WO2013162114A1

WO2013162114A1 - Sustained-release preparation using gastroretentive drug delivery system

Info

Publication number: WO2013162114A1
Application number: PCT/KR2012/004001
Authority: WO
Inventors: 박영준; 신경민; 진홍철; 성보현; 노현정; 김성준
Original assignee: 씨제이제일제당 주식회사
Priority date: 2012-04-27
Filing date: 2012-05-21
Publication date: 2013-10-31
Also published as: KR101269829B1

Abstract

The present invention relates to a sustained-release preparation which limits release and absorption of drug using a gastroretentive system and which can minimize the effect of in vivo environment, and to a method for preparing the sustained-release preparation. More particularly, the sustained-release preparation according to the present invention comprises a swellable polymer, and a first controlled-release base and a second controlled-release base. Therefore, the sustained-release preparation of the present invention may adjust the degree of swelling and floating of a polymer in order to effectively achieve gastric retention. Thus, drugs may ultimately be retained in the gastrointestinal tract over a long period of time, and the bioavailability of drugs may be improved in order to enable once-a-day administration.

Description

Sustained-release formulations using gastric drug delivery system

The present invention relates to a sustained-release preparation and a method for preparing the same, which can minimize the effect of the environment in the body to limit the release and absorption of the drug using a gastric retention system, the preparation according to the present invention is a drug for a long time in the gastrointestinal tract The present invention relates to a pharmaceutical composition capable of maximizing the drug's efficacy by improving the bioavailability of the drug by allowing the drug to be continuously released.

The gastroretentive drug delivery system is a technique for continuously maintaining the release of the drug while the agent stays in the gastrointestinal tract, and can be divided into various techniques according to the mechanism of the gastroretentive system. Typically a floating system for the formulation, a mucoadhesive system for adhering the formulation to the mucous membranes of the stomach or small intestine, a high density system that causes the formulation to settle, and It can be divided into swelling system and magnetic system that swell the formulation beyond the size of the anastomosis.

Pharmaceutical preparations using such a gastroretentive drug delivery system have been studied in various ways and have been widely published. For example, US Patent No. 6340475 and Korean Patent No. 0545480 disclose patents for intragastric retention formulations of highly soluble drugs. However, because only the hydrophilic polymer, polyethylene oxide or hydroxypropyl methylcellulose (HPMC), is designed to hold the gastric retention type, the formulation is highly likely to collapse due to the dissolution of the drug and lacks floating ability. It is difficult to achieve retention, which makes it very difficult to control the release of drugs in vivo.

In addition, Korean Patent Publication No. 2011-0048317 discloses a capsule formulation comprising an active ingredient, a gas generating material and a suspended polymer. The patent is characterized in that the capsule is again coated with a water-insoluble polymer base in order to overcome the formulation limitations that the general capsule formulation is difficult to maintain the appearance, it is difficult to ensure uniform coating of the capsule during the manufacturing process, the actual administration There is a problem in that the drug is released excessively (ie dumping).

International Patent Publication No. WO09 / 144558 and Korean Patent Publication No. 2011-0015549 disclose a technique for preparing a strip containing a drug by ultrasonic bonding, which is a special process, and rolling it up and encapsulating it into a capsule. However, in order to realize the technique of ultrasonic bonding and encapsulation into capsules, there is a problem that not only a separate special equipment is required, but also the types and amounts of drugs applicable are limited.

In addition, U.S. Patent Publication No. 20070269511 and Korean Patent Publication No. 2008-0059427 use a mixture of polyvinylacetate and polyvinylpyrrolidone as a matrix to keep the active ingredient in the stomach, and crosslinked polyvinylpyrrolidone. Formulations are used as swelling agents to swell to at least 9 mm when administered after meals or before bedtime. However, these formulations have a problem that the hardness of the formulation in the body may be affected by the crosslinked polyvinylpyrrolidone used for rapid swelling, and lack of floating ability may result in a lack of gastric retention ability. .

