KR20170001545A - Mosapride sustained-release formulation and Composite formulation comprising mosapride and rabeprazole - Google Patents

Abstract

The present invention relates to a sustained release preparation which contains small-sized mosapride having the total weight less than or equal to 200 mg, and is orally taken once a day. The present invention further relates to a composite preparation of mosapride and rabeprazole. According to the present invention, the sustained release preparation releases drugs by controlling the elution rate.

Description

[0001] The present invention relates to a combined preparation of sustained-release sustained-release formulation and mosaapride and rabeprazole,

The present invention relates to a once-a-day oral sustained-release preparation containing a small amount of simulated friable having a total weight of 200 mg or less and a combined preparation of simfried and rabeprazole.

(4-amino-5-chloro-2-ethoxy-N - {[4- (4- fluorobenzyl) -2-morpholinyl] methyl} benzamide is a known compound having the structural formula Mossafrid and its physiologically acceptable salts are serotonin 5-HT4 receptors present in the sarcomere plexus as selective serotonin 5-hydroxytryptamine 4 (hereinafter referred to as '5-HT4') receptor agonist And the acetylcholine contracts the smooth muscle of the digestive tract and promotes digestive tract movement, resulting in diabetic gastropathy, dyspepsia, dyspepsia, Gastritis, gastroesophageal reflux disease, and the like. Mossafrid has no fear of arrhythmia or cardiogenic death due to the prolongation of QT interval in the non-selective 5-HT4 receptor agonist Sissaflide, and has no dopamine-2 (D-2) receptor antagonism, CNS) side effects (extrapyramidal symptoms), hyperprolactinemia (lactation, feminized breast), and other side effects.

[Chemical Formula 1]

Mossafrid has a digestive tract absorption rate of 93% or more and is distributed at a concentration more than 10 times higher than plasma concentration in the liver, small intestine, stomach, kidney, and adrenal glands. It is distributed at high concentration in the spleen and low in the brain and eyeball, about half of the blood concentration. Mossafrid exhibits a time of about 0.5 to 1.4 hours to reach the peak plasma concentration when administered orally.

Since the half-life is as short as 1.3 to 2 hours, the drug is quickly lost after being absorbed into the body and has a short duration of effect. Thus, it has to be taken several times a day. Mossafrid is currently being developed and marketed in the form of tablets, and one tablet containing 5 mg of mossafide should be administered three times a day. Therefore, it is necessary to increase the patient's compliance with the medication through the reduction of the number of doses, and to maintain the drug efficacy by continuously maintaining the blood concentration of the drug.

In the case of a general slow-release tablet, it takes a long time to reach an effective blood concentration at an early stage. In addition, it is difficult to maintain effective pharmacological activity for 24 hours by expressing rapid pharmacological activity after oral administration.

The object of the present invention is to provide a pharmaceutical composition for oral administration which comprises a small amount of a mash fide having a total weight of 200 mg or less, preferably 150 mg to 160 mg, for sustaining effective pharmacological activity for 24 hours while exhibiting rapid pharmacological activity after oral administration To provide a sustained-release formulation.

Another object of the present invention is to provide a combination preparation comprising a mosaic pride or a pharmaceutically acceptable salt thereof and rabeprazole or a pharmaceutically acceptable salt thereof.

In order to achieve the above object, the present invention provides a once-daily oral dosage form for improving digestive symptoms, comprising moscafide, a salt thereof or a hydrate thereof as an active ingredient, wherein the total weight of the preparation is 200 mg or less, Wherein the content of the active ingredient in the middle is from 10 mg to 20 mg, and the preparation is administered before the meal.

The present invention also relates to once-a-day oral sustained-release or controlled-release preparations containing moscafide or a salt thereof as an active ingredient,

The above preparation has a retention time of 18 hours to 24 hours in the gastrointestinal tract. When passing through the gastrointestinal tract, 20 to 50% of the simulated fried or salt thereof is eluted and 50 to 80% of the simulated fried or salt thereof is eluted Lt; / RTI &

An active ingredient, a filler, a disintegrant and an additive;

An active ingredient, a filler, a disintegrant, a release control agent and an additive,

The release control agent may be prepared by mixing a high viscosity hydroxypropylmethylcellulose having a viscosity of 80,000 cps to 120,000 cps at a weight ratio of low viscosity hydroxypropylmethylcellulose of 2,000 cps to 20,000 cps of 10 to 1: 2 < / RTI > method (paddle method) at 37 DEG C pH 4.0, 6.8. 1.2, and the elution profile of water in the water eluate is as follows:

1) The active ingredient contained in the pH 4.0, pH 1.2 and water elution conditions elutes 25-45% after 1 hour, 60-80% after 8 hours, and 85% after 24 hours.

2) In the pH 6.8 eluent condition, the active ingredient contained was eluted to less than 45% for 16 hours.

Hereinafter, the present invention will be described in detail.

The drug is released from the dosage form through the gastrointestinal tract and eventually dissolved and absorbed. In order for the drug to be absorbed, it must first be eluted and dissolved in body fluids at the site of absorption. For example, drugs orally administered in the form of tablets or capsules are only absorbed until the drug molecules are eluted and dissolved in the gastrointestinal tract. In addition, in order to exhibit a 24-hour continuous effect in the case of once-a-day dosing, the simulated freedop or its salt having a short half-life in blood is eluted, dissolved and absorbed for 20 hours or more while staying in the gastrointestinal tract for 20 hours or more desirable. The residence time in the gastrointestinal tract can be controlled through the type of ingredients in the formulation and / or the composition ratio.

On the other hand, the pH of the stomach is 5 to 7, the pH of the ascending colon is 7 to 8, and the pH of the plant is 6.5. When all the drugs are eluted from various organs in the gastrointestinal tract within 16 hours after oral administration, the drug has a short half-life of 1.3 to 2 hours, so that the drug is rapidly absorbed into the body and disappears rapidly, Can not be sustained.

The oral pharmaceutical preparations according to the present invention may be formulated for oral administration in the form of a pharmaceutical composition comprising a core layer comprising mosaic fibrids or salts thereof (e.g., citrates), fillers, disintegrants, additives (e.g., binders), mosaic fibrils or salts thereof, , A release control agent and an additive (e. G., A binder), which may be bi-layer or multi-layer, and optionally include a lubricant.

Due to the small size of the drug, which has a total weight of 200 mg or less, preferably 150 mg to 160 mg, it is easy to take the drug when taking it, and it is easy to take, and it is economical.

Meanwhile, the present invention relates to a pharmaceutical composition for oral administration, which comprises an immediate-release layer for rapidly releasing a drug and a sustained-release layer for gradually releasing the drug to satisfy the simultaneous expression of the pharmacological activity for 24 hours, (HPMC) and low-viscosity hydroxypropyl methylcellulose (HPMC) as a release-controlling agent in the sustained-release layer while preparing a two-layered tablet, it is possible to control the dissolution rate and / or the residence time in the gastrointestinal tract in each part of the gastrointestinal tract having different pH.

As a result of the dissolution rate experiment at pH 4, the present inventors found that when only low-viscosity HPMC is used as the sustained-release agent, the mothafide or its salt is eluted 100% before 6 hours, and when only the high viscosity HPMC is used as the sustained- It was found that the salt did not elute 100% even after 24 hours. On the basis of this, the inventors of the present invention have found that not only the residence time and dissolution rate before the small intestine but also the dissolution rate and the dissolution rate of the small intestine and / or the large intestine, By adjusting the residence time and dissolution rate after the small intestine, once-a-day oral sustained-release preparations were produced that maintained effective pharmacological activity for 24 hours (FIGS. 9 and 10).

In particular, the sustained effect of pharmacological activity over a 24 hour period is possible because the mothafide or salt thereof can be eluted at a pH of 6.8 eluate under a condition of less than 45% for 16 hours, preferably for 24 hours.

