KR101438546B1 - Controlled-release formulations comprising pregabalin - Google Patents

Abstract

The present invention relates to sustained release preparations containing pregabalin suitable for once-a-day oral administration. The preparation according to the present invention is intended to release stable and sustained release of pregabalin, so that the desired effect is obtained even if it is administered only once a day.

Description

[0001] CONTROLLED-RELEASE FORMULATIONS COMPRISING PREGABALIN [0002]

The present invention relates to sustained release formulations containing pregabalin suitable for once-a-day administration.

Pregabalin is a drug exhibiting anti-seizure efficacy as described in US Pat. No. 5,563,175 (RB Silverman), and is useful for the treatment of epilepsy, pain, physiological symptoms associated with psychomotor stimulants, inflammation, gastrointestinal injury, Insomnia, fibromyalgia, and various psychiatric disorders including anxiety, depression, mania, and bipolar disorder. Pregabalin has been approved for the treatment of adult diabetic peripheral neuropathy, postherpetic neuralgia and adjuvant therapy for partial early seizures in the United States. Pregabalin is available as an immediate release (IR) formulation of capsules and is administered to the patient twice a day or three times a day (BID or TID).

However, if a formulation capable of once-daily (QD) administration of pregabalin is administered twice or more per day to such symptoms, the patient's drug compliance can be improved and the drug concentration in the blood can be kept constant The drug side effects can be reduced and the effect of the drug can be sustained.

In general slow-release preparations, since the average absorption time of the drug is about 6 to 8 hours, it is difficult to expect a desirable drug effect only once per day. Therefore, in order to develop a pregabalin preparation that can be taken once a day, a special formulation design of the formulation that can extend the absorption time of the drug is needed.

Formulation design systems used for sustained-release preparations include swelling systems, floating systems, and bio-film attachment systems. Polyethylene oxide, which is a matrix-forming agent used in a conventional swelling system, has a problem of low swelling, which can withstand external resistance after swelling, although swelling is good. US patent publications US6340475 and US6488962 describe a swelling system containing polyethylene oxide and xanthan gum. The polymer used in such a swelling system has a low resistance after swelling, and thus there is a risk that the form of the preparation may collapse rapidly due to gastrointestinal motility. The Journal of Pharmaceutical Sciences (2009) Vol. 39, No. 4 discloses the preparation of a swellable supernatant tablet by preparing a swellable tablet and coating a semi-permeable membrane on the surface of the tablet. The system is disadvantageous in that the semi-permeable membrane is damaged due to the movement of the gastrointestinal tract, and controlled release becomes impossible.

In addition, a conventional floating system has a disadvantage in that it can not be floated within a short time (within about 30 minutes after administration) due to a relatively high-density main component and other additives.

On the other hand, the biomembrane attachment system is difficult to maintain due to the movement of the gastrointestinal tract and the influence of foods, and there is a problem that the product is not actually produced.

U.S. Patent No. 5,563,175 U.S. Patent No. 6,340,475 U.S. Patent No. 6,488,962

Journal of Pharmaceutical Sciences (2009) Volume 39 Issue 4

The present invention provides a sustained release preparation of pregabalin which is formulated so as to obtain a desired effect even when pregabalin is administered only once a day.

The present invention provides a sustained release preparation further comprising at least one of a swelling agent, a matrix forming agent and a gas generating agent in a sustained release preparation comprising pregabalin or a pharmaceutically acceptable salt thereof as an active ingredient .

According to one embodiment of the present invention, it is preferable that the matrix forming agent is hypromellose.

According to another embodiment of the present invention, the viscosity of the matrix forming agent is preferably 4,000 to 150,000 cps.

According to another embodiment of the present invention, the swelling agent is sodium starch glycolate, and the gas generating agent is preferably sodium bicarbonate.

According to another embodiment of the present invention, the amount of the swelling agent is 2 to 8 wt%, the amount of the matrix forming agent is 20 to 35 wt%, and the amount of the gas generating agent is 4 to 10 wt% desirable.

According to another embodiment of the present invention, the sustained-release preparation preferably floats in a solution having a pH of 1.2 to pH 4.0 within 30 minutes, and the suspension is maintained for 5 hours to 24 hours.

According to another embodiment of the present invention, it is preferred that the sustained-release preparation is increased from 1.5 to 2 times the total volume of the first sustained release formulation within 1 hour in a solution of pH 1.2 to pH 4.0.

