TWI834984B - Controlled-release oral formulation and preparation method thereof - Google Patents

Abstract

An oral formulation is provided, which includes a first composition and a second composition. The first composition includes a xanthine derivative. The second composition includes a xanthine derivative and an enteric excipient. The xanthine derivative of the second composition releases less than 35% by weight within 90 minutes from in vitrodissolution, and the xanthine derivative of the second composition releases more than 50% by weight within 3 hours from in vitrodissolution. As such, the first composition may be used as an immediate release layer, and the second composition may be used as a delayed release layer to achieve a bilayer controlled-release oral formulation.

Description

Controlled release oral preparation and preparation method thereof

The present invention relates to an oral preparation, and in particular to a controlled release oral preparation and a preparation method thereof.

Caffeine is a xanthine derivative and a bipolar substance soluble in water and lipids. Its chemical structure is very similar to adenosine. Adenosine is the skeleton of adenosine triphosphate (ATP), the body's energy source, and is also a neuromodulator. In addition to reducing wakefulness and alertness, adenosine and adenylate compounds themselves reduce the concentration of stimulating neurotransmitters. Caffeine has a similar structure to adenylate and competes with adenylate for receptors, so caffeine has a refreshing effect. On the other hand, caffeine can reduce the pain in muscles during exercise, thereby achieving the anti-fatigue effect of exercise.

According to reports, approximately 74% of elite athletes use caffeine as a supplement before or during competition, with endurance athletes showing a higher prevalence of use. Possible reasons for the popularity of caffeine are its easy availability, low side effects, and studies showing that certain ergogenic effects can be achieved at low doses (<6 mg/kg).

Generally speaking, the absorption rate of caffeine reaches its highest blood concentration within 30 minutes to 90 minutes after taking it. Therefore, according to the results of most clinical trials, it is recommended that users should take it 30-60 minutes before exercise to obtain the boosting effect of caffeine during competition. For general endurance sports, such as marathon, the average completion time is about 4.5 hours. When caffeine is consumed 30-60 minutes before a game, it will enter a state below the half-life about 3 to 3.5 hours into the game. This is also the high-pressure period or wall-breaking period of the game. Therefore, in order to avoid the fatigue caused by hitting the wall, many users will add low to medium doses of caffeine (~3 mg/kg) in the middle and late stages of the race (with 1 to 2 hours left to finish) for supplementation.

However, endurance exercise requires multiple supplements such as carbohydrate energy gels, electrolytes, amino acids, etc. It is very inconvenient to carry and replenish caffeine during the journey. In addition, a single dose of caffeine on the way still requires about an hour to be absorbed, which is not as good as the sustained-release caffeine supplement that can be provided by the sustained-release dosage form. In addition, for sustained-release caffeine, the technology is to release caffeine through the gradual erosion of polymers in the body, but there is no specific release section in the human gastrointestinal tract. Therefore, it cannot meet the demand for controlled release to reach the preset target within a specific time period after taking it, so as to support the maintenance of high blood caffeine concentration throughout the entire exercise period, thereby enhancing exercise performance.

Based on this, how to effectively control the release of xanthine derivatives to maintain high blood concentrations and meet the need for multiple supplements/refreshers during long-term activities. For example, during endurance sports such as marathons, additional swallows are required to improve performance. Caffeine, or the inconvenience or interference of needing to be distracted while driving long distances to replenish caffeine, is a problem that is currently being addressed.

The present invention provides an oral preparation that can effectively control the release of xanthine derivatives to maintain high blood concentrations, thereby meeting long-term supplementation/refreshing needs. For example, the oral formulation of the present invention can avoid the interference of additionally taking and swallowing caffeine during endurance exercise, and can maintain high caffeine content/high blood concentration during the entire exercise period.

An oral preparation of the present invention includes a first component and a second component. The first component includes xanthine derivatives. The second component includes xanthine derivatives and enteric excipients. The xanthine derivatives in the second component release less than 35% by weight within 90 minutes of dissolution outside the body, and the xanthine derivatives in the second component release more than 50% by weight within 3 hours of dissolution outside the body.

In one embodiment of the present invention, the xanthine derivative in the second component is released from more than 50% to less than 70% by weight within 3 hours of dissolution in vitro.

In one embodiment of the present invention, more than 80% by weight of the xanthine derivative in the first component is released within 1 hour after dissolution in vitro.

In one embodiment of the present invention, the xanthine derivative in the first component is released to 100% by weight within 90 minutes of dissolution outside the body, and the xanthine derivative in the second component is released within 8 to 12 hours outside the body. The release rate reaches more than 90% by weight, and the xanthine derivative in the second component is released by 100% by weight within 12 hours to 18 hours after dissolution in vitro.

In one embodiment of the present invention, the xanthine derivative in the second component is released within 2 hours after dissolution in vitro, and the release rate is less than 40% by weight.

In one embodiment of the present invention, the oral preparation is an oral two-layer tablet, which includes a first layer composed of a first component, and a second layer composed of a second component.

In an embodiment of the present invention, the weight ratio of the first component to the second component is 1:1 to 1:1.2.

