Pregabalin oral solution and methods of making and using the same

Abstract

The application discloses a pregabalin oral solution and a preparation method and application thereof. The preparation method comprises the following steps: adding a bacteriostatic agent and pregabalin into a solvent, adding a flavoring agent after complete dissolution, stirring and dissolving, and filtering to obtain the pregabalin oral solution. The pregabalin oral solution obtained by the application has good stability in appearance and related substances.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparations, and specifically relates to pregabalin oral solution, its preparation method, and its application. Background Technology

[0002] Felines often experience fear and anxiety when faced with situations such as clinic visits, transportation, nail trimming, ear cleaning, bathing, guests at home, or the arrival of a new cat. These emotions not only affect their behavior but can also trigger aggressive behavior, increasing stress for both pet owners and the cats themselves. To improve this situation, cooperative care measures and special education training are particularly important. For example, crate training to help cats adapt to transportation and the appropriate use of anti-anxiety medication before veterinary visits can significantly improve the cat's experience at the clinic and reduce their anxiety and fear.

[0003] Pregabalin, chemically known as (S)-3-(aminomethyl)-5-methylhexanoic acid (CAS No.: 148553-50-8), is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It was initially developed to treat epilepsy, neuropathic pain, and generalized anxiety disorder in humans. Notably, pregabalin was approved in the European Union by Orion in July 2021 as the first drug specifically for feline anxiety, primarily used to relieve acute anxiety and fear in cats caused by traffic and veterinary visits.

[0004] Patent CN113631150A discloses a liquid pharmaceutical composition with pregabalin as the active ingredient and its uses. This composition ensures drug stability and palatability for animals by precisely controlling the pH value between 3.0 and 4.4, making it convenient for pet owners to administer. However, pregabalin itself suffers from poor solubility and storage stability, and adjusting the pH value alone is insufficient to fully address these issues.

[0005] Patent CN116172951A discloses a pregabalin pharmaceutical composition for pets, its preparation method, and its application. The stability of the pregabalin oral solution is increased by adding sodium sulfobutyl betacyclodextrin or hydroxypropyl betacyclodextrin. Although this method improves drug stability, the complex formulation may limit the widespread application and popularity of the product. Summary of the Invention

[0006] This invention addresses the technical problems existing in the prior art by providing a method for preparing pregabalin oral solution. The method involves adding an antibacterial agent and pregabalin to a solvent, dissolving them completely, adding a flavoring agent, stirring to dissolve, and filtering to obtain the pregabalin oral solution.

[0007] Furthermore, the method includes the following step: adding the antibacterial agent and pregabalin to the solvent at a temperature below 50°C.

[0008] Furthermore, the temperature is from room temperature to 47°C.

[0009] Furthermore, the process includes the following steps: after the antibacterial agent and pregabalin are completely dissolved, the mixture is cooled to room temperature, and then the flavoring agent is added.

[0010] Furthermore, the method also includes the step of adjusting the pH of the pregabalin oral solution to 3.0–3.4.

[0011] Furthermore, hydrochloric acid was added along with the antibacterial agent and pregabalin.

[0012] Furthermore, in the above-mentioned method for preparing pregabalin oral solution, the composition of the pregabalin oral solution, by weight, includes 80-120 parts pregabalin, 1-10 parts antibacterial agent, 0.01-1 part flavoring agent, 10-50 parts hydrochloric acid, pH adjuster, and the balance solvent; wherein, the amount of pH adjuster is the amount required to adjust the pH value to 3.1-3.4; the antibacterial agent is sodium benzoate, the flavoring agent is ethyl maltol, the pH adjuster is hydrochloric acid and / or sodium hydroxide, and the solvent is water.

[0013] Furthermore, the preparation method of the pregabalin oral solution includes the following steps:

[0014] Weigh out 50%–80% of the prescribed amount of solvent, heat to 33–47°C, add sodium benzoate, pregabalin, and hydrochloric acid in sequence, and stir until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir until completely dissolved, adjust the pH to 3.0–3.4 using a pH adjuster, add solvent to make up to the full volume, stir, filter, and fill according to the predetermined volume.

[0015] Secondly, the present invention provides a pregabalin oral solution prepared by the above method, wherein the pregabalin oral solution is a colorless and clear solution with a lactam content ≤0.5%.

