TW202304454A - 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 is a bipolar substance soluble in water and lipids. Its chemical structure is very similar to adenosine. Adenosine is the backbone of adenosine triphosphate (ATP), the body's energy source, and a neuromodulator. Adenosine and adenosine compounds themselves reduce levels of stimulating neurotransmitters in addition to reducing wakefulness and alertness. Caffeine has a similar structure to adenosine, and it competes with adenosine for receptors, so caffeine has a refreshing effect. On the other hand, caffeine can reduce muscle pain during exercise, so as to achieve the effect of exercise anti-fatigue.

According to reports, about 74% of elite athletes use caffeine as a supplement before or during competition, and endurance athletes show a higher prevalence of use. The possible reasons for the popularity of caffeine are its easy availability, low side effects, and research indicating that a certain supplementary effect can be achieved at low doses (<6 mg/kg).

Generally speaking, the absorption rate of caffeine can reach the highest blood concentration within 30 minutes to 90 minutes after taking it. Therefore, according to the results of most clinical trials, users should take it 30-60 minutes before exercise to obtain the supplementary effect of caffeine during the competition. For general endurance sports, such as marathons, the average completion time is about 4.5 hours. When caffeine is used 30-60 minutes before the game, it enters a state of less than half-life about 3 to 3.5 hours into the game, and it is also in the high-pressure period of the game or the wall-hitting period. Therefore, in order to avoid the fatigue caused by hitting the wall, many users will supplement it with 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 the race).

However, many supplements are required during endurance exercise, such as carbohydrate energy gels, electrolytes, amino acids, etc., and it is very inconvenient to carry and replenish caffeine on the way. In addition, a single dose of caffeine on the way still takes about an hour to absorb, not as good as a sustained-release formulation that provides a sustained caffeine boost. In addition, for caffeine in a sustained-release dosage form, 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 is impossible to meet the controlled-release requirement of releasing the preset target within a specific time period after taking it, so as to support the maintenance of high blood caffeine concentration throughout the exercise period, thereby enhancing exercise performance.

Accordingly, how to effectively control the release of xanthine derivatives, so as to maintain a high blood concentration, and meet the needs of multiple supplements/refreshing during long-term activities, such as during endurance sports such as marathons, it is necessary to swallow additionally to improve performance Caffeine, or the inconvenience or interference of long-distance driving requiring distraction to replenish caffeine, is a problem to be solved at present.

The invention provides an oral preparation, which can effectively control the release of xanthine derivatives so as to maintain a high concentration in the blood, thereby meeting the long-term replenishment/refreshing needs. For example, the oral formulation of the present invention can avoid the interference of taking and swallowing caffeine during endurance exercise, and can maintain a high content/high blood level of caffeine throughout the exercise period.

An oral formulation of the present invention includes a first component and a second component. The first component includes a xanthine derivative. The second component includes a xanthine derivative and an enteric excipient. The xanthine derivatives in the second component release less than 35% by weight within 90 minutes of in vitro elution, and the release of more than 50% by weight of the xanthine derivatives in the second component within 3 hours of in vitro elution.

In one embodiment of the present invention, the xanthine derivatives in the second component are released within 3 hours of in vitro dissolution up to 50% by weight to 70% by weight.

In one embodiment of the present invention, the xanthine derivatives in the first component are released to more than 80% by weight within 1 hour of in vitro elution.

In one embodiment of the present invention, the release of xanthine derivatives in the first component reaches 100% by weight within 90 minutes of elution in vitro, while the release of xanthine derivatives in the second component is within 8 hours to 12 hours of elution in vitro The release of the xanthine derivatives in the second component reaches more than 90% by weight, and the release of the xanthine derivatives in the second component reaches 100% by weight within 12 hours to 18 hours of elution in vitro.

In an embodiment of the present invention, the release of xanthine derivatives in the second component does not reach 40% by weight within 2 hours of elution in vitro.

In one embodiment of the present invention, the oral preparation is an oral bilayer 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 ratio of the second ingredient is 100%, the weight ratio of the zein enteric coating is 5.5% to 10% of the second ingredient.

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

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

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

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

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

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

A preparation method of an oral preparation of the present invention, comprising: forming a double-layer tablet with the powder of the first component and the powder of the second component.

In one embodiment of the present invention, the preparation of the powder of the second component includes the following steps. A coating solution comprising an enteric excipient is provided. Green tea compounds including xanthine derivatives are provided. Spray and granulate the green tea pigment with a coating solution to cover the range of 5% to 15% weight gain.

