KR102289011B1 - Oral sustained-release combined formulation comprising NSAIDs and a proton pump inhibitor - Google Patents

Abstract

a core containing non-steroidal anti-inflammatory drugs (NSAIDs) and pharmaceutically acceptable excipients;
a sustained-release coating layer formed on the core and containing a sustained-release coating base; and
As an oral sustained-release complex formulation formed on the sustained-release coating layer and comprising a proton pump inhibitor layer containing a proton pump inhibitor and a basic additive,
The sustained-release coating layer is
According to the second method paddle method according to the United States Pharmacopoeia (USP), after dissolution test at 50 rpm for 120 minutes in an aqueous buffer of 37±0.5 ℃, pH 1.2, 900 mL, 37±0.5 ℃ continuously, When dissolution test at 50 rpm for 60 minutes in aqueous buffer of pH 6.8,
exhibiting a dissolution rate of less than 5% by weight of the non-steroidal anti-inflammatory agent for 120 minutes in said pH 1.2 aqueous buffer,
It provides an oral sustained-release combination formulation that exhibits a dissolution rate of 80% or more of the non-steroidal anti-inflammatory agent within 60 minutes in the pH 6.8, aqueous buffer, and a method for preparing the same.

Description

TECHNICAL FIELD [0001] Oral sustained-release combined formulation comprising NSAIDs and a proton pump inhibitor

The present invention relates to an oral sustained-release combination formulation comprising a non-steroidal anti-inflammatory agent and a proton pump inhibitor, and more specifically, it can be administered twice a day by controlling the release of the non-steroidal anti-inflammatory agent, and a proton pump inhibitor It provides an oral sustained-release combination formulation comprising a non-steroidal anti-inflammatory agent and a proton pump inhibitor, which can significantly reduce gastrointestinal side effects caused by non-steroidal anti-inflammatory agents by including them together.

Controlled release formulations offer important advantages in terms of patient compliance and control of blood drug concentrations.

The controlled-release agent can reduce the number of doses of a drug that must be taken in order to exhibit a desired effect by controlling the release of the drug, thereby improving patient compliance. For example, when a formulation that has been conventionally administered three times a day is used as an effective release-controlling agent, the drug is continuously released and may remain above the effective blood concentration for a long time in the body, so even if it is administered twice a day, the desired drug effect can be obtained. Therefore, the controlled-release preparation can reduce the patient's discomfort by lowering the administration frequency.

Another advantage of controlled-release preparations is control of blood drug concentration. From a therapeutic point of view, all drugs must maintain a certain level of blood concentration or higher, and in the case of multi-administered drugs, the time to maintain the therapeutic blood concentration tends to be shorter than that of controlled-release agents in general. In addition, the blood concentration of multi-administered drugs tends to deviate from or maintain the range of minimum effective concentration (MEC) and minimum toxicity concentration (MTC) compared to release-controlled agents. .

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause side effects including gastric bleeding and kidney damage. In the United States, there are over 13 million regular NSAID users, 70 million annual NSAID prescriptions, and 30 billion over-the-counter NSAIDs tablets sold annually. NSAIDs-induced disease causes 130,000 hospitalizations per year and an estimated 16,500 deaths per year. It is known that 20% of all NSAIDs users develop peptic ulcers, and NSAIDs users have a 3 to 4 times greater risk for upper gastrointestinal bleeding. In addition, people over the age of 60 are significantly more likely to experience complications associated with oral administration of NSAIDs.

Naproxen ((S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid) is a type of non-steroidal anti-inflammatory drug. It is an anti-inflammatory analgesic with excellent effects on the back. It is known that naproxen is generally administered at 500 - 1000 mg per day at 8 - 12 hour intervals. Naproxen also cannot avoid the side effects of nonsteroidal anti-inflammatory drugs.

Dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole (Pantoprazole), Studies have been conducted to improve the symptoms of patients in the high-risk group for gastrointestinal side effects by taking anti-ulcer agents such as proton pump inhibitors such as rabeprazole) or tenatoprazole at the same time or in advance with NSIADs.

Esomeprazole ((S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzoimidazole) is used for peptic ulcer, gastric As a representative proton pump inhibitor used for , esophageal reflux disease, etc., despite its clinical usefulness due to its strong gastric acid secretion inhibitory action, it is very unstable under acidic to neutral conditions, so there are significant limitations in formulation. In fact, esomeprazole has a half-life of less than 10 minutes under acidic conditions of pH 4 or less, and the decomposition product also exhibits acidity. In order to improve the stability problem, a method of converting into an alkali salt such as esomeprazole magnesium salt has been studied, but esomeprazole alkali salt also does not secure sufficient stability.

It is an object of the present invention to provide oral administration containing NSAIDs and proton pump inhibitors, in which the storage stability of the proton pump inhibitor and the stability in the stomach during administration are significantly improved, while the variation in the release pattern of NSAIDs is small depending on the intake or content of food. It is to provide a sustained-release combination formulation for

One aspect of the present invention is

a core containing non-steroidal anti-inflammatory drugs (NSAIDs) and pharmaceutically acceptable excipients;

a sustained-release coating layer formed on the core and containing a sustained-release coating base; and

As an oral sustained-release complex formulation formed on the sustained-release coating layer and comprising a proton pump inhibitor layer containing a proton pump inhibitor and a basic additive,

The sustained-release coating layer is

According to the second method paddle method according to the United States Pharmacopoeia (USP), after dissolution test at 50 rpm for 120 minutes in an aqueous buffer of 37±0.5 ℃, pH 1.2, 900 mL, 37±0.5 ℃ continuously, When dissolution test at 50 rpm for 60 minutes in aqueous buffer of pH 6.8,

the dissolution rate of the non-steroidal anti-inflammatory agent for 120 minutes in the pH 1.2 aqueous buffer is less than 5% by weight;

It provides an oral sustained-release combination formulation such that the dissolution rate of the non-steroidal anti-inflammatory agent is 80% or more within 60 minutes in the pH 6.8, aqueous buffer solution.