As such, although many efforts have been made to develop a conventional gastroretentive drug delivery system, the conventional technologies have often been unable to release the drug effectively due to the environmental impact of the drug release or disintegration of the formulation. This problem is primarily due to the fact that not only rapid pH changes in the gastrointestinal tract, but also the release behavior of the drug or the time of stay is itself affected by a more volatile gastrointestinal environment such as anoxia or hyperacidity (JCR. 111 2006.1- 18, Gastroretentive dosage forms: Overview and special case of Helicobacter pylori.PL Bardonnet a, b, et al.)

The present inventors have devised a study to confirm and improve the release of the drug significantly due to the hydrophilic polymer forming the swellable matrix is affected by the degree of swelling according to the in vivo environment, in particular the pH of the gastrointestinal tract. As a result, when adding a controlled release mechanism that dissolves easily in acidic conditions in the body and a controlled release mechanism that dissolves in relatively weak or basic conditions, both the dissolution and swelling of the drug are minimized by minimizing the effect of the pH environment in the body. It was confirmed that the formulation can be designed to be easily adjusted, and completed the present invention.

The present invention provides a sustained-release preparation using a physiologically active ingredient, a swellable polymer, a controlled release drug comprising a first controlled release agent dissolved in an acidic condition and a second controlled release agent dissolved in a weakly acidic or basic condition, and a preparation method thereof. It is to provide.

The sustained-release preparation according to the present invention, by adding a first controlled release agent and a second controlled release agent in addition to the swellable polymer, to adjust the degree of swelling of the polymer to effectively achieve gastric retention, swelling and floating properties of the formulation in vivo Has the effect of improving. Through this, it is possible to ultimately enable the drug to stay in the gastrointestinal tract for a long time, and to continuously release the drug, thereby improving the bioavailability of the drug and thus enabling the once-daily administration.

1 is a graph showing the results of the dissolution test according to the pharmacologic comparative dissolution test method 2 for 150 mg of Lyrica capsules, a control formulation according to Example 2 of the present invention.

FIG. 2 is a graph comparing pharmacokinetic patterns when Beagle dogs were administered in Example 3 and 150 mg of Lyrica capsule, a control formulation, according to an experimental example of the present invention.

In order to solve the above problems, the present invention uses a physiologically active drug delivery system comprising a pharmacologically active ingredient, a swellable polymer, a first controlled release agent dissolved in an acidic condition and a second controlled release agent dissolved in a weakly acidic or basic condition. A sustained release formulation is provided.

The sustained-release preparation according to the present invention uses a swellable polymer as a matrix of pharmacologically active ingredients for swelling in the gastrointestinal tract, and induces rapid swelling of the swellable polymer and floating of the formulation. Contains the base.

The formulations of the present invention comprise a therapeutically effective amount of the pharmacologically active ingredient. The pharmacologically active ingredient according to the present invention includes a drug which is pharmacologically effective or pharmacologically effective by a chemical or enzymatic method in the body, and specifically, the drug itself, a pharmaceutically acceptable salt or ester thereof, Can be used.

The pharmacologically active ingredient according to the present invention is a drug that can prolong the duration of the drug or improve the absorption or efficacy of the drug by regulating the release of the pharmacologically active ingredient. Drugs that are not absorbed in the gastrointestinal tract and act pharmacologically, drugs with a large difference in the degree of drug absorption between individuals, or drugs in which the absorption of the drug does not appear uniformly over the entire length of the gastrointestinal tract, especially in the upper part of the gastrointestinal tract. This is preferable. The pharmacologically active ingredient is pregabalin, gabapentin, metformin, ciprofloxacin, levodopa, trazodone, levamipid, etoprid, mosaprid, teprenon, simvastatin, atorvastatin, pravastatin, pitavastatin, baltan , Rojatan, candesartan, olmesartan, azisartan, active metabolites and mixtures thereof, but is not limited thereto. Preferably the pharmacologically active ingredient may be pregabalin or levamifeed, more preferably pregabalin.

Sustained-release preparations according to the present invention may be used to have a therapeutically effective amount of the pharmacologically active ingredient per unit dosage form, and once a day in comparison with a dosage form of an immediate release drug administered once to three times a day. Dosage designs are possible and formulations with less absorption differences between individuals can be provided.

