WO2018151580A1 - Immediate-release and sustained-release pharmaceutical preparation including itopride hydrochloride - Google Patents

Abstract

The present invention provides a pharmaceutical preparation comprising: (a) a sustained-release part including itopride or a pharmaceutically acceptable salt thereof, a sustained-release polymer, a CO2 supply component, an organic acid and an optional pharmaceutically acceptable filler; and (b) an immediate-release part including itopride or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable filler. The present invention is taken once a day and thus can increase drug compliance.

Description

Fast-acting and Sustainable Pharmaceutical Formulations Containing Itopride Hydrochloride

This application claims priority based on Korean Patent Application No. 10-2017-0022040, filed February 20, 2017, and all contents disclosed in the specification and drawings of the application are incorporated in this application. The present invention relates to a pharmaceutical formulation comprising itopride hydrochloride, and more particularly, the present invention relates to a pharmaceutical formulation that can improve medication compliance with a daily administration while having a rapid analgesic effect.

Itopride hydrochloride (N-[[4- [2- (dimethylamino) ethoxy] phenyl] methyl] -3,4-dimethoxybenzamide hydrochloride) inhibits acetylcholine esterase and inhibits dopamine D2 It acts as an antagonist of receptors to increase the amount of acetylcholine, and this acetylcholine promotes gastrointestinal peristalsis, which is used for digestive symptoms such as bloating, epigastric pain, anorexia, chest pain and vomiting due to functional dyspepsia to be. This drug is suitable for long-term use because peripheral dopamine D2 antagonism shows little side effects such as gynecomastia and milk secretion, which is a side effect of gastrointestinal function improving agents such as domperidone.

Itopride Hydrochloride (N-[[4- (2-Dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide) has an effect time of 30 minutes oral administration orally and reaches a peak blood concentration. 0.5-1.5 hours, duration is about 12 hours. Etoprid is known to excrete about 80% in the urine during oral administration and the rate of excretion (half life) is about 6 hours.

Although patients have poor digestive function and have to take long-term medications due to frequent symptoms due to stress, there is still no development of a dosage form that can be taken once a day. Inconvenience in medication guidance and medication compliance may result.

In order to solve this problem, there has been an effort to develop the conventional discomfort of eating three times a day as a dosage form that can be taken once a day. However, due to the nature of rapid pain relief, the general sustained release preparations were somewhat insufficient in alleviating the symptoms of patients.

The present invention aims to provide a pharmaceutical formulation comprising etoprid hydrochloride, which has both fast-acting and long-lasting efficacy.

In addition, the present invention is to provide a pharmaceutical formulation that can improve the compliance with the drug once a day by delaying drug release while having a rapid analgesic effect including both immediate release and sustained release.

The present invention can reduce the side effects that can be experienced by initially releasing excess drug.

The present invention relates to pharmaceutical preparations containing active ingredients such as etofried or pharmaceutically acceptable salts of etofried (preferably etopried hydrochloride), which is administered once daily to increase the drug compliance while expressing initial drug efficacy. It provides this excellent pharmaceutical formulation.

The present invention relates to oral preparations formulated with etoprid or a pharmaceutically acceptable salt thereof, which is a very useful drug for treating gastrointestinal abnormalities. More specifically, the present invention relates to etoprid or a pharmaceutically acceptable salt thereof for 24 hours. Provided is an oral pharmaceutical preparation with improved medication compliance that can be taken once daily by eluting at a constant rate.

The formulation of the present invention provides a pharmaceutical formulation comprising etoprid or a pharmaceutically acceptable salt of etoprid, preferably etoprid hydrochloride, which has excellent initial drug expression but is capable of continuous dissolution at a constant rate.

Pharmaceutically acceptable salts of the etoprid include acid addition salts and quaternary ammonium salts. Acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, iodide, sulfate, phosphate, oxalate, maleic acid, fumaric acid salt, lactic acid salt, malic acid salt, succinic acid salt, tartaric acid salt, benzoic acid salt and methane. Organic acid salts, such as a sulfonic acid salt and a citric acid salt, are mentioned, As a quaternary ammonium salt, Lower alkylhalogenides, such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, methylmethanesulfonate And lower alkyl sulphonates such as ethylmethanesulfonate, lower alkyl aryl sulfonates such as methyl-p-toluene sulfonate, and the like, and preferably topofid hydrochloride can be used. Etoprided hydrochloride can be used for sustained release with excellent initial drug expression rate, including immediate release and sustained release.

The present invention provides a composition comprising (a) etoprid or a pharmaceutically acceptable salt thereof; Sustained release polymers; CO ₂ feed component; Organic acid; And a sustained release portion comprising any pharmaceutically acceptable filler; And

(b) itopride or a pharmaceutically acceptable salt thereof; And an immediate release portion including a diluent.

Preferably, the topofrid or pharmaceutically acceptable salt of the topofrid may be used as the topofrid hydrochloride.

The inventors of the present invention have completed the present invention by investigating a method for sustaining the effect simply by taking once a day while showing a quick effect including the etoprid or a pharmaceutically acceptable salt thereof.

The term "sustained release" as used herein may be understood to mean an agent that is slowly dissolved in the body after administration and slowly elutes the drug.

As used herein, the term “immediate release” may be understood to mean an agent in which the drug is eluted rapidly in the body after administration.

The sustained release portion of the present invention may use a sustained release polymer in order to effectively control the release of the etoprid hydrochloride having a very high water solubility. The sustained-release polymer means a material used to slowly release the drug over a long time, and can be used without limitation as long as it is used in the industry as a sustained-release polymer, preferably the sustained-release polymer is hydroxypropyl methyl cellulose, At least one selected from the group consisting of hydroxypropyl cellulose and povidone may be used, and more preferably hydroxypropyl methyl cellulose (HPMC) may be used. Still more preferably, the hydroxypropyl methyl cellulose may be used hydroxypropyl methyl cellulose 2910, hydroxypropyl methyl cellulose 2208, or a mixture thereof. The hydroxypropyl methyl cellulose may be preferably used in the formulation of the present invention because there is little change in viscosity or release pattern depending on pH. The hydroxypropyl methylcellulose may have 100 to 100,000 cps to form a drug release matrix, preferably HPMC having an average viscosity of 5,000 to 30,000 cPs may be used. The viscosity is measured at 20 ° C. with a 2% by weight aqueous solution by the USP.

In the sustained-release polymer included in the sustained-release portion of the present invention, in consideration of the fact that bubbles are generated using a CO ₂ supply component and an organic acid, the polymer may be selected to be less affected by drug release and less change in viscosity by bubbles. have.

The sustained release polymer included in the sustained release part is 10 to 40% by weight, preferably 15 to 35% by weight, more preferably 17 to 30% by weight, even more preferably 20 to 29% by weight, and even more, based on the total weight of the sustained release part. Preferably 26 to 28% by weight may be included. The content range may be preferable for the purpose of delayed release of the drug of the present invention and in consideration of characteristics such as bubbles generated in the sustained release portion. It can have sustained release without excessively delaying the dissolution of the drug in the content range.