Another aspect of the present invention is

preparing a core containing non-steroidal anti-inflammatory drugs (NSAIDs) and pharmaceutically acceptable additives;

forming a sustained-release coating layer containing a sustained-release coating base on the core; and

Forming a proton pump inhibitor layer containing a proton pump inhibitor and a basic additive on the sustained-release coating layer,

The sustained-release coating layer is

According to the second method paddle method according to the United States Pharmacopoeia (USP), after dissolution test at 50 rpm for 120 minutes in an aqueous buffer of 37±0.5 ℃, pH 1.2, 900 mL, 37±0.5 ℃ continuously, When dissolution test at 50 rpm for 60 minutes in aqueous buffer of pH 6.8,

the dissolution rate of the non-steroidal anti-inflammatory agent for 120 minutes in the pH 1.2 aqueous buffer is less than 5% by weight;

It provides a method for preparing an oral sustained-release combination formulation so that the dissolution rate of the non-steroidal anti-inflammatory agent is 80% or more within 60 minutes in the pH 6.8, aqueous buffer solution.

The oral sustained-release combination formulation according to the present invention can obtain sustained-release properties of the non-steroidal anti-inflammatory agent, so that it can exhibit sufficient medicinal effect only by administering twice a day, and the content of meals, including whether or not to eat, compared to the case of introducing an enteric coating. Since the drug dissolution profile of the non-steroidal anti-inflammatory drug according to the , concomitant drug, or the patient's posture is small, stable blood concentration can be exhibited, and thus stable drug efficacy and reduced side effects of the non-steroidal anti-inflammatory drug can be obtained. In particular, when administered after a meal, the absorption of the drug in the upper small intestine is faster than when an enteric coating is introduced, so that it is possible to quickly express the drug effect of the non-steroidal anti-inflammatory agent compared to the enteric coating agent.

In addition, since the oral sustained-release combination formulation according to the present invention includes a proton pump inhibitor layer together, the effect of preventing or treating side effects such as gastrointestinal bleeding and ulceration caused by the non-steroidal anti-inflammatory agent can be obtained at the same time. In addition, by incorporating the basic additive into the proton pump inhibitor layer, it is preferable to improve the storage stability of the proton pump inhibitor and the stability of the drug to a low pH environment when released from the stomach.

Therefore, according to the present invention, it is possible to administer twice a day regardless of whether or not a meal is taken, and while obtaining a stable and rapid effect of the non-steroidal anti-inflammatory agent, the possibility of gastrointestinal side effects caused by the non-steroidal anti-inflammatory agent is low, and storage stability It is possible to provide a combination formulation of this excellent non-steroidal anti-inflammatory agent and a proton pump inhibitor.

1 is a graph showing the results of measuring the dissolution rate of naproxen in a buffer solution and pH 6.8 according to a change in the amount of a sustained-release coating base for a core containing a sustained-release coating layer according to an embodiment of the present invention.
2 is a graph showing the results of measuring the dissolution rate of naproxen in a buffer solution and pH 6.8 according to a change in the type of the sustained-release coating base for the sustained-release coating layer-containing core according to an embodiment of the present invention.
3 is a graph showing the results of measuring the dissolution rate of naproxen in a buffer solution at pH 6.8, in combination with a conventional composite tablet having an enteric coating layer introduced therein, in a composite tablet having a sustained-release coating layer introduced thereto according to an embodiment of the present invention.
4 is a graph showing the results of a pharmacokinetic comparative test for the sustained-release combination formulation and the enteric combination formulation according to an embodiment of the present invention.
5A is a graph showing the results of a comparative pharmacokinetic test of naproxen for each case of preprandial and postprandial administration of a conventional enteric complex tablet to human males.
FIG. 5B is a graph showing the results of a comparative pharmacokinetic test of naproxen for each case of preprandial and postprandial administration of the sustained-release complex tablet according to an embodiment of the present invention to human males.
6A is a graph showing the results of measuring the dissolution rate of naproxen of the sustained-release complex tablet and the enteric complex tablet according to an embodiment of the present invention by the pH shift dissolution method according to the environment before meals.
6B is a graph showing the results of measuring the naproxen dissolution rate of the sustained-release complex tablet and the enteric complex tablet according to an embodiment of the present invention by the pH shift dissolution method according to the environment after meals.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless otherwise defined, have the meaning as commonly understood by one of ordinary skill in the art of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention. The contents of all publications incorporated herein by reference are hereby incorporated by reference in their entirety.

One aspect of the present invention is

a core containing non-steroidal anti-inflammatory drugs (NSAIDs) and pharmaceutically acceptable excipients;

a sustained-release coating layer formed on the core and containing a sustained-release coating base; and

As an oral sustained-release complex formulation formed on the sustained-release coating layer and comprising a proton pump inhibitor layer containing a proton pump inhibitor and a basic additive,

The sustained-release coating layer is

According to the second method paddle method according to the United States Pharmacopoeia (USP), after dissolution test at 50 rpm for 120 minutes in an aqueous buffer of 37±0.5 ℃, pH 1.2, 900 mL, 37±0.5 ℃ continuously, When dissolution test at 50 rpm for 60 minutes in aqueous buffer of pH 6.8,

the dissolution rate of the non-steroidal anti-inflammatory agent for 120 minutes in the pH 1.2 aqueous buffer is less than 5% by weight;

It provides an oral sustained-release combination formulation such that the dissolution rate of the non-steroidal anti-inflammatory agent is 80% or more within 60 minutes in the pH 6.8, aqueous buffer solution.

The sustained-release coating layer serves to control the release of the non-steroidal anti-inflammatory agent contained in the core. Specifically, the sustained-release coating layer is a core equipped with the sustained-release coating layer according to the second method paddle method according to the United States Pharmacopoeia (USP) in an aqueous buffer of 37 ± 0.5 ° C, pH 1.2, 900 mL for 120 minutes for 50 minutes. After the dissolution test at rpm, the dissolution rate of the non-steroidal anti-inflammatory agent is less than 5% by weight for 120 minutes in the pH 1.2 aqueous buffer solution when the dissolution test is continuously performed at 50 rpm for 60 minutes in an aqueous buffer of 37±0.5 ° C., pH 6.8, It is a sustained-release coating layer exhibiting a dissolution rate of 80% or more of the non-steroidal anti-inflammatory agent within 60 minutes in the pH 6.8, aqueous buffer solution.

