TW201834643A - Pharmaceutical formulation containing itopride hydrochloride and having immediate and sustained release properties - Google Patents

Abstract

The present disclosure provides a pharmaceutical formulation, containing: (a) a sustained release part containing itopride or a pharmaceutically acceptable salt thereof, a sustained release polymer, a CO2 source, an organic acid and a pharmaceutically acceptable filler; and (b) an immediate release part containing itopride or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable filler. The present disclosure may improve medication compliance through once-daily administration.

Description

Instant release and sustained release pharmaceutical preparation containing itopride hydrochloride

The present application claims priority to Korean Patent Application No. 10-2017-0022040, filed on Jan. 20,,,,,,,,,,,,,,,,, The present disclosure relates to a pharmaceutical preparation comprising etoriride hydrochloride, and more particularly to a pharmaceutical preparation capable of improving drug compliance via a once-a-day administration while providing a rapid analgesic effect.

Ettoride hydrochloride (N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide hydrochloride) is a kind A drug that increases the amount of acetylcholine by inhibiting the acetylcholinesterase and the dopamine D2 receptor. Acetylcholine promotes peristalsis of the gastrointestinal tract, thereby treating gastrointestinal symptoms caused by functional dyspepsia, such as bloating, upper abdominal pain, anorexia, chest pain, and vomiting. This drug is suitable for long-term use because it hardly exhibits side effects of the peripherally selective dopamine D2 antagonist domperidone, which is used to improve gastrointestinal function, such as male breast milk, lactation and the like.

Onset time after oral administration of etorride hydrochloride (N-[[4-(2-dimethylaminoethoxy)phenyl]methyl]-3,4-dimethoxybenzamide) The highest blood concentration was reached in about 0.5 to 1.5 hours in 30 minutes and lasted for about 12 hours. It is well known that after oral administration of etomiride, about 80% is excreted (eliminated) via urination, and the excretion rate (half-life) is about 6 hours.

Patients with poor digestion require long-term medication because symptoms often occur due to stress. However, patients who take etotopril for a long time may find inconvenience in drug teaching and drug compliance because they have not yet developed a once-daily dosing formulation.

In order to avoid the inconvenience of taking the medicine 3 times a day, efforts have been made to develop a preparation for once-daily administration. However, it is difficult to quickly relieve pain using a general sustained release preparation.

technical problem

The present disclosure is directed to providing a pharmaceutical formulation comprising etopride hydrochloride with both immediate and sustained release properties.

The present disclosure is also directed to providing a pharmaceutical preparation comprising an immediate release portion and a sustained release portion which can be improved in drug compliance by once-daily administration due to sustained release of the drug, while providing a rapid analgesic effect.

The present disclosure can reduce side effects that may occur due to the release of excess drug at an early stage. Technical solutions

The present disclosure relates to a pharmaceutical preparation comprising an pharmaceutically acceptable salt of etidride or etopride (specifically, etopride hydrochloride) as an active ingredient, and provides excellent efficacy at the initial stage and simultaneously A pharmaceutical formulation that provides improved drug compliance via once-daily dosing.

The present disclosure relates to an oral formulation of etodoride or a pharmaceutically acceptable salt thereof, wherein it is very useful in treating digestive disorders. More specifically, the present disclosure provides oral pharmaceutical preparations with improved drug compliance, as the drug can be administered once a day because it is released at a constant rate for 24 hours with etomiride or a pharmaceutically acceptable salt thereof.

The present disclosure provides a formulation comprising a pharmaceutically acceptable salt of etoriride or etopride, in particular a pharmaceutical formulation comprising etofride hydrochloride, which provides sustained release of the drug at a constant rate, while at the beginning The stage shows excellent results.

The pharmaceutically acceptable salt of etodoride may be, for example, an acid addition salt, a quaternary ammonium salt or the like. The acid addition salt may be a mineral acid salt such as a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a phosphate or the like, or an organic acid salt such as an oxalate, maleate or the like. Butenedioate, lactate, malate, succinate, tartrate, benzoate, methanesulfonate, citrate, etc., and the quaternary ammonium salt can be a lower alkyl halide, such as a Base iodine, methyl bromide, ethyl iodide, ethyl bromide, etc., or lower alkyl sulfonate, such as methyl methanesulfonate, ethyl methanesulfonate, etc., lower alkyl aryl sulfonate, such as p-toluene Methyl sulfonate and the like. Specifically, itopride hydrochloride can be used. In order to provide sustained release and excellent efficacy at an initial stage by including an immediate release portion and a sustained release portion together, it is possible to use itopride hydrochloride.

The present disclosure may provide a pharmaceutical preparation comprising: (a) a sustained release portion comprising: etofride or a pharmaceutically acceptable salt thereof; a sustained release polymer; a CO ₂ source; an organic acid; A pharmaceutically acceptable filler (diluent); and (b) an immediate release portion comprising: etodoride or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable filler (diluent).

In particular, hydrochloric acid can be used as a pharmaceutically acceptable salt of etoriride or etoride.

The inventors of the present disclosure have developed a pharmaceutical preparation which provides sustained release of etomiride or a pharmaceutically acceptable salt thereof while providing a rapid effect by only one administration per day, and the inventors have completed This disclosure.

The term "sustained release portion" as used in the present disclosure is understood to mean a portion which allows the drug to be slowly dissolved and released in a sustained manner after administration to a human.

The term "immediate release portion" as used in the present disclosure is understood to mean a portion that allows rapid release of a drug after administration to a human.

