Oseltamivir phosphate taste masking preparation and preparation method thereof

Abstract

The invention belongs to the field of medicine, and relates to an oseltamivir phosphate taste-masking preparation and a preparation method thereof.The oseltamivir phosphate taste-masking preparation comprises a drug-loading pill, an isolation layer and a taste-masking layer, the drug-loading pill comprises oseltamivir phosphate and a blank pill core, the blank pellet core is selected from one of a sucrose pellet core, a microcrystalline cellulose pellet core, a starch pellet core, a lactose pellet core and a silicon dioxide pellet core; the isolation layer comprises an isolation material, the taste masking layer comprises a taste masking component, and the taste masking component is one or more of a methacrylic acid amine alkyl ester copolymer and polyacrylic resin IV. The taste of the active ingredients of the medicine is masked through a multi-layer coating technology, the taking taste is improved, the active ingredients of the medicine are endowed with good stability, the medicine can be rapidly released, meanwhile, the good taste is achieved, the taste masking effect is good, and meanwhile the stability of the medicine is guaranteed.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to an oseltamivir phosphate taste-masking preparation and a preparation method thereof. Background Art

[0002] As an antiviral drug, oseltamivir phosphate plays a key role in the treatment and prevention of influenza A and B. Its unique mechanism of action is to inhibit the neuraminidase activity of influenza virus, prevent the release of the virus in infected cells, and thus effectively reduce the spread of the virus in the body. This mechanism of action makes oseltamivir phosphate one of the first choice drugs for influenza treatment.

[0003] The oseltamivir phosphate preparations that have been listed include capsules, granules, and dry suspensions, etc., but these dosage forms are inconvenient to take or have obvious bitterness for children. Since oseltamivir phosphate has a very strong bitter taste, it is currently not possible to make satisfactory granules that are easy to absorb and suitable for children to take. In the prior art, in order to achieve the taste masking effect, a large amount of flavoring agents, sweeteners, etc. are added to hide the peculiar smell of the drug itself, which not only cannot completely cover the peculiar smell of the drug, but also the encapsulation rate of the peculiar smell and bitterness of the drug is insufficient. After taking, a significant taste will remain in the oral cavity, which makes the patient feel bored after taking it, and for granules, the sugar content is too high, which is easy to absorb moisture and agglomerate, resulting in reduced drug efficacy, and it cannot be stored for a long time, and loses its practical application value. Therefore, for oseltamivir phosphate, taste masking is a technical problem that needs to be broken through in order to support preparations that are easy to take for children.

[0004] In order to solve the bitter taste problem of oseltamivir phosphate, researchers have tried some taste-masking technologies. For example, the bitter taste of the drug can be masked by adding sweeteners, spices and other excipients; or by changing the dosage form of the drug, such as making it into capsules, tablets and other forms to reduce direct contact with the bitter taste, but this will also bring some new problems. For example, although the capsule dosage form can mask the bitter taste, for children, they may not be able to swallow the capsule correctly; and the tablet form may be too hard to chew or swallow. These problems may cause patients to have difficulty taking medication or resist taking medication.

[0005] Currently, oseltamivir phosphate products on the market generally have problems such as poor taste and poor taste-masking technology, which limit their application scope and efficacy. Therefore, it is of great significance to develop an oseltamivir phosphate taste-masking preparation that is easy to swallow, has a good taste and is highly stable. Summary of the invention

[0006] The present invention provides an oseltamivir phosphate taste-masking preparation that is easy to swallow and a preparation method thereof, mainly solving the problems that existing oseltamivir phosphate products on the market immediately produce an unpleasant bitter taste after being taken by children, the taste during taking is extremely poor, the compliance of children taking the medicine is poor, and it is inconvenient to take the medicine. Through the multi-layer coating technology, the taste of the drug active ingredient is masked, the taste during taking is improved, and good stability is imparted to the drug active ingredient, so that the drug can be rapidly released while having a good taste and a good taste-masking effect while ensuring the stability of the drug. Thus, the compliance of drug use is effectively improved, the applicable population of patients is increased, and it is especially beneficial for pediatric administration.

