WO2015174684A1 - Release-controlled gastroretentive extended-release preparation - Google Patents

Abstract

The present invention relates to a gastroretentive extended release preparation for the gastric retention of drugs and the release control thereof and, particularly, to a gastroretentive extended release preparation capable of controlling the release of a drug while floating/staying in the stomach instantly after being administered. The present invention is not affected by the pH of the stomach, floats instantly when coming in contact with gastric juice, and can readily control drug release according to the control of the content % of a release controller. Therefore, the present invention can continuously release active ingredients for a long time while a drug stays in the stomach without the possibility of migrating to the small intestine when orally administered even in an environment in which the pH of the gastric juice and the amount of gastric juice are changed greatly according to a diet, such as in a patient with hypoacidity, during pre-meal administration, and when there is an increase in the pH of the stomach or a deficiency of gastric juice.

Description

Controlled Release Sustained Sustained Release

The present invention relates to a formulation for controlling gastric retention and release of a drug, and relates to a gastroretentive sustained release formulation capable of controlling the release of the drug while suspended / staying in the stomach immediately after administration.

The main purpose of the oral drug delivery system is to efficiently deliver drugs to reduce side effects of the drugs and to achieve high bioavailability, wherein the residence time of the drug at the absorption site is one of the very important factors affecting the bioavailability.

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 is divided into various types according to the mechanism of the gastroretentive drug delivery system. Typically a floating system of the formulation, a mucoadhesive system for the mucous membrane of the stomach or small intestine, a high density system to cause the formulation to settle, and a pyloric stomach It can be classified into swelling system and magnetic system that swell more than size.

Pharmaceutical preparations using the gastric retention drug delivery system have been variously studied, and among them, the gastric retention system through floating of the formulation is most actively studied, and as a gastric retention system through floating of the formulation, the Republic of Korea Patent No. 1268215 Nos. 12,698, 1270751, 1270251, and 1313192 use the properties of a swelling polymer when in contact with gastric fluid or use a swellable polymer and a bubbler in combination to trap bubbles in the swellable polymer. A gastroretentive drug delivery system is disclosed.

However, the gastroretentive drug delivery system due to the swellable polymer used in the gastroretentive system through suspension of the formulation requires time for the polymer to swell, and the formulation is transferred to the small intestine before the polymer is swollen to have sufficient suspension. There are disadvantages that can be made. In addition, the bubble generator reacts with gastric acid to generate CO _{2. In} this case, the pH in the stomach may vary depending on the diet, thereby degrading the ability to generate bubbles.

In order to make up for this drawback, a gastric drug delivery system has recently been studied in which uncoated tablets are added to the tablets to make uncoated tablets and then heated to sublimate the Camphor to lower the tablet density than the contents of the stomach, resulting in floating immediately upon ingestion. (ref. Preparation of highly porous gastroretentive metformin tablets using a sublimation method, European Journal of Pharmaceutics and Biopharmaceutics , 2013). However, this porous uncoated tablet has a disadvantage in that the manufacturing process is complicated because Camphor, which is a sublimable material, needs to be removed after the sublimation of Camphor is added to improve flotation.

Accordingly, the present inventors have attempted to develop a low-density gastric sustained-release preparation having a simple manufacturing process in order to overcome the above problems in the gastroretentive system through suspension of the formulation.

It is an object of the present invention to provide a low-density gastric sustained release formulation that floats upon contact with gastric fluid without affecting gastric pH in the gastroretentive system through suspension of the formulation.

In order to achieve the above object, the present invention provides a low-density gastric sustained-release preparation comprising a pharmacologically active ingredient, crospovidone and a release controlling agent.

Gastric drug delivery system through the suspension of the formulation according to the present invention to efficiently deliver the drug by reducing the side effects of the drug and achieve a high bioavailability of the gastric juice and the gastric juice (Migrating motor complex) Because of the possibility that the preparation may be transferred to the small intestine by MMC, the gastroretentive system preparation should be able to have sufficient suspension even in hypoacidic patients, even when taken before meals, due to elevated pH in the stomach or lack of gastric fluid. .

The present invention essentially contains crospovidone and can be prepared by simple mixing and tableting of the pharmacologically active ingredient and the release modulator, and the preparation according to the present invention is immediately suspended and can control the release of the pharmacologically active substance. have.