[0016] Thirdly, the present invention provides the use of the above-mentioned pregabalin oral solution in products for the treatment or prevention of anxiety and fear in companion animals, particularly cats.

[0017] The beneficial effects of this invention are:

[0018] This invention provides a method for preparing a pregabalin oral solution. The method is simple, and the resulting pregabalin oral solution exhibits good stability in terms of appearance and related substances, surpassing the stability of commercially available products. It solves the problem of significant impurity increase in existing products at high temperatures and also possesses excellent palatability. This oral solution is particularly suitable for treating or preventing anxiety and fear symptoms in companion animals, especially cats. Through the technical solution of this invention, not only can the therapeutic effect of the drug be improved, but the pet's medication experience can also be significantly improved, providing a more convenient and effective solution for the health management of companion animals. Detailed Implementation

[0019] The technical solutions in the embodiments of this application are clearly described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0020] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0021] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0022] This invention relates to a method for preparing a pregabalin oral solution. As an oral solution, its conventional preparation method is relatively simple, but this type of dosage form generally has poor stability. Pregabalin oral solutions marketed in the EU require low-temperature storage (2-8°C) to better ensure their stability. In existing technologies, formulation optimization is often used to improve drug stability. However, the specific preparation process of pregabalin oral solutions has not received sufficient attention or in-depth research in the prior art. The inventors, through designing and optimizing the preparation process, have achieved significant improvements in appearance and related substances while maintaining a simple preparation procedure, greatly enhancing the stability and quality of the pregabalin oral solution. The specific preparation method is as follows:

[0023] Weigh a certain amount of solvent and heat it to below 50°C. This can be room temperature to 50°C, room temperature to 40°C, 30–50°C, 30–47°C, or 33–40°C, preferably 33–47°C. Examples include 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, or 47°C, but not limited to the listed values; other unlisted values ​​within this range are also applicable. Then, add the antibacterial agent, pregabalin, and hydrochloric acid sequentially, stirring until completely dissolved. After cooling to room temperature, continue adding the flavoring agent and stirring until completely dissolved. Adjust the pH to 3.0–3.4 using a pH adjuster, preferably 3.1–3.4, more preferably 3.1–3.3, such as 3.1, 3.2, 3.3, or 3.4, but not limited to the listed values; other unlisted values ​​within this range are also applicable. Add solvent to bring the volume to the final volume, stir, filter, and then fill according to the predetermined volume.

[0024] The specified amount of solvent is 50% to 80% of the total solvent formulation. This invention does not limit the amount of solvent used, as long as it can completely dissolve the raw materials and excipients. The formulation amount refers to the total amount of ingredients used in preparing the drug formulation.

[0025] The room temperature described in this invention is around 25°C, which is the temperature of a typical indoor environment.

[0026] Adding a certain amount of hydrochloric acid along with the antibacterial agent and pregabalin can effectively ensure the solubility of pregabalin. This invention does not limit the amount of hydrochloric acid used here.

[0027] In one embodiment of the present invention, the method for preparing pregabalin oral solution comprises, by weight, 80-120 parts pregabalin, 1-10 parts antibacterial agent, 0.01-1 part flavoring agent, 10-50 parts hydrochloric acid, pH adjuster, and the balance solvent; preferably, 90-110 parts pregabalin, 3-5 parts antibacterial agent, 0.05-0.10 parts flavoring agent, 30-50 parts hydrochloric acid, pH adjuster, and the balance solvent; more preferably, 100 parts pregabalin, 4 parts antibacterial agent, 0.08 parts flavoring agent, 40 parts hydrochloric acid, pH adjuster, and the balance solvent.

[0028] The amount of pH adjuster is the amount required to adjust the pH value to 3.1-3.4; the antibacterial agent is sodium benzoate, the flavoring agent is ethyl maltol, the pH adjuster is hydrochloric acid and / or sodium hydroxide, and the solvent is water, preferably purified water.

[0029] The pregabalin oral solution obtained by this invention is a colorless and clear solution with a lactam content of ≤0.5%, or even ≤0.2%.

[0030] The pregabalin oral solution obtained by this invention can be used in products for the treatment or prevention of anxiety and fear in companion animals, especially cats.

[0031] The composition of pregabalin oral solution is relatively simple. However, in order to achieve a direct balance between raw materials and excipients to obtain a pregabalin oral solution that better meets pharmaceutical standards, the inventors conducted in-depth research and optimization of the preparation process, especially pH value, temperature, and order of addition. Through systematic experiments and analysis, the optimal preparation method was finally determined.

