KR20200061225A - Dry manufacturing method of sustained release pharmaceutical formulation of varenicline - Google Patents

Abstract

The present invention comprises the steps of i) mixing varenicline or a pharmaceutically acceptable salt thereof with a matrix polymer to prepare a first mixture; ii) mixing the first mixture with a pharmaceutically acceptable additive to prepare a second mixture by mixing with a dry granulation method; And ii) formulating an oral sustained-release preparation with the second mixture, provides a method for preparing a sustained-release preparation comprising varenicline or a pharmaceutically acceptable salt thereof. The present invention improves medication compliance by administration once a day, can provide a sustained release formulation with reduced side effects, and can provide a formulation with reduced impurities and increased stability.

Description

Dry manufacturing method of sustained release pharmaceutical formulation of varenicline}

The present invention relates to a method for preparing a pharmaceutical composition containing varenicline or a pharmaceutically acceptable salt thereof using a sustained-release matrix drug delivery system (Matrix-type sustained release drug delivery system). More specifically, the present invention exhibits continuous absorption when administered to the human body, improves patient compliance with medication once a day, improves content uniformity and improves the stability of varenicline, or varenicline. It relates to a new method for preparing a pharmaceutical composition containing a pharmaceutically acceptable salt thereof.

Varenicline acts as a partial agonist to α4β2 neuronal nicotinic acetylcholine receptors, blocking the binding of nicotine to receptors and at the same time significantly lowering receptor activity than nicotine. ) To suppress excessive dopamine release by nicotine and to relieve nicotine craving and withdrawal symptoms during smoking cessation by releasing a small amount of dopamine, and is used as an anti-smoking treatment supplement.

Champix ^® is a commercially available product, but common side effects include nausea, sleep disorders (nightmares, strange dreams, etc.), constipation, abdominal distention, and vomiting. In particular, nausea is temporary, but in some patients, it is difficult to continue taking the drug, and problems such as nausea persist. These symptoms were also observed in clinical trials with a dose-dependent increase. To solve this, the drug was taken through dose titration. First, 0.5 mg of barenicline was taken once a day for 3 days. Then, from 4 to 7 days, 0.5 mg is taken twice a day. Thereafter, by taking the dose of 1.0 mg twice a day as varenicline until the 12th week, the effective blood level is maintained and the withdrawal symptoms are alleviated. Due to this complex dosing method, there is a disadvantage in that medication compliance is significantly reduced.

On the other hand, it has been found that poor content uniformity results in a significant decrease in bioavailability when the content uniformity in the formulation is insufficient to have an acceptable drug content. In addition, poor content uniformity may cause toxicity when the amount of the drug substance is too high. In addition, the content of the main component planned in the initial formulation process is not maintained uniformly in the final formulation, and a related substance is generated, which also acts as a barrier to the drug expression.

In the pharmaceutical industry, this uniformity of content or reduction of related substances is a major issue in the formulation process.

The present invention is to delay the drug release of a sustained-release preparation containing varenicline or a pharmaceutically acceptable salt thereof, and once a day administration, to provide a method for dry preparation of a pharmaceutical composition capable of improving medication compliance .

The present invention is to provide a novel manufacturing method capable of reducing the impurity or related substance content of a sustained release preparation containing varenicline or a pharmaceutically acceptable salt thereof.

The present invention seeks to provide a novel method for preparing varenicline or a pharmaceutically acceptable salt thereof to improve content uniformity in a formulation.

The present invention provides a sustained-release matrix system comprising varenicline or a pharmaceutically acceptable salt thereof and a matrix polymer. The formulation of the present invention provides a pharmaceutical formulation with improved administration convenience by oral administration once a day through a formulation containing varenicline or a pharmaceutically acceptable salt thereof and a matrix polymer.

One embodiment of the present invention comprises the steps of i) mixing varenicline or a pharmaceutically acceptable salt thereof with a matrix polymer to prepare a first mixture, ii) mixing the first mixture with a pharmaceutically acceptable additive. A sustained release comprising varenicline or a pharmaceutically acceptable salt thereof, comprising the step of mixing the dry granulation method to prepare a second mixture, and iii) formulating an oral sustained release preparation with the second mixture. It provides a method for preparing a sex preparation.

The formulation of one embodiment of the present invention may be preferably prepared by a dry granulation method.

