Taste masking composition and preparation method thereof

Abstract

The invention discloses a taste masking composition and a preparation method thereof. The composition comprises active pharmaceutical ingredients and pregelatinized starch, wherein the pregelatinized starch is used as a taste masking agent. The invention further provides a specific suspension drying process. According to the invention, the peculiar smell of indissolvable bitter drugs such as letemovir is obviously covered, the release rate of the drugs is not influenced, and the dissolution behavior is consistent with that of the original developed agent. The composition disclosed by the invention is excellent in quality and good in taste, is easy to take by children, old people and other patients with dysphagia, and is convenient for personalized dosage adjustment, so that the compliance of the patients and the accuracy of the dosage are improved; the preparation process is simple, feasible, good in reproducibility and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a taste-masking composition and its preparation method. Background Technology

[0002] The palatability of medications (taste, odor, dosage form, etc.) is a core influencing factor in pediatric medication use, directly determining medication adherence and treatment efficacy. Children have a much higher sensitivity to taste than adults and have extremely low tolerance for bitter or unpleasant tastes in medications. Poor palatability can easily lead to refusal to take the medication, vomiting, or missed doses, resulting in insufficient drug concentration in the body. This can prolong the course of the disease or, in severe cases, induce drug resistance.

[0003] Azithromycin, lemetmovir, and utpatinib are commonly used medications in pediatric clinical treatment, but their significant bitterness poses a major challenge to pediatric medication use. Young children have extremely low tolerance for bitterness, and the unpleasant taste of these medications easily triggers resistance and crying in children, significantly increasing the difficulty for parents to administer the medication. Forced administration can even lead to choking, vomiting, and other complications, affecting the patient's experience and potentially resulting in insufficient dosage, directly weakening the drug's efficacy and delaying recovery. Furthermore, repeated medication resistance can cause psychological fear in children, reducing adherence to subsequent treatments and creating a vicious cycle. Therefore, improving the palatability of these bitter medications for children is an urgent need to enhance pediatric medication adherence and ensure clinical treatment effectiveness.

[0004] Currently, common masking techniques in pharmaceutical formulations all have their own limitations. For example, microcapsule coating masking has disadvantages such as uneven coating thickness leading to easy membrane breakage and taste leakage, coating materials being greatly affected by the pH of gastrointestinal fluids, potentially delaying drug dissolution; complex processes, high equipment requirements, and high production costs. Flavoring agent mixing masking has limited effectiveness for strongly bitter drugs, and excessive flavoring agents may affect drug stability and dissolution behavior. Other masking techniques, such as cyclodextrin inclusion masking, suffer from high cyclodextrin excipient costs and inclusion rates easily affected by temperature and concentration; ion exchange resin masking has unstable resin-drug binding, easily leading to delayed drug release and affecting the efficiency of achieving target blood drug concentrations.

[0005] Therefore, developing a taste-masking composition that is easy to administer, has a good taste, and whose excipients are readily available and whose material and production costs are low is an urgent problem to be solved in this field. Summary of the Invention

[0006] The purpose of this invention is to address the shortcomings of existing technologies, particularly the significant bitterness of bitter drugs and the difficulty in meeting the medication needs of pediatric or geriatric patients with dysphagia, by providing a taste-masking composition that is easy to administer, has a good taste, and whose excipients are readily available and whose material and production costs are low.

[0007] A taste-masking composition, characterized in that the composition comprises a pharmaceutically active ingredient and pregelatinized starch. Preferably, the mass ratio of the pharmaceutically active ingredient to the pregelatinized starch is 1:2 to 1:5.

[0008] Preferably, the above-mentioned taste-masking composition is prepared by suspending the pharmaceutical active ingredient with the pregelatinized starch in a solvent and then drying. Further, the pharmaceutical active ingredient is a poorly soluble bitter drug. For example, the active ingredient is selected from one or more of lutemovir, azithromycin, utpatinib, and roxithromycin. This invention is particularly applicable to lutemovir.