In the present invention, the swellable polymer refers to a polymer that swells rapidly upon contact with an aqueous medium such as gastric fluid, thereby lowering the density of the formulation and controlling initial rapid release of the drug. Swellable polymers according to the present invention are polyethylene oxide, ethyl cellulose, polyvinylacetate, cellulose acetate, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, propylene glycol, polyethylene glycol and carboxymethyl cellulose Sodium may be any one or more selected from the group consisting of, preferably polyethylene oxide.

The polyethylene oxide swells upon contact with water to form a kind of gel layer through which the formulation is continuously suspended and swelled so that the formulation remains in the gastrointestinal tract for a long time. In addition, by delaying the release of the pharmacologically active ingredient, the pharmacologically active ingredient can be specifically retained at the absorption site or the site of action, thereby increasing the bioavailability of the pharmacologically active ingredient.

On the other hand, the swellable polymer is generally affected by environmental conditions such as pH during swelling and suspending in the gastrointestinal tract, and these environmental conditions simply use only the swellable polymer because there are differences in vivo and between individuals. In some cases, clinical pharmacologically significant drug delivery is difficult.

Thus, the present invention uses a first controlled release mechanism that can impart porosity to the formulation, thereby controlling the release of the drug by rapidly dissolving in an acidic environment as described above in order to effectively control the swelling and floating of the swellable polymer. .

The first controlled release agent according to the invention is an acid soluble base consisting of basic butylated methacrylate copolymer (Eudragit EPO), chitosan and propylene glycol alginate or sodium bicarbonate, calcium carbonate, sodium citrate, sodium chloride, calcium chloride, phosphoric acid Any one or more selected from alkalizing agents consisting of sodium hydrogen, sodium hydrogen phosphate and potassium dihydrogen phosphate can be used, but is not limited thereto.

The first controlled release agent may be included in an amount of 1 to 30% by weight, preferably 1 to 10% by weight, based on the total weight of the formulation. In addition, the first controlled release agent may preferably be included in 10 to 20% by weight relative to the weight of the swellable polymer.

In addition, the present invention provides a second controlled release mechanism so that, when an agent that becomes primarily porous under an acidic environment moves to the intestinal tract, the formulation collapses more quickly, leading to rapid release of the remaining pharmacologically active ingredient. use.

The second controlled release agent does not dissolve in the stomach, which is an acidic condition, and acts as a structure that maintains a certain strength so that the formulation imparted porosity by the first controlled release agent does not collapse at once. . In addition, the second controlled release mechanism serves to control the release of the formulation to overcome the deviation of the pharmacologically active ingredient and gastric retention due to anoxia or the difference in gastric acidity between individuals due to diet.

To this end, the second controlled release agent is characterized by dissolving in weakly acidic or basic conditions. The second controlled release agent according to the present invention is, for example, alginic acid, sodium alginate, ethyl methacrylate acrylic acid copolymer (Eudragit L100 D55), methacrylic acid methyl methacrylate copolymer (Eudragit L100, Eudragit S100), hydroxypropylmethyl At least one selected from the group consisting of cellulose phthalate (HP-50 / HP-55), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), polyvinylacetyl phthalate (PVAP) and cellulose acetate phthalate (CAP) can be used. This is not restrictive.

The second controlled release agent may be 1 to 30% by weight, preferably 1 to 10% by weight based on the total weight of the formulation. In addition, the second controlled release agent may be preferably 10 to 40% by weight based on the weight of the swellable polymer.

Since the second controlled release agent according to the present invention has a property of dissolving in weakly acidic or basic conditions, it promotes rapid release of the remaining pharmacologically active ingredient by inducing rapid disintegration of the dosage form after the preparation is discharged into the small intestine.

The sustained-release preparation according to the present invention includes both the first controlled release agent and the second controlled release agent, and thus exhibits a property of stably staying for more than 2 hours to 8 hours in the stomach. Adjust to maintain for at least 8 hours.