[0032] The specific embodiments and comparative examples of the present invention are listed below, but the present invention is not limited to the following examples.

[0033] Example 1

[0034] The prescription composition is shown in Table 1.

[0035] Table 1 Prescription Composition

[0036] Raw material names mg / bottle effect Pregabalin 100 Active ingredients Sodium benzoate 4 antibacterial agent Ethyl maltol 0.08 Flavoring agents hydrochloric acid* 40 pH adjuster Hydrochloric acid / sodium hydroxide Appropriate amount pH adjuster Purified water Adjust the volume to 2ml solvent

[0037] *: Prepare a 10% hydrochloric acid solution.

[0038] Preparation process:

[0039] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 33°C, and add sodium benzoate, pregabalin, and hydrochloric acid in sequence, stirring until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir for 10 minutes until completely dissolved. Measure the pH value, which should be 3.1. If the pH value is not correct, adjust the pH to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to bring the volume to the total volume and continue stirring for 10 minutes.

[0040] (3) Filtration: Filtration is carried out using a 5μm PP material filter element.

[0041] (4) Filling: Fill the filtered medicine into a sodium-calcium glass molded medicine bottle with a pharmaceutical polypropylene bottle cap, with a filling volume of 2ml / bottle.

[0042] Example 2

[0043] Adjust the heating temperature in step (1) to 40°C. The specific operation is as follows: the prescription composition and other process steps are the same as in Example 1.

[0044] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 40℃, add sodium benzoate, pregabalin, and hydrochloric acid in sequence, and stir until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir for 10 minutes until completely dissolved, and measure the pH value, which should be 3.1. If the pH value is not correct, the pH can be adjusted to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to make up to the total volume, and continue stirring for 10 minutes.

[0045] Example 3

[0046] The heating temperature in step (1) is adjusted to 47°C. The specific operation is as follows: the prescription composition and other process steps are the same as in Example 1.

[0047] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 47°C, and add sodium benzoate, pregabalin, and hydrochloric acid in sequence, stirring until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir for 10 minutes until completely dissolved. Measure the pH value, which should be 3.1. If the pH value is not correct, adjust the pH to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to bring the volume to the total volume and continue stirring for 10 minutes.

[0048] Example 4

[0049] The pH value of the solution in step (1) is adjusted to 3.3. The specific operation is as follows, and the prescription composition and other process steps are the same as in Example 1.

[0050] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 33°C, and add sodium benzoate, pregabalin, and hydrochloric acid in sequence, stirring until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir for 10 minutes until completely dissolved. Measure the pH value, which should be 3.3. If the pH value is not correct, adjust the pH to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to bring the volume to the total volume and continue stirring for 10 minutes.

[0051] Example 5

[0052] The pH value of the solution in step (1) was adjusted to 3.4. The specific operation is as follows, and the prescription composition and other process steps are the same as in Example 1.

[0053] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 33°C, and add sodium benzoate, pregabalin, and hydrochloric acid in sequence, stirring until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir for 10 minutes until completely dissolved. Measure the pH value, which should be 3.4. If the pH value is not correct, adjust the pH to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to bring the volume to the total volume and continue stirring for 10 minutes.

[0054] Comparative Example 1

[0055] Adjust the heating temperature in step (1) to 50°C. The specific operation is as follows: the prescription composition and other process steps are the same as in Example 1.

[0056] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 50°C, and add sodium benzoate, pregabalin, and hydrochloric acid in sequence, stirring until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir for 10 minutes until completely dissolved. Measure the pH value, which should be 3.1. If the pH value is not correct, adjust the pH to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to bring the volume to the total volume and continue stirring for 10 minutes.

[0057] Comparative Example 2

[0058] Adjust the heating temperature in step (1) to 80°C. The specific operation is as follows: the prescription composition and other process steps are the same as in Example 1.

[0059] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 80℃, add sodium benzoate, pregabalin, and hydrochloric acid in sequence, and stir until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir for 10 minutes until completely dissolved, and measure the pH value, which should be 3.1. If the pH value is not correct, the pH can be adjusted to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to make up to the total volume, and continue stirring for 10 minutes.