The formulation of the present invention further comprises a CO ₂ feed ingredient and an organic acid in the sustained release portion. The CO ₂ supply component is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate in consideration of compatibility with the drug of the present invention, in consideration of excellent bubble generation effect, the purpose of minimizing gastric pH change, etc. One or more may be used, but for the purposes of the present invention, sodium bicarbonate is preferably used. The CO ₂ feed component may comprise 1 to 10% by weight, preferably 3 to 8% by weight, even more preferably 4 to 7% by weight relative to the total weight of the sustained release portion.

The organic acid may be used together with the CO ₂ supply component to use at least 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, which may be bubbled. Citric acid may be preferably used for the purposes of the present invention. The organic acid may be included 1 to 10% by weight, preferably 3 to 8% by weight, even more preferably 4 to 7% by weight relative to the total weight of the sustained-release portion.

In an embodiment of the present invention, the content ratio of the CO ₂ supply component and the organic acid included in the sustained release part may be a weight ratio of the CO ₂ supply component: organic acid may be 1: 0.1 to 10, preferably 1: 0.5 to 5 days have.

The CO ₂ feed ingredient and the organic acid can float the preparation in gastric juice, which can allow the drug to remain in the stomach for a long time. The CO ₂ feed component and the organic acid can achieve excellent flotation effects in the above content range. In addition, for the purpose of the present invention comprising two or more tablets in the capsule, when the content ratio of the CO ₂ feed component and the organic acid is in the above range can be expected excellent floating effect, slow release effect.

The inventors of the present invention have found that a formulation comprising the etoprid of the present invention or a pharmaceutically acceptable salt thereof includes a CO ₂ feed ingredient and an organic acid, so that the formulation of the present invention may be capable of long-term gastrointestinal retention.

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

The sustained release portion may further include a lubricant.

The lubricant is used to improve the moldability of the formulation, and examples thereof may be any one or more selected from the group consisting of hard silicic anhydride, silicon dioxide, talc, stearic acid, magnesium stearate or mixtures thereof. It is not limited to this.

In addition, the sustained release portion may further include antioxidants, flavoring agents, preservatives, fragrances, sweeteners, pigments, pH adjusting agents and viscosity adjusting agents to prevent the formulation from being oxidized, which may be etoprid or pharmaceutically acceptable thereof. It is preferable to add in the usual usage-amount normally used with respect to salt.

Immediate release portions of the formulations of the present invention may be etoprid or a pharmaceutically acceptable salt of etoprid; And pharmaceutically acceptable fillers. The rapid release part may further include a disintegrant, a lubricant, and the like.

The disintegrant, lubricant and the like may be uniformly dispersed in the immediate release portion.

For example, the disintegrant may be at least one selected from the group consisting of sodium croscarmellose sodium, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, crospovidone, starch, copovidone, low-substituted hydroxypropyl cellulose. , Preferably croscarmellose sodium may be used.

The filler included in the immediate release portion may be the same kind as the filler included in the sustained release portion, or other types of fillers may be used.

The present invention provides a composition comprising (a) an active ingredient which is itoprid or a pharmaceutically acceptable salt thereof; Sustained release polymers; CO ₂ feed component; Organic acid; And a sustained release portion comprising any pharmaceutically acceptable filler; And (b) itopride or a pharmaceutically acceptable salt thereof; And an immediate release portion containing a pharmaceutically acceptable filler, and provides an oral preparation using a gastroretentive drug delivery system. The oral preparation may have a sustained release portion and a rapid release portion at the same time, and may be present in a separate form, preferably separately in a capsule. Both the sustained release portion and the immediate release portion may be in the form of pellets or tablets, and only one of the sustained release portion and the immediate release portion may be in a tablet form, and preferably, both the sustained release portion and the immediate release portion may be provided in a tablet form.

When both the immediate release portion and the sustained release portion are in the form of a tablet, since the bubble generation rate is excellent in the gastric fluid and the release rate can be expected, both the immediate release portion and the sustained release portion may be provided in a tablet form.

The preparation preferably comprises an itofried hydrochloride as an active ingredient, and the content of the itofried hydrochloride contained in (a) the sustained release portion may include 3 to 5 times more than the itoprid hydrochloride contained in the (b) immediate release portion. And preferably 3.5 to 4.5 times more. Preferably, (a) the content of itopride hydrochloride contained in the sustained release portion may be included in four times the weight of the topofrid hydrochloride contained in (b) the immediate release portion. When it has the above content range, it can have a sustainable dose once a day while getting a quick effect.

The formulation comprising the sustained release portion and the immediate release portion of the present invention may be provided in a form that is orally administered simultaneously by formulating the immediate release portion and the sustained release portion in the form of a tablet or the like. For example, it may be provided as a hard capsule in which the sustained release tablet and the immediate release tablet are mixed together in the hard capsule.

One embodiment of the present invention (a) 40 to 70% by weight of etoprid hydrochloride relative to the total weight of the sustained-release portion; 17-30% by weight of hydroxypropylmethylcellulose; 10-25% by weight of a filler which is microcrystalline cellulose, lactose, starch, calcium dihydrogen phosphate or a mixture thereof; 1 to 10% by weight of a CO ₂ feed component which is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or mixtures thereof; 1 to 10% by weight of an organic acid which is oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid or a mixture thereof; And a sustained release portion including 0.1 to 5 wt% of a lubricant, which is magnesium stearate, stearic acid, light silicic anhydride, or a mixture thereof; And

(b) 30 to 60% by weight of etoprid hydrochloride relative to the total weight of the immediate release portion; 20 to 45% by weight of a filler which is microcrystalline cellulose, lactose, starch, calcium dihydrogen phosphate, or a mixture thereof; 18-30% by weight of croscarmellose sodium; And an immediate release portion containing 0.1 to 5% by weight of a lubricant, which is hard silicic anhydride, magnesium stearate, stearic acid, or a mixture thereof.

Preferably the formulation comprises (a) 45 to 60% by weight of etoprid hydrochloride relative to the total weight of the sustained release portion; 20-25% by weight of hydroxypropylmethylcellulose; 12-20% by weight of a filler which is microcrystalline cellulose, lactose, starch, calcium dihydrogen phosphate or a mixture thereof; 3.5 to 8% by weight of a CO ₂ feed component which is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or mixtures thereof; 3 to 6% by weight of an organic acid which is oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid or mixtures thereof; and 0.5 to 3% by weight of glidants which are magnesium stearate, stearic acid, hard silicic acid or a mixture thereof Sustained release; and

(b) 35-50% by weight of etopri hydrochloride relative to the total weight of the immediate release portion; 25-40% by weight of a filler which is microcrystalline cellulose, lactose, starch, calcium dihydrogen phosphate or a mixture thereof; 20-28% by weight of croscarmellose sodium; And an immediate release portion containing 0.5 to 2% by weight of a lubricant, such as hard silicic anhydride, magnesium stearate, stearic acid, or a mixture thereof, is provided for a daily oral administration.

In a preferred embodiment of the present invention the preparation may comprise at least two or more tablets of sustained release, for example two, three, four, five, six or more tablets, most preferred In an embodiment, the sustained release portion consists of two tablets.

Preferably, the formulation of the present invention may be a hard capsule comprising two separate tablets of sustained release and one tablet of immediate release.

The formulation may comprise (a) sustained release two tablets, each tablet containing 55 to 65 mg of itoprid hydrochloride, and (b) an immediate release portion to 20 to 40 mg of itoprid hydrochloride. .

