WO2018097629A1

WO2018097629A1 - Varenicline sustained-release preparation and production method thereof

Info

Publication number: WO2018097629A1
Application number: PCT/KR2017/013447
Authority: WO
Inventors: 김관영; 조경아; 신호철; 김남호; 유헌승; 박여진; 이규호; 사준호; 곽용규
Original assignee: 에스케이케미칼 주식회사
Priority date: 2016-11-24
Filing date: 2017-11-23
Publication date: 2018-05-31
Also published as: KR20180058644A; KR102479497B1; KR20190059868A; KR20180127951A

Abstract

The present invention provides an oral sustained-release preparation which is a sustained-release matrix system comprising varenicline or a pharmaceutically acceptable salt and matrix polymer thereof. The present invention increases medication adherence by once-daily administration, and provides a sustained-release preparation with reduced side effects.

Description

Varenic sustained release formulation and preparation method thereof

This application claims priority based on Korean Patent Application No. 10-2016-0157714, filed November 24, 2016, and all the contents disclosed in the specification and drawings of the application are incorporated in this application.

The present invention relates to a pharmaceutical composition containing varenicline or a pharmaceutically acceptable salt thereof by using a matrix-type sustained release drug delivery system, and an oral sustained-release preparation using the same. More specifically, the present invention is a pharmaceutical composition containing varenicline or a pharmaceutically acceptable salt thereof, and oral using the same, which shows continuous absorption when administered to the human body and improves the patient's compliance with the daily dose. It relates to a sustained release formulation.

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 significantly lower receptor activity than nicotine. It suppresses excessive dopamine release by nicotine and releases a small amount of dopamine, which can be used as a smoking cessation aid by relieving nicotine craving and withdrawal symptoms during smoking cessation.

Commercial products include Champix ^® , but side effects such as nausea, sleep disorders (nightmares, strange dreams, etc.), constipation, bloating and vomiting are known. In particular, the nausea is temporary, but in some patients, it is difficult to continue taking the medicine, and the nausea persists. In clinical trials, this symptom has been shown to increase in dose-dependent manner. To solve this problem, the drug is administered via dose titration, which is first given 0.5 mg of varenicline once a day for 3 days. After that, take 0.5 mg twice a day from 4 to 7 days. After week 12, the dose of 1.0 mg twice daily with varenicline is used to maintain effective blood levels and alleviate withdrawal symptoms.

The present invention provides a pharmaceutical composition capable of improving drug compliance with a once-a-day administration by delaying the release of a sustained-release preparation containing varenicline or a pharmaceutically acceptable salt thereof, and an oral sustained-release preparation using the same. 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 improved orally administered by oral administration once a day through a formulation comprising varenicline or a pharmaceutically acceptable salt thereof and a matrix polymer.

The present invention provides a method of using the pharmaceutical formulation to reduce nicotine poisoning in a subject or to help stop or reduce tobacco use. The method comprises administering to the subject an oral administration of the drug in an amount of varenicline effective to reduce nicotine poisoning, or to help stop or reduce tobacco use. Varenicline has a structure such as the following formula.

As used herein, "vareniclin" shall include a compound having a structure such as the above formula, a pharmaceutically acceptable salt, solvate and / or hydrate, racemate, polymorph or prodrug thereof. The active ingredient used herein may be not only varenicline having a structure of the above formula, but also pharmaceutically acceptable salts, solvates and / or hydrates, racemates, polymorphs thereof of varenicline. Or prodrugs.

As used herein, “pharmaceutically acceptable salts” may refer to nontoxic 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, als Decanoate, cycloalkylalkanoate, arylalkanoate, adipate, alginate, aspartate, benzoate, fumarate, glucoheptanoate, glycerophosphate, lactate, maleate, nicotinate, oxalate Salicylate, Palmitate, pectinate, picrate, pivalate, succinate, tartrate, citrate, camphorrate, camphorsulfonate, digluconate, trifluoroacetate, and the like, but are not limited to these, preferably May comprise varenicline tartrate.