[0007] The technical solution provided by the present invention is as follows:

[0008] An oseltamivir phosphate taste-masking preparation, the preparation comprising a drug-loaded pill, a barrier layer, and a taste-masking layer. The drug-loaded pill comprises oseltamivir phosphate and a blank pill core, and the blank pill core is selected from one of a sucrose pill core, a microcrystalline cellulose pill core, a starch pill core, a lactose pill core, and a silica pill core; the barrier layer comprises a barrier material, and the barrier material is selected from one or more of methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, and sodium carboxymethylcellulose; the taste-masking layer comprises a taste-masking component, and the taste-masking component is one or more of an alkyl methacrylate copolymer and polyacrylic resin IV.

[0009] Furthermore, the oseltamivir phosphate taste-masking preparation further comprises a flavoring material, and the flavoring material comprises sorbitol, a mixed fruit flavor essence, and sodium carboxymethylcellulose.

[0010] Furthermore, the mass ratio of oseltamivir phosphate to the blank pill core in the drug-loaded pill is 1:1 to 20.

[0011] Furthermore, the mass percentage of the barrier material in the barrier layer is 20% to 80%.

[0012] Furthermore, the mass percentage of the taste-masking component in the taste-masking layer is 30% to 90%.

[0013] Furthermore, the mass ratio of the drug-loaded pill to the taste-masking layer is 1:1 to 10.

[0014] The present invention also provides a method for preparing the above-mentioned oseltamivir phosphate taste-masking preparation, and the preparation method includes the following steps: formulating oseltamivir phosphate and drug-carrying pill excipients into a suspension solution, using blank pill cores as drug-carrying base pills, and preparing drug-carrying pills by means of fluidized bed spraying; dissolving or dispersing the isolating material and isolating layer excipients in water to formulate an isolating coat solution, and coating the drug-carrying pills with the isolating coat solution by means of fluidized bed coating technology, and drying after the coating is completed to obtain isolating coat pills; dissolving or dispersing the taste-masking components and taste-masking layer excipients in water to formulate a suspension solution, and coating and drying the above-mentioned isolating coat pills by means of fluidized bed coating technology to obtain the oseltamivir phosphate taste-masking preparation.

[0015] Further, the drug-carrying pill excipients include one or more of polyvinylpyrrolidone K30, talcum powder, and polyethylene glycol 6000.

[0016] Further, the isolating layer excipients include one or more of polyethylene glycol 6000, hydroxypropyl cellulose, and talcum powder.

[0017] Further, the taste-masking layer excipients include one or more of sodium lauryl sulfate, stearic acid, talcum powder, and methacrylic acid amine alkyl ester copolymer.

[0018] Beneficial effects

[0019] The present invention provides an oseltamivir phosphate taste-masking preparation that is easy to swallow and a preparation method thereof, mainly solving the problems of existing oseltamivir phosphate products on the market that immediately produce an unpleasant bitter taste after being taken by children, with extremely poor taste during taking, poor compliance of children in taking medicine, and inconvenient medicine taking. The present invention for the first time masks the taste of oseltamivir phosphate through a multi-layer coating technology, improves the taste during taking, and gives good stability to the active ingredient of the drug, enabling the drug to be rapidly released while having a good taste, meeting the requirement of swallowing without water, having a good taste-masking effect while ensuring the stability of the drug. Thus, it effectively improves the compliance of medication, expands the applicable population of patients, and is especially beneficial for pediatric administration. Specific embodiments

[0020] Example 1

[0021] The original excipients and their dosages are as follows:

[0022]

[0023] The preparation method of Example 1 is as follows:

[0024] 1. Preparation of drug-carrying pills

[0025] Dissolve povidone K30 in purified water. While stirring the solution, add oseltamivir phosphate and talc powder in sequence. Stir to form a homogeneous suspension solution. Using microcrystalline cellulose pellets as the drug-loaded base pellets, perform the drug-loading process of the suspension by bottom spraying in a fluidized bed. After the drug-loading is completed, continue to dry the pellets.

[0026] 2. Coating of the isolation layer

[0027] Prepare an aqueous solution of hydroxypropyl cellulose with a concentration of 5%. Add polyethylene glycol 6000 and talc powder, and perform the coating of the isolation layer by a fluidized bed.

[0028] 3. Coating of the taste-masking layer

[0029] Sodium lauryl sulfate, stearic acid, and methacrylic acid amine alkyl ester copolymer are added to water in sequence and dispersed by a stirrer. Then add the prescribed amount of talc powder to the polymer solution and disperse it by a stirrer to make it uniformly mixed to form a homogeneous suspension. Perform the coating of the taste-masking layer by a fluidized bed.

