KR102479497B1 - Sustained release pharmaceutical formulation of varenicline and preparation method thereof - Google Patents

Abstract

The present invention provides an oral sustained-release preparation characterized in that it is a sustained-release matrix system comprising varenicline or a pharmaceutically acceptable salt thereof and a matrix polymer. The present invention can provide a sustained-release formulation with improved medication compliance and reduced side effects with once-a-day administration.

Description

Sustained release pharmaceutical formulation of varenicline and preparation method thereof}

The present invention relates to a pharmaceutical composition containing varenicline or a pharmaceutically acceptable salt thereof using a matrix-type sustained release drug delivery system and an oral sustained-release formulation using the same. More specifically, the present invention provides a pharmaceutical composition containing varenicline or a pharmaceutically acceptable salt thereof, which exhibits continuous absorption when administered to the human body and improves the patient's medication compliance through once-a-day administration, and an oral cavity using the same It relates to a sustained-release formulation for use.

Varenicline acts as a partial agonist on α4β2 neuronal nicotinic acetylcholine receptors, blocking the binding of nicotine to the receptor and at the same time showing significantly lower receptor activity than nicotine. ), it inhibits excessive release of dopamine by nicotine, and releases a small amount of dopamine to alleviate nicotine craving and withdrawal symptoms during smoking cessation, and is used as an adjuvant for smoking cessation treatment.

There is Champix ^® as a commercially available product, but side effects such as nausea, sleep disorders (nightmares, strange dreams, etc.), constipation, abdominal distension, and vomiting are known as common side effects. In particular, in the case of nausea, it is temporary, but in some patients, it is difficult to continue taking the medicine, and problems such as persistent nausea occur. It has been shown in clinical trials that these symptoms increase in a dose-dependent manner, and to solve this, the drug is taken through dose titration. First, take 0.5 mg once a day as varenicline for 3 days. After that, from the 4th to the 7th, take 0.5 mg twice a day. Thereafter, 1.0 mg of varenicline is administered twice a day until the 12th week to maintain the effective blood concentration and alleviate withdrawal symptoms.

The present invention relates to a pharmaceutical composition capable of improving medication compliance with once-a-day administration by delaying drug release of a sustained-release preparation containing varenicline or a pharmaceutically acceptable salt thereof, and an oral sustained-release preparation using the same want to provide

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

The present invention provides a method for reducing nicotine addiction in a subject using the pharmaceutical formulation or helping to stop or reduce tobacco use. The method includes administering varenicline in an amount effective to reduce nicotine addiction to a subject by oral administration of the drug or to assist in cessation or reduction of tobacco use. Varenicline has a structure shown in the following chemical formula.

As used herein, “varenicline” may include a compound having the structure shown in the above formula, a pharmaceutically acceptable salt, solvate and/or hydrate thereof, racemate, polymorph or prodrug thereof. may, and the active ingredient used herein is not only varenicline having the same structure as the above formula, but also pharmaceutically acceptable salts, solvates and/or hydrates thereof, racemates, and polymorphs of varenicline. ) or prodrugs.

As used herein, “pharmaceutically acceptable salts” may refer to non-toxic acid addition salts derived from inorganic and organic acids. Suitable salt derivatives include halides, thiocyanates, sulfates, bisulfates, sulfites, bisulfites, arylsulfonates, alkylsulfates, phosphonates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, al Kanoate, cycloalkylalkanoate, arylalkanoate, adipate, alginate, aspartate, benzoate, fumarate, glucoheptanoate, glycerophosphate, lactate, maleate, nicotinate, oxalate , salicylates, palmitate, pectinate, picrate, pivalate, succinate, tartrate, citrate, camphorate, camphorsulfonate, digluconate, trifluoroacetate, etc., but not limited to, preferably may include varenicline tartrate.

As used herein, the term "effective amount" refers to an amount determined in view of what is known in the art to reduce nicotine addiction in a subject or to assist in cessation or reduction of tobacco use, where it is Measurable relief, such as showing improvement, including but not limited to, faster recovery, improvement or elimination of symptoms, or reduction of complications, necessarily in the treated patient, lack of dependence on nicotine-containing compounds , 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 can exhibit effects such as treatment, improvement, recovery, relief, etc. to a subject, preferably by administration 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, most preferably in a dose in the range of 0.5 to 2mgA / day. However, variations in these dosages must be made depending on the weight and condition of the subject to be treated. Depending on the individual's response, dosage levels below the lower limit of the aforesaid ranges may be more appropriate, while in other cases much larger doses may be used without causing any adverse side effects.