The continuous dissolution test in an aqueous buffer of pH 6.8 means that the dissolution test is performed at pH 6.8 by the pH shift dissolution method, and specifically, an additional basifying agent is added to the aqueous buffer previously tested for dissolution. This means that the dissolution test is continuously performed by adjusting the pH to 6.8.

The proton pump inhibitor layer is not a sustained-release layer, and therefore, the sustained-release coating layer determines the dissolution rate of the non-steroidal anti-inflammatory agent contained in the core.

The sustained-release coating layer may exhibit the dissolution rate of the non-steroidal anti-inflammatory agent under the above conditions according to the type of the sustained-release coating base and the content of the sustained-release coating base.

The sustained-release coating base may include any sustained-release coating base that satisfies the dissolution rate of the non-steroidal anti-inflammatory agent of the above conditions, and includes, for example, a hydrophilic polymer, a hydrophobic polymer, and a combination thereof. Examples include a combination of a hydrophilic polymer and a hydrophobic polymer.

The hydrophilic polymer may be selected from the group consisting of, for example, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and combinations thereof. However, the present invention is not limited thereto. The hydrophobic polymer may be selected from the group consisting of cellulose ethers, cellulose esters, polyvinyl esters, and combinations thereof, but is not limited thereto. As a non-limiting example, the cellulose ether includes ethylcellulose or butylcellulose, the cellulose ester includes cellulose acetate or cellulose propionate, and the polyvinyl ester includes polyvinyl acetate or polyvinyl butyrate.

In one embodiment of the present invention, the sustained-release coating layer includes a combination of ethyl cellulose and hydroxypropylmethyl cellulose. Specifically, the ethyl cellulose and hydroxypropylmethyl cellulose may be used in a weight ratio of about 1: 0.5-2, and more specifically, may be used in a weight ratio of about 1:1.

The sustained-release coating layer may vary depending on the type of the sustained-release coating base, for example, the sustained-release coating base may be present in a ratio of about 1 to 10 parts by weight based on 100 parts by weight of the core. More specifically, the sustained-release coating base may be present in an amount of about 5 to 10 parts by weight based on 100 parts by weight of the core. When the weight ratio of the sustained-release coating base does not fall within the above range, it is difficult to obtain the desired effect of release control, and when it exceeds the above range, the thickness of the sustained-release coating layer becomes thick and the dissolution rate is excessively slowed or the drug may not be released at all.

In one embodiment, the combination formulation has a slow disintegration of the non-steroidal anti-inflammatory agent before reaching the small intestine, and the already disintegrated anti-inflammatory agent is rapidly dissolved when it reaches the upper small intestine so that the drug can be absorbed quickly, so fast-acting is required In terms of the characteristics of the non-steroidal anti-inflammatory agent, it is relatively preferable compared to the case of including an enteric coating layer in which the drug disintegrates in the core only when it reaches the small intestine.

Due to the introduction of the sustained-release coating layer, the combination formulation according to the present invention has significantly less effect of diet on the drug blood concentration profile than when it includes an enteric coating layer. After ingestion of a meal, the gastric emptying time and rate (GER) is slowed, and thus, the time to reach the small intestine is delayed. In this case, the deviation of the dissolution profile of the drug depending on whether or not a meal is eaten may increase. On the other hand, since the combined preparation of the present invention contains a sustained-release coating layer even if the gastric emptying rate is slowed, disintegration of the drug can be made slowly even in the stomach, and thus the disintegration of the drug that has already been disintegrated is faster when it reaches the upper part of the small intestine Since it can be made, the effect of the dissolution profile of the non-steroidal anti-inflammatory agent depending on whether or not a meal is significantly less than that of the enteric coating layer (see Test Example 6, FIGS. 5A and 5B, Test Example 7, see FIGS. 6A and 6B).

Therefore, compared to the case in which the enteric coating is introduced, the combination preparation of the present invention can obtain a stable blood drug concentration regardless of whether or not a meal is eaten, so it can be expected to have stable drug efficacy, and when administered after a meal, it is faster than when the enteric coating is introduced. efficacy can be expected. In addition, since the gastric emptying rate is affected not only by meal status, but also by meal contents, concomitant medications, patient posture, etc., the combination formulation of the present invention can reduce the possibility of occurrence of deviations in the blood drug concentration profile due to these various factors. Therefore, a stable drug effect can be expected.

In one embodiment, the sustained-release coating layer is a coating layer that enables the disintegration of the non-steroidal anti-inflammatory agent in the core for about 120 minutes by gradually eroding the coating layer in a delayed manner in a pH 1.2 aqueous buffer, and the ratio The steroidal anti-inflammatory agent is poorly soluble at a pH of about 1.2 and soluble at a pH of about 6.8. The disintegration of the non-steroidal anti-inflammatory agent may be, for example, at least 50%, 60%, 70%, 80%, or 90%, or 100%. An example of the sustained-release coating layer is a combination of ethyl cellulose and hydroxypropylmethyl cellulose, and the non-steroidal anti-inflammatory agent is naproxen. In this case, when orally administered to a living body, if the gastric emptying time is about 2 hours due to meals, etc., the disintegration of the non-steroidal anti-inflammatory agent is gradually made by erosion of the sustained-release coating layer for 2 hours in the stomach, and then in the upper part of the small intestine. Upon arrival, dissolution of the already disintegrated drug is rapidly achieved, so that absorption of the drug in the upper small intestine can be achieved quickly.

The core present in the sustained-release coating layer includes a non-steroidal anti-inflammatory agent and a pharmaceutically acceptable additive.

The nonsteroidal anti-inflammatory agent contained in the core may be present in an amount of about 50-90% by weight, more specifically, 70-90% by weight based on the total weight of the core. If the non-steroidal anti-inflammatory agent contained in the core does not fall within the above range, the size of the combined formulation increases, making oral administration inconvenient, and when it exceeds the above range, it is difficult to control the release of the NSAID .