The components of the formulation of the present invention and the principles of the invention will be described in more detail below.

Pharmacologically active ingredients as defined herein include pharmacologically effective or pharmacologically effective drugs by chemical or enzymatic methods in the body, specifically their precursors, such as pharmacologically acceptable salts or esters thereof. Can be used.

The pharmacologically active ingredient according to the present invention is a drug that can improve the duration of the drug by improving the release of the pharmacologically active ingredient by the release controlling agent, or the drug can be absorbed or improved efficacy of the drug, solubility in the proximal gastrointestinal tract, solubility Drugs that are small or degraded by base pH in the lower gastrointestinal tract, drugs whose absorption pattern changes with changes in gastric emptying time, drugs that must be released locally in the proximal small intestine and stomach for the treatment of certain conditions, and H. pylori infection Drugs used for the treatment of inflamed gastric ulcers are preferred. Specifically, the pharmacologically active ingredients are leaf extract, corydalis and nut extract, pregabalin, gabapentin, ciprofloxacin, metformin, levodopa, limaprost, fenofibric acid, trazodone, levamipid, etoprid, mosaprid , Can be selected from the group consisting of Tefrenone, simvastatin, atorvastatin, pravastatin, pitavastatin, balsatan, rozatan, candesartan, olmesartan, azilsatan, active metabolites thereof, and mixtures thereof It doesn't work. Preferably the pharmacologically active ingredient may be a leaf extract, corydalis and aza extract, limaprost, pregabalin, metformin, levodopa, gabapetin, ciprofloxacin, and more preferably leaf extract, corydalis and aza extract Or limafrost.

The leaf extract in the present invention is mugwort Artermisia priceps Pamp. The leaves and young stems of var orientalis hara (Asteraceae compositae) are extracted, and the extraction solvent is most preferably ethanol, but is not limited thereto, and may be extracted using an organic solvent such as isopropanol and butanol.

In the present invention, the corydalis and the nut extract are extracted from the herbal cortex (Korean medicinal herbs, Tuber (Copper Root) of Corydalis ternata Nakai (Papaver Papaveraceae)]] and the nut [Chrysanthemum medicinal plants, Seed (seed) of Phabitis nil Choisy (Mortis and Convolvulaceae)]. As the extraction solvent, ethanol is most preferred but not limited thereto, and may be extracted using an organic solvent such as isopropanol and butanol. In addition, the corydalis and cow's milk extract may be extracted by mixing the corydalis and the cow's milk, respectively, or by mixing the corydalis and the cow's milk together, and the corydale and the cow's milk may be mixed in a weight ratio of 1: 1 to 10: 1 And, most preferably, corydalis and cow's milk are extracts mixed in a 5: 1 weight ratio (w / w%).

Crospovidone is essentially contained in the present invention, more preferably may be Crospovidone Type B.

In the present invention, crospovidone is added to 10 to 80% by weight of the total weight of the uncoated tablet, the formulation containing it is not only suspended immediately, tablet tablets when tableting has an excellent hardness of less than 0.3% during tableting Retention formulations can be prepared. However, when the crospovidone is less than 10% by weight, it does not immediately float and sinks, and when it exceeds 80% by weight, the floating capacity is not satisfactory and easily disintegrates, and in particular, when more than 90% by weight, the formulation disintegrates within 20 minutes. As a result, they do not play the role of Western dissemination.

The release controlling agent defined in the present invention is hypromellose, polyethylene oxide, povidone, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, Xanthan gum, gelatin, carbomer, polyvinylacetate, polyethyleneglycol and the like. Preferably the release controlling agent may be hypromellose, polyethylene oxide and povidone, more preferably hypromellose.

In the present invention, the release controlling agent can easily control the drug release by adjusting the content% according to the characteristics of the preparation, and preferably may comprise 10 to 50% by weight relative to the total weight of the preparation. In addition, the present invention can manufacture a gastric retention system that can freely control the suspension holding time by adjusting the content% of the release control agent.

In addition, in addition to the active ingredient, the gastroretentive sustained-release preparation of the present invention may include pharmaceutically acceptable excipients such as diluents, binders, glidants or coating bases.

The gastroretentive sustained release preparation according to the present invention is suspended immediately upon contact with gastric fluid without being affected by pH in the stomach, and can easily control drug release by adjusting the release control agent content%.