In another embodiment of the present invention can provide a method for preparing a formulation comprising the active ingredient is itoprid or a pharmaceutically acceptable salt thereof.

In one embodiment (S1) itopride or a pharmaceutically acceptable salt thereof; Sustained release polymers; CO ₂ feed component; Organic acid; And tableting a sustained release portion comprising any pharmaceutically acceptable filler,

(S2) itopride or a pharmaceutically acceptable salt thereof; And tableting an immediate release portion comprising a pharmaceutically acceptable filler, and

(S3) The tablet may include both the sustained release portion and the immediate release portion, and the sustained release portion and the immediate release portion may be separately filled and formulated in an independent form.

The tableting method may be any method used by those skilled in the art to prepare tablets, and is not particularly limited to the tableting method.

The tableting of the sustained release part of the step (S1) may be performed such that the sustained release part may be formed of at least two tablets.

Formulation of the step (S3) is not particularly limited in the formulation, preferably can be prepared in capsules, more preferably in hard capsules.

In one embodiment of the present invention, containing orthopred hydrochloride as an active ingredient, it is possible to rapidly release the topofrid hydrochloride, and at the same time characterized in that the continuous release of itoprid hydrochloride from the matrix polymer, oral once a day Provided are formulations for administration.

The formulation may be characterized by the following dissolution profiles.

The formulation may be provided as an oral formulation for once-a-day administration, and etoprid hydrochloride is used as an elution medium by using 900 ml of pH 1.2 buffer and rotating the paddle at 50 rpm, measuring 15-40% at 30 minutes. , Eluting at 41-70% in 3 hours, 80% or more in 9 hours.

In the dissolution test according to the present invention, specific conditions other than those mentioned above are carried out according to the method described in the international process such as the Korean Pharmacopoeia or the US Pharmacopoeia.

Checking the drug dissolution profile and the pharmacokinetics of the formulations confirmed the effect on the expression of the effect of the drug (itopred or its pharmaceutically acceptable salt) in the human body, according to the in vitro dissolution pattern Or it was confirmed that the pharmacological dynamics of the pharmaceutically acceptable salt thereof is varied, it can be seen that it shows excellent pharmacological activity and bioavailability in vivo according to the dissolution profile of the present invention.

In the present invention, the term 'Tmax' means a time to peak plasma concentration rat ion, and the plasma concentration of the drug (itopred hydrochloride) is maximum after administration of the pharmaceutical preparation of the present invention. It means the time until

The term 'Cmax' in the present invention means the maximum plasma concentrat ion, and means the maximum concentration in the plasma of the drug (itopred hydrochloride) due to the administration of the pharmaceutical preparation of the present invention.

In the present invention, the term 'AUC' means the area under the plasma concentration-time curve, and in pharmacokinetics, the term “AUC” refers to the time measured from the start time of the administration to the time “t” after the start of the administration. The area under the curve obtained in the subject by plotting the serum concentration of the benefit agent (drug or active ingredient). For steady state drug administration, the AUC is the area under the curve during the administration period with doses administered periodically to infinity time. AUC can be obtained by analyzing serum samples of the subject to be administered.

The pharmaceutical preparations of the present invention include itofried or a pharmaceutically acceptable salt thereof, and include three doses of drug fast-acting and fast-acting preparations that allow the patient to be rapidly exposed to a sufficient amount of drug early for expression. It is characterized by satisfying the same drug persistence at the same time. In other words, the present invention is a formulation having both characteristics of a fast-acting oral formulation and a sustained oral formulation, which is characterized by initial high release rate of itoprid or its pharmaceutically acceptable salt after administration of the formulation. Exposure to a sufficient amount of drug, ie an increase in Cmax and a reduction in Time to Peak Plasma Concentration, and an initial AUC increase are achieved.

Unlike the formulations that were previously administered three times a day, the preparations of the present invention can be easily taken by oral administration once a day.

The pharmaceutical preparations according to the present invention can be taken once a day, which is excellent in taking convenience.

The pharmaceutical preparations of the present invention can achieve both sustained release and immediate effect expression when administered to a human body.

The formulation of the present invention can reduce side effects caused by rapid blood concentration rise.

1 is a diagram showing the process of the inventors of the present invention developed the formulation of the present invention.

Pellet coated with SR polymer of 0.8 mm in stage 1 → 2mm mini tablet → 3 delayed-release tablets → 2 capsules containing two immediate-release tablets and 1 delayed-release tablet It was.

Figure 2 is a picture showing a pellet type capsule, which is one of the development process of the topofid hydrochloride capsule formulation.

3 is a graph comparing dissolution of P01 and a commercial product Ganaton.

Figure 4 is a photograph confirming the degree of floating or swelling in the medium of Preparation Example 1. Pellet was not rich and no swelling was observed.

5 is a graph comparing the pK result of P01 and a commercial product Ganaton.

6 is a view showing a mini tablet capsule, which is one of the development process of the topofrid hydrochloride capsule formulation.

7 is a graph comparing dissolution of M02-1 and a commercial product, Ganaton.

8 is a photograph confirming the degree of floating or swelling in the medium of Preparation Example 2. The prepared mini tablet was suspended in the upper portion of the medium and swelling was confirmed.

The features are as follows.

-2mm mini tablets.

-Dissolution: Delayed release pattern.

Hydrophilic polymer matrix type (+ CO ₂ feed ingredient)

Floating & Swelling (O)

9 is a graph comparing the pK result of M02-1 and a commercial product Ganaton.

10 is a graph comparing dissolution of M02-2 and M02-1 and a commercial product Ganaton.

11 is a photograph confirming the degree of floating or swelling in the medium of M02-2. The manufactured mini tablet was partially suspended in the upper layer of the medium and swelling was confirmed.

The features are as follows.

-2mm mini tablet

Dissolution: Delayed release pattern

Hydrophilic polymer matrix type (+ CO2 feedstock + lipid)

Floating (△) & Swelling (O)

12 is a graph comparing the pK result of M02-2 and a commercial product Ganaton.

Figure 13 is one of the processes for the development of the preparation of Itoprid 150mg, a capsule containing three 50 mg tablets of Itoprid hydrochloride is shown in the figure.

14 is a graph comparing dissolution of T03-1 and a commercial product, Ganaton.

15 is a photograph confirming the degree of floating or swelling in the medium of T03-1. The prepared tablets were suspended in the upper portion of the medium, and swelling was confirmed.

The features are as follows.

-Hydrophilic Polymer + CO ₂ Feed Ingredient

-Delayed-release tablets 3

Floating & Swelling (O)

Figure 16 is a graph comparing the pK result of T03-1 and commercially available Ganaton.

17 is a graph comparing dissolution of T02-2, T02-1, and Ganaton, a commercial product.

18 is a photograph confirming the degree of floating or swelling in the medium of T03-2. The prepared tablets were suspended in the upper portion of the medium, and swelling was confirmed.

The features are as follows.

-Higher dissolution rate than T03-1

-Hydrophilic Polymer + CO ₂ Feed Ingredient

-Delayed-release tablets 3

Floating & Swelling (O)

19 is a graph comparing the pK result of T03-2 and Ganaton, a commercial product.