In an 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 compounds including xanthine derivatives are provided. The alcoholic aqueous solution of polyvinylpyrrolidone is added to the powder including 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 of the present invention, comprising: 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, the embodiment of the present invention can release the first component quickly after taking the oral preparation with the first component and the second component, provide early caffeine supplementation, and release the caffeine of the second component in the later stage. . Accordingly, the double-layer release-controlled oral preparation of the present invention can effectively control the release of xanthine derivatives (such as caffeine), so that it maintains a high concentration in the blood, thereby meeting the long-term replenishment/refreshing demand. For example, the oral formulation of the present invention can avoid the interference of taking and swallowing caffeine during endurance exercise, and can prolong the high content/high blood level of caffeine during the whole exercise period through the controlled release of the second component. concentration time. In addition, the oral formulation of the present invention can also avoid the inconvenience or interference of distracted caffeine supplementation during long-distance driving.

Fig. 1 is a schematic diagram of an oral formulation according to an embodiment of the present invention. Referring to FIG. 1 , the oral preparation 100 of the embodiment of the present invention is composed of, for example, 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 a powder 102A of a first composition, and the second layer 104 includes a powder 104A of a second composition. In some embodiments, the preparation method of the oral formulation 100 includes punching the powder 102A of the first component and the powder 104A of the second component into a double-layer ingot by a double-layer tablet maker to form the oral formulation 100 . Although the oral formulation 100 in FIG. 1 is exemplified by an oral bilayer tablet dosage form, the present invention is not limited thereto.

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

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

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

In one embodiment, the preparation of the powder 102A of the first component may include the following steps, but it is not limited thereto. First, green tea is provided, which includes xanthine derivatives. The green tea element, microcrystalline cellulose and cross-linked polyvinylpyrrolidone are sieved and granulated, mixed evenly and put into a rapid mixing granulator. Next, the alcoholic aqueous solution of polyvinylpyrrolidone is added to the above-mentioned powder containing the green tea element, and after being granulated by a granulator, drying and sieving are carried out. Next, cross-linked polyvinylpyrrolidone, microcrystalline cellulose and silicon dioxide are added and mixed evenly to form the powder 102A of the first component. Accordingly, the obtained powder 102A of the first component can be used to form the above-mentioned oral preparations 100 in different dosage forms.

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

In some embodiments, microcrystalline cellulose may be replaced by lactose or cornstarch. 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 excipient can also be ethyl acrylate/methacrylic acid copolymer (Ethyl Acrylate/methacrylic Acid Copolymer), hydroxypropyl methylcellulose acetate Hydroxypropyl Methylcellulose Acetate Succinate, Cellulose Acetate Phthalate or Hydroxypropyl Methylcellulose Phthalate, etc., or a mixture thereof.

In one embodiment, the preparation of the powder 104A of the second component may include the following steps, but it is not limited thereto. First, weigh an appropriate amount of alcoholic aqueous solution, add medium-chain triglycerides while stirring, then mix zein as an enteric excipient with film coating 145K290001, and then slowly add it to the alcoholic aqueous solution to make it completely Dissolve and disperse to obtain coating solution. Next, green tea elements including xanthine derivatives are provided. Spray and granulate the green tea pigment with the coating solution to coat the green tea to a weight gain of 5% to 15%, and then dry and sieve the granules. Next, add microcrystalline cellulose, polyvinylpyrrolidone, magnesium stearate and silicon dioxide and mix well to form the powder 104A of the second component. Accordingly, the obtained powder 104A of the second component can be used to form the above-mentioned oral preparations 100 in 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 component to the second component in the oral formulation 100 is 1:1 to 1:1.2. In addition, when the weight ratio of the second component is 100%, the weight ratio of the zein enteric coating 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 the use of enteric material coating to reduce the release in the first stage, and release after reaching the intestinal tract Effect.

In the oral preparation 100 of the present invention, the xanthine derivative in the first component is released in an amount of more than 80% by weight within 1 hour of in vitro elution. The xanthine derivatives in the first component are released up to 100% by weight within 90 minutes of in vitro elution. In addition, the release of xanthine derivatives in the second component is less than 35% by weight within 90 minutes of in vitro elution, and the release of xanthine derivatives in the second component reaches more than 50% by weight within 3 hours of in vitro elution. In some embodiments, the xanthine derivative in the second component is released within 3 hours of elution in vitro to a level of more than 50% by weight and less than 70% by weight. In addition, the release of xanthine derivatives in the second component does not reach 40% by weight within 2 hours of in vitro elution, while the release of xanthine derivatives in the second component reaches more than 90% by weight within 8 hours to 12 hours of in vitro elution , and the release of xanthine derivatives in the second component reaches 100% by weight within 12 hours to 18 hours of in vitro dissolution. Accordingly, in the oral preparation 100 of the present invention, the first component (the powder 102A of the first component) can be used as the quick-release layer, and the second component (the powder 104A of the second component) can be used as the controlled-release layer, To achieve the initial rapid release and control to the later release (or delayed release) of the bilayer controlled oral preparation 100.