The dry granulation method may be a dry granulation method generally used in the pharmaceutical field. In one embodiment, varenicline, one or more diluents and one or more matrix polymers, and one or more binders can be mixed with the fluidizing agent. Before mixing, each component or mixture itself may be passed through a mesh screen, for example, a 290-1000 μm mesh screen. The fluidizing agent can also be sieved and added to the mixture to continue mixing until a homogeneous mixture is obtained. Subsequently, the mixture is prepared by using a punching machine or a roller compressor, etc., and then compressed granules on a slug or sheet are prepared, followed by pulverization, etc., to prepare a dry granule having a homogeneous and increased fluidity, and finally a lubricant. It can be prepared by further mixing and compressed into tablets.

The tablet may further include forming a coating. The step of forming the coating part may be performed by coating the coating agent according to a conventional method known in the pharmaceutical field. Preferably, the coating agent can be obtained by spraying the coating agent while flowing the screw containing the active ingredient to obtain a stabilized coating tablet.

The first mixture of step i) may further include a diluent, a fluidizing agent, or a mixture thereof.

The second mixture of step ii) may further include magnesium stearate as a lubricant.

For the purposes of the present invention, it is preferable to use magnesium stearate as a lubricant included in the second mixture.

The first mixture and the second mixture may be substantially free of a solvent selected from water, ethanol, or a mixture thereof, and the meaning of the substantially non-comprising is that of the solvent contained in the first mixture or the second mixture. It can be interpreted as meaning that the content may be included less than 1% by weight, preferably less than 0.5% by weight, more preferably less than 0.1% by weight, even more preferably less than 0.05% by weight based on the total weight of the mixture.

One embodiment of the present invention can provide a sustained-release preparation for oral use comprising varenicline or a pharmaceutically acceptable salt thereof, formulated by the above-described manufacturing method. Preferably, in a severe test for 1 week under the conditions of 80°C, an oral sustained-release preparation comprising varenicline or a pharmaceutically acceptable salt thereof having a total content of varenicline analogs or impurities of less than 0.2% can be provided. And more preferably less than 0.15%, even more preferably less than 0.13%.

One embodiment of the present invention is excellent in the uniformity of the content of the varenicline or a pharmaceutically acceptable salt thereof in the formulation, by evaluating the uniformity of the drug content in the formulation, the relative standard deviation (RSD) is less than 3%, preferably Preferably 2.5%, more preferably less than 2%.

The uniformity of the drug content can be estimated by obtaining the relative standard deviation of the drug (API) in the formulation.

Preferably, in a severe test for 1 week under the conditions of 80°C, an oral sustained-release preparation comprising varenicline or a pharmaceutically acceptable salt thereof having a total content of varenicline analogs or impurities of less than 0.2% can be provided. And more preferably less than 0.15%, even more preferably less than 0.13%.

The present invention provides a method of reducing nicotine addiction in a subject using the pharmaceutical preparation, or helping to stop or reduce tobacco use. The method includes administering an effective amount of varenicline to reduce nicotine addiction to the subject by oral administration of the drug, or to help stop or reduce tobacco use. Varenicline (varenicline) has the following structure.

"Barenicline" as used herein includes a compound having a structure as in the above formula, pharmaceutically acceptable salts, solvates and/or hydrates thereof, racemates, polymorphs or prodrugs The active ingredient used in the present specification may include not only varenicline having the structure as in the above formula, but also pharmaceutically acceptable salts, solvates and/or hydrates thereof, racemates, polymorphs of the varenicline. ) Or prodrugs.

“Pharmaceutically acceptable salt” as used herein may mean a non-toxic acid addition salt derived from inorganic and organic acids. Suitable salt derivatives include halide, thiocyanate, sulfate, bisulfate, sulfite, bisulphite, arylsulfonate, alkylsulfate, phosphonate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, al Canoate, cycloalkylalkanoate, arylalkanoate, adipate, alginate, aspartate, benzoate, fumarate, glucoheptanoate, glycerophosphate, lactate, maleate, nicotinate, oxalate , Salicylate, Palmitate, pectinate, picrate, pivalate, succinate, tartrate, citrate, camphorate, camphorsulfonate, digluconate, trifluoroacetate, and the like, but is not limited thereto, preferably Can include barenicline tartrate, barenicline salicylate, or mixtures thereof.

As used herein, the term “effective amount” refers to an amount determined in consideration of the same as known in the art to help reduce nicotine addiction or stop or reduce tobacco use in an individual, wherein this is Measurable palliative, lack of dependence on nicotine-containing compounds, including, but not limited to, improvement, including faster recovery, improvement or elimination of symptoms, or reduction of complications in treated patients. , Lack of desire for nicotine-containing compounds, or other measures known and appropriate to those skilled in the medical arts.

