Sevelamer carbonate oral gel as well as preparation method and application thereof

Abstract

The invention provides sevelamer carbonate oral gel as well as a preparation method and application thereof, and belongs to the technical field of veterinary drug preparation. The sevelamer carbonate oral gel is prepared from 3% of sevelamer carbonate, 0.5%-1.0% of gel, 1%-3% of phagostimulant, 0-1.5% of potassium gluconate, 5% of glycerinum and the balance purified water. The sevelamer carbonate oral gel can effectively control hyperphosphatemia of cats suffering from chronic kidney diseases and prevent hypokalemia to a certain extent. The oral gel is convenient to use and only needs to be mixed for administration every day, and the oral gel is added with a cat phagostimulant, so that the mouth feel and the fragrance are improved to better conform to the taste of cats, and the cats can conveniently take medicine by themselves. Compared with tablets, the sevelamer carbonate oral gel has a better serum phosphorus concentration control effect and is more suitable for sick cats to use for a long time.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug preparation technology, and in particular relates to an oral gel containing sevelamer carbonate, its preparation method, and its application. Background Technology

[0002] Chronic kidney disease (CKD) in dogs and cats is a chronic, progressive disease characterized by unilateral or bilateral structural and functional abnormalities of the kidneys for more than 3 months. While it can occur at any age, it is more common in older dogs and cats. Declining kidney function leads to phosphorus retention, causing hyperparathyroidism, tissue mineralization, and further exacerbation of CKD. In stages 1 and 2 of CKD, the number of damaged nephrons means that serum phosphorus levels remain within the normal range. However, in stages 2 to 4, as kidney damage worsens, phosphorus excretion becomes difficult, leading to elevated serum phosphorus levels. Therefore, management of hyperphosphatemia is necessary at this stage to control serum phosphorus concentration within a specific range (target serum phosphorus levels for stage 2 CKD are 3.5 mg / dL-4.5 mg / dL; for stage 3, 3.5 mg / dL-5.0 mg / dL; and for stage 4, 3.5 mg / dL-6.0 mg / dL). Typically, dietary management begins with feeding a low-phosphorus prescription diet for the kidneys. However, for cats and dogs whose blood phosphorus levels remain below target even after feeding a low-phosphorus prescription diet, intestinal phosphate binders are necessary. Since phosphate binders are not included in the "List of Human Drugs Urgently Needed in Pet Clinical Use (61 types)" or the "List of Veterinary Prescription Drugs," there is an urgent need to develop a safe and effective phosphate binder to safeguard pet health.

[0003] Sevelamer carbonate is a non-absorbable phosphate-bound cross-linked polymer, free of calcium or other metals; it contains multiple amine groups, each linked to the polymer backbone by a carbon atom. The amine groups exist in the intestine in a partially protonated form and bind to negatively charged phosphorus via ionic and hydrogen bonds. Sevelamer carbonate reduces serum phosphate concentration by binding to phosphate groups in the digestive tract and decreasing their absorption. As a high-molecular-weight drug, sevelamer carbonate is not absorbed through the intestines and is excreted unchanged, posing no risk of systemic accumulation and allowing for long-term use. Currently, sevelamer carbonate formulations are used to control hyperphosphatemia in adult patients with chronic kidney disease (CKD) undergoing dialysis, and it is a first-line human drug for controlling hyperphosphatemia. This drug has not yet been used in veterinary medicine; this invention aims to use sevelamer carbonate as a phosphate binder for pets.