[0009] This invention discovers that simply mixing flavoring agents with drugs that have a significantly bitter taste, such as azithromycin, utpatinib, and letermovir, or performing conventional granulation, cannot effectively mask the strong bitterness of the active pharmaceutical ingredient. This invention creatively combines bitter drugs with pregelatinized starch to form a flavor-masking layer. In the pharmaceutical field, pregelatinized starch is typically used as a filler, disintegrant, or binder. This invention creatively discovers that pregelatinized starch can serve as a flavor masking agent for bitter drugs, especially those that are poorly soluble. Pregelatinized starch forms a physical barrier against these poorly soluble bitter drugs, preventing the bitter substances from contacting the taste buds and reducing the dissolution time of the drug in the oral cavity, thereby masking the unpleasant taste.

[0010] The pregelatinized starch selected in this invention is a commonly used excipient with high safety profile, making it suitable for pediatric and elderly patients. Pregelatinized starch exhibits good drug compatibility: it is chemically stable, does not react with most drugs, and is suitable for the vast majority of bitter-tasting active pharmaceutical ingredients (APIs). Pregelatinized starch has a lower cost, significantly lower than excipients such as cyclodextrin, acrylic resin, and polyethylene glycol (PEG), substantially reducing formulation production costs. Furthermore, pregelatinized starch does not affect drug dissolution and bioavailability; its coating rapidly swells and decomposes in the gastrointestinal tract without dissolution lag, easily matching the dissolution profile of the original drug, thus facilitating in vivo bioequivalence with the original drug.

[0011] The flavor-masking composition of the present invention comprises the following components in weight percentage: 1%~15% bittering agent, 2%~50% pregelatinized starch, 5%~60% filler, and 0.1%~5% suspending agent. The filler is one or more of mannitol, sorbitol, lactose, and xylitol; the suspending agent is one or more of dispersible cellulose (Avitol RC-591, CL-611), gum arabic, guar gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose (CMC-Na), and xanthan gum. It may also include a pH adjuster of 0.1%~3%; the pH adjuster is one or more of sodium bicarbonate, anhydrous sodium citrate, and citric acid.

[0012] To further optimize the taste, the flavor-masking composition may also contain a flavoring agent, preferably in the following mass percentages: 0.1% to 10.0% sweetener and 0.1% to 5.0% flavoring agent. Further, the sweetener is one or more of sucralose, steviol glycosides, sucrose, and aspartame (other sweeteners may be added); the flavoring agent is one or more of orange flavoring, strawberry flavoring, peppermint flavoring, and banana flavoring.

[0013] As a specific example, the filler of the termovir oral suspension is mannitol, the suspending agent is xanthan gum, the pH adjuster is sodium bicarbonate, the sweeteners are sucralose and steviol glycosides, and the flavoring agent is orange flavoring.

[0014] The taste-masking composition of the present invention can be further prepared into dosage forms such as oral suspensions, granules, dispersible tablets, and orally disintegrating tablets. It is particularly suitable for preparation into oral suspensions, which include both dry suspensions and oral liquid suspensions, so as to flexibly select according to the clinical application of the drug.

[0015] The present invention also provides a method for preparing the above-mentioned flavor-masking composition. This method includes the following steps: (1) Add the pregelatinized starch to the matrix solvent and stir until homogeneous; (2) Add the active pharmaceutical ingredient, stir and mix, grind and disperse or homogenize to form a suspension; (3) Dry the suspension to form a solid, then pulverize it; (4) Mix the product obtained in step (3) with other excipients and / or formulation solvents until homogeneous.

[0016] When preparing the dry suspension, step (4) specifically involves weighing the remaining mannitol, sodium bicarbonate, xanthan gum, sucralose, steviol glycosides, and orange flavoring, and mixing them evenly with the product from step (3). After mixing, the mixture is packaged as a suspension.

[0017] When preparing the suspension, step (4) specifically involves: swelling xanthan gum with a small amount of water, weighing the remaining mannitol, sodium bicarbonate, sucralose, steviol glycosides, and orange flavor, mixing them evenly with the product from step (3), adding the remaining water and stirring to prepare the suspension.

[0018] To improve the odor masking effect, the process and parameters are further optimized. Preferably, the matrix solvent in process step (1) is water and an organic solvent, and the organic solvent includes at least one of ethanol, acetonitrile, acetone, 2-propanol, and dimethylacetamide; the volume concentration of the organic solvent in the mixed solvent is not higher than 40%, more preferably 1-30%. The mixing method selected in process step (2) is ball milling or homogenization. The drying temperature in process step (3) is 40℃-70℃, more preferably 50℃-60℃. The sieve mesh size in process step (3) is 50-80 mesh, more preferably 65 mesh.

