A veterinary olaratumab maleate chewable tablet and a preparation method thereof

Abstract

The application relates to the field of veterinary drugs, in particular to a veterinary olaratumab maleate chewable tablet and a preparation method thereof. The application provides the olaratumab maleate chewable tablet without adding glycerol, which is prepared by forming a coordination among monofatty acid glyceride, monofatty acid polyethylene glycol ester, polyethylene glycol and sodium octenyl succinate starch, and provides a granulation liquid with good coating and good fluidity, the granulation liquid has good coating on the olaratumab maleate, and the chewable tablet obtained is uniform and has good resistance to super-humid environment.

Description

Technical Field

[0001] This application relates to the field of veterinary drugs, and in particular to a veterinary olalatinib maleate chewable tablet and its preparation method. Background Technology

[0002] Olapinib maleate is a targeted JAK enzyme inhibitor. By inhibiting JAK1, the drug can effectively block the signaling of various pruritus and inflammatory cytokines, especially interleukin-31 (IL-31) – a core factor that triggers itching in canine atopic dermatitis. At the same time, it can also inhibit other allergy-related cytokines such as IL-2, IL-4, and IL-6. It can quickly and safely control itching and inflammation caused by allergies in dogs. It can quickly relieve itching after administration, and obvious effects can usually be observed within 4 hours.

[0003] Currently, the core formulation of olatinib maleate is chewable tablets or soft chewable tablets. For example, European patent EP3927315B1 discloses a chewable tablet form containing olatinib maleate, which uses pork liver powder and brewer's yeast as palatability agents and adopts a melt granulation method. First, PEG 3350, glyceryl monostearate and glycerol are heated to melt, xanthan gum is dispersed in it, and then the remaining components are added before granulation and tableting.

[0004] Olapinib maleate is relatively stable in heat and does not easily decompose upon heating, making it a stable choice for melt granulation. However, in the aforementioned method, a high amount of glycerol was used to improve granulation flowability, plasticity, and coating uniformity, with glycerol accounting for 11-14% of the system's mass. This high glycerol content significantly increases the system's hygroscopic properties, making granules and tablets more prone to deliquescence during preparation and use, resulting in poor mechanical strength and uniformity of the chewable tablets. Furthermore, glycerol oxidation upon heating easily produces irritating substances such as acrolein, which also reduces palatability in animals. Conversely, insufficient glycerol can lead to excessive dryness and hardness, also reducing palatability. Summary of the Invention

[0005] Based on the above problems, the purpose of this application is to provide an olatinib maleate chewable tablet with lower glycerol and other polyol content, while ensuring its processing uniformity, granulation and tableting plasticity, and moderate tablet strength.

[0006] First, this application provides a method for preparing veterinary olatinib maleate chewable tablets, wherein the olatinib maleate chewable tablets comprise the following components by weight: API 10 copies; Flavoring agent: 150-400 parts; 5-20 parts of polyethylene glycol; 20-50 parts of sodium octenyl succinate starch; 50-100 parts of mono-fatty acid polyethylene glycol ester; 10-30 parts of mono-fatty acid glycerides; Add 10-30 parts of disintegrant; Add 10-30 parts of disintegrant; Other adjuvants: 0-50 parts; The preparation method includes the following steps: S1. Heat mono-fatty acid glycerides, mono-fatty acid polyethylene glycol esters, polyethylene glycol, and sodium octenyl succinate starch to a temperature not exceeding 90°C and mix them evenly to obtain a granulation solution. S2. Mix API, internal disintegrant, flavoring agent, sodium octenyl succinate starch and other additives evenly, add granulation liquid, stir to form soft material and granulate to obtain granules; S3. Mix the granules with the added disintegrant and the remaining raw materials evenly, and compress them into tablets to obtain veterinary olatinib maleate chewable tablets.