Therefore, the present invention is a hypoacidic patients, when taking pre-meal, when the pH of the gastric juice or the amount of gastric juice greatly varies depending on the diet, such as when the pH of the stomach or lack of gastric juice, oral administration, without the possibility of drug transfer to the small intestine It can stay in the stomach and release the active ingredient continuously for a long time.

1 is a view showing the dissolution test results of the sustained-release gastric body tablets prepared in Examples 1 to 4 and Comparative Example 7.

Figure 2 is a view showing the dissolution and suspension behavior of the sustained-release gastric suspension tablet prepared by Example 8.

3 is an X-ray photograph of tablets of Comparative Example 5 and Example 10.

FIG. 4 shows the gastric retention behavior of Comparative Example 5 using a beagle dog, and is an abdominal X-ray photograph of a beagle dog with time after rapid administration of Comparative Example 5. FIG.

FIG. 5 is a view showing gastric retention behavior of a tablet of Example 10 using a beagle dog, and is an abdominal X-ray photograph of a beagle dog with time after administration of the tablet of Example 10. FIG.

Figure 6 shows the in-vitro elution behavior of the sustained release gastric tablets prepared in Example 11.

FIG. 7 is a diagram showing an in-vivo blood concentration profile in beagle dogs of the sustained-release gastric retention tablet prepared in Example 11. FIG.

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

<Examples 1 to 4> Preparation of gastroretentive sustained release preparation according to the present invention (1)

As pharmacologically active ingredients, fenofibric acid and crospovidone Type B, hypromellose, and magnesium stearate were weighed to the amounts shown in Table 1 per tablet and sieved through No. 30. Each of the sieved ingredients were mixed, compressed into 500 mg of circular tablets using an Erweka single tablet tablet, and used in Examples 1 to 4, respectively.

Table 1

Example 5 Preparation of gastroretentive sustained release preparation according to the present invention (2)

A formulation was prepared using Limaprost-alphadex as the pharmacologically active ingredient, to give Example 5. The content of each component is shown in Table 2, to prepare a tablet using the same production method as in Example 1.

TABLE 2

<Example 6> Preparation of gastroretentive sustained release preparation according to the present invention (3)

As a pharmacologically active ingredient, a preparation was prepared using calendula red color and the nut extract, and the preparation of Example 6 was carried out.

1. Preparation of Corydalis and Cattle Extract

83.5 kg of Chinese herbal medicine [Tuber of Corydalis ternata Nakai (Popaver Papaveraceae)] and nut [Chinese Pharmacopoeia, Seed of Phabitis nil Choisy (Madflower and Convolvulaceae)] Add 6 ~ 8 times (w / w) of 50% ethanol and extract for 48 hours at 10 ~ 20 ℃. Impurities were removed from the extract using activated carbon and an adsorbent, filtered, and concentrated under reduced pressure at 55 ° C. or lower to produce about 10 kg of lead extract.

2. Preparation of Sustained-release Sustained-release Formulations Containing Corydalis and Peas

The binding solution was prepared by uniformly dispersing the cotyledon and cow 5: 5 (w / w%) extract, poloxamer, and copovidone prepared above, wherein 50% ethanol was used as 120 mg per tablet. Separately, calcium silicate, microcrystalline cellulose, crospovidone Type B, and hypromellose were mixed, and the mixture was placed in a fluid bed granulator to spray a binder to prepare granules. The granules produced were apples in No. 18. Apple water was lubricated with magnesium stearate, and then compressed into 399 mg elliptical tablets using a rotary tablet press. The content of each component is shown in Table 3.

Fluid bed granulator conditions

Inlet Temperature: 80 ℃

Sprayrate: 50 rpm

Bed Temperature: 40 ℃

-Out let Temperature: 35 ℃

TABLE 3

<Example 7> Preparation of gastroretentive sustained release preparation according to the present invention (4)

Example 7 was prepared by using the same production method as in Example 6 using polyethylene oxide WSR-301 instead of hypromellose as a release controlling agent.

Table 4

<Example 8> Preparation of gastroretentive sustained release preparation according to the present invention (5)

As shown in Table 5 below, gastric releasing sustained-release tablets were prepared using a leaf extract as a pharmacologically active ingredient.