[0019] The present invention has the following beneficial effects: 1. This invention achieves excellent taste masking effect and high palatability. By transforming pregelatinized starch from a traditional filler into a functional taste masking agent, this invention effectively blocks direct contact between bitter drugs and taste buds on the tongue, especially for poorly soluble drugs with extremely bitter taste such as lemetmovir, resulting in a significant improvement in taste masking score.

[0020] 2. This invention achieves a balance between taste masking and rapid dissolution. Conventional taste masking techniques (such as polymer coating) often lead to delayed drug dissolution, while the dissolution profile of the composition of this invention highly overlaps with that of the original formulation (such as Prumin tablets), with a cumulative dissolution rate of over 80% within 15 minutes. While ensuring no taste leakage in the oral cavity, it does not affect the release and absorption of the drug in the body, reducing the risk of bioequivalence.

[0021] 3. This invention features a simple process, low production cost, and easy scale-up. Compared to expensive ion exchange resins, cyclodextrin inclusion, or complex microparticle coating technologies, this method offers significant industrial advantages. Pregelatinized starch is a commonly used and inexpensive excipient in the pharmaceutical field, significantly reducing the overall cost of formulations. Furthermore, this invention employs a suspension-drying-pulverizing process, eliminating the need for complex equipment and temperature control systems. The simple preparation process not only reduces equipment investment but also minimizes batch-to-batch variations during production.

[0022] 4. The pharmaceutical preparations prepared by this invention exhibit excellent stability and safety. After prolonged exposure to high temperature and strong light, the taste-masking composition of this invention shows minimal increase in related substances, maintains stable content, and exhibits no change in taste (Table 6). Pregelatinized starch has a good safety record in pediatric medications, with no specific intake limit, and demonstrates higher clinical safety compared to some synthetic polymer coating materials.

[0023] 5. This invention is highly targeted, significantly improving medication adherence in pediatric or geriatric patients with swallowing difficulties. Experiments have demonstrated that this technology is particularly effective for poorly soluble, bitter-tasting medications, precisely addressing the current pain point of poor medication adherence in pediatric and geriatric clinics. By improving the taste, it reduces refusal to take the medication and vomiting, ensuring accurate dosage and thus guaranteeing clinical treatment efficacy. Attached Figure Description

[0024] Figure 1 Dissolution curve of the sample in pH 4.5 + 0.6% Tween 80 solution medium. Detailed Implementation

[0025] The present invention will be further illustrated by specific embodiments below, but is not intended to limit the scope of protection of the present invention.

[0026] Examples 1-5 describe the preparation of dry suspensions of different bitter-tasting drugs using pregelatinized starch. Examples 1, 6, and 7 describe the preparation of dry suspensions of letermovir using different amounts of pregelatinized starch. Example 8 describes the preparation of a taste-masking layer without the addition of any external materials to fully evaluate the taste-masking effect of pregelatinized starch.

[0027] 1. The flavor-masking composition is prepared into a dry suspension.

[0028] Preparation method: (1) Add the pregelatinized starch to a 20% volume fraction of ethanol aqueous solution at a mass ratio of 1:25 and stir until homogeneous; (2) Add the active pharmaceutical ingredient to (1) and use a high-speed disperser (XHF-DY) or intelligent planetary ball mill (ZQM-P2) to uniformly disperse and mix it into a suspension; (3) Drying is carried out under normal or reduced pressure using rotary evaporator (RE-3000B), fluidized bed (LBL-1), spray dryer (BILON-1000), etc. The drying temperature is set to 60℃. After drying into a solid, it is crushed and passed through a 65-mesh sieve. (4) Weigh the remaining mannitol, sodium bicarbonate, xanthan gum, sucralose, steviol glycosides, and orange flavoring, and mix them evenly with the granules in (3). After mixing, package them as a suspension. This step is not included in Example 8.

[0029] 2. The taste-masking composition is prepared into a suspension.