The present invention is intended to construct and provide a sustained-release matrix system using a matrix polymer. In particular, since the matrix for application to varenicline or a pharmaceutically acceptable salt thereof has a relatively high proportion of polymers and other excipients in the prescription due to the low dosage due to the characteristics of varenicline drug, they may be greatly affected. In addition, since varenicline is a drug with very high solubility in water, if the matrix is eroded in a short time or swelling occurs greatly and the surface area is widened, the drug cannot be delayed and is released quickly. found In order to solve this problem, it was confirmed that it is necessary to select the type and ratio of the polymer that does not erode, and at the same time, it is necessary to use a polymer 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, and includes hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), 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-methacrylated trimethylammonium ethyl copolymer ( Eudragit RS), methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, or mixtures thereof may be used, but is not limited thereto, preferably hydroxypropylmethylcellulose , hydroxypropylcellulose, hydroxyethylcellulose, xanthan gum, alginic acid, carbomer, pre-gelatinized starch Or a mixture thereof may be used, and most preferably hydroxypropylmethylcellulose, carbomer, or a mixture thereof may be used.

The inventors of the present invention confirmed that the formulation had a particularly excellent sustained release profile when hydroxypropylmethylcellulose (HPMC) and carbomer were used together as matrix polymers.

In another embodiment, the inventors of the present invention confirmed for the first time 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 at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, alginic acid, and pre-gelatinized 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 hydroxypropylmethylcellulose (HPMC), carbomer, or a mixture thereof as a matrix polymer, when the mixture of HPMC and carbomer is used together, the object of the present invention may be most desirable to achieve.

The mixing ratio of HPMC and carbomer is preferably 1:0.5 to 1.5 by weight, preferably 1:0.8-1.3, more preferably 1:0.9-1.2, and even more preferably 1:0.5 to 1.5. 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 is included in an amount of 15 to 35% by weight based on the total weight of the formulation, and both HPMC and carbomer are included as the matrix polymer, A formulation containing HPMC and carbomer at a weight ratio of 1:0.5 to 1.5 may have an excellent sustained-release dissolution profile. Specifically, it takes about 60 minutes to achieve release of 10 to 50% without a rapid increase in blood concentration, and it may take about 2 to 16 hours to release 90% or more of the drug. Preferably, 10 to 50% in 1 hour, less than 80% in 2 hours, and 90% or more in 16 hours may be eluted.

When the matrix polymer is dissolved at 2% by weight in purified water at room temperature (20), 500 mPaS to 400,000 mPaS, preferably 1,000 to 380,000 mPaS, preferably 3,000 to 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 the desired drug release rate, or two or more polymers having different viscosities may be mixed and used. Viscosity may be appropriately changed according to the content of the matrix polymer.

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

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

The formulation of the present invention may further comprise a swelling controlling polymer. The swelling control polymer has low hydrophilicity and does not gel when used alone, so its matrix maintenance effect and sustained release effect are reduced, but it is added to the above-listed matrix polymers to prevent erosion of the matrix formed by the matrix polymer, resulting in synergistic effect of sustained release effect and rapid release. restrain

The swelling control polymer is polyvinyl acetate and polyvinyl acetate/polyvinylpyrrolidone mixture (eg Kollidon SR®), polyvinylpyrrolidone and polyvinylpyrrolidone vinylacetate copolymer ( Polyvinylpryrroldidone-vinylacetae copolymer (copovidone), Crospovidon, Ethyl cellulose (EC), Hydroxypropyl methylcellulose acetate succinate, Hydroxypropyl methylcellulose phthalate etc. may be used, but are not limited thereto, and preferably polyvinyl acetate and polyvinyl acetate/polyvinylpyrrolidone mixtures, polyvinylpyrrolidone and Polyvinylpyrrolidone vinyl acetate copolymers and the like can be selected.

The swelling-controlling polymer may be included in an amount of 1 to 20% by weight, preferably 2 to 15% by weight, and more preferably 3 to 10% by weight, based on the total weight of the formulation in order to have sustained-release properties in the formulation of the present invention.