[0030] Evaluation indexes:

[0031] 1. Evaluation of the effect of swallowing without water: After the drug preparation of Example 1 is made into the final product, 10 male volunteers aged 20 - 30 and 10 female volunteers aged 20 - 30 are asked to try swallowing without water. As a result, 95% of the volunteers reported that the saliva secretion volume and secretion speed after the drug preparation of Example 1 entered the oral cavity could meet the requirements for drug swallowing, and the drug-taking could be completed within 1 minute without any bad smell. The remaining 5% of the volunteers, due to individual differences, thought that individual pellets were broken in the oral cavity, resulting in a slight bitter taste in the oral cavity, but it was within an acceptable range. It can be seen that the drug preparation of Example 1 meets the quality requirements in terms of taste masking and swallowing effect.

[0032] 2. The dissolution test results are as follows:

[0033] Dissolution: Take this product and use the apparatus of the second method in the dissolution and release determination method (General Chapter 0931 of the Chinese Pharmacopoeia 2020 Edition). Use 900 mL of hydrochloric acid solution (9→1000) as the dissolution medium, with a rotation speed of 50 revolutions per minute. Operate according to the law. At 30 minutes, take 10 mL of the solution, filter it, and take the subsequent filtrate as the test solution; Take an appropriate amount of oseltamivir phosphate reference substance, accurately weigh it, and prepare a reference substance solution. According to the chromatographic conditions under the content determination item, accurately measure 20 μL of the test solution and the reference substance solution respectively, inject them into the liquid chromatograph, and record the chromatogram. Calculate the dissolution amount per bag by the external standard method based on the peak area, and the limit is 85% of the labeled amount, and it should meet the requirements.

[0034]

[0035] Results description: The pharmaceutical preparation meets the requirements of taste masking and rapid drug release in acid, and also achieves rapid drug release in the stomach, realizing rapid onset of action.

[0036] 3. Stability:

[0037] Method for detecting related substances:

[0038] Determined by high performance liquid chromatography (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition), freshly prepared before use.

[0039] Diluent: Methanol - water (1:1).

[0040] Test solution: Take an appropriate amount of this product (equivalent to about 15 mg of oseltamivir), place it in a 25 mL volumetric flask, add an appropriate amount of methanol, dissolve it by ultrasonic treatment, then dilute to the mark with methanol, shake well, filter, accurately measure 5 mL of the subsequent filtrate and place it in a 10 mL volumetric flask, dilute to the mark with water, and shake well.

[0041] Control solution: Accurately measure 1 mL of the test solution and place it in a 100 mL volumetric flask, dilute to the mark with the diluent, and shake well.

[0042] System suitability solution: Take appropriate amounts of oseltamivir phosphate reference substance, impurity II, impurity III, and impurity IV, accurately weigh them, dissolve and dilute with the diluent to prepare a mixed solution containing about 0.3 mg of oseltamivir, about 0.9 μg of impurity II, and about 1.5 μg of each of impurity III and impurity IV in 1 mL.

[0043] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (Waters Xbridge C8 250 mm × 4.6 mm, 5 μm or a chromatographic column with equivalent efficiency); use 0.05 mol / L potassium dihydrogen phosphate solution (adjust the pH to 6.1 with potassium hydroxide solution) as mobile phase A, and methanol - acetonitrile (22:8) as mobile phase B, and perform gradient elution according to the following table; the column temperature is 35 °C; the detection wavelength is 220 nm; the flow rate is 1.0 mL per minute; the injection volume is 50 μL.

[0044]

[0045] System suitability requirements: In the chromatogram of the system suitability solution, impurity III, impurity II, oseltamivir, and impurity IV elute in sequence, and the resolution between each peak should meet the requirements.