[0007] In the above scheme, a combination of four components—mono-fatty acid glycerides, mono-fatty acid polyethylene glycol esters, polyethylene glycol, and sodium octenyl succinate starch (SSOS)—is used as a substitute for the glycerol system, providing basic melting and granulation properties. Mono-fatty acid glycerides, as the lipid backbone material, exhibit good fluidity and spreadability in the molten state. Polyethylene glycol esters possess both hydrophilic and lipophilic properties, improving the spreadability of the melt and forming a stable solid backbone after cooling. Polyethylene glycol primarily serves to lower the melting point, preventing API decomposition at high temperatures. During melting, mono-fatty acid glycerides form a continuous oil phase, into which polyethylene glycol esters can intercalate, forming an oil-water connecting phase. This allows the oil-phase mono-fatty acid glycerides to better coat other components. Sodium octenyl succinate starch (SSOS) possesses a hydrophobic structure with a long octyl chain and a hydrophilic structure with a carboxyl group, compensating for the relatively weak film-forming and spreadability of the aforementioned system. In an oil-based system, SSOS provides better encapsulation of APIs and their excipients, improving system compatibility, especially with cellulose and starch disintegrant compounds, thereby enhancing the uniformity and processability of chewable tablets. Furthermore, the hydrophobic lipid matrix formed by mono- and fatty acid polyethylene glycol esters in this system is not easily wetted by saliva in the oral environment, effectively preventing direct contact between the drug and taste buds, thus significantly improving palatability.

[0008] Preferably, in step S1, 5 to 10 parts by weight of poloxamer are also added.

[0009] Poloxamer offers superior compatibilizing properties in the aforementioned systems. Its molecular chain contains polyoxypropylene segments, resulting in better lipophilicity and flowability. It also further improves the film-forming properties of the granulation solution and significantly enhances the wettability of chewable tablets, reducing solid-liquid interfacial tension and leading to higher dissolution rates. Furthermore, poloxamer exhibits low melt viscosity in its molten state and good compatibility with SSOS, contributing to improved powder spreading and dispersion uniformity, and reducing localized agglomeration.

[0010] Preferably, the poloxamer is poloxamer 407.

[0011] Poloxamer 407 has an HLB value of approximately 22, exhibiting both good hydrophilicity and moderate lipophilicity. It has the best compatibility with the fatty acid polyethylene glycol esters and mono-fatty acid glycerides in this invention. Overall, it has a good effect on improving flow properties and enhancing granulation uniformity. In addition, poloxamer 407 can form a thermoreversible gel at body temperature, which helps to delay the burst release of the drug in the stomach after oral administration, thus achieving a stable drug release.

[0012] Preferably, in step S1, the monofatty acid glycerides, monofatty acid polyethylene glycol esters, and polyethylene glycol are first heated and mixed until melted, and then sodium octenyl succinate starch and poloxamer are added. The sodium octenyl succinate starch and poloxamer are added to the molten mixture of monofatty acid glycerides, monofatty acid polyethylene glycol esters, and polyethylene glycol by high shear dispersion at a speed of 500-3000 rpm for a dispersion time of 5-20 minutes.

[0013] In the above scheme, the main purpose of high-speed shearing of the system is to improve the dispersibility of SSOS. Since SSOS itself has general solubility in the above system, after high-speed shearing, SSOS can be uniformly dispersed in the system, and it is not easy to form hydrophilic groups or polymeric micelle systems with polyethylene glycol. This avoids local overheating and degradation caused by direct contact between solid powder and high-temperature heating surface, forming a uniform molten medium, which provides an environmental basis for subsequent good dispersion.

[0014] Preferably, in step S1, the heating temperature is 70-80°C.

[0015] The above temperature ensures that the raw materials are completely melted and the overall temperature is low. At this temperature, the viscosity of the granulation solution is moderate, which is beneficial to both high-shear dispersion operation and the continuous stability of the subsequent granulation process, ensuring that SSOS does not undergo gelatinization and degradation.

[0016] Preferably, the viscosity of the sodium octenyl succinate starch aqueous solution at 25°C is 50–100 mPa·s.