The sustained-release preparation according to the present invention is intended to release stable and sustained release of pregabalin, so that even when administered once a day, the desired effect is exerted.

FIG. 1 is a graph showing the dissolution rates of Example 1 and Comparative Examples 2 and 3 with time. FIG.
FIG. 2 is a graph showing the time-blood concentration in Example 1 and a beagle dog of a reference drug (Pfizer Inc., Lilica). FIG. In the above graph, Reference shows the results of the actual test in the first group (reference drug) as the control agent and Test shows the results of the experiment in the second group (use of Example 1) as the sustained-release test agent.

The present invention relates to a sustained release formulation comprising pregabalin or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the sustained release formulation further comprises at least one of a swelling agent, a matrix forming agent and a gas generating agent do.

The pregabalin sustained release preparation of the present invention may contain at least one of a swelling agent, a matrix forming agent and a gas generating agent, and it is preferable that both the swelling agent, the matrix forming agent and the gas generating agent are included. In the case where only the swelling agent and the matrix forming agent are used for the pregabalin, since the size of the pylorus and the Gastric emptying time are individually different due to the characteristics of individual patients, the pills may pass through the pylorus before the preparation sufficiently swells In addition to the swelling agents and matrix formers of the present invention, the formulation containing the gaseous agent should be thoroughly swollen, and then the pylorus Let it pass.

The pregabalin of the present invention may be prepared using known methods. In some of these methods, a racemic mixture of 3-aminomethyl-5-methyl-hexane is synthesized and subsequently decomposed into its R- and S-enantiomers. The pregabalin of the present invention may be an enantiomer of R- or S-, and the pharmaceutically acceptable salt of the pregabalin of the present invention may be a known alkali or acidic salt.

The swelling agent of the present invention means a component capable of swelling in a short time, and may be crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, and the like, but is not limited thereto.

The swelling agent is preferably contained in an amount of 2 to 8% by weight based on the total weight of the preparation according to the present invention. When the amount of the matrix forming agent is less than 2% by weight, the matrix forming agent can not be expanded due to the high viscosity. In the case of exceeding 8% by weight, the matrix system may be destroyed due to excessive swelling.

The matrix-forming agent means a component used for the purpose of forming a matrix of a sustained-release pharmaceutical preparation. The matrix-forming agent complements the disadvantage that the residence time of the sustained-release pharmaceutical preparation is shortened due to weak resistance after swelling in vivo. Preferably, the matrix forming agent is a formulation having a high degree of rigidity and a high viscosity. The matrix forming agent of the present invention may be polyethylene oxide, carbomer, hydroxyethyl cellulose, methyl cellulose, xanthan gum, hypromellose and the like. Preferably, hypromellose having high viscosity and rigidity may be used And more preferably, a viscosity of 100,000 cps may be used. However, the present invention is not limited thereto. Hypromellose 2208, which is commercially available from Shinetsu of Japan, may be used as the hydro-melose having a viscosity of 100,000 cps.

The viscosity of the matrix forming agent of the present invention is preferably 4000 to 150000 cps. If the viscosity of the matrix-forming agent is less than 4000 cps, there is a risk that the drug release rate can not be controlled due to the rapid expansion of the swelling agent and the movement of the gastrointestinal tract in the human body and destruction of the matrix system. If the viscosity exceeds 150000 cps, An excessive amount of swelling agent has to be added and there is an undesirable problem in oral dosage form in an oversized size, typically taking into account the weight of the additive added to the formulation.

The matrix forming agent is preferably included in an amount of 20 to 40% by weight based on the total weight of the formulation according to the present invention. If it is less than 20% by weight, there is a risk that the matrix system may be destroyed due to insufficient expansion of the swelling agent and movement of the gastrointestinal tract. If it exceeds 40% by weight, the swelling speed is lowered, There is a problem that when an excessive swelling agent is added to achieve the above-mentioned oral dosage form, it is produced in an undesirable size.

The gas generating agent according to the present invention refers to a component having a function of suspending a pharmaceutical preparation according to the present invention by generating gas in the body.