[0046] Determination method: Accurately measure the test solution and the control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0047] Limit: If there are impurity peaks in the test solution, the peak area of impurity II (calculated based on the peak area multiplied by the correction factor of 0.43) shall not be greater than 0.3 times (0.3%) of the peak area of the control solution; the peak areas of impurity III and impurity IV (calculated based on the peak areas multiplied by the correction factors of 1.7 and 1.0 for each impurity respectively) shall not be greater than 0.5 times (0.5%) of the peak area of the control solution; the peak area of any other single unknown impurity shall not be greater than 0.3 times (0.3%) of the peak area of the control solution; the sum of the peak areas of known impurities multiplied by the correction factors and the peak area of unknown impurities shall not be greater than 3 times (3.0%) of the peak area of the control solution; any chromatographic peak in the chromatogram of the test solution that is less than 0.05 times the main peak area of the reference solution can be ignored. The specific results are as follows:

[0048]

[0049] The results show that: under the conditions of 40 °C for 30 days and 60 days, the related substances of Example 1 and Comparative Example 1 both show an increasing trend compared with day 0, but the impurities in both Example 1 and Comparative Example 1 do not exceed the limit, and the increasing amplitude of Example 1 is lower than that of Comparative Example 1. Therefore, the product stability of Example 1 is better than that of Comparative Example 1, and the product of Example 1 has good stability.

[0050] The raw and auxiliary materials and their dosages of Example 2 are as follows:

[0051]

[0052] The preparation method of Example 2 is as follows:

[0053] 1. Preparation of drug-loaded pellets

[0054] Dissolve povidone K30 in purified water. While stirring the solution, add oseltamivir phosphate and talc powder in sequence, and stir to form a uniform suspension solution. Using microcrystalline cellulose pellets as the drug-loaded base pellets, perform the drug-loading process of the suspension by bottom spraying in a fluidized bed. After the drug-loading is completed, continue to dry the pellets.

[0055] 2. Coating of the isolation layer

[0056] Prepare an aqueous solution of hydroxypropyl cellulose with a concentration of 5%, add polyethylene glycol 6000 and talc powder, and perform the coating of the isolation layer by a fluidized bed.

[0057] 3. Coating of the taste-masking layer

[0058] Sodium dodecyl sulfate, stearic acid, and methacrylic acid amine alkyl ester copolymer are added to water in sequence, dispersed with a stirrer, and then the prescribed amount of talc powder is added to the polymer solution, and dispersed with a stirrer to make it uniformly mixed to form a uniform suspension, and perform the coating of the taste-masking layer by a fluidized bed.

[0059] Evaluation index:

[0060] 1. Evaluation of the effect of swallowing without water: After the drug preparation of Example 2 was made into the final product, 10 male volunteers aged 20 - 30 and 10 female volunteers aged 20 - 30 were asked to try swallowing without water. The results showed that 95% of the volunteers reported that the amount and rate of saliva secretion after the drug preparation of Example 2 entered the mouth could meet the requirements for drug swallowing. They could complete taking the medicine within 1 minute without any unpleasant odor. For the remaining 5% of the volunteers, due to individual differences, they thought that the slight bitterness in the mouth was caused by the fragmentation of individual pellets in the mouth, but it was within the acceptable range. It can be seen that the drug preparation of Example 2 meets the quality requirements in terms of taste masking and swallowing effect.

[0061] 2. The dissolution test results are as follows:

[0062] Dissolution: The determination method is the same as that in Example 1.

[0063]

[0064] Results show that: While meeting the requirement of taste masking, the drug preparation achieves rapid drug release in acid and also meets the effect of rapid drug release in the stomach, realizing rapid onset.

[0065] 3. Stability:

[0066] Method for detecting related substances: See Example 1. The specific results are as follows:

[0067]

[0068] Results show that: Under the conditions of 40°C for 30 days and 60 days, the related substances of Example 2 and Comparative Example 2 showed an increasing trend compared with day 0. However, the impurities of both Example 2 and Comparative Example 2 did not exceed the limit, and the increasing amplitude of Example 2 was lower than that of Comparative Example 2. Therefore, the product stability of Example 2 is better than that of Comparative Example 2, and the stability of the product of Example 2 is good.

[0069] In Example 3, to further improve the taste of taking medicine, flavoring materials were mixed in the taste - masking preparation for swallowing without water. The prescription and preparation method of the flavoring materials are as follows. The oseltamivir phosphate taste - masking pellets prepared in Example 1 were mixed with the flavoring materials, and then the effect of swallowing without water, release rate, and stability of the drug preparation were evaluated.

[0070] Prescription of flavoring materials:

[0071]

[0072] Preparation method: Weigh the prescribed amounts of sorbitol, mixed fruit - flavored essence, and sodium carboxymethylcellulose and mix them to form the flavoring materials. After coating the taste - masking layer, the pellets and the flavoring materials were mixed evenly in a mixing tank to obtain the oseltamivir phosphate taste - masking preparation.

