Low-tablet-weight dexibuprofen chewable tablet
By using specific excipient combinations in dextroibuprofen chewable tablets, the pharmacologically acceptable problems of flavour masking and hydration under tablet weight are solved, and the preparation of high drug loading and good taste is achieved, and industrial production is improved feasibility.
Patent Information
- Application Number
- CN202311041547.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-08-18
- Publication Date
- 2025-02-21
AI Technical Summary
The prior art is difficult to effectively mask the taste and solve the problem of melting the dextroibuprofen chewable tablets under a pharmacologically acceptable tablet weight, resulting in difficulties in industrial production.
By using specific combinations of excipients, including high melting point crystalline diluents and polymer inert excipients, in the preparation of dextroibuprofen chewable tablets, the powdery properties of the material are changed, and the weight of the unit preparation tablet is reduced, and Avoid fusion and melting.
The preparation of dextroibuprofen chewable tablets with high loading doses at low tablet weights is achieved, which avoids the problem of fusion, improves the patient's medication compliance, and ensures a good taste.
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Abstract
Description
Technical Field
[0001] The present application relates to the field of pharmaceutical preparations, and in particular to pharmaceutical preparations of dexibuprofen chewable tablets and a preparation process thereof. Background Art
[0002] Among oral preparations, chewable tablets are chewed and swallowed without any disintegration process. The surface area increases after chewing, which promotes the dissolution and absorption of the drug in the body. They are more convenient to take and take effect more quickly. They are one of the dosage forms with better patient compliance.
[0003] Dexibuprofen is a highly effective antipyretic and analgesic drug. It is a good clinical wish to prepare it into chewable tablets. However, the dexibuprofen raw material has a strong spicy and bitter taste. If the taste is not properly masked, it is very likely to cause physiological and psychological discomfort to the patient when chewing, resulting in a decrease in the compliance of patients, especially children, in taking the medicine.
[0004] Existing technologies attempt to correct the taste of drugs by adding sweeteners, aromatics and other flavor correctors to drugs; or by using ion exchange resins, cyclodextrins and other inclusion complexes to form a molecular barrier around the active drug ingredients to prevent the active drug ingredients from binding to taste receptors, so as to mask the taste of drugs at the molecular level; or by coating the active drug ingredients or the surface of the preparation to form a physical barrier to isolate the active drug ingredients from the taste receptors; or by using large particle size raw materials to reduce the surface area of the material, thereby reducing its dissolution rate, and ultimately achieve the effect of masking the taste. However, dexibuprofen has another more difficult problem to overcome in terms of pharmaceutical preparations, that is, the melting point is very low, only 49 to 53 ° C, which is very easy to cause melting. Even though the existing technologies have tried to solve the taste problem of APIs from different aspects, the results of these existing methods are either that the unit dosage form tablet weight is too large, which is not easy to take and has poor compliance; or that the tablet weight is appropriate but the tablet surface melts, which results in the need to shut down the machine in less than 10 minutes during the large-scale continuous production of tablets. Otherwise, the heat generated by the melting pressure softens the low-melting-point dextrorotatory ibuprofen raw material, causing the surface in contact with the punch to melt, making it impossible to continuously produce dextrorotatory ibuprofen chewable tablets that are acceptable in terms of pharmaceutics. It is precisely because of the practical difficulties that no industrially produced dextrorotatory ibuprofen chewable tablets are currently on the market.
[0005] Therefore, how to effectively mask the taste of dexibuprofen while solving the dissolution problem during the preparation of dexibuprofen at a pharmaceutically acceptable tablet weight and achieve a multi-directional balance is the focus of industrial production of dexibuprofen chewable tablets and a long-standing problem that has plagued peers.
[0006] For low-melting point drugs, in order to control the occurrence of melting phenomenon, some methods in the preparation process will reduce adhesion by controlling the moisture content of the material, controlling the particle size, selecting the thickness of the die coating, or controlling the ambient humidity. However, industrial production is still very difficult. It can be said that for low-melting point drugs, each has its own particularity. Although adjusting the production equipment and production methods has a certain universality and can be moderately improved, the prescription process is the fundamental solution to the problem.