The non-steroidal anti-inflammatory agent contained in the core may be any drug known as a conventional non-steroidal anti-inflammatory agent, for example, naproxen (Naproxen), dexibuprofen (Dexibuprofen), fenoprofen (Fenoprofen), Miroprofen, Flurbiprofen, Dexketoprofen, Loxoprofen, Indomethacin, Etodolac, Aspirin, Sulfur Sulindac, Diclofenac, Aceclofenac, Meloxicam, Droxicam, Lornoxicam, Piroxicam, Mefenamic acid, It may be selected from the group consisting of flufenamic acid, a pharmaceutically acceptable salt, hydrate, or precursor thereof, and any combination thereof, but is not limited thereto. In a preferred embodiment of the present invention, the non-steroidal anti-inflammatory agent is naproxen or a pharmaceutically acceptable salt thereof.

The non-steroidal anti-inflammatory agent may vary depending on the specific type of drug, for example, may be contained in an amount of 100 mg to 1000 mg, preferably 100 mg to 500 mg per unit dosage form, but is not limited thereto.

Pharmaceutically acceptable additives included in the core include at least one additive selected from the group consisting of a disintegrant, a binder, and a lubricant. By selecting the additive included in the core, the release of the non-steroidal anti-inflammatory agent of the combination can be further controlled.

The disintegrant serves to promote the release of the drug in the digestive juice, and the dissolution rate of the drug may vary depending on the specific type of the disintegrant. The disintegrant may be selected from the group consisting of, for example, sodium starch glycolate, crospovidone, croscarmellose sodium, starch, alginic acid, and any combination thereof, but is not limited thereto. The disintegrant may be used in an amount of about 2-30% by weight, specifically, about 5-20% by weight based on the total weight of the core. In the case of using an excessive amount of disintegrant, it is difficult to maintain an appropriate hardness, and when a small amount of disintegrant is used, there is a problem in that the release of the drug is not performed well.

The binder may be selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, and any combination thereof. The binder may be used in an amount of about 1-10% by weight, specifically, about 2-5% by weight based on the total weight of the core.

The lubricant may be selected from the group consisting of stearic acid, stearic acid metal salts, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, wax, glyceryl fatty acid ester, glycerol dibehenate, and any combination thereof. there is. The lubricant may be used in an amount of about 0.1 to 5% by weight, specifically 0.5 to 2% by weight, based on the total weight of the core.

The composite formulation according to the present invention may further include a primary film coating layer between the core and the sustained-release coating layer.

The primary film coating layer improves the adhesion rate of the sustained-release coating layer between the core and the sustained-release coating layer, and improves the instability of the drug due to contact between the coating base of the sustained-release coating layer and the non-steroidal anti-inflammatory agent contained in the core. can do.

The primary film coating layer may be present in an amount of about 1 - 5 parts by weight, specifically 2 - 3 parts by weight, based on 100 parts by weight of the core. If the weight of the primary film coating layer does not fall within the above range, the film coating layer is too thin and the contact area between the sustained-release coating layer and the drug in the core is widened. there is. The primary film coating layer may be prepared with a film coating base commonly used in the art, for example, hydroxypropylmethylcellulose, povidone, hydroxypropylcellulose, talc, titanium oxide, polyvinyl alcohol, and their It may be selected from the group consisting of any combination. In one embodiment of the present invention, the primary film coating layer is a combination of hydroxypropylmethylcellulose and povidone.

The proton pump inhibitor layer is formed on the sustained-release coating layer, and contains a proton pump inhibitor and a basic additive.

The proton pump inhibitor layer may be present in an amount of about 5 to 30 parts by weight, specifically 10 to 20 parts by weight, based on 100 parts by weight of the core.

The proton pump inhibitor is used for the purpose of preventing and treating upper gastrointestinal bleeding and/or gastrointestinal ulcer, which are side effects that may occur when NSAIDs are administered, and any proton pump known to be effective for upper gastrointestinal bleeding and/or gastrointestinal ulcer. Inhibitors may be used.

Proton pump inhibitors suppress the proton pump (H+/K+-ATPase) of parietal cells, thereby suppressing the production of hydrochloric acid and weakening the strength of acid in the digestive tract. The proton pump inhibitors include, for example, dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, tenatoprazole, pharmaceutically acceptable salts, hydrates, or precursors thereof, and these It may be selected from the group consisting of a combination of, but is not limited thereto. In a preferred embodiment of the present invention, the proton pump inhibitor is esomeprazole or a pharmaceutically acceptable salt thereof.

The proton pump inhibitor may vary depending on the specific drug type, but may be, for example, contained in an amount of about 5 - 50 mg, specifically 7 - 45 mg, more specifically, about 10 - 40 mg per unit dosage form.

Since the basic additive is present in the same layer as the proton pump inhibitor, the storage stability of the proton pump inhibitor is improved, and in vivo, when the proton pump inhibitor is released in the stomach, the basic microenvironmental condition is provided, thereby preventing the acid of the proton pump inhibitor. It can increase the bioavailability by reducing the instability.

The basic additive is sodium hydrogen carbonate (NaHCO ₃ ), calcium carbonate (CaCO ₃ ), magnesium carbonate (MgCO ₃ ), potassium dihydrogen phosphate (KH ₂ PO ₄ ), potassium hydrogen phosphate (K ₂ HPO ₃ ), calcium hydroxide (Ca (OH) ₂ ), magnesium hydroxide (Mg(OH) ₂ ), sodium hydrogen phosphate (Na ₂ HPO ₄ ), sodium dihydrogen phosphate (NaH ₂ PO ₄ ), sodium phosphate (Na ₃ PO ₄ ), calcium trichloride phosphate, etc. It may be selected from the group consisting of basic minerals such as arginine, lysine, histidine, meglumine, aluminum magnesium silicate, aluminum magnesium metasilicate, salts, and any combination thereof. Preferably, the basic additive may be selected from the group consisting of sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, calcium hydroxide, magnesium hydroxide, potassium dihydrogen phosphate, potassium hydrogen phosphate, and any combination thereof, more preferably may be selected from the group consisting of sodium hydrogen carbonate, calcium carbonate, magnesium hydroxide, and any combination thereof.

The basic additive may be included in an amount of 0.5 to 20 parts by weight, preferably 1 to 10 parts by weight, based on 100 parts by weight of the proton pump inhibitor.