1. Preparation of Petal Extract

Mugwort Artermisia priceps Pamp. To 2,000 kg of leaves and young stems of var orientalis hara (Asteraceae compositae), about 16,000 L of ethanol are added and filtered by cooling for 20 hours. The residue is impregnated with about 16,000 L of ethanol for about 4 hours and filtered again. The combined filtrates were concentrated under reduced pressure at 78 ° C. or less to produce about 100 kg of soft-core extract.

2. Preparation of Lactobacillus Extract-Containing Gastric Retention Sustained-Release Formulations

Ethanol 265 mg / T The leaf extract, poloxamer and copovidone described in Table 5 below were uniformly dispersed to prepare a binding solution. Calcium silicate, microcrystalline cellulose, crospovidone Type B and hypromellose were mixed. The mixture was placed in a high speed mixer and mixed for 3 minutes, and granules were prepared while slowly pouring the prepared binder solution. The granules produced were apples with No. 18 sieve. Apple water was lubricated with magnesium stearate, and then compressed into 516 mg elliptical tablets using a rotary tablet press.

Table 5

Example 9 Preparation of gastric releasing sustained release preparation according to the present invention (6)

The uncoated tablet prepared in Example 8 was coated using a fan coater as shown in Table 6 to prepare Example 9.

Table 6

<Example 10> Preparation of gastric releasing sustained-release preparation according to the present invention (7)

In order to confirm the gastrointestinal behavior of the gastric body sustained-release preparation according to the present invention, Example 10 was prepared by the addition of radiocontrast barium sulfate. The preparation method was prepared in the same manner as in Example 8. The composition of each component is shown in Table 7.

TABLE 7

<Example 11> Preparation of gastroretentive sustained release preparation according to the present invention (8)

In order to confirm the blood concentration profile of the gastro-retentive sustained-release preparation according to the present invention, the preparation was prepared in Example 11 using limaprost-alphadex as a pharmacologically active ingredient. The content of each component is shown in Table 8, to prepare a tablet using the same production method as in Example 1.

Table 8

<Comparative Example 1 and Comparative Example 2> Preparation of Gastric Sustained-Release Formulations Containing Superdisintegrants

Crospovidone Type B is pharmaceutically often classified as a superdisintegrant, such as croscarmellose sodium (trade name: Primellose®) and sodium starch glycolate (trade name: Primojel®).

Therefore, instead of crospovidone Type B of the present invention, a superdisintegrator, croscarmellose sodium and sodium starch glycolate, was used to prepare a formulation. The content of each component is shown in Table 9, to prepare a tablet using the same production method as in Example 1.

Table 9

<Comparative Example 3 and Comparative Example 4> Preparation of Inflation-Exposure Gastric Retention Sustained-Release Formulations

The prior art expansion-foamed floating tablets were prepared with the compositions shown in Table 10 below. In the expansion-foaming tablets, citric acid and sodium bicarbonate, which are bubble generators, were added instead of crospovidone type B. The preparation method was prepared in the same manner as in Example 8, and was prepared as Comparative Example 3, and the uncoated tablet of Comparative Example 3 was coated with the composition of Example 9. To Comparative Example 4.

Table 10

Comparative Example 5 Preparation of immediate release formulations containing leaflet extract

In order to evaluate the gastric retention behavior of the gastric retention slow-release tablet and general rapid-release tablet, a rapid-release tablet was prepared by adding barium sulfate, a radiocontrast contrast agent, to make Comparative Example 5. Comparative Example 5, which is a rapid-release tablet, is a formulation containing no low-density agent and a release controlling agent in the composition of Example 8, and each component is shown in Table 11, and the preparation method was prepared by the method of Example 8.

Table 11

<Comparative Example 6 and Comparative Example 7> Preparation of Gastric Sustained-Release Formulations with Different Contents of Crospovidone

Crospovidone Type B was prepared in the same manner as in Example 1, using 5% of the total weight of the formulation, to obtain Comparative Example 6. In Comparative Example 7, crospovidone Type B was prepared in the same manner as in Example 1, with 90% of the total weight of the formulation. Each component is shown in Table 12.