[0007] The present invention starts with the selection of formulation excipients and seeks a balance between taste masking and melting or between taste masking and reducing the tablet weight to a pharmaceutically acceptable level, thereby preparing a low-weight dexibuprofen chewable tablet with a suitable taste and no melting phenomenon on the tablet surface. Summary of the invention
[0008] Although the melting problem caused by the low melting point of the active ingredient can be improved by increasing the amount of excipients, it still cannot be fundamentally solved. For example, if the tablet is 200 mg, adding at least 3 times the dose of the main drug component (that is, the tablet weight needs to be as high as 800 mg, of which the main drug component accounts for only 25%) can get some improvement, but it cannot be fundamentally solved, and this will lead to the tablet size being too large. Ordinary technicians in this field generally believe that a tablet weight greater than 800 mg will seriously affect the patient's compliance with medication. The invention provides a dexibuprofen chewable tablet preparation composition. The composition is used to prepare tablets under a drug powder direct compression process. The powder properties of the material are changed by combining specific excipients. The tablets prepared by the excipient composition can greatly reduce the unit preparation tablet weight of the active ingredient at the same dose, improve patient compliance, and completely avoid the problem of tabletting melt (the raw material has a low melting point, and the tablet raw material will soften due to compression heat generated by continuous production during the tabletting process, causing the surface contacting the punch to melt, resulting in a rough and uneven tablet surface or a dent, and a phenomenon of mottling, which is called melt). Not only can a high drug loading of 50% be achieved, but also the taste is good.
[0009] The present invention provides a unit preparation of dexibuprofen chewable tablet preparation composition, wherein the content of dexibuprofen in the composition is 20-55%, the content of flavoring agent is 0.1-6%, the content of excipient is 44-75%, and the tablet weight does not exceed 700 mg.
[0010] Furthermore, the flavoring agent includes sweeteners, acidulants and flavors. The sweeteners include any one or more combinations of aspartame, sucralose, saccharin sodium, sodium cyclamate (sodium cyclamate) and steviol glycosides; the acidulants include pharmaceutically acceptable acid adjuvants such as anhydrous citric acid and citric acid; the flavors include any one or more combinations of lemon flavor, orange flavor, lychee flavor, cherry flavor, strawberry flavor, mint flavor, vanilla flavor and cranberry flavor.
[0011] Further, the excipient used in the dextrorotatory ibuprofen chewable tablet preparation composition of the present invention is a high melting point crystalline diluent and a polymer inert excipient compounded with the high melting point crystalline diluent, wherein the crystalline diluent is selected from sugar alcohols, including but not limited to any one or more of mannitol, sorbitol, erythritol, maltitol and lactose, and the polymer inert excipient includes but is not limited to any one or more of microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl cellulose. The high melting point crystalline diluent accounts for 30-65% (W / W) in the prescription, preferably 35-55% (W / W), and the polymer inert excipient compounded with the crystalline diluent accounts for 5-25% (W / W) in the prescription, preferably 10-20% (W / W).
[0012] Furthermore, the dexibuprofen chewable tablet preparation composition of the present invention may further contain other pharmaceutically acceptable excipients such as a glidant, a colorant, and / or a flavor.
[0013] Furthermore, the glidant includes but is not limited to one or more of silicon dioxide, talc, and magnesium stearate.
[0014] In a specific embodiment of the present invention, 200 mg is used as a fixed dose, and different specifications of dexibuprofen chewable tablets of the present invention can be obtained by increasing or decreasing the ratio of dexibuprofen to excipients in equal proportion, but the unit preparation tablet weight does not exceed 700 mg, and the dexibuprofen content is between 20-55%.
[0015] The content of dexibuprofen in the dexibuprofen chewable tablet preparation composition of the unit dosage form of the present invention is selected from 50-300 mg, preferably 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg or 300 mg. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 Schematic diagram of effect evaluation criteria Specific research content
[0017] The present invention will be further described below through specific implementation examples.
[0018] 1. Evaluation criteria
[0019] 1. Melting degree classification standard
[0020] Mild: Melting occurs, spots appear on the surface of the preparation, and the spots are scattered, with an area of ≤10%;
[0021] Moderate: Melting occurs, large areas of the preparation are spotted, 10% of the preparation surface area ≤ spot area ≤ 30% of the preparation surface area, and there are dents;
[0022] Severe: Melting occurs, large areas of the preparation are spotted, 30% of the preparation surface area is less than the spot area and there are dents, and tablet compression is extremely difficult.
[0023] 2. Taste evaluation criteria
[0024] Twenty oral health subjects who can accurately evaluate sour, sweet, bitter, spicy and salty and can clearly describe their feelings were selected and divided into two groups at a ratio of 1:1. The preparations were numbered in sequence. The evaluation was carried out by cross-mouth tasting. Each person took one tablet (unit preparation) each time, put it in the mouth, chewed it for 10 seconds, and then spit it out. The expression scale was immediately marked and scored. The chewing experience (ease of chewing, whether there is a sense of gravel, taste) ranged from difficult to accept (≤40) - difficult to accept (40 < taste ≤60) - acceptable (60 < taste ≤80) - easy to accept (80 < taste ≤100), with scores ranging from 0 to 100. The higher the score, the better the chewing experience, and the score is 1.