As a sustained release portion of the present disclosure, a sustained release polymer can be used to effectively control the release of etopride hydrochloride having a very high water solubility. The sustained release polymer means a material for slowly releasing the drug for a long period of time, and any sustained release polymer used in the art can be used without limitation. Specifically, one or more selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone can be used as the sustained-release polymer. More specifically, hydroxypropyl methyl cellulose (HPMC) can be used. Further more specifically, as with hydroxypropyl methylcellulose, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 2208 or a mixture thereof can be used. In particular, hydroxypropyl methylcellulose can be used in the formulations of the present disclosure because it exhibits little viscosity or release mode change depending on the pH. The hydroxypropyl methylcellulose may have a viscosity of from 100 to 100,000 cPs to form a drug release matrix. Specifically, HPMC having an average viscosity of 5,000 to 30,000 cPs can be used. Viscosity was measured according to the United States Pharmacopeia (USP) using a 2% by weight aqueous solution at 20 °C.

In view of the occurrence of foaming due to the use of a source of CO ₂ and an organic acid, the polymer described above can be used because the release of the drug is less affected by foaming and the viscosity does not change significantly.

The sustained-release polymer contained in the sustained-release portion may be contained in an amount of 10% by weight to 40% by weight, based on the total weight of the sustained-release portion, specifically 15% by weight to 35% by weight, more specifically 17% by weight. Up to 30% by weight, further more specifically 20% to 29% by weight, even more specifically 26% to 28% by weight. This range may be desirable when considering the sustained release of the drug, foaming in the sustained release portion, and the like. Within this range, sustained release of the drug can be achieved without unduly delaying drug release.

The formulation of the present disclosure further comprises a source of CO ₂ and an organic acid in the sustained release portion. As the CO ₂ source, one selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate can be used in consideration of compatibility with the drug of the present disclosure, excellent foaming, minimized pH change, and the like. Or more. In particular, sodium bicarbonate can be used for the purposes of this disclosure. The CO ₂ source may be included in an amount of from 1% by weight to 10% by weight, based on the total weight of the sustained-release portion, specifically from 3% by weight to 8% by weight, more specifically from 4% by weight to 7% by weight.

As the organic acid, one selected from the group consisting of oxalic acid, maleic acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, benzoic acid, methanesulfonic acid, and citric acid may be used. Further, this organic acid can be generated by using it with a CO ₂ source. In particular, citric acid can be used for the purposes of this disclosure. The organic acid may be included in an amount of from 1% by weight to 10% by weight, based on the total weight of the sustained-release portion, specifically from 3% by weight to 8% by weight, more specifically from 4% by weight to 7% by weight.

The weight ratio of the organic acid may be 1:: 0.1 to 10, particularly 1: In this example, the sustained-release part containing CO ₂ in the CO ₂ source and an organic acid source in an exemplary embodiment of the present disclosure 0.5-5.

The CO ₂ source and the organic acid can cause the drug to float in the gastric fluid, and thereby allow the drug to stay in the gastrointestinal tract for a long time. When the content of the CO ₂ source and the organic acid is in the above range, an excellent floating effect can be achieved. Further, for the preparation containing two or more tablets in the capsule, when the ratio of the CO ₂ source to the organic acid is within the above range, an excellent floating effect and a sustained release effect can be expected.

The inventors of the present disclosure have recognized that the formulation of the present invention comprising etomiride or a pharmaceutically acceptable salt thereof can remain in the gastrointestinal tract for a long time because the formulation comprises a source of CO ₂ and an organic acid.

As the filler, one or more selected from the group consisting of microcrystalline cellulose, lactose, starch, mannitol, glucose, sorbitol, dextrin, and sucrose may be used, but is not limited thereto.

The sustained release portion may further comprise a lubricant.

Lubricants are used to improve the formability of the formulation. For example, one or more selected from the group consisting of light anhydrous citric acid, cerium oxide, talc, stearic acid, magnesium stearate or a mixture thereof may be used, but is not limited thereto.

In addition to etodoride or a pharmaceutically acceptable salt thereof, the sustained release portion may further comprise an antioxidant, an odorant, a preservative, a fragrance, a sweetener, a colorant, a pH adjuster, and a viscosity control for preventing oxidation of the preparation. Agent.

The immediate release portion of the formulation of the present disclosure may comprise: a pharmaceutically acceptable salt of etidride or etopride; and a pharmaceutically acceptable filler. The immediate release portion may further contain a disintegrant, a lubricant, and the like.

A disintegrant, a lubricant, or the like may be present in a form uniformly dispersed in the immediate release portion.

For example, a sodium carboxymethylcellulose selected from the group consisting of crosslinked carboxymethylcellulose sodium, hydroxymethylcellulose calcium, sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, starch, copolyvinylpyrrolidone, and low substituted hydroxypropyl can be used. One or more of the group of base cellulose compositions acts as a disintegrant. Specifically, crosslinked hydroxymethylcellulose sodium can be used.

The filler contained in the immediate release portion may be the same as or different from the filler contained in the sustained release portion.

The present disclosure provides an oral preparation using a gastric retention drug delivery system, the oral preparation comprising: (a) a sustained release portion comprising: etoiride or a pharmaceutically acceptable salt thereof as an active ingredient; a sustained release polymer; a CO ₂ source; an organic acid; and a pharmaceutically acceptable filler; and (b) an immediate release portion comprising: etodoride or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable filler. The oral preparation has both a sustained release portion and an immediate release portion. Specifically, the sustained release portion and the immediate release portion may be independently present in the capsule in a form separated from each other. Both the sustained release portion and the immediate release portion may be in the form of granules or tablets, or only one of the sustained release portion and the immediate release portion may be in the form of a tablet. Specifically, both the sustained release portion and the immediate release portion may be in the form of a tablet.

When both the immediate release portion and the sustained release portion of the capsule are in the form of tablets, foaming may occur well in the gastric juice, and sustained release may be expected. Specifically, both the sustained release portion and the immediate release portion may be in the form of a tablet.