Surprisingly, the present inventors have surprisingly found that when a high viscosity HPMC and a low viscosity HPMC are mixed in a sustained-release layer as a control agent for the release of moscafide or its salt, the dissolution rate is 100% at 24 hours, while the dissolution rate is significantly lower at pH 6.8 . Therefore, by lowering the dissolution rate in the duodenum or the digestive tract after the stomach, the drug can be eluted from the intestinal tract even 16 hours after the oral administration, so that the drug efficacy can be exerted even in the vicinity of 20 to 24 hours.

Therefore, the oral dosage form of the oral dosage form according to the present invention can control the mixing ratio of the high-viscosity HPMC and the low-viscosity HPMC to elute the uppermost 20 to 50% of the simulated fibrin or its salt upon passage through the gastrointestinal tract, 50 to 80% of the simulated fibrids or salts thereof can be eluted.

The viscosity of the high viscosity HPMC is 80,000 cps to 120,000 cps, and HPMC having a viscosity of 100,000 cps is preferred. The viscosity of the low viscosity HPMC is from 2,000 cps to 20,000 cps. In this embodiment, 4,000 cps of low viscosity HPMC was used. In the present invention, the weight ratio of high viscosity HPMC: low viscosity HPMC may be 10: 1 to 1: 1, preferably 2.6: 1: 1.

Hydroxypropylmethylcellulose (HPMC), which is a slow-release base, is a kind of release-controlling polymer and can control a relatively constant dissolution rate with relatively longer dissolution time than general release control polymers such as methyl cellulose and polyvinyl acetate. HPMC is easy to control viscosity. However, low-viscosity HPMC requires a larger amount of HPMC than high-viscosity HPMC, resulting in an increase in the size of tablets, resulting in increased manufacturing cost, and inability to take bulky tablets. However, HPMC with a viscosity of 120,000 cps or more is difficult to uniformly mix with a pharmacologically active ingredient, mosafide citrate, as compared to a low viscosity HPMC. Uneven mixing of the release control polymer with the pharmacologically active ingredient results in a non-uniform dissolution rate of the sustained release, and for this reason, low viscosity hydroxypropyl methylcellulose was used primarily in the prior art despite the increased weight of the tablet.

In order to solve such problems, the present invention uses HPMC having a high viscosity and a low viscosity to have a weight ratio of 10 to 1: 1, and then povidone as a binder and microcrystalline cellulose, lactose and disintegrant low-substituted hydroxypropylcellulose, In addition, it is possible to overcome the disadvantages of high viscosity HPMC and to achieve uniform mixing. In addition, by reducing the parameters that can occur during the scale-up of the tablets, It is difficult to obtain reproducibility due to the change of the elution speed depending on the size of the granules and the static pressure which are pointed out as disadvantages of the polymethyl methacrylate type PL-PO (Ammonio Methacrylate Copolymer Type A) The problem is also solved.

On the other hand, solving the problem of rapid dissolution time, which is a problem that occurs when the use amount of the high viscosity HPMC is higher than the use amount of the low viscosity HPMC, The formulation was prepared.

Particularly, hydroxypropylmethylcellulose (HPMC) is preferably a physical form having a more uniform degree of pulverization and an excellent dispersion even at the same viscosity.

Hydroxypropylmethylcellulose (HPMC) is added in an amount of 5 to 20% by weight, preferably 8 to 16% by weight, of the preparation. When HPMC is added in an amount of less than 5% by weight, rapid drug elution is exhibited. When the amount of HPMC is more than 20% by weight, drug elution is not uniform.

The active ingredient of the present invention, simapride, selectively acts on the serotonin (5-HT) receptors on the digestive tract cholinergic neurons to accelerate the release of acetylcholine at the nerve endings. The acetylcholine promotes smooth muscle movement in the digestive tract, As a serotonin receptor agonist that promotes exercise and gastric emptying, it is a kind of simafil, which is pharmacologically identical. Simafil citrate has better water solubility than simafil and has a melting point It is easy to manufacture and purify.

The oral dosage form of the present invention has a biological activity equivalent to that of the conventional art and is designed to release the active ingredient slowly while controlling the drug release rate by using a slow release base, , Oral administration of moscapride citrate orally three times a day is not only possible to orally administer once a day, but also achieves rapid effective therapeutic blood concentration and sustained effective therapeutic blood concentration upon administration, thereby increasing the therapeutic effect , It is possible to simplify the administration regimen of the patient so as to improve the convenience of taking and the compliance of the administration to the patient.

The pharmacologically active ingredient, moscafide or a salt thereof, is preferably contained in an amount of 10 to 20% by weight based on the weight of the preparation. If it is contained in an amount less than 10% by weight, the pharmacological effect is deteriorated. If it is contained in an amount exceeding 20% by weight, side effects such as Yanbyeol, diarrhea and dryness may occur. When it is manufactured in a sustained-release form, it is preferable that the weight of the active ingredient is about 10 to 20 mg per one unit when taken once a day.

The once-daily oral dosage form containing moscafide, a salt thereof or a hydrate thereof as an active ingredient according to the present invention is characterized in that it comprises a immediate-release immediate-release layer and a sustained- It can be a three-layer system consisting of two extended layers. When the two sustained-release layers are each produced in a matrix type having different viscosities, the elution of the drug is sequentially generated, so that the elution of the drug can be controlled more easily than when it is formed as one sustained layer. For example, one layer of the two sustained-release layers may be formed by adding one compound selected from xanthan gum, guar gum and gum arabic as a thickening agent to a higher viscosity than the other sustained-release layer.

For further explanation, the specification of Korean Patent Application No. 10-2013-0164433 is incorporated herein.

In accordance with the present invention, a once-a-day oral dosage form containing moscafide, a salt thereof or a hydrate thereof as an active ingredient can be used in place of high-viscosity hydroxypropyl methylcellulose (hereinafter referred to as HPMC) And the dissolution profile can be exerted. That is, it can be prepared by mixing waxes with low viscosity HPMC instead of high viscosity HPMC as a release layer control agent of the slow layer. At this time, waxes and low viscosity HPMC (Hydroxypropyl methylcellulose) may be mixed in a weight ratio of 20: 1 to 5: 1.

Non-limiting examples of waxes include but are not limited to waxes such as microcrystalline waxes, anionic waxes, anionic emulsified waxes, bleached waxes, carnauba waxes, cetyl esters waxes, beeswax, caster waxes, cationic emulsified waxes, Nonionic emulsified waxes, paraffins, petroleum waxes, wax waxes, white waxes, yellow waxes, mixtures thereof, and the like can be used as the emulsified waxes. Preferably, the waxes are effective when using a microcrystalline wax, carnauba wax, glyceryl behenate or the like. The waxes are preferably used in an amount of 20 to 32% by weight, more preferably 24 to 31% by weight, based on the total weight of the preparation.

For further explanation, the specification of Korean Patent Application No. 10-2013-0164429 is incorporated herein.

According to the present invention, a once-a-day oral dosage form containing moscafide, a salt thereof or a hydrate thereof as an active ingredient may be in the form of a uniformly dispersed pellet containing the active ingredient in the matrix containing the above-mentioned effective ingredient. At this time, the preparation uses a pellet showing a dissolution pattern similar to a zero-order pattern, and can show a dissolution pattern similar to a zero-order pattern.

For example, the active ingredient, the excipient and the disintegrant are mixed, and then a binding agent is added to the combined and granulated process. After the drying and sieving, the pellet is prepared by mixing the lubricant and the pellet, and the active ingredient, excipient and disintegrant The binder and the pellet prepared above are added to the granulated and granulated process, and after drying and sizing, the lubricant is mixed and kneaded.

For further explanation, the specification of Korean Patent Application No. 10-2013-0164432 is incorporated herein.

According to the present invention, once-a-day oral dosage formulations containing moscafide, a salt thereof or a hydrate thereof as an active ingredient can contain not only the active ingredient but also various additives independently in each of the matrix of the immediate- and / have.