In the embodiment of the present invention, the in vitro elution data of xanthine derivatives can be used to simulate/control the in vivo elution results. In some embodiments, the in vitro dissolution test method is to use a stirring paddle device (ie, USP apparatus II) to perform the test at 50 to 75 rotations per minute and a temperature of 37±0.5°C. Oral formulations were tested in at least three buffers adequate to simulate the gastrointestinal tract (pH range should be between 1.2 and 6.8). For example, in a dissolution test with a total test time of 4 hours, in a pHH 1.2 buffer over a 0-1 hour period, and in a pHH 4.5 buffer over a 1-2 hour period, and The assay was performed by displacement into pH 6.8 buffer over a period of 2-4 hours. More specifically, the pH 1.2 buffer was used to simulate the gastric fluid environment, the pH 4.5 buffer was used to simulate the duodenal fluid environment, and the pH 6.8 buffer was used to simulate the intestinal fluid ( Intestinal fluid) environment. In the test, the solution was collected at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes and 240 minutes after the start of elution, and the elution ratio was calculated through the control group (standard).

In some embodiments of the present invention, the oral formulation 100 will reach the maximum blood level of the xanthine derivative (caffeine) within 90 minutes after ingestion. 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 , 3mg/kg (3 mg per kilogram) to 6mg/kg. After taking the oral formulation 100 of the present invention, it is possible to avoid the interference of taking and swallowing caffeine during endurance exercise, and through the use of the second component of controlled release, the high content/high blood level of caffeine can be maintained at least 6 hours to 8 hours.

In some embodiments, endurance athletes can take the oral preparation 100 of the present invention 30 minutes before the competition. For example, if the player's body weight is 60 kg, about 180 mg to 360 mg of the oral preparation 100 is taken. In addition, the weight ratio of the first component to the second component in the oral formulation 100 is about 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 xanthine derivatives (caffeine), the user can Maintain high blood levels of xanthine derivatives during the pre-endurance exercise period (up to 2 hours) to provide a supplementary effect.

In the late stage 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, the blood concentration of the xanthine derivative (caffeine) of the first component will slowly decrease. In contrast, the second component (control release layer) of the oral preparation 100 releases less than 35% by weight of its xanthine derivative (caffeine) during the pre-exercise period, such as within 90 minutes after taking More than 50% by weight and less than 70% by weight will be released within 3 hours. Thus, the second component (controlled release layer) is able to increase and maintain high blood levels of xanthine derivatives (caffeine) during the later stages of endurance exercise (2 hours to 4.5 hours) and give endurance athletes a second dose of coffee Because of the promotion (caffeine boost) effect.

Accordingly, endurance athletes are able to maintain high blood levels of xanthine derivatives (caffeine) throughout endurance exercise and facilitate/support their exercise-related performance. In addition, since the xanthine derivative (caffeine) in the second component is released up 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, May also be extended to maintain its replenishing/refreshing effect. Experimental example

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

Fig. 2 is a flow chart of the preparation of the first component powder according to the embodiment of the present invention. The various materials used in FIG. 2 were formulated with the contents in Preparation Example A1 to Preparation Example A5 recorded in Table 1.

Table 1: Recipe table for powders of the first component first component Preparation A1 Preparation A2 Preparation A3 Preparation A4 Preparation Example A5 Substance name Proportion(%) Proportion(%) Proportion(%) Proportion(%) Proportion(%) 1 Alcohol solution 95% - - - - - 2 Green tea 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 of FIG. 2 and Table 1, firstly, green tea element, microcrystalline cellulose and cross-linked polyvinylpyrrolidone are mixed and prepared. Next, after sieving and sizing as in step A12, the above-mentioned ingredients are mixed uniformly in step A14 and then put into a rapid mixing granulator. Next, as in step A16, polyvinylpyrrolidone was added to 95% alcohol aqueous solution, and stirred until 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 with a rapid mixing granulator. After the wet granulation is completed, the drying process is carried out in step A22, and the sieving and sizing is carried out in step A24. Next, in step A26, the cross-linked polyvinylpyrrolidone, magnesium stearate and silicon dioxide are formulated at the contents listed in Table 1, and then sieved in step A28. Next, in step A30, the powder obtained in step A28 is mixed with the powder obtained in step A24. Accordingly, the powder of the first component can be obtained in step A32. Preparation example of the powder of the second component