Common gas generators react in an acidic environment to generate carbon dioxide and are therefore often used in combination with an acidifying agent. However, since the preparation according to the present invention is designed to prolong the residence time in the acid environment in consideration of absorption and release of pregabalin, it is preferable to use a gas generating agent capable of causing a reaction without an acidifying agent. As the gas generating agent, sodium carbonate or sodium bicarbonate is used, and sodium bicarbonate is more preferably used.

The gas generating agent is preferably contained in an amount of 1 to 20% by weight based on the total weight of the preparation. When the amount is less than 1% by weight, there is a problem that the amount of gas generated is low and the preparation is difficult to float. When the amount is more than 20% by weight, excessive gas is generated at the initial stage of oral administration and the matrix system is destroyed.

The preparation according to the present invention can float within 60 minutes in an acidic solution having a pH of 1 to 4 and can maintain floating for 5 to 24 hours so that sustained release can be maintained in the stomach for a long time.

In addition, since the preparation according to the present invention can be increased to 1.5 times to 2 times the total volume of the initial preparation within 1 hour in the solution of pH 1 to pH 4, Lt; / RTI >

The preparation according to the present invention may further contain an excipient such as an excipient and a binder and a lubricant which increase the hardness. As the binder, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose and the like can be used. As the lubricant, talc, stearyl fumarate, magnesium stearate and the like can be used, but it is not limited thereto.

In addition, the pharmaceutical preparation according to the present invention may be coated as a material capable of preventing hygroscopicity after tablet molding to secure the stability of pregabalin, and may be coated with waxes, paraffins, phthalic acid derivatives, polyvinyl alcohol, cellulose acetate, Hydroxypropylmethylcellulose, ethylcellulose, and the like, and a combination thereof can be used.

The preparation of the present invention can be administered to an adult in a total dose of 150 to 600 mg per day on the basis of pregabalin, and can be administered once a day.

In addition, the preparation of the present invention can be prepared in various formulations and can be formulated into tablets, powders, granules, capsules, etc., for example, tablets, coated tablets, multi-layer tablets, or oily tablets.

The route of administration of the preparation of the present invention is not particularly limited, but oral administration is preferable.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples and the like.

Tablet manufacturing method

Components other than magnesium stearate were passed through 35 wells and mixed for 15 minutes using a mixer (P-20087, Drum mixer). The resulting mixture was granulated using an oscillator (YBK-60, Zhangjiagang Create Mechanical Manufacturing) equipped with a No. 18 sieve after preparing a slurry using a compressor (MFL-01, Freund). Subsequently, magnesium stearate passed through the 35th tumbler was added to the granules and mixed in a mixer (P-20087, Drum mixer) at 14 rpm for 5 minutes. This mixture was molded into tablets having a hardness of 15 to 20 kgf using a tablet machine equipped with a rectangular punch having a major axis of 19 mm and a minor axis of 9 mm.

Example 1  And Comparative Example 1 ~ 4

Example 1 was composed of a composition including both a matrix forming agent, a swelling agent and a gas generating agent. In Comparative Examples 1 to 3, one of the three functional materials was excluded. In Comparative Example 4, all three materials were excluded . The elution of the drug and the change of physical properties of the drug were observed according to the presence of each substance in the tablets prepared according to the above tablets production method. Table 1 shows the composition (mg / tablet) of Example 1 and Comparative Examples 1 to 4.

fair ingredient Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 compression Pregabalin 300 300 300 300 300 Hypromellose  2208 100000 300 - 300 300 - Starch glycolate sodium 40 40 - 40 - Sodium bicarbonate 80 80 80 - - Microcrystalline cellulose (balance) 118 418 158 198 538 Hydroxypropylcellulose 155 155 155 155 155 After mixing Magnesium stearate 7 7 7 7 7 Sum 1000 1000 1000 1000 1000

Example 2 , 3 and Comparative Example 5 ~ 8

Examples 2 and 3 and Comparative Examples 5 to 8 are compositions designed to determine the difference in the amount and viscosity of hypromellose as a matrix forming agent. The manufacturing method was the same as described above. Table 2 shows the compositions (mg / tablet) of Examples 2 and 3 and Comparative Examples 5 to 8.

fair ingredient Example 2 Example 3 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 compression Pregabalin 300 300 300 300 300 300 Hypromellose  2208 100000 200 350 150 400 Hypromellose  2208 4000 350 Hypromellose  2208 150000 200 Starch glycolate sodium 40 40 40 40 40 40 Sodium bicarbonate 80 80 80 80 80 80 Microcrystalline cellulose (balance) 218 68 268 18 68 218 Hydroxypropylcellulose 155 155 155 155 155 155 After mixing Magnesium stearate 7 7 7 7 7 7 Sum 1000 1000 1000 1000 1000 1000