[0004] Sevelamer carbonate, currently marketed as an original formulation, is available in tablet and dry suspension forms. Developed by Genzyme, it is marketed under the brand name Renvela. The recommended starting dose is 0.8g or 1.6g three times daily with food. Administering with food allows sevelamer carbonate to mix thoroughly with food, more effectively binding with phosphate ions produced in the food and reducing intestinal absorption of phosphate. However, when using sevelamer carbonate tablets or dry suspensions to treat feline hyperphosphatemia, pets often refuse to take the tablets. Owners must manually administer the medication immediately after meals (morning, noon, and evening), but this timing is difficult to pinpoint, leading to missed doses and hindering disease control. Multiple daily administrations also increase the complexity for owners. Dry suspensions, requiring water to dissolve, are even more inconvenient. Therefore, developing a sevelamer carbonate formulation suitable for pets to administer willingly is essential. Furthermore, since sevelamer carbonate has not yet been used in pets, the therapeutic effects of different formulations may vary, and relevant clinical studies are needed. Summary of the Invention

[0005] Based on the above problems, this invention provides a method for preparing and applying sevelamer carbonate oral gel. The sevelamer carbonate oral gel can be used to control hyperphosphatemia in cats with chronic kidney disease, and solves the problem of administering sevelamer carbonate preparations to pets with meals from the dosage form perspective. At the same time, palatability enhancers are added to the preparation to increase the pet's willingness to eat. This invention also adds potassium gluconate to prevent hypokalemia, a common complication of chronic kidney disease in cats.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows: A sevelamer carbonate oral gel, calculated on a total basis of 100%, comprises the following components by weight percentage: 3% sevelamer carbonate, 0.5%-1.0% gelling agent, 1%-3% palatability enhancer, 0-1.5% potassium gluconate, 5% glycerin, and the balance being purified water, preferably 3% sevelamer carbonate, 0.5% gelling agent, 2% palatability enhancer, 1.5% potassium gluconate, 5% glycerin, and the balance being purified water.

[0007] Furthermore, the gelling agent is one or more of gelatin, carrageenan, and sodium alginate, preferably gelatin.

[0008] Furthermore, the palatability enhancer is one or more of the following: hydrolyzed powder of caramelized fish flavor cat food, hydrolyzed powder of caramelized chicken flavor cat food, and hydrolyzed powder of caramelized roasted beef flavor cat food, preferably hydrolyzed powder of caramelized fish flavor cat food.

[0009] This invention also provides a method for preparing the above-mentioned sevelamer carbonate oral gel, comprising the following steps in sequence: (1) After mixing the gelling agent and potassium gluconate evenly, add purified water, stir evenly, heat to 40-60℃, and keep at 40-60℃ until the excipients are fully swollen and dissolved, and stir evenly; (2) Add sevelamer carbonate and the palatability enhancer to the solution obtained in step (1), and keep it warm at 40-60℃ while stirring until homogeneous; (3) After adding glycerol to the mixture obtained in step (2), keep it warm at 40-60℃ and stir until homogeneous; (4) After homogenizing and dispersing the mixture obtained in step (3) for 20-30 minutes using a high-speed dispersion homogenizer, the mixture is then subjected to vacuum-assisted filtration, preferably using a 50-mesh filter screen. (5) The mixture obtained in step (4) is filled and sealed using a back-sealing automatic liquid packaging machine to produce the finished product of Desvelam oral gel; Furthermore, the rotational speed of the high-speed dispersion homogenizer is 5000-20000 rpm.

[0010] Furthermore, the filling parameters of the back-sealed automatic liquid packaging machine in step (5) are as follows: heat sealing temperature is 125℃, sealing pressure is 0.4MPa, packaging speed is 50 bags / minute, and filling amount per bag is 20.6g±0.2g / bag.

[0011] Furthermore, the inner packaging material used for the sevelamer carbonate oral gel in step (5) is PET / AL / PE (polyester / aluminum / polyethylene).

[0012] This invention also provides the application of the above-mentioned sevelamer carbonate oral gel or the sevelamer carbonate oral gel prepared by the above method in the preparation of drugs for controlling chronic kidney disease in dogs and cats, preferably in the preparation of drugs for controlling hyperphosphatemia caused by chronic kidney disease in cats.

[0013] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows: (1) The sevelamer carbonate oral gel prepared by the present invention has good stability, good water holding capacity and suitable viscosity. The inner packaging is a strip-shaped back-sealed bag. In clinical practice, only one bag of sevelamer carbonate oral gel with a specification of 600mg / bag (calculated as dry sevelamer carbonate) needs to be added to the daily diet and stirred evenly. It is then divided into three portions for the cat to eat in the morning, noon and evening. Since the sevelamer carbonate oral gel adheres to the surface of the cat food, it can achieve the effect of allowing the cat to take the medicine with the meal while eating on its own, avoiding the trouble of artificial feeding and multiple feedings, and is convenient for daily storage and use.

