KR20170044633A - Contorlled release formulation for the gastroretentive drug delivery system - Google Patents

Abstract

The present invention relates to a gastric retention sustained-release formulation for releasing and controlling gastric retention of a drug and, more specifically, to a gastric retention sustained-release formulation, which can control release of a drug while suspending and retaining the drug after taking the drug. The present invention is suspended immediately after coming into contact with gastric juice without being affected by pH in stomach, and can easily control drug release depending on controlling a release control agent content (%). Therefore, the present invention can continuously release an active ingredient for a long time, while the drug can stay in the stomach without transition to the small intestine, during the case of oral administration in the environment where pH and the amount of gastric juice vary greatly depending on the diet due to increase in gastric pH or lack of the gastric juice.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a controlled release sustained-

The present invention relates to an agent for controlling uptake and release of a drug, and relates to a sustained-release sustained release agent capable of controlling the release of a drug while floating / staying in the stomach immediately upon taking.

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

The over-the-counter drug delivery system is a technique for continuously maintaining the drug release while the drug remains in the gastrointestinal tract and is divided into several types according to the mechanism of the drug delivery system. Typical examples include floating system, floating system, mucoadhesive system for stomach or intestinal mucosa, high density system for inducing sedimentation of formulation, A swelling system that swells to a size larger than a predetermined size (swelling system), and a magnetic system (a magnetic system).

The pharmaceutical preparations using such uptake drug delivery systems have been extensively studied. Especially, the uptake system based on the suspension of the formulation has been actively studied, and as the uptake system through suspension of the formulation, Korean Patent No. 1268215 No. 1269829, No. 1270751, No. 1277021 and No. 1317592 disclose the use of a polymer swelling property in contact with stomach fluids or by trapping bubbles in a swellable polymer using a swelling polymer and a bubble generator together, Uptake drug delivery system is disclosed.

However, the uptake drug delivery system due to the swellable polymer used in the stagnation system through the suspension of the formulation requires time for the polymer to swell, so that the drug migrates to the small intestine before the polymer is swollen to have sufficient buoyancy There is a drawback to be able to. In addition, the bubbling agent reacts with gastric acid to generate CO _{2. In} such a case, the pH value of the stomach varies depending on the diet, and the bubble generating ability may be deteriorated.

In order to compensate for these disadvantages, we have recently developed a drug delivery system in which a sublimable substance, Camphor, is added to the tablets, and then the tablet is heated to sublimate the glassphor, (ref. Preparation of highly porous gastroretentive metformin tablets using a sublimation method, European Journal of Pharmaceutical Sciences and Biopharmaceutics, 2013). However, in order to improve the floatability of such a porous tongue, the manufacturing process is complicated because it is necessary to remove the glassphor after adding the sublimable material Camphor.

Therefore, in order to overcome the above problems, the inventors of the present invention intend to develop a low-density sustained-release preparation having a simple manufacturing process in a stagnation system through suspension of a formulation.

It is an object of the present invention to provide a sustained-release low-density preparation which floats immediately upon contact with stomach fluids without being influenced by gastric pH, in a gastric retention system through suspension of a formulation.

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

The uptake drug delivery system through the suspension of the formulation according to the present invention is a system for efficiently transferring drugs to reduce side effects of drugs and achieve high bioavailability, , MMC), the upper stomach system formulation should be able to have sufficient buoyancy even in hypotonic patients, due to lack of gastric pH elevation or stomach uptake during pre-meal administration .

The present invention essentially comprises crospovidone, and the preparation can be prepared by simple mixing and tableting of the pharmacologically active ingredient and the release-controlling agent. The preparation according to the present invention can be immediately floated upon administration 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 now be described in more detail.

The pharmacologically active ingredient as defined in the present invention includes a pharmacologically active or pharmacologically effective drug by an in-body chemical or enzymatic method, and specifically includes a precursor thereof such as a drug itself, a pharmaceutically acceptable salt thereof or an ester thereof Can be used.

