Pregabalin oral administration paste for pets and preparation method of pregabalin oral administration paste

Abstract

The invention belongs to the technical field of pet medicines, and discloses an oral pregabalin paste for pets, which comprises pregabalin, a thickening agent, an acidity regulator, a phagostimulant and water, the pH value of the paste is 3-4; the concentration of pregabalin in the paste is not more than 5wt%. Compared with a traditional pregabalin water aqua medicine, the pregabalin oral administration paste provided by the invention has the advantages that the stability of pregabalin can be improved, and the pregabalin oral administration paste still has relatively good stability in a normal temperature state; besides, the palatability of the pregabalin is greatly improved and the convenience of pet administration is improved by screening the phagostimulant in a specific combination and combining the characteristic that the paste is convenient for pet administration.

Description

Technical Field

[0001] The present invention relates to the technical field of medicines, and in particular to a pregabalin oral paste for pets and a preparation method thereof. Background Art

[0002] Cats are naturally cautious, timid, and sensitive pets. They are prone to stress when exposed to external factors, especially during transportation and veterinary visits. Stress in cats can lead to common illnesses and symptoms such as ringworm, flu-like symptoms, vomiting, diarrhea, anorexia, and endocrine disorders, which can even cause death. Many cats are reluctant to visit the veterinarian because the process can be highly stressful and distressing for owners. This is largely because owners are reluctant to subject their cats to the stress of a veterinary visit, which can delay treatment and worsen their condition.

[0003] Pregabalin is a new active substance that acts on the central nervous system by reducing the release of various neurotransmitters (glutamate and monoamine neurotransmitters) to produce an anti-anxiety effect. It has good anti-stress effects, small and controllable side effects, and has the advantages of small dosage, rapid absorption, rapid onset, safety and controllability compared to similar gabapentin-like drugs. It was approved by the FDA in December 2004 for the treatment of pain associated with postherpetic neuralgia and diabetic neuropathy, and in March 2006 it was approved by the European Medicines Agency (EMA) for anxiety disorders (long-term anxiety or nervousness). In human medicine, oral capsules, oral solutions, sustained-release tablets and other dosage forms are on the market, mainly used to treat peripheral neuropathy, postherpetic neuralgia and auxiliary treatment of localized partial epileptic seizures. In addition to its use in human medicine, it was formally approved by the European Medicines Agency (EMA) in July 2021 as a stress-relieving drug for pet cats to treat acute anxiety and fear.

[0004] Existing pregabalin formulations for pets are generally aqueous solutions, such as oral solutions. Patent CN116172951A discloses a pregabalin pharmaceutical composition and oral solution for pets, and patent CN113631150A discloses pregabalin formulations and their uses. As can be seen from the above solutions, their dosage forms are all aqueous solutions. Due to pregabalin's poor solubility and storage stability, it needs to be adjusted to a pH of 3-4 for optimal dissolution. However, at this pH, pregabalin easily decomposes into lactams in aqueous solutions, resulting in more stringent storage conditions. Furthermore, aqueous solutions have poor palatability for cats and generally require administration using a syringe, which is extremely inconvenient.

[0005] Based on this, the problem to be solved by the present invention is: how to prepare a pregabalin oral paste for pets with good stability and palatability. Summary of the Invention

[0006] The object of the present invention is to provide a pregabalin oral paste for pets, which comprises pregabalin, a thickener, an acidity regulator, an attractant and water. Compared with aqueous solutions, the prepared paste has better stability, palatability and convenience of administration.

[0007] At the same time, the invention also provides a preparation method of the paste.

[0008] To achieve the above object, the present invention provides the following technical solutions:

[0009] A pregabalin paste for internal use for pets comprises pregabalin, a thickener, an acidity regulator, an attractant and water; the pH of the paste is 3-4; and the concentration of pregabalin in the paste does not exceed 5wt%.

[0010] In the research of the present invention, it was found that when pregabalin and related adjuvants were prepared into an aqueous solution, the solubility of pregabalin was poor when the pH was above 4, and it was difficult to meet the formulation requirements. If the solubility of pregabalin is to be increased, the pH needs to be further reduced to 3-4. However, the stability of pregabalin in the oral solution at this pH is poor, and it is easy to decompose to form lactams, which affects the product quality. Therefore, the aqueous solutions for pets on the market need to be stored at low temperatures, which brings great inconvenience to transportation and storage, and greatly increases the cost. The present invention provides a pregabalin oral paste that can improve the stability of pregabalin so that it still has good stability at room temperature; in addition, we have greatly improved the palatability of pregabalin and improved the convenience of pet administration by screening a specific combination of attractants and combining the characteristics of the paste itself that is convenient for pet administration.