Table 12

Experimental Example 1 Flotation

Floatability tests of the formulations prepared in Examples and Comparative Examples of the present invention were carried out at pH 1.2, 4.0, 6.8 and distilled water (DW). After administration of the sample to each solution, the time taken to float was observed.

As a result, as shown in Table 13, Examples 1 to 11 and Comparative Example 7 in which crospovidone Type B contained 10% or more of the total weight of the formulation was suspended on the surface immediately after administration in each solvent. In particular, in the case of Example 9 coated with Example 8 according to the present invention also showed an aspect that the floating immediately without the floating delay phenomenon by the coating film. It was also suspended immediately in all pH ranges without being affected by pH.

In contrast, it was observed that Comparative Examples 1 and 2 containing the superdisintegrant did not immediately float but settle for 90 minutes. Therefore, it can be seen that the effect of the present invention is not achieved because crospovidone Type B is a superdisintegrant.

In addition, Comparative Examples 3 to 4 were of the prior art, and the floating was delayed until the expansion of the polymer and the floating force by the bubble generator were sufficiently produced. In particular, in Comparative Example 4, the coating film was dissolved, and then the time was further increased until the polymer was expanded and the floating force caused by the bubble generator was generated. In Comparative Examples 3 and 4, the higher the pH, the longer the suspension time, but did not become suspended in distilled water (DW) and pH 6.8. Hughes et al. According to (Clinical Pharmacology and Therapeutics, 1989, 46, 674-685), the gastric pH increased from 1.2 to 3.0 before meals by 4 or more by drugs such as dietary or antacids. In the case of foam-expanded floating tablets, such as Comparative Examples 3 and 4, the floating capacity is lost at a pH of 4 or more, and thus, it may be confirmed that there is a risk that the preparation does not stay in the stomach and moves to the small intestine.

Therefore, the gastroretentive system preparations according to the present invention may have sufficient suspension even in cases of hypoacidity, even when taken before meals, due to a rise in gastric pH or lack of gastric fluid.

Table 13

Experimental Example 2 Dissolution Assessment and Disintegration Behavior

1) Dissolution test of uncoated tablets prepared by Examples 1 to 4 and Comparative Example 7

The eluate was proceeded by a 50 rpm paddle method using a first solution containing 1% SLS, and fenofibric acid was quantified by HPLC. During the dissolution test, all of the formulations of Examples 1 to 4 were added to the eluent and floated on the surface of the eluent, and the test formulation suspended on the surface gradually released the drug. On the other hand, Comparative Example 7 containing 90% of crospovidone Type B was suspended immediately after elution evaluation, but all the drugs were released within 20 minutes, and the tablets were lost. On the other hand, uncoated tablets prepared by Examples 1 to 4 controlled release of the drug up to 24 hours or more according to the weight percent of hypromellose contained in the formulation (Table 14 and FIG. 1). That is, by adjusting the weight percentage of hypromellose it was possible to manufacture a gastric retention system that can be easily controlled release.

Table 14

2) Dissolution test of uncoated tablet prepared by Example 8

In addition, the dissolution and suspension behavior of the formulation prepared according to Example 8 of the present invention is shown in FIG. 2. The dissolution test was carried out by a 0.5% SLS, 50 rpm paddle method, and the amount of eufatlin in the leaf extracts was quantified by HPLC to show the dissolution pattern.

As shown in Figure 2, Example 8 of the present invention was suspended on the surface of the eluate immediately after administration, and was suspended on the surface and slowly released the drug over 8 hours.

Experimental Example 3 Evaluation of Gastric Retention Using Beagle Dogs

Animal experiments were conducted using the formulations prepared in Example 10 and Comparative Example 5 to confirm the in vivo gastric retention behavior of the gastroretentive sustained release formulation. The experiment was conducted using male beagle dogs (approximately 12 kg), and each subject was fasted for 12 hours and fed 275 ml of feeding (Jevity®) into the stomach through a feeding tube. After 30 minutes, each drug was orally administered once.

Example 10 sustained-release tablet and Comparative Example 5 in immediate-release tablet according to the present invention pre-feeding, post-feeding, immediately after administration (0 min), at 30 min, 2 hr, 4 hr, 8 hr, respectively, abdominal lateral and abdominal Compensation X-ray images are shown in FIGS. 4 and 5.