[0014] (2) The sevelamer carbonate oral gel prepared by this invention can more effectively help cats control blood phosphorus concentration compared with conventional tablets. Since it takes about 8-10 hours for sevelamer carbonate to reach adsorption saturation for phosphate, the conventional tablet administration method, where cat food and tablets are digested and disintegrated in the stomach, only then can it adsorb phosphate in the food. The drug reaches the small intestine with the food before it can fully adsorb phosphate ions in the body. However, the oral gel prepared by this invention is mixed with cat food in advance. When the oral gel moistens and softens the cat food, it can adsorb some of the phosphate ions contained in the cat food in advance, and exert its adsorption effect in vitro. At the same time, the moistened and softened cat food is more likely to disintegrate into food in the stomach after eating and mix fully with sevelamer. This increases the contact time and contact area between sevelamer and cat food in the body and in vitro, so that sevelamer can more fully adsorb phosphate in the cat food and achieve a better phosphorus control effect.

[0015] (3) The oral gel containing sevelamer carbonate prepared in this invention is improved by adding an appropriate amount of cat palatability enhancer to improve the taste and aroma of the oral gel, making it more palatable to cats and facilitating pets to take the medication on their own.

[0016] (4) The oral gel containing sevelamer carbonate prepared in this invention contains an appropriate amount of potassium gluconate, which is used to prevent hypokalemia, a common complication of chronic kidney disease in pets, or to help pets with mild hypokalemia supplement potassium ions. Detailed Implementation

[0017] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0018] Unless otherwise specified, "%" in this application document refers to the percentage content by mass.

[0019] The sources of some of the excipients in this invention embodiment are as follows: Gelatin: Rousselot (Wenzhou) Gelatin Co., Ltd.; Carrageenan: DowDuPont; Sodium alginate: Hunan Ercon Pharmaceutical Co., Ltd.; Potassium gluconate, hydrolyzed powder of caramel fish flavor cat food, hydrolyzed powder of caramel chicken flavor cat food: Shanxi Zhongnuo Biotechnology Co., Ltd.; Glycerin: Rovo Pharmaceuticals (Shanghai) Co., Ltd.; Sevelamer carbonate was purchased as commercial sevelamer carbonate tablets, Genzyme tablets, specification: 0.8g / tablet.

[0020] In the following examples, the filling parameters of the back-sealing automatic liquid packaging machine are as follows: heat sealing temperature is 125℃, sealing pressure is 0.4MPa, packaging speed is 50 bags / minute, filling amount per bag is 20.6g±0.2g / bag, and the inner packaging material used is PET / AL / PE (polyester / aluminum / polyethylene).

[0021] Example 1: A method for preparing sevelamer carbonate oral gel, comprising the following steps in sequence: Prepare the raw materials and excipients according to the following mass ratio: sevelamer carbonate, gelatin, potassium gluconate, hydrolyzed caramelized fish flavor cat food powder, glycerin, and purified water: 0.6:0.1:0.3:0.4:1:17.6. Prepare 5L gel solutions, then fill and seal the solutions to obtain the sevelamer carbonate oral gel packaged in pouches. The specific preparation steps are as follows: 1) Mix gelling agent gelatin and potassium gluconate in proportion, add purified water, stir well, heat to 50℃, and keep at 50℃ until the excipients are fully swollen and dissolved, and stir well.

[0022] 2) Add the hydrolyzed powder of sevelam carbonate and caramelized fish flavor cat to the solution obtained in step 1), and keep it at 50°C while stirring until homogeneous; 3) Add glycerin to the mixture obtained in step 2), and keep it at 50°C while stirring until homogeneous; 4) After homogenizing and dispersing the mixture obtained in step 3) using a high-speed dispersion homogenizer, the homogenization speed is 10000 rpm and the homogenization time is 20-30 min. The resulting mixture is then subjected to vacuum-assisted filtration with a 50-mesh filter. 5) The mixture obtained in step 4) is filled and sealed in bags using a back-sealing automatic liquid packaging machine, with each bag containing 20.6g ± 0.2g, to obtain the finished sevelamer carbonate oral gel.