The diluent may be included in the preparation of the sustained-release formulation of the present invention in order to maintain 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.

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

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

In a preferred embodiment, the oral sustained-release formulation of the present invention contains (a) 0.1 to 10% by weight of varenicline or a pharmaceutically acceptable salt thereof, (b) hydroxypropylmethylcellulose, hydroxypropyl, based on the total weight of the formulation. 3 to 75% by weight of one or two or more matrix polymers selected from the group consisting of cellulose, carbomer, xanthan gum, alginic acid, pre-gelatinized 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 contains (a) 0.2 to 5% by weight of varenicline or a pharmaceutically acceptable salt thereof, (b) hydroxypropylmethylcellulose, carbomer or these, based on the total weight of the preparation. Oral sustained release of a sustained-release matrix system comprising 5 to 60% by weight of any one matrix polymer selected from the group consisting of a mixture of, and (c) 30 to 85% by weight of microcrystalline cellulose and administered orally once a day. preparations can be provided.

In a more preferred embodiment, the sustained-release oral formulation of the present invention contains (a) 0.1 to 2.5% by weight of varenicline or a pharmaceutically acceptable salt thereof, (b) hydroxypropyl, based on the total weight of the formulation. 10 to 45% by weight of any one matrix polymer selected from the group consisting of methylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, alginic acid, pregelatinized starch, or mixtures thereof, and (c) 40 to 80% by weight of microcrystalline cellulose It is possible to provide an oral sustained-release formulation of a sustained-release matrix system that is administered orally once a day.

One embodiment of the present invention, (a) contains 0.1 to 2.5% by weight of varenicline or a pharmaceutically acceptable salt thereof based on the total weight of the formulation, (b) hydroxypropylmethylcellulose, carbomer or a mixture thereof 10 to 45% by weight based on the total weight of the formulation, and (c) 40 to 80% by weight of microcrystalline cellulose based on the total weight of the formulation.

One embodiment of the present invention, (a) contains 0.1 to 2.5% by weight of varenicline or a pharmaceutically acceptable salt thereof based on the total weight of the formulation, (b) hydroxypropylmethylcellulose, carbomer or a mixture thereof 10 to 45% by weight based on the total weight of the formulation, (c) 40 to 80% by weight of microcrystalline cellulose 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 is possible to provide a sustained-release formulation for oral administration 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 hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, alginic acid, and pre-gelatinized starch, and the matrix polymer is It may be included in 3 to 75% by weight based on the total weight, 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 hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, alginic acid, and pre-gelatinized starch, and the total weight of the formulation is 3 to 75% by weight, and the polymer may have a viscosity of 1,000 mPaS in a 0.5% to 10% aqueous solution (70 mPaS in a 2% aqueous solution of pregelatinized starch).

The formulation of the present invention may further contain other pharmaceutically acceptable ingredients commonly used in preparation, particularly ingredients commonly used in tablet preparation. For example, an excipient, a lubricant, a lubricant, a disintegrant, an antioxidant, a flavoring agent, a preservative, a flavoring agent, a sweetener, a colorant, a pH adjuster, and other additives may be further included.

The excipient may include, but is not limited to, any one selected from lactose, starch, lactose, mannitol, kaolin inorganic salts (eg, sodium chloride), powdered sugar and powdered cellulose derivatives, microcrystalline cellulose, 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 lubricants commonly used in the industry may be used without limitation. For example, saccharides such as white sugar, malaion taffy, white sugar, gelatin, sugar and starch syrup, magnesium stearate, talc, colloidal silicon dioxide, and the like may be used as lubricants.

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

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

In addition, preservatives and antioxidants include, for example, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and citric acid, metal chelating reagents such as ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid. can include

The dosage form of the oral preparation of the present invention may be prepared in the form of granules, ellipsoids, matrix multiparticles, etc., and may have dosage forms of tablets, granules, and hard capsules. Varenicline or a pharmaceutically acceptable salt is incorporated into a sustained release matrix, which may be compressed into tablets or encapsulations. The oral dosage form of the present invention may optionally contain other pharmaceutically acceptable ingredients (eg, diluents, binders, coloring agents, lubricants, etc.).

According to an embodiment of the sustained-release formulation of the present invention, it is characterized by a sustained-release matrix system containing varenicline or a pharmaceutically acceptable salt thereof as an active ingredient and comprising a matrix polymer, for once-a-day administration A sustained release formulation for oral use may have the following dissolution profile.