The present invention has a number of embodiments. In any embodiment, the pharmaceutical composition of varenicline may exhibit the effect of treatment, improvement, recovery, remission, etc., to the subject, preferably once a day. About 0.1 mgA to about 6 mgA (where mgA means mg of active drug based on the free base form of the drug), more preferably about 0.2 to 5 mgA/day, most preferably about 0.3 to 4 It can be administered in a dose in the range of mgA/day, and most preferably in a dose in the range of 0.5 to 2 mgA/day. However, this change in dosage must be dependent on the weight and condition of the subject being treated. Depending on the subject's response, dosage levels below the lower limit of the above-mentioned range may be more appropriate, while in other cases, even higher doses may be used without causing any harmful side effects.

The present invention is to construct and provide a sustained-release matrix system using a matrix polymer. In particular, the matrix for application to varenicline or a pharmaceutically acceptable salt thereof can be greatly affected by the relatively high dosage of polymers and other excipients in the prescription due to the small dosage of varenicline drug. In addition, since varenicline is a drug with very high solubility in water, when the matrix is eroded or swelled rapidly and the surface area is widened, the drug cannot be delayed and released quickly. Found. In order to solve this, it is necessary to select the type and ratio of polymers that do not undergo erosion, and it was confirmed that there is a need to use polymers with a low degree of swelling.

The matrix polymer according to the present invention is a polymer capable of forming a matrix system in a formulation, hydroxypropyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (hydroxyethyl cellulose, HEC), carbomer, xanthan gum, alginic acid, pregelatinized starch, carboxymethylcellulose, polyethylene oxide, propylene glycol alginate ), methacrylic acid-acrylic acid ethyl polymer, methacrylic acid dimethylaminoethyl-methacrylic acid methyl copolymer (Dimethylaminoethyl MethacrylateㆍMethyl Methacrylate Copolymer (Eudragit E)), methacrylic acid ethyl-methacrylate acrylate trimethylammonium ethyl copolymer ( Eudragit RS), methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer or a mixture thereof can be used, but is not limited thereto, preferably hydroxypropylmethylcellulose , Hydroxypropylcellulose, hydroxyethylcellulose, xanthan gum, alginic acid, carbomer, luxury starch Alternatively, a mixture thereof can be used, most preferably hydroxypropylmethylcellulose, carbomer or a mixture thereof.

The inventors of the present invention have confirmed that the formulation has a particularly good sustained release profile when hydroxypropylmethylcellulose (HPMC) and carbomer are used together as a matrix polymer.

In another embodiment, the inventors of the present invention first confirmed that varenicline or a pharmaceutically acceptable salt thereof has different sustained release profiles depending on the type, composition ratio, content, etc. of the matrix polymer.

In another embodiment, the formulation of the present invention may include any one or more selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, alginic acid, and luxurious starch as a matrix polymer, preferably Hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, or mixtures thereof, more preferably hydroxypropylmethylcellulose, carbomer, or mixtures thereof.

In another embodiment of the present invention, when the formulation of the present invention includes hydroxypropyl methylcellulose (HPMC), carbomer or a mixture thereof as a matrix polymer, the purpose of the present invention is when a mixture of HPMC and carbomer is used together. It may be the most desirable to achieve.

The mixing ratio of HPMC and carbomer is preferably included in the weight ratio of HPMC and carbomer 1:0.5 to 1.5, preferably 1:0.8-1.3, more preferably 1:0.9-1.2, even more preferably 1: It may be a weight ratio of 1.

In one embodiment, in a formulation containing varenicline or a pharmaceutically acceptable salt thereof, the matrix polymer contains 15 to 35% by weight based on the total weight of the formulation, and the matrix polymer includes HPMC and carbomer together, Formulations in which the weight ratio of HPMC and carbomer is 1:0.5 to 1.5 may have an excellent sustained release dissolution profile. Specifically, without rapidly increasing the blood concentration, it takes about 60 minutes to achieve 10 to 50% release, and it may take about 2 to 16 hours to release more than 90% of the drug. Preferably, it can be eluted at 10 to 50% in 1 hour, less than 80% in 2 hours, and 90% or more in 16 hours.

When the matrix polymer is dissolved at 2% by weight in purified water at room temperature (20° C.), 500 mPaS to 400,000 mPaS, preferably 1,000 to 380,000 mPaS, preferably 3,000, according to a process viscosity measurement method such as NF/EP/JP It may have a viscosity of 350,000 mPaS, more preferably 3,500 to 300,000 mPaS, and the viscosity may be appropriately adjusted within the above range according to a desired drug release rate or a mixture of two or more different viscosity polymers may be used. The viscosity may be appropriately changed depending on the content of the matrix polymer and used.

For example, the matrix polymer included in the sustained release formulation of the present invention may have the following viscosity.