In one embodiment of the present invention, the enteric excipient is zein enteric coating.

In an embodiment of the present invention, when the weight proportion of the second component is 100%, the weight proportion of the zein enteric coating is 5.5% to 10% of the second component.

In one embodiment of the present invention, the total weight of the xanthine derivative in the oral preparation is 50 mg to 400 mg.

In an embodiment of the present invention, the weight of the xanthine derivative in the first component is 25 mg to 200 mg.

In one embodiment of the present invention, the weight of the xanthine derivative in the second component is 25 mg to 200 mg.

In an embodiment of the present invention, the first component further includes green tea pigment, polyvinylpyrrolidone, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, magnesium stearate and silicon dioxide, and the green tea pigment includes the yellow tea pigment. Purine derivatives.

In one embodiment of the present invention, the second component further includes green tea pigment, polyvinylpyrrolidone, microcrystalline cellulose, medium chain triglyceride, magnesium stearate, silicon dioxide and film coating 145K290001 (Nutrafinish ® Dietary Supplement Coating 145K290001 Clear (NSC)), and the green tea pigment includes the xanthine derivative.

In one embodiment of the present invention, the oral preparation reaches the highest blood concentration of the xanthine derivative within 90 minutes after taking it.

The preparation method of an oral preparation of the present invention includes: forming the powder of the first component and the powder of the second component into a double-layer tablet.

In an embodiment of the present invention, the preparation of the powder of the second component includes the following steps. A coating solution including enteric excipients is provided. Green tea pigments including xanthine derivatives are provided. The green tea element is sprayed and granulated with a coating solution to coat it to a weight gain ranging from 5% to 15%.

In one embodiment of the present invention, the preparation method further includes: after spray granulation, drying and sieving to form the powder of the second component.

In an embodiment of the present invention, the preparation of the powder of the first component includes the following steps. Green tea pigments including xanthine derivatives are provided. The alcohol aqueous solution of polyvinylpyrrolidone is added to the powder including green tea pigment, and after granulation, it is dried and sieved to form the powder of the first component.

A method of using an oral preparation of the present invention includes: taking the oral preparation within 30 minutes to 60 minutes before endurance exercise, and the dosage of the oral preparation is 3 mg/kg to 6 mg/kg.

Based on the above, by using an oral preparation with a first component and a second component, embodiments of the present invention can quickly release the first component in the early stage after taking it, provide early caffeine supplementation, and control the release of the second component of caffeine in the later stage. . Accordingly, the double-layer controlled release oral preparation of the present invention can effectively control the release of xanthine derivatives (such as caffeine) to maintain high blood concentrations, thereby meeting long-term supplementation/refreshing needs. For example, the oral formulation of the present invention can avoid the interference of additionally taking and swallowing caffeine during endurance exercise, and can maintain high caffeine levels/high blood levels during the entire exercise period through the controlled release of the second component. concentration time. In addition, the oral preparation of the present invention can also avoid the inconvenience or interference of distracting caffeine supplementation during long-distance driving.

Figure 1 is a schematic diagram of an oral preparation according to an embodiment of the present invention. Referring to FIG. 1 , the oral preparation 100 according to the embodiment of the present invention is composed of a first layer 102 composed of a first component, and a second layer 104 composed of a second component. For example, the first layer 102 includes powder 102A of a first component, and the second layer 104 includes powder 104A of a second component. In some embodiments, the preparation method of the oral preparation 100 includes beating the powder 102A of the first component and the powder 104A of the second component into a double-layer tablet using a double-layer tableting machine to form the oral preparation 100 . Although the oral preparation 100 in FIG. 1 is an oral double-layered tablet as an example, the present invention is not limited thereto.

In some other embodiments, the oral formulation 100 may also include other types of dosage forms and preparation methods. In one embodiment, preparation of the oral preparation 100 includes separately granulating the powder 102A of the first component and the powder 104A of the second component, and then filling the capsules in the form of pellets. In one embodiment, preparation of the oral preparation 100 includes separately granulating the first component powder 102A and the second component powder 104A, and then filling the sachet in the form of pellets. In another embodiment, the preparation of the oral preparation 100 includes separately tableting the powder 102A of the first component and the powder 104A of the second component, and filling the capsules in the form of micro-tablets/mini-tablets. . In yet another embodiment, the preparation of the oral preparation 100 includes separately tableting the powder 102A of the first component and the powder 104A of the second component, and then filling them in the form of micro-tablets/mini-tablets. In a sachet.

It can be understood from the above description that the oral preparation 100 of the present invention is not limited to the dosage form of a double-layer tablet. For example, as long as the oral preparation 100 includes the powder 102A of the first component as an immediate release layer and the powder 104A of the second component as a controlled release layer, the oral preparation can be 100 dosage forms to make appropriate adjustments. In one embodiment, the powder 104A of the second component serves as a delayed release layer. The first component/powder 102A of the first component and the second component/powder 104A of the second component will be further described below.