[0060] Comparative Example 3

[0061] Adjust the order of adding materials in step (1). The specific operation is as follows. The prescription composition and other process steps are the same as in Example 1.

[0062] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 40°C, add sodium benzoate and ethyl maltol in sequence, stir until completely dissolved, cool to room temperature, add pregabalin raw material and hydrochloric acid, and stir until completely dissolved; adjust the pH value to 3.1 using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to make up to the total volume, and continue stirring for 10 min.

[0063] Comparative Example 4

[0064] Adjust the heating temperature and feeding sequence in step (1). The specific operation is as follows. The prescription composition and other process steps are the same as in Example 1.

[0065] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 50°C, add sodium benzoate and ethyl maltol in sequence, stir until completely dissolved, cool to room temperature, add pregabalin raw material and hydrochloric acid, and stir until completely dissolved; adjust the pH value to 3.1 using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to make up to the total volume, and continue stirring for 10 min.

[0066] Comparative Example 5

[0067] The pH value of the solution in step (1) is adjusted to 3.0. The specific operation is as follows, and the prescription composition and other process steps are the same as in Example 1.

[0068] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 33°C, and add sodium benzoate, pregabalin, and hydrochloric acid in sequence, stirring until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir for 10 minutes until completely dissolved. Measure the pH value, which should be 3.0. If the pH value is not correct, adjust the pH to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to bring the volume to the total volume and continue stirring for 10 minutes.

[0069] Comparative Example 6

[0070] The pH value of the solution in step (1) is adjusted to 3.5. The specific operation is as follows, and the prescription composition and other process steps are the same as in Example 1.

[0071] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 33°C, and add sodium benzoate, pregabalin, and hydrochloric acid in sequence, stirring until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir for 10 minutes until completely dissolved. Measure the pH value, which should be 3.5. If the pH value is not correct, adjust the pH to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to bring the volume to the total volume and continue stirring for 10 minutes.

[0072] Comparative Example 7

[0073] The adjustment step (1) is to directly mix the solution. The specific operation is as follows, and the prescription composition and other process steps are the same as in Example 1.

[0074] (1) At room temperature, dissolve sodium benzoate, ethyl maltol and pregabalin raw materials in purified water, adjust the pH value to 3.5 with 10% hydrochloric acid solution or 0.1M sodium hydroxide solution, and stir until completely dissolved.

[0075] Comparative Example 8

[0076] Adjust the order and temperature of adding the solution in step (1). The specific operation is as follows. The prescription composition and other process steps are the same as in Example 1.

[0077] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 45°C, and add sodium benzoate, ethyl maltol, and pregabalin raw materials sequentially to dissolve in the purified water. Measure the pH value; it should be 3.1. If the pH value is not correct, adjust the pH to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to bring the volume to the total volume and continue stirring for 10 minutes.

[0078] Comparative Example 9

[0079] Adjust the order and temperature of adding the solution in step (1). The specific operation is as follows. The prescription composition and other process steps are the same as in Example 1.

[0080] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water. At room temperature, add sodium benzoate, ethyl maltol, pregabalin raw material, and hydrochloric acid sequentially to the purified water and dissolve them. Measure the pH value; it should be 3.2. If the pH value is not correct, adjust the pH to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to bring the volume to the total volume and continue stirring for 10 minutes.

[0081] Comparative Example 10

[0082] Adjust the order and temperature of adding the solution in step (1). The specific operation is as follows. The prescription composition and other process steps are the same as in Example 1.

[0083] (1) Solution preparation: Weigh 70% of the prescribed amount of purified water, heat to 45°C, and add sodium benzoate, ethyl maltol, pregabalin raw material and hydrochloric acid in sequence to dissolve in the purified water. Measure the pH value, which should be 3.1. If the pH value is not correct, adjust the pH to the set value using 10% hydrochloric acid solution or 0.1M sodium hydroxide solution. Add purified water to make up to the total volume and continue stirring for 10 minutes.

[0084] Table 2 Comparison of conditions between the examples and comparative examples.