The matrix polymer may be included 3 to 75% by weight based on the total weight of the formulation, more preferably 5 to 60% by weight, even more preferably 10 to 45% by weight, even more preferably 15 to 35% by weight have.

The formulation of the present invention may further include a swelling control polymer. The swelling control polymer has low hydrophilicity, and thus does not gel when used alone, thereby maintaining its own matrix retention effect and sustained release effect, but it is added to the matrix polymers listed above to prevent erosion of the matrix formed by the matrix polymer to prevent synergy and rapid release of the sustained effect. Suppress.

The swelling control polymer is polyvinyl acetate (Polyvinyl acetate) and polyvinyl acetate/polyvinylpyrrolidone mixture (eg Kollidon SR®), polyvinyl pyrrolidone and polyvinyl pyrrolidone vinyl acetate copolymer ( Polyvinylpryrroldidone-vinylacetate copolymer, copovidone, Crospovidon, ethyl cellulose, EC, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate The like may be used, but is not limited thereto, and preferably, polyvinyl acetate and polyvinyl acetate/polyvinylpyrrolidone mixture, polyvinylpyrrolidone, and the like to prevent rapid drug release of the matrix system containing varenicline. Polyvinylpyrrolidone vinyl acetate copolymer and the like can be selected.

The swelling control polymer may include 1 to 20% by weight, preferably 2 to 15% by weight, more preferably 3 to 10% by weight, based on the total weight of the formulation, in order to have the sustained release properties of the formulation of the present invention.

Diluents can be prepared by being included in the preparation of the sustained release formulations of the present invention in terms of maintaining the structure of the sustained release matrix. The diluent may include microcrystalline cellulose, calcium monohydrogen phosphate, starch, mannitol, lactose, and the like, and microcrystalline cellulose may be preferably used for the purpose of the present invention.

For the purpose of the present invention, the diluent may be included in an amount of 20 to 90% by weight based on the total weight of the formulation, preferably 30 to 85% by weight, and more preferably 40 to 80% by weight.

One embodiment of the present invention provides a sustained-release oral preparation comprising varenicline or a pharmaceutically acceptable salt thereof, preferably (a) varenicline or a pharmaceutically acceptable salt thereof, (b ) The matrix polymer may contain 5 to 60% by weight of the total weight of the formulation, and (c) the diluent may contain 20 to 80% by weight of the total weight of the formulation. Preferably, the formulation may contain 0.1 to 10% by weight of the total weight of the formulation of varenicline or a pharmaceutically acceptable salt thereof, and the varenicline or a pharmaceutically acceptable salt thereof is preferably varenicline free A free base, varenicline salicylate, varenicline tartrate, varenicline oxalate, or mixtures thereof may be used and more preferably Varenicline free base, varenicline salicylate, varenicline tartrate, or mixtures thereof can be used.

In a preferred embodiment, the oral sustained-release preparation of the present invention comprises (a) varenicline or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 10% by weight, (b) hydroxypropylmethylcellulose, hydroxypropyl, relative to the total weight of the preparation. 3 to 75% by weight of one or more matrix polymers selected from the group consisting of cellulose, carbomer, xanthan gum, alginic acid, gelatinous starch or mixtures thereof, and (c) 20 to 90% by weight of microcrystalline cellulose can do. More preferably, the oral sustained-release preparation of the present invention comprises (a) varenicline or a pharmaceutically acceptable salt thereof in an amount of 0.2 to 5% by weight, (b) hydroxypropylmethylcellulose, carbomer, or 5 to 60% by weight of any one of the matrix polymers selected from the group consisting of mixtures, and (c) 30 to 85% by weight of microcrystalline cellulose, oral sustained release of the sustained-release matrix system administered orally once a day Formulations may be provided.

In a more preferred embodiment, in a preferred embodiment, the oral sustained release preparation of the present invention comprises 0.1 to 2.5% by weight of (a) varenicline or a pharmaceutically acceptable salt thereof, (b) hydroxypropyl, relative to the total weight of the preparation. 10 to 45% by weight of any matrix polymer selected from the group consisting of methylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, alginic acid, gelatinous starch or mixtures thereof, and (c) 40 to 80% by weight of microcrystalline cellulose Including, oral sustained-release preparation of a sustained-release matrix system orally administered once a day can be provided.

One embodiment of the present invention, (a) comprises a varenicline or a pharmaceutically acceptable salt thereof 0.1 to 2.5% by weight relative to the total weight of the formulation, (b) hydroxypropylmethylcellulose, carbomer or mixtures thereof It may provide a sustained-release preparation for oral administration once a day containing 10 to 45% by weight of the total weight of the formulation, and (c) 40 to 80% by weight of the microcrystalline cellulose relative to the total weight of the formulation.