The proton pump inhibitor layer may further include a pharmaceutically acceptable additive. The pharmaceutical additive includes a binder, a surfactant, or a combination thereof, and the like. In addition, the pharmaceutical additive is any additive that does not impair the dissolution conditions of the non-steroidal anti-inflammatory drug of the combination formulation of the present invention. The binder may be appropriately selected from binders commonly used in the pharmaceutical field, for example, it may be selected from the group consisting of celluloses such as povidone, copovidone, and hydroxypropylmethylcellulose, and any combination thereof. and is not limited thereto. The surfactant may be appropriately selected from surfactants commonly used in the pharmaceutical field, and the surfactant includes an anionic active agent, a cationic active agent, a nonionic active agent, and an amphoteric active agent, and Pluron, which is not classified into these surfactants. There is a polymer activator of the type or Poloxamer type. As the cationic activator, for example, a sulfur oxide such as sodium lauryl sulfate may be used. As the nonionic active agent, sorbitan esters or polysorbates may be used. Among the polysorbates, polysorbate 80 may be used. In a preferred embodiment of the present invention, the pharmaceutical additive is a combination of povidone, hydroxypropylmethylcellulose, and polysorbate 80. The pharmaceutical additive may be present in an amount of about 20-80% by weight, preferably about 30-60% by weight, based on the total weight of the propon pump inhibitor layer.

The composite formulation according to the present invention may further include a secondary film coating layer between the proton pump inhibitor layer and the sustained-release coating layer.

The secondary film coating layer suppresses the generation of related substances of the proton pump inhibitor that may occur between the proton pump inhibitor layer and the sustained-release coating layer, thereby improving storage stability of the proton pump inhibitor.

The secondary film coating layer may be present in an amount of about 5 to 15 parts by weight based on 100 parts by weight of the core. If the weight of the secondary film coating layer does not fall within the above range, the secondary film coating layer is thin and the contact area between the sustained-release coating layer and the proton pump inhibitor drug is widened. results may appear. The secondary film coating layer may be a film coating commonly used in the art, for example, hydroxypropylmethylcellulose, povidone, hydroxypropylcellulose, talc, titanium oxide, polyvinyl alcohol, and mixtures thereof. may be selected from the group. In a preferred embodiment of the present invention, the secondary film coating layer is a combination of hydroxypropylmethylcellulose and povidone.

In one embodiment of the present invention, the combination preparation is

a core containing naproxen and a pharmaceutically acceptable additive;

a primary film coating layer formed on the surface of the core;

a sustained-release coating layer formed on the surface of the primary film coating layer and containing ethyl cellulose and hydroxypropylmethyl cellulose;

a secondary film coating layer formed on the surface of the sustained-release coating layer;

Formed on the surface of the secondary film coating layer, it is an oral sustained-release combination formulation comprising a proton pump inhibitor layer containing esomeprazole or a pharmaceutically acceptable salt thereof, and a basic additive.

In a preferred embodiment of the present invention, the sustained-release combination preparation is a tablet.

The sustained-release combination formulation according to the present invention may be administered twice a day regardless of whether before or after a meal.

Another aspect of the present invention is

preparing a core containing non-steroidal anti-inflammatory drugs (NSAIDs) and pharmaceutically acceptable additives;

forming a sustained-release coating layer containing a sustained-release coating base on the core; and

Forming a proton pump inhibitor layer containing a proton pump inhibitor and a basic additive on the sustained-release coating layer,

The sustained-release coating layer is

According to the second method paddle method according to the United States Pharmacopoeia (USP), after dissolution test at 50 rpm for 120 minutes in an aqueous buffer of 37±0.5 ℃, pH 1.2, 900 mL, 37±0.5 ℃ continuously, When dissolution test at 50 rpm for 60 minutes in aqueous buffer of pH 6.8,

the dissolution rate of the non-steroidal anti-inflammatory agent for 120 minutes in the pH 1.2 aqueous buffer is less than 5% by weight;

It provides a method for preparing an oral sustained-release combination formulation so that the dissolution rate of the non-steroidal anti-inflammatory agent is 80% or more within 60 minutes in the pH 6.8, aqueous buffer solution.

For details of the manufacturing method of the combination preparation, the description of the combination preparation according to an aspect of the present invention may be applied as it is.

The manufacturing method adds the step of forming a film coating layer between the step of preparing the core and the step of forming the sustained-release coating layer, or between the step of forming the sustained-release coating layer and the step of forming the proton pump inhibitor layer may further include

The method for preparing the oral sustained-release combination formulation according to the present invention includes any means known in the art for a core manufacturing method, a film coating method, a method for preparing a sustained-release coating layer, and a method for preparing a drug-containing coating layer, and method can be used.

According to one embodiment of the present invention, the core may be prepared by mixing a non-steroidal anti-inflammatory agent, a disintegrant, a binder, a lubricant, and the like, and applying a constant compression pressure.

The sustained-release coating layer is a sustained-release coating base coating solution prepared by dispersing or dissolving the sustained-release coating base together with a plasticizer in water, ethanol, or a mixed solvent thereof, in one embodiment, in a mixed solvent of water and ethanol, on the core. and drying.

The proton pump inhibitor layer is a coating solution prepared by dispersing or dissolving a proton pump inhibitor, a basic additive, and a binder together with a stabilizer in water, ethanol or a mixed solvent thereof, in one embodiment, water on the sustained-release coating layer and dried It can be formed by

The forming of the film coating layer may be formed by applying a solution of a base material for film coating on the surface of the core or on the surface of the sustained-release coating layer and drying.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1 and Comparative Examples 1-3: Preparation of sustained-release coating layer-containing core

According to the composition shown in Table 1 below, the core having the sustained-release coating layer of Example 1 and Comparative Examples 1-3 was prepared.

Specifically, naproxen and croscarmellose sodium, a disintegrant, were mixed, and a binding solution consisting of water and povidone was administered, followed by association, drying and sizing. Then, light anhydrous silicic acid and magnesium stearate were mixed and purified to prepare uncoated tablets. Then, a coating solution was prepared by dissolving the coating base in a mixed solvent of water and ethanol, and then, the prepared uncoated tablet was placed in a coater pan, and first film coating was performed under the following conditions, followed by sustained release coating.