In one embodiment of the present invention, a formulation containing varenicline or a pharmaceutically acceptable salt thereof may be provided as a tablet of a sustained-release matrix system, preferably containing 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 is 0.01 N at a rate of 100 rpm in a basket at 37 ± 0.5 ° C. It can be eluted at 10 to 50% in 1 hour, less than 80% in 2 hours, and more than 90% in 16 hours in the dissolution test under the condition of HCl 900 ml medium.

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

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

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

The oral sustained-release preparation containing varenicline or a pharmaceutically acceptable salt thereof according to the present invention adjusts the drug release rate, so that it can show continuous absorption when administered to the human body, and can be taken once a day through It can improve patient adherence to medication.

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

1 shows the elution pattern of Test Example 1.
2-4 shows the dissolution pattern of Test Example 2.
5 shows the dissolution pattern of Test Example 3.
6 shows the dissolution pattern of Test Example 4.
7 shows the dissolution pattern of Test Example 5.
8 shows the dissolution pattern of Test Example 7.
9 shows the dissolution pattern of Test Example 8.
10 shows the dissolution pattern of Test Example 9.
11 shows the dissolution pattern of Test Example 10.

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

<Example 1> Preparation of sustained-release matrix using hydroxypropylmethylcellulose polymer

Sustained-release matrix tablets containing varenicline were prepared according to the composition tables shown in Tables 2 and 3 below.

Varenicline tartaric acid, microcrystalline cellulose, hydroxypropylmethylcellulose, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Magnesium stearate was then added, mixed, and tableted.

<Example 2> Preparation of sustained-release matrix using hydroxypropylcellulose polymer

Sustained-release matrix tablets containing varenicline were prepared according to the composition table shown in Table 4 below.

Varenicline tartaric acid, microcrystalline cellulose, hydroxypropyl cellulose, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Magnesium stearate was then added, mixed, and tableted.

<Example 3> Preparation of sustained-release matrix using hydroxyethylcellulose polymer

Sustained-release matrix tablets containing varenicline were prepared according to the composition table shown in Table 5 below. Varenicline tartaric acid, microcrystalline cellulose, hydroxyethyl cellulose, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Magnesium stearate was then added, mixed, and tableted.

<Example 4> Preparation of sustained-release matrix using xanthan gum and alginic acid

Sustained-release matrix tablets containing varenicline were prepared according to the composition table shown in Table 6 below.

Varenicline tartaric acid, microcrystalline cellulose, matrix polymer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by tableting.

<Example 5> Preparation of sustained-release matrix using carbomer polymer

Sustained-release matrix tablets containing varenicline were prepared according to the composition table shown in Table 7 below.

Varenicline, microcrystalline cellulose, carbomer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by tableting.

<Example 6> Preparation of sustained-release matrix using pregelatinized starch

Sustained-release matrix tablets containing varenicline were prepared according to the composition table shown in Table 8 below.

Varenicline, microcrystalline cellulose, pregelatinized starch, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by tableting.

<Comparative Example 1> Preparation of sustained-release matrix using only swelling-controlling polymer

Sustained-release matrix tablets containing varenicline were prepared according to the composition table shown in Table 9 below.

Varenicline, microcrystalline cellulose, swelling controlling polymer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate as a lubricant was added, mixed, and tableted.

<Comparative Example 2> Preparation of sustained-release matrix using only swelling-controlling polymer

Sustained-release matrix tablets containing varenicline were prepared according to the composition table shown in Table 10 below. Varenicline, microcrystalline cellulose, swelling control polymer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by tableting.

<Comparative Example 3> Preparation of sustained-release matrix using only swelling-controlling polymer

Sustained-release matrix tablets containing varenicline were prepared according to the composition table shown in Table 11 below. Varenicline, microcrystalline cellulose, swelling control polymer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by tableting.

<Example 7> Preparation of sustained-release matrix using matrix polymer and swelling control polymer

Sustained-release matrix tablets containing varenicline were prepared according to the composition table shown in Table 12 below. Varenicline, microcrystalline cellulose, pregelatinized starch, swelling control polymer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by tableting.