Example 4 , 5 and Comparative Example 9 , 10

Examples 4 and 5 and Comparative Examples 9 and 10 are compositions designed to examine the physical properties of a preparation according to the amount of sodium starch glycolate, which is a swelling agent. The manufacturing method was the same as described above. Table 3 shows the compositions (mg / tablet) of Examples 4 and 5 and Comparative Examples 9 and 10.

fair ingredient Example 4 Example 5 Comparative Example 9 Comparative Example 10 compression Pregabalin 300 300 300 300 Hypromellose 2208 100000 300 300 300 300 Starch glycolate sodium 20 80 10 100 Sodium bicarbonate 80 80 80 80 Microcrystalline cellulose (balance) 138 78 148 58 Hydroxypropylcellulose 155 155 155 155 After mixing Magnesium stearate 7 7 7 7 Sum 1000 1000 1000 1000

Example 6 , 7 and Comparative Example 11 , 12

Examples 6 and 7 and Comparative Examples 11 and 12 are compositions designed to investigate changes in the physical properties of formulations according to the amounts of sodium bicarbonate which is a gas generating agent. The manufacturing method was the same as described above. Table 4 shows the compositions (mg / tablet) of Examples 6 and 7 and Comparative Examples 11 and 12.

fair ingredient Example 6 Example 7 Comparative Example 11 Comparative Example 12 compression Pregabalin 300 300 300 300 Hypromellose 2208 100000 300 300 300 300 Starch glycolate sodium 40 40 40 40 Sodium bicarbonate 40 100 20 120 Microcrystalline cellulose (balance) 158 98 178 78 Hydroxypropylcellulose 155 155 155 155 After mixing Magnesium stearate 7 7 7 7 Sum 1000 1000 1000 1000

Experimental Example  1-Evaluation of dissolution rate

The dissolution test was carried out in 900 ml of pH 1.2 according to the dissolution test method 1 (basket method) in the general test method of KP. 3 mL each was taken at 0.5, 1, 2, 4, 6, 8, 10, 16, and 24 hours and 2 mL was passed through a 0.45 μm PVDF filter. 1 mL was taken and the drug was quantitated by HPLC under the following conditions.

- Detector: UV absorptiometer

- Column: Capcell Pak-C18, 150 x 4.6 mm, particle size 5 μm or equivalent column

- Column temperature: 30 ° C

- Flow rate: 1.0 mL / min

- Injection amount: 50 μl

- Detector wavelength: 210 nm

- mobile phase: buffer / methanol / acetonitrile = 800/150/50 adjusted to pH 7.0 with phosphoric acid (buffer = 3.5 g of K2HPO4 dissolved in 1000 mL of purified water)

Table 5 shows the dissolution rates of Example 1 and Comparative Examples 1 to 4, and FIG. 1 shows dissolution rates of Light Comparative Examples 2 and 3 of Example 1. FIG. Table 5 shows the dissolution rate (%) of pregabalin (Example 1 and Comparative Examples 1 to 4) with time.

Time (hr) Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 0 0 0 0 0 0 0.5 7.3 98.1 3.2 4.3 97.5 One 12.6 99.2 8.4 8.7 99.4 2 20.5 99.5 15.9 13.2 100.5 4 36.8 30.8 28.7 6 50.4 42.1 43.1 8 60.9 54.2 53.2 10 68.9 62.3 63.7 16 88.1 82.1 83.4 24 97.8 99.9 95.2

As a result of the above test results, in Comparative Example 1 and Comparative Example 4 in which hypromellose was not added as a matrix-forming agent, there was a sudden burst of the drug due to disintegration of the initial elution. The rate of release of the drug according to the presence or absence of the swelling agent and the gas generating agent is not greatly different, and it can be predicted that the additive for controlling the release rate of the drug is the matrix forming agent, hypromellose.

Table 6 shows the dissolution test results of Examples 2 and 3 and Comparative Examples 5 to 8 in which the release rate of the drug according to the amount and viscosity of the hydromellose was compared. Table 6 shows dissolution rates (%) of pregabalin (Examples 2 and 3 and Comparative Examples 5 to 8) with time.