20 is a graph comparing dissolution of T03-3, T03-1, T03-2, and Ganaton, a commercial product.

21 is a photograph confirming the degree of floating or swelling in the medium of T03-3. The prepared tablets were suspended in the upper portion of the medium, and swelling was confirmed.

The features are as follows.

In order to maximize the floating and swelling effect, more hydrophilic polymer and CO2 feedstock were used, resulting in more delayed dissolution rate than T03-2.

-Delayed-release tablets 3

Floating & Swelling (O)

22 is a graph comparing the pK result of T03-3 and Ganaton, a commercial product.

Figure 23 is one of the processes for the development of the preparation of the Itofried 150mg, a capsule containing two 50 mg tablets of sustained-release itoprid hydrochloride and 50 mg tablets of immediate release itoprid hydrochloride is shown in the figure.

24 is a graph comparing dissolution between T04-1 and Ganaton, a commercial product.

25 is a graph showing the dissolution of T04-1. The degree of dissolution of the immediate release portion alone and the sustained release portion was compared.

Figure 26 is a photograph confirming the degree of floating or swelling in the medium of T04-1. The immediate release part of the prepared tablet was neither suspended nor swollen. The sustained release portion was suspended in the upper portion of the medium and the degree of swelling was confirmed.

In case of IR part, Floating (X), Swelling (X)

For SR Part, floating and swelling are maintained.

Itopride API's ratio: IR 50mg, SR 100mg

FIG. 27 is a graph comparing pK result of T04-1 and Ganaton which is a commercial product.

FIG. 28 is a graph comparing dissolution of T04-2, T04-1, and Ganaton, a commercial product.

Fig. 29 is a graph showing the dissolution of T04-2. The degree of dissolution of the immediate release portion alone and the sustained release portion was compared.

30 is a photograph confirming the degree of floating or swelling in the medium of T04-2. Both the immediate release portion and the sustained release portion are suspended in the upper layer of the medium.

Figure 31 is a graph comparing the pK result of T04-2 and commercially available Ganaton.

32 is a graph comparing dissolution of T04-3 and T04-1, T04-2 and a commercially available Ganaton.

Fig. 33 is a graph showing the dissolution of T04-3. The dissolution degree of the immediate release part alone was compared.

34 is a photograph confirming the degree of floating or swelling in the medium of T04-3. While the immediate release portion of the prepared tablet was not suspended, the sustained release portion was suspended in the upper portion of the medium and the degree of swelling was confirmed.

35 is a graph comparing the pK result of T04-3 and the commercially available Ganaton.

36 is an example of an etoprid 150 mg formulation. A capsule containing two 60 mg tablets of sustained-release etoprid hydrochloride and one 30 mg tablet of immediate-release iptoprid hydrochloride is shown in the figure.

FIG. 37 is a graph comparing dissolution of an Itofried 150mg formulation (T05) and commercially available Ganaton, T04-1, T04-2, and T04-3 according to an embodiment of the present invention.

38 is a graph showing the dissolution of T05. The degree of dissolution of the immediate release portion alone and the sustained release portion was compared.

39 is a photograph confirming the degree of floating or swelling in the medium of T05. The immediate release portion of the prepared T05 was not suspended, but the sustained release portion was suspended in the upper portion of the medium and the degree of swelling was confirmed.

40 is a graph comparing pK results of T05 and Ganaton, a commercial product.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<API Preparation>

Compound Name: N-[[4- [2- (Dimethylamino) ethoxy] phenyl] methyl] -3,4-dimethoxy benzamide hydrochloride, C ₂ 0H ₂₇ ClN ₂ O ₄

Molecular weight (M.W.): 394.89

Solubility: Soluble in water (≥48 mg / mL) or methanol. Recording in acetic acid.

<Preparation Example 1>-Pellets type in Capsule

1. Prescription (Batch No .: P01)

Etoprid hydrochloride 150 mg was prepared as a hard capsule with the following composition.

Ingredient	Prescription (mg / F)	Remarks
Itofried Hydrochloride	150.00 mg
Microcrystalline cellulose	150.00 mg	PH101
White sugar	20.00 mg
Povidone	10.00 mg
Polysorbate 80	10.00 mg		Tween 80
Ethyl Cellulose	51.00 mg	Viscosity: 7cps
Citric Acid Triethyl	5.10 mg
Talc	2.55 mg
Total	398.65 mg

Itofried hydrochloride and microcrystalline cellulose are mixed and sieved through a 30 mesh sieve. Separately, white sugar, povidone and polysorbate 80 are dissolved in 80% ethanol and used as a binding solution. Using this binding solution, it is added to the mixture of itoprid hydrochloride to produce wet granules. The wet granules are placed in an extruder and extruded. The extruded granules are put back into the spheronizer and spheronized. The spherical granules are placed in a 60 ° C dryer and dried for 4 hours. The dried product is placed in a fluidized bed process, and separately coated with ethyl cellulose, citric acid triethyl, and talc as a coating solution in which 80% ethanol is dissolved and dispersed.

Figure 2 shows a capsule comprising the etopri pellets prepared according to Preparation Example 1.

2. Characteristics

(1) dissolution rate

Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.

The results are shown in FIG. 3 and Table 2 below.

Hour	P01	Hour	Ganaton
0.00	0.00%	0	0.00%
0.17	4.82%	0.08	16.80%
0.25	10.53%	0.17	47.50%
0.50	28.00%	0.25	68.30%
1.00	49.31%	0.50	85.30%
1.50	61.34%
2.00	67.76%
5.00	84.71%
6.00	86.66%
8.00	88.83%
12.00	90.43%

Compared to Ganaton, a commercially available product, it can be released continuously, but dissolves more than 80% in about 4 to 5 hours.

(2) pharmacokinetic parameters

Geometric mean
Parameter	Test (Production Example 1) (ng / mL)	Ref. (Ganaton) (ng / mL)	T / R
AUC (last)	1228.2	2850.2	0.43
AUC (inf)	1272.3	2950.1	0.43
Cmax	246.9	443.3	0.56
Tmax	1.3	7.2	0.19
t1_2	5.5	4.3	1.29

The formulation prepared in Preparation Example 1 was evaluated to have a lower bioavailability than Ganaton, a commercial product. Low AUC (Area under curve) and Cmax (maximum concentration) are thought to be due to the water-insoluble coating layer on the pellet surface not floating in the stomach.

In order to solve this problem, experiments were carried out by reducing the density of particles, using hydrophilic polymers and CO2 supply components, and floating pellets to increase the adhesion time to gastrointestinal mucosa.

Preparation Example 2-Mini Tablets type in Capsule

1.Prescription (Batch No .: M02-1)

Etoprid hydrochloride 150mg was prepared as a hard capsule containing a mini tablet of about 2mm in size with the following composition.

Ingredient	Prescription (mg / F)	Remarks
Itofried Hydrochloride	150.00 mg
Microcrystalline cellulose	25.00 mg	PH101
Hypromellose	160.00 mg	2208 (90SH-100M SR)
Magnesium Stearate	2.00 mg
Total	337. 00 mg

Itofried hydrochloride, microcrystalline cellulose and hypromellose were mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. The dried product is sieved to 18 mesh, and magnesium stearate is added and tableted with a multitool punch in a rotary tableting machine. Fill this mini-tablet with capsules.