One embodiment of the present invention, (a) comprises a varenicline or a pharmaceutically acceptable salt thereof 0.1 to 2.5% by weight relative to the total weight of the formulation, (b) hydroxypropylmethylcellulose, carbomer or mixtures thereof It contains 10 to 45% by weight based on the total weight of the formulation, (c) 40 to 80% by weight based on the total weight of the formulation, (d) polyvinyl acetate, polyvinyl acetate-polyvinylpyrrolidone, polyvinyl Any one selected from the group consisting of pyrrolidone, poly(vinylpyrrolidone-vinyl acetate) copolymer, crospovidone, ethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and mixtures thereof It may provide a sustained-release preparation administered orally once a day containing 3 to 10% by weight.

In one embodiment of the present invention, the matrix polymer of the formulation is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer, xanthan gum, alginic acid, and luxurious starch, and the matrix polymer is a formulation 3 to 75% by weight based on the total weight may be included, more preferably 5 to 60% by weight.

The matrix polymer of the formulation according to another embodiment of the present invention is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer, xanthan gum, alginic acid, and luxury starch, and the total weight of the formulation is 3 It contains 75% by weight, and the polymer may have a viscosity of 0.5 m to 10% in an aqueous solution of 1,000 mPaS (however, gelatinous starch is 70 mPaS in a 2% aqueous solution).

The formulation of the present invention may further include other pharmaceutically acceptable ingredients commonly used in manufacturing, particularly those commonly used in tablet manufacturing. For example, it may further include excipients, fluidizing agents, lubricants, lubricants, disintegrants, antioxidants, flavoring agents, preservatives, fragrances, sweeteners, pigments, pH adjusting agents, and other additives.

The excipient may include, but is not limited to, lactose, starch, lactose, mannitol, kaolin inorganic salts (e.g., sodium chloride), powdered sugar and powdered cellulose derivatives, microcrystalline cellulose, or mixtures thereof. .

The fluidizing agent may include light anhydrous silicic acid, talc, or mixtures thereof.

The lubricant may be included in an amount of 0.5 to 5% by weight based on the total weight of the formulation, and the lubricant may be used without limitation. For example, sugars such as white sugar, malt syrup, white sugar, gelatin, sugar and starch syrup, magnesium stearate, talc, colloidal silicon dioxide, and the like can be used as a lubricant.

The lubricant may be selected from glycerol distearate and glycerol dibenate, but is not limited thereto.

The disintegrant in the preferred composition of the present invention may be selected from sodium carboxymethylcellulose, copovidone, and sodium starch glycolate, but is not limited thereto.

Preservatives and antioxidants also include metal chelating reagents such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid. It can contain.

The formulation of the oral preparation of the present invention may be prepared in the form of granules, ellipsoids, matrix multi-particles, and the like, and may have formulations of tablets, granules, and hard capsules. Varenicline or a pharmaceutically acceptable salt is included in the sustained release matrix, which may be compressed into tablets or encapsulation. The oral dosage form of the present invention may optionally contain other pharmaceutically acceptable ingredients (eg, diluents, binders, colorants, lubricants, etc.).

According to an embodiment of the sustained-release preparation of the present invention, for administration once a day, characterized by a sustained-release matrix system containing varenicline or a pharmaceutically acceptable salt thereof as an active ingredient and a matrix polymer. Oral sustained release formulations can be characterized by the following dissolution profiles:

In one embodiment of the present invention, a formulation comprising varenicline or a pharmaceutically acceptable salt thereof may be provided as a tablet of a sustained-release matrix system, preferably comprising a matrix polymer.

The formulation may be provided as an oral sustained release formulation for once-daily administration, and the release of total varenicline or a pharmaceutically acceptable salt thereof at a rate of 100 rpm in a basket at 37±0.5°C at a rate of 100 rpm. In the condition of 900 ml of HCl, it can be eluted at 10-50% in 1 hour, less than 80% in 2 hours, and 90% or more in 16 hours in the dissolution experiment.

Preferably, the oral sustained-release preparation contains 0.1 to 10% by weight of the total weight of the varenicline free base, and includes hydroxypropylmethylcellulose and carbomer as a matrix polymer, and the matrix polymer has a total weight of the formulation. Containing 10 to 45% by weight, the mixing ratio of the hydroxypropyl methylcellulose and carbomer has a mass ratio of hydroxypropyl methylcellulose: carbomer is 1: 0.2 to 1.5, and microcrystalline cellulose contained in the formulation is a formulation 40 to 80% by weight based on the total weight may be included.