[0030] Preparation method: (1) Add the pregelatinized starch to a 20% volume fraction of ethanol aqueous solution at a mass ratio of 1:25 and stir until homogeneous; (2) Add the active pharmaceutical ingredient to (1) and use a high-speed disperser (XHF-DY) or intelligent planetary ball mill (ZQM-P2) to uniformly disperse and mix it into a suspension; (3) Drying is carried out under normal or reduced pressure using rotary evaporator (RE-3000B), fluidized bed (LBL-1), spray dryer (BILON-1000), etc. The drying temperature is set to 60℃. After drying into a solid, it is crushed and passed through a 65-mesh sieve. (4) Xanthan gum was swollen with a small amount of purified water. Mannitol, sodium bicarbonate, sucralose, steviol glycosides and orange flavoring were dissolved in an appropriate amount of water and then mixed with (3) particles and xanthan gum solution. The remaining purified water was added and stirred to prepare a suspension.

[0031] 3. Preparation of Letermovir dry suspension using the direct mixing method

[0032] Preparation method: Weigh and mix pregelatinized starch, lemetmovir, mannitol, xanthan gum, sodium bicarbonate, sucralose, steviol glycosides, and orange flavoring. After mixing, package the mixture as lemetmovir dry suspension.

[0033] 4. Preparation of Letermovir dry suspension using wet granulation

[0034] Preparation method: (1) Weigh pregelatinized starch, levamovir, mannitol, xanthan gum, sodium bicarbonate, sucralose, steviol glycosides and orange flavoring and mix them in a wet granulator for 3 minutes at a stirring speed of 150 rpm and a cutting speed of 500 rpm. (2) Add purified water to a wet granulator for granulation. The stirring speed is 200 rpm and the cutting speed is 1500 rpm to obtain wet granules. (3) Pass the wet granules through a 20-mesh sieve; (4) Dry the material at an inlet air temperature of 60℃ and an inlet air volume of 30Hz until the moisture content is ≤3.0%; (5) After drying, the granules are passed through a 0.8 mm sieve and granulated at a speed of 400 rpm; (6) Add the particles from step (5) to the mixer, add colloidal silica, mix evenly, and package as Letermovir dry suspension after mixing.

[0035] 5. Drug release performance test Dissolution profile determination: paddle method, dissolution medium was 900 ml of pH 4.5 + 0.6% Tween 80 solution, and the rotation speed was 75 rpm.

[0036] The results are shown in Table 5 and Figure 1 As shown.

[0037]

[0038] Examples 1 and 6 were prepared as dry suspensions using pregelatinized starch and the bitter drug letermovir. The ratio of the bitter drug to pregelatinized starch in Example 1 was 1:3, and the ratio in Example 6 was 1:5. Comparative Examples 1 and 2 had the same formulations as Example 1, but were processed using direct mixing and wet granulation, respectively.

[0039] The results showed that the samples of Example 1, Example 6, Comparative Example 1, and Comparative Example 2 exhibited similar dissolution behavior to the original Letermovir tablets under the same dissolution conditions.

[0040] 6. Stability test The stability of the sample from Example 1 was investigated by placing it under high temperature conditions for 30 days. The results are shown in Table 6.

[0041] Stability results showed that the sample in Example 1 was stable in quality under high temperature, light, and high humidity conditions, and its taste did not change significantly.

[0042] 7. Taste test Letermovir oral suspensions prepared in Examples 1-8 and Comparative Examples 1-2 were added to warm water at approximately 37°C, shaken to suspend, and then subjected to taste tests together with samples from Examples 9 and 10. Fifteen testers were selected for each sample to evaluate the taste using one of the following four options: 1) sweet and good taste; 2) sweet and average taste; 3) sweet with a slight bitterness; 4) slightly sweet and somewhat bitter. The results are shown in Table 7.

[0043]

[0044] Comparison of taste of flavor-masking compositions prepared by different methods: Compared with the sample of Example 1, the sample of Comparative Example 1 was prepared by directly mixing bitter drugs and excipients, resulting in a more bitter taste that could not mask the bitterness. Comparative Example 2, prepared using a wet granulation process, also failed to mask the bitterness of letemovir. This indicates that the preparation method of the present invention is feasible.