Specifically, the preparation may contain etodoride hydrochloride as an active ingredient. The content of etopride hydrochloride contained in the sustained-release portion (a) may be 3 to 5 times higher than the content of etopride hydrochloride contained in the immediate release portion (b), specifically 3.5 to 4.5 times higher. Specifically, the content of etopride hydrochloride contained in the sustained-release portion (a) may be 4 times the weight of the etotopril hydrochloride contained in the immediate release portion (b). Within this range, sustained release allowing one administration per day can be achieved while providing a rapid effect.

The formulation comprising the sustained release portion and the immediate release portion of the present disclosure can be provided in an oral administration form by formulating the immediate release portion and the sustained release portion, for example, in the form of a tablet. For example, it can be provided as a hard capsule preparation in which a sustained release portion and an immediate release portion are mixed together.

In an exemplary embodiment, the present disclosure provides a pharmaceutical preparation for oral administration once a day, the pharmaceutical preparation comprising: (a) a sustained release portion comprising: 40% by weight to the total weight of the sustained release portion 70% by weight of etotopril hydrochloride; 17% by weight to 30% by weight of hydroxypropylmethylcellulose; 10% by weight to 25% by weight of microcrystalline cellulose, lactose, starch, calcium monohydrogen phosphate or a mixture thereof Filler; 1% by weight to 10% by weight of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or a mixture thereof as a source of CO ₂ ; 1% by weight to 10% by weight of oxalic acid, maleic acid, counter-butyl Adipic acid, malic acid, tartaric acid, citric acid, benzoic acid or a mixture thereof as an organic acid; and 0.1% by weight to 5% by weight of magnesium stearate, stearic acid, light anhydrous citric acid or a mixture thereof as a lubricant And (b) an immediate release portion comprising: from 30% by weight to 60% by weight, based on the total weight of the immediate release portion, of etotopril; 20% by weight to 45% by weight of microcrystalline cellulose, lactose, starch, Calcium monohydrogen phosphate or a mixture thereof as a filler; 18% to 30% by weight of crosslinked hydroxy Sodium carboxymethyl cellulose; and 0.1% to 5% by weight of light anhydrous silicate, magnesium stearate, stearic acid or mixtures thereof as a lubricant.

In particular, the present disclosure provides a pharmaceutical preparation for oral administration once a day, the pharmaceutical preparation comprising: (a) a sustained release portion comprising: 45% to 60% by weight based on the total weight of the sustained release portion Etotopril hydrochloride; 20% to 25% by weight of hydroxypropyl methylcellulose; 12% to 20% by weight of microcrystalline cellulose, lactose, starch, monohydrogen phosphate or a mixture thereof as a filler; 3.5% to 8% by weight of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or a mixture thereof as a source of CO ₂ ; 3 to 6% by weight of oxalic acid, maleic acid, fumaric acid , malic acid, tartaric acid, citric acid, benzoic acid or a mixture thereof as an organic acid; and 0.5% by weight to 3% by weight of magnesium stearate, stearic acid, light anhydrous citric acid or a mixture thereof as a lubricant; b) an immediate release portion comprising: 35 to 50% by weight of etodoride hydrochloride, based on the total weight of the immediate release portion; 25% to 40% by weight of microcrystalline cellulose, lactose, starch, monohydrogen phosphate Calcium or a mixture thereof as a filler; 20% to 28% by weight of crosslinked hydroxymethyl fibers Sodium; and 0.5 wt% to 2% by weight of light anhydrous silicate, magnesium stearate, stearic acid or mixtures thereof as a lubricant.

In certain exemplary embodiments of the present disclosure, the sustained release portion may comprise at least two tablets, such as 2, 3, 4, 5, 6 or more tablets. More specifically, the sustained release portion may consist of 2 tablets.

Specifically, the preparation of the present disclosure may be a hard capsule preparation comprising two separate tablets as a sustained release portion and one tablet as an immediate release portion.

The sustained release portion (a) may comprise two tablets, each tablet containing 55-65 mg of etopride hydrochloride, and the immediate release portion (b) may comprise 20-40 mg of etopride hydrochloride.

In another exemplary embodiment, the present disclosure may provide a method for preparing a formulation comprising etoriride or a pharmaceutically acceptable salt thereof as an active ingredient.

In an exemplary embodiment, the method may comprise: (S1) the step of preparing the sustained-release portion into a tablet, the sustained-release portion comprising etomiride or a pharmaceutically acceptable salt thereof, a sustained-release polymer, CO ₂ source, organic acid and pharmaceutically acceptable filler; (S2) a step of preparing the immediate release portion into tablets, the immediate release portion comprising etoriride or a pharmaceutically acceptable salt thereof and medicinal An acceptable filler; and (S3) a step of preparing a formulation comprising a tablet sustained release portion and an immediate release portion, wherein the sustained release portion and the immediate release portion are separately and independently filled.

The method for preparing the tablet is not particularly limited, and any method commonly used by those skilled in the art can be used.

In the step (S1) of preparing the sustained-release portion into a tablet, the sustained-release portion may be prepared into at least two tablets.

In the step (S3) of preparing the preparation, the preparation is not particularly limited. The formulation may in particular be a capsule formulation, more specifically a hard capsule formulation.

In an exemplary embodiment, the present disclosure provides a formulation for oral administration once daily, which comprises etofride hydrochloride as an active ingredient, thereby allowing simultaneous release of etopride hydrochloride and sustained release hydrochloric acid from a matrix polymer. Relying on Tony.

The formulation may have the following dissolution profile.

The preparation may be provided as a preparation for oral administration once a day, and when 900 mL of pH 1.2 buffer is used as a dissolution medium and measured at a stirring paddle rotation speed of 50 rpm, the dissolution rate of etoride hydrochloride in the preparation may be 15% to 40% in 30 minutes, 41% to 70% in 3 hours, and 80% or higher in 9 hours.