<Example 8> Preparation of a sustained-release matrix containing varenicline or a salt thereof as an active ingredient and using a matrix polymer

Sustained-release matrix tablets containing varenicline or a salt thereof were prepared according to the composition table shown in Table 13 below. Varenicline or a salt thereof, microcrystalline cellulose, hydroxypropylmethylcellulose, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by tableting.

<Example 9> Sustained-release matrix preparation 1 using two matrix polymers

According to the composition table shown in Table 14 below, sustained-release matrix tablets containing varenicline tartrate were prepared. Varenicline tartrate, microcrystalline cellulose, matrix polymer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by tableting.

<Example 10> Sustained-release matrix preparation 2 using two matrix polymers

Sustained-release matrix tablets containing varenicline free base were prepared according to the composition table shown in Table 15 below.

Varenicline, microcrystalline cellulose, matrix polymer, and light anhydrous silicic acid were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by tableting.

<Test Example 1> Evaluation of the effect of sustained-release formulations

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

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

<Analysis conditions>

- 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% trifluoroacetic acid) = 70 : 30, v/v

- Injection amount: 10 μl

- Flow rate: 1 ml/min

- Detector: UV 237 nm

- column temperature: 40 ℃

The dissolution test results are shown in Tables 16-17 and FIG. 1 below.

From the results in the table above, it was confirmed that commercially available Champix tablets were completely dissolved within 2 hours, and the release delay effect of varenicline by various grades of hydroxypropylmethylcellulose was confirmed.

<Test Example 2> Evaluation of the effect of sustained-release formulations

The dissolution test for Example 2, Example 3 and Example 4 was performed according to the dissolution test method of the 10th revision of the Korean Pharmacopoeia. The elution method used a basket method, and the stirring speed was 100 rpm, and the elution temperature was carried out at 37 ± 0.5 ° C. Elution was performed in 900 ml of 0.01 N HCl. Dissolution test results are shown in Table 18 and Figures 2-4 below.

From the results in the table above, it was confirmed that the release delay effect of hydroxypropyl cellulose, hydroxyethyl cellulose, xanthan gum, and alginic acid was confirmed. However, Klucel EXF ^® (Examples 2-3, 2-4, 300-600 mPaS @ 10% sol.) and Natrosol 250GR (Example 3-3) having low viscosity in aqueous solution of hydroxypropylcellulose and hydroxyethylcellulose , 3-4, 150~400 mPaS @2% sol.) failed to retain the matrix and showed a high release of more than 90% within 5 hours.

<Test Example 3> Evaluation of the effect of sustained-release formulations

The dissolution test of Examples 5 and 6 was conducted according to the dissolution test method of the 10th revision of the Korean Pharmacopoeia. The elution method used a paddle method, and the stirring speed was 100 rpm, and the elution temperature was carried out at 37 ± 0.5 ° C. Tablets were evaluated by placing them in a sinker. Elution was performed in 900 ml of 0.01 N HCl. Dissolution test results are shown in Table 19 and FIG. 5 below.

From the results in the table above, it was shown that the carbomer exhibits an appropriate release delay at a ratio of 30 to 45%. The release delay was observed in 60 to 75% of the pregelatinized starch, but rapid release was observed between 2 and 5 hours in the case of 60% (Example 6-4). This seems to be due to a rapid increase in surface area due to erosion of the matrix without being densely maintained.

<Test Example 4> Evaluation of the effect of sustained-release formulations

Comparative Example 1 was tested for dissolution according to the dissolution test method of the 10th revision of the Korean Pharmacopoeia. The elution method used a basket method, and the stirring speed was 100 rpm, and the elution temperature was carried out at 37 ± 0.5 ° C. Elution was performed in 900 ml of 0.01 N HCl. Dissolution test results are shown in Table 20 and FIG. 6 below.

From the results in the table above, it was shown that all matrix polymers did not show a sustained-release effect. In the case of methylhydroxyethyl cellulose, even when about 45% was used, almost 100% dissolution was shown within 5 hours, showing an unsuitable dissolution profile as a sustained release agent.

<Test Example 5> Comparison of the effect of the swelling control polymer alone

Dissolution tests were performed on Comparative Examples 2 and 3 according to the dissolution test method of the 10th revision of the Korean Pharmacopoeia. The elution method used a paddle method, and the stirring speed was 100 rpm, and the elution temperature was carried out at 37 ± 0.5 ° C. Tablets were evaluated by placing them in a sinker. Elution was performed in 900 ml of 0.01 N HCl. Dissolution test results are shown in Table 21 and FIG. 7 below.