In the embodiment of the present invention, the first component/first component powder 102A may include at least green tea, polyvinylpyrrolidone (Polyvinylpyrrolidone), microcrystalline cellulose (Microcrystalline Cellulose), cross-linked polyvinylpyrrolidone (Crospovidone), hard Magnesium Stearate and silicon dioxide. Green tea pigments can include xanthine derivatives (or caffeine). In some embodiments, microcrystalline cellulose can be replaced by lactose or corn starch. Cross-linked polyvinylpyrrolidone can be replaced by Sodium Carboxymethyl Starch, Croscarmellose Sodium, Hydroxypropyl Cellulose, and pregelatinized starch. .

In one embodiment, the preparation of the first component powder 102A may include the following steps, but is not limited thereto. First, green tea pigments including xanthine derivatives are provided. Sieve the green tea pigment, microcrystalline cellulose and cross-linked polyvinylpyrrolidone into granules, mix them evenly and put them into a rapid mixing granulator. Next, the alcohol aqueous solution of polyvinylpyrrolidone is added to the above-mentioned powder including the green tea pigment, and is granulated using a granulator, followed by drying and sieving to granulate. Next, cross-linked polyvinylpyrrolidone, microcrystalline cellulose and silica are added and mixed evenly to form the first component powder 102A. Accordingly, the obtained powder 102A of the first component can be used to form the above-mentioned oral preparations 100 of different dosage forms.

In an embodiment of the present invention, the second component/second component powder 104A may include green tea, enteric excipients, polyvinylpyrrolidone, microcrystalline cellulose, medium chain triglycerides, Magnesium stearate, silica and film coating 145K290001 (Nutrafinish ® Dietary Supplement Coating 145K290001 Clear (NSC)). Green tea pigments can include xanthine derivatives (or caffeine). Film coating 145K290001 is a mixture of Hydroxypropyl Methyl Cellulose, Triacetin and Talc. The enteric excipient can be zein enteric coating.

In some embodiments, microcrystalline cellulose can be replaced by lactose or corn starch. Medium chain triglycerides can be replaced by glycerol (Glycerol), polyethylene glycol (PEG), mineral oil (Mineral Oil) or fatty acid (Fatty Acid). In addition, in some embodiments, in addition to zein enteric coating, the enteric excipients can also be ethyl acrylate/methacrylic acid copolymer (Ethyl Acrylate/methacrylic Acid Copolymer), hydroxypropyl methyl fiber acetate Hydroxypropyl Methylcellulose Acetate Succinate, Cellulose Acetate Phthalate or Hydroxypropyl Methylcellulose Phthalate, etc., or mixtures thereof.

In one embodiment, the preparation of the second component powder 104A may include the following steps, but is not limited thereto. First, weigh an appropriate amount of alcohol aqueous solution, add medium chain triglyceride while stirring, then mix zein as an enteric excipient with film coating 145K290001 and slowly add it to the alcohol aqueous solution to make it completely Dissolve and disperse to obtain coating liquid. Next, green tea pigments including xanthine derivatives are provided. The green tea element is sprayed and granulated with the coating liquid to coat it to a weight gain range of 5% to 15%, and then dried and sieved to granulate. Next, microcrystalline cellulose, polyvinylpyrrolidone, magnesium stearate and silica are added and mixed evenly to form the second component powder 104A. Accordingly, the obtained powder 104A of the second component can be used to form the above-mentioned oral preparations 100 of different dosage forms.

In the embodiment of the present invention, the total weight of the xanthine derivative (caffeine) in the oral preparation 100 is 50 mg to 400 mg. For example, the weight of the xanthine derivative in the first component is 25 mg to 200 mg, and the weight of the xanthine derivative in the second component is 25 mg to 200 mg. In some embodiments, the weight ratio of the first ingredient to the second ingredient in the oral formulation 100 is from 1:1 to 1:1.2. In addition, when the weight proportion of the second component is 100%, the weight proportion of the zein enteric coating used as the enteric excipient is 5.5% to 10% of the second component. When the weight ratio of the zein enteric coating is controlled within the above range, a more ideal controlled release effect can be achieved, especially when the enteric substance coating is used to reduce the release in the early stage and then release after reaching the intestinal tract. Effect.

In the oral preparation 100 of the present invention, more than 80% by weight of the xanthine derivative in the first component is released within 1 hour after dissolution in vitro. The xanthine derivative in the first component is released up to 100% by weight within 90 minutes of dissolution in vitro. In addition, the xanthine derivatives in the second component are released by less than 35% by weight within 90 minutes of dissolution in vitro, and the xanthine derivatives in the second component are released by more than 50% by weight within 3 hours of dissolution in vitro. In some embodiments, the xanthine derivative in the second component is released from more than 50% to less than 70% by weight within 3 hours of dissolution in vitro. In addition, the xanthine derivatives in the second component are released less than 40% by weight within 2 hours of dissolution in vitro, while the release of the xanthine derivatives in the second component is more than 90% by weight within 8 hours to 12 hours of dissolution in vitro. , and the xanthine derivative in the second component is released by 100% by weight within 12 hours to 18 hours after dissolution in vitro. Accordingly, in the oral preparation 100 of the present invention, the first component (the powder 102A of the first component) can be used as a rapid release layer, and the second component (the powder 104A of the second component) can be used as a controlled release layer. A dual-layer controlled release oral preparation 100 is used to achieve initial rapid release and control to later release (or delayed release).