When carrying out the dissolution test according to the present disclosure, the above conditions and other specific conditions are to comply with the Korean Pharmacopoeia, the United States Pharmacopoeia or other international standards.

As a result of investigating the drug dissolution profile and pharmacokinetics of the formulation to study the effect of the drug (etoride or its pharmaceutically acceptable salt) in the human body, it has been confirmed that it is a pharmaceutically acceptable salt thereof. The pharmacokinetics vary depending on the in vitro dissolution pattern and achieve excellent pharmacological activity and bioavailability in vivo.

As used in this disclosure the term "T _max" means time to maximum plasma concentration (time to peak plasma concentration), and the means from the administration of the present case discloses a pharmaceutical formulation until the drug (hydrochloride relying cisapride) of The plasma concentration becomes the time between the maximum.

As used in this disclosure the term "C _Maximum" means maximum plasma concentration of the drug and the means (relying cisapride hydrochloride) after administration of the present case discloses a pharmaceutical formulation of the maximum plasma concentration.

The term "AUC" as used in this disclosure refers to the area under the plasma concentration-time curve. In pharmacokinetics, the term "AUC" refers to the area under the curve obtained by plotting the serum concentration of a beneficial agent (drug or active ingredient) versus the time from the start of administration until the time "t" after the start of administration. Typically, the AUC is the area under the curve throughout the entire administration period. AUC can be obtained by analyzing a serum sample of a subject.

The pharmaceutical preparation of the present disclosure, which comprises etomiride or a pharmaceutically acceptable salt thereof, ensures both immediate release of the drug and sustained release of the drug, and immediate release allows a sufficient amount of the drug to be rapidly exposed at an early stage, Slow release is equivalent to 3 doses. That is, the present disclosure provides a preparation for oral administration which exhibits an immediate release and sustained release effect. After administration of the formulation, exposure to a sufficient amount of drug is achieved via a very high initial release rate of etoride or a pharmaceutically acceptable salt thereof, that is, a _maximum increase in C and a decrease in the time to peak plasma concentration, And the initial AUC increase.

Unlike the existing preparations which require three times a day, the preparation of the present disclosure can be conveniently administered by oral administration once a day. Favorable effect

The pharmaceutical preparation according to the present disclosure has excellent drug convenience because it can be administered once a day.

When administered to a human, the pharmaceutical preparation of the present disclosure can achieve both immediate release and sustained release effects.

The formulations of the present disclosure can reduce side effects caused by a rapid increase in blood concentration.

Best mode

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, preferred embodiments of the present disclosure will be described in detail with reference to the accompanying drawings. Before the description, it should be understood that the terms used in the specification and the accompanying claims should not be construed as limited to the general and dictionary meanings, but rather based on the principle that the inventor is allowed to define the terms appropriately for the best explanation. The meaning and concept of the technical aspects of this disclosure are interpreted. Therefore, the descriptions of the present invention are intended to be illustrative only, and are not intended to limit the scope of the disclosure, and it is understood that other equivalents may be implemented without departing from the scope of the disclosure. modify.

<Preparation of API> - Compound name: N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide hydrochloride, C ₂ 0H ₂₇ ClN ₂ O ₄ . - Molecular weight (MW): 394.89. - Solubility: soluble in water (≧48 mg/mL), methanol or acetic acid.

<Preparation Example 1> Granular capsule

1. Prescription (batch number: P01)

150 mg of etotopril hydrochloride was prepared into a hard capsule preparation having the following composition.

Table 1

Etotopril hydrochloride and microcrystalline cellulose were mixed and sieved through a 30 mesh sieve. Separately, white sugar, polyvinylpyrrolidone and polysorbate 80 were dissolved in 80% ethanol for use as a binder solution. The ittoride hydrochloride mixture was added to the binder solution and prepared into wet granules. The wet granules were extruded using an extruder. The extruded pellets were rounded using a spheronizer. The spheronized granules were dried in a drier at 60 ° C for 4 hours. The dried product was added to a fluidized bed processor and a sustained release coating was carried out using the coating solution, in which ethyl cellulose, triethyl citrate and talc were dissolved and dispersed in 80% ethanol.

Fig. 2 is a view showing a capsule preparation containing the etofride particles prepared according to Preparation Example 1.

2. Characteristics

(1) Dissolution rate

The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.

The results are shown in Figure 3 and Table 2.

Table 2

Sustained release is possible compared to commercially available Ganaton, and a dissolution rate of 80% or higher is achieved at about 4 to 5 hours.

(2) Pharmacokinetic parameters

table 3

The formulation prepared in Preparation Example 1 exhibited a higher bioavailability than the commercially available Ganaton. Low AUC (area under the curve) and _Cmax (maximum concentration) may be because the water insoluble coating on the surface of the particles does not float in the gastrointestinal tract.

To solve this problem, the hydrophilic polymer and the CO ₂ source are used to convert the particles into mini-tablets while reducing the particle density and increasing the time of floating and adhering to the gastrointestinal mucosa.

<Preparation Example 2> Mini tablet type capsule

1. Prescription (batch number: M02-1)

150 mg of etotopril hydrochloride was prepared as a hard capsule preparation containing mini tablets of about 2 mm size, with the following composition.

Table 4

Ettoride hydrochloride, microcrystalline cellulose, and hypromellose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding magnesium stearate. The prepared mini tablets were placed in capsules.

Fig. 6 is a view showing a capsule preparation comprising an etalride mini tablet prepared according to Preparation Example 2.

2. Characteristics

(1) Dissolution rate

The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.

The results are shown in Figure 7 and Table 5.

table 5

Although the sustained release of Preparation Example 2 was possible as compared with the commercially available Ganaton, Preparation Example 2 was difficult to use as a controlled release preparation due to a high initial release rate.