- Primary film coating conditions

Supply air temperature: 74 ℃

Exhaust temperature: 41 ℃

Atomizer air : 3 kgf/cm ²

Coating liquid spray amount: 450g/min

- Conditions for sustained release coating

Supply air temperature: 54 ℃

Exhaust temperature: 32 ℃

Atomizer air : 3 kgf/cm ²

Coating liquid spray amount: 300g/min

[Table 1]

Test Example 1: Evaluation of the release of naproxen according to the amount of the sustained-release coating base

The dissolution rate of the sustained-release coating layer-containing cores prepared in Example 1 and Comparative Examples 1-3 was evaluated under the following conditions.

[ Elution conditions ]

Eluent: pH 6.8 phosphate buffer, 900 mL

Apparatus: USP method II (paddle method), 50 rpm

Temperature: 37±0.5℃

The dissolution rate over time is shown in FIG. 1 .

According to FIG. 1, when the weight of the sustained-release coating layer in the artificial intestinal fluid is about 5 parts by weight or less based on 100 parts by weight of the core (Comparative Example 1), dissolution similar to that of the general naproxen tablet (Comparative Example 3) without the sustained-release coating layer formed When it is about 10 parts by weight or more based on 100 parts by weight of the core, the sustained-release ability is too strong, so that the release of naproxen is excessively delayed.

As in Example 1, when the sustained-release coating layer is adjusted within the range of about 5 to 10 parts by weight based on 100 parts by weight of the core, the release of naproxen, the active ingredient in the core, is within about 60% for 30 minutes, indicating an appropriate sustained-release effect. can be known

Test Example 2: Evaluation of the release of naproxen according to the type of sustained-release coating base

The sustained-release coating layer was introduced into the naproxen core using the composition shown in Table 2 below, and then the dissolution rate of the core provided with the sustained-release coating layer was evaluated under the following conditions.

[ Elution conditions ]

Eluent: pH 6.8 phosphate buffer, 900 mL

Apparatus: USP method II (paddle method), 50 rpm

Temperature: 37±0.5℃

The dissolution rate over time is shown in FIG. 2 .

[Table 2]

As shown in FIG. 2 , as a result of dissolution in artificial intestinal fluid, Comparative Examples 4 and 6 did not exhibit a distinct sustained-release ability of the sustained-release agent, and Comparative Example 3 did not exhibit sustained-release properties because the sustained-release coating was not applied. did. In addition, Comparative Example 5 had too strong a sustained-release ability, so that the release did not freeze. In contrast, the core provided with the sustained-release coating layer of Example 1 exhibited a naproxen sustained-release property of 60% or less within 30 minutes. Therefore, it can be seen that the sustained-release properties of the active ingredient in the core may vary depending on the selection of the sustained-release coating base.

Examples 2-6 and Comparative Example 7: Preparation of oral sustained-release combination formulation

According to the composition shown in Table 3 below, the core provided with the sustained-release coating layer prepared in Example 1 was coated with esomeprazole magnesium dihydrate-containing layer.

Specifically, after dissolving povidone, hydroxypropylmethylcellulose, polysorbate 80 and a basic additive in water in the same proportions as in Examples 2-6 and Comparative Example 7 of Table 3 below, esomeprazole magnesium salt dihydrate After preparing a drug coating solution by adding water, it was coated according to the following conditions.

- Coating conditions

Supply air temperature: 40 ℃

Exhaust temperature: 32 ℃

Atomozer air: 1.5 bar

Coating liquid spray rate: 650 g/min

[Table 3]

Test Example 3: Evaluation of the stability of esomeprazole according to the type of basic additive in the proton pump inhibitor layer

The stability of esomeprazole in the oral sustained-release combination formulations of Examples 2-6 and Comparative Example 7 was evaluated. After storage at 60° C. for 4 weeks, the content of related substances was measured under the following analysis conditions, and the results are shown in Table 4 below.

[ Analysis conditions ]

Column: A column filled with octadecyl silylated silica gel for liquid chromatography with a particle diameter of 5 μm in a stainless tube with an inner diameter of about 4.6 mm and a length of 15 cm.

Mobile phase: A - Acetonitrile: Phosphate buffer (pH7.6): Water

= 100 : 100 : 800

B - Acetonitrile: Phosphate buffer (pH7.3): Water

= 800 : 10 : 190

Detector: Ultraviolet absorbance spectrometer (measurement wavelength 302 nm)

Flow rate: 1.0 mL/min

Injection volume: 10 μl

[Table 4]

According to the results of Table 4, it can be confirmed that the stability difference of esomeprazole according to the type of the basic additive remarkably appears. According to Comparative Example 7, the increase of related substances was very clear due to the absence of basic additives in the esomeprazole drug coating, and in the case of Examples 2 - 6, the production amount of related substances was significantly lower than that of Comparative Example 7, even under harsh conditions, The stability of esomeprazole was found to be excellent. In addition, it can be seen that Example 2-4 has a relatively low production amount of related substances compared to Examples 5-6, so that esomeprazole stability can be further increased depending on the type of basic additive.

Example 7 and Comparative Example 8: Preparation of composite tablets

A secondary film coating layer was formed on the core provided with the sustained-release coating layer prepared in Example 1 according to the composition shown in Table 5 below, and the esomeprazole magnesium salt dihydrate-containing layer was coated, and then the outer coating layer was formed. By forming, a complex tablet of naproxen and esomeprazole magnesium salt dihydrate was prepared.

In order to carry out the comparative dissolution test with Example 7, Comparative Example 8 comprising an enteric coating was prepared. The specific manufacturing method is as follows.

After dissolving Eudragit L30D-55 and polysorbate 80 in a mixed solvent of water and ethanol (water:ethanol = 3:1 V/V), according to the following conditions, enteric properties were applied to the primary film-coated tablet of Example 1 The coating layer was coated.

- Coating conditions

Supply air temperature: 54 ℃

Exhaust temperature: 32 ℃

Atomozer air: 2.0 bar

Coating liquid spray rate: 300 g/min

[Table 5]

test example 4: Comparative dissolution test

Comparative dissolution test was performed under the following conditions for the composite formulation in which the sustained-release coating layer of Example 7 was introduced (hereinafter, the sustained-release composite tablet) and the composite formulation in which the enteric coating layer of Comparative Example 8 was introduced (hereinafter, the enteric composite tablet) carried out. The results are shown in FIG. 3 .

