 List of Pharmacokinetic Results in Cats

[0132] Compartment parameter Unit Parameter value <![CDATA[t 1 / 2α > h 27.85 <![CDATA[t 1 / 2β > h 61.62 <![CDATA[C max > mg / L 3.85 <![CDATA[T max > h 2 V1 / F L 5.478 CL / F L / h 0.107 <![CDATA[AUC (0-t) > mg / L*h 89.308 <![CDATA[AUC (0-∞) > mg / L*h 93.161 <![CDATA[K 10 > 1 / h 0.02 <![CDATA[K 21 > 1 / h 0.025 <![CDATA[K a > 1 / h 0.025 <![CDATA[t 1 / 2Ka > h 27.786

[0133] FromFigure 5 As can be seen from Table 13, the half-life of the pregabalin sustained-release tablet P1 prepared by the present invention in cats can be extended to 61.62 h. Based on the pharmacokinetic parameters in cats, after calculation, the dosing interval can be much greater than 48 h. Considering the clinical symptoms, it is determined to administer the drug once every 48 h.

[0134] In summary, the pregabalin sustained-release tablet prepared by the present invention is used to relieve acute anxiety and fear in animals (especially dogs, cats, etc.), and the effective duration is more than 48 h. It can be administered once every two days (i.e., once every 48 h), reducing the dosing frequency, improving compliance, improving the quality of life of animals, and bringing benefits to animals.

[0135] II. Blood pressure measurement

[0136] One effect of pregabalin is to reduce the release of norepinephrine. Norepinephrine is a strong α-receptor agonist that can cause the contraction of small arteries and small veins, thereby increasing systolic and diastolic blood pressures. Therefore, taking traditional pregabalin may cause a decrease in the blood pressure of cats.

[0137] A paired t-test was performed on the blood pressure of cats before and after taking the pregabalin sustained-release tablet P1 of the present invention, and the results Figure 6 .

[0138] From Figure 6 it can be seen that at 4 h, 8 h, 12 h, and 24 h after the administration of the pregabalin sustained-release tablet P1 to the test cats, there were no significant differences in the blood pressure of the test cats. Only 2 h after the administration, the blood pressure of the test cats was significantly lower than that 2 h before the administration.

[0139] In summary, the pregabalin sustained-release tablet prepared by the present invention has little effect on blood pressure. Only 2 h after the administration, the blood pressure of the test cats decreased significantly. At 4 h, 8 h, 12 h, and 24 h after the administration, there were no significant changes in the blood pressure of the test cats, and it has high safety.

[0140] Examples 5-8 of pregabalin sustained-release tablets and their preparation methods and applications

[0141] Examples 5-8 are respectively a pregabalin sustained-release tablet and its preparation method and application. Based on the optimized formula given in Example 2, the formula range of the pregabalin sustained-release tablet that can be administered once every 48 h is further explored to obtain the formulas and preparation methods in Examples 5-8. The preparation process of the pregabalin sustained-release tablets in Examples 5-8 is basically the same as that in Example 2, except for the differences in the raw material dosages and some process parameters. For details, see Table 14:

[0142] Table 14 List of process parameters in Examples 5-8

[0143]

[0144]

[0145] The contents of other parts of Examples 5 to 8 are the same as those of Example 2 and will not be repeated here.

[0146] Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of them. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

Claims

1. A pregabalin sustained-release tablet, characterized in that, The formulation of the pregabalin sustained-release tablets, in parts by weight, is as follows: Active ingredient: 40 parts of pregabalin; Excipients: 44.638 parts of hydroxypropyl methylcellulose with a viscosity of K4M, 1.662 parts of polyvinylpyrrolidone with a viscosity of K16-18, 3.436 parts of polyvinylpyrrolidone with a viscosity of K23-27, 2.264 parts of sodium bicarbonate, 0.6 part of silicon dioxide, and 2.264 parts of microcrystalline cellulose.

2. A preparation method of pregabalin sustained-release tablets, characterized in that, The preparation method is to weigh the active ingredient and excipients according to the formulation of the pregabalin sustained-release tablets as claimed in claim 1, mix them evenly, granulate them after sieving, then add a glidant and mix evenly, and press tablets to obtain the pregabalin sustained-release tablets.

3. The preparation method of the pregabalin sustained-release tablet according to claim 2, wherein, The aperture of the sieve used for sieving is 35-50 meshes; the granulation is dry granulation.

4. The preparation method of the pregabalin sustained-release tablet according to claim 2 or 3, characterized in that, Before the preparation of the pregabalin sustained-release tablets, the active ingredient, excipients, and glidant are pulverized and sieved.

5. Use of a pregabalin sustained-release tablet, characterized in that, The pregabalin sustained-release tablets as claimed in claim 1 are used for preparing a drug for relieving anxiety and fear in animals.

6. The use of the pregabalin sustained-release tablets according to claim 5, characterized in that, The pregabalin sustained-release tablets are administered once every 48 hours.

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