[0011] Preferably, the acidity regulator is at least one of citric acid / citrate buffer, lactic acid / lactate buffer, acetic acid / acetate buffer, propionic acid / propionate buffer, hydrochloric acid, and dilute hydrochloric acid / 10% sodium hydroxide.

[0012] Preferably, the thickener is one or a combination of carboxymethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, gum arabic, polyethylene glycol 300 / 400, agar, and anhydrous silicon dioxide.

[0013] Preferably, the attractant is one or a combination of chocolate powder, beef flavor attractant, and yeast extract.

[0014] Preferably, the amount of the thickener is 1wt% to 10wt%, the amount of the attractant is 2wt% to 10wt%, and the amount of water added to the total amount of the formula is 100 parts by weight.

[0015] Preferably, the paste further comprises a preservative and a flavoring agent.

[0016] More preferably, the amount of the preservative is 0.2 wt% to 2 wt%, and the amount of the flavoring agent is 0.1 wt% to 3 wt%.

[0017] More preferably, the preservative is at least one of benzyl alcohol, sodium benzoate, sorbitol, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate; and the flavoring agent is at least one of sucralose, stevia, aspartame, sucrose, fructose, sodium saccharin, and ethyl maltol.

[0018] In addition, the present invention also discloses a method for preparing the paste as described above, which specifically comprises the following steps:

[0019] Step 1: Dissolve the acidity regulator and pregabalin in water respectively, stir evenly to completely dissolve the raw materials, and obtain a mixed solution 1;

[0020] Step 2: Add preservatives and flavoring agents to the mixed solution 1 and dissolve them completely to obtain mixed solution 2;

[0021] Step 3: Add the thickener to the mixed solution 2, dissolve and stir evenly to obtain mixture 3;

[0022] Step 4: Add the phagostimulant to the mixture 3 and homogenize it completely to obtain a paste for internal use.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention provides a pregabalin paste for internal use. Compared with traditional pregabalin aqueous solutions, the paste can improve the stability of pregabalin and maintain good stability at room temperature. In addition, by screening a specific combination of flavoring agents and combining the paste's inherent properties for easy pet administration, the paste greatly improves the palatability of pregabalin and the convenience of pet administration. DETAILED DESCRIPTION

[0025] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0026] Product Information:

[0027] Yeast extract was purchased from Angel Yeast Co., Ltd.; the main components were: 60 wt% protein and amino acids, 12 wt% nucleotides, 5 wt% vitamins, 3% trace elements, and 20 wt% carbohydrates.

[0028] The preparation method of the paste of each embodiment and embodiment is:

[0029] Step 1: Dissolve the acidity regulator and pregabalin in water respectively, stir evenly to completely dissolve the raw materials, and obtain a mixed solution 1;

[0030] Step 2: Add preservatives and flavoring agents to the mixed solution 1 and dissolve them completely to obtain mixed solution 2;

[0031] Step 3: Add thickener (if any) to mixed solution 2, dissolve and stir evenly to obtain mixture 3;

[0032] Step 4: Add the phagostimulant to the mixture 3 and homogenize it completely to obtain a paste for internal use.

[0033] Example 1

[0034] A pregabalin internal paste for pets, comprising the following components in parts by mass:

[0035] Active substance: Pregabalin 5 parts;

[0036] Thickener: 6 parts of sodium carboxymethyl cellulose;

[0037] Preservatives: 0.05 parts of methyl paraben, 0.15 parts of propyl paraben;

[0038] Acidity regulator: 3 parts of citric acid / citrate buffer;

[0039] Flavoring agent: 0.1 part of sucralose;

[0040] Attractant: 5 parts of chocolate powder;

[0041] Water: Add to the total amount of the formula to 100 parts by weight.

[0042] wherein the pH of the paste is 3.5-4.0;

[0043] The specific composition of citric acid / citrate buffer is:

[0044] Citric acid: 25wt%;

[0045] Sodium citrate: 75wt%.

[0046] Example 2

[0047] A pregabalin internal paste for pets, comprising the following components in parts by mass:

[0048] Active substance: 1 part of pregabalin;

[0049] Thickener: 1.5 parts of xanthan gum;

[0050] Preservative: benzyl alcohol 0.5 parts;

[0051] Acidity regulator: 2 parts of lactic acid / lactate buffer;

[0052] Flavoring agent: 3 parts of sucrose;

[0053] Attractant: 10 parts of yeast extract;

[0054] Water: Add to the total amount of the formula to 100 parts by weight.