Fig. 3 is a flow chart of the preparation of the second component powder according to the embodiment of the present invention. The various materials used in FIG. 3 were prepared according to the content in Preparation Example B1-Preparation Example B4 recorded in Table 2.

Table 2: Recipe table 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 solution 95% - - - - 2 purified water - - - - 3 Green tea 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 coat 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 of FIG. 3 and Table 2, the purified water and alcohol are mixed to form an alcohol solution. Next, medium chain triglycerides are provided in step B12, and medium chain triglycerides are added into the alcohol aqueous solution while stirring in step B14 for mixing. Next, referring to step B16, after mixing the zein enteric coating and the film coating 145K290001, it is slowly added into the above-mentioned aqueous alcohol solution for mixing in step B18. In step B20, the ingredients added to the alcohol aqueous solution are stirred until completely dissolved and dispersed to form a coating solution. After the coating solution is obtained, green tea is provided in step 22, and in step B24, the coating solution in step B20 is used to spray and granulate the green tea. In step B24, spray granulation was carried out with Yuancheng fluidized granulation bed (model FBDD-2), and its parameters are shown in Table 3.

Table 3: Spray granulation parameters Into the wind (℃) Outlet (℃) Product temperature (℃) Exhaust (%) flow rate(rpm) Vibration (sec/sec) windmill (rpm) Diameter (Ø) 45~60 32~42 31~38 100 5~25 5 / 55 1500~2500 6

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

Fig. 4 is a flow chart of the preparation of the long-acting release powder according to the comparative example of the present invention. The various materials used in FIG. 4 were formulated with the contents in Preparation Example C5 described in Table 4.

Table 4: Formulation Form for Extended Release Powders Long-lasting release powder Preparation example C5 (Ex 5) Substance name Proportion(%) 1 Alcohol solution 95% - 2 purified water - 3 Green tea 71.43% 4 microcrystalline cellulose 16.07% 5 Zein Enteric Coating 10.00% 6 medium chain triglycerides 0.00% 7 Film coat 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 FIG. 4 and Table 4, green tea, microcrystalline cellulose and zein enteric coating are mixed. Next, after sieving and sizing as in step C12, the above-mentioned ingredients are mixed uniformly in step C14 and then put into the rapid mixing granulator. Next, provide polyvinylpyrrolidone and 95% alcohol aqueous solution in step C16 and step C18. And, in step C20, polyvinylpyrrolidone is added to the 95% alcohol aqueous solution for mixing and stirring until completely dissolved. In step C22, enteric coating of zein is provided, and then in step C24, it is added to the above-mentioned alcoholic aqueous solution for mixing to suspend and disperse. Referring to step C26, the liquid obtained in step C24 is added to the powder in step C14 above, and wet granulation is performed with a rapid mixing granulator. After the wet granulation, drying treatment is carried out in step C28, and sieving and sizing is carried out in step C30. Next, in step C32, the contents of magnesium stearate and silicon dioxide are prepared in Table 4, and then sieved in step C34. Next, in step C36, the powder obtained in step C30 is mixed with the powder obtained in step C34. Accordingly, a traditional long-acting release powder can be obtained in step C38. In Vitro Dissolution Test I

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

In the in vitro dissolution test of this experimental example, the test was carried out using a stirring paddle device (ie USP apparatus II) at 50 rotations per minute and a temperature of 37±0.5°C. The second component of the present invention (preparation examples B1~B4) and the traditional long-acting release powder (preparation example C5) are in the simulated gastric juice of pHH 1.2 in the period of 0-1 hour, in the period of 1-2 hours in Tests were performed 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 is 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, the ultraviolet-visible spectrometer (UV/VIS) is used for concentration analysis, and the dissociation ratio is calculated and confirmed through the control group (standard). The test results are shown in Figure 5 and Table 5.