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

As a result of confirming the effect on the expression of the effect of the drug (varenicline or a pharmaceutically acceptable salt thereof) in the human body by confirming the drug dissolution profile and the pharmacological kinetics of the preparation, according to the in vitro dissolution pattern, It was confirmed that the pharmacological kinetics of Renicline or a pharmaceutically acceptable salt thereof was changed, and it was confirmed that it exhibits excellent pharmacological activity and bioavailability in vivo according to the dissolution profile of the present invention.

Oral sustained-release preparations containing varenicline or a pharmaceutically acceptable salt thereof according to the present invention may exhibit sustained absorption when administered to the human body by controlling the rate of drug release, and are administered once a day. Improve patient compliance with medication.

The formulation of the present invention can reduce side effects due to a rapid increase in blood concentration.

The preparation prepared according to the method of the present invention can reduce the content of impurities or related substances and increase stability.

The formulation containing varenicline or a pharmaceutically acceptable salt thereof prepared by the method for preparing dry granules of the present invention may increase the uniformity of API content in the formulation.

1 shows the dissolution rate of Example 1.
2 is a result of confirming the degree of occurrence of the related substances in Example 2 and Comparative Example 2.
3 is a result of confirming the degree of occurrence of the related substances in Example 3 and Comparative Example 3.

Hereinafter, examples and the like will be described in detail to help understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be interpreted as being limited to the following examples. The embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

[ Western medicine  Confirmation of dissolution rate]

The dissolution test of Example 1 was conducted according to the dissolution test method of the Korean Pharmacopoeia 10th revision. The elution method was performed using a basket method, the stirring speed was 100 rpm, and the elution temperature was 37±0.5°C. The eluate was carried out in 900 ml of 0.01 N HCl.

As for the analysis conditions, the concentration of varenicline was evaluated by HPLC using a liquid obtained by filtering the solution obtained in the above dissolution test with a 0.45 μm membrane filter.

<Analysis condition>

-Column: Agilent Poroshell 120 EC-C18, 2.7um, 4.6 X 100 mm

-Mobile phase: pH4.0 ammonium acetate buffer (5 mM): methanol (0.1% trichloroacetic acid) = 70: 30, v/v

-Injection volume: 10 µl

-Flow rate: 1 ml/min

-Detector: UV 237 nm

-Column temperature: 40 ℃

[Stability check]

Stability was evaluated by checking the impurity. The formulation HDPE Bottle was packaged and stored in a harsh environment (80°C) to measure the amount of impurities in the initial and 1 week period.

It confirmed by the following analysis conditions.

<Analysis condition>

-Column: Agilent XDB SB-C18, 5um, 4.6 X 150 mm

-Mobile phase: 0.1% phosphate buffer (5 mM 1-octanesulfonate): methanol (66:34 v/v)

-Injection volume: 20µl

-Flow rate: 1.5 ml/min

-Detector: UV 210 nm

-Column temperature: 50 ℃

[Confirmation of content uniformity]

A content test was conducted to evaluate the content of the formulated formulations, and the content uniformity was predicted by obtaining a relative standard deviation (RSD, unit %) based on the formulation results.

It confirmed by the following analysis conditions.

<Analysis condition>

Column: Agilent Poroshell 120 EC-C18, 2.7um, 4.6 X 100 mm

Mobile phase: pH3.0 Potassium phosphate (20 mM): methanol = 90: 10, v/v

Injection volume: 5 μL

Flow rate: 0.6 ml/min

Detector: UV 235 nm

Column temperature: 45℃

1. Using two kinds of matrix polymers Bareniclin Salicylate  Western matrix manufacturing

A sustained-release matrix tablet containing varenicline salicylate was prepared according to the composition table in Table 2 below.

Barenicline, microcrystalline cellulose, matrix polymer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed by adding magnesium stearate, followed by a slug to prepare a slug. After granulation using No. 20 sieve, dry granules were prepared and tableted.

Classification ingredient Example 1-1 Example 1-2 Example 1-3 Example 1-4 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Barenicline Salicylate 3.31 1.66 3.31 1.66 3.31 1.66 3.31 1.66 Matrix polymer Hydroxypropylmethylcellulose (2208 K200M) 25 12.5 22 11 20 10 30 15 Carbopol 71G® 20 10 24 12 30 15 30 15 diluent Microcrystalline cellulose
(PH 200) 148.69 74.35 147.68 73.84 143.69 71.85 133.69 66.85 Fluidizing agent Light anhydrous silicic acid One 0.5 One 0.5 One 0.5 One 0.5 Lubricant Magnesium stearate 2 One 2 One 2 One 2 One Tablet total weight 200 100 200 100 200 100 200 100

The dissolution test of Example 1 was conducted according to the dissolution test method of the Korean Pharmacopoeia 10th revision. The elution method was performed using a basket method, the stirring speed was 100 rpm, and the elution temperature was 37±0.5°C. The eluate was carried out in 900 ml of 0.01 N HCl.