[0055] Among them, the pH of the paste is 3.5-3.8;

[0056] The specific composition of lactic acid / lactate buffer is:

[0057] Lactic acid: 66.7 wt%;

[0058] Sodium lactate: 33.3wt%.

[0059] Example 3

[0060] A pregabalin internal paste for pets, comprising the following components in parts by mass:

[0061] Active substance: 2 parts of pregabalin;

[0062] Thickener: 5 parts of anhydrous silicon dioxide;

[0063] Preservative: 0.5 parts of sorbitol;

[0064] Acidity regulator: 1.25 parts of sodium hydroxide / hydrochloric acid;

[0065] Flavoring agent: 0.1 part of saccharin sodium;

[0066] Attractant: 10 portions of beef flavor attractant;

[0067] Water: Add to the total amount of the formula to 100 parts by weight.

[0068] wherein the pH of the paste is 3.0-3.6;

[0069] Sodium hydroxide: hydrochloric acid The specific ingredients are:

[0070] Sodium hydroxide: 20wt%;

[0071] Hydrochloric acid: 80wt%.

[0072] Example 4

[0073] A pregabalin internal paste for pets, comprising the following components in parts by mass:

[0074] Active substance: Pregabalin 5 parts;

[0075] Thickener: xanthan gum 10 parts;

[0076] Preservative: 2 parts benzyl alcohol;

[0077] Acidity regulator: 2 parts of lactic acid / lactate buffer;

[0078] Flavoring agent: 3 parts of sucrose;

[0079] Attractant: 10 parts of yeast extract;

[0080] Water: Add to the total amount of the formula to 100 parts by weight.

[0081] Among them, the pH of the paste is 3.2-3.4;

[0082] The specific composition of lactic acid / lactate buffer is:

[0083] Lactic acid: 66.7 wt%;

[0084] Sodium lactate: 33.3wt%.

[0085] Example 5

[0086] A pregabalin internal paste for pets, comprising the following components in parts by mass:

[0087] Active substance: 1 part of pregabalin;

[0088] Thickener: 1 part xanthan gum;

[0089] Preservative: 0.5 parts benzyl alcohol

[0090] Acidity regulator: 2 parts lactic acid / lactate buffer

[0091] Flavoring agent: 1 part sucrose

[0092] Attractant: 2 parts yeast extract

[0093] Water: Add to the total amount of the formula to 100 parts by weight.

[0094] Among them, the pH of the paste is 3.3-3.5;

[0095] The specific composition of lactic acid / lactate buffer is:

[0096] Lactic acid: 66.7 wt%;

[0097] Sodium lactate: 33.3wt%.

[0098] Comparative Example 1

[0099] A pregabalin oral solution for pets, comprising the following components by weight: active substance: 5 parts of pregabalin;

[0100] Preservatives: 0.05 parts of methyl paraben, 0.15 parts of propyl paraben

[0101] Acidity regulator: 3 parts citric acid / citrate buffer

[0102] Flavoring agent: 0.1 part sucralose

[0103] Attractant: 5 parts chocolate powder

[0104] Water: Add to the total amount of the formula to 100 parts by weight.

[0105] The specific composition of citric acid / citrate buffer is:

[0106] Citric acid: 25wt%;

[0107] Sodium citrate: 75wt%.

[0108] Comparative Example 2

[0109] It is generally the same as Example 1, except that the attractant is chicken flavor.

[0110] Comparative Example 3

[0111] It is generally the same as Example 1, except that the attractant is apple flavor.

[0112] Comparative Example 4

[0113] It is generally the same as Example 1, except that the attractant is chicken liver powder.

[0114] Performance testing

[0115] Stability testing

[0116] The pastes prepared in Examples 1 to 5 and the aqueous solution prepared in Comparative Example 1 were stored under illumination (4500 ± 500 lx) and high temperature conditions of 40°C. The properties of the preparations and the content of pregabalin were tested on day 0, day 5, and day 10, respectively. The test results are shown in Table 1.

[0117] Table 1 Stability results data table

[0118]

[0119] Analysis of the data in Table 1 shows that the pastes prepared according to the formulation of the technical solution of the present invention in Examples 1 to 5 were stored under light and at 40°C for 5 days and 10 days, respectively. The changes in the pregabalin content were lower than that of the aqueous solution of Comparative Example 1. Among them, after 10 days of storage under light conditions, the pregabalin content of Example 3 decreased by only 1.3%, while that of Comparative Example 1 decreased by 2.9%; after 10 days of storage at 40°C, the pregabalin content of Example 5 decreased by only 2.5%, while that of Comparative Example 1 decreased by 5.1%. By comparison, it can be seen that, whether under light or high temperature of 40°C, the trend of decreasing the pregabalin content in the aqueous solution prepared in Comparative Example 1 is more than twice as fast as that of the pastes prepared in Examples 1 to 5. In other words, the paste system has better stability. In the tests of light and high temperature factors, the paste system has a certain improvement effect on isolating light and oxygen and improving the stability of the preparation.