In the embodiments of the present invention, the in vitro dissolution data of xanthine derivatives can be used to simulate/control the results of its in vivo dissolution. In some embodiments, the test method for in vitro dissolution is to use a stirring paddle device (i.e., USP apparatus II) to perform the test at 50 to 75 rpm and a temperature of 37±0.5°C. Oral formulations are tested in at least three buffers sufficient to simulate the gastrointestinal tract (pH range should be between 1.2 and 6.8). For example, when performing a dissolution test with a total test time of 4 hours, the solution is in a pHH 1.2 buffer during the 0-1 hour period, and is replaced into a pHH 4.5 buffer during the 1-2 hour period, and The test was carried out by exchanging to pH 6.8 buffer over a period of 2-4 hours. More specifically, the buffer at pH 1.2 is used to simulate a gastric fluid environment, the buffer at pH 4.5 is used to simulate a duodenal fluid environment, and the buffer at pH 6.8 is used to simulate intestinal fluid ( intestinal fluid) environment. In the experiment, solutions were collected at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes and 240 minutes after the start of dissolution, and the proportion of dissolution was calculated through the control group (standard).

In some embodiments of the present invention, the oral formulation 100 reaches the highest blood concentration of the xanthine derivative (caffeine) within 90 minutes after administration. When the oral preparation 100 is used as a supplement for endurance exercise, the method of use is to take the oral preparation 100 within 30 minutes to 60 minutes before the endurance exercise, and the dosage of the oral preparation 100 is calculated based on the body weight of the user. , 3 mg/kg (3 mg per kilogram) to 6 mg/kg. After taking the oral preparation 100 of the present invention, the interference of having to take and swallow caffeine during endurance exercise can be avoided, and through the use of the second component of controlled release, the high content/blood concentration of caffeine can be maintained at least 6 hours to 8 hours.

In some embodiments, endurance sports athletes can take the oral formulation 100 of the present invention 30 minutes before competition. For example, if a player weighs 60 kg, he or she will take approximately 180 mg to 360 mg of oral preparation 100. In addition, the weight ratio of the first component to the second component in the oral formulation 100 is approximately 1:1 to 1:1.2. Within 1 hour to 2 hours after taking the oral preparation 100, since the first component (quick release layer) of the oral preparation 100 has released more than 80% by weight of the xanthine derivative (caffeine), the user can Maintain high blood concentrations of xanthine derivatives during the early stages of endurance exercise (up to 2 hours from the start) to provide a supplemental effect.

In the later stages of endurance exercise, such as within 2 hours to 4.5 hours after taking the oral preparation 100, since the first component has been fully released and entered the half-life, therefore, the blood concentration of the xanthine derivative (caffeine) of the first component will slowly decrease. In comparison, the xanthine derivative (caffeine) of the second component (controlled release layer) of the oral preparation 100 does not release up to 35% by weight during the pre-exercise period, such as within 90 minutes after taking it. It will take more than 50% by weight and less than 70% by weight to be released within 3 hours. Therefore, the second component (controlled release layer) can increase and maintain high blood concentrations of xanthine derivatives (caffeine) in the later stages of endurance exercise (2 hours to 4.5 hours), and give endurance athletes a second dose of coffee. Because of the caffeine boost effect.

Accordingly, endurance athletes can maintain high blood concentrations of xanthine derivatives (caffeine) throughout endurance exercise and promote/support their exercise-related performance. In addition, since the xanthine derivative (caffeine) in the second component is only released to 100% by weight within 12 hours to 18 hours after taking it, even after the end of endurance exercise, during the period of continuous release of caffeine, It can also continue to prolong and maintain its tonic/refreshing effects. Experimental example

In order to prove the difference in the in vitro dissolution release effect between the oral preparation 100 of the present invention and the traditional matrix type long-acting release dosage form, the following examples will be described in detail. Hereinafter, the preparation of the first component powder 102A, the second component powder 104A and the traditional matrix-type long-acting release powder will be described. Preparation example of powder of first component

Figure 2 is a flow chart for preparing the first component powder according to an embodiment of the present invention. Various materials used in Figure 2 are prepared according to the contents in Preparation Examples A1 to A5 described in Table 1.