Table 5: The in vitro dissolution table of the second component (controlled release layer) and comparative example 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%

Fig. 5 is a graph showing the in vitro dissolution curves of the second component according to the embodiment of the present invention and the comparative example. Referring to FIG. 5 and Table 5, it can be seen that Preparation Example B1 (Ex1) and Preparation Example B2 (Ex2) have better controlled release effects. The release of xanthine derivatives (caffeine) within 2 hours of elution in vitro does not reach 30% by weight, and is 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) released 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 promoting effect of xanthine derivatives (caffeine) after 2 hours, and can enter the intestinal environment (pH 6.8) before the controlled release. Accordingly, the prepared second component can effectively supplement and maintain a high blood concentration of xanthine derivatives in the later period of administration.

Refer to Preparation B4 (Ex4), which also has an acceptable controlled release effect. As shown in Figure 5 and Table 5, for the ingredients of Preparation Example B4, the release of its xanthine derivative (caffeine) does not reach 35% by weight within 90 minutes of in vitro elution, and the release of its xanthine derivative within 2 hours of in vitro elution (Caffeine) release does not amount to 40% by weight. Therefore, the second component of Preparation Example B4 can also be controlled to be released later in the later period of taking (after 2 hours), so as to supplement and maintain a high blood concentration of xanthine derivatives. As shown in the above Table 2, the weight ratio of the zein enteric coating of Preparation Examples B1, B2 and B4 is controlled within 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 contrast, 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), its 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 exceeded 40% by weight within 90 minutes of in vitro dissolution, and it was comparable to that of the traditional long-acting release powder dosage form (Preparation Example C5). Dissolution curves are similar. Therefore, the second component of Preparation B3 cannot effectively achieve the controlled release effect in 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 mixing granulation, the test results of Preparation Example B2 (Ex2) and Preparation Example C5 (Ex5) were compared separately. Fig. 6 is a graph comparing the in vitro dissolution curves of the enteric granulation (Ex2) according to the present invention and the traditional matrix-type mixed granulation (Ex5). Preparation Example B2 (Ex2) and Preparation Example C5 (Ex5) have the same ratio of zein enteric coating to green tea (both 10% by weight and 71.43% by weight). However, Preparation B2 was prepared by enteric granulation (step in Figure 3), while Preparation C5 was prepared by matrix mixing (step in Figure 4) , there is a big difference in the way the two are prepared.

Referring to Figure 6, it can be seen that even if the same weight ratio of zein is used for granulation, if the powder is not prepared by the steps of enteric granulation (enteric granulation) of the present invention, the control cannot be effectively achieved. release effect. As shown in FIG. 6 , the release of xanthine derivative (caffeine) in Preparation Example C5 reached 40% by weight within 90 minutes of in vitro elution, which belongs to the dosage form of sustained release. 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 elution, and the release of xanthine derivatives (caffeine) within 150 minutes of in vitro elution It can reach 46% by weight, and 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 oral formulations of bilayer tablets, 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 repeated here. The difference is that in the dissolution test of oral preparations (double-layer tablets), the extraction of the solution is continued to 1440 minutes (24 hours). The test results are shown in Figure 7 and Figure 8 .

Fig. 7 is an in vitro dissolution curve of the first component (quick-release layer) according to an embodiment of the present invention. Referring to FIG. 7 , it can be known that the first component prepared by Preparation Example A1 of the present invention has 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 100%. Accordingly, the first component of the present invention can effectively release xanthine derivatives quickly (within 2 hours) in the early stage after taking them, maintain their high blood concentration, and provide supplementary effects.

Fig. 8 is an in vitro dissolution curve of an oral formulation according to an embodiment of the present invention. Referring to Figure 8, no matter the oral double-layer tablet formed by combining Preparation Example A1 with Preparation Example B1 or the oral double-layer tablet formed by combining Preparation Example A2 with Preparation Example B2 can achieve xanthine derivatization within 90 minutes of in vitro dissolution. More than 50% of the drug (caffeine) is released. That is, the first component in the oral bilayer tablet has been fully released, while the second component is slowly controlled release. 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 100 wt. %. Accordingly, through the rapid release of the first component and the controlled release of the second component, the double-layer release controlled oral preparation of the present invention can effectively control the release of xanthine derivatives (such as caffeine), so that it maintains a high blood concentration, thereby Satisfy long-term replenishment/refreshment needs.