(2) Pharmacokinetic parameters

Table 6 shows the pharmacokinetic parameters of Preparation Example 2.

Table 6

As can be seen, compared to the commercially available Ganaton, Preparation Example 2 while demonstrating higher AUC (area under the curve) and _Maximum C (maximum concentration) values. This may be due to the floating and swelling of the formulation.

<Preparation Example 3> Mini tablet type capsule

1. Prescription (batch number: M02-2)

150 mg of etotopril hydrochloride was prepared as a hard capsule preparation containing mini tablets of about 2 mm size, with the following composition.

Table 7

Etotopril hydrochloride, palmityl stearin and hypromellose were mixed and sieved through a 30 mesh sieve. The mixture was heated to 80 ° C or higher using a fluidized bed processor. After melting, cooling and subsequent preparation into 30-mesh particles, the mixture was prepared into wet granules using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding sodium hydrogencarbonate and magnesium stearate. The prepared mini tablets were placed in capsules.

Fig. 6 is a view showing a capsule preparation comprising an etalride mini tablet prepared according to Preparation Example 3.

2. Characteristics

(1) Dissolution rate

The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.

The results are shown in Figure 10 and Table 8.

Table 8

No significant difference in dissolution rate was observed compared to Ganaton.

(2) Pharmacokinetic parameters

Table 9 shows the pharmacokinetic parameters of Preparation Example 3.

Table 9

The _largest increase in AUC and C has been confirmed. This may be due to the use of ingredients that help the formulation swell and float. However, since many additives are used, it is difficult to put a tablet into a capsule, and productivity is lowered. In addition, the lipids used in the preparation of Example 3 adversely affected the productivity or economic efficiency of the mini tablet formulation.

<Preparation Example 4> SR tablet type capsule

1. Prescription (batch number: T03-1)

150 mg of etotopril hydrochloride was prepared into three SR tablets and filled into capsule preparations.

Table 10

Etotopril hydrochloride, microcrystalline cellulose, hypromellose and polyvinylpyrrolidone were mixed, sieved through a 30 mesh sieve, prepared into wet granules using 80% ethanol, and then dried in a dryer at 60 ° C. 4 hour. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding magnesium stearate.

The prepared tablets were filled into capsules.

Figure 13 is a view showing a capsule preparation containing three etopride SR tablets prepared according to Preparation Example 4.

2. Characteristics

(1) Dissolution rate

The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.

The results are shown in Figure 14 and Table 11. A decrease in the dissolution rate has been confirmed.

Table 11

(2) Pharmacokinetic parameters

Table 12 shows the pharmacokinetic parameters of Preparation Example 4.

Table 12

It is believed that BE (bioequivalence) will be low due to very low dissolution rates.

<Preparation Example 5> SR tablet type capsule

1. Prescription (batch number: T03-2)

150 mg of etotopril hydrochloride was prepared into three SR tablets and filled into capsule preparations.

Table 13

Etotopril hydrochloride, microcrystalline cellulose, hypromellose and lactose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding sodium hydrogencarbonate and magnesium stearate. The prepared tablets were filled into capsules.

Fig. 13 is a view showing a capsule preparation comprising three etopride SR tablets prepared according to Preparation Example 5.

2. Characteristics

(1) Dissolution rate

The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.

The results are shown in Figure 14 and Table 14.

Table 14

(2) Pharmacokinetic parameters

Table 15 shows the pharmacokinetic parameters of Preparation Example 5.

Table 15

The formulation of Preparation Example 5 exhibited an increased dissolution rate and a slightly increased bioavailability compared to Preparation Example 4.

<Preparation Example 6> SR tablet type capsule

1. Prescription (batch number: T03-3)

150 mg of etotopril hydrochloride was prepared into three SR tablets and filled into capsule preparations. The preparation was prepared in the same manner as in Preparation Example 5.

Table 16

Fig. 13 is a view showing a capsule preparation comprising three etopride SR tablets prepared according to Preparation Example 6.

2. Characteristics

(1) Dissolution rate

The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.

The results are shown in Figure 20 and Table 17.

Table 17

A decrease in the dissolution rate was confirmed as compared with Preparation Example 3.

(2) Pharmacokinetic parameters

Table 18 shows the pharmacokinetic parameters of Preparation Example 6.

Table 18

Although the preparation of Preparation Example 6 exhibited a decrease in the dissolution rate, the AUC value was close to the target value. Immediate release formulations are believed to improve _Cmax .

<Preparation Example 7> IR and SR tablet type capsules

1. Prescription (batch number: T04-1)

150 mg of etotopril hydrochloride was prepared into two SR tablets and one IR tablet and filled into a capsule preparation. In the table below, the content of the SR portion is the total content of the two tablets.

Table 19

Etotopril hydrochloride, microcrystalline cellulose and hypromellose, lactose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then two sustained-release tablets were prepared by adding a sodium hydrogencarbonate and magnesium stearate using a rotary tableting machine.

Ettoride hydrochloride, microcrystalline cellulose, lactose, crosslinked sodium carboxymethylcellulose and light anhydrous citric acid were mixed, sieved through a 30 mesh sieve, and wet granules were prepared using 80% ethanol, and then at 60 Dry in a desiccator at °C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding magnesium stearate. The prepared immediate release tablet is filled into a capsule together with the sustained release tablet.

Figure 23 is a view showing a capsule preparation comprising two etopride SR tablets and an IR tablet prepared according to Preparation Example 7.

2. Characteristics

(1) Dissolution rate

The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.

The results are shown in Figure 24 and Table 20.

Table 20

(2) Pharmacokinetic parameters

Table 21 shows the pharmacokinetic parameters of Preparation Example 7.

Table 21

It has been found, although quite achieve the _maximum C, but due to reduced residence time in the gastrointestinal tract, AUC decreased.