Further, according to the present invention, once-a-day oral dosage formulations containing moscafide, a salt thereof or a hydrate thereof as an active ingredient can be administered to a combination of a matrix of the immediate-release layer, a matrix of the slow- With the coating material containing the active ingredient.

As a coating agent, natural and synthetic starch, natural and synthetic cellulose, acryl, resin, methacrylate, shellac, ammonia methacrylate copolymer (Eudragit RS), ammonia methacrylate copolymer (Eudragit RL) Acrylate copolymer (Eudragit NE), a methacrylic acid copolymer (Eudragit L), and a methacrylic acid copolymer (Eudragit S). .

For further details, the specification of Korean Patent Application No. 10-2013-0164427 is incorporated herein.

A once-a-day oral dosage form containing moscafide, its salt or hydrate thereof as an active ingredient according to the present invention may comprise a sustained-release tablet in the form of granules and a tablet in the form of a mini tablet. The preparation process is relatively simple by filling the capsules with the granules and the mini tablets after the mini tablets having the effect are produced. The preparation can be prepared by mixing mini-tablets and granules, combining and granulating them, respectively, and then tableting the mini-tablets and filling the capsules with granules and mini-tablets.

For further explanation, the specification of Korean Patent Application No. 10-2013-0164431 is incorporated herein.

In one embodiment, a once-a-day oral dosage form containing moscafide, a salt thereof or a hydrate thereof as an active ingredient according to the present invention comprises a plurality of drug layers comprising one or more immediate layers and one or more sustained layers Wherein a plurality of drug layers are bonded to each other through a swellable polymer layer having different viscosities so that the swellable polymer layers having different viscosities are sequentially disintegrated with time so that the drug layers are sequentially disintegrated, have. It is possible to make a specific amount of the simulated freedoms elute within a specific time, ultimately to realize a 'Zero-order' type dissolution profile, and also to achieve a rapid effective therapeutic blood concentration and a constant effective therapeutic blood concentration Thereby improving the therapeutic effect and simplifying the administration regimen of the patient, thereby improving the ease of taking and the compliance of the administration to the patient.

The swellable polymer layer includes, but is not limited to, one or more swelling polymers selected from the group consisting of polyvinyl alcohol, carbomer, polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose.

The content of the swelling polymer may vary depending on the kind of the polymer, but it is preferable that the content of the swelling polymer is 40 to 95% by weight based on the total weight of the preparation, and that the drug layers have different viscosities.

The swelling polymer layer plays a role of sequentially dissolving each drug layer owing to different viscosities so that the dissolution profile of the drug becomes 'Zero-order' type, and ultimately, it is suitable after a specific time So that a positive drug is eluted. The viscosity of each of the swelling polymer layers is preferably increased sequentially from the first swelling polymer layer.

The viscosity of each swellable polymer layer is preferably from 4000 cps to 140,000 cps. When the viscosity is less than 4000 cps, swelling of the swellable polymer layer is not sufficiently performed and drug elution may occur, and an ideal 'zero-order' type dissolution can not be realized. When the viscosity exceeds 140,000 cps, swelling It is difficult to uniformly mix with the other components forming the polymer layer and the dissolution of the drug is delayed, so that an ideal 'zero-order' type dissolution can not be realized.

The swellable polymer layer may be prepared by blending a swellable polymer such as polyvinyl alcohol or carbomer in an amount of 20 to 80% by weight of the swellable polymer layer and a filler consisting of at least one additive selected from an excipient, a disintegrant and a lubricant, 80% by weight of the mixture is mixed and granulated, and dried and sieved to a LOD of 2% or less at a temperature of 50 to 60 ° C in a cabinet dryer. Then, the preparation to be contained in the multi-layer tablet, such as the drug layer and the swellable polymer layer, is sequentially filled into a 12.0 mm diameter die, and a pressure of 8 MPa is applied using a hydraulic press to produce a unified multi-layer tablet.

Each of the drug layers having the mimic primes as an active ingredient may be another drug layer that can be used in combination with the mimic free. Examples of effective components that can be used in combination with the simulated frit include itopride, sissaflide, ranitidine, nizatidine, cimetidine, famotidine, tamsulosin, simvastatin, levodropropazine, fluvastatin and the like.

For further explanation, the specification of Korean Patent Application No. 10-2013-0164434 is incorporated herein.

The disintegrant is used to absorb water and promote disintegration of the formulation to improve the dissolution of the simulated fried or its salt. Non-limiting examples of disintegrants used in the immediate and extended layers in the present invention are each independently selected from the group consisting of Croscamellose sodium, Sodium starch glycolate, microcrystalline cellulose, Crospovidone (cross-linked povidone) and other commercially available polyvinylpyrrolidone (PVP, Povidone), low-substituted hydroxypropylcellulose (low substituted), alginic acid, powdered cellulose Starch, sodium alginate, or a mixture thereof. As the disintegrant, low-substituted hydroxypropylcellulose, crospovidone is preferred. Disintegrants may additionally be added in a pharmaceutically acceptable manner in addition to the oral solid preparations, and a secondary disintegrant may be further used for the purpose of faster release of the formulation. The disintegrant is preferably used in an amount of 10 to 30% by weight, and most preferably 20 to 30% by weight, based on the total weight of the disintegrant.

In the present invention, non-limiting examples of excipients for use in the immediate and extended layers may each independently be lactose, mannitol, glucose, sorbitol, dextrin, sucrose or a mixture thereof. Lactose improves the ease of tableting and facilitates the formation of water-soluble channels when coexisting with hydroxypropylmethylcellulose (HPMC) in the effluent, and plays a role in maintaining the tablet form. Also, lactose is mixed with high viscosity HPMC, allowing uniform mixing with the simfried citrate and HPMC. The lactose is preferably added in an amount of 15 to 30% by weight of the preparation. When the lactose is used in an amount less than 15% by weight of the preparation, it is difficult to uniformly mix the high viscosity HPMC and the salt thereof, and the mixture may stick to the punch of the tablet machine during sticking, The use of more than 1% by weight of the composition causes an increase in the total weight of the preparation. 10 to 30% by weight of mannitol, 10 to 30% by weight of sorbitol by weight of the preparation, 20 to 40% by weight of glucose in weight of the preparation, 20 to 30% by weight of dextrin in weight of the preparation, And may be used in an amount of 20 to 40% by weight.

In the present invention, a binder that can dissolve in the organic solvent as the water-soluble polymer in the immediate layer and the sustained-release layer and increase the binding force of the preparation can be used. Non-limiting examples of binders that can be used are polyvinylpyrrolidone (povidone, commonly known as povidone K-30, having a molecular weight of 30). When the binder is added in an amount of less than 3% by weight, it is difficult to tablet the tablets because the binding force is too weak. When the binder is added in an amount exceeding 10% by weight, the dissolution rate of the drug Becomes difficult.

Non-limiting examples of lubricants that can be used in the immediate and extended layers in the present invention may each be independently light silicic anhydride, silicon dioxide, talc, stearic acid, magnesium stearate, or mixtures thereof. The lubricant improves the fluidity of the powder, increases the filling of the die, which is the lower part of the tablet machine, and reduces the friction between the powder and the punch-die, which is the upper part of the powder and the tablet. Thereby facilitating compression and release of the tablet.

The lubricant is preferably added in an amount of 0.5 to 5% by weight based on the weight of the preparation. When the lubricant is added in an amount of less than 0.5% by weight, tableting becomes difficult. When the lubricant is added in an amount of more than 5% by weight, Which affects the dissolution profile of the tablet.

The composition of the oral dosage form according to the present invention is 10 to 15% by weight of a pharmacologically active ingredient, moscafide or a salt thereof, 5 to 10% by weight of a high viscosity hydroxypropylmethyl cellulose, a low viscosity hydroxypropylmethyl 5 to 10% by weight of cellulose, 15 to 30% by weight of lactose, 3 to 10% by weight of povidone, and 0.5 to 5% by weight of a lubricant. It is a two-layered tablet-like sustained-release citrate sustained-release tablet composition consisting of immediate-release layer and sustained-release layer.