As used herein, the term “effective amount” means an amount determined in consideration of such points as is known in the art to help reduce nicotine poisoning in an individual or to stop or reduce the use of tobacco, wherein this is Measurable alleviation, lack of dependency on nicotine-containing compounds, such as indicating improvement, including but not limited to faster recovery, amelioration or elimination of symptoms, or reduction of complications, necessarily in the treated patient , 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 exert an effect such as treatment, improvement, recovery, alleviation, etc. on the subject, preferably once daily administration. 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 may be administered at a dose in the range of mgA / day, most preferably at a dose in the range of 0.5 to 2 mgA / day. However, changes in this dosage 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 aforementioned range may be more appropriate, while in other cases even larger doses may be used without causing any adverse side effects.

The present invention is to configure 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 may be greatly influenced by the low dosage of the varenicline drug due to the high dosage of polymers and other excipients in the formulation. In addition, varenicline is a drug that has a very high solubility in water, so if the matrix is eroded or swelled in a short time, and the surface area is increased, the drug is not delayed and released quickly. Found. In order to solve this problem, it is necessary to select the type and ratio of the polymer that is not eroded and at the same time, it is necessary to use a polymer having 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 hydroxypropyl methyl 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, dimethyl methacrylate methyl methacrylate (dimethyl methyl ethyl methacrylate, methyl methacrylate copolymer (Eudragit E)), methacrylic acid meth-methacrylate trimethylammonium ethyl copolymer ( Eudragit RS), methacrylic acid-acrylic acid ethyl ester copolymer, dimethylamino Ethyl methacrylate-methacrylic acid ester copolymers or mixtures thereof may be used, but are not limited to these, preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, xanthan gum, alginic acid, Carbomer, luxury starch Or mixtures thereof, most preferably hydroxypropylmethylcellulose, carbomer or mixtures thereof.

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

In another embodiment, the inventors of the present invention first confirmed that varenicline or its pharmaceutically acceptable salts had 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 comprise any one or more selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, alginic acid, and gelatinized starch as the matrix polymer. 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 comprises hydroxypropylmethylcellulose (HPMC), carbomer or a mixture thereof as a matrix polymer, an object of the present invention is used when a mixture of HPMC and carbomer is used together. It may be most desirable to achieve.

The mixing ratio of HPMC and carbomer is preferably a weight ratio of HPMC and carbomer is 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 comprising varenicline or a pharmaceutically acceptable salt thereof, the matrix polymer may include 15 to 35 wt% of the total weight of the formulation, and HPMC and carbomer may be included as the matrix polymer. Formulations in which the weight ratio of HPMC to carbomer is comprised between 1: 0.5 and 1.5 may have an excellent sustained release dissolution profile. Specifically, it may take about 60 minutes to achieve 10 to 50% release, and about 2 to 16 hours to release more than 90% of the drug without sharply raising blood levels. Preferably eluted at 10 to 50% in 1 hour, less than 80% in 2 hours, 90% or more in 16 hours.

The matrix polymer is 500 mPaS to 400,000 mPaS, preferably 1,000 to 380,000 mPaS, and preferably 3,000 to 38, when dissolved at 2% by weight in purified water at room temperature 20, according to a process oral 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 may be used by appropriately adjusting the viscosity or mixing two or more different polymers within the above range according to the desired drug release rate. Viscosity may be appropriately changed depending on 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 viscosity.

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

The formulation of the present invention may further comprise a swelling control polymer. The swelling control polymer has a low hydrophilicity and thus does not gel when used alone, so its matrix retention effect and sustained release effect are inferior, but it is added to the matrix polymers listed above to prevent erosion of the matrix formed by the matrix polymer, thereby promoting a synergistic and sudden release of the sustained effect. Suppress

The swelling control polymers include polyvinyl acetate and polyvinylacetate / polyvinylpyrrolidone mixtures (e.g. Kollidon SR®), polyvinylpyrrolidone and polyvinylpyrrolidone vinylacetate copolymers ( Polyvinylpryrroldidone-vinylacetae copolymer, copovidone), crospovidone, ethyl cellulose (EC), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate And the like, but are not limited thereto, and preferably, polyvinylacetate and polyvinylacetate / polyvinylpyrrolidone mixtures, polyvinylpyrrolidone, and the like to prevent rapid drug release of matrix systems comprising varenicline. Polyvinylpyrrolidone vinyl acetate ball There are copolymers such as may 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 relative to the total weight of the formulation in order for the formulation of the present invention to have sustained release properties.