From the above results, ethyl cellulose had no sustained-release effect. Uniquely, high molecular weight ethylcellulose showed very rapid drug release without complete erosion of the matrix. Kollidon SR ^® , a mixture of polyvinyl acetate and polyvinylpyrrolidone, did not completely erode when used alone, but had no sustained-release effect at 30%, and even at 45%, close to 90% was released in 5 hours. Therefore, it is not suitable for use alone. Because of this property of preventing erosion of the matrix without swelling, it seemed that a sustained synergistic effect could be expected by using it together when selecting the ratio of the matrix polymer.

<Test Example 6> Comparison of the effect of the swelling control polymer alone

Dissolution tests were performed on Comparative Examples 1 and 3 according to the dissolution test method of the 10th revision of the Korean Pharmacopoeia. The elution method used a basket method, and the stirring speed was 100 rpm, and the elution temperature was carried out at 37 ± 0.5 ° C. Elution was performed in 900 ml of 0.01 N HCl. The dissolution test results are shown in Table 22 below.

From the results in the table above, it was found that even low molecular weight ethyl cellulose had no sustained release effect. In particular, low-viscosity ethyl cellulose (Comparative Examples 3-1 to 3-4), unlike high-viscosity ethyl cellulose (Comparative Examples 3-5 to 3-8), did not have a matrix maintenance effect, making it unsuitable as a swelling control polymer.

<Test Example 7> Comparison of effects of matrix polymer and swelling control polymer

Example 7 was tested for dissolution according to the dissolution test method of the 10th revision of the Korean Pharmacopoeia. The elution method used a basket method, and the stirring speed was 100 rpm, and the elution temperature was carried out at 37 ± 0.5 ° C. Elution was performed in 900 ml of 0.01 N HCl. Dissolution test results are shown in Table 23 and FIG. 8 below.

From the results in the table above, it was confirmed that the matrix retention effect was obtained when the swelling controlling polymer was used. From the dissolution results of Test Example 3 above, in the case of Example 6-4, rapid release was seen between 5 and 8 hours, but it was confirmed that the extent was reduced in Examples 7-1 to 7-4.

<Test Example 8> Preparation of a sustained-release matrix containing varenicline or a salt thereof as an active ingredient and using a matrix polymer

The dissolution test of Example 8 was performed according to the dissolution test method of the 10th revision of the Korean Pharmacopoeia. The elution method used a basket method, and the stirring speed was 100 rpm, and the elution temperature was carried out at 37 ± 0.5 ° C. Elution was performed in 900 ml of 0.01 N HCl.

As shown in FIG. 9, it was confirmed that when varenicline or a salt thereof was contained in a sustained-release matrix using hydroxypropylmethylcellulose as a matrix polymer, a stable sustained-release effect was exhibited without a change in dissolution rate.

<Test Example 9> Sustained-release matrix preparation 1 using two matrix polymers

Example 9 was tested for dissolution according to the 10th revised dissolution test method of the Korean Pharmacopoeia. The elution method used a basket method, and the stirring speed was 100 rpm, and the elution temperature was carried out at 37 ± 0.5 ° C. Elution was performed in 900 ml of 0.01 N HCl.

As shown in FIG. 10, it was confirmed that the sustained-release matrix using a combination of 10 to 15% by weight of hydroxypropylmethylcellulose and 10 to 15% by weight of carbomer showed a stable sustained-release effect without a change in the dissolution rate of active ingredients. In addition, it was confirmed that even when the ratio of the individual matrix polymers is relatively low, such as 10 to 15% by weight, a desired sustained release pattern can be exhibited by an appropriate combination of polymers.

<Test Example 10> Sustained-release matrix preparation 2 using two matrix polymers

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

As shown in FIG. 11, it was confirmed that a stable sustained-release effect was exhibited without a change in active ingredient dissolution rate in the sustained-release matrix using a combination of 10 to 15% by weight of hydroxypropylmethylcellulose and 5 to 10% by weight of carbomer. In addition, it was confirmed that even when the ratio of individual matrix polymers is relatively low, such as 5 to 15% by weight, a desired sustained release pattern can be exhibited by an appropriate combination of polymers.