In one embodiment, the oral dosage form according to the present invention may be prepared by mixing and coagulating and granulating the sustained-release layer and the immediate-release layer, respectively, followed by tabletting. In the sustained-release layer, 13 to 15% by weight of moscafide or its salt as a pharmacologically active ingredient based on the total weight of the sustained-release layer is mixed with 15 to 30% by weight of lactose, 25 to 35% by weight of hydroxypropylmethylcellulose, Cellulose was mixed in an amount of 15 to 30% by weight, and 3 to 10% by weight of povidone previously dissolved in an appropriate amount of ethanol was added to the binding solution, followed by coalescence and granulation, and the mixture was dried in a cabinet dryer at 50 to 60 [ LOD) 2% or less. Followed by mixing with an appropriate amount of lubricant. In the immediate-release layer, 6 to 8% by weight of mothafide or a salt thereof is mixed with 15 to 30% by weight of lactose and 25 to 40% by weight of low-substituted hydroxypropylcellulose, based on the total weight of the immediate layer, 3 to 10% by weight of povidone is added to the binding solution, followed by coalescence and granulation, and dried and sieved to a LOD of 2% or less at a temperature of 50 to 60 DEG C in a cabinet dryer. Followed by mixing with an appropriate amount of lubricant. Among the above-mentioned mixtures, the sustained-release layer may be subjected to first-type tabletting, and then the pre-filled layer may be filled thereon to perform secondary tableting. At this time, it is not always necessary to tablet the immediate layer after tableting the slow layer, but tableting of the immediate layer is preferentially performed, and tableting can be performed by filling the granules of the slow layer. Further, it is also possible to fill the inner layer and the middle layer sequentially or in reverse order, and to fix them once.

The oral preparation for oral administration according to the present invention may be a pellet-type tablet prepared by mixing the immediate-release layer and the sustained-release layer or may be a multiple tablet.

Therefore, in the In-Vivo test using a healthy human, the maximum serum concentration (Cmax ng / ml) of the morphine-free citrate is 40 to 50 ng / ml and the blood concentration- (AUC _t h * ng / ml) is 200 to 240 h * ng / ml, and the maximum blood concentration reaching time (Tmax, h) can be 1.0 to 4.0 h.

The two-layer tablet comprising the same active ingredient-containing immediate-release layer and the extended-release layer according to the present invention was subjected to a dissolution test with a paddle method (Korean Pharmacopoeia 10th edition, dissolution test No. 2 method) at a rate of 50 revolutions per minute , The dissolution rates after 1 hour, 8 hours and 24 hours after the start of the dissolution test were 25 to 45%, 60 to 80% and 85% or more. As a result of the dissolution test of the drug in water, pH 1.2, pH 4.0, and pH 6.8 elution, the prior art and the sustained-release preparation of simfurf citrate according to the present invention showed different dissolution profiles according to pH, respectively.

 In order to predict the effect on the expression of drug effects in the human body by comparing the dissolution profile and the pharmacokinetics of the preparation, pharmacological activity was confirmed in beagle dogs as the formulation of the examples. As a result, it was confirmed that the pharmacokinetic behavior of the simfried citrate was changed according to the in vitro dissolution profile, and the proper mode of the simfried citrate dissolution in the in-vitro was in-vivo, And thus the pharmacological activity is preferably exhibited.

Further, it was confirmed that the pharmacological behavior of the morphophyll citrate in the human body was confirmed by the above-mentioned pharmacological dynamics. As a result, it was confirmed that the pharmacological activity of the morphyrid citrate was fast, The serum citrate concentration was maintained for 24 hours.

The preparations of the present invention can be taken before or after meals, but it has been confirmed that taking them at the time of fasting at a meal is less affected by foods.

The formulation of the present invention may be effective in the prevention, treatment or amelioration of gastrointestinal diseases, and may also be useful in the improvement of gastrointestinal symptoms.

The gastrointestinal disorder may be referred to as various names such as chronic dyspepsia, non-ulcerative dyspepsia, chronic diarrhea, irritable bowel, irritable bowelitis, chronic gastritis, chronic abdominal pain, neurogenic gastroenteritis and gastrointestinal pain, constipation, diarrhea, vomiting It is a disease that has various symptoms repeatedly. Examples include various symptoms occurring in the gastrointestinal tract, but the type is not limited thereto. In addition, the gastrointestinal symptoms include dyspepsia and are specifically classified according to the Rome Criteria, more specifically functional dyspepsia classified in the Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders But is not limited thereto.

According to the present invention, a once-a-day oral dosage form containing moscafide, a salt thereof or a hydrate thereof as an active ingredient can be obtained by coating a pancreate containing moscafide, a salt thereof or a hydrate thereof with waxes, have. The initial drug release rate can be controlled by controlling the thickness and viscosity of the coating layer of the wax, and the initial dissolution time can be adjusted at a desired time when the drug is taken. The capsule preparation may be filled into capsules in the form of pellets or may be encapsulated with a capsule base.

For example, a controlled-release capsule preparation containing a mashafide, a salt thereof or a hydrate thereof may be prepared by mixing a mashafide, etc., an excipient and a disintegrant, followed by a coalescing and granulating process, The pellets prepared through the pellet manufacturing process are coated with waxes to prepare a pellet coating, and then filled into capsules.

The waxes are coated on the pellets and used for delaying the elution time. Examples of waxes that can be used in the formulation of the present invention include microcrystalline waxes, anionic waxes, anionic emulsified waxes, bleached waxes Emulsified waxes, emulsified waxes, glyceryl behenates, microcrystalline waxes, nonionic waxes, nonionic waxes, nonionic waxes, nonionic waxes, Emulsified wax, paraffin, petroleum wax, waxy wax, white wax, and yellow wax, or a mixture thereof. Preferably, the waxes are effective when using a microcrystalline wax, carnauba wax, glyceryl behenate or the like. The waxes are preferably used in an amount of 20 to 32% by weight, more preferably 24 to 31% by weight, based on the total weight of the pellets. However, it is also possible to deviate from the above-mentioned weight range in that the rate of the dissolution rate can be controlled according to the thickness of the wax coating layer and the viscosity of the wax.

In the present invention, it is preferable that the pellets are prepared by mixing 5: 1 to 1: 5 weight ratio (w / w) based on the dry weight of the mashafide citrate and the waxes.

For further details, the specification of Korean Patent Application No. 10-2013-0164426 is incorporated herein.

In another aspect, the present invention also provides a combination preparation comprising moscapride or a pharmaceutically acceptable salt thereof and rabeprazole or a pharmaceutically acceptable salt thereof.

The present invention provides a combination comprising a first composition comprising mosapride or a pharmaceutically acceptable salt thereof and a second composition comprising rabeprazole or a pharmaceutically acceptable salt thereof, Lt; / RTI >

The first effective ingredient of the present invention is as described above.

The second active ingredient of the present invention, rabeprazole, is a benzimidazole derivative, which inhibits gastric acid secretion and has a structure represented by the following formula (2). Rabeprazole is known as a proton pump inhibitor (PPI) that inhibits H + / K + ATPase and inhibits gastric acid secretion on the acid secretion surface of the parietal cell of the gastric mucosa. This effect is dose-dependent and induces inhibition of acid secretion by basic acid secretion and stimulation, and is attracting attention as a therapeutic agent for gastric and duodenal ulcers.

(2)

In the present invention, the first composition and the second composition may each further comprise a pharmaceutically acceptable additive selected from the group consisting of a diluent, a disintegrant, a binder, a stabilizer, a lubricant, a colorant, and mixtures thereof . As diluents, disintegrants, binders, stabilizers, lubricants and coloring agents, as described above, those conventionally used in the production of formulations in the art can be used.

Also, in the present invention, the first and second compositions may be in the form of tablets, pellets or granules, preferably in the form of tablets. In the case of tablets, the most commonly used formulations are those which can contain a certain amount of active ingredient and can be mass-produced at low cost according to various purposes, functions and sizes. Thus, the simulated fried, rabeprazole, or pharmaceutically acceptable salt thereof of the present invention may be present in the form of tablets.