[ Elution conditions ]

Eluent: pH 6.8 phosphate buffer, 900 mL

Apparatus: USP method II (paddle method), 50rpm

Temperature: 37 ± 0.5℃

According to the results of FIG. 3 , it was confirmed that the sustained-release complex tablet according to the present invention exhibited a dissolution profile similar to that of the enteric complex tablet in artificial intestinal fluid.

Test Example 5: Pharmacokinetic Comparative Test

For the sustained-release compound tablet of Example 7 and the enteric compound tablet of Comparative Example 8, a pharmacokinetic comparative test was performed on 24 human males, pre-meal, under double-blind, crossover test conditions. did. The results are shown in FIG. 4 .

Figure 4 is a graph showing the results of performing a pharmacokinetic comparative test for the sustained-release complex tablet according to an embodiment of the present invention and the conventional enteric complex tablet.

According to the results of FIG. 4 , as a result of administration to the living body, the enteric complex tablet showed a slight increase in the blood concentration of the drug after 1.5 hours after absorption of naproxen was insignificant until about 1.5 hours after administration. On the other hand, the sustained-release complex tablet according to the present invention increased the blood concentration of naproxen faster than the enteric complex tablet, and after reaching the maximum blood concentration, the blood concentration was almost the same as that of the enteric complex tablet. Therefore, in the case of the sustained-release complex tablet according to the present invention, the absorption of the non-steroidal anti-inflammatory agent is faster than that of the enteric complex tablet, so that the effect of the drug is relatively faster, and the drug effect is maintained for almost the same time as the enteric complex tablet. that can be checked Therefore, the combination formulation according to the present invention is preferable because it can significantly improve patient compliance in that it simultaneously satisfies a relatively fast drug effect and continuity of effect.

Test Example 6: Comparative test of pharmacokinetics before and after meals

For the sustained-release compound tablet of Example 7 and the enteric compound tablet of Comparative Example 8, for each case of pre-meal and post-meal, in 24 men, a double-blind, crossover test A pharmacokinetic comparative test was performed under the conditions. The results are shown in FIG. 5 .

5A is a graph showing the results of a comparative pharmacokinetic test of naproxen for each case of preprandial and postprandial administration of a conventional enteric complex tablet to human males.

5B is a graph showing the results of a comparative pharmacokinetic test of naproxen for each case of pre- and post-prandial administration of the sustained-release complex tablet according to an embodiment of the present invention to a human male.

According to the results of Figure 5a, the enteric combination drug administration after a meal showed a rapid decrease in the rate of increase in the blood concentration of the drug compared to the administration before a meal, and the absorption of the drug into the living body was very delayed. On the other hand, according to the result of Figure 5b, the sustained-release combination according to the present invention, when administered after a meal compared to the administration before a meal, the blood concentration of the drug is lowered up to 8 hours after administration, but the degree of reduction is significantly lower than that of the enteric coating agent appeared to be In addition, although the postprandial administration lowered the rate of increase in the blood concentration of the drug compared to the preprandial administration, the rate of decrease was also significantly lower than that of the enteric compound.

As such, when administered after a meal, the decrease in the rate of increase in the blood concentration of the drug appears to be because the gastric emptying time is increased, and the time for the drug to reach the small intestine is delayed, thereby delaying the absorption of the drug. However, the sustained-release combination agent according to the present invention enables disintegration of the drug in the core in the stomach when it stays in the stomach for a long time, so the degree of delay in absorption of the drug by the meal is significantly lower than that of the enteric combination agent. Therefore, it is possible to obtain rapid absorption, sufficient bioavailability and duration of the non-steroidal anti-inflammatory agent regardless of whether or not a meal is taken, thereby stably acquiring the effect of the drug.

Test Example 7: Comparative dissolution test according to pH shift dissolution method

For the composite formulation in which the sustained-release coating layer of Example 7 was introduced (hereinafter, the sustained-release composite tablet) and the composite formulation in which the enteric coating layer of Comparative Example 8 was introduced (hereinafter, the enteric composite tablet), the pH shift dissolution method under the following conditions A comparative dissolution test was performed. The pH shift dissolution method is a method that can predict the release according to the pH of the summoning organ when the drug moves through the digestive tract in the body. In general, the pH is adjusted to 6.8 by adding a buffer solution from the pH 1.2 solution, and the elution proceeds continuously. use the method The release pattern of naproxen according to the pH shift dissolution method was evaluated by dividing the pre-meal environment (pH 1.2 solution 30 minutes, pH 6.8 solution 120 minutes) and post-meal environment (pH 1.2 solution 120 minutes, pH 6.8 solution 120 minutes), and the results were evaluated. 6A and 6B, respectively.

[ Elution conditions ]

Eluate: pH 1.2 solution US Pharmacopoeia (USP) disintegration test method 1 solution

pH 6.8 liquid 2.5M KH ₂ PO ₄ /16.72% (w/v) NaOH solution 10 mL

Apparatus: USP method II (paddle method), 50rpm

Temperature: 37 ± 0.5℃

6A is a graph showing the results of measuring the dissolution rate of naproxen of the sustained-release complex tablet and the enteric complex tablet according to an embodiment of the present invention by the pH shift dissolution method according to the environment before meals.

6B is a graph showing the results of measuring the naproxen dissolution rate of the sustained-release complex tablet and the enteric complex tablet according to an embodiment of the present invention by the pH shift dissolution method according to the environment after meals.

According to the results of FIG. 6A, both the sustained-release composite tablet and the enteric composite tablet had a dissolution rate of naproxen close to 100% by weight for 30 minutes at pH 1.2 and 150 minutes at pH 6.8 (that is, for 2 hours). and the enteric complex tablet showed a similar dissolution pattern of naproxen.

According to the results of FIG. 6B, the naproxen dissolution rate was close to 100% by weight in the case of the sustained-release tablet for 1 hour (ie, for a total of 3 hours) at pH 1.2, 120 minutes and pH 6.8, corresponding to the environment after meals, In the case of the enteric complex tablet, the dissolution rate of naproxen was less than 80% by weight. Therefore, when the sustained-release composite tablet is actually administered to the living body, the dissolution rate of the drug and the resulting bioavailability deviation according to the administration before and after a meal are expected to be significantly lower than that of the enteric composite tablet.