Diluents may be included in the preparation of the sustained release formulation of the present invention in view of maintaining the structure of the sustained release matrix. The diluent may include microcrystalline cellulose, calcium dihydrogen phosphate, starch, mannitol, lactose and the like, preferably microcrystalline cellulose may be used for the purposes of the present invention.

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

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 A) 5 to 60% by weight of the matrix polymer, and (c) 20 to 80% by weight of the total weight of the formulation. Preferably the formulation may comprise 0.1 to 10% by weight of varenicline or a pharmaceutically acceptable salt thereof relative to the total weight of the formulation, and the varenicline or a pharmaceutically acceptable salt thereof is preferably tartrate varenyl Varenicline tartrate, varenicline free base, varenicline salicylate, varenicline oxalate or mixtures thereof may be used and more preferably Varenicline free base can be used.

In a preferred embodiment, the oral sustained release preparation of the present invention comprises (a) 0.1 to 10% by weight of varenicline or a pharmaceutically acceptable salt thereof, (b) hydroxypropylmethylcellulose, hydroxypropyl, relative to the total weight of the preparation. 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, 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 comprises (a) 0.2 to 5% by weight of varenicline or a pharmaceutically acceptable salt thereof, (b) hydroxypropylmethylcellulose, carbomer or their Oral sustained release of the sustained release matrix system containing 5 to 60% by weight of any one matrix polymer selected from the group consisting of (c) 30 to 85% by weight of microcrystalline cellulose, and orally administered once daily Formulations may be provided.

In a more preferred embodiment, in the preferred embodiment the oral sustained release preparation of the invention comprises (a) 0.1 to 2.5% by weight of varenicline or a pharmaceutically acceptable salt thereof, (b) hydroxypropyl 10 to 45% by weight of any one of the matrix polymers selected from the group consisting of methylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, alginic acid, gelatinized starch or mixtures thereof, and (c) 40 to 80% by weight of microcrystalline cellulose. It may include, and can provide an oral sustained release formulation of the sustained release matrix system administered orally once a day.

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

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

In one embodiment of the present invention, the matrix polymer of the formulation is any one or more selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, alginic acid, and gelatinized starch, wherein the matrix polymer is a formulation 3 to 75% by weight relative to the total weight may be included, more preferably 5 to 60% by weight may be included.

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 gelatinized starch, 3 to the total weight of the formulation To 75% by weight, the viscosity of the polymer in 0.5% to 10% aqueous solution may be 1,000 mPaS (However, gelatinized starch may be 70 mPaS in 2% aqueous solution).

The formulations of the present invention may further comprise other pharmaceutically acceptable ingredients commonly used in the manufacture, in particular those commonly used in the manufacture of tablets. For example, excipients, lubricants, lubricants, disintegrants, antioxidants, flavoring agents, preservatives, fragrances, sweeteners, pigments, pH adjusting agents, other additives and the like can be further included.

The excipient may include any one selected from lactose, starch, lactose, mannitol, kaolin inorganic salt (eg, sodium chloride), powdered sugar and powdered cellulose derivative, microcrystalline cellulose, or a mixture 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, macion syrup, 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 sodium carboxymethylcellulose, copovidone, and sodium starch glycorate, but is not limited thereto.

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

The formulation of the oral preparation of the present invention may be prepared in the form of granules, ellipsoids, matrix multiparticulates, and the like, and may have a formulation 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. Oral formulations of the present invention may optionally include other pharmaceutically acceptable ingredients (eg, diluents, binders, colorants, lubricants, etc.).

According to an embodiment of the sustained release preparation of the present invention, for once-daily administration, characterized by a sustained-release matrix system containing varenicline or a pharmaceutically acceptable salt thereof as an active ingredient and comprising a matrix polymer Oral sustained release formulations may 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, wherein the release of total varenicline or its pharmaceutically acceptable salt is 0.01 N at a rate of 100 rpm into a basket at 37 ± 0.5 ° C. Under conditions of 900 ml of HCl, eluting can be eluted at 10-50% in 1 hour, less than 80% in 2 hours, and at least 90% in 16 hours.