The pharmacologically active ingredient according to the present invention is a drug which can improve the duration of the drug by controlling the release of the pharmacologically active ingredient by the release control agent or improve the absorption or the drug efficacy of the drug. Of the gastrointestinal tract, a drug that is degraded by the pH of the base in the lower gastrointestinal tract, a drug that changes its absorption pattern with changes in gastric emptying time, a drug that needs to be released locally to the proximal small intestine for treatment of certain conditions, and H. pylori infection Drugs used in the treatment of gastric ulcers are preferred. Specifically, the pharmacologically active ingredient is at least one selected from the group consisting of a lysolecule extract, a progeny and a scion extract, pregabalin, gabapentin, cyprofloxacin, metformin, levodopa, lima frost, phenobic acid, trazodone, rebamipide, , At least one selected from the group consisting of atorvastatin, simvastatin, atorvastatin, pravastatin, pitavastatin, valsatan, rozatan, candesartan, olmesartan, azide, active metabolites thereof and mixtures thereof. It does not. Preferably, the pharmacologically active ingredient may be a lysolecule extract, a pale and queen extract, lima frost, pregabalin, metformin, levodopa, gabapetin, cephlofloxacin, more preferably a lysolecule extract, Or lima frost.

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

In the present invention, the pale and pale yellowish extracts were extracted from the herbal corymbs (Tuber of Corydalis ternata Nakai (Papaveraceae)) and the seedlings of Pharynis nil Choisy (Seed of Convolvulaceae) As the extraction solvent, ethanol is most preferable, but the extraction solvent is not limited thereto, and extraction can be performed using an organic solvent such as isopropanol or butanol. In addition, the pale green and the pale green can be extracted by mixing the pale green and the pale green and the pale green and the pale green, respectively, and the pale green and the pale green can be mixed in the ratio of 1: 1 to 10: 1 (w / w) , Most preferably ascorbate, and the extract is mixed with a 5: 1 weight ratio (w / w%).

In the present invention, crospovidone is essentially contained, more preferably, crospovidone Type B.

In the present invention, crospovidone is added in an amount of 10 to 80% by weight based on the total weight of the tablet, the tablet containing the tablet is not only suspended immediately but also has an excellent hardness of less than 0.3% A retention agent can be prepared. If the content of crospovidone is less than 10% by weight, it does not immediately float and sink. If it exceeds 80% by weight, the floatation is unsatisfactory and disintegration easily occurs. It does not play the role of the above-mentioned stay-of-war.

The release controlling agent as defined in the present invention may be selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Xanthan gum, gelatin, carbomer, polyvinyl acetate, polyethylene glycol, and the like. Preferably, the release control agent may be hypromellose, polyethylene oxide and povidone, more preferably hypromellose.

In the present invention, the release control agent can easily control the drug release by adjusting the content percentage according to the characteristics of the preparation, and may preferably include 10 to 80% by weight based on the total weight of the preparation. In addition, the present invention can manufacture a stagnation system capable of freely adjusting the suspension holding time by controlling the content percentage of the release control agent.

In addition to the active ingredient, the sustained-release sustained-release preparation of the present invention may also include a pharmaceutically acceptable excipient such as a diluent, a binder, a lubricant or a coating agent.

The sustained-release sustained-release preparation according to the present invention floats immediately upon contact with the gastric juice without being affected by the stomach pH, and the drug release can be easily controlled by controlling the% of the release control agent.

Accordingly, the present invention provides a method for preventing the transplantation of a drug into the small intestine in oral hypoglycemic patients, in an environment where the gastric pH and gastric juice amount vary greatly depending on dietary habits such as increased gastric pH, So that the active ingredient can be continuously released for a long time.