Table 1: Recipe list of the first ingredient powder first ingredient Preparation Example A1 Preparation Example A2 Preparation Example A3 Preparation Example A4 Preparation Example A5 Substance name Proportion(%) Proportion(%) Proportion(%) Proportion(%) Proportion(%) 1 Alcohol aqueous solution 95% - - - - - 2 green tea pigment 78.13% 78.13% 83.33% 83.33% 83.33% 3 microcrystalline cellulose 7.18% 7.18% 7.97% 7.97% 7.97% 4 Cross-linked polyvinylpyrrolidone 10.00% 10.00% 4.00% 4.00% 4.00% 5 Polyvinylpyrrolidone 3.00% 3.00% 3.00% 3.00% 3.00% 6 Magnesium stearate 1.50% 1.50% 1.50% 1.50% 1.50% 7 Silicon dioxide 0.20% 0.20% 0.20% 0.20% 0.20% 100.00% (320mg) 100.00% (320mg) 100.00% (300mg) 100.00% (300mg) 100.00% (300mg)

Referring to step A10 in Figure 2 and Table 1, first, green tea element, microcrystalline cellulose and cross-linked polyvinylpyrrolidone are mixed and prepared. Next, after sieving and granulating as in step A12, the above ingredients are mixed evenly in step A14 and then put into a rapid mixing granulator. Next, as in step A16, add polyvinylpyrrolidone to the 95% alcohol aqueous solution, and stir it until it is completely dissolved in step A18. Next, referring to step A20, the liquid obtained in step A18 is added to the powder in step A14, and wet granulation is performed using a rapid mixing granulator. After the wet granulation is completed, drying is performed in step A22, and sieving and granulation are performed in step A24. Next, in step A26, cross-linked polyvinylpyrrolidone, magnesium stearate and silicon dioxide are prepared at the contents listed in Table 1, and then sieved in step A28. Next, in step A30, the powder obtained in step A28 and the powder obtained in step A24 are mixed. Accordingly, the powder of the first component can be obtained in step A32. Preparation example of the second component powder

Figure 3 is a flow chart for preparing the second component powder according to an embodiment of the present invention. Various materials used in Figure 3 are prepared according to the contents in Preparation Examples B1 to B4 described in Table 2.

Table 2: Recipe list for the powder of the second component second component Preparation Example B1 (Ex 1) Preparation Example B2 (Ex 2) Preparation Example B3 (Ex 3) Preparation Example B4 (Ex 4) Substance name Proportion(%) Proportion(%) Proportion(%) Proportion(%) 1 Alcohol aqueous solution 95% - - - - 2 Purify water - - - - 3 green tea pigment 71.43% 71.43% 71.43% 71.43% 4 microcrystalline cellulose 16.00% 13.14% 22.64% 19.43% 5 Zein enteric coating 8.00% 10.00% 3.00% 5.50% 6 medium chain triglycerides 1.64% 2.14% 0.64% 1.07% 7 Film coating 145K290001 1.07% 1.43% 0.43% 0.71% 8 Polyvinylpyrrolidone 0.36% 0.36% 0.36% 0.36% 9 Magnesium stearate 1.00% 1.00% 1.00% 1.00% 10 Silicon dioxide 0.50% 0.50% 0.50% 0.50% 100.00% (350mg) 100.00% (350mg) 100.00% (350mg) 100.00% (350mg)

Referring to step B10 in Figure 3 and Table 2, purified water and alcohol are mixed to prepare an alcohol aqueous solution. Next, in step B12, medium-chain triglyceride is provided, and in step B14, the medium-chain triglyceride is added to the aqueous alcohol solution while stirring for mixing. Next, referring to step B16, after mixing the zein enteric coating and film coating 145K290001, in step B18, slowly add them to the above-mentioned alcohol aqueous solution for mixing. In step B20, the ingredients added to the alcohol aqueous solution are stirred until they are completely dissolved and dispersed to form a coating liquid. After obtaining the coating liquid, green tea element is provided in step 22, and in step B24, the green tea element is sprayed and granulated with the coating liquid of step B20. In step B24, the Yuancheng fluid granulation bed (model FBDD-2) is used for spray granulation, and its parameters are shown in Table 3.

Table 3: Spray granulation parameters Incoming air(℃) Outlet air(℃) Product temperature(℃) Exhaust air(%) Flow rate(rpm) Vibration(sec/sec) Windmill(rpm) Pipe diameter(Ø) 45~60 32~42 31~38 100 5~25 5/55 1500~2500 6

After spray granulation, drying is performed in step B26, and sieving and granulation are performed in step B28. Next, in step B30, microcrystalline cellulose, polyvinylpyrrolidone, magnesium stearate and silicon dioxide are prepared at the contents listed in Table 2, and then sieved in step B32. Next, in step B34, the powder obtained in step B28 and the powder obtained in step B32 are mixed. Accordingly, the powder of the second component can be obtained in step B36. Preparation example of traditional long-lasting release powder

Figure 4 is a flow chart for the preparation of long-lasting release powder according to a comparative example of the present invention. The various materials used in Figure 4 were prepared at the contents in Preparation Example C5 described in Table 4.