In one specific experimental example, as a result of measuring the suspension and swelling of the sustained-release drug delivery system according to the present invention, it is confirmed that it is immediately suspended in gastric conditions (pH 1.2) to maintain a completely wet and swelled state It was confirmed that it floated relatively fast in the intestinal condition (pH 6.8) to maintain a swelling state similar to the intestinal condition.

In another specific experimental example, a pharmacokinetic test was performed by administering the sustained-release drug delivery system of the present invention to a beagle dog, and a Tmax value of 4 hours or more was compared to that of a control drug showing a Tmax of 1 hour. It was confirmed that it is not affected by the surrounding environment, and shows an excellent drug release pattern (FIG. 2).

As such, the sustained-release preparation using the gastroretentive drug delivery system according to the present invention effectively controls the swelling and floating properties of the swellable polymer by using the first controlled release agent and the second controlled release agent, thereby maintaining the pharmacologically active ingredient. Has the effect of achieving a gastric retention effect.

Preferred gastric sustained release formulations of the present invention may comprise, in addition to the active ingredient, pharmaceutically acceptable excipients such as diluents, binders, glidants or coating agents.

The diluent may include lactose, microcrystalline cellulose, starch, and the like. Specifically, lactose includes lactose monohydrate, lactose anhydride, spray-dried lactose monohydrate, and microcrystalline cellulose includes microcrystalline cellulose and silicate. Microcrystalline cellulose and the like, starch may be corn starch, pregelatinized starch and the like.

The binder is a polyvinylpyrrolidone vinylacetate (PVP VA-64 ^TM BASF), a hydroxypropyl cellulose (HPC), and a polyacrylate having a binding force at low pH (Polyacrylate; Carbopol) 71G ^™ Lubrizol).

The lubricant may be magnesium alluminometasilicate, magnesium stearate, sodium stearyl fumarate, glyceryl behenate, or the like.

In addition, the sustained-release preparation using the gastroretentive drug delivery system according to the present invention may further include a film coating through a process using a small amount of an aqueous or organic solvent. For example, the formulation of the present invention may further comprise a coating base of at least one of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR White, red et al., BASF) or Opadry I / II. You can give a specific color to, and make it easier to see.

The present invention also provides a gastric drug delivery system comprising mixing a pharmacologically active ingredient, a swellable polymer, a granule, powder or granulated powder of a first controlled release agent and a second controlled release agent and filling it into a tablet or capsule. It provides a method for producing a sustained release formulation using.

As a representative example, the sustained-release preparation using the gastroretentive drug delivery system of the present invention comprises the steps of: (1) mixing the pharmacologically active ingredient with the swellable polymer; And (2) mixing the first controlled release agent and the second controlled release agent; And after mixing the mixture of step (1) and (2) with each other, it can be prepared by tableting.

The formulation of the present invention may be granulated separately from the first controlled release agent or the second controlled release agent in consideration of the stability of the pharmacologically active ingredient. The preparation method of the preparation according to the present invention may further include coating the outside of the prepared tablet or capsule by using a release control coating base, or may include a drug in the coating solution to induce immediate release.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited by these examples.

실시예 1 Example 1

As a pharmacologically active ingredient, 300 g of pregabalin, 244 g of polyethylene oxide (POLYOX WSR 303), 80 g of polyvinyl alcohol-polyethylene glycol graft copolymer (colicoat eye) and 8 g of magnesium aluminate silicate (noicillin) The mixture was sieved through a No. 30 sieve. Separately from the above mixture, 40 g of basic butyrate-methacrylate copolymer (eudragit ipio) was mixed with 40 g of sodium alginate, 40 g of copovidone, and 40 g of low-substituted hydroxypropyl cellulose (L-HPC), followed by No. 30. I passed. After the two mixtures, which were sieved, were mixed with each other, 8 mg of magnesium stearate, which was sieved through No. 30, was mixed and compressed into an elliptic tablet of 800 mg using an Erweka single tablet tablet. The tablets were coated with 3% of Opadry II to prepare sustained release tablets using a gastroretentive drug delivery system. The content of each component in the prepared tablets is shown in Table 1 below.