From the above results, it was found that even with the same amount of matrix polymer, the sustained-release effect was better and the delayed-release aspect was more excellent when the two were combined.

In addition, compared to the case of using HPMC alone, when prepared with HPMC+Carbomer, an excellent sustained-release effect could be achieved while using a smaller amount of polymer. Through this, it was confirmed that an excellent oral formulation with improved medication compliance while achieving sustained release of the drug could be prepared.

Claims (19)

An oral sustained-release preparation characterized in that it is a sustained-release matrix system comprising varenicline or a pharmaceutically acceptable salt thereof and a matrix polymer,
The formulation includes hydroxypropylmethylcellulose and carbomer as a matrix polymer, and the matrix polymer is contained in an amount of 10 to 45% by weight based on the total weight of the formulation,
The mixing ratio of the hydroxypropylmethylcellulose and the carbomer is characterized in that the weight ratio of hydroxypropylmethylcellulose:carbomer is 1:0.2 to 1.5,
An oral sustained-release formulation that does not contain a solubilizing agent selected from the group consisting of sodium lauryl sulfate, Labrafil, Labrasol, Tween 60, and mixtures thereof. The oral sustained-release formulation of claim 1, wherein the formulation is administered once a day. delete delete delete delete delete delete delete delete According to claim 1, wherein the formulation is characterized in that it further comprises a swelling control polymer, oral sustained-release formulation. The method of claim 11, wherein the swelling control polymer is polyvinyl acetate, polyvinyl acetate-polyvinylpyrrolidone, polyvinylpyrrolidone, poly(vinylpyrrolidone-vinyl acetate) copolymer, crospovidone, ethylcellulose, Hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and characterized in that at least one selected from the group consisting of mixtures thereof, oral sustained-release preparation. delete The oral sustained-release formulation of claim 1, wherein the formulation further comprises a diluent. 15. The oral sustained-release preparation according to claim 14, wherein the diluent is microcrystalline cellulose. The method of claim 15, wherein the formulation contains (a) 0.1 to 2.5% by weight of varenicline or a pharmaceutically acceptable salt thereof based on the total weight of the formulation,
(b) 10 to 45% by weight of hydroxypropylmethylcellulose, carbomer, or a mixture thereof based on the total weight of the formulation,
(c) an oral sustained-release formulation comprising 40 to 80% by weight of microcrystalline cellulose based on the total weight of the formulation. The method of claim 16, wherein the formulation,
Polyvinyl acetate, polyvinyl acetate-polyvinylpyrrolidone, polyvinylpyrrolidone, poly(vinylpyrrolidone-vinylacetate) copolymer, crospovidone, ethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxy A sustained-release preparation for oral use, further comprising 1 to 20% by weight of any one selected from the group consisting of propylmethylcellulose phthalate, and mixtures thereof. In the formulation containing varenicline or a pharmaceutically acceptable salt thereof, oral sustained-release formulation for once-daily administration having the following characteristics, characterized by a sustained-release matrix system containing a matrix polymer:
When the release of total varenicline or a pharmaceutically acceptable salt thereof was tested under the conditions of 0.01 N HCl 900 ml medium in a basket test method at a rate of 37 ± 0.5, 100 rpm,
10 to 50% in 1 hour, less than 80% in 2 hours, and more than 90% in 16 hours,
The formulation includes hydroxypropylmethylcellulose and carbomer as a matrix polymer, and the matrix polymer is contained in an amount of 10 to 45% by weight based on the total weight of the formulation,
The mixing ratio of the hydroxypropylmethylcellulose and the carbomer is hydroxypropylmethylcellulose: the weight ratio of the carbomer is 1:0.2 to 1.5,
An oral sustained-release preparation characterized in that it does not contain a solubilizing agent selected from the group consisting of sodium lauryl sulfate, Labrafil, Labrasol, Tween 60, and mixtures thereof. The method of claim 18, wherein the oral sustained-release formulation
Contains 0.1 to 10% by weight of varenicline free base based on the total weight of the formulation,
Contains hydroxypropylmethylcellulose and carbomer as a matrix polymer, and the matrix polymer is included in an amount of 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 an oral sustained-release formulation, characterized in that it contains 40 to 80% by weight of microcrystalline cellulose relative to the total weight of the formulation.

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