[0017] In the above scheme, the viscosity of sodium octenyl succinate starch indicates its low molecular weight. Due to its low overall viscosity, it can be uniformly dispersed in molten lipids, improving the granulation effect. In this system, since it is predominantly oily and does not contain hydrophilic components such as glycerol, and the hydrophilic polyethylene glycol has good flowability and compatibility, its addition will not cause abrupt viscosity changes or phase separation, improving process controllability. Therefore, using a lower viscosity SSOS will have virtually no negative impact; on the contrary, it will have a positive effect on improving overall flowability and uniformity. Using a higher aqueous solution viscosity SSOS will result in a higher system viscosity, poorer dispersion uniformity, and a significant reduction in the uniformity between chewable tablets.

[0018] Preferably, the monofatty acid glyceride is a 16-20 carbon saturated monofatty acid glyceride, and / or, the monofatty acid polyethylene glycol ester is a 12-16 carbon saturated monofatty acid polyethylene glycol ester, and / or, in the fatty acid polyethylene glycol, the polyethylene glycol has a molecular weight of 400-600.

[0019] In the above scheme, mono-fatty acid glycerides with longer fatty acid carbon chains are used. During cooling crystallization, this allows for the formation of a dense and complete lipid crystal network, reducing water penetration and bitterness release, while also avoiding the difficulty of drug dissolution caused by excessively long carbon chains. The use of 12-16 carbon saturated mono-fatty acid polyethylene glycol esters, with a PEG molecular weight limited to 400-600, synergistically determines the optimal HLB value. Excessively large molecular weight or excessively short fatty acid carbon chains lead to excessive hydrophilicity, resulting in easy individual crystallization upon cooling and causing a patchy, heterogeneous structure in the tablets, affecting content uniformity and mechanical strength. Conversely, excessively small polyethylene glycol molecular weight or excessively long fatty acid carbon chains result in excessively high hydrophobicity, leading to decreased dissolution performance, weak emulsification ability, and reduced API coating performance.

[0020] Preferably, the other additives include a lubricant, which is one or more of magnesium stearate, calcium stearate, zinc stearate, talc, and hydrogenated vegetable oil, and the lubricant is added in step S2, and / or... The other additives include a pH adjuster, which is one or more of citric acid, sodium citrate, fumaric acid, and malic acid, added in step S2, and / or... The other adjuvants include antioxidants, which are one or more selected from the following: mixed tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, propyl gallate, and sodium metabisulfite. The antioxidants are added in step S2 or S3, and / or... The other additives include a release agent, which is one or more of sodium fumarate stearate and carnauba wax, and is added in step S3, and / or... The other adjuvants include flavor enhancers, which are one or more selected from sodium chloride, potassium chloride, monosodium glutamate, disodium inosinate, and glycine. The flavor enhancers are added in step S2 or S3, and / or... The other additives include colorants, which are one or more of iron oxide red, iron oxide yellow, caramel color, and sodium copper chlorophyll salt, and are added in step S2 or S3.

[0021] The above scheme generally limits the addition of various excipients. pH adjusters stabilize and regulate the pH of the system, adjusting the pH value of the microenvironment within the particles to ensure olatinib reaches the optimal dissolution pH in the dissolution medium. Antioxidants, added in step S2 or S3, effectively extend shelf life. Lubricants improve the lubricity of materials during granulation, reducing friction between the materials and equipment walls and improving particle flowability. Release agents facilitate tableting and prevent tablets from sticking to the mold. Flavor enhancers improve palatability, and colorants improve product recognition through coloring.

[0022] Preferably, both the internal and external disintegrants are selected from one or more of sodium carboxymethyl starch, crospovidone, and hydroxypropyl cellulose.

[0023] In the above scheme, good drug dissolution is achieved by combining internal and external disintegrants.

[0024] In addition, this application also relates to veterinary olalatinib maleate chewable tablets prepared by the above preparation method.

[0025] The olatinib maleate chewable tablets prepared using the above method exhibit higher content uniformity compared to commercially available products. Their disintegration time and dissolution rate are essentially consistent with commercially available products, and they also show significantly lower friability. When stored in a humid environment, their overall dissolution rate does not decrease significantly, and their disintegration time remains largely unchanged.