<Preparation Example 8> IR and SR tablet type capsules

1. Prescription (batch number: T04-2)

150 mg of etotopril hydrochloride was prepared into two SR tablets and one IR tablet and filled into a capsule preparation. In the table below, the content of the SR portion is the total content of the two tablets.

Table 22

Etotopril hydrochloride, microcrystalline cellulose and hypromellose, lactose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then two sustained-release tablets were prepared by adding a sodium hydrogencarbonate and magnesium stearate using a rotary tableting machine.

Ettoride hydrochloride, hypromellose hydrochloride, microcrystalline cellulose, lactose, crosslinked sodium carboxymethylcellulose and sodium hydrogencarbonate were mixed, sieved through a 30 mesh sieve, and wet granules were prepared using 80% ethanol. And then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh pellets, which were prepared into tablets by the addition of magnesium stearate using a rotary tableting machine. The prepared immediate release tablet is filled into a capsule together with the sustained release tablet.

Figure 23 is a view showing a capsule preparation comprising two etopride SR tablets and an IR tablet prepared according to Preparation Example 8.

2. Characteristics

(1) Dissolution rate

The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.

The results are shown in Figure 28 and Table 23.

Table 23

(2) Pharmacokinetic parameters

Table 24 shows the pharmacokinetic parameters of Preparation Example 8.

Table 24

It has been shown to increase the AUC, but C _maximum reduction.

<Preparation Example 9> IR and SR tablet type capsules

1. Prescription (batch number T04-3)

150 mg of etotopril hydrochloride was prepared into two SR tablets and one IR tablet and filled into a capsule preparation. In the table below, the content of the SR portion is the total content of the two tablets.

Table 25

Etotopril hydrochloride, microcrystalline cellulose, hypromellose, mannitol and lactose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a dryer at 60 ° C. 4 hour. The dried product was prepared into 18-mesh granules, and then two sustained-release tablets were prepared by adding a sodium hydrogencarbonate and magnesium stearate using a rotary tableting machine.

Etoopril hydrochloride, hypromellose hydrochloride, microcrystalline cellulose, lactose, cross-linked sodium carboxymethylcellulose, sodium hydrogencarbonate and light anhydrous citric acid, sieved through a 30 mesh sieve, using 80% Ethanol was prepared into wet granules and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding magnesium stearate. The prepared immediate release tablet is filled into a capsule together with the sustained release tablet.

Figure 36 is a view showing a capsule preparation comprising two SR tablets and one IR tablet prepared according to Preparation Example 9.

2. Characteristics

(1) Dissolution rate

The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.

The results are shown in Figure 37 and Table 26.

Table 26

(2) Pharmacokinetic parameters

Table 27 shows the pharmacokinetic parameters of Preparation Example 9.

Table 27

Although various formulations were prepared, satisfactory AUC and C _maximum results were not exhibited.

<Preparation Example 10> IR and SR tablet type capsules

1. Prescription (batch number: T05)

150 mg of etotopril hydrochloride was prepared into two SR tablets and one IR tablet and filled into a capsule preparation. In the table below, the content of the SR portion is the total content of the two tablets.

Table 28

Etotopril hydrochloride, microcrystalline cellulose and hypromellose, lactose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then two sustained-release tablets were prepared by adding a sodium hydrogencarbonate and magnesium stearate using a rotary tableting machine.

Ettoride hydrochloride, microcrystalline cellulose, lactose, crosslinked sodium carboxymethylcellulose and light anhydrous citric acid were mixed, sieved through a 30 mesh sieve, and wet granules were prepared using 80% ethanol, and then at 60 Dry in a desiccator at °C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding magnesium stearate. The prepared immediate release tablet is filled into a capsule together with the sustained release tablet.

Figure 36 is a view showing a capsule preparation comprising two etopride SR tablets and an IR tablet prepared according to Preparation Example 10.

2. Characteristics

(1) Dissolution rate

The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.

The results are shown in Figure 37 and Table 29.

Table 29

(2) Pharmacokinetic parameters

Table 20 shows the pharmacokinetic parameters of Preparation Example 10.

Table 30

The capsule formulations exhibit satisfactory prepared in Preparation Example 10 AUC and C of _{the maximum.} This result is believed to be due to the floating of the formulation and the increased residence time of the drug in the gastrointestinal tract.

<Formulation stability>

A stability test was carried out for the preparation of Preparation Example 10.

Table 31

As can be seen from Table 31, the stability of 3 months was not affected. Industry applicability

The present disclosure provides a pharmaceutical preparation comprising etoriride hydrochloride.

The present disclosure relates to a pharmaceutical preparation capable of improving drug compliance via a once-daily administration while providing a rapid analgesic effect.

no

Figure 1 depicts the process of developing a formulation of the present disclosure. 0.8-mm SR polymer coated granules → 2-mm mini tablets → three sustained release tablets → capsule preparations comprising two immediate release tablets and one sustained release tablet.

Figure 2 is a diagram showing the granule capsules prepared during the development of the formulation of the etoride hydrochloride capsule.

Figure 3 depicts the results of comparing the dissolution rates of P01 with commercially available Ganaton.

Fig. 4 is a graph showing the results of investigating the degree of floating or swelling in the medium in Preparation Example 1. The particles show neither floating nor swelling.

Figure 5 depicts the results of comparing the PK results of P01 with commercially available Ganaton.

Figure 6 depicts a mini tablet capsule formulation prepared during the development of a formulation of the etoride hydrochloride capsule.

Figure 7 is a graph showing the results of comparing the dissolution rates of M02-1 with commercially available Ganaton.

Fig. 8 is a graph showing the results of investigating the degree of floating or swelling in the medium in Preparation Example 2. It has been observed that the prepared mini tablets float to the upper part of the medium and swell. -2-mm mini tablets. - Dissolution mode: sustained release. - Hydrophilic polymer matrix type (+CO ₂ source). - Floating and expanding (O).