[0085] condition Dissolution temperature (°C) Order of adding ingredients pH value Example 1 33 Sodium benzoate + pregabalin + hydrochloric acid, ethyl maltol 3.1 Example 2 40 Sodium benzoate + pregabalin + hydrochloric acid, ethyl maltol 3.1 Example 3 47 Sodium benzoate + pregabalin + hydrochloric acid, ethyl maltol 3.1 Example 4 33 Sodium benzoate + pregabalin + hydrochloric acid, ethyl maltol 3.3 Example 5 33 Sodium benzoate + pregabalin + hydrochloric acid, ethyl maltol 3.4 Comparative Example 1 50 Sodium benzoate + pregabalin + hydrochloric acid, ethyl maltol 3.1 Comparative Example 2 80 Sodium benzoate + pregabalin + hydrochloric acid, ethyl maltol 3.1 Comparative Example 3 40 Sodium benzoate + ethyl maltol, pregabalin + hydrochloric acid 3.1 Comparative Example 4 50 Sodium benzoate + ethyl maltol, pregabalin + hydrochloric acid 3.1 Comparative Example 5 33 Sodium benzoate + pregabalin + hydrochloric acid, ethyl maltol 3.0 Comparative Example 6 33 Sodium benzoate + pregabalin + hydrochloric acid, ethyl maltol 3.5 Comparative Example 7 normal temperature Sodium benzoate + pregabalin + ethyl maltol 3.5 Comparative Example 8 45 Sodium benzoate + pregabalin + ethyl maltol 3.1 Comparative Example 9 normal temperature Sodium benzoate + pregabalin + ethyl maltol + hydrochloric acid 3.2 Comparative Example 10 45 Sodium benzoate + pregabalin + ethyl maltol + hydrochloric acid 3.1

[0086] Pregabalin oral solution manufactured by Orion Corporation (trade name Bonqat, batch number: 2155612), approved by the European Union, was used as the reference preparation. The products and reference preparations obtained in the examples and comparative examples of this invention were placed at high temperature (40°C) and under light (5000 Lx ± 500 Lx) for 30 days. Samples were taken at 0, 10, and 30 days for analysis, and the appearance and related substances of the samples were determined.

[0087] The relevant substances were determined by high performance liquid chromatography (Appendix 0512, Part I, Chinese Pharmacopoeia 2020).

[0088] Table 3 Product Appearance

[0089]

[0090]

[0091] Table 3 shows that the preparation process of pregabalin oral solution directly affects the product's properties. The reference formulation and the pregabalin oral solutions obtained in Examples 1-5 remained colorless and clear solutions after 30 days under high temperature and light exposure, exhibiting good appearance. Comparative Examples 1 and 2 used higher dissolution temperatures than Example 1, and their products showed discoloration after 30 days of high temperature and light exposure. In particular, Comparative Example 2 (dissolution temperature 80℃) turned into a yellow solution after 30 days of light exposure, showing severe discoloration. Comparative Examples 3 and 4 used different feeding sequences than Example 1, and their products showed slight discoloration after 30 days of high temperature and light exposure. The appearance of the products obtained in Comparative Examples 1-4 was unstable. Comparative Example 7 used a method of directly mixing raw materials and excipients at room temperature. During the preparation process, the raw materials and excipients failed to completely dissolve within 2 hours, making the preparation process unsuitable for production. The inventors further increased the mixing temperature (as in Comparative Example 8) in an attempt to promote the dissolution of raw materials and excipients. However, the raw materials and excipients still did not completely dissolve after 2 hours. Although adjusting the pH value allowed for rapid dissolution, the resulting solution was a slightly pink, clear liquid. Simultaneously, the inventors attempted to add a certain amount of hydrochloric acid during the mixing process (as in Comparative Example 9) to address the incomplete dissolution of the raw materials and excipients. Table 3 shows that the raw materials and excipients could dissolve, but the resulting product exhibited discoloration after 30 days of light exposure. If the temperature was increased and hydrochloric acid was added simultaneously compared to Comparative Example 7, the discoloration of the resulting product was even more severe, as in Comparative Example 10.

[0092] Therefore, it can be seen that in the preparation of pregabalin oral solution, conventional direct mixing methods or heating / adding hydrochloric acid methods cannot produce a product that meets drug standards. However, by optimizing the reaction conditions, especially the temperature and the order of addition, a pregabalin oral solution with good appearance and stability can be obtained.

[0093] Table 4. Related Substances in the Product - Harsh Conditions

[0094]

[0095]

[0096] Note: Impurity A is a lactam (CAS No.: 957507-85-6), which is a major degradation impurity of pregabalin oral solution.