[0023] Example 2: A method for preparing sevelamer carbonate oral gel, comprising the following steps in sequence: Prepare the raw materials and excipients according to the following mass ratio: sevelamer carbonate, carrageenan, potassium gluconate, hydrolyzed caramelized fish flavor cat food, glycerin, and purified water: 0.6:0.1:0.3:0.4:1:17.6. Prepare 5L gel solutions, then fill and seal the solutions to obtain the sevelamer carbonate oral gel packaged in pouches. The specific preparation steps are as follows: 1) Mix the gelling agent carrageenan and potassium gluconate evenly in proportion, add purified water, stir evenly, heat to 50℃, and keep at 50℃ until the excipients are fully swollen and dissolved, and stir evenly.

[0024] 2) Add the hydrolyzed powder of sevelam carbonate and caramelized fish flavor cat to the solution obtained in step 1), and keep it at 50°C while stirring until homogeneous; 3) Add glycerin to the mixture obtained in step 2), and keep it at 50°C while stirring until homogeneous; 4) The mixture obtained in step 3) is homogenized and dispersed using a high-speed dispersion homogenizer at a speed of 10,000 rpm for 20-30 minutes. The resulting mixture is then vacuum-assisted filtered using a 50-mesh filter. 5) The mixture obtained in step 4) is filled and sealed in bags using a back-sealing automatic liquid packaging machine, with each bag containing 20.6g ± 0.2g, to obtain the finished sevelamer carbonate oral gel.

[0025] Example 3: A method for preparing sevelamer carbonate oral gel, comprising the following steps in sequence: Prepare the raw materials and excipients according to the following mass ratio: sevelamer carbonate, sodium alginate, potassium gluconate, hydrolyzed caramelized fish flavor cat food powder, glycerin, and purified water: 0.6:0.1:0.3:0.4:1:17.6. Prepare 5L gel solutions, then fill and seal the solutions to obtain the sevelamer carbonate oral gel packaged in pouches. The specific preparation steps are as follows: 1) Mix sodium alginate and potassium gluconate in proportion, add purified water, stir well, heat to 50°C, and keep at 50°C until the excipients are fully swollen and dissolved, and stir well.

[0026] 2) Add the hydrolyzed powder of sevelam carbonate and caramelized fish flavor cat to the solution obtained in step 1), and keep it at 50°C while stirring until homogeneous; 3) Add glycerin to the mixture obtained in step 2), and keep it at 50°C while stirring until homogeneous; 4) The mixture obtained in step 3) is homogenized and dispersed using a high-speed dispersion homogenizer at a speed of 10,000 rpm for 20-30 minutes. The resulting mixture is then vacuum-assisted filtered using a 50-mesh filter. 5) The mixture obtained in step 4) is filled and sealed in bags using a back-sealing automatic liquid packaging machine, with each bag containing 20.6g ± 0.2g, to produce the finished Desvelam oral gel.

[0027] Example 4: A method for preparing sevelamer carbonate oral gel, comprising the following steps in sequence: Prepare the raw materials and excipients according to the following mass ratio: sevelamer carbonate, gelatin, potassium gluconate, hydrolyzed caramelized fish flavor cat food powder, glycerin, and purified water: 0.6:0.2:0.3:0.4:1:17.5. Prepare 5L gel solutions, then fill and seal the solutions to obtain the sevelamer carbonate oral gel packaged in pouches. The specific preparation steps are as follows: 1) Mix gelling agent gelatin and potassium gluconate in proportion, add purified water, stir well, heat to 50℃, and keep at 50℃ until the excipients are fully swollen and dissolved, and stir well.