Figure 6 shows a capsule containing an etofried mini tablet prepared according to Preparation Example 2.

2. Characteristics

(1) dissolution rate

Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.

The results are shown in FIG. 7 and Table 5 below.

Hour	M02-1	Hour	Ganaton
0.00	0.00%	0	0.00%
0.17	2.98%	0.08	16.80%
0.25	7.34%	0.17	47.50%
0.50	21.49%	0.25	68.30%
1.00	47.91%	0.50	85.30%
1.50	66.89%
2.00	79.50%
5.00	97.53%
6.00	98.57%

Preparation Example 2 can be sustained release compared to commercially available products Ganaton, but the initial release rate was still high, it was difficult to use as a sustained release formulation.

(2) pharmacokinetic parameters

Table 6 below shows the pharmacokinetic parameters of Preparation Example 2.

Geometric mean
Parameter	Test (ng / mL)	Ref. (ng / mL)	T / R
AUC (last)	1753.0	2898.2	0.60
AUC (inf)	1858.6	3009.2	0.62
Cmax	307.9	420.1	0.73
Tmax	2.0	6.8	0.30
t1_2	4.9	4.3	1.15

In Preparation Example 2, it can be seen that AUC (Area under curve) and Cmax (highest concentration) have larger values at the same time than ganatons sold in the market. This is believed to be due to the floating and swelling effects of the formulation.

Preparation Example 3-Mini Tablets type in Capsule

1.Prescription (Batch No .: M02-2)

Etoprid hydrochloride 150mg was prepared as a hard capsule containing a mini tablet of about 2mm in size with the following composition.

Ingredient	Prescription (mg / F)	Remarks
Itofried Hydrochloride	150.00 mg
Hypromellose	140.00 mg	2208 (90SH-100M SR)
Glyceryl Palmitostearate	54.00 mg		Precirol ATO 5
Sodium bicarbonate	13.00 mg
Magnesium Stearate	2.00 mg
Total	350. 00 mg

Itofried hydrochloride, glyceryl palmitostearate, and hypromellose were mixed and sieved to 30 mesh, and the mixture was heated to 80 degrees or more using a fluidized bed process, melted and cooled, and then again stipulated to 30 mesh, followed by 80% After wet granulation with ethanol, dry for 4 hours in a 60-degree dryer. The dried product is sieved to 18 mesh, and sodium bicarbonate and magnesium stearate are added and compressed into a multitool punch in a rotary tablet press. Fill this mini-tablet with capsules.

Figure 6 shows a capsule containing an etofried mini tablet prepared according to Preparation Example 3.

2. Characteristics

(1) dissolution rate

Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.

The results are shown in FIG. 10 and Table 8 below.

Hour	M02-2	Hour	Ganaton
0.00	0.00%	0	0.00%
0.17	1.79%	0.08	16.80%
0.25	5.87%	0.17	47.50%
0.50	19.68%	0.25	68.30%
1.00	41.19%	0.50	85.30%
1.50	55.13%
2.00	66.24%
5.00	94.42%
6.00	96.86%

There was no significant difference in terms of ganaton and dissolution rate.

(2) pharmacokinetic parameters

Table 9 below shows the pharmacokinetic parameters of Preparation Example 3.

Geometric mean
Parameter	Test (ng / mL)	Ref. (ng / mL)	T / R
AUC (last)	2145.4	2850.2	0.73
AUC (inf)	2191.0	2950.1	0.74
Cmax	389.6	443.3	0.82
Tmax	2.1	7.2	0.21
t1_2	4.2	4.3	1.34

An increase in AUC and Cmax has been identified, which is believed to be the result of using components that aid in swelling and flotation of the formulation. However, as the excipients are used a lot, the filling in the capsule is difficult, and thus the formulation productivity is lowered. In addition, due to the lipid used in Preparation Example 3, there was a problem in that the production of the mini tablet formulation was inferior in productivity or economic efficiency.

<Preparation 4>-SR Tablets type in Capsule

Prescription (Batch No .: T03-1)

150 mg of etopri hydrochloride was prepared with three SR tablets to prepare a formulation filled in capsules.

Ingredient	Prescription (mg / F)	Remarks
Itofried Hydrochloride	150.00 mg
Microcrystalline cellulose	25.00 mg	PH101
Hypromellose	160.00 mg	2208 (90SH-4M SR)
Povidone	13.00 mg
Magnesium Stearate	2.00 mg
Total	350. 00 mg

Itofried hydrochloride, microcrystalline cellulose, hypromellose and povidone are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. The dried product is sieved to 18 mesh, magnesium stearate is added, tableted in a rotary tableting machine, and the tablets are filled into capsules.

FIG. 13 shows a capsule containing three tablets of Itofried SR tablet prepared according to Preparation Example 4. FIG.

2. Characteristics

(1) dissolution rate

Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.

The results are shown in FIG. 14 and Table 11 below. The delay of dissolution was confirmed.

Hour	T03-1	Hour	Ganaton
0.00	0.00%	0	0.00%
0.17	0.27%	0.08	16.80%
0.25	1.03%	0.17	47.50%
0.50	5.12%	0.25	68.30%
1.00	12.58%	0.50	85.30%
1.50	19.06%
2.00	25.33%
5.00	57.50%
6.00	65.17%

(2) pharmacokinetic parameters

Table 12 below shows the pharmacokinetic parameters of Preparation Example 4.

geometric mean
Parameter	Test (ng / mL)	Ref. (ng / mL)	T / R
AUC (last)	1292.1	2898.2	0.45
AUC (inf)	1348.4	3009.2	0.45
Cmax	142.9	420.1	0.34
Tmax	4.6	6.8	0.67
t1_2	4.6	4.3	1.08

The BE (Bioequivalence) result is thought to be low due to the very low dissolution rate.

<Preparation 5>-SR Tablets type in Capsule

1.Prescription (Batch No .: T03-2)

150 mg of etopri hydrochloride was prepared with three SR tablets to prepare a formulation filled in capsules.

Ingredient	Prescription (mg / F)	Remarks
Itofried Hydrochloride	150.00 mg
Hypromellose	45.00 mg	2208 (90SH-4M SR)
Microcrystalline cellulose	18.00 mg	PH101
Lactose	24.00 mg	200M
Sodium bicarbonate	15.00 mg
Magnesium Stearate	3.00 mg
Total	255. 00 mg

Itofried hydrochloride, microcrystalline cellulose, hypromellose and lactose are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. The dried product is sieved to 18 mesh, and sodium bicarbonate and magnesium stearate are added and tableted in a rotary tableting machine, and the tablets are filled into capsules.

FIG. 13 shows a capsule containing three tablets of Itofried SR tablet prepared according to Preparation Example 5. FIG.

2. Characteristics

(1) dissolution rate

Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.

The results are shown in FIG. 14 and Table 14 below.