[0097] Table 4 shows that the related substances in pregabalin oral solution change significantly under harsh conditions. In the reference formulation, impurity A and total impurities both exceeded the limits after 30 days at high temperature.

[0098] The pregabalin oral solutions obtained in Examples 1-5 still had impurity content within the limit after being placed under high temperature and light for 30 days. In Examples 3 and 5, after 30 days at high temperature, the content of impurity A slightly exceeded the limit, but was still better than the reference preparation and the comparative example.

[0099] Comparative Examples 1 and 2 used higher dissolution temperatures than Example 1. After 30 days at high temperatures, the content of impurity A in the products obtained significantly exceeded the limit value. In particular, Comparative Example 2 not only exceeded the limit value for impurity A, but its total impurity content was also 0.956%, which was very close to the limit value of 1%.

[0100] Comparative Examples 3 and 4 adopted different feeding sequences compared to Example 1. The products obtained by them exceeded the limit value starting from 10 days under high temperature conditions, and after 30 days, both impurity A and total impurities far exceeded the limit value; the stability under high temperature conditions was also poor.

[0101] Compared to Example 1, Comparative Example 6 had a higher final pH control, and the product obtained from it had impurity A exceeding the limit value after 30 days at high temperature.

[0102] In preparation methods involving direct mixing of raw materials and auxiliary materials, if the mixing temperature is increased (e.g., Comparative Example 8), the resulting product exceeds the limit value starting from day 10 under high-temperature conditions, and after 30 days, both impurity A and total impurities far exceed the limit value; the product also exhibits poor stability under high-temperature conditions. Adding a certain amount of hydrochloric acid during the mixing process (e.g., Comparative Example 9) results in the product exceeding the limit value for impurity A after 30 days at high temperature. If the mixing temperature is simultaneously increased and some hydrochloric acid is added (e.g., Comparative Example 10), the resulting product exceeds the limit value starting from day 10 under high-temperature conditions, and after 30 days, both impurity A and total impurities far exceed the limit value.

[0103] Changes in the appearance color of general solution products may be related to an increase in impurities. However, as shown in Tables 3 and 4, the appearance color change of pregabalin oral solution is not directly related to the impurity content. For example, the reference preparation appears as a colorless and clear solution after 30 days of high temperature and light exposure, but its impurity A and total impurity content are both high. Similarly, comparative examples 1 to 4 showed different degrees of appearance changes after 30 days of light exposure, while the impurity content under the corresponding conditions still met the limit values.

[0104] The pregabalin oral solution obtained by the formulation process of this invention not only has a good appearance and is stable, but also the impurity content is within the limit value.

[0105] Table 5. Related substances in the product - Acceleration conditions (high temperature 25°C - high humidity 60% RH)

[0106]

[0107] As shown in Table 5, in the longer-term accelerated test, the content of impurity A (0.532%) in the reference formulation exceeded the limit value (0.5%) after 3 months, while the pregabalin oral solution obtained in Examples 1 to 5 of this invention only slightly exceeded the limit value after 6 months. In particular, Examples 1, 2, 4 and 5 showed much better stability than the reference formulation.

[0108] Palatability Study: Following the EU guidelines on the demonstration of palatability of veterinary medicinal products, palatability studies were conducted on 50 cats using Examples 1 and 5. The cats were given a dose of 8 mg / kg in three separate administrations. If a cat did not voluntarily consume the full dose within 5 minutes (more than 50% of the remaining food), the product was administered with food. If the cat did not voluntarily consume the product within 5 minutes (more than 50% of the food remained), the product was forcibly administered using a syringe. The results show that the oral solution prepared in Example 1 has good palatability, while Comparative Example 5 has poor palatability.

[0109] Table 6. Palatability test results

[0110] product Active eating With food syringe administration The syringe was used to induce resistance or frothing at the mouth. Example 1 10％ 20％ 70％ 0 Comparative Example 5 4％ 8％ 86％ 2％

[0111] Clinical efficacy study:

[0112] This randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical study evaluated the efficacy and safety of the pregabalin oral solution prepared in Example 1 for the treatment or prevention of transport and veterinary visit anxiety and fear in cats. Cats were randomly assigned to receive either 5 mg / kg pregabalin or 5 mg / kg Bonqat. Oral administration. This study had two main efficacy data points: the first was owner assessment of treatment effectiveness based on the cats' stress, anxiety, and / or fear during car transport; 60 stressed cats in each of the experimental and control groups. The second was an assessment of treatment effectiveness based on the cats' stress, anxiety, and / or fear during clinical visits at the veterinary clinic.