Preferably, the oral sustained release preparation contains barrenicline free base in an amount of 0.1 to 10% by weight based on the total weight of the preparation, and includes hydroxypropylmethylcellulose and carbomer as a matrix polymer, wherein the matrix polymer is the total weight of the preparation. 10 to 45% by weight of the hydroxypropylmethylcellulose and carbomer, the mixing ratio of hydroxypropylmethylcellulose: carbomer mass ratio of 1: 0.2 to 1.5, 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 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.

The drug dissolution profile and the pharmacokinetics of the formulation were checked to determine the effect on the expression of the effect of the drug (vareniclin or its pharmaceutically acceptable salts) in the human body, and according to the in vitro dissolution pattern. It was confirmed that the pharmacological kinetics of reniclin or its pharmaceutically acceptable salts were varied, and showed 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 control the rate of drug release, exhibit sustained absorption when administered to the human body, and are administered once daily. Improve patient compliance.

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

1 shows the elution pattern of Test Example 1.

2-4 shows the elution pattern of Test Example 2.

5 shows the elution pattern of Test Example 3.

6 shows the elution pattern of Test Example 4.

7 shows the elution pattern of Test Example 5.

8 shows the elution pattern of Test Example 7.

9 shows the elution pattern of Test Example 8. FIG.

10 shows the elution pattern of Test Example 9.

11 shows the elution pattern of Test Example 10.

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.

Example 1 Preparation of Sustained Release Matrix Using Hydroxypropylmethylcellulose Polymer

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

Varenicline tartaric acid, microcrystalline cellulose, hydroxypropylmethylcellulose, and hard silicic anhydride were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added, mixed, and tableted.

Example 2 Preparation of Sustained Release Matrix Using Hydroxypropyl Cellulose Polymer

According to the composition table described in Table 4 below, sustained-release matrix tablets containing varenicline were prepared.

Varenicline tartaric acid, microcrystalline cellulose, hydroxypropyl cellulose, and hard silicic anhydride were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added, mixed, and tableted.

Example 3 Preparation of Sustained Release Matrix Using Hydroxyethylcellulose Polymer

According to the composition table described in Table 5 below, sustained-release matrix tablets containing varenicline were prepared. Varenicline tartaric acid, microcrystalline cellulose, hydroxyethyl cellulose and hard silicic anhydride were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was 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 described in Table 6 below.

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

Example 5 Preparation of Sustained Release Matrix Using Carbomer Polymer

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

Varenicline, microcrystalline cellulose, carbomer, and hard silicic anhydride were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by compression.

Example 6 Preparation of Sustained Release Matrix Using Gelatinized Starch

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

Varenicline, microcrystalline cellulose, gelatinized starch, and hard silicic anhydride were filtered through No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by compression.

Comparative Example 1 Preparation of a Sustained Release Matrix Using Swelling Control Polymer Only

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

Varenicline, microcrystalline cellulose, swelling control polymer, and hard silicic anhydride were filtered through No. 30 sieve and mixed. Thereafter, magnesium stearate, a lubricant, was added, mixed, and compressed.

<Comparative Example 2> Sustained release matrix production using swelling control polymer alone

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

<Comparative Example 3> Sustained release matrix production using swelling control polymer alone

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

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 described in Table 12 below. Varenicline, microcrystalline cellulose, gelatinized starch, swelling control polymer, and hard silicic anhydride were filtered through No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by compression.

Example 8 Preparation of Sustained-release Matrix Containing Varenicline or Its Salts as an Active Ingredient and Using Matrix Polymers

Sustained-release matrix tablets containing varenicline or salts thereof were prepared according to the composition table described in Table 13 below. Varenicline or its salt, microcrystalline cellulose, hydroxypropylmethylcellulose, and hard silicic anhydride were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by compression.

Example 9 Preparation of Sustained Release Matrix Using 2 Matrix Polymers 1

Sustained-release matrix tablets containing varenicline stannate were prepared according to the composition table described in Table 14 below. Varenicline stannate, microcrystalline cellulose, matrix polymer, and hard silicic anhydride were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by compression.

Example 10 Sustained Release Matrix Production Using 2 Matrix Polymers 2

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

Varenicline, microcrystalline cellulose, matrix polymer, and hard silicic anhydride were filtered through a No. 30 sieve and mixed. Thereafter, magnesium stearate was added and mixed, followed by compression.