[0025] After each test drug is tasted, it is necessary to rinse the mouth with water. After 30 minutes of oral washing, the next test drug is tested. The results are completed in sequence. Finally, the average value of each group is calculated (data processing: rounding, integer), and compared. The comparison effect standard is as follows: Figure 1 Evaluate as shown.
[0027] 3. Comprehensive evaluation criteria for preparations
[0028] * The comprehensive evaluation score of the preparation is set from 1 to 5 according to the degree of melting and the taste after masking. The higher the score, the better the preparation form and taste. No melting and taste ≥ 2 points are qualified. The specific scoring criteria are as follows:
[0029] Comprehensive evaluation score of preparation = melting score + taste score
[0030] Melting score: 0 points for melting and 2 points for no melting
[0031] Taste rating:
[0032] 0 points: Spicy taste, slightly bitter, irritating to the throat, with a noticeable gritty feeling when chewing, difficult to accept (expression caliper score ≤ 40)
[0033] 1 point: slightly bitter, spicy, irritating to the throat, gritty when chewed, not easily accepted (40 < expression caliper score ≤ 60)
[0034] 2 points: slightly bitter, slightly spicy, slightly irritating to the throat, slightly gritty when chewed, but acceptable (60 < expression caliper score ≤ 80)
[0035] 3 points: The taste is not bitter, the spiciness is not easy to feel without deliberate reminders, no irritation to the throat, no gritty feeling when chewing, easy to accept (80 < expression caliper score ≤ 100)
[0036] (II) Example 1: Effect of Crystallization Diluent on Melting
[0037] Sample preparation:
[0038] Dextrorotatory ibuprofen: crystalline diluent = 1:2, wherein the crystalline diluent is selected from mannitol, sorbitol, lactitol, erythritol, xylitol, maltitol, powdered sugar, lactose (α-hydrated lactose) and glucose. A conventional direct compression tableting process is adopted, the raw materials are sieved through a 100-mesh sieve, the auxiliary materials are sieved through a 60-mesh sieve, the materials are evenly mixed, and the powder is directly compressed into tablets.
[0039] Table 1 Analysis of the effects of different crystal diluents on melting
[0040]
[0041] As can be seen from Table 1, the crystalline diluents that are relatively good at improving the dissolution effect are mannitol, sorbitol, erythritol, maltitol and lactose (α-hydrous lactose). These sugar alcohols have a melting point greater than 110°C and stable physical properties (do not decompose and are not easy to absorb moisture).
[0042] (III) Example 2: Effect of different crystalline diluents and multiple polymer inert excipients on the mixing and melting
[0043] Since a single diluent cannot improve the melting problem well, and considering that the compression state of the tablet is closely related to the plasticity, elasticity and microscopic morphology of the raw materials and excipients, we try to use high-molecular inert excipients with different densities and different microstructures, hoping to solve the melting problem by changing the powder properties of the material. Since the types of glidants and lubricants are relatively single, and the proportion of functional excipients such as color lakes and flavors is extremely low (for example, the combined proportion is less than 6%), it is not enough to change the physical properties of the diluent, so it is not considered when studying the factors affecting the melting problem.
[0044] Sample preparation:
[0045] Dexibuprofen 200 mg, the content of crystalline diluent in the prescription is 225 mg, and the content of high molecular weight inert excipient in the prescription is 75 mg. The conventional direct compression tablet process is also adopted, the raw materials are passed through a 100 mesh sieve, the excipients are all passed through a 60 mesh sieve, the materials are mixed evenly by equal amount stepwise addition method, and the powder is directly compressed into tablets.
[0046] When we further studied the effects of the combination of crystalline diluents and polymer excipients on the dissolution and melting, we were surprised to find that the inert excipients conventionally defined in pharmaceutical pharmaceutics are not "inert" at all, but seriously affect the physical properties of the entire mixed material.
[0047] When specific crystalline sugar alcohols are used in combination with specific polymer excipients, and when the proportion of crystalline diluent sugar alcohols in the prescription is 30-65% (W / W), and the polymer excipients compounded with them account for 10-25% (W / W) in the prescription, the eutectic point of the mixed material will be significantly improved, at least 15 degrees higher than the melting point of the dexibuprofen material, thereby having a certain resistance to the instantaneous high heat generated during the tableting process, which not only solves the process melting problem of dexibuprofen chewable tablets, but also can well balance the taste and solve the problem of low tablet weight and high drug loading. See Table 2 for details.