[0113] Table 7 Clinical Results in Cats

[0114]

[0115]

[0116] The results of the main variables are shown in Table 7. Statistically significant therapeutic effects were observed in both main variables: the assessment of the therapeutic effect by cat owners during transport (p < 0.05) and the assessment of the therapeutic effect by researchers during clinical examination (p < 0.05). There were no statistically significant differences in the therapeutic effects between the control group and the test group during transport and clinical examination (p > 0.05). Taking the pregabalin oral solution prepared in Example 1 did not produce significant ataxia or excessive sedation.

[0117] Patent CN113631150A improves the water solubility of pregabalin by controlling pH. It compares the stability of pregabalin oral solutions under refrigeration conditions when the pH is between 3.5 and 4.0, and provides a direct mixing preparation method. This application reproduces the method of this patent (e.g., Comparative Example 7) and finds that the raw materials and excipients fail to completely dissolve within 2 hours during the preparation process. Further adjustments to the reaction temperature and pH (e.g., Comparative Examples 8-10) do not achieve satisfactory results. The inventors further verified that a higher pH (e.g., pH 3.5 in Comparative Example 6) results in products with poor impurity stability, while a lower pH (e.g., pH 3.0 in Comparative Example 7) results in products with poor palatability. The ideal pH range is 3.1-3.4. When the pH is appropriate, the dissolution temperature and the order of addition are equally important. All three factors collectively affect the quality of the pregabalin oral solution.

[0118] Studies on appearance, changes in impurities under harsh conditions, accelerated testing, and clinical efficacy have shown that the pregabalin oral solution prepared by the method of this invention has good appearance and stability. Furthermore, clinical studies (evaluation of treatment efficacy by cat owners during transport and by researchers during clinical examinations) have demonstrated good results. This invention solves the problems of poor stability, easy deterioration at high temperatures, and complex preparation processes associated with pregabalin oral solutions.

[0119] The embodiments of this application have been described above, but this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A method for preparing a pregabalin oral solution, characterized in that, Add the antibacterial agent and pregabalin to the solvent, add hydrochloric acid, dissolve completely, add the flavoring agent, stir to dissolve, filter to obtain pregabalin oral solution; In this process, the antibacterial agent and pregabalin are added to the solvent at room temperature to 47°C. After the antibacterial agent and pregabalin are completely dissolved, the mixture is cooled to room temperature, then the flavoring agent is added and stirred until completely dissolved. The pH is then adjusted to 3.0~3.4 using a pH adjuster. The antibacterial agent is sodium benzoate, and the flavoring agent is ethyl maltol.

2. The method for preparing pregabalin oral solution according to claim 1, characterized in that: The pregabalin oral solution comprises, by weight, 80-120 parts pregabalin, 1-10 parts antibacterial agent, 0.01-1 part flavoring agent, 10-50 parts hydrochloric acid, pH adjuster, and the balance solvent; wherein the amount of pH adjuster is the amount required to adjust the pH value to 3.1-3.4; the antibacterial agent is sodium benzoate, the flavoring agent is ethyl maltol, the pH adjuster is hydrochloric acid and / or sodium hydroxide, and the solvent is water.

3. The method for preparing pregabalin oral solution according to claim 2, characterized in that, Includes the following steps: Weigh out 50% to 80% of the prescribed amount of solvent, heat to 33 to 47°C, add sodium benzoate, pregabalin and hydrochloric acid in sequence, and stir until completely dissolved; after cooling to room temperature, continue to add ethyl maltol and stir until completely dissolved, adjust the pH to 3.1 to 3.4 with a pH adjuster, add solvent to make up to the full volume, stir, filter and fill according to the predetermined volume.

4. The pregabalin oral solution prepared by the method according to any one of claims 1 to 3, wherein the pregabalin oral solution is a colorless and clear solution with a lactam content ≤0.5%.

5. The use of the pregabalin oral solution as described in claim 4 in the preparation of products for the treatment or prevention of anxiety and fear in companion animals.

6. The application of the pregabalin oral solution according to claim 5, characterized in that, The companion animal mentioned is a cat.

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