Figure 9 is a graph showing the results of comparing the PK results of M02-1 with commercially available Ganaton.

Figure 10 shows the results of comparing the dissolution rates of M02-2 with M02-1 and commercially available Ganaton.

Figure 11 shows the results of the degree of floating or swelling of M02-2 in the investigation medium. It has been observed that the prepared mini tablet portion floats to the upper portion of the medium and expands. -2-mm mini tablet - dissolution mode: sustained release. - Hydrophilic polymer matrix type (+CO ₂ source + lipid). - Floating (D) and expanding (O).

Figure 12 depicts the results of comparing the PK results of M02-2 with commercially available Ganaton.

Figure 13 depicts a capsule formulation comprising three etopride hydrochloride 50-mg tablets prepared during the development of the etoride 150-mg formulation.

Figure 14 depicts the results of comparing the dissolution rates of T03-1 with commercially available Ganaton.

Figure 15 is a graph showing the results of the degree of floating or swelling of T03-1 in the investigation medium. It has been observed that the prepared tablets float to the upper part of the medium and swell. - a hydrophilic polymer + CO ₂ source. - Sustained release tablets. - Floating and expanding (O).

Figure 16 depicts the results of comparing the PK results of T03-1 with commercially available Ganaton.

Figure 17 depicts the results of comparing the dissolution rates of T02-2 with T02-1 and commercially available Ganaton.

Figure 18 shows the results of the degree of floating or swelling of T03-2 in the investigation medium. It has been observed that the prepared tablets float to the upper part of the medium and swell. - Increased dissolution rate compared to T03-1. - a hydrophilic polymer + CO ₂ source. - Sustained release tablets. - Floating and expanding (O).

Figure 19 depicts the results of comparing the PK results of T03-2 with commercially available Ganaton.

Figure 20 depicts the results of comparing the dissolution rates of T03-3 with T03-1, T03-2 and commercially available Ganaton.

Figure 21 shows the results of the degree of floating or swelling of T03-3 in the investigation medium. It has been observed that the prepared tablets float to the upper part of the medium and swell. - In order to maximize the effect of floating and expansion, more hydrophilic polymers and CO ₂ sources are used. As a result, the dissolution rate was lowered as compared with T03-2. - Sustained release tablets. - Floating and expanding (O).

Figure 22 depicts the results of comparing the PK results of T03-3 with commercially available Ganaton.

Figure 23 depicts a capsule formulation comprising two sustained release etopride hydrochloride 50-mg tablets and one immediate release etoopril 50-mg tablet prepared during the development of the etoride 150-mg formulation.

Figure 24 depicts the results of comparing the dissolution rates of T04-1 with commercially available Ganaton.

Figure 25 shows the dissolution rate of T04-1. Compare the dissolution rate of the immediate release portion and the sustained release portion.

Figure 26 is a graph showing the results of the degree of floating or swelling of T04-1 in the investigation medium. The immediate release portion of the prepared tablet neither floats nor swells. It has been observed that the sustained release portion floats to the upper portion of the medium and expands. IR part: floating (X), swelling (X). SR part: floating and expanding (O). Ettopril API ratio: IR 50 mg, SR 100 mg.

Figure 27 depicts the results of comparing the PK results of T04-1 with commercially available Ganaton.

Figure 28 shows the results of comparing the dissolution rates of T04-2 with T04-1 and commercially available Ganaton.

Figure 29 shows the dissolution rate of T04-2. Compare the dissolution rate of the immediate release portion and the sustained release portion.

Figure 30 shows the results of the degree of floating or swelling of T04-2 in the investigation medium. Both the immediate release portion and the sustained release portion float to the upper portion of the medium.

Figure 31 is a graph showing the results of comparing the PK results of T04-2 with commercially available Ganaton.

Figure 32 is a graph showing the results of comparing the dissolution rates of T04-3 with T04-1, T04-2 and commercially available Ganaton.

Figure 33 shows the dissolution rate of T04-3. Compare the dissolution rate of the immediate release portion and the sustained release portion.

Figure 34 is a graph showing the results of the degree of floating or swelling of T04-3 in the investigation medium. It has been observed that the immediate release portion does not float, and the sustained release portion floats to the upper portion of the medium and expands.

Figure 35 depicts the results of comparing the PK results of T04-3 with commercially available Ganaton.

Figure 36 depicts an etofride 150-mg formulation in accordance with an exemplary embodiment. The capsule preparation comprises two sustained-release etoride hydrochloride 60-mg tablets and one immediate release etoride hydrochloride 30-mg tablet.

Figure 37 is a graph showing the results of comparing the dissolution rates of the etopride 150-mg formulation (T05) with commercially available Ganaton, T04-1, T04-2 and T04-3 according to an exemplary embodiment of the present disclosure.

Figure 38 shows the dissolution rate of T05. Compare the dissolution rate of the immediate release portion and the sustained release portion.

Figure 39 is a graph showing the results of the degree of floating or swelling of T05 in the investigation medium. It has been observed that the immediate release portion of T05 does not float, and the sustained release portion floats to the upper portion of the medium and expands.

Figure 40 depicts the results of comparing the P05 results of T05 with commercially available Ganaton.