The combination preparation of the present invention may also be a capsule contained in a hard or soft capsule. The base material of the capsules may be selected from the group consisting of hypromellose, pluran, gelatin, polyvinyl alcohol, and mixtures thereof. However, it is not limited thereto, and materials usually used as capsules, Can be included.

Preferably, in the present invention, the first composition comprising the mimifϊr or a pharmaceutically acceptable salt thereof may be a sustained-release composition. More specifically, in the present invention, the first composition may be a sustained-release tablet of the mothafide citrate, and the same is as described above.

In yet another aspect, the invention provides a sustained-release composition comprising a sustained-release first composition comprising moscafride or a pharmaceutically acceptable salt thereof, a second release composition comprising moscafide or a pharmaceutically acceptable salt thereof, Sol or a pharmaceutically acceptable salt thereof. ≪ Desc / Clms Page number 4 >

Preferably, the first and second compositions may also be in the form of tablets, pellets or granules, preferably in the form of tablets, preferably tablets, more particularly mini-tablets. In the present invention, the mini-tablet refers to a tablet made by compressing a medicine into a certain shape, but it is possible to vary the diameter of the mini-tablet differently from the ordinary tablet without change in diameter, The smaller the number of mini tablets that can be injected into the capsule, the smaller the number.

The combination preparation of the present invention may also be a capsule contained in a hard or soft capsule. The capsules may be prepared by filling a capsule in the form of a liquid, a tablet, a powder, a granule, a mini tablet, or a pellet or by encapsulating the capsule with a capsule base. However, A method of simultaneously charging the capsules in the form of mini tablets or capsulating the capsules with a capsule base may be used.

In another aspect, the present invention provides a pharmaceutical composition comprising a first composition comprising a three-layered tablet consisting of one immediate-release layer and two sustained-release layers comprising a mothafide or a pharmaceutically acceptable salt thereof; And a second composition comprising rabeprazole or a pharmaceutically acceptable salt thereof.

The first composition according to the present invention is characterized in that it comprises a core layer containing an active ingredient, a filler, a disintegrant, and an additive, and at least one of an active ingredient, a filler, a disintegrant, a controlled release (slow release) And may include a western layer, as described above.

The viscosity of the first and second sustained-release layers may be different from each other. The viscosity of the first and second sustained-release layers may be adjusted by controlling the viscosity of the controlled-release base material to a range of 10: 1 to 1: 1 by weight of hydroxypropylmethylcellulose Can be mixed.

Specifically, the first composition was prepared according to Method 2 (Paddle Method) of Korea Pharmacopoeia Dissolution Test at 37 DEG C pH 4.0, 6.8. 1.2 The following elution profile can be satisfied in the effluent:

1) The active ingredient contained in the pH 4.0 and pH 1.2 eluate elutes 25-45% after 1 hour, 60-80% after 8 hours, and 85% or more after 24 hours.

2) In the pH 6.8 eluent condition, the active ingredient contained is eluted to less than 45% for 24 hours.

Likewise, the combination preparation of the present invention may be a capsule containing the first composition, the second composition and the third composition.

The triple-layer sustained-release preparation of the present invention has the same time to reach the initial effective blood concentration of the drug, but can more easily control the dissolution delay time of the drug as compared with the prior art bilayer preparation consisting of the immediate layer and the extended layer There are advantages.

In addition, the sustained-release sustained-release preparation formed of the triple layer consisting of the immediate-release layer and the two sustained-release layers of the present invention has an immediate effect of improving the gastrointestinal motility disorder, and the sustained action of the active ingredient and the active metabolite Because it maintains constant concentration constantly, it is very useful because it reduces the number of doses and improves the convenience of taking, and consequently improves drug compliance to patients and improves compliance.

The two-layered tablet for oral administration made up of the immediate-release layer and the sustained-release layer produced according to the present invention can be controlled to release and control the dissolution rate of the drug using a pharmaceutically acceptable sustained release agent, The same effective dose of the active treatment reaches the blood concentration and the immediate gastrointestinal motility disorder improves immediately. In addition, the active ingredient and the active metabolite continuously maintain a constant concentration in the plasma for a considerable time. Therefore, it is very useful because it can increase the convenience of taking the medicine by reducing the size of the medicine while decreasing the number of times of medication compared to the conventional medicine, thereby increasing the drug adaptability to patients and improving the compliance.

In addition, the combined preparation according to the present invention enables rapid release of drug without deterioration of elution due to the interaction of mosaic fibril and rabeprazole, thereby exhibiting improved drug dissolution rate and bioavailability, The amount of the excipient can be greatly reduced, and the compliance of the patient with the medication can be increased due to the size of the formulation.

FIG. 1 shows the dissolution rate in the pH 4.0 eluant for the preparation prepared in Comparative Example 1 and 5 mg of the gasotropin tablet as a control agent.
Fig. 2 shows the dissolution rates in the pH 4.0 eluant for the preparations prepared in Comparative Examples 2 to 4. Fig.
FIG. 3 shows the dissolution rates in the pH 4.0 eluant for the preparations prepared in Comparative Examples 5 to 6. FIG.
Figure 4 shows the dissolution rates in the pH 4.0 eluant for the formulations prepared in Examples 1-7.
Fig. 5 shows the dissolution rate in the pH 4.0 eluant for the preparation prepared in Example 3. Fig.
6 shows the dissolution rate in the effluent for the formulation prepared in Example 3. FIG.
FIG. 7 shows the dissolution rate in the pH 1.2 eluant for the preparation prepared in Example 3. FIG.
Fig. 8 shows the dissolution rate in the pH 6.8 eluant for the formulation prepared in Example 3. Fig.
FIG. 9 shows the results of the pre-clinical test conducted in Experimental Example 3. FIG.
Fig. 10 shows the results of the clinical test conducted in Experimental Example 4. Fig.
11 is a schematic diagram of a matrix formulation containing a simulated fried citrate in which pellets according to the present invention are dispersed in a matrix.
FIG. 12 is a schematic view of a triple-layer sustained-release preparation containing an active ingredient such as a simulated freeze composed of a double layer and two sustained layers according to the present invention.
FIG. 13 is a schematic view of a multi-layer tablet formed of a binding layer comprising a drug layer containing an active ingredient such as a plurality of simulated fibrils and a swellable polymer layer according to the present invention.
FIG. 14 is a schematic view of a multi-layer tablet formed of a binding layer comprising a drug layer containing an active ingredient such as a plurality of simulated fibrils and a swellable polymer layer according to the present invention.
Fig. 15 shows an example of a formulation according to the present invention, and schematically shows a schematic diagram of a matrix preparation containing a matrix and a coating layer containing the active ingredient.
Figure 16 illustrates an example of a formulation in accordance with the present invention, which is a simplified representation of the composition of the immediate layer and the western layer.

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

< Example  1 to 7 and Comparative Example  1 to 6>

Preparation of the immediate-release layer: Mixed with microfibrillated citrate, microcrystalline cellulose, lactose hydrate and low-substituted hydroxypropylcellulose (L-HPC) according to the ingredient contents shown in Tables 1 and 2, povidone K -30 solution was added and granulated, and dried in a cabinet dryer at 50 to 60 ° C for 30 to 40 minutes (LOD 2% or less). After the formulation, the remaining lubricants were mixed.

Preparation of the sustained-release layer : Microfibrillated citrate, microcrystalline cellulose, lactose hydrate, low viscosity hydroxypropyl methylcellulose (4000 cps, HPMC 2910), high viscosity hydroxypropyl methylcellulose (100,000 cps, HPMC 2208) and low-substituted hydroxypropylcellulose (L-HPC) were mixed, and then povidone K-30 solution previously dissolved in ethanol was added thereto and granulated. The mixture was granulated in a cabinet dryer at 50 to 60 ° C for 30 to 40 minutes Dried (LOD 2% or less). After the formulation, the remaining lubricants were mixed.