[0028] 2) Add the hydrolyzed powder of sevelam carbonate and caramelized fish flavor cat to the solution obtained in step 1), and keep it at 50°C while stirring until homogeneous; 3) Add glycerin to the mixture obtained in step 2), and keep it at 50°C while stirring until homogeneous; 4) The mixture obtained in step 3) is homogenized and dispersed using a high-speed dispersion homogenizer at a speed of 10,000 rpm for 20-30 minutes. The resulting mixture is then vacuum-assisted filtered using a 50-mesh filter. 5) The mixture obtained in step 4) is filled and sealed in bags using a back-sealing automatic liquid packaging machine, with each bag containing 20.6g ± 0.2g, to obtain the finished sevelamer carbonate oral gel.

[0029] Example 5: A method for preparing sevelamer carbonate oral gel, comprising the following steps in sequence: Prepare the raw materials and excipients according to the following mass ratio: sevelamer carbonate, gelatin, potassium gluconate, hydrolyzed powder of caramelized chicken flavor, glycerin, and purified water: 0.6:0.1:0.3:0.4:1:17.6. Prepare 5L gel solutions, then fill and seal the solutions to obtain the sevelamer carbonate oral gel packaged in pouches. The specific preparation steps are as follows: 1) Mix gelling agent gelatin and potassium gluconate in proportion, add purified water, stir well, heat to 50℃, and keep at 50℃ until the excipients are fully swollen and dissolved, and stir well.

[0030] 2) Add the hydrolyzed powder of sevelam carbonate and caramelized chicken flavor to the solution obtained in step 1), and keep it at 50°C while stirring until homogeneous; 3) Add glycerin to the mixture obtained in step 2), and keep it at 50°C while stirring until homogeneous; 4) The mixture obtained in step 3) is homogenized and dispersed using a high-speed dispersion homogenizer at a speed of 10,000 rpm for 20-30 minutes. The resulting mixture is then vacuum-assisted filtered using a 50-mesh filter. 5) The mixture obtained in step 4) is filled and sealed in bags using a back-sealing automatic liquid packaging machine, with each bag containing 20.6g ± 0.2g, to obtain the finished sevelamer carbonate oral gel.

[0031] Example 6: A method for preparing sevelamer carbonate oral gel, comprising the following steps in sequence: Prepare the raw materials and excipients according to the mass ratio of sevelamer carbonate, gelatin, hydrolyzed caramelized fish flavor cat food, glycerin, and purified water of 0.6:0.2:0.4:1:17.8, mix them to form 5L gel solutions, and then fill and seal the solutions to obtain the sevelamer carbonate oral gel packaged product. The specific preparation steps are as follows: 1) Add gelling gelatin to purified water, stir well, heat to 50°C, and keep at 50°C until the excipients are fully swollen and dissolved, and stir well.

[0032] 2) Add the hydrolyzed powder of sevelam carbonate and caramelized fish flavor cat to the solution obtained in step 1), and keep it at 50°C while stirring until homogeneous; 3) Add glycerin to the mixture obtained in step 2), and keep it at 50°C while stirring until homogeneous; 4) The mixture obtained in step 3) is homogenized and dispersed using a high-speed dispersion homogenizer at a speed of 10,000 rpm for 20-30 minutes. The resulting mixture is then vacuum-assisted filtered using a 50-mesh filter. 5) The mixture obtained in step 4) is filled and sealed in bags using a back-sealing automatic liquid packaging machine, with each bag containing 20.6g ± 0.2g, to obtain the finished sevelamer carbonate oral gel.

[0033] To ensure the ease of use of sevelamer carbonate oral gel, the product is designed to be used by adding one packet of sevelamer carbonate oral gel to the daily required amount of cat food, stirring well, and allowing the pet to eat freely. Therefore, to ensure that the sevelamer carbonate oral gel can effectively adhere to the food and maintain a moist texture throughout the day, the product's viscosity and moisturizing properties need to be tested. Moisturizing ability and viscosity tests were conducted on the sevelamer carbonate oral gel products prepared in Examples 1-6. Product viscosity was measured using a rotational viscometer.