As a result, the sustained-release coating layer is less affected by the pH to the extent that the coating layer is destroyed, so even if it stays for a long time in the condition of pH 1.2, the sustained-release coating layer is destroyed and the disintegration of the core drug is made, and then the pH 6.8 condition It is interpreted that this is because the disintegration of the drug can be rapidly disintegrated when it reaches .

On the other hand, in the enteric coating layer, since the degree of dissolution of the coating layer is dependent on pH, if it stays for a long time at the condition of pH 1.2, the coating layer is maintained without dissolution, and then the coating layer is dissolved only when the condition of pH 6.8 is reached. It is understood that the dissolution and dissolution of the coating layer and the disintegration and dissolution of the core drug are all made under the conditions, so that the dissolution of the core drug is significantly delayed compared to the sustained-release complex tablet.

Therefore, when administered after a meal, the sustained-release composite tablet according to the present invention can be rapidly absorbed in the upper small intestine compared to the enteric composite tablet, and variations in drug efficacy due to meals and other drug intake can be minimized.

So far, with respect to the present invention, the preferred embodiments have been looked at. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (17)

a core containing naproxen and a pharmaceutically acceptable additive;
a sustained-release coating layer formed on the core and containing a sustained-release coating base; and
As an oral sustained-release complex formulation formed on the sustained-release coating layer and comprising a proton pump inhibitor layer containing a proton pump inhibitor and a basic additive,
The sustained-release coating layer is
According to the second method paddle method according to the United States Pharmacopoeia (USP), after dissolution test at 50 rpm for 120 minutes in an aqueous buffer of 37±0.5 ℃, pH 1.2, 900 mL, 37±0.5 ℃ continuously, When dissolution test at 50 rpm for 60 minutes in aqueous buffer of pH 6.8,
wherein the dissolution rate of said naproxen for 120 minutes in said pH 1.2 aqueous buffer is less than 5% by weight;
An oral sustained-release combination formulation that exhibits a dissolution rate of 80% or more of naproxen within 60 minutes in an aqueous buffer at the pH of 6.8,
The sustained-release coating base agent is a composite formulation that is present in an amount of 5-10 parts by weight based on 100 parts by weight of the core. The composite formulation of claim 1, wherein the sustained-release coating base is a combination of a hydrophilic polymer and a hydrophobic polymer. The method of claim 2, wherein the hydrophilic polymer is dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and any combination thereof. Combination formulations selected from the group consisting of. The combination formulation of claim 2, wherein the hydrophobic polymer is selected from the group consisting of ethyl cellulose, cellulose ether, cellulose ester, polyvinyl ester, and any combination thereof. [Claim 5] The composite formulation of claim 4, wherein the cellulose ether is ethyl cellulose or butyl cellulose, the cellulose ester is cellulose acetate or cellulose propionate, and the polyvinyl ester is polyvinyl acetate or polyvinyl butyrate. The combination formulation of claim 1, wherein the sustained-release coating layer comprises a combination of ethyl cellulose and hydroxypropyl methyl cellulose. delete The combination formulation of claim 1, wherein the pharmaceutically acceptable additive in the core is at least one additive selected from the group consisting of a disintegrant, a binder, and a lubricant. The method of claim 8, wherein the disintegrant is at least one selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, starch, alginic acid, and any combination thereof, and the binder is hydroxypropyl at least one selected from the group consisting of cellulose, hydroxypropylmethylcellulose, povidone, and any combination thereof, and the lubricant is stearic acid, metal stearic acid salt, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, A combination preparation of at least one selected from the group consisting of wax, glyceryl fatty acid ester, glycerol dibehenate, and any combination thereof. The combination formulation of claim 1, further comprising a film coating layer between the core and the sustained-release coating layer, or between the sustained-release coating layer and the proton pump inhibitor layer. The composite of claim 10, wherein the film coating layer comprises a base for film coating selected from hydroxypropylmethylcellulose, povidone, hydroxypropylcellulose, talc, titanium oxide, polyvinyl alcohol, and combinations thereof. formulation. delete The complex according to claim 1, wherein the proton pump inhibitor is selected from the group consisting of lansoprazole, omeprazole, rabeprazole, esomeprazole, pharmaceutically acceptable salts thereof, hydrates, and any combination thereof. formulation. The combination formulation of claim 1, wherein the proton pump inhibitor is esomeprazole or a pharmaceutically acceptable salt thereof. The method according to claim 1, wherein the naproxen or pharmaceutically acceptable salt thereof is contained in an amount of 100 mg to 1000 mg per unit dosage form, and the proton pump inhibitor or pharmaceutically acceptable salt thereof is contained in an amount of 5 mg to 50 mg. Combination formulations comprising an amount. The method of claim 1, wherein the basic additive is sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, calcium hydroxide, magnesium hydroxide, potassium dihydrogen phosphate, potassium hydrogen phosphate, pharmaceutically acceptable salts thereof, and any combination thereof. Combination formulations selected from the group. preparing a core containing naproxen and a pharmaceutically acceptable additive;
forming a sustained-release coating layer containing a sustained-release coating base on the core; and
Forming a proton pump inhibitor layer containing a proton pump inhibitor and a basic additive on the sustained-release coating layer,
The sustained-release coating layer is
According to the second method paddle method according to the United States Pharmacopoeia (USP), after dissolution test at 50 rpm for 120 minutes in an aqueous buffer of 37±0.5 ℃, pH 1.2, 900 mL, 37±0.5 ℃ continuously, When dissolution test at 50 rpm for 60 minutes in aqueous buffer of pH 6.8,
wherein the dissolution rate of said naproxen for 120 minutes in said pH 1.2 aqueous buffer is less than 5% by weight;
17. The method of claim 1 to 6, 8 to 11 and 13 to 16, wherein the dissolution rate of naproxen within 60 minutes in the pH 6.8, aqueous buffer is 80% or more. As a method for producing the sustained-release combination formulation for oral use according to any one of the preceding claims,
The method for producing the sustained-release coating base is present in an amount of 5-10 parts by weight based on 100 parts by weight of the core.

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