Table 4: Prescription list for long-lasting release powder long lasting release powder Preparation Example C5 (Ex 5) Substance name Proportion(%) 1 Alcohol aqueous solution 95% - 2 Purify water - 3 green tea pigment 71.43% 4 microcrystalline cellulose 16.07% 5 Zein enteric coating 10.00% 6 medium chain triglycerides 0.00% 7 Film coating 145K290001 0.00% 8 Polyvinylpyrrolidone 1.00% 9 Magnesium stearate 1.00% 10 Silicon dioxide 0.50% 100.00% (350mg)

Referring to step C10 of Figure 4 and Table 4, green tea element, microcrystalline cellulose and zein enteric coating are mixed. Next, after sieving and granulating in step C12, the above ingredients are mixed evenly in step C14 and then put into a rapid mixing granulator. Next, a 95% aqueous solution of polyvinylpyrrolidone and alcohol is provided in steps C16 and C18. Furthermore, in step C20, polyvinylpyrrolidone is added to the 95% alcohol aqueous solution, mixed and stirred until completely dissolved. In step C22, zein enteric coating is provided, and then in step C24, it is added to the above-mentioned alcohol aqueous solution and mixed to cause suspension and dispersion. Referring to step C26, the liquid obtained in step C24 is added to the powder in step C14, and wet granulation is performed with a rapid mixing granulator. After wet granulation, drying is performed in step C28, and sieving and granulation are performed in step C30. Next, in step C32, magnesium stearate and silicon dioxide are prepared at the contents listed in Table 4, and then sieved in step C34. Next, in step C36, the powder obtained in step C30 and the powder obtained in step C34 are mixed. Accordingly, traditional long-lasting release powder can be obtained in step C38. In vitro dissolution test I

In order to confirm the difference in caffeine release effects between the second component of the present invention (Preparation Examples B1 to B4) and the traditional long-lasting release powder (Preparation Example C5), an in vitro dissolution test was conducted in the following manner.

In the in vitro dissolution test of this experimental example, a stirring paddle device (i.e. USP apparatus II) was used to conduct the test at 50 rpm and a temperature of 37±0.5°C. The second component of the present invention (Preparation Examples B1 to B4) and the traditional long-acting release powder (Preparation Example C5) are placed in simulated gastric juice of pHH 1.2 during a period of 0-1 hour, and in a period of 1-2 hours. Tests were conducted in simulated duodenal fluid at pH 4.5, and in simulated intestinal fluid at pH 6.8 over a period of 2-4 hours. Among them, a certain amount of solution was extracted at different time points (30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes and 240 minutes) to calculate the concentration of xanthine derivatives. Among them, an ultraviolet-visible spectrometer (UV/VIS) is used to conduct concentration analysis, and the dissolution ratio is calculated and confirmed through the control group (standard). The test results are shown in Figure 5 and Table 5.

Table 5: In vitro dissolution table of the second component (controlled release layer) and comparative examples time (minutes) Preparation Example B1 (Ex 1) Preparation Example B2 (Ex 2) Preparation Example B3 (Ex 3) Preparation Example B4 (Ex 4) Preparation Example C5 (Ex 5) pH 1.2 0 0.0% 0.0% 0.0% 0.0% 0.0% 30 8.7% 8.5% 17.4% 17.0% 21.6% 60 14.1% 12.6% 38.1% 25.9% 33.0% pH 4.5 90 18.2% 15.4% 46.4% 30.7% 40.4% 120 23.5% 17.9% 52.9% 35.8% 46.0% pH 6.8 150 48.1% 44.1% 57.7% 50.1% 50.6% 180 52.3% 50.1% 62.2% 55.2% 54.5% 240 64.3% 59.8% 69.3% 61.5% 60.7%

Figure 5 is an in vitro dissolution curve diagram of the second component according to the embodiment of the present invention and the comparative example. Referring to Figure 5 and Table 5, it can be seen that Preparation Example B1 (Ex1) and Preparation Example B2 (Ex2) have better controlled release effects. Within 2 hours of dissolution in vitro, the release of xanthine derivatives (caffeine) did not reach 30% by weight, and were only 23.5% by weight and 17.9% by weight respectively. Moreover, the xanthine derivatives (caffeine) of Preparation Example B1 (Ex1) and Preparation Example B2 (Ex2) will be released up to 48.1% by weight and 44.1% by weight respectively after 2.5 hours. Therefore, the second component prepared in Preparation Example B1 (Ex1) and Preparation Example B2 (Ex2) can start to have an obvious xanthine derivative (caffeine) promoting effect after 2 hours, and can enter the intestinal environment (pH 6.8) before performing controlled release. Accordingly, the prepared second component can effectively supplement and maintain high blood concentrations of xanthine derivatives in the later stages of administration.

Referring to Preparation Example B4 (Ex4), it also has acceptable controlled release effect. As shown in Figure 5 and Table 5, the component of Preparation Example B4 has a xanthine derivative (caffeine) release of less than 35% by weight within 90 minutes of in vitro dissolution, and its xanthine derivatives (caffeine) have not been released within 2 hours of in vitro dissolution. (Caffeine) release is less than 40% by weight. Therefore, the second component of Preparation Example B4 can also be controlled to be released in a delayed manner at the later stage of administration (after 2 hours) to facilitate supplementation and maintenance of high blood concentrations of xanthine derivatives. As shown in Table 2 above, the weight ratio of the zein enteric coating in Preparation Examples B1, B2 and B4 is controlled in the range of 5.5% by weight to 10% by weight of the second component. Therefore, the control of the present invention can be achieved. Release effect.