Fig. 1 is a view showing the dissolution test results of the sustained-release stagnant tablets prepared in Examples 1 to 4 and Comparative Example 7. Fig.
FIG. 2 is a view showing dissolution and floating behavior of the sustained-release stagnant tablet prepared in Example 8. FIG.
3 is an X-ray photograph of tablets of Comparative Example 5 and Example 10.
FIG. 4 is a photograph of the stomach retention behavior of Comparative Example 5 using a beagle dog, and an abdominal X-ray photograph of a beagle dog according to the time after the intrathecal administration of Comparative Example 5.
FIG. 5 is an X-ray photograph of the abdomen of a beagle dog according to the time after administration of the tablet of Example 10 by observing the uptake behavior with respect to the tablet of Example 10 using a beagle dog.
6 shows the in-vitro dissolution behavior of the sustained-release supernatant tablet prepared in Example 11. FIG.
7 is a graph showing an in-vivo blood concentration profile in a beagle dog 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 for illustrating the present invention specifically, and the scope of the present invention is not limited by these examples.

≪ Examples 1 to 4 > Preparation of a sustained-release sustained-release preparation according to the present invention (1)

As the pharmacologically active ingredient, phenobic acid and crospovidone Type B, hypromellose and magnesium stearate were weighed in the amounts shown in Table 1 below and sieved through a No. 30 sieve, respectively. Each of the ingredients was mixed and compressed into a 500-mg round-shaped tablet using an Erweka single-hand tableting machine to prepare Examples 1 to 4, respectively.

≪ Example 5 > Preparation of a sustained-release sustained-release preparation according to the present invention (2)

The preparation was prepared using Limafost-Alphadex as the pharmacologically active ingredient, and was designated as Example 5. The content of each component is shown in Table 2, and tablets were prepared using the same manufacturing method as in Example 1.

< Example  6> According to the invention Stay  Preparation of sustained-release preparations (3)

The preparation was prepared as in Example 6 using a pale yellowish and astringent extract as a pharmacologically active ingredient.

1. Manufacture of pale yellow and blueberry extract

83.5 kg of Corydalis ternata Nakai (tuber root of Corydalis ternata Nakai (Papaveraceae)] and 16.7 kg of Phiteris nil Choisy (Seed of Convolvulaceae) were obtained by crushing, respectively. Add 6 to 8 times (w / w) of 50% ethanol and extract it at 10 ~ 20 ℃ for 48 hours and filter. Activated charcoal and adsorbent were used in the extract to remove impurities, followed by filtration and concentration under reduced pressure at 55 ° C or lower to prepare a soft extract of about 10 kg.

2. Preparation of a sustained-release sustained-release preparation containing a pale yellow and a pine needle extract

The binding solution was prepared by uniformly dispersing the above-prepared colorless and astringent 5: 1 (w / w%) extracts, poloxamer and copovidone, and 120 mg of 50% ethanol was used per tablet. Separately, calcium silicate, microcrystalline cellulose, crospovidone Type B and hypromellose were mixed, the mixture was placed in a fluid bed granulator, and the binding solution was sprayed to prepare granules. The prepared granules were sieved with a No. 18 sieve. The apple juice was poured into magnesium stearate and tableted with 399 mg of oval tablet using a rotary continuous tablet machine. The content of each component is shown in Table 3.

Fluid bed granulator condition

- Inlet Temperature: 80 ^o C,

- Sprayrate: 50 rpm,

- Bed Temperature: 40 ^o C,

- Out let Temperature: 35 ^o C

&Lt; Example 7 > Preparation of a sustained-release sustained-release preparation according to the present invention (4)

As a release control agent, tablets were produced using polyethylene oxide WSR-301 instead of hypromellose, using the same production method as in Example 6,

&Lt; Example 8 > Preparation of a sustained-release sustained-release preparation according to the present invention (5)

As shown in the following Table 5, the sustained-release tablets prepared above were used as the pharmacologically active ingredient to obtain Example 8.