As a result of the experiment, as shown in Figures 4 and 5, in the case of Comparative Example 5 quickly disappeared within 30 minutes, in the case of Example 10 (gastrointestinal sustained-release tablet) according to the present invention suspended in / up to 4 hours in the stomach Could confirm.

Experimental Example 4 Assessment of Limaprost Blood Levels Using Beagle Dogs

In order to evaluate the in vivo blood concentration of pharmacologically active substance Limaprost, an animal test was conducted using the formulation prepared in Example 11 and the commercially available opalmon tablet ^® as a comparative example.

In addition, in order to evaluate the in-vitro drug release behavior of Example 11 and the control drug of the present invention prior to the animal test, the dissolution test was performed and shown in FIG. 6. The dissolution test was performed by pH 4.0, 50 rpm paddle method, and the amount of limaprost was quantified by HPLC to show the dissolution pattern.

Animal testing was conducted using male beagle dogs (approximately 12 kg), each of which was fasted for 12 hours, and then the opal opalmon tablet ^® in each of 5 beagle dogs in Example 11 and Comparative Example, respectively. After forced oral administration once a dose, 3 ml of blood was collected from cephalic vein at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6 hours before and after administration of the control drug. In the case of Example, 3 ml of blood was collected before administration and 0.25, 0.5, 0.75, 1, 2, 4, 6, 9, 12, 18, 24 hours. The collected blood was centrifuged to separate plasma and stored in the freezer until analysis. Drug concentration in plasma was analyzed by LC-MS / MS, and in-vitro drug release behavior and in-vivo blood concentration of limaprost are shown in FIG. 7.

As a result, as shown in FIG. 6, the control drug Opalmon Tablet ^® released 100% of limaprost in the tablet within 30 minutes, whereas Example 11 according to the present invention slowly released limaprost over 16 hours.

In addition, as can be seen in Figure 7, in-vivo evaluation using beagle dogs, it was confirmed that the blood concentration of limaprost in Example 11 compared to Opalmon tablet ^® was maintained at a higher concentration.

Claims (12)

1. A gastroretentive sustained release formulation comprising a pharmacologically active ingredient, a release controlling agent and essentially crospovidone.
2. The method of claim 1, wherein the pharmacologically active ingredient is aeyeop extract, Corydalis and gyeonwooja extract, limaprost, pregabalin, gabapentin, metformin, ciprofloxacin, levodopa, trazodone, rebamipide, page nopi brick acid, Ito Fried, Simulation Gastric sustained-release sustained-release preparations selected from the group consisting of frid, terpenone, simvastatin, atorvastatin, pravastatin, pitavastatin, balsatan, rozatan, candesartan, olmesartan and azatritan.
3. The agent according to claim 2, wherein the pharmacologically active ingredient is selected from a leaf extract, corydalis and canine extract or limaprost.
4. The preparation according to claim 1 or 2, wherein the pharmacologically active ingredient of the cortex and cow's milk extract is the extract of the mother's skin: cow's milk in a 5: 1 weight ratio (w / w%).
5. 2. The formulation of claim 1, wherein said crospovidone is crospovidone Type B.
6. The preparation according to claim 1 or 5, wherein the crospovidone is contained in an amount of 10 to 80 wt% based on the total weight of the preparation.
7. The formulation of claim 1, wherein the release controlling agent is hypromellose.
8. 8. The formulation of claim 1 or 7, wherein the release controlling agent comprises 10 to 80 wt% based on the total weight of the formulation.
9. The method of claim 1, wherein the gastroretentive sustained-release preparation further comprises a bubble generator, a binder, an excipient.
10. The gastrointestinal sustained-release preparation according to claim 9, wherein the foaming agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, citric acid, malic acid and folic acid.
11. The method of claim 9, wherein the binder is selected from the group consisting of white sugar, glucose, starch, gelatin, sodium carboxymethyl cellulose, methyl cellulose, gum arabic, ethyl cellulose and polyvinylpyrrolidone Sex preparations.
12. 10. The excipient according to claim 9, wherein the excipient consists of calcium silicate, lactose, starch, lactose, mannitol, kaolin inorganic salt, powdered sugar, powdered cellulose derivatives, microcrystalline cellulose, calcium dihydrogen phosphate and magnesium aluminate silicate. Gastric retention sustained-release preparation, characterized in that selected from the group consisting of.

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