Preparation of two-layer tablet : The two-layer tablet was tableted using the prepared mixture of the inner layer and the middle layer, and film-coated with a coating agent of Opadry-OY-C-7000A (trade name of Colorcon Co.) To prepare a simfried citrate sustained-release tablet containing 15 mg.

division Classification ingredient Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 genus

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layer chief ingredient Mosaic pride citrate 5.29 5.29 5.29 5.29 5.29 5.29 5.29 5.29 Excipient Microcrystalline cellulose 21.00 21.00 21.00 21.00 21.00 21.00 21.00 21.00 Excipient Lactose baggage 18.76 18.76 18.76 18.76 18.76 18.76 18.76 18.76 Disintegration Low-substituted propyl cellulose 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 Binder Povidone K-30 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Lubricant Light anhydrous silicic acid 0.33 0.33 0.33 0.33 0.33 0.33 0.33 0.33 Lubricant Magnesium stearate 0.62 0.62 0.62 0.62 0.62 0.62 0.62 0.62 Total (mg / tablet) 75.00 75.00 75.00 75.00 75.00 75.00 75.00 75.00 book

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layer chief ingredient Mosaic pride citrate - 10.58 10.58 10.58 10.58 10.58 10.58 10.58 Excipient Microcrystalline cellulose - 13.00 13.00 13.00 13.00 13.00 13.00 13.00 Excipient Lactose baggage - 9.49 9.49 9.49 9.49 9.49 9.49 9.49 Westernization
Mechanism Low viscosity
Hydroxypropylmethylcellulose
( HPMC  2910) - 2.00 6.00 8.00 10 14 16 20 Westernization
Mechanism High viscosity
Hydroxypropylmethylcellulose
( HPMC  2208) - 20.00 16.00 14.00 12 8 6 2 Binder Povidone K-30 - 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Disintegration Low-substituted propyl cellulose - 14.00 14.00 14.00 14.00 14.00 14.00 14.00 Lubricant Light anhydrous silicic acid - 0.31 0.31 0.31 0.31 0.31 0.31 0.31 Lubricant Magnesium stearate - 0.62 0.62 0.62 0.62 0.62 0.62 0.62 Coating agent Opa Dry OY-C-7000A - 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Total (mg / tablet) 75.00 155.00 155.00 155.00 155.00 155.00 155.00 155.00

division Classification ingredient Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Immediate layer chief ingredient Mosaic pride citrate 5.29 5.29 5.29 5.29 5.29 Excipient Microcrystalline cellulose 21.00 21.00 21.00 21.00 21.00 Excipient Lactose baggage 18.76 18.76 18.76 18.76 18.76 Disintegration Low-substituted propyl cellulose 24.00 24.00 24.00 24.00 24.00 Binder Povidone K-30 5.00 5.00 5.00 5.00 5.00 Lubricant Light anhydrous silicic acid 0.33 0.33 0.33 0.33 0.33 Lubricant Magnesium stearate 0.62 0.62 0.62 0.62 0.62 Total (mg / tablet) 75.00 75.00 75.00 75.00 75.00 West floor chief ingredient Mosaic pride citrate 10.58 10.58 10.58 10.58 10.58 Excipient Microcrystalline cellulose 20.00 15.00 10.00 10.00 5.00 Excipient Lactose baggage 9.49 9.49 9.49 9.49 9.49 Soviet firearms Low viscosity Hydroxypropylmethylcellulose  ( HPMC  2910) 15.00 20.00 25.00 - - Soviet firearms High viscosity Hydroxypropylmethylcellulose  ( HPMC  2208) - - - 25.00 30.00 Binder Povidone K-30 5.00 5.00 5.00 5.00 5.00 Disintegration Low-substituted propyl cellulose 14.00 14.00 14.00 14.00 14.00 Lubricant Light anhydrous silicic acid 0.31 0.31 0.31 0.31 0.31 Lubricant Magnesium stearate 0.62 0.62 0.62 0.62 0.62 Coating agent Opa Dry OY-C-7000A 5.00 5.00 5.00 5.00 5.00 Total (mg / tablet) 155.00 155.00 155.00 155.00 155.00

< Experimental Example  1>

The tablets consisting of only 5 mg of a commercially available gasmotin tablet (5 mg of Mossafrid, manufactured by Daewoong Pharmaceutical Co., Ltd.) and the immediate-release layer prepared in Comparative Example 1 were compared in terms of dissolution profiles at a pH 4.0 eluate. The in-vitro dissolution test was performed by rotating the paddles at 50 rpm / min. The results are shown in Fig. In the case of Comparative Example 1 which consisted of the immediate layer, 100% drug was eluted within 30 minutes, similar to that of the gasymetry.

On the other hand, in order to confirm whether or not the release control agent (release agent) of high viscosity or low viscosity was added to the sustained-release layer and the change in the dissolution profile of the preparation according to the addition amount (weight) To 6 were prepared. However, the weight of the tablet was corrected with a microcrystalline cellulose excipient as a filler. The elution patterns at pH 4.0 for the tablets of Comparative Examples 2 to 6 were confirmed, and the results are shown in Figs.

Review

The dissolution rate of the tablets prepared using only the low-viscosity sustained release agent (HPMC 2910) as in Comparative Examples 2 to 4 did not show sustain-release due to 100% elution of the drug before 6 hours (Fig. 2 ). On the other hand, as in Comparative Examples 5 and 6, the dissolution rate of the tablets prepared using only the high-viscosity sustained release agent (HPMC 2208) showed that the drug was not eluted 100% even after 24 hours, and showed long sustained release (FIG.

On the other hand, Fig. 4 shows dissolution rates of tablets prepared by mixing low-viscosity and high-viscosity sustained-release agents at a constant ratio as in Examples 1 to 7. In the case of Examples 5 to 7, the greater the amount of the low-viscosity sustained-release agent used, the faster the initial dissolution and the faster the time for the drug to dissolve 100%, so that the effect of once-daily dosing is hardly expected.

In Examples 1 and 4, when the high-viscosity sustained-release agent is more than the low-viscosity sustained-release agent, the drug elutes to 60% or less even after 4 hours. In the case of Example 3, the dissolution rate was about 30% at the beginning of the dissolution rate similar to the drug content of the immediate-release layer, and the dissolution rate was constantly extended until around 20 hours and the drug was eluted at about 20 to 24 hours . Therefore, the ideal minimum effective blood concentration and the highest blood concentration can be expected, so it is preferable to use a sustained-release preparation intended to be taken once a day.

< Experimental Example  2>

The sustained-release formulation of Example 3 was established as the final formulation for clinical trials, and the amounts and composition ratios of the drug substance of the sustained-release formulation of Example 4 are shown in Table 3.

division Classification ingredient 1 party (mg) Total weight
Contrast ratio (%) Percentage of right-wing / western-style floor (%) genus

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layer chief ingredient Mosaic pride citrate 5.29 3.53 7.05 Excipient Microcrystalline cellulose 21.00 14.00 28.00 Excipient Lactose baggage 18.76 12.51 25.01 Disintegration Low-substituted propyl cellulose 24.00 16.00 32.00 Binder Povidone K-30 5.00 3.33 6.67 Lubricant Light anhydrous silicic acid 0.33 0.22 0.44 Lubricant Magnesium stearate 0.62 0.41 0.83 Total (mg / tablet) 75.00 - 100.45
(? 100) book

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layer chief ingredient Mosaic pride citrate 10.58 7.05 14.11 Excipient Microcrystalline cellulose 13.00 8.67 17.33 Excipient Lactose baggage 9.49 6.33 12.65 Soviet firearms Low viscosity
Hydroxypropylmethylcellulose
( HPMC  2910) 8.00 5.33 10.67 Soviet firearms High viscosity
Hydroxypropylmethylcellulose
( HPMC  2208) 14.00 9.33 18.67 Binder Povidone K-30 5.00 3.33 6.67 Disintegration Low-substituted propyl cellulose 14.00 9.33 18.67 Lubricant Light anhydrous silicic acid 0.31 0.21 0.41 Lubricant Magnesium stearate 0.62 0.41 0.83 Coating agent Opa Dry OY-C-7000A 5.00 100 100.01
(? 100) Total (mg / tablet) 155.00

Example 3 is a two-layer tablet composed of a core layer and a sustained layer. In the sustained-release layer, hydroxypropyl methylcellulose having a high viscosity and a low viscosity, each of which is a sustained-release base, A significant drug can also be eluted in the small intestine and / or large intestine with a pH of 6.8, which may be the best candidate for which the drug can be continuously eluted for 24 hours. In addition, when the pH of the solution is kept at a constant pH 4.0 range, the dissolution rate is 25% to 45% after 1 hour and the dissolution rate after 60 hours is 60% to 80% %, And the dissolution rate after 24 hours was 85% or more.