[0034] Moisturizing ability evaluation method: Approximately 20g of the sevelamer carbonate oral gel prepared in Examples 1-6 was added to dry cat food (record the cat food mass m1, approximately 100g), stirred evenly, and weighed and recorded the mass m2 (g) before storage; after storage at 25℃ and 20%RH for 1 day, it was removed, weighed, and recorded the mass m3 (g) after storage. The difference in mass between the two was calculated and compared with the mass of the added gel to obtain the water loss: water loss (%) = (m2-m3) / (m2-m1)×100%. This was used to evaluate the moisturizing ability, and the evaluation criteria are shown in Table 1. Table 1. Evaluation Criteria for Moisturizing Ability Table 2. Test results of sevelamer carbonate oral gel Test results show that the oral gel containing sevelamer carbonate in Examples 1-6 of this invention has a viscosity within the common viscosity range of gels, and can effectively adhere to cat food. Furthermore, according to the moisturizing ability evaluation results, the product made according to this invention has excellent moisturizing properties within one day.

[0035] To evaluate the physical, chemical, and biological stability of the formulation under low-temperature freezing and room-temperature thawing cycles, and to simulate the impact of extreme temperature fluctuations that the drug may encounter during transportation and storage on its quality, freeze-thaw experiments were conducted on the sevelamer carbonate oral gel samples prepared in Examples 1-6.

[0036] Freeze-thaw test method: The oral gel samples of sevelamer carbonate prepared in Examples 1-6 were retained in their inner packaging and placed at -20~-10℃ for 2 days, then at 40℃ for 2 days, for a total of three cycles. Samples were taken at the end of the third cycle, and the properties, phosphate binding degree, titratable amine, soluble oligomers, allylamine, and content were tested according to the key stability testing items, using methods referencing the imported registration quality standards for sevelamer carbonate tablets.

[0037] Table 4 Results of freeze-thaw experiment The test results showed that the properties, phosphate binding degree, titratable amine, soluble oligomer, allylamine, and content (purity) of the sevelamer carbonate oral gel in Examples 1-6 of this invention did not change significantly before and after freeze-thaw. The samples were stable in quality under freeze-thaw conditions.

[0038] To examine the quality similarity between the self-made formulation and the original (tablet) formulation, accelerated stability studies were conducted on Examples 1 and 5 and the original (tablet) formulation.

[0039] Accelerated experimental testing method: The oral gel samples of sevelamer carbonate prepared in Examples 1 and 5 (with inner packaging retained) and the original formulation (Genzyme tablets, specification: 0.8g / tablet, with inner packaging retained) were placed in an environment of 40±2℃ and 75±5% relative humidity for 6 months. Samples were taken at 0, 1, 2, 3 and 6 months and the stability was investigated according to the key test items, including appearance, phosphate binding degree, titratable amine, soluble oligomer, allylamine and content.

[0040] Table 5. Accelerated stability results of Example 1 Table 6. Accelerated stability results of Example 5 Table 7. Accelerated stability results of the original formulation (tablets) The test results show that the sevelamer carbonate oral gels of Examples 1 and 5, as well as the original formulation, did not show significant changes in appearance, phosphate binding degree, titratable amine, soluble oligomer, allylamine, and content during the accelerated stability test period. Furthermore, the quality indicators of the samples prepared in Examples 1 and 5 are similar to those of the original formulation, indicating that the sevelamer carbonate oral gel prepared by this invention has good stability and its quality is similar to that of the original formulation.

[0041] To ensure accurate dosage delivery, it is necessary to study the residual amount of the drug solution in the packaging bag after administration to determine the additional dosage required for filling during production. The sevelamer carbonate oral gel prepared in Examples 1-6 was tested for weight before and after extrusion (3 bags for each example). Simultaneously, the packaging bags were washed, dried, and the empty bags were weighed and recorded. The residual amount in the packaging bag was calculated as follows: Residual amount = Weight of bag after extrusion - Weight of empty bag. The test results are shown in Table 8. Table 8. Drug Residue Test After Medication Administration Test results show that the average residual amount of the sevelamer carbonate oral gel prepared in Examples 1-6 of this invention is between 0.445g / bag and 0.737g / bag. In order to ensure production quality and delivery dosage accuracy, the overfilling range is set at 0.6g±0.2g / bag, and the actual filling range is 20.6g±0.2g / bag.