In comparison, referring to Preparation Example B3 (Ex3), when the weight ratio of zein enteric coating as an enteric excipient is 3% by weight of the second component (as shown in Table 2), the The controlled release effect cannot be effectively achieved. As shown in Figure 5, the release of xanthine derivatives (caffeine) of the ingredients in Preparation Example B3 has exceeded 40% by weight within 90 minutes of in vitro dissolution, and is different from the traditional long-acting release powder dosage form (Preparation Example C5). The dissolution curves are similar. Therefore, the second component of Preparation Example B3 cannot effectively achieve the controlled release effect within a specific period of time.

In order to further confirm the difference between the enteric granulation of the present invention and the traditional matrix-type mixed granulation, the test results of Preparation Example B2 (Ex2) and Preparation Example C5 (Ex5) were individually compared. Figure 6 is a comparison chart of the in vitro dissolution curves of enteric granulation (Ex2) according to the present invention and traditional matrix-type mixed granulation (Ex5). Preparation Example B2 (Ex2) and Preparation Example C5 (Ex5) have the same ratios of zein enteric coating and green tea pigment (both 10% by weight and 71.43% by weight). However, Preparation Example B2 was prepared by enteric granulation (step 3), while Preparation Example C5 was prepared by matrix mixing (step 4). , the preparation methods of the two are very different.

Referring to Figure 6, it can be known that even if the same weight ratio of zein is used for granulation, if the powder is not prepared by the enteric granulation step of the present invention, control cannot be effectively achieved. Release effect. As shown in Figure 6, the release of xanthine derivatives (caffeine) in Preparation Example C5 has reached 40% by weight within 90 minutes of in vitro dissolution, which is a sustained-release dosage form. In comparison, the release of xanthine derivatives (caffeine) in Preparation Example B2 of the present invention did not reach 20% by weight within 2 hours of in vitro dissolution, and the release of xanthine derivatives (caffeine) within 150 minutes of in vitro dissolution was It can reach 46% by weight, which can obviously achieve the effect of delayed release under control. In vitro dissolution test II

In order to confirm that the first component of the present invention has a rapid release effect, the first component of Preparation Example A1 was used to conduct an in vitro dissolution test. In addition, in order to confirm the dissolution effect of the oral preparation 100 of the present invention, the first component of Preparation Example A1 was mixed with the second component (A1+B1) of Preparation Example B1, and the first component of Preparation Example A2 was mixed with the second component of Preparation Example B2. Two components (A2+B2) were used to form a double-layered tablet oral preparation, and an in vitro dissolution test was performed. The steps of the in vitro dissolution test are similar to those mentioned in "In vitro dissolution test I", so they will not be described again. The difference is that in the dissolution test of oral preparations (double-layer tablets), the extraction of the solution is continued until 1440 minutes (24 hours). The test results are shown in Figures 7 and 8.

Figure 7 is an in vitro dissolution curve diagram of the first component (rapid release layer) according to an embodiment of the present invention. Referring to Figure 7, it can be seen that the first component prepared by Preparation Example A1 of the present invention has an obvious rapid release effect. As shown in the test results in Figure 7, the release of xanthine derivatives (caffeine) has reached more than 80% within 60 minutes of in vitro dissolution, and the release of xanthine derivatives (caffeine) has reached 90 minutes of in vitro dissolution. 100%. Accordingly, the first component of the present invention can effectively release the xanthine derivative quickly in the early stage (within 2 hours) after taking it, maintain its high concentration in the blood, and provide a supplementing effect.

Figure 8 is an in vitro dissolution curve diagram of an oral preparation according to an embodiment of the present invention. Referring to Figure 8, both the oral double-layer tablet formed by Preparation Example A1 and Preparation Example B1 or the oral double-layer tablet formed by Preparation Example A2 and Preparation Example B2 can achieve xanthine derivatization within 90 minutes of in vitro dissolution. More than 50% of the substance (caffeine) is released. That is, the first component of the oral double-layer tablet has been fully released, while the second component is released slowly and controlled. In addition, the release of xanthine derivatives (caffeine) will increase to more than 90% within 90 minutes to 720 minutes (12 hours) of in vitro dissolution, and the release of xanthine derivatives (caffeine) will reach 100 wt. within 12 hours to 18 hours of in vitro dissolution. %. Accordingly, through the rapid release of the first component and the controlled release of the second component, the double-layer controlled release oral preparation of the present invention can effectively control the release of xanthine derivatives (such as caffeine) to maintain high blood concentrations, thereby Satisfies long term energizing/refreshing needs.

To sum up, embodiments of the present invention use an oral preparation having a first component and a second component, and the second component has an enteric excipient prepared by enteric granulation. Therefore, the oral preparation of the present invention can quickly release the first component in the early stage after taking it, provide early caffeine supplementation, and control the release of the second component of caffeine in the later stage. Since the second component has an edible enteric-coated material, it can gradually dissolve in an alkaline intestinal environment, creating a second-stage release effect. Accordingly, the double-layer release controlled oral preparation of the present invention can effectively control the release of xanthine derivatives (such as caffeine) to maintain high blood concentrations, thereby meeting long-term supplementation/refreshing needs. For example, the double-layer controlled release oral preparation of the present invention can meet the need for multiple supplements/refreshers during long-term activities. For example, during endurance sports such as marathons, caffeine needs to be swallowed to improve performance, or during long-distance running. Driving requires distraction to supplement the inconvenience or interference of caffeine, and through the controlled release of the second component, the high content/blood concentration of caffeine can be maintained throughout the exercise period, and it can also continue to provide a tonic/refreshing effect after exercise. .