- Test for dissolution rate under various pH eluate conditions

Specimen: The simulated free citrate sustained-release preparation of Example 4

Dissolution Test Solution: 900 ml of the Korean Pharmacopoeia Disintegration Test Method (pH 1.2, 4.0, 6.8, water)

Test temperature: 37 ± 0.5 ℃

Elution method: Korean Pharmacopoeia dissolution test Method 2 (paddle method), 50 rotations per minute

A dissolution rate test was conducted in vitro to confirm the dissolution profile of the simfried citrate sustained-release preparation according to the pH change. The results are shown in Table 4 and FIGS. 5 to 8.

Test solution Average dissolution rate (%) 0.5 hours 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours 16 hours 20 hours 24 hours pH 4.0 29.88 43.36 53.86 62.87 71.38 78.20 84.97 94.47 100.20 100.10 water 24.61 39.13 51.92 64.34 73.77 81.44 86.67 89.85 88.62 88.99 pH 1.2 34.04 43.75 54.66 58.75 64.91 72.31 79.04 91.35 100.65 103.01 pH 6.8 16.02 24.49 27.55 30.70 32.61 34.46 35.23 36.79 37.56 39.68

The dissolution rate was constant and constant even at pH 1.2 and water conditions, and it can be expected that the bioavailability of the active ingredient of moscapride citrate is maintained for 24 hours. In addition, at pH 6.8, the dissolution rate was low due to the physicochemical properties of the mashafide citrate and the effect of the sustained release agent and the excipient.

< Experimental Example  3>

The pk of the simfried citrate was confirmed by the following pre-clinical test with the simulated free citrate sustained-release preparation of Example 3 which confirmed the elution pattern at various pH conditions in vitro.

The test method was to orally administer the test substance (simfried citrate sustained-release tablet) and the commercially available gaskymine (5 mg) to beagle dogs (male, n = 6) The concentrations of the simulated fibrids and their salts in plasma were measured. The pharmacokinetic parameters were calculated using the BA Calc 2007 program, the area under the plasma concentration-time curve (AUCt), the area under the plasma concentration-time curve from the dosing time to the infinite time (AUC8) , Peak blood concentration (Cmax), peak blood concentration (tmax), and serum half - life (t1 / 2). AUC8 and Cmax divided by dose were used and expressed as AUCi / doseC and max / dose, and the ratio of AUCt to AUCi was expressed as AUCt / AUCi. The results were confirmed by Student-t-test (Student's t-test) at 95% confidence interval, and the results are shown in Table 5 and FIG.

division PK
parameters G1 G2 G3 G4 G5 G6 mean stdev Treaty
( Gasmotin tablets ) AUC (last) 24.66 41.80 30.55 19.24 40.38 29.55 31.036 8.78 AUC (inf) 25.33 43.16 31.58 20.24 41.81 31.44 32.26 8.98 Cmax 7.480 15.62 12.89 5.783 11.14 9.406 10.38 3.60 Tmax 5.67 5.67 0.67 10.67 11 5.67 6.55 3.84 Test substance
(Sustained-release of Example 3) AUC (last) 37.94 48.16 30.11 24.34 22.95 21.66 30.86 10.39 AUC ( inf ) 40.91 50.70 33.35 27.22 25.80 23.67 33.61 10.45 Cmax 7.12 7.98 6.40 5.23 5.37 4.45 6.09 1.32 Tmax 3 4 4 3 3 3 3.33 0.52 Test / Ref  (%) - AUC ( last ): 99.4, AUC ( inf ): 104.2, Cmax  : 58.7

As a result of observing the pk of the simulated fly in a beagle dog with a single 5 mg of the control (gasoline) and the sustained release of the simfried citrate of Example 3, the maximum peak concentration (Cmax) at an early stage was increased, (Tmax) was delayed to have the same pattern as the in vitro elution pattern. This can be predicted as a result corresponding to the object of the technical solution of the present invention, and based on this test, the optimal effect was confirmed in the clinical test which is the final objective of the present invention.

< Experimental Example  4>

In order to evaluate the pharmacodynamic equivalence of the preparation of the present invention, the pharmacokinetic characteristics and the pharmacokinetic properties of the simfried citrate sustained-release preparations having the composition of Example 3 and the simulated free-radical formulations (5 mg of gasmotin, Daewoong Pharmaceutical) , 3 treatment groups, and 3 phase Williams design phase 1 clinical trials to compare and evaluate the effects of the treatment. Subjects consisted of 48 healthy volunteers who were aged between 20 and 55 and who were selected according to criteria for selection and exclusion of the study protocol. The specific test conditions are shown in Table 6 below, and the results of the clinical tests are shown in Table 7 and FIG.

Clinical trial
Medication  Width ■ Test drug: UI05MSP015CT, once daily oral administration
(Mosapride citrate 15 mg, Korea United Pharmaceutical Co., Ltd.)
Formulation - Tablets, Capacity - 15 mg / 1T
■ Control agent: Gasmotine tablets, 3 times a day (every 6 hours) Oral administration
(Mosapride citrate 5 mg, Daewoong Pharmaceutical Co., Ltd.)
Formulation - Film Coated Tablets, Capacity - 5 mg / 1T Test design ■ Single-dose, Randomized, Open-label, 3-Treatment, 3-Period Williamsdesign Study
■ Randomly assigned to a total of 6 groups of treatments (fasting), test drug (fasting), and test drug (postprandial)
■ Cancellation period: 7 days or more from the start date of the first dose
■ Blood collection time:
Control subjects: 0.33, 0.67, 1, 1.5, 2, 3, 6 (second administration after blood sampling), 6.33, 6.67, 7, 7.5, 8, 10, 12 (third administration after blood collection),
12.33, 12.67, 13, 13.5, 14, 15, 16 and 24 h (total 23 times)
Tests: 0 h before each dose (first dose after blood sampling), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10,
■ Drug analysis method: LC-MS / MS Number of subjects

■ 대조약 (Reference, R) 치료군: 가스모틴정(Mosapride citrate 5 mg) 1정, 1일 3회(6시간마다) 공복투여 (총 15 mg)
■ 시험약 (Test/fasted, T) 치료군: UI05MSP015CT (Mosapride citrate 15 mg) 1정, 1일 1회 공복투여 (총15 mg)
■ 식후 시험약 (Test/fed, TF) 치료군: UI05MSP015CT (Mosapride citrate 15 mg) 1정, 1일 1회 식후투여 (총15 mg)■ Total number of subjects - 48

■ Reference (R) treatment group: 1 tablet of mosapride citrate (5 mg), 3 times a day (every 6 hours)
■ Test (fasted, T) treatment group: 1 tablet of UI05MSP015CT (Mosapride citrate 15 mg), fasting once a day (total 15 mg)
■ Tested / fed (TF) treatment group: One dose of UI05MSP015CT (Mosapride citrate 15 mg), administered once a day (15 mg total) Statistical analysis After calculating the pharmacokinetic parameters, the pharmacokinetic parameters were calculated, and the 90% confidence interval of the mean value difference logarithm of the first evaluation item value of the control drug (fasting) test drug (fasting) for the first evaluation items Cmax and AUCt was calculated as log 0.8 to log 1.25 or less.
In addition, pharmacokinetic parameters were calculated after analyzing drug concentration, and test drug (fasting) and test drug
And the 90% confidence interval of the mean value difference obtained by log-transforming the value of the first evaluation item (postprandial) is evaluated to evaluate the food effect.