[0073] Evaluation indicators:

[0074] 1. Evaluation of the effect of swallowing without water: After the drug preparation of Example 3 was made into the final product, 10 male volunteers aged 20 - 30 and 10 female volunteers aged 20 - 30 were asked to try swallowing without water. The results showed that for 100% of the volunteers, the amount and rate of saliva secretion after the drug entered the mouth could meet the requirements for drug swallowing. The drug-taking could be completed within 2 minutes and the swallowing experience was pleasant. The drug met the quality requirements in terms of taste masking and swallowing effect.

[0075] 2. The dissolution test results are as follows:

[0076] Dissolution: The method is the same as that in Example 1.

[0077]

[0078] Results show that: While meeting the taste masking requirement, the drug preparation achieved rapid drug release in acid, and also met the requirement of rapid drug release in the stomach, realizing rapid onset.

[0079] 3. Stability:

[0080] Method for detecting related substances: See Example 1. The specific results are as follows:

[0081]

[0082] Results indicate that: Under the conditions of 40°C for 30 days and 60 days, the related substances of Example 3 showed an increasing trend compared with day 0, and the impurities did not exceed the limit. There was no obvious difference in the related substances between Example 3 and Example 1, indicating good stability of the preparation of Example 3.

Claims

1. An oseltamivir phosphate taste-masking preparation, characterized in that, The preparation comprises a drug-loaded pill, a separating layer and a taste-masking layer. The drug-loaded pill comprises oseltamivir phosphate and a blank pill core, and the blank pill core is selected from one of sucrose pill cores, microcrystalline cellulose pill cores, starch pill cores, lactose pill cores and silicon dioxide pill cores; the separating layer comprises a separating material, and the separating material is selected from one or more of methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and sodium carboxymethylcellulose; the taste-masking layer comprises a taste-masking component, and the taste-masking component is one or more of an alkyl methacrylate copolymer and polyacrylic resin IV.

2. The oseltamivir phosphate taste-masking preparation according to claim 1, wherein, The oseltamivir phosphate taste-masking preparation further comprises a flavoring material, and the flavoring material comprises sorbitol, a mixed fruit flavor essence and sodium carboxymethylcellulose.

3. The oseltamivir phosphate taste-masking preparation according to claim 1, wherein The mass ratio of oseltamivir phosphate to the blank pill core in the drug-loaded pill is 1:1 to 20.

4. The oseltamivir phosphate taste-masking preparation according to claim 1, characterized in that, The mass percentage of the separating material in the separating layer is 20% to 80%.

5. The oseltamivir phosphate taste-masking preparation according to claim 1, characterized in that, The mass percentage of the taste-masking component in the taste-masking layer is 30% to 90%.

6. The oseltamivir phosphate taste-masking preparation according to claim 1, characterized in that, The mass ratio of the drug-loaded pill to the taste-masking layer is 1:1 to 10.

7. The preparation method of the oseltamivir phosphate taste-masking preparation according to any one of claims 1 to 6, characterized in that, The preparation method comprises the following steps: formulating oseltamivir phosphate and drug-loaded pill excipients into a suspension solution, using the blank pill core as the drug-loading base pill, and preparing the drug-loaded pill by means of a fluidized bed spraying method; dissolving or dispersing the separating material and separating layer excipients in water to formulate a separating coat solution, and coating the drug-loaded pill with the separating coat solution by means of a fluidized bed coating technique, and drying after the coating is completed to obtain a separating coat pill; dissolving or dispersing the taste-masking component and taste-masking layer excipients in water to formulate a suspension solution, and coating and drying the above-mentioned separating coat pill by means of a fluidized bed coating technique to obtain the oseltamivir phosphate taste-masking preparation.

8. The preparation method of the oseltamivir phosphate taste-masking preparation according to claim 7, characterized in that, The drug-loaded pill excipients include one or more of polyvinylpyrrolidone K30, talcum powder and polyethylene glycol 6000.

9. The preparation method of the oseltamivir phosphate taste-masking preparation according to claim 1, characterized in that, The separating layer excipients include one or more of polyethylene glycol 6000, hydroxypropyl cellulose and talcum powder.

10. The preparation method of the oseltamivir phosphate taste-masking preparation according to claim 1, characterized in that, The taste-masking layer excipients include one or more of sodium lauryl sulfate, stearic acid, talcum powder and an alkyl methacrylate copolymer.

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