[0120] Palatability test

[0121] In order to investigate the effect of each experimental example and comparative example of pregabalin oral paste on the palatability of cats, a palatability animal test was carried out. The test selected 8 adult cats of similar weight and half male and half female, and the palatability of the self-made preparation and the reference preparation was studied. The preparation was fed to the cat at the same dose. If the cat did not voluntarily ingest the entire dosage preparation within 5 minutes (more than 50% of the remaining dose), the product was fed together with the food. If the cat did not voluntarily consume the product together with the food within 5 minutes (more than 50% of the remaining particles), the product was given using a dispenser. Each pet was kept alone in a pet cage with free drinking water, and the feeding situation and adverse reactions of each cat to different pregabalin oral pastes were recorded. The test results are shown in Tables 2 and 3.

[0122] Table 2 Feeding situation statistics

[0123]

[0124]

[0125] Table 3 Palatability data

[0126] project Active feed intake rate Feed rate Adverse reactions Example 1 75％ 87.5％ 0 Example 2 75％ 100％ 0 Example 3 87.5％ 100％ 0 Example 4 75％ 100％ 0 Example 5 75％ 100％ 0 Comparative Example 2 25％ 37.5％ 0 Comparative Example 3 50％ 50％ 0 Comparative Example 4 62.5％ 100％ 0

[0127] From the palatability test results, it can be seen that Examples 1 to 5 have better palatability than Comparative Examples 2 to 4. The cat's active feeding rate in the examples is above 75%, which significantly improves the cat's feeding desire. Moreover, when the cat is fed with feed, the feeding rate can reach above 87.5%, and there are no obvious adverse reactions. In Comparative Examples 2 to 3, the cat's active feeding rate and the feeding rate with feed are relatively low. In Comparative Example 4, when chicken liver powder is added, the cat's active feeding rate can reach 62.5%. However, in actual preparation, the prepared paste is prone to deterioration and stratification, which does not meet the preparation requirements. The palatability test shows that the paste prepared by combining the attractant and pregabalin used in the technical solution of the present invention can better improve the cat's palatability and greatly improve the convenience of administration.

[0128] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations that come within the meaning and range of equivalents of the claims be embraced therein.

Claims

1. A pregabalin oral paste for pets, characterized in that: The paste comprises pregabalin, a thickener, an acidity regulator, an attractant and water; the pH value of the paste is 3-4; and the concentration of pregabalin in the paste does not exceed 5wt%.

2. The paste according to claim 1, characterized in that The acidity regulator is at least one of citric acid / citrate buffer, lactic acid / lactate buffer, acetic acid / acetate buffer, propionic acid / propionate buffer, and dilute hydrochloric acid / 10% sodium hydroxide.

3. The paste according to claim 1, characterized in that The thickener is one or a combination of carboxymethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, gum arabic, polyethylene glycol 300 / 400, agar, and anhydrous silicon dioxide.

4. The paste according to claim 1, characterized in that The attractant is one or a combination of chocolate powder, beef flavor attractant, and yeast extract.

5. The paste according to any one of claims 1 to 4, characterized in that The amount of the thickener is 1wt% to 10wt%, the amount of the attractant is 2wt% to 10wt%, and the amount of water added to the total amount of the formula is 100 parts by weight.

6. The paste according to claim 1, characterized in that The paste also includes preservatives and flavoring agents.

7. The paste according to claim 6, characterized in that The amount of the preservative is 0.2 wt% to 2 wt%, and the amount of the flavoring agent is 0.1 wt% to 3 wt%.

8. The paste according to claim 7, characterized in that The preservative is at least one of benzyl alcohol, sodium benzoate, sorbitol, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate; the flavoring agent is at least one of sucralose, stevia, aspartame, sucrose, fructose, sodium saccharin, and ethyl maltol.

9. A method for preparing the paste according to any one of claims 1 to 8, characterized in that: The specific steps include: Step 1: Dissolve the acidity regulator and pregabalin in water respectively, stir evenly to completely dissolve the raw materials, and obtain a mixed solution 1; Step 2: Add preservatives and flavoring agents to the mixed solution 1 and dissolve them completely to obtain mixed solution 2; Step 3: Add the thickener to the mixed solution 2, dissolve and stir evenly to obtain mixture 3; Step 4: Add the phagostimulant to the mixture 3 and homogenize it completely to obtain a paste for internal use.

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