100: Oral preparation 102:First level 102A: Powder of the first component 104:Second level 104A: Powder of the second component A10, A12, A14, A16, A18, A20, A22, A24, A26, A28, A30, A32: steps B10, B12, B14, B16, B18, B20, B22, B24, B26, B28, B30, B32, B34, B36: Steps C10, C12, C14, C16, C18, C20, C22, C24, C26, C28, C30, C32, C34, C36, C38: Steps

Figure 1 is a schematic diagram of an oral preparation according to an embodiment of the present invention. Figure 2 is a flow chart for preparing the first component powder according to an embodiment of the present invention. Figure 3 is a flow chart for preparing the second component powder according to an embodiment of the present invention. Figure 4 is a flow chart for the preparation of long-lasting release powder according to a comparative example of the present invention. Figure 5 is an in vitro dissolution curve diagram of the second component according to the embodiment of the present invention and the comparative example. Figure 6 is a comparison chart of the in vitro dissolution curves of enteric granulation according to the present invention and traditional matrix-type mixed granulation. Figure 7 is an in vitro dissolution graph of the first component according to an embodiment of the present invention. Figure 8 is an in vitro dissolution curve diagram of an oral preparation according to an embodiment of the present invention.

B10, B12, B14, B16, B18, B20, B22, B24, B26, B28, B30, B32, B34, B36: Steps

Claims (19)

An oral preparation, comprising: a first component, which includes caffeine, and the caffeine in the first component releases more than 80% by weight within 1 hour of dissolution outside the body; and a second component, which includes the caffeine and enteric excipients, wherein the caffeine in the second component is released within 90 minutes of dissolution in vitro, less than 35% by weight, and the caffeine in the second component is dissociated in vitro within 3 hours The release reaches more than 50% by weight. The oral preparation according to claim 1, wherein the caffeine in the second component is released from 50% to 70% by weight within 3 hours of dissolution in vitro. The oral preparation according to claim 1, wherein the caffeine in the first component is released in vitro to 100% by weight within 90 minutes, and the caffeine in the second component is dissolved in vitro in 8 The release rate reaches more than 90% by weight within 12 hours to 12 hours, and the release of the caffeine in the second component reaches 100% by weight within 12 hours to 18 hours after dissolution in vitro. The oral preparation as claimed in claim 1, wherein the caffeine in the second component is released within 2 hours of dissolution in vitro and does not reach 40% by weight. The oral preparation according to claim 1, wherein the oral preparation is an oral two-layer tablet, which includes a first layer composed of the first component, and a second layer composed of the second component. The oral preparation according to claim 1, wherein the weight ratio of the first component to the second component is 1:1 to 1:1.2. The oral preparation according to claim 1, wherein the enteric excipient is zein enteric coating. The oral preparation according to claim 7, wherein when the weight ratio of the second component is 100%, the weight ratio of the zein enteric coating is 5.5% to 10% of the second component. The oral preparation according to claim 1, wherein the total weight of caffeine in the oral preparation is 50 mg to 400 mg. The oral preparation according to claim 9, wherein the weight of the caffeine in the first component is 25 mg to 200 mg. The oral preparation according to claim 9, wherein the weight of the caffeine in the second component is 25 mg to 200 mg. The oral preparation according to claim 1, wherein the first component further includes green tea, polyvinylpyrrolidone, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, magnesium stearate and silicon dioxide, and the green tea Vitamins include the caffeine. The oral preparation according to claim 1, wherein the second component further includes green tea, polyvinylpyrrolidone, microcrystalline cellulose, medium chain triglycerides, magnesium stearate, silicon dioxide and film coating 145K290001 , and the green tea element includes the caffeine. The oral preparation of claim 1, wherein the oral preparation reaches the highest blood concentration of caffeine within 90 minutes after taking it. A method for preparing an oral preparation according to claim 1, comprising: forming the powder of the first component and the powder of the second component into a double-layer tablet. The preparation method according to claim 15, wherein the preparation of the powder of the second component includes: providing a coating liquid including the enteric excipient; providing green tea element, the green tea element including the caffeine ; And the green tea element is sprayed and granulated with the coating liquid to coat it to a weight gain range of 5% to 15%. The preparation method according to claim 16, further comprising: after the spray granulation, drying and sieving to form the powder of the second component. The preparation method according to claim 15, wherein the preparation of the powder of the first component includes: providing green tea element, the green tea element includes the caffeine; and adding the alcohol aqueous solution of polyvinylpyrrolidone to the solution including the caffeine. into the powder of green tea element, and after granulation, drying and sieving are performed to form the powder of the first component. A method of using the oral preparation as described in claim 1, including: taking the oral preparation within 30 minutes to 60 minutes before endurance exercise, and the dosage of the oral preparation is 3 mg/kg to 6 mg/kg.

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