[0026] In summary, this application provides a nilatinib maleate chewable tablet without added glycerol, which provides a granulation solution with good coating properties and good flowability through the formation of a complex between mono-fatty acid glycerides, mono-fatty acid polyethylene glycol esters, polyethylene glycol and sodium octenyl succinate starch. It has good coating properties for nilatinib maleate and can produce a uniform chewable tablet with good tolerance to ultra-humid environments. Detailed Implementation

[0027] The technical solutions in this application will be further described through the following specific embodiments.

[0028] Example 1: This example provides a veterinary olatinib chewable tablet, the raw materials of which are as follows by weight: 10 portions of API olalatinib maleate; 10 parts of polyethylene glycol 3350; 200 portions of pork liver powder (flavoring agent, spray-dried, passed through an 80-mesh sieve); Brewer's yeast (flavoring agent, spray-dried, passed through an 80-mesh sieve) 50 parts; 30 parts of SSOS (octenyl substitution degree 0.05, viscosity of 6wt% aqueous solution at 25℃ 68mPa·s); 407 copies of Polosham; 80 parts of PEG-400-monolaroate; 15 parts of crospovidone XL-10 (with added disintegrant); Sodium carboxymethyl starch (with added disintegrant) 5 parts; Cross-linked polyvinylpyrrolidone XL-10 (with internal disintegrant) 15 parts; Sodium carboxymethyl starch (with internal disintegrant) 5 parts; 20 parts of glyceryl monostearate; Citric acid (pH adjuster), 1 part; Sodium chloride (flavor enhancer) 1 part; Magnesium stearate (lubricant) 2 parts; Sodium fumarate stearate (release agent) 1 part; Mixed tocopherols (antioxidants) 0.2 parts.

[0029] Specifically, this embodiment includes the following steps: S1. Glyceryl monostearate, PEG-400-monolaroate, and polyethylene glycol 3350 were mixed and added to a reaction vessel. The mixture was heated to 75°C, and high-speed dispersion was started at 1500 rpm. SSOS and poloxamer were then slowly added in three batches, with a 3-minute interval between each batch. After all the ingredients were added, the mixture was stirred for another 3 minutes, for a total dispersion time of 12 minutes, to obtain the granulation solution.

[0030] S2. Mix the internal disintegrant, pork liver powder, brewer's yeast, citric acid, sodium chloride, magnesium stearate, and API raw materials, pass through a 25-mesh sieve, and add to a mixing granulator. Turn on the stirring speed of 200 rpm to mix evenly. Maintain the temperature and inject the granulation liquid evenly into the above mixture within 3 minutes. After the injection is completed, continue stirring for 15 minutes to obtain a soft material. Transfer the soft material to a swing granulator and granulate it through a 30-mesh sieve. Then transfer it to a fluidized bed to dry until the moisture content is not higher than 10% at a drying temperature of 60℃. After drying, granulate it through a lower 30-mesh sieve and an upper 18-mesh sieve to obtain granules.

[0031] S3. The granules, along with the added disintegrant and sodium stearate fumarate, are compressed into tablets using a mold. The pre-compression pressure is 2 kN, and the main pressure is 8 kN. The average content of olatinib maleate in each chewable tablet is controlled to be 8 mg, thus obtaining olatinib maleate chewable tablets.

[0032] Examples 2-12 and Comparative Examples 1-2: In the above examples and comparative examples, the selection and amount of monofatty acid glycerides and monofatty acid polyethylene glycol esters were adjusted, as shown in Table 1.

[0033]

[0034] Examples 13-21: In the above examples, the addition and selection of poloxamer were adjusted, and the results are shown in Table 2.

[0035]

[0036] Examples 22-24 and Comparative Examples 3-4 show that the use of sodium octenyl succinate starch was adjusted in the above examples, as shown in Table 3.

[0037]

[0038] The following experiments were conducted to verify Examples 1-24 and Comparative Examples 1-4: 1. Friability test: Refer to the 0923 Tablet Friability Test Method in the Chinese Pharmacopoeia. The friability tester is used for the test. The drum parameters are as follows: inner diameter 286mm, depth 39mm, rotation speed 25rpm. After rotating 100 times, the sample is taken out, the dust is removed, and the weight is weighed. The weight loss is the friability.