실시예 2 및 3Examples 2 and 3

Tablets were prepared using the same preparation method as in Example 1, except for changing the ratio of the pharmacologically active ingredient and excipient. The content of each component in the prepared tablets is shown in Table 1 below.

Table 1

ingredient	Example 1	Example 2	Example 3
Pregabalin	300	300	150
Polyethylene oxide 303	244	176	256
Microcrystalline cellulose			70
Collicoat eye	80	70	70
Eudragit Ippio	40	35	35
Sodium alginate	40	35	35
Copovidone	40	35	35
L-HPC	40	35	35
Neucillin	8	7	7
Magnesium stearate	8	7	7
Total weight (mg)	800	700	700
Opadry II	3%	3%	3%

(Content standard: mg / T)

실시예 4 및 5 Examples 4 and 5

Tablets were prepared using the same preparation as in Example 1, except for using Eudragit L100 or hydroxypropylmethylcellulose phthalate (HPMCP) instead of sodium alginate. The content of each component in the prepared tablets is shown in Table 2 below.

TABLE 2

ingredient	Example 4	Example 5
Pregabalin	300	300
Polyethylene oxide 303	244	244
Collicoat eye	80	80
Eudragit Ippio	40	40
Eudragit L100	40
Hydroxypropylmethylcellulose phthalate		40
Copovidone	40	40
L-HPC	40	40
Neucillin	8	8
Magnesium stearate	8	8
Total weight (mg)	800	800
Opadry II	3%	3%

(Content standard: mg / T)

실시예 6Example 6

As a pharmacologically active component, 300 g of pregabalin was mixed with 204 g of polyethylene oxide (POLYOX WSR 303) and 80 g of polyvinyl alcohol-polyethylene glycol graft copolymer (colicoat eye) to be sieved through No. 30 sieve. Apart from the mixture, 40 g of sodium bicarbonate was mixed with 80 g of alginic acid, 40 g of copovidone, and 40 g of low-substituted hydroxypropyl cellulose (L-HPC), and then sieved through a No. 30 sieve, and mixed with 8 g of magnesium aluminate silicate (noicillin). The sieve was again sifted into No. 30. The two mixtures, which were sieved, were mixed with each other, and then mixed with 8 mg of magnesium stearate, which was sieved through No. 30, and compressed into an 800 mg rectangular tablet using an Erweka single tablet tablet. The tablets were coated with 3% of Opadry II to prepare sustained release tablets using a gastroretentive drug delivery system. The content of each component in the tablets is shown in Table 3 below.

실시예 7 및 8Examples 7 and 8

Tablets were prepared using the same preparation method as in Preparation Example 6, except for using sodium citrate instead of sodium bicarbonate and hydroxypropylmethylcellulose phthalate (HPMCP) instead of alginic acid. The content of each component in the tablets is shown in Table 3 below.

TABLE 3

ingredient	Example 6	Example 7	Example 8
Pregabalin	300	300	300
Polyethylene oxide 303	204	204	204
Collicoat eye	80	80	80
Sodium bicarbonate	40		40
Sodium citrate		40
Alginic acid	80
Hydroxypropylmethylcellulose phthalate		80	80
Copovidone	40	40	40
L-HPC	40	40	40
Neucillin	8	8	8
Magnesium stearate	8	8	8
Total weight (mg)	800	800	800
Opadry II	3%	3%	3%

(Content standard: mg / T)

실시예 9Example 9

300 g of levamipid as a pharmacologically active ingredient was mixed with 267 g of polyethylene oxide (POLYOX WSR 303) and 90 g of polyvinyl alcohol-polyethylene glycol graft copolymer (colicoat eye) to be sieved through No. 30 sieve. Separately from the mixture, 45 g of sodium bicarbonate was mixed with 45 g of alginic acid, 45 g of copovidone, and 45 g of low-substituted hydroxypropyl cellulose, and then sieved through No. 30 sieve, and then mixed with 9 g of magnesium aluminate silicate (noicillin) again to No. 30 sieve. I passed. The two mixtures were mixed with each other, and then mixed with 9 mg of magnesium stearate, which was sieved through No. 30, and compressed into 900 mg rectangular tablets using an Erweka single tablet tablet. The tablets were coated with 3% of Opadry II to prepare sustained release tablets using a gastroretentive drug delivery system. The content of each component in the prepared tablets is shown in Table 4 below.