[0042] Example 7 In vitro bioequivalence test According to the FDA's guidance for sevelamer carbonate individual drugs, a self-designed in vitro bioequivalence study is required. In vitro phosphate binding kinetics is used to confirm the time required for drug phosphate adsorption to reach saturation, while in vitro equilibrium binding is a key study for assessing bioequivalence. The oral gel of Example 1 (weighing 26.67g of oral gel containing 800mg of sevelamer carbonate) and the original drug tablets (800mg / tablet) were incubated with at least eight different concentrations of phosphate. Based on the total phosphate binding concentration, the binding constant k1 and capacity constant k2 were calculated using the Langmuir equation. Bioequivalence was assessed using the confidence interval of the k2 ratio between the self-developed formulation and the original drug tablets. In vitro binding kinetics data are shown in Tables 9-10, and in vitro equilibrium binding data are shown in Tables 11-14.

[0043] Table 9. Phosphoric acid kinetic test data of the original drug tablets Table 10 Phosphoric acid kinetic test data from Example 1 Table 11 Data from phosphoric acid equilibrium binding experiments (acid-free treatment, pH 4 medium) Table 12 Phosphoric acid equilibrium binding test data (acid treatment, pH 4 medium) Table 13 Phosphoric acid equilibrium binding test data (acid-free treatment, pH 7 medium) Table 14 Phosphoric acid equilibrium binding test data (acid treatment, pH 7 medium) Phosphoric acid kinetics tests showed that the oral gel prepared in Example 1 and the original tablets, under acid-treated or non-acid-treated conditions, reached a saturated adsorption plateau in 8-10 hours under pH 4 and pH 7 media conditions. Phosphoric acid equilibrium binding assay data showed that the k2 values ​​obtained from the in vitro phosphate equilibrium binding assay of the samples prepared in Example 1 were close to those of the original drug, indicating that the in vitro phosphate adsorption capacity of the oral gel prepared in Example 1 was similar to that of the original drug.

[0044] Example 8: Palatability Evaluation Twenty healthy adult Chinese domestic cats were selected for palatability evaluation. The palatability evaluation method followed the "Guidelines for Palatability Demonstration of Veterinary Drug Products." During feeding, 5ml of oral gel was placed in the food container. Cats that finished it within 2 minutes indicated they liked it; those that finished it within 2-10 minutes indicated they were okay with it; and those that finished it after more than 10 minutes or did not eat it indicated they disliked it. A cat acceptance rate of ≥80% was considered good palatability. The results of the palatability evaluation according to this standard are shown in Table 15.

[0045] Table 15 Palatability Evaluation Results Table 15 shows that the acceptance rate of all six oral gels was greater than 80%, indicating that the sevelamer carbonate oral gel of the present invention has good palatability. The types and amounts of gelling agents, and the types of palatability enhancers differed among the six formulations, but the results indicate that these variations did not significantly affect palatability.

[0046] Example 9: Effect Evaluation The application of the sevelamer carbonate oral gel prepared in Example 1 of this invention in the treatment of hyperphosphatemia caused by chronic kidney disease in cats.

[0047] 1) Materials Example: The sevelamer carbonate oral gel (containing 600 mg sevelamer carbonate / sachet) prepared in Example 1 and Example 6 was used as the administration sample in the example group; Comparative example: The original tablet (manufacturer: Genzyme, specification: 0.8g / tablet) was cut open, and 1 / 4 tablet (containing 200mg sevelamer carbonate) was taken as the control group sample; 2) Method Administration method of the example: The oral gel containing sevelamer carbonate (600mg / bag) prepared in the example was added to the renal low phosphorus prescription diet (100g / day) daily, mixed well, and divided into three portions for the cat to eat in the morning, noon and evening.