In summary, the embodiment of the present invention uses an oral formulation with 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 rapidly release the first component in the early stage after taking it, provide early caffeine supplementation, and control release the caffeine of the second component in the later stage. Since the second component has an edible enteric-coated material, it can gradually dissolve in the alkaline intestinal environment, resulting in the second-stage release. Accordingly, the double-layer release-controlled oral preparation of the present invention can effectively control the release of xanthine derivatives (such as caffeine), so that it maintains a high concentration in the blood, thereby meeting the long-term replenishment/refreshing demand. For example, the bilayer controlled-release oral formulation of the present invention can meet the needs of multiple replenishment/refreshments during long-term activities, such as during endurance sports such as marathons, where additional caffeine is required to enhance performance, or long-distance Driving needs to be distracted to supplement the inconvenience or interference of caffeine, and through the controlled release of the second component, it can maintain high caffeine content/high blood concentration throughout the exercise period, and can continue to provide supplementary/refreshing effects after exercise .

100: Oral preparations 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

Fig. 1 is a schematic diagram of an oral formulation according to an embodiment of the present invention. Fig. 2 is a flow chart of the preparation of the first component powder according to the embodiment of the present invention. Fig. 3 is a flow chart of the preparation of the second component powder according to the embodiment of the present invention. Fig. 4 is a flow chart of the preparation of the long-acting release powder according to the comparative example of the present invention. Fig. 5 is a graph showing the in vitro dissolution curves of the second component according to the embodiment of the present invention and the comparative example. Fig. 6 is a graph comparing the in vitro dissolution curves of the enteric granulation according to the present invention and the traditional matrix-type mixing granulation. Fig. 7 is an in vitro dissolution curve of the first component according to an embodiment of the present invention. Fig. 8 is an in vitro dissolution curve of an oral formulation according to an embodiment of the present invention.

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

Claims (20)

An oral formulation comprising: a first component comprising a xanthine derivative; and The second component, which includes the xanthine derivative and an enteric excipient, wherein the release of the xanthine derivative in the second component does not reach 35% by weight within 90 minutes of in vitro dissolution, and the second component The xanthine derivatives in the two components are released to more than 50% by weight within 3 hours of in vitro dissolution. The oral preparation according to claim 1, wherein the xanthine derivative in the second component is released within 3 hours of in vitro dissolution up to 50% by weight or more and 70% by weight or less. The oral preparation according to claim 1, wherein the xanthine derivative in the first component is released to more than 80% by weight within 1 hour of in vitro elution. The oral formulation as claimed in claim 1, wherein the xanthine derivative in the first component releases 100% by weight within 90 minutes of in vitro dissolution, and the xanthine derivative in the second component The release of the xanthine derivatives in the second component reaches 100% by weight within 8 hours to 12 hours of in vitro dissolution, and the release of the xanthine derivatives in the second component reaches 100% by weight within 12 hours to 18 hours of in vitro dissolution. The oral preparation according to claim 1, wherein the release of the xanthine derivative in the second component does not reach 40% by weight within 2 hours of elution in vitro. The oral formulation according to claim 1, wherein the oral formulation is an oral bilayer 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 formulation according to claim 1, wherein the enteric excipient is zein enteric coating. The oral formulation according to claim 8, wherein when the weight ratio of the second ingredient is 100%, the weight ratio of the zein enteric coating is 5.5% to 10% of the second ingredient. The oral preparation according to claim 1, wherein the total weight of the xanthine derivatives in the oral preparation is 50 mg to 400 mg. The oral preparation according to claim 10, wherein the weight of the xanthine derivative in the first component is 25 mg to 200 mg. The oral preparation according to claim 10, wherein the weight of the xanthine derivative 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 Xanthines include said xanthine derivatives. 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 elements include the xanthine derivatives. The oral formulation according to claim 1, wherein the oral formulation will reach the maximum blood concentration of the xanthine derivative within 90 minutes after taking it. A preparation method of oral preparation as described in claim 1, comprising: The powder of the first component and the powder of the second component are formed into a double layer ingot. The preparation method as described in claim item 16, wherein the preparation of the powder of the second component comprises: providing a coating solution comprising the enteric excipient; providing green tea, said green tea including said xanthine derivative; and The green tea element is sprayed and granulated with the coating solution to cover the weight gain range of 5% to 15%. The preparation method as described in claim item 17, further comprising: After the spray granulation, drying and sieving are carried out to form the powder of the second component. The preparation method as described in claim item 16, wherein the preparation of the powder of the first component comprises: providing green tea, said green tea including said xanthine derivative; and The alcoholic aqueous solution of polyvinylpyrrolidone is added to the powder including the green tea element, granulated, dried and sieved to form the powder of the first component. A method for using the oral preparation as described in claim 1, comprising: The oral preparation is taken 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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