As shown in FIG. 1, it was confirmed that the sustained release effect without changing the active ingredient dissolution rate in the sustained release matrix using a combination of 10 to 15% by weight of hydroxypropyl methylcellulose and 10 to 15% by weight of carbomer was shown. In addition, it was confirmed that even if the proportion of the individual matrix polymer is relatively low, 10 to 15% by weight, a desired sustained release pattern can be exhibited by appropriate combination of polymers.

Time(h) Example 1-1 HPMC2208 12.5% + Carbomer 10% Example 1-2 HPMC2208 11% + Carbomer 12% Example 1-3 HPMC2208 10% + Carbomer 15% Example 1-4 HPMC2208 15% + Carbomer 15% 0 0.0 0.0 0.0 0.0 0.5 16.8 17.3 13.5 13.6 One 27.6 28.1 23.9 22.7 2 44.6 44.3 40.5 37.2 4 69.9 67.2 68 58.4 8 98.4 92.3 95.9 81.4 10 99.7 96.4 97.6 88.6 12 100.1 98.8 98.3 93.9 16 100.8 100.3 98.7 99.7 24 101.6 101.1 101.5 102.3

2. Wet Granulation Method Dry Granulation Law  Western matrix production

A sustained-release matrix tablet containing varenicline salicylate was prepared according to the composition table in Table 4 below. In the case of Comparative Example 2, varenicline, microcrystalline cellulose, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed, followed by wet granulation using a binding solution in which hydroxypropyl cellulose was dissolved in an appropriate amount of purified water. Hydroxylpropyl methylcellulose, carbomer, extra light anhydrous silicic acid, and magnesium stearate were added to the drafted wet granules to make them lubricated and tabletted. In the case of Example 2, after preparing the dry granules as in Example 1, final tableting was performed to prepare a sustained release matrix.

Classification ingredient Comparative Example 2 Example 2 Content (mg) Content (mg) Pharmacologically active ingredient Barenicline Salicylate 3.31 3.31 Matrix polymer Hydroxypropylmethylcellulose (2208 K200M) 25.0 25.0 Carbopol 71G® 20.0 20.0 diluent Microcrystalline cellulose
(PH 102) 141.69 148.69 Binder Hydroxypropyl cellulose (Klucel-LF) 6.0 - Fluidizing agent Light anhydrous silicic acid 2.0 1.0 Lubricant Magnesium stearate 2.0 2.0 Tablet total weight 200.0 200.0 Manufacturing method Wet granulation method Dry granulation method

HDPE Bottle was packaged for Comparative Example 2 and Example 2, and stored in a harsh environment (80°C) to measure the amount of impurities after the initial and 1 week, and the results are shown in Table 5 and FIG. 2 below.

Compared to Comparative Example 2, it was confirmed that Example 2 was severely reduced by more than 2 times on the 7th day. Through this, it was confirmed that the amount of impurities was changed during the storage period according to the manufacturing process.

For Example 2, The content of the varenicline analog was found to be less than 0.2% after one week.

Time points Comparative Example 2 Example 2 Total Impurity (%) Single Max Impurity (%) Total Impurity (%) Single Max Impurity (%) Initial 0.07 0.07 0.11 0.08 7day 0.37 0.26 0.11 0.11

From the above results, it was found that even with the same amount of the matrix polymer, the sustained release effect was better when the two types were combined, the delayed release pattern was more excellent, and the incidence of related substances could be reduced.

As can be seen from the results in Table 5, the content of the related substances could be further reduced by the dry granulation method.

With the composition shown in Table 6, the formulations were prepared by the wet granulation method and the dry granulation method using the varenicline free base in the same manner as in Comparative Example 2 and Example 2 to confirm the degree of occurrence of the related substances.