[0048] Comparative administration method: 100g / day of renal low-phosphorus prescription diet is provided daily, divided into three portions for the cat to eat in the morning, noon and evening. Immediately after eating, administer 1 / 4 weight of the original sevelamer carbonate tablet (about 0.26g, containing 200mg of sevelamer carbonate), that is, the medication needs to be administered three times a day.

[0049] Thirty cats with chronic kidney disease (stages 2-4) causing hyperphosphatemia were selected from a pet store. The cats should have no gastrointestinal diseases, normal blood potassium levels, weigh 4-7 kg, and be 7-11 years old. They were divided into three groups of 10 cats each, and administered the drugs according to the methods described in the example and comparative examples, respectively. Blood phosphorus and potassium levels were measured on days 0, 10, 20, and 30, and daily dietary intake was recorded. The results of the efficacy evaluation are shown in Table 16.

[0050] Table 16. Effects of the products in the comparative and example studies on controlling hyperphosphatemia in cats. The experimental results show that, compared with the comparative tablets, the sevelamer carbonate oral gels of Examples 1 and 6 resulted in slightly higher average daily dietary intake in cats administered via the oral gel route, indicating that the cats' appetite was better after using the oral gel. Regarding the reduction in serum phosphorus concentration, the oral gels of Examples 1 and 6 were more effective than the original tablets in controlling serum phosphorus levels. Simultaneously, the oral gel of Example 1 showed a certain increase in serum potassium concentration in cats, indicating that the addition of potassium gluconate helps supplement serum potassium and is beneficial in preventing hypokalemia, a common complication of chronic kidney disease.

Claims

1. A sevelamer carbonate oral gel, characterized in that, Based on a total content of 100%, it includes the following components by weight percentage: 3% sevelamer carbonate, 0.5%-1.0% gelling agent, 1%-3% palatability enhancer, 0-1.5% potassium gluconate, 5% glycerin, and the balance being purified water as a solvent.

2. The sevelamer carbonate oral gel according to claim 1, characterized in that, The gelling agent is one or more of gelatin, carrageenan, and sodium alginate.

3. The sevelamer carbonate oral gel according to claim 1, characterized in that, The palatability enhancer is one or a combination of two or more of the following: hydrolyzed powder of caramelized fish flavor cat food, hydrolyzed powder of caramelized chicken flavor cat food, and hydrolyzed powder of caramelized roasted beef flavor cat food.

4. A method for preparing a sevelamer carbonate oral gel according to any one of claims 1-3, characterized in that, Includes the following steps: (1) After mixing the gelling agent and potassium gluconate evenly, add purified water, stir evenly, heat to 40-60℃, and keep at 40-60℃ until fully swollen and dissolved; (2) Add sevelamer carbonate and the palatability enhancer to the solution obtained in step (1), and keep it warm at 40-60℃ while stirring until homogeneous; (3) After adding glycerol to the mixture obtained in step (2), keep it warm at 40-60℃ and stir until homogeneous; (4) After homogenizing and dispersing the mixture obtained in step (3) for 20-30 minutes using a high-speed dispersion homogenizer, the mixture is then subjected to vacuum-assisted filtration. (5) The mixture obtained in step (4) is filled and sealed using a back-sealing automatic liquid packaging machine to produce Desvelam oral gel.

5. The preparation method according to claim 4, characterized in that, The high-speed dispersion homogenizer described in step (4) has a rotational speed range of 5000-20000 rpm.

6. The preparation method according to claim 4, characterized in that, The filling parameters of the back-sealed automatic liquid packaging machine in step (5) are: heat sealing temperature of 125℃, sealing pressure of 0.4MPa, packaging speed of 50 bags / minute, and filling amount of 20.6g±0.2g / bag.

7. The use of the sevelamer carbonate oral gel according to any one of claims 1-3 in the preparation of a drug for controlling chronic kidney disease in dogs and cats.

8. The use of a sevelamer carbonate oral gel obtained by the preparation method according to any one of claims 4-6 in the preparation of a drug for controlling chronic kidney disease in dogs and cats.

9. The application according to claim 7 or 8, characterized in that, The application is in the preparation of drugs for controlling hyperphosphatemia caused by chronic kidney disease in cats.

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