실시예 10 및 11Examples 10 and 11

Tablets were prepared using the same preparation as in Example 9, except for using hydrazite ipio instead of sodium bicarbonate and hydroxypropylmethylcellulose phthalate (HPMCP) instead of alginic acid. The content of each component in the prepared tablets is shown in Table 4 below.

Table 4

ingredient	Example 9	Example 10	Example 11
Levamifeed	300	300	300
Polyethylene oxide 303	312	312	312
Collicoat eye	90	90	90
Sodium bicarbonate	45		45
Eudragit Ippio		45
Alginic acid	45
Sodium alginate		45	45
Copovidone	45	45	45
L-HPC	45	45	45
Neucillin	9	9	9
Magnesium stearate	9	9	9
Total weight (mg)	900	900	900
Opadry II	3%	3%	3%

(Content standard: mg / T)

비교예 1Comparative Example 1

Comparative Example 1 was prepared for comparison with a technique of floating a tablet using conventional bicarbonate sodium bicarbonate. As a pharmacologically active ingredient, 300 mg of pregabalin was mixed with 332 mg of polyethylene oxide (POLYOX WSR 303), which was then mixed with 40 mg of silicate microcrystalline cellulose and sieved through No. 30 sieve. The sieved mixture was mixed with 80 mg of sodium bicarbonate (NaHCO ₃ ) 40 mg of citric acid, mixed with 8 mg of magnesium stearate, which was sieved through No. 30, and compressed into an 800 mg rectangular tablet using an Erweka single tablet tablet. It was. Tableted tablets were coated using 3% Opadry II. The content of each component in the tablets is shown in Table 5 below.

Table 5

ingredient	Comparative Example 1
Pregabalin	300
Polyethylene Oxide (PolyoxWSR303)	332
Silicateed Microcrystalline Cellulose (SMCC 90)	40
Sodium bicarbonate (NaHCO ₃ )	80
Citric acid	40
Magnesium Stearate (S-mg)	8
Total weight (mg)	800
Opadry II	3%

(Content standard: mg / T)

비교예 2Comparative Example 2

In the case where only the swellable polymer is included without the controlled release agent according to the present invention, a tablet containing only polyethylene oxide and a lubricant in addition to the pharmacologically active ingredient was prepared in order to compare the swelling property, floating property and bioavailability of the tablet. 300 mg of pregabalin as a pharmacologically active ingredient was mixed with 445.5 mg of polyethylene oxide (POLYOX WSR 303) and sieved through a No. 30 sieve. The sieved mixture was mixed with 5 mg of magnesium stearate, sieved through No. 30, and compressed into 750 mg of rectangular tablets using an Erweka single tablet press. Tableting the tablets were coated using the opadry AMB ^TM (Opadry AMB ^TM) of the AMB system of 22.5mg. The content of each component in the tablets is shown in Table 6 below.

Table 6

ingredient	Comparative Example 2
Pregabalin	300
Polyethylene Oxide (PolyoxWSR303))	492
Magnesium Stearate (S-mg)	8
Total weight (mg)	800
Opadry II	3%

(Content standard: mg / T)

시험예 1 Test Example 1

A Buoyancy test was performed to determine whether the tablets prepared in Examples 1-11 and Comparative Examples 1 and 2 remained in the gastrointestinal tract to control drug release. Specifically, the suspension test was performed in a 50 mL tube at pH 1.2 and pH6.8 eluate conditions. The tablets of Examples 1 to 11 and Comparative Examples 1 and 2 were placed in each eluate and observed regularly, and the time and properties of the tablets suspended and the final form after 12 hours are shown in Table 7 below.