Hour	T03-2	Hour	Ganaton
0.00	0.00%	0	0.00%
0.17	5.63%	0.08	16.80%
0.25	10.27%	0.17	47.50%
0.50	20.85%	0.25	68.30%
1.00	35.94%	0.50	85.30%
1.50	48.18%
2.00	57.94%
5.00	95.10%
6.00	101.84%

(2) pharmacokinetic parameters

Table 15 below shows the pharmacokinetic parameters of Preparation Example 5.

geometric mean
Parameter	Test (ng / mL)	Ref. (ng / mL)	T / R
AUC (last)	2092.5	2850.2	0.73
AUC (inf)	2234.6	2950.1	0.76
Cmax	369.8	443.3	0.83
Tmax	2.4	7.2	0.32
t1_2	5.8	4.3	1.37

Preparation of Preparation Example 5, the dissolution rate is increased compared to Preparation Example 4, the bioavailability was slightly increased.

<Preparation 6>-SR Tablets type in Capsule

Prescription (Batch No .: T03-3)

150 mg of etopri hydrochloride was prepared with three SR tablets to prepare a formulation filled in capsules. It prepared in the same manner as in Preparation Example 5.

Ingredient	Standard (mg / F)	Note
	Standard
Itofried Hydrochloride	150.00 mg
Hypromellose	60.00 mg	2208 (90SH-15M SR)
Microcrystalline cellulose	18.00 mg	PH101
Lactose	24.00 mg	200M
Sodium bicarbonate	15.00 mg
Magnesium Stearate	3.00 mg
Total	270. 00 mg

Figure 13 shows a capsule containing three tablets of etoprired SR tablet prepared according to Preparation Example 6.

2. Characteristics

(1) dissolution rate

Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.

The results are shown in FIG. 20 and Table 17 below.

Hour	T03-3	Hour	Ganaton
0.00	0.00%	0	0.00%
0.17	2.70%	0.08	16.80%
0.25	4.91%	0.17	47.50%
0.50	11.20%	0.25	68.30%
1.00	22.54%	0.50	85.30%
1.50	32.32%
2.00	40.26%
5.00	72.75%
6.00	78.87%

The decrease of the dissolution rate was confirmed compared with the manufacture example 3.

(2) pharmacokinetic parameters

Table 18 below shows the pharmacokinetic parameters of Preparation Example 6.

geometric mean
Parameter	Test (ng / mL)	Ref. (ng / mL)	T / R
AUC (last)	1985.8	2150.1	0.92
AUC (inf)	2089.2	2285.9	0.91
Cmax	273.7	342.6	0.80
Tmax	2.8	6.1	0.46
t1_2	5.3	4.6	1.15

Although the dissolution rate of the formulation of Preparation Example 6 was reduced, the AUC value showed a result close to the target value. In order to improve Cmax, immediate release formulations with fast dissolution are considered.

<Preparation 7>-IR & SR Tablets type in Capsule

1. Prescription (Batch No .: T04-1)

150 mg of etoprid hydrochloride were prepared with two SR tablets and one IR tablet to prepare a formulation filled in a capsule. The SR part content below represents the total amount of two tablets.

SR Part Raw Material Name	Standard (mg / F)	Note
	Standard
Itofried Hydrochloride	100.00 mg
Hypromellose	40.00 mg	2208 (90SH-15M SR)
Microcrystalline cellulose	12.00 mg	PH101
Lactose	16.00 mg	200M
Sodium bicarbonate	10.00 mg
Magnesium Stearate	2.00 mg
Total	180. 00 mg
IR Part Raw Material Name	Standard (mg / F)	Note
	Standard
Itofried Hydrochloride	50.00 mg
Microcrystalline cellulose	8.00 mg	PH101
Lactose	30.00 mg	200M
Croscarmellose sodium	30.00 mg	Ac-Di-Sol
Light anhydrous silicic acid	1.00 mg
Magnesium Stearate	1.00 mg
Total	120. 00 mg

Itofried hydrochloride, microcrystalline cellulose, hypromellose and lactose are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. The dried product is sieved to 18 mesh, and sodium bicarbonate and magnesium stearate are added and tableted in a rotary tableting machine. Two tablets are used as sustained-release tablets.

Itofried hydrochloride, microcrystalline cellulose, lactose, croscarmellose sodium, and hard silicic anhydride are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. The dried product is set to 18 meshes, and magnesium stearate is added to the tablets in a rotary tableting machine, and a fast-soluble tablet is filled into the capsule together with the western portion.

FIG. 23 shows a capsule including two tablets of Itofried SR tablet and one tablet IR tablet prepared according to Preparation Example 7.

2. Characteristics

(1) dissolution rate

Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.

The results are shown in FIG. 24 and Table 20 below.

Hour	T04-1 (Surface, West)	T04-1 (Slow-release tablet)	Hour	T04-1 (fast-release tablet)	Ganaton
0.00	0.00%	0.00%	0	0.00%	0.00%
0.17	28.36%	2.70%	0.08	36.30%	16.80%
0.25	37.13%	4.91%	0.17	76.40%	47.50%
0.50	43.08%	11.20%	0.25	95.50%	68.30%
1.00	50.42%	22.54%	0.50	100.50%	85.30%
1.50	56.19%	32.32%
2.00	61.46%	40.26%
5.00	82.04%	72.75%
6.00	86.28%	78.87%

(2) pharmacokinetic parameters

Table 21 below shows the pharmacokinetic parameters of Preparation Example 6.

geometric mean
Parameter	Test (ng / mL)	Ref. (ng / mL)	T / R
AUC (last)	1883.2	2338.7	0.81
AUC (inf)	1931.5	2454.7	0.79
Cmax	369.7	369.9	1.00
Tmax	1.0	4.4	0.23
t1_2	4.1	4.3	0.94

As can be seen from the above results, Cmax gained equivalence, but a decrease in AUC appeared as the gastrointestinal residence time became shorter.

Preparation Example 8 IR & SR Tablets type in Capsule

1.Prescription (Batch No .: T04-2)

150 mg of etoprid hydrochloride were prepared with two SR tablets and one IR tablet to prepare a formulation filled in a capsule. The SR part content below represents the total amount of two tablets.

SR Part Raw Material Name	Standard (mg / F)	Note
	Standard
Itofried Hydrochloride	100.00 mg
Hypromellose	40.00 mg	2208 (90SH-15M SR)
Microcrystalline cellulose	12.00 mg	PH101
Lactose	16.00 mg	200M
Sodium bicarbonate	10.00 mg
Magnesium Stearate	2.00 mg
Total	180. 00 mg
IR Part Raw Material Name	Standard (mg / F)	Note
	Standard
Itofried Hydrochloride	50.00 mg
Hypromellose	20.00 mg	2208 (90SH-15M SR)
Microcrystalline cellulose	6.00 mg	PH101
Lactose	8.00 mg	200M
Sodium bicarbonate	10.00 mg
Croscarmellose sodium	20.00 mg	Ac-Di-Sol
Magnesium Stearate	1.00 mg
Total	115. 00 mg

Itofried hydrochloride, microcrystalline cellulose, hypromellose and lactose are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. The dried product is sieved to 18 mesh, and sodium bicarbonate and magnesium stearate are added and tableted in a rotary tableting machine. Two tablets are used as sustained-release tablets.

Itofried hydrochloride, hypromellose, microcrystalline cellulose, lactose, croscarmellose sodium and sodium bicarbonate were sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. The dried product is set to 18 meshes, and magnesium stearate is added to the tablets in a rotary tableting machine, and a fast-soluble tablet is filled into the capsule together with the western portion.

FIG. 23 shows a capsule containing two SR tablets of Itofried and one IR tablet prepared according to Preparation Example 8. FIG.