[0048] Table 2 Analysis of the effect of different crystalline diluents and polymer inert excipients on the impact of the melt
[0049]
[0050] It can be seen from the experiments in the above table that when solving the melting problem existing in the mass production of dextrorotatory ibuprofen chewable tablets, the combination of crystalline diluents such as mannitol, sorbitol, erythritol, maltitol and lactose with specific high molecular weight inert excipients such as ordinary microcrystalline cellulose, microcrystalline cellulose 101, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl cellulose can solve the melting problem well, and the preparation can also have a taste masking effect at a low tablet weight, ensuring an acceptable taste (taste score ≥ 2).
[0051] The present invention will be better described below with a complete formulation process and specific examples.
[0052] Example 3: Preparation of Dexibuprofen Chewable Tablets
[0053] The conventional direct compression tablet process is adopted, the raw materials are passed through a 100-mesh sieve, the auxiliary materials are passed through a 60-80 mesh sieve, the materials are mixed evenly, and the powder is directly compressed into tablets.
[0054]
[0055]
[0056] It can be seen that when a specific crystalline diluent is added to a dextrorotatory ibuprofen chewable tablet preparation and a specific polymer inert excipient is compounded, the occurrence of melt in the dextrorotatory ibuprofen chewable tablet preparation can be significantly reduced within a low tablet weight range, and the taste can be well masked. This discovery has well solved the melt problem of dextrorotatory ibuprofen chewable tablets in large-scale production. The addition of more excipients dilutes the bitter and astringent taste of dextrorotatory ibuprofen, making it more acceptable. However, larger tablets (>700 mg) are not easy to swallow and cannot meet the two coexisting modes of chewing and swallowing of chewable tablets. Not only is patient compliance poor, but there is also a risk of jamming when taking.
Claims
1. A unit dosage form of dexibuprofen chewable tablet preparation composition, wherein the content of dexibuprofen in the composition is 20-55%, the content of the flavoring agent is 0.1-6%, the content of the excipient is 44-75%. , and the tablet weight does not exceed 700 mg.
2. The unit dosage form of dexibuprofen chewable tablet preparation composition according to claim 1, characterized in that: The flavoring agent includes any one or more combinations of aspartame, sucralose, saccharin sodium, sodium cyclamate (sodium cyclamate) and steviol glycoside.
3. The unit dosage form of dexibuprofen chewable tablet preparation composition according to claim 1, characterized in that: The excipients are a high melting point crystalline diluent and a high molecular weight inert auxiliary material compounded with the high melting point crystalline diluent, wherein the crystalline diluent is selected from any one or more of mannitol, sorbitol, erythritol, maltitol and lactose, and the high molecular weight inert auxiliary material is selected from any one or more of microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl cellulose.
4. The unit dosage form of dexibuprofen chewable tablet preparation composition according to claim 3, characterized in that: The high melting point crystalline diluent accounts for 30-65% (W / W) in the prescription, and the high molecular weight inert auxiliary material compounded with the crystalline diluent accounts for 5-25% (W / W) in the prescription.
5. The unit dosage form of dexibuprofen chewable tablet preparation composition according to claim 4, characterized in that: The high melting point crystalline diluent accounts for 35-55% (W / W) in the prescription, and the high molecular weight inert auxiliary material compounded with the crystalline diluent accounts for 10-20% (W / W) in the prescription.
6. The unit dosage form of dexibuprofen chewable tablet preparation composition according to claim 1, characterized in that: The dexibuprofen chewable tablet preparation composition may further contain a glidant, a colorant, and / or flavors and other pharmaceutically acceptable excipients.
7. The unit dosage form of dexibuprofen chewable tablet preparation composition according to claim 1, characterized in that: The glidant is selected from one or more of silicon dioxide, talc and magnesium stearate.
8. The unit dosage form of dexibuprofen chewable tablet preparation composition according to claim 1, characterized in that: The flavor is selected from any one or more combinations of lemon flavor, orange flavor, lychee flavor, cherry flavor, strawberry flavor, mint flavor, vanilla flavor and cranberry flavor.
9. The unit dosage form of dexibuprofen chewable tablet preparation composition according to claim 1, characterized in that: The content of dexibuprofen in the dexibuprofen chewable tablet preparation composition of the unit preparation is 50-300 mg.
10. The unit dosage form of dexibuprofen chewable tablet preparation composition according to claim 8, characterized in that: The content of dexibuprofen in the dexibuprofen chewable tablet preparation composition of the unit dosage form is 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg or 300 mg.