TABLE 7

Time (min.)	Example											Comparative example
Time (min.)	One	2	3	4	5	6	7	8	9	10	11	One	2
pH1.2	Immediate floating											9	87
pH6.8	0			9	0	3	0		5	0		40	X
Constellation	Maintain complete wetting and swelling											#	*

(#: Mode loss, *: unwet core / incomplete swelling)

As a result, as shown in Table 7, the tablets of Examples 1 to 11 immediately floated in an environment of pH 1.2, but the formulations of Comparative Examples 1 and 2 took 9 minutes and 87 minutes, respectively, to float. It confirmed that it became. In addition, even in an environment of pH6.8, the tablets of Examples 1 to 11 were suspended immediately (mostly 0 minutes) or relatively quickly, but Comparative Example 1 took 40 minutes, and Comparative Example 2 was confirmed to not be suspended at all. It was. In addition, when comparing the final form (appearance) after 12 hours, the tablets of Examples 1 to 11 were completely swollen and kept wet, but the tablets of Comparative Examples 1 and 2 were completely lost or unwet. Incomplete swollen form.

As a result, the tablet according to the present invention comprises a first controlled release agent in addition to the swellable polymer, so that it can be rapidly dissolved in an acidic environment to impart porosity and floatability to the tablet, and also include a second controlled release agent. It was confirmed that the formulation serves as a structure so as not to disintegrate while being dissolved in a weakly acidic or basic environment to maintain the suspension of the formulation.

시험예 2 Test Example 2

A swelling test was performed to confirm that the sustained release tablets according to the present invention stay in the gastrointestinal tract to control drug release. Specifically, a swelling test was performed in a 50 mL tube at pH 1.2 and pH6.8 eluate conditions. The results of regular observation using the tablets of Examples 2, 3, 5, and 11 and the tablets of Comparative Examples 1 and 2, and the swelling degree measured using calipers after 2 hours are shown in Table 8 below. .

Table 8

Swelling degree		L (mm)	S (mm)	H (mm)
Example 2	Swelling I	16.30	10.28	7.02
	pH1.2	19.06	13.42	10.04
	pH6.8	18.98	13.37	10.13
Example 3	Swelling I	16.29	10.25	7.03
	pH1.2	18.98	13.32	9.97
	pH6.8	18.64	13.12	9.80
Example 5	Swelling I	17.11	8.62	6.93
	pH1.2	19.64	12.83	10.03
	pH6.8	19.33	12.34	9.85
Example 11	Swelling I	19.11	9.12	7.65
	pH1.2	22.10	12.68	10.92
	pH6.8	21.46	12.05	10.17
Comparative Example 1	Swelling I	16.43	10.28	7.20
	pH1.2	X	X	X
	pH6.8	11.64	6.81	5.43
Comparative Example 2	Swelling I	16.26	10.18	7.06
	pH1.2	18.34	13.64	9.23
	pH6.8	17.97	12.83	9.08

As shown in Table 8, the tablets of Examples 2, 3, 5, and 11 remained significantly swollen in an environment of pH 1.2 and pH6.8 compared to before swelling (before swelling). However, the tablet of Comparative Example 1 did not swell in the environment of pH 1.2, it was confirmed that the size of the tablet rather reduced in the environment of pH6.8.

시험예 3 Test Example 3

Tablets prepared in Example 2 and commercially available Lyrica capsules 150mg (Lyrica Cap Pfizer Pharmaceutical Co., Ltd.) was used as a control formulation, and the dissolution test was conducted according to Method 2 of the KPSI. The results are shown in FIG.

As a result, as shown in FIG. 1, all of the control formulations were rapidly released within 15 minutes, whereas the tablets prepared in Example 2 exhibited pseudo-zero order release behavior until 12 hours, thereby maintaining an ideal dissolution pattern.