2. Characteristics

(1) dissolution rate

Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.

The results are shown in FIG. 28 and Table 23.

Hour	T04-2 (Surface, West)	T04-2 (Slow-release tablet)	Hour	T04-2 (fast-release tablet)	Ganaton
0.00	0.00%	0.00%	0	0.00%	0.00%
0.17	6.75%	2.70%	0.08	13.59%	16.80%
0.25	11.42%	4.91%	0.17	26.45%	47.50%
0.50	21.22%	11.20%	0.25	35.61%	68.30%
1.00	33.71%	22.54%	0.50	47.12%	85.30%
1.50	43.29%	32.32%	1.00	59.05%
2.00	51.10%	40.26%	1.50	67.65%
5.00	80.13%	53.84%	2.00	74.41%
6.00	85.45%	64.75%

(2) pharmacokinetic parameters

Table 24 below shows the pharmacokinetic parameters of Preparation Example 8.

geometric mean
Parameter	Test (ng / mL)	Ref. (ng / mL)	T / R
AUC (last)	1790.1	2125.4	0.84
AUC (inf)	1846.3	2235.8	0.83
Cmax	270.3	344.1	0.79
Tmax	2.7	5.0	0.55
t1_2	4.6	4.5	1.02

As can be seen from the above results, AUC was increased, but Cmax was decreased.

Preparation 9-IR & SR Tablets type in Capsule

1.Prescription (Batch No .: T04-3)

150 mg of etoprid hydrochloride were prepared with two SR tablets and one IR tablet to prepare a formulation filled in a capsule. The SR part content below represents the total amount of two tablets.

SR Part Raw Material Name	Standard (mg / F)	Note
	Standard
Itofried Hydrochloride	100.00 mg
Hypromellose	45.00 mg	2208 (90SH-15M SR)
Microcrystalline cellulose	18.00 mg	PH101
Lactose	6.00 mg	200M
Mannitol	18.00 mg	160C
Sodium bicarbonate	15.00 mg
Magnesium Stearate	2.00 mg
Total	170. 00 mg
IR Part Raw Material Name	Standard (mg / F)	Note
	Standard
Itofried Hydrochloride	50.00 mg
Hypromellose	20.00 mg	2208 (90SH-100M SR)
Microcrystalline cellulose	6.00 mg	PH101
Lactose	8.00 mg	200M
Sodium bicarbonate	10.00 mg
Croscarmellose sodium	20.00 mg	Ac-Di-Sol
Light anhydrous silicic acid	1.00 mg
Magnesium Stearate	1.00 mg
Total	124. 00 mg

Itofried hydrochloride, microcrystalline cellulose, hypromellose, mannitol, and lactose are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. The dried product is sieved to 18 mesh, and sodium bicarbonate and magnesium stearate are added and tableted in a rotary tableting machine. Two tablets are used as sustained-release tablets.

Itofried hydrochloride, hypromellose, microcrystalline cellulose, lactose, croscarmellose sodium, sodium hydrogencarbonate, and hard silicic acid were sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. Do The dried product is set to 18 meshes, and magnesium stearate is added to the tablets in a rotary tableting machine, and a fast-soluble tablet is filled into the capsule together with the western portion.

FIG. 36 shows a capsule including two tablets of etofried SR and one tablet IR prepared according to Preparation Example 9.

2. Characteristics

(1) dissolution rate

Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.

The results are shown in FIG. 37 and Table 26 below.

Hour	T04-3 (Surface, West)	T04-3 (Slow-release tablet)	T04-3 (quick release tablet)	Hour	Ganaton
0.00	0.00%	0.00%	0.00%	0	0.00%
0.17	15.12%	5.90%	2.57%	0.08	16.80%
0.25	28.85%	9.55%	20.05%	0.17	47.50%
0.50	40.69%	18.67%	54.75%	0.25	68.30%
1.00	51.05%	32.92%	74.07%	0.50	85.30%
1.50	57.61%	43.66%	87.29%
2.00	62.79%	53.16%	95.07%
5.00	83.94%	94.87%
6.00	88.53%	100.00%

(2) pharmacokinetic parameters

Table 27 below shows the pharmacokinetic parameters of Preparation Example 9.

geometric mean
Parameter	Test (ng / mL)	Ref. (ng / mL)	T / R
AUC (last)	1850.1	2275.5	0.81
AUC (inf)	1938.7	2393.1	0.81
Cmax	319.3	364.3	0.88
Tmax	1.9	5.3	0.35
t1_2	4.9	4.5	1.10

Experiments were conducted with various formulations made, but in no case were satisfactory results for AUC and Cmax.

<Production Example 10>-IR & SR Tablets type in Capsule

1.Prescription (Batch No .: T05)

150 mg of etoprid hydrochloride were prepared with two SR tablets and one IR tablet to prepare a formulation filled in a capsule. The SR part content below represents the total amount of two tablets.

SR Part Raw Material Name	Standard (mg / F)	Note
	Standard
Itofried Hydrochloride	120.00 mg
Hypromellose	60.00 mg	15000cps
Microcrystalline cellulose	7.00 mg
Lactose	9.00mg
Citric acid	9.00 mg
Sodium bicarbonate	12.00 mg
Magnesium Stearate	3.00 mg
Total	220.00 mg
IR Part Raw Material Name	Standard (mg / F)	Note
	Standard
Itofried Hydrochloride	30.00 mg
Microcrystalline cellulose	4.80 mg	PH101
Lactose	18.00 mg	200M
Croscarmellose sodium	18.00 mg	Ac-Di-Sol
Light anhydrous silicic acid	0.60 mg
Magnesium Stearate	0.60 mg
Total	72. 00 mg

Itofried hydrochloride, microcrystalline cellulose, hypromellose and lactose are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. The dried product is sieved to 18 mesh, and sodium bicarbonate and magnesium stearate are added and tableted in a rotary tableting machine. Two tablets are used as sustained-release tablets.

Itofried hydrochloride, microcrystalline cellulose, lactose, croscarmellose sodium, and hard silicic anhydride are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. The dried product is set to 18 meshes, and magnesium stearate is added to the tablets in a rotary tableting machine, and a fast-soluble tablet is filled into the capsule together with the western portion.

36 shows a capsule including two tablets of Itofried SR tablet and one tablet IR tablet prepared according to Preparation Example 10.

2. Characteristics

(1) dissolution rate

Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.

The results are shown in FIG. 37 and Table 29.

Hour	T05 (Surface, West)	T05 (Slow Release Tablet)	T05 (fast-release tablet)	Hour	Ganaton
0.00	0.00%	0.00%	0.00%	0	0.00%
0.17	24.00%	2.77%	29.96%	0.08	16.80%
0.25	27.28%	5.67%	81.84%	0.17	47.50%
0.50	32.98%	12.86%	92.56%	0.25	68.30%
1.00	40.55%	23.52%	100.74%	0.50	85.30%
1.50	46.79%	32.26%	102.34%
2.00	54.05%	39.99%	102.43%
5.00	76.00%	74.93%
6.00	81.05%	82.34%

(2) pharmacokinetic parameters

Table 30 below shows the pharmacokinetic parameters of Preparation Example 10.

geometric mean
Parameter	Test (ng / mL)	Ref. (ng / mL)	T / R
AUC (last)	2017.3	2037.2	0.99
AUC (inf)	2095.7	2086.6	1.00
Cmax	306.4	331.4	0.92
Tmax	1.5	2.1	0.68
t1_2	5.3	3.8	1.41

The capsules made in Preparation Example 10 were able to achieve the desired AUC and Cmax. This result is believed to be achieved by suspending the formulation and increasing the gastrointestinal residence time.