Time (hr) Example 2 Example 3 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 0 0 0 0 0 0 0 0.5 12.3 6.2 28.8 4.2 8.2 7.3 One 18.6 10.6 40.8 8.2 12.8 10.5 2 27.9 17.3 52.3 12.6 20.5 17.6 4 43.2 33.8 67.9 24.2 38.7 34.5 6 56.8 47.2 77.8 35.4 53.4 46.2 8 67.5 57.8 86.4 45.6 62.3 58.1 10 76.4 65.7 93.8 55.3 70.5 66.2 16 93.4 85.4 98.7 74.3 90.5 87.5 24 97.5 95.8 99.4 87.5 99.2 98.4

At the same viscosity, the release rate of the drug tended to increase with decreasing addition amount, and the dissolution rate tended to decrease with increasing viscosity.

Experimental Example  2- Evaluation of swelling degree

The degree of swelling of the tablets of Examples 4 and 5 and Comparative Examples 9 and 10 was measured in order to compare the degree of swelling according to whether or not the swelling agent and the gas generating agent were included in the tablets containing 30% of the total amount of hydromellose 2208. [ The tablets were put into the basket at the outlet of 900 mL of the pH 1.2 solution and stirred at a rotating speed of 50 rpm and the size of the tablets with time was measured using a vernier caliper (CD-20CPX, Mitutoyo Corp.). The results are shown in Table 7. Table 7 shows the results of the tablet size evaluation over time (Examples 4 and 5 and Comparative Examples 9 and 10).

Example 4 Example 5 time
(hr) Long axis
(mm) shorten
(mm) Height
(mm) volume
(mm ³ ) Long axis
(mm) shorten
(mm) Height
(mm) volume
(mm ³ ) 0 19.2 9.2 6.9 1216.1 19.2 9.2 6.9 1213.3 0.5 19.9 10.9 8.1 1756.1 21.3 12.7 9.1 2457.4 One 20.2 13.6 9.1 2514.1 22.5 14.7 10.1 3333.2 2 20.6 14.5 10.3 3083.8 23.0 16.2 11.5 4263.3 Comparative Example 9 Comparative Example 10 time
(hr) Long axis
(mm) shorten
(mm) Height
(mm) volume
(mm ³ ) Long axis
(mm) shorten
(mm) Height
(mm) volume
(mm ³ ) 0 19.2 9.3 6.8 1211.1 19.1 9.2 6.8 1203.7 0.5 19.4 9.3 7.0 1263.3 Tablets destroyed One 19.9 9.5 7.1 1349.7 2 20.0 9.7 7.3 1405.9

As shown in Table 7, the swelling speed of the tablet was increased as the amount of the swelling agent was increased. In Comparative Example 10 in which the added amount was 10% of the total weight, the matrix system was maintained due to the disintegration of the initial tablet, I could not see. In Comparative Example 9 in which the amount of swelling agent is 1% by weight, the length of the short axis was less than 10 mm until 2 hours, and there was a fear of passing through the pylorus upon oral administration.

Experimental Example  3- Float time evaluation

In order to evaluate the floating time of the designed tablets, the tablets were dropped into the outlet of 900 mL of each of pH1.2 and pH 4.0 (warmed at 37 ° C) and the time for the tablets to float was measured. The results are shown in Table 8. Table 8 shows the measurement results of the suspension time of the tablets containing the gas generating agent.

Specimen Float time (minutes) in pH 1.2 solution Float time (minutes) at pH 4.0 solution Example 6 10-12 15 ~ 18 Example 7 3 to 5 7 to 10 Comparative Example 3 180 ~ 200 180 ~ 200 Comparative Example 11 60 to 70 80 ~ 90 Comparative Example 12 Five minutes to refinement of tablets Between 5 and 8 minutes Tablet breakage

Referring to Table 8, the tablets of Comparative Example 3 in which sodium bicarbonate was not added showed a tendency that the tablets slowly floated after about 180 minutes, and the uptake time tended to increase as the addition amount increased. Examples 6 and 7 showed favorable results with a suspension time of the tablet within about 20 minutes. However, in Comparative Example 12 in which sodium bicarbonate was contained in a total amount of 12%, the tablet was destroyed in about 5 to 8 minutes after the tablet release, and the matrix system could not be maintained.