1. Manufacture of leaf extract

Artermisia priceps Pamp. About 2,000 kg of leaves of var orientalis hara (chrysanthemum compositae) and 2,000 kg of young stem are added with about 16,000 liters of ethanol, followed by cooling for about 20 hours and filtration. The residue is air-cooled for about 4 hours using about 16,000 liters of ethanol and filtered again. The pre-filtrate was combined and concentrated under reduced pressure at 78 占 폚 or lower to prepare about 100 kg of softened extract.

2. Preparation of sustained-release sustained-release formulation containing fenugreek extract

Ethanol 265 mg / T , The polymyxamer and copovidone described in Table 5 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 the prepared binding solution was gradually poured to prepare granules. The prepared granules were sieved with a No. 18 sieve. The apple juice was poured into magnesium stearate and tableted with 516 mg of oval tablet using a rotary continuous tablet machine.

&Lt; Example 9 > Preparation of a sustained-release sustained-release preparation according to the present invention (6)

Example 9 was prepared by coating the rug prepared in Example 8 with a pan coater as shown in Table 6 below.

&Lt; Example 10 > Preparation of a sustained-release sustained-release preparation according to the present invention (7)

Example 10 was prepared by adding barium sulfate as a radioactive contrast agent in order to confirm the stagnation behavior of the sustained-release sustained-release preparation according to the present invention. The preparation method was the same as that of Example 8, and the composition of each component is shown in Table 7.

&Lt; Example 11 > Preparation of a sustained-release sustained-release preparation according to the present invention (8)

In order to confirm the blood concentration profile of the sustained-release sustained-release preparation according to the present invention, a preparation was prepared using Limafost-Alphadx as a pharmacologically active ingredient to give Example 11. The content of each component is shown in Table 8, and tablets were prepared using the same manufacturing method as that of Example 1.

* Lima Frost 15 ug

&Lt; Comparative Example 1 and Comparative Example 2 > Preparation of a sustained-release sustained-release preparation containing super-disintegrant

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

Therefore, the preparation was prepared using croscarmellose sodium and sodium starch glycolate, which are superb disintegrants instead of crospovidone Type B of the present invention. The content of each component is shown in Table 9, and tablets were produced using the same manufacturing method as in Example 1. [

&Lt; Comparative Example 3 and Comparative Example 4 > Expansion - Manufacture of sustained-release sustained-release preparation on foaming

Prior art expanded-foam zone wells were prepared with the compositions of Table 10 below. The expanded-foamed suspension was prepared by adding citric acid, a bubble generator, bubbling agent, instead of crospovidone Type B, and the preparation method was the same as that of Example 8 to prepare Comparative Example 3, and Comparative Example 3 was coated with the composition of Example 9 Thereby obtaining Comparative Example 4.

< Comparative Example  5> Lady  Extract-containing Accelerated  Manufacture of pharmaceutical preparations

In order to evaluate the uptake stability and the general uptake behavior, barium sulfate, a radioactive contrast agent, was added to prepare a fast spinneret. Comparative Example 5, which is a proprietary formulation, is a formulation which does not contain a low-density agent and a release control agent in the composition of Example 8, and the components are shown in Table 11 and the preparation method was prepared by the method in Example 8.

< Comparative Example  6 and Comparative Example  7> Crospovidone  With different contents Stay  Manufacture of sustained release formulations

Crospovidone Type B was prepared in the same manner as in Example 1, except that the total weight of the preparation was 5%. Comparative Example 7 was prepared in the same manner as in Example 1 except that crospovidone Type B was used in an amount of 90% of the total weight of the preparation.

<Experimental Example 1> Negative Competence Assessment

Adducts of the preparations prepared in Examples and Comparative Examples of the present invention were tested in pH 1.2, 4.0, 6.8 and distilled water (DW). After the sample was administered to each solution, the time taken for the suspension to flow was observed.

As a result, as shown in the following 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 preparation did not float on the surface immediately after administration to each solvent and did not sink. In particular, even in the case of Example 9 coated with Example 8 according to the present invention, the coating was immediately suspended without floating delay. It was also suspended immediately in all pH ranges without being affected by pH.