[0039] 2. Dissolution test: The test conditions were paddle method, 50 rpm, dissolution medium was pH 4.5 acetate buffer, temperature was 37℃±0.5℃, and the dissolution rate was measured after 30 min.

[0040] 3. Disintegration time limit: The disintegration time limit test method in Chinese Pharmacopoeia (Veterinary) 0921 was used as a reference, and the test was conducted in accordance with the standard for whole powder tablets.

[0041] 4. Appearance and morphology inspection: The formability and surface appearance of the particles are evaluated separately during the preparation process.

[0042] 5. The prepared chewable tablets were placed at 40℃ and 90% relative humidity for 7 days, then dried, and the friability was measured.

[0043] 6. Content uniformity: Referring to the content uniformity test method in Chinese Pharmacopoeia 0941, take 10 tablets and determine the content of olatinib maleate in each tablet by HPLC, and calculate A+2.2S.

[0044] The experimental results are shown in Table 4.

[0045]

[0046] Among them, the commercially available formulation is Apoquel® chewable tablets (trade name: Apoquel), 16mg specification.

[0047] By comparing Example 1 with Comparative Examples 1 and 2, it can be seen that, even without the addition of glycerol, the combination of mono-fatty acid glycerides and mono-fatty acid polyethylene glycol esters can still form a good coating system with high overall uniformity, low content difference between tablets, and low friability. The dissolution and disintegration characteristics of Example 1 are basically consistent with commercially available products, with slightly better uniformity. Furthermore, after long-term storage in a humid environment, the friability and dissolution of this product remained essentially unchanged, while the friability of commercially available products increased significantly, and the dissolution rate decreased to some extent. Compared to Comparative Example 1, it can be seen that the absence of mono-fatty acid glycerides leads to poor particle flowability and coating properties during granulation, making particle formation difficult, resulting in poor coating uniformity, rough particle surface, and significantly increased brittleness. The absence of mono-fatty acid polyethylene glycol esters leads to a significant reduction in the dispersion and coating performance of particles on APIs, resulting in a more obvious decrease in the uniformity of chewable tablets, poor overall flowability, significantly increased tablet roughness, poor dispersion performance, and difficulty in the system disintegration process, with a significantly longer disintegration time and reduced dissolution.

[0048] In Examples 1-12, the selection and dosage of mono-fatty acid glycerides and mono-fatty acid polyethylene glycol esters were adjusted. Overall, using mono-fatty acid glycerides with 16-20 carbon atoms and mono-fatty acid polyethylene glycol esters with 12-16 carbon atoms was more beneficial to the overall performance. Short-chain fatty acid glycerides led to a slight reduction in the dispersion of the system, similar to the effect in Comparative Example 1, but to a relatively lower degree. Conversely, using mono-fatty acid polyethylene glycol esters with excessively long carbon chains resulted in a certain decrease in the solubility of the system and a significant increase in disintegration time. In PEG segments, as the segment length increased, the flowability during processing was somewhat reduced, resulting in a loss of particle uniformity and surface gloss. Conversely, excessively short PEG segments led to poor coating performance, reduced uniformity, and a significant decrease in dissolution performance.

[0049] In Examples 13-21, orthogonal experiments were conducted on the selection and dosage of poloxamer. It was observed that in Example 21, without the addition of poloxamer, the overall dissolution rate decreased, and the tablet surface became rougher, with a slight decrease in uniformity. Comparisons between various uses and dosages of poloxamer showed that, overall, excessive poloxamer dosage increased overall brittleness; therefore, the overall dosage should not exceed 10 parts by weight. Furthermore, poloxamer 407 exhibits better properties overall compared to poloxamer 188 and poloxamer 124.

[0050] In Examples 22-24 and Comparative Examples 3-4, experiments were conducted on the use of sodium octenyl succinate starch. It can be seen that without the addition of sodium octenyl succinate starch, in addition to a certain increase in disintegration time, there are also significant problems such as increased particle surface roughness and decreased uniformity, excessive powder during particle forming, and significantly poorer processing and forming performance.