<Stability of formulation>

A stability test was conducted with the formulation of Preparation Example 10.

Storage condition		term	Packing	result
Long-term Preservation	25 ℃, 60% RH	3 months	Alu-Alu Bag or HDPE Bottle	No change
Accelerated Test	40 ℃, 75% RH	3 months	Alu-Alu Bag or HDPE Bottle	No change
Hard Test	60 ℃, 75% RH	15th	Alu-Alu Bag or HDPE Bottle	No change
Test items: Appearance, Identification, Assay, Dissolution, Related Substances

As can be seen in Table 31, there was no effect on stability for three months.

The present invention provides a pharmaceutical formulation comprising itopride hydrochloride.

The present invention relates to a pharmaceutical formulation capable of improving medication compliance with a daily administration while having a rapid analgesic effect.

Claims (21)

1. (a) itopride or a pharmaceutically acceptable salt thereof; Sustained release polymers; CO ₂ feed component; Organic acid; And a sustained release portion comprising any pharmaceutically acceptable filler; And

   (b) itopride or a pharmaceutically acceptable salt thereof; And a rapid release portion comprising a pharmaceutically acceptable diluent.
2. According to claim 1, wherein the sustained-release portion and the immediate release portion pharmaceutical formulation, characterized in that it comprises an itopride hydrochloride.
3. The pharmaceutical preparation according to claim 2, wherein (a) the content of the itopride hydrochloride contained in the sustained release part is (b) 3 to 5 times more added than the topofrid hydrochloride contained in the immediate release part.
4. The pharmaceutical formulation of claim 1, wherein the sustained-release polymer is at least one selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and povidone.
5. The pharmaceutical formulation of claim 4, wherein the sustained-release polymer is hydroxypropylmethylcellulose having an average viscosity of 4,000 to 100,000 cPs measured at 20 in an aqueous solution of 2% by weight.
6. The pharmaceutical formulation of claim 1, wherein the CO ₂ feed component is at least one member selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium bicarbonate.
7. The pharmaceutical formulation of claim 1, wherein the organic acid is at least one selected from the group consisting of oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid.
8. The pharmaceutical formulation of claim 7, wherein the organic acid is citric acid.
9. The dissolution rate according to claim 1, wherein the dissolution rate of the preparation is 900 ml of pH 1.2 buffer as the elution medium, and the paddle is rotated at 50 rpm to measure 15-40% at 30 minutes, 41-70% at 3 hours, and 9 hours. A pharmaceutical formulation, characterized by dissolution of at least 80%.
10. The pharmaceutical formulation of claim 1, wherein the formulation is administered orally once a day.
11. According to claim 1, wherein the pharmaceutical formulation is the sustained release portion and the immediate release portion is separated into a separate type of tablet, respectively

    Pharmaceutical formulation, characterized in that the sustained release portion and immediate release portion is orally administered at the same time.
12. The pharmaceutical formulation of claim 11, wherein the formulation is a hard capsule comprising at least two separate tablets that are sustained release and one tablet that is immediate release.
13. The method of claim 1, wherein the pharmaceutically acceptable filler is one selected from the group consisting of microcrystalline cellulose, lactose, starch, mannitol, kaolin inorganic salt, powdered sugar, powdered cellulose derivative, and calcium dihydrogen phosphate. Pharmaceutical formulations characterized in that above.
14. The pharmaceutical formulation of claim 1, wherein the immediate release portion further comprises a disintegrant.
15. The pharmaceutical formulation of claim 1, wherein the sustained-release portion and the immediate release portion further comprise one or more lubricants selected from the group consisting of hard silicic anhydride, magnesium stearate, and stearic acid.
16. The pharmaceutical preparation according to claim 1, wherein the content ratio of the CO ₂ feed component and the organic acid is 1: 0.1 to 10 by weight ratio of the CO ₂ feed component: organic acid.
17. According to claim 1, wherein the sustained-release polymer contained in the sustained-release portion is 17 to 30% by weight based on the total weight of the sustained-release portion, the CO ₂ feed component included in the sustained-release portion is 1 to 10% by weight relative to the total weight of the sustained-release portion, The organic acid included in the sustained-release portion is 1 to 10% by weight based on the total weight of the sustained-release portion pharmaceutical formulation.
18. (a) 40 to 70% by weight of etoprid hydrochloride relative to the total weight of the sustained release portion; 17-30% by weight of hydroxypropylmethylcellulose; 10-25% by weight of a filler which is microcrystalline cellulose, lactose, starch, calcium dihydrogen phosphate or a mixture thereof; 1 to 10% by weight of a CO ₂ feed component which is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or mixtures thereof; 1 to 10% by weight of an organic acid which is oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid or a mixture thereof; And a sustained release portion including 0.1 to 5 wt% of a lubricant, which is magnesium stearate, stearic acid, light silicic anhydride, or a mixture thereof; And

    (b) 30 to 60% by weight of etoprid hydrochloride relative to the total weight of the immediate release portion; 20 to 45% by weight of a filler which is microcrystalline cellulose, lactose, starch, calcium dihydrogen phosphate, or a mixture thereof; 18-30% by weight of croscarmellose sodium; And an immediate release portion comprising 0.1 to 5% by weight of a lubricant, which is hard silicic anhydride, magnesium stearate, stearic acid, or a mixture thereof.
19. The method of claim 18, wherein the formulation is

    (a) 45 to 60% by weight of itoprid hydrochloride relative to the total weight of the sustained release portion; 20-25% by weight of hydroxypropylmethylcellulose; 12-20% by weight of a filler which is microcrystalline cellulose, lactose, starch, calcium dihydrogen phosphate or a mixture thereof; 3.5 to 8% by weight of a CO ₂ feed component which is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or mixtures thereof; 3-6% by weight of an organic acid which is oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid or mixtures thereof; And a sustained release portion containing 0.5 to 3% by weight of a lubricant, which is magnesium stearate, stearic acid, light silicic anhydride, or a mixture thereof; and

    (b) 35-50% by weight of etopri hydrochloride relative to the total weight of the immediate release portion; 25-40% by weight of a filler which is microcrystalline cellulose, lactose, starch, calcium dihydrogen phosphate or a mixture thereof; 20-28% by weight of croscarmellose sodium; And an immediate release portion comprising 0.5 to 2% by weight of a lubricant, which is hard silicic anhydride, magnesium stearate, stearic acid, or a mixture thereof.
20. The method of claim 18, wherein the formulation is

    (A) the sustained-release portion consists of at least two tablets, each tablet containing 55-65 mg of itoprid hydrochloride,

    (B) A pharmaceutical preparation for oral administration once daily, comprising 20-40 mg of etoprid hydrochloride in the immediate release portion.
21. The pharmaceutical formulation of claim 20, wherein the sustained release portion of the formulation consists of two tablets.

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