Classification ingredient Comparative Example 3 Example 3 Content (mg) Content (mg) Pharmacologically active ingredient Barenicline free base 2 2 Matrix polymer Hydroxypropylmethylcellulose (2208 K200M) 30.0 30.0 Carbopol 71G® 20.0 20.0 diluent Microcrystalline cellulose
(PH 102) 138.00 145.00 Binder Hydroxypropyl cellulose (Klucel-LF) 6.0 - Fluidizing agent Light anhydrous silicic acid 2.0 1.0 Lubricant Magnesium stearate 2.0 2.0 Tablet total weight 200.0 200.0 Manufacturing method Wet granulation method Dry granulation method

Free base Example 3 (dry granulation method) Comparative Example 3 (wet granulation method) Total Impurity (%) Single Max Impurity (%) Total Impurity (%) Single Max Impurity (%) Initial 0.00 0.00 1.54 1.19

In the case of Example 3 of Table 7, the content of the related substances was about 0%, and when looking at these results, it was found that, when prepared by the dry granulation method, there was little incidence of related substances in the initial varenicline free base. have.

3. Direct Act Division Dry Granulation Law  Western matrix production

With the composition of Table 8, it was confirmed the content uniformity of the main components according to the direct punching method and the dry granulation method.

Classification ingredient Content (mg) Content ratio (%) Pharmacologically active ingredient Barenicline free base 2 One Matrix polymer Hydroxypropylmethylcellulose (2208 K200M) 30 15 Carbopol 71G® 20 10 diluent Microcrystalline cellulose
(PH 200) 145 72.5 Fluidizing agent Light anhydrous silicic acid One 0.5 Lubricant Magnesium stearate 2 One Tablet total weight 200 100

In the case of the direct hitting method, varenicline, microcrystalline cellulose, matrix polymer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed, and magnesium stearate was added thereto for tableting.

In the case of the dry granulation method, varenicline, microcrystalline cellulose, matrix polymer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed, magnesium stearate was added, and a slug was prepared using a bang. After granulation using a No. 20 sieve, dry granules were prepared and tabletted.

As can be seen in Table 9, the formulation prepared by the direct hit method had a relative standard deviation (RSD) of about ±3.4, and the dry granulation method showed a deviation of about ±1.8, which is less than half. That is, it was confirmed that the formulation prepared by the dry granulation method has a more even distribution of the main component, varenicline, in the formulation.

content (%) RSD(%) Direct hit 96.2 ±3.4 Dry granulation method 100.1 ±1.8

RSD was higher in the formulation prepared by the direct method than in the dry granulation method, which indicates that the dry granulation method has a high content uniformity.

Claims (9)

i) preparing a first mixture by mixing varenicline or a pharmaceutically acceptable salt thereof with a matrix polymer;
ii) mixing the first mixture with a pharmaceutically acceptable additive to prepare a second mixture by mixing with a dry granulation method; And
iii) formulating an oral sustained release preparation with the second mixture,
A method for preparing a sustained release preparation comprising varenicline or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the varenicline or a pharmaceutically acceptable salt thereof is characterized in that the varenicline free base, varenicline salicylate, varenicline tartrate, or mixtures thereof.
A method for preparing a sustained release preparation comprising varenicline or a pharmaceutically acceptable salt thereof. According to claim 1, wherein the matrix polymer is hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carbomer, xanthan gum, alginic acid, and any one or more selected from the group consisting of starch,
A method for preparing a sustained release preparation comprising varenicline or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the first mixture of step i) further comprises a diluent, a fluidizing agent, or a mixture thereof,
A method for preparing a sustained release preparation comprising varenicline or a pharmaceutically acceptable salt thereof. According to claim 1, The second mixture of step ii) further comprises magnesium stearate as a lubricant,
A method for preparing a sustained release preparation comprising varenicline or a pharmaceutically acceptable salt thereof. According to claim 1, wherein the first mixture and the second mixture does not contain a solvent selected from water, ethanol or mixtures thereof,
A method for preparing a sustained release preparation comprising varenicline or a pharmaceutically acceptable salt thereof. An oral sustained-release preparation comprising varenicline or a pharmaceutically acceptable salt thereof, wherein the content of varenicline analog is less than 0.2%, prepared by the method of any one of claims 1 to 6 . Varenicline or a pharmaceutical thereof having a relative standard deviation (RSD) of varenicline or a pharmaceutically acceptable salt content thereof of less than 3%, prepared by the method of claim 1. Oral sustained-release preparations containing acceptable salts. The method of claim 7, wherein the formulation is
Barenicline or a pharmaceutically acceptable salt thereof containing 0.1 to 10% by weight based on the total weight of the formulation,
The hydroxypropylmethylcellulose and carbomer are included as a matrix polymer, and the matrix polymer contains 10 to 45% by weight based on the total weight of the formulation, and the mixing ratio of the hydroxypropylmethylcellulose and carbomer is hydroxypropylmethylcellulose. : The weight ratio of carbomer is 1: 0.2 to 1.5,
The formulation is characterized in that it comprises 40 to 80% by weight of the total weight of the microcrystalline cellulose, oral sustained-release preparations.

Images