시험예 4 Test Example 4

To confirm the pharmacokinetics, tablets prepared in Example 2 and commercially available Lyrica capsules 150 mg (Lyrica Cap PK experiment was conducted using Pfizer Korea) as a control formulation. Specifically, two groups of 12 beagle dogs were divided into two groups to confirm the pharmacokinetics of the daily administration of Example 2 in comparison with twice daily administration of 150 mg of Lyrica capsule, a commercial product. Each formulation was administered postprandial and at defined times (controls were 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 13.5, 14, 15, 16, 18 and 24 hours, the tablets of Example 2 were bled at 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 18 and 24 hours, respectively. The results are shown in Table 9 and FIG. 2.

Table 9

	Lyrica Capsules 150mg, Bid	Example 2, QD	Remarks
Tmax (hr)	After Dosing	5.3	-
Cmax	25.7	27.7	106.6%
AUC _last	235.7	257.7	110.2

As a result, as shown in Table 9, it was confirmed that the tablet of Example 2 had a Cmax value of 106.6% and an AUC of 110.2% as compared to the control group of two doses of 150 mg of Lyrica capsule. In addition, Tmax was different from the Lyrica capsule in about 1 hour, whereas the tablet of Example 2 showed a Tmax value of 4 hours or more, and was not affected by the surrounding environment, and it was confirmed that the drug release was consistently excellent.

Claims

A sustained-release preparation using a gastroretentive drug delivery system comprising a pharmacologically active ingredient, a swellable polymer, a first controlled release agent dissolved in acidic conditions and a second controlled release agent dissolved in weakly acidic or basic conditions.
The method of claim 1, wherein the pharmacologically active ingredient is pregabalin, gabapentin, metformin, ciprofloxacin, levodopa, trazodone, levamipid, etoprid, mosaprid, teprenon, simvastatin, atorvastatin, pravastatin, A formulation which is at least one selected from the group consisting of pitavastatin, balsa, rozatan, candesartan, olmesartan and azyl satan.
The formulation of claim 1, wherein the pharmacologically active ingredient is pregabalin or levamifeed.
The formulation of claim 1, wherein the pharmacologically active ingredient is pregabalin.
The method of claim 1, wherein the swellable polymer is polyethylene oxide, ethyl cellulose, polyvinylacetate, cellulose acetate, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, propylene glycol, polyethylene glycol and A formulation which is at least one selected from the group consisting of carboxymethyl cellulose sodium.
The method of claim 1, wherein the first controlled release agent is an acid soluble base consisting of basic butylated methacrylate copolymer (Eudragit EPO), chitosan and propylene glycol alginate or sodium bicarbonate, calcium carbonate, sodium citrate, sodium chloride, calcium chloride , Sodium dihydrogen phosphate, sodium hydrogen phosphate and potassium dihydrogen phosphate alkalizing agent selected from any one or more.
The method of claim 1, wherein the second controlled release agent is alginic acid, sodium alginate, ethyl methacrylate acrylic acid (Eudragit L100 D55), methyl methacrylate acrylate copolymer (Eudragit L100, Eudragit S100), hydroxypropylmethyl At least one agent selected from the group consisting of cellulose phthalate (HP-50 / HP-55), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), polyvinylacetylphthalate (PVAP) and cellulose acetate phthalate (CAP).
The formulation of claim 1, wherein the formulation further comprises a coating base of at least one of a polyvinyl alcohol-polyethylene glycol graft copolymer or an Opadry.
The formulation of claim 1, wherein the first controlled release agent is included in an amount of 1 to 30% by weight based on the total weight of the formulation.
The formulation of claim 1, wherein the first controlled release agent is included in an amount of 10 to 20 wt% based on the weight of the swellable polymer.
The formulation of claim 1, wherein the second controlled release agent is included in an amount of 1 to 30% by weight based on the total weight of the formulation.
The formulation of claim 1, wherein the second controlled release agent is comprised in an amount of 10 to 40 wt% based on the weight of the swellable polymer.
The formulation of claim 1, wherein the formulation comprises microcrystalline cellulose.
A method of preparing a formulation of claim 1 comprising mixing a pharmacologically active ingredient, a swellable polymer, a first controlled release agent and a granulated powder, powder or granulated powder of a second controlled release agent and filling it into a tablet or capsule.