On the contrary, Comparative Examples 1 and 2 including the super disintegration were observed not to float immediately and to sink for 90 minutes. Therefore, it can be seen that the effect of the present invention is not achieved because crospovidone Type B is a super-disintegrant.

In addition, Comparative Examples 3 to 4 were based on the prior art, and the suspension was delayed until the expansion of the polymer and sufficient floating force by the bubble generating agent were generated. Especially in the case of Comparative Example 4, it took more time to float as compared with Comparative Example 3 until the coating film was melted and the polymer expanded and the floating force by the bubble generating agent was generated. Also, in Comparative Examples 3 and 4, as the pH was increased, the floating time was prolonged, and no floating was observed at distilled water (DW) and pH 6.8. Hughes et al. (Clinical Pharmacology and Therapeutics, 1989, 46, 674-685), the pH of the stomach is increased to pH 4 or higher by drugs such as dietary or antacid drugs at 1.2-3.0 before meals. In the case of the foam-expanding flotation as in Comparative Examples 3 and 4, the adverse effect is lost at a pH of 4 or higher, and thus it can be confirmed that the preparation does not stay in the stomach but is transferred to the small intestine.

Therefore, the upper gastrointestinal system formulation according to the present invention can have sufficient affinity even in the case of hypotonic patients, when taken before meals, due to a rise in stomach pH or insufficient amount of gastric juice.

<Experimental Example 2> Evaluation of dissolution and observation of disintegration behavior

1) Dissolution tests of the nets prepared according to Examples 1 to 4 and Comparative Example 7

The eluate was eluted with 50 rpm paddle method using the first liquid containing 1% SLS. Phenopric acid was quantitated by HPLC. During the dissolution test, both the preparations of Examples 1 to 4 were added to the dissolution apparatus and suspended on the surface of the dissolution liquid, and the test agent suspended on the surface gradually released the drug. On the other hand, in the case of Comparative Example 7 in which 90% of crospovidone Type B was contained, the drug was suspended immediately after the elution evaluation, but the drug was completely released within 20 minutes and the tablet disappeared. On the other hand, the tablets prepared according to Examples 1-4 controlled release of the drug for up to 24 hours or more, depending on the weight percentage of hypromellose contained in the formulation (Table 14 and Figure 1). That is, by controlling the weight percentage of the hydromellose, it is possible to manufacture a stagnation system which can be easily controlled and released.

2) The release test of the tablets prepared according to Example 8

The elution and floatation behavior of the formulation prepared in Example 8 of the present invention is shown in Fig. The elution test was carried out by 0.5% SLS and 50 rpm paddle method, and the amount of milk tiller was determined by HPLC.

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

<Experimental Example 3> Assessment of stomach uptake using beagle dog

Animal experiments were conducted using the formulation prepared in Example 10 and Comparative Example 5 to confirm the in vivo stomal retention behavior of the sustained-release sustained-release preparation. Male beagle dogs (about 12 kg) were used for the experiment. Twenty-seven (275) ml of feed diets (Jevity®) were fed into the stomachs through the feeding tube after fasting for 12 hours. After 30 minutes, each drug was orally administered once.

The sustained-release sustained-release sustained-release formulation of Example 10 and Comparative Example 5 was administered at 30 min, 2 hr, 4 hr, 8 hr after pre-feeding, post-feeding and administration (0 min) The X-ray was taken and the results are shown in FIG. 4 and FIG.

As a result of the experiment, as shown in FIG. 4 and FIG. 5, in Comparative Example 5, the tablets disappeared quickly within 30 minutes. On the other hand, in Example 10 according to the present invention, I could confirm.

<Experimental Example 4> Evaluation of lima frost blood concentration using beagle dog

A commercially available product of opal monjeong ^® as the preparation and comparative examples prepared by the example 11 in order to assess the blood concentrations in vivo of limaprost pharmacologically active substance was carried out a test animal to a control drug.