<Test Example 1> Evaluation of the Effect of Sustained Release Preparation

Example 1 was eluted by the KEPCO Tenth Amendment Dissolution Test. The elution method was carried out using the basket method, the stirring speed was 100rpm, the elution temperature at 37 ± 0.5 ℃. The eluate was carried out in 900 ml of 0.01 N HCl.

Analytical conditions were evaluated by evaluating the concentration of varenicline using HPLC to filter the solution obtained in the above dissolution test with a 0.45㎛ membrane filter.

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

Mobile phase: pH 4.0 ammonium acetate buffer (5 mM): methanol (0.1% trifluoroacetic acid) = 70: 30, v / v

Injection volume: 10 μl

Flow rate: 1 ml / min

Detector: UV 237 nm

Column temperature: 40 ° C

Dissolution test results are shown in Tables 16-17 and FIG. 1.

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

<Test Example 2> Effect evaluation of the sustained release preparation

Example 2, Example 3 and Example 4 were eluted by the KEPCO 10th Dissolution Dissolution Test. The elution method was carried out using the basket method, the stirring speed was 100rpm, the elution temperature at 37 ± 0.5 ℃. The eluate was carried out in 900 ml of 0.01 N HCl. Dissolution test results are shown in Table 18 below and FIGS. 2-4.

From the results of the above table, the release delay effects of hydroxypropyl cellulose, hydroxyethyl cellulose, xanthan gum and alginic acid were confirmed. However, low viscosity Klucel EXF ^® (Example 2-3, 2-4, 300-600 mPaS @ 10% sol.) And Natrosol 250GR (Example 3-3) in aqueous solution of hydroxypropylcellulose and hydroxyethylcellulose , 3-4, 150-400 mPaS @ 2% sol.) Did not maintain the matrix and showed a high emission of more than 90% within 5 hours.

<Test Example 3> Effect evaluation of the sustained release preparation

The dissolution test of Examples 5 and 6 was carried out according to the KEPCO Tenth Amendment Dissolution Test Method. The elution method was a paddle method, the stirring speed was 100rpm, the elution temperature was carried out at 37 ± 0.5 ℃. Tablets were evaluated by placing them in a sinker. The eluate was carried out in 900 ml of 0.01 N HCl. Dissolution test results are shown in Table 19 and FIG. 5.

From the results in the table it was shown that the carbomer exhibited an appropriate release delay at 30-45% ratio. Gelatinized starch showed a release delay in 60-75%, but in 60% (Example 6-4) there was a rapid release between 2-5 hours. This seems to be due to the rapid increase in surface area due to the erosion of the matrix rather than its compactness.

<Test Example 4> Effect evaluation of the sustained release preparation

The comparative example 1 was eluted by the KEPCO 10th Dissolution Dissolution Test. The elution method was carried out using the basket method, the stirring speed was 100rpm, the elution temperature at 37 ± 0.5 ℃. The eluate was carried out in 900 ml of 0.01 N HCl. Dissolution test results are shown in Table 20 and FIG. 6.

From the results in the table, it was shown that all the matrix polymers did not exhibit a sustained release effect. In the case of methyl hydroxyethyl cellulose, almost 100% of elution was observed within 5 hours even when used about 45%, which showed an unsuitable dissolution profile as a sustained release agent.

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

The comparative example 2 and the comparative example 3 were eluted by the pharmacopeia 10th revision dissolution test method. The elution method was a paddle method, the stirring speed was 100rpm, the elution temperature was carried out at 37 ± 0.5 ℃. Tablets were evaluated by placing them in a sinker. The eluate was carried out in 900 ml of 0.01 N HCl. Dissolution test results are shown in Table 21 and FIG. 7.

From the above results, ethyl cellulose had no sustained release effect. Specifically, high molecular weight ethylcellulose showed no rapid erosion of the matrix but very fast drug release. Kollidon SR ^® , a mixture of polyvinylacetate and polyvinylpyrrolidone, had no complete erosion when used alone, but had no sustained release at 30% and almost 90% at 45%. Use alone was not suitable. Due to this property that prevents swelling and prevents erosion of the matrix, it seems that the synergistic effect of the sustained release can be expected by using the matrix polymer together with the ratio selection.