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Foreign deposit information (please note in the order of country, organization, date, number)

Claims (21)

A pharmaceutical preparation comprising: (a) a sustained release portion comprising: etodoride or a pharmaceutically acceptable salt thereof; a sustained release polymer; a CO ₂ source; an organic acid; and a pharmaceutically An acceptable filler (diluent); and (b) an immediate release portion comprising: etodoride or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable filler (diluent). The pharmaceutical preparation according to claim 1, wherein the sustained-release portion and the immediate-release portion comprise etopride hydrochloride. The pharmaceutical preparation according to claim 2, wherein the content of etodoride hydrochloride in the sustained-release portion (a) is 3 to 5 times greater than the content of etodoride hydrochloride in the immediate-release portion (b). The pharmaceutical preparation according to claim 1, wherein the sustained-release polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone. One or more. The pharmaceutical preparation according to claim 4, wherein the sustained-release polymer is hydroxypropylmethylcellulose having an average viscosity of 4,000 to 100,000 cPs when measured at 20 ° C using a 2% by weight aqueous solution. The pharmaceutical preparation according to claim 1, wherein the CO ₂ source is one or more selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate. The pharmaceutical preparation according to claim 1, wherein the organic acid is one selected from the group consisting of oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid. Or more. The pharmaceutical preparation according to claim 7, wherein the organic acid is citric acid. The pharmaceutical preparation according to claim 1, wherein the dissolution rate of the preparation is 15% within 30 minutes when 900 mL of one pH 1.2 buffer is used as a dissolution medium at a stirring paddle rotation speed of 50 rpm. Up to 40%, 41% to 70% in 3 hours, and 80% or higher in 9 hours. The pharmaceutical preparation according to claim 1, wherein the preparation is orally administered once a day. The pharmaceutical preparation according to claim 1, wherein the sustained-release portion and the immediate-release portion are independently present in the tablet in a form separated from each other, and the sustained-release portion and the immediate-release portion are simultaneously administered orally. The pharmaceutical preparation according to claim 11, wherein the preparation is a hard capsule preparation comprising at least two separated tablets as the sustained release portion and one tablet as the immediate release portion. The pharmaceutical preparation according to claim 1, wherein the pharmaceutically acceptable filler is selected from the group consisting of microcrystalline cellulose, lactose, starch, mannitol, kaolin, an inorganic salt, icing sugar, and a powdered cellulose. And one or more of the group consisting of calcium monohydrogen phosphate. The pharmaceutical preparation according to claim 1, wherein the immediate release portion further comprises a disintegrant. The pharmaceutical preparation according to claim 1, wherein the sustained release portion and the immediate release portion further comprise one or more selected from the group consisting of light anhydrous citric acid, magnesium stearate, and stearic acid. Lubricant. The pharmaceutical preparation according to claim 1, wherein the CO ₂ source and the organic acid have a CO ₂ source:organic acid weight ratio of 1:0.1-10. The pharmaceutical preparation according to claim 1, wherein the sustained-release polymer is contained in the sustained-release portion in an amount of 17% by weight to 30% by weight based on the total weight of the sustained-release portion, and the CO ₂ source is An amount of 1% by weight to 10% by weight based on the total weight of the sustained-release portion is contained in the sustained-release portion, and an amount of the organic acid in an amount of 1% by weight to 10% by weight based on the total weight of the sustained-release portion It is included in the sustained release portion. A pharmaceutical preparation for oral administration once a day, comprising: (a) a sustained-release portion comprising: 40% by weight to 70% by weight, based on the total weight of the sustained-release portion, of etotopril; 17% by weight To 30% by weight of hydroxypropylmethylcellulose; 10% by weight to 25% by weight of microcrystalline cellulose, lactose, starch, calcium monohydrogen phosphate or a mixture thereof as a filler; 1% by weight to 10% by weight Sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or a mixture thereof as a source of CO ₂ ; 1% by weight to 10% by weight of oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid And citric acid, benzoic acid or a mixture thereof as an organic acid; and 0.1% by weight to 5% by weight of magnesium stearate, stearic acid, light anhydrous citric acid or a mixture thereof as a lubricant; and (b) An immediate release portion comprising: from 30% by weight to 60% by weight, based on the total weight of the immediate release portion, of etoride; 20% to 45% by weight of microcrystalline cellulose, lactose, starch, and phosphoric acid Hydrogen calcium or a mixture thereof as a filler; 18% to 30% by weight of crosslinked hydroxymethylcellulose sodium And 0.1% to 5% by weight of light anhydrous silicate, magnesium stearate, stearic acid or a mixture as a lubricant. The pharmaceutical preparation for oral administration once a day as described in claim 18, comprising: (a) a sustained-release portion comprising: 45% by weight to 60% by weight of hydrochloric acid based on the total weight of the sustained-release portion Etodoride; 20% to 25% by weight of hydroxypropyl methylcellulose; 12% to 20% by weight of microcrystalline cellulose, lactose, starch, calcium monohydrogen phosphate or a mixture thereof as a filler; 3.5% by weight to 8% by weight of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or a mixture thereof as a source of CO ₂ ; 3% by weight to 6% by weight of oxalic acid, maleic acid, antibutene a diacid, malic acid, tartaric acid, citric acid, benzoic acid or a mixture thereof as an organic acid; and 0.5% to 3% by weight of magnesium stearate, stearic acid, light anhydrous citric acid or a mixture thereof a lubricant; and (b) an immediate release portion comprising: 35 to 50% by weight, based on the total weight of the immediate release portion, of etotopril; 25% to 40% by weight of microcrystalline cellulose , lactose, starch, calcium monohydrogen phosphate or a mixture thereof as a filler; 20% to 28% by weight of crosslinked Sodium carboxymethylcellulose; and 0.5 wt% to 2% by weight of light anhydrous silicate, magnesium stearate, stearic acid or a mixture as a lubricant. The pharmaceutical preparation for oral administration once a day as described in claim 18, wherein the sustained-release portion (a) comprises at least two tablets each containing 55-65 mg of itopride hydrochloride, and the The immediate release portion (b) contains 20-40 mg of etopride hydrochloride. A pharmaceutical preparation for oral administration once daily as described in claim 20, wherein the sustained release portion comprises two tablets.