Prior to the animal test, the dissolution test was carried out to evaluate the in-vitro drug release behavior of Example 11 of the present invention and the reference drug, and is shown in FIG. The elution test was carried out by a paddle method at pH 4.0, 50 rpm, and limaprost amount was quantified by HPLC to reveal the elution pattern.

Animal studies of male beagle dogs were used (about 12 kg) the experiment, each test object to beagle dogs 5 to the reference product opal monjeong ^® as in Example 11 and Comparative Examples was fasted for 12 hours, respectively, horses each After the oral administration of 1 tablet, the cephalic vein was sampled at a dose of 3 ml at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4 and 6 hours before and after the administration of the control drug. In the case of the example, 3 ml of blood was collected before and after administration at 0.25, 0.5, 0.75, 1, 2, 4, 6, 9, 12, 18 and 24 hours. The collected blood was centrifuged to separate the plasma and stored in the freezer until analysis. The concentration of drug in the plasma was analyzed by LC-MS / MS, and the in-vitro drug release behavior and in-vivo blood concentration of lima frost are shown in FIG.

The experimental results, also the reference product of opal monjeong as shown in 6 ^® is a limaprost was slowly release embodiments described for Example 11 over 16 hours in accordance with the invention, whereas within 30 minutes purified my limaprost is released 100%.

Further, it was confirmed maintained at a high blood level concentrations of limaprost in Example 11 than in opal monjeong ^® in the in-vivo evaluation using beagle dogs as can be seen in Fig.

Claims (12)

A sustained release formulation comprising a pharmacologically active ingredient, a release regulator and essentially crospovidone.
The pharmaceutical composition according to claim 1, wherein the pharmacologically active ingredient is selected from the group consisting of a lysolecule extract, a curcumin and a scion extract, lima frost, pregabalin, gabapentin, metformin, ciprofloxacin, levodopa, trazodone, rebamipide, phenopyrric acid , itopride, Wherein the sustained release sustained release preparation is selected from the group consisting of fried, terfenone, simvastatin, atorvastatin, pravastatin, pitavastatin, valsatan, rozatan, candesartan, olmesartan and azithromycin.
3. The formulation according to claim 2, wherein the pharmacologically active ingredient is selected from the group consisting of a lyophilized extract, a pale yellow and scarlet extract or a lima frost.
The pharmaceutical preparation according to any one of claims 1 to 3, wherein the pharmacologically active ingredient is an extract of Pseudomonas sylvestris and Pseudomonas sphaeroa, and the extract of Pseudomonas sp. Is a 5: 1 weight ratio (w / w%).
The formulation according to claim 1, wherein the crospovidone is crospovidone type B.
6. The preparation according to any one of claims 1 to 5, wherein the crospovidone is contained in an amount of 10 to 80% by weight based on the total weight of the preparation.
The formulation according to claim 1, wherein the release control agent is hypromellose.
The preparation according to any one of claims 1 to 7, wherein the release control agent is contained in an amount of 10 to 80% by weight based on the total weight of the preparation.
The sustained-release sustained-release preparation according to claim 1, wherein the sustained-release sustained-release preparation further comprises a bubble generator, a binder, and an excipient.
10. The sustained-release sustained-release preparation according to claim 9, wherein the bubbling agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, citric acid, malic acid and folic acid.
The method of claim 9, wherein the binder is selected from the group consisting of saccharin, glucose, starch, gelatin, sodium methylcellulose, carboxymethylcellulose, gum arabic, ethylcellulose and polyvinylpyrrolidone Sustained release formulation.
The pharmaceutical composition according to claim 9, wherein the excipient is composed of calcium silicate, lactose, starch, lactose, mannitol, kaolin inorganic salt, powdered sugar, powdered cellulosic derivative, microcrystalline cellulose, calcium monohydrogenphosphate and magnesium aluminum metasilicate Wherein the sustained-release sustained-release preparation is selected from the group consisting of:

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