[0051] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A method for preparing veterinary olatinib maleate chewable tablets, characterized in that, The olatinib maleate chewable tablets contain the following components by weight: API 10 copies; Flavoring agent: 150-400 parts; 5-20 parts of polyethylene glycol; 20-50 parts of sodium octenyl succinate starch; 50-100 parts of mono-fatty acid polyethylene glycol ester; 10-30 parts of mono-fatty acid glycerides; Add 10-30 parts of disintegrant; Add 10-30 parts of disintegrant; Other adjuvants: 0-50 parts; The preparation method includes the following steps: S1. Heat mono-fatty acid glycerides, mono-fatty acid polyethylene glycol esters, polyethylene glycol, and sodium octenyl succinate starch to a temperature not exceeding 90°C and mix them evenly to obtain a granulation solution. S2. Mix API, internal disintegrant, flavoring agent, sodium octenyl succinate starch and other additives evenly, add granulation liquid, stir to form soft material and granulate to obtain granules; S3. Mix the granules with the added disintegrant and the remaining raw materials evenly, and compress them into tablets to obtain veterinary olatinib maleate chewable tablets.

2. The method for preparing veterinary olatinib maleate chewable tablets according to claim 1, characterized in that, In step S1, 5 to 10 parts by weight of poloxamer are also added.

3. The method for preparing veterinary olalatinib maleate chewable tablets according to claim 2, characterized in that, The poloxamer in question is poloxamer 407.

4. The method for preparing veterinary olatinib maleate chewable tablets according to claim 3, characterized in that, In step S1, monofatty acid glycerides, monofatty acid polyethylene glycol esters, and polyethylene glycol are first heated and mixed until melted. Then, sodium octenyl succinate starch and poloxamer are added. The sodium octenyl succinate starch and poloxamer are added to the molten mixture of monofatty acid glycerides, monofatty acid polyethylene glycol esters, and polyethylene glycol by high-shear dispersion at a speed of 500–3000 rpm for a dispersion time of 5–20 minutes.

5. The method for preparing veterinary olatinib maleate chewable tablets according to claim 4, characterized in that, In step S1, the heating temperature is 70-80℃.

6. The method for preparing veterinary olatinib maleate chewable tablets according to claim 1, characterized in that, The viscosity of the sodium octenyl succinate starch aqueous solution at 25°C is 50–100 mPa·s (6 wt%).

7. The method for preparing veterinary olatinib maleate chewable tablets according to claim 1, characterized in that, The monofatty acid glyceride is a 16-20 carbon saturated monofatty acid glyceride, and / or, the monofatty acid polyethylene glycol ester is a 12-16 carbon saturated monofatty acid polyethylene glycol ester, and / or, In the fatty acid polyethylene glycol, the molecular weight of polyethylene glycol is 400-600.

8. The method for preparing veterinary olatinib maleate chewable tablets according to claim 1, characterized in that, The other additives include lubricants, which are one or more selected from magnesium stearate, calcium stearate, zinc stearate, talc, and hydrogenated vegetable oil. The lubricant is added in step S2, and / or... The other additives include a pH adjuster, which is one or more of citric acid, sodium citrate, fumaric acid, and malic acid, added in step S2, and / or... The other adjuvants include antioxidants, which are one or more selected from the following: mixed tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, propyl gallate, and sodium metabisulfite. The antioxidants are added in step S2 or S3, and / or... The other additives include a release agent, which is one or more of sodium fumarate stearate and carnauba wax, and is added in step S3, and / or... The other adjuvants include flavor enhancers, which are one or more selected from sodium chloride, potassium chloride, monosodium glutamate, disodium inosinate, and glycine. The flavor enhancers are added in step S2 or S3, and / or... The other additives include colorants, which are one or more of iron oxide red, iron oxide yellow, caramel color, and sodium copper chlorophyll salt, and are added in step S2 or S3.

9. The method for preparing veterinary olalatinib maleate chewable tablets according to claim 1, characterized in that, Both the internal and external disintegrants can be selected from one or more of sodium carboxymethyl starch, crospovidone, and hydroxypropyl cellulose.

10. Olapinib maleate chewable tablets for veterinary use prepared by the preparation method according to any one of claims 1 to 9.

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