As shown in Table 7 and FIG. 10, the results of the pharmacodynamic equivalence test of the simfurf citrate sustained-release preparation and the 5 mg of the gasphosphate tablets of Example 3, which were conducted under the test conditions of Table 6 above, showed that both preparations had pharmacologically equivalent pharmacological effects .

2. Fasting pharmacokinetic parameter results of the reference and test drugs

As a result of the statistical analysis, it was found that the 90% confidence interval of log transformed AUClast and Cmax average values satisfied log 0.8 to log 1.25. Therefore, the two drugs showed similar pharmacokinetic properties in the control and test drug through comparison of pharmacokinetic evaluation items.

3. Effect of food on the fasting and post-prandial pharmacokinetic parameters of the test drug

The 90% confidence interval of log transformed AUClast and Cmax mean values deviates from log 0.8 to log 1.25 in both items. In other words, AUClast and Cmax were increased by 39.5% and 78.5%, respectively, when the test drug was taken after the meal, compared with fasting. Therefore, the pharmacokinetics of the test drug were judged to be affected by food.

(2) Safety evaluation result

Forty - eight subjects who received the test drug and the reference drug underwent a safety evaluation. Five cases of adverse events occurred in five subjects during the clinical trial. One of these patients had severe adverse events and the rest of them had mild to moderate severity.

Considering the temporal relationship between dosing time and occurrence or the mechanism of action of the principal component, the causal relationship between the harmful case and the principal component was evaluated as the possibility of epistaxis only. The test drug has been proven to be safe in 48 subjects and is therefore considered to be a relatively safe clinical trial drug.

PREPARATION EXAMPLE 1 Preparation of capsules containing mini-tablets containing moscafide citrate

1-1. Manufacture of Granules Containing Modified Fried Citrate

The mashafrid citrate and lactose hydrate were mixed and kneaded in a high-speed coater, and granules were prepared by co-and granulation process by adding povidone K-30 solution previously dissolved in ethanol.

1-2. Preparation of Mini Tablets Containing Modified Fried Citrate

HPC 2910), high viscosity hydroxypropyl methylcellulose (100,000 cps, HPMC 2208), low-substituted hydroxypropylcellulose (L-HPC), low viscosity hydroxypropyl methylcellulose ) Are mixed and granulated by previously adding povidone K-30 solution dissolved in ethanol, and dried in a cabinet dryer at 50 to 60 for 30 to 40 minutes (LOD 2% or less). After the preparation, silicon dioxide and magnesium stearate are added and mixed to prepare a mini tablet.

1-3. Preparation of capsule preparation

The granules and mini tablets prepared above were filled into capsules using a capsule filling machine and coated with methanol as a solvent to prepare a capsule preparation.

&Lt; Preparation Example 2 >

For the preparation of the immediate-release layer, the microfibrillated citrate, microcrystalline cellulose 101, lactose hydrate and low-substituted hydroxypropylcellulose (L-HPC) were mixed and then povidone K-30 solution previously dissolved in ethanol was added thereto and granulated. Dry in a drier at 50 to 60 ° C for 30 to 40 minutes (LOD 2% or less). After sizing, mix the remaining glidants.

The first sustained-release layer was prepared by dissolving the microfibrillated citrate, microcrystalline cellulose, lactose hydrate, low viscosity hydroxypropyl methylcellulose (4000 cps, HPMC 2910), high viscosity hydroxypropyl methylcellulose (100,000 cps, HPMC 2208) Cellulose (LHPC) is mixed and fixed, and then povidone K-30 solution previously dissolved in ethanol is added and granulated, and dried in a cabinet dryer at 50 to 60 ° C for 30 to 40 minutes (LOD 2% or less ) After mixing, mix the remaining lubricants and adjust the viscosity to 50,000 cps.

The second sustained-release layer is composed of a mixture of microporous citrate and microcrystalline cellulose, lactose hydrate, low viscosity hydroxypropylmethylcellulose (4000 cps, HPMC 2910), high viscosity hydroxypropylmethylcellulose (100,000 cps, HPMC 2208) Cellulose (L-HPC) is mixed and fixed, and then povidone K-30 solution and xanthan gum dissolved in ethanol are coalesced and granulated and dried in a cabinet dryer at 50 to 60 ° C for 30 to 40 minutes (LOD 2 %). After formulation, mix the remaining lubricants and adjust the viscosity to 100,000 cps.

In order to prepare a three-layered tablet using the mixture of the inner layer and the first and second sustained-release layers prepared above, the inner layer, the first sustained layer and the second sustained layer were successively filled in a die having a diameter of 12.0 mm, The pressure was applied at 8 MPa using a press to form a three-layer tablet, and film-coated with a coating agent of Opadry-OY-C-7000A (trade name of Colorcon Co.) in a conventional manner to obtain a mixture of 15 mg of sima fried citrate Prepare a three-layer sustained-release formulation. Table 10 shows the constituent components and contents of the above examples.

Claims (7)

A once-daily oral dosage form for improving gastrointestinal symptoms, comprising as an active ingredient a mothafide, a salt thereof or a hydrate thereof,
The total weight of the formulation is 200 mg or less,
The content of the active ingredient is 10 mg to 20 mg,
Wherein the preparation is administered before the meal.
The method according to claim 1,
The formulation may be a sustained or controlled release formulation,
The above preparation has a retention time of 18 hours to 24 hours in the gastrointestinal tract. When passing through the gastrointestinal tract, 20 to 50% of the simulated fried or salt thereof is eluted and 50 to 80% of the simulated fried or salt thereof is eluted Lt; / RTI &
An active ingredient, a filler, a disintegrant and an additive;
An active ingredient, a filler, a disintegrant, a release control agent and an additive,
The release control agent may be prepared by mixing a high viscosity hydroxypropylmethylcellulose having a viscosity of 80,000 cps to 120,000 cps at a weight ratio of low viscosity hydroxypropylmethylcellulose of 2,000 cps to 20,000 cps of 10 to 1: 2 &lt; / RTI &gt; method (paddle method) at 37 DEG C pH 4.0, 6.8. 1.2, and the water elution solution satisfies the following dissolution profile.
1) The effective components contained in the pH 4.0, pH 1.2 and water elution conditions eluted 25-45% after 1 hour, 60-80% after 8 hours, and 85% after 24 hours.
2) In the pH 6.8 eluent condition, the active ingredient contained was eluted to less than 45% for 16 hours.
3. The method of claim 2,
Wherein the weight ratio of high viscosity hydroxypropyl methylcellulose: low viscosity hydroxypropyl methylcellulose is 2.6 to 1: 1.
The method according to claim 1,
Wherein the formulation has a total weight of from 150 mg to 160 mg.
3. The method of claim 2,
wherein the active ingredient contained in the pH 6.8 eluate is eluted to 45% or less for 24 hours.
3. The method of claim 2,
The sustained release layer contained 14.11 parts by weight of simaflid citrate, 10.67 parts by weight of hydroxypropylmethylcellulose having a viscosity of 4,000 cps, 18.67 parts by weight of hydroxypropylmethylcellulose having a viscosity of 100,000 cps, 17.33 parts by weight of microcrystalline cellulose 12.65 parts by weight of lactose hydrate, 18.67 parts by weight of low-substituted hydroxypropyl cellulose, 6.67 parts by weight of polyvinylpyrrolidone, 0.41 part by weight of light silicic anhydride, and 0.83 parts by weight of magnesium stearate.
The method according to claim 1,
Wherein the digestive symptom is a functional dyspepsia.

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