Experimental Example  4- Prediction of gastrointestinal motility resistance

For the purpose of predicting the resistance in the gastrointestinal tract of the tablets of Example 1, the tablets placed in the sinker according to the second method (paddle method) of the dissolution test method of the Korean Pharmacopoeia (General Practice) 50 rpm, and 100 rpm, respectively. The amount of the drug was assayed in the same manner as in Experimental Example 1. The results are shown in Table 9. Table 9 shows the dissolution rate comparison result of Example 1 according to the stirring speed.

Time (hr) 50rpm 100 rpm 0 0 0 0.5 7.3 13.2 One 12.6 18.3 2 20.5 26.8 4 36.8 41.6 6 50.4 54.8 8 60.9 66.2 10 68.9 75.3 16 88.1 93.5 24 97.8 99.1

As shown in Table 9, the dissolution rate according to the rotation speed is within about 6%, and it is predicted that the rapid release of the drug is less likely to occur due to the movement of the gastrointestinal tract.

Experimental Example  5-Stability evaluation

In order to evaluate the stability of the tablets prepared in Example 1, the samples were placed in a high density polyethylene (HDPE) bottle and stored at 40 ° C. and 75% relative humidity, and pregabalin and lactam, And the tendency of change of contents was observed.

The experimental results are shown in Table 10 below. Table 10 shows the stability evaluation results of Example 1.

time content(%) Lactam content (%) Start 99.6 0 2 weeks 99.4 0.03 4 weeks 99.5 0.02 6 weeks 99.4 0.03 3 months 98.8 0.05 6 months 98.4 0.07

Referring to Table 10, the change in the content up to 6 months was negligible, and the content of lactam, which is the main degradation product, was also less than 0.1%, indicating that the preparation of Example 1 was stable.

Experimental Example  6 - Pharmacokinetic evaluation in animals

To examine the bioavailability and pharmacokinetic parameters of the test drug containing 300 mg of pregabalin, a test using beagle dogs was performed on a commercially available ricalin capsule (150 mg pregabalin) as a control. The test drug was prepared and used in the same composition as in Example 1. Twelve healthy beagle dogs (9.45 to 12.60 kg, 28 to 29 months old) were divided into two groups of 6 animals each, and the control group was divided into two groups: one capsule twice a day (150 mg as pregabalin) And group 2 received oral dosing once a day, once per day (300 mg as pregabalin) orally. After oral administration, blood samples were collected for 48 hours for each of the control and test drug groups, and the plasma pregabalin concentration was quantitatively analyzed by LC-MS / MS. Based on the results, pharmacokinetic parameters such as Cmax, Tmax, AUCt, T1 / 2, Vd / F and CL / F of control and test compounds were calculated.

The experimental results are shown in FIG. 2 and Table 11. In FIG. 2 and Table 11, the reference is the result of actual test in the first group, which is the control agent, and Test, the test result in the second group, the sustained-release test agent. Table 11 shows the pharmacokinetic parameters after oral administration of pregabalin preparation in beagle dogs.

Referring to FIG. 2 and Table 11, in the case of pregabalin plasma, the sustained release test drug showed a relative bioavailability of about 70 to 73% relative to the immediate release control drug, and tmax and t1 / The results are shown in Table 1.

Claims (7)

A sustained release preparation comprising pregabalin or a pharmaceutically acceptable salt thereof as an active ingredient, the composition further comprising a swelling agent, a matrix forming agent and a gas generating agent,
Wherein the matrix former is hypromellose, the swelling agent is sodium starch glycolate, the gas generant is sodium bicarbonate,
Wherein the amount of the swelling agent is 2 to 8 wt%, the amount of the matrix forming agent is 20 to 35 wt%, and the amount of the gas generating agent is 4 to 10 wt% with respect to the total weight of the sustained release agent.
delete The method according to claim 1,
Wherein the matrix forming agent has a viscosity of 4000 to 150000 cps.
delete delete The method of claim 3,
Wherein the sustained-release preparation is suspended within 30 minutes in a solution having a pH of 1.2 to 4.0 and maintained in suspension for 5 to 24 hours.
The method of claim 3,
Wherein the sustained release preparation is increased from 1.5 to 2 times the total volume of the initial sustained release formulation within 1 hour in a solution of pH 1.2 to pH 4.0.

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