[0045] Comparison of taste results of masking compositions for different bitter drugs: Examples 2-5 are masking compositions for different bitter drugs. The main difference lies in the different water solubility of the selected bitter drugs. Compared with Examples 2-4, the bitter drug in Example 5 has better water solubility, so the masking effect of pregelatinized starch is limited, the bitterness is obvious, and the taste is poor. This indicates that the present invention is more suitable for poorly soluble bitter drugs.

[0046] Comparison of taste profiles of flavor-masking compositions with different proportions of pregelatinized starch: In Example 1, the ratio of bitter agent to pregelatinized starch was 1:3; in Example 6, the ratio was 1:5; and in Example 7, the ratio was 1:2. Example 6 had a higher proportion of pregelatinized starch than Example 1, resulting in a slightly gritty texture, but the taste was still acceptable. Example 7 had a lower proportion of pregelatinized starch than Example 1, resulting in a slightly less sweet taste, but the taste was still acceptable.

[0047] The masking effect of pregelatinized starch alone: ​​In Example 8, no external materials were added, and only a masking layer was prepared to fully evaluate the masking effect of pregelatinized starch. The results showed that pregelatinized starch alone could still significantly mask the bitterness of letemovir, further illustrating that pregelatinized starch plays the main masking role in this invention, while sweeteners and flavoring agents play an auxiliary role.

Claims

1. A flavor-masking composition, characterized in that, The composition comprises a pharmaceutically active ingredient and pregelatinized starch.

2. The flavor-masking composition as claimed in claim 1, characterized in that, The mass ratio of the active pharmaceutical ingredient to the pregelatinized starch is 1:2 to 1:

5.

3. The flavor-masking composition according to claim 1 or 2, characterized in that, The masking composition is prepared by suspending the pharmaceutical active ingredient with the pregelatinized starch in a solvent and then drying it.

4. The flavor-masking composition according to any one of claims 1-3, characterized in that, The active pharmaceutical ingredient is a poorly soluble bitter drug; preferably, the active pharmaceutical ingredient is selected from one or more of letermovir, azithromycin, utpatinib, and roxithromycin.

5. The flavor-masking composition according to any one of claims 1-4, characterized in that, By mass percentage, it includes the following components: Active pharmaceutical ingredient: 1%~15%; Pregelatinized starch: 2%~50%; Filler: 5%~60%; Suspension agent: 0.1%~5%.

6. The flavor-masking composition according to claim 5, characterized in that, The filler is selected from one or more of mannitol, sorbitol, lactose, and xylitol; the suspending agent is selected from one or more of xanthan gum, guar gum, gum arabic, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, and dispersible cellulose.

7. The flavor-masking composition according to claim 5, characterized in that, The product, by weight percentage, also includes sweeteners: 0.1% to 10%; flavoring agents: 0.1% to 5%; the sweeteners are one or more of sucralose, steviol glycosides, sucrose, and aspartame; the flavoring agents are one or more of orange flavoring, strawberry flavoring, peppermint flavoring, and banana flavoring.

8. The flavor-masking composition according to any one of claims 1-7, characterized in that, The dosage form of the composition is a dry suspension, a suspension liquid, a dispersible tablet, an orally disintegrating tablet, or a powder, etc.

9. A method for preparing the flavor-masking composition according to any one of claims 1-8, characterized in that, Includes the following steps: (1) Add the pregelatinized starch to the matrix solvent and stir until homogeneous; (2) Add the active pharmaceutical ingredient, stir and mix, grind and disperse or homogenize to form a suspension; (3) Dry the suspension to form a solid, then pulverize it; (4) Mix the product obtained in step (3) with other excipients and / or formulation solvents until homogeneous.

10. The preparation method according to claim 9, characterized in that, The matrix solvent in step (1) is water and an organic solvent. The organic solvent includes at least one of ethanol, acetonitrile, acetone, 2-propanol and dimethylacetamide. The volume concentration of the organic solvent in the solvent is not higher than 40%. Preferably, it is an aqueous ethanol solution with a volume concentration of 1 to 30%.

11. The preparation method according to claim 9, characterized in that, The drying method in step (3) is selected from rotary evaporation drying, fluidized bed drying or spray drying; the drying temperature is 40℃~70℃, preferably 50℃~60℃.

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