<Test Example 6> Influence of the swelling control polymer alone

The comparative example 1 and the comparative example 3 were eluted by the pharmacopeia tenth revision dissolution test method. The elution method was carried out using the basket method, the stirring speed was 100rpm, the elution temperature at 37 ± 0.5 ℃. The eluate was carried out in 900 ml of 0.01 N HCl. The dissolution test results are shown in Table 22 below.

The results of the above table also showed that low molecular weight ethylcellulose 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 retention effect and was not suitable as a swelling control polymer.

Test Example 7 Influence of Matrix Polymer and Swelling Control Polymer

The dissolution test of Example 7 was carried out by the pharmacopeia 10th modified dissolution test method. The elution method was carried out using the basket method, the stirring speed was 100rpm, the elution temperature at 37 ± 0.5 ℃. The eluate was carried out in 900 ml of 0.01 N HCl. Dissolution test results are shown in Table 23 and FIG. 8.

From the results in the above table, it was confirmed that the matrix retention effect when the swelling control polymer was used. In the dissolution results of Test Example 3, the release of Example 6-4 showed a rapid release between 5 and 8 hours, but the decrease was confirmed in Examples 7-1 to 7-4.

<Test Example 8> Preparation of 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 by the Pharmacopeia Tenth Amendment Dissolution Test Method. The elution method was carried out using the basket method, the stirring speed was 100rpm, the elution temperature at 37 ± 0.5 ℃. The eluate was carried out in 900 ml of 0.01 N HCl.

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

Test Example 9 Sustained Release Matrix Production Using Two Matrix Polymers 1

Example 9 was eluted by the KEPCO 10th Dissolution Dissolution Test. The elution method was carried out using the basket method, the stirring speed was 100rpm, the elution temperature at 37 ± 0.5 ℃. The eluate was carried out in 900 ml of 0.01 N HCl.

As shown in FIG. 10, it was confirmed that the sustained-release effect was exhibited without a change in the effective ingredient dissolution rate in the sustained-release matrix using a combination of 10-15 wt% hydroxypropylmethylcellulose and 10-15 wt% carbomer. In addition, it can be seen that even if the ratio of the individual matrix polymers is relatively low (10 to 15% by weight), the desired sustained release pattern can be obtained by appropriate combination of the polymers.

Test Example 10 Sustained Release Matrix Production Using 2 Matrix Polymers 2

The dissolution test of Example 10 was carried out by the pharmacopeia 10th modified dissolution test method. The elution method was carried out using the basket method, the stirring speed was 100rpm, the elution temperature at 37 ± 0.5 ℃. The eluate was carried out in 900 ml of 0.01 N HCl.

As shown in FIG. 11, it was confirmed that the sustained-release effect was exhibited without a change in the effective 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 if the ratio of the individual matrix polymers is relatively low (5 to 15% by weight), the desired sustained release pattern can be obtained by appropriate combination of the polymers.

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

In addition, when using the HPMC + Carbomer, it was possible to achieve an excellent sustained release effect using a smaller amount of polymer than when using HPMC alone. Through this, it was confirmed that it is possible to prepare an excellent oral formulation that achieves the sustained release of the drug while improving medication compliance.

The present invention can provide a sustained release pharmaceutical formulation comprising varenicline or a pharmaceutically acceptable salt thereof.

The formulations of the present invention may be conveniently administered once daily.

Claims

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 oral sustained release preparation of claim 1, wherein the preparation is administered once daily.
The method of claim 1, wherein the matrix polymer is hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carbomer, xanthan gum, alginic acid, gelatinized starch, carboxymethylcellulose, polyethylene oxide, propylene glycol alginate, methacrylic acid -Ethyl acrylate copolymer, dimethyl methacrylate methyl methacrylate-methacrylic acid methyl copolymer, methacrylate methacrylate-trimethylammonium ethyl copolymer, methacrylic acid-acrylate ethyl ester copolymer, dimethylaminoethyl methacrylate -Oral sustained release formulation, characterized in that any one selected from the group consisting of methacrylic acid ester copolymers and mixtures thereof.
The oral sustained release preparation of claim 3, wherein the matrix polymer is dissolved in 2 wt% of purified water at 20 ° C. and has a viscosity of 500 to 400,000 mPaS as measured by US Pharmacopeia viscometry.
According to claim 1, wherein the matrix polymer is 3 to 75% by weight based on the total weight of the formulation, oral sustained release formulation.
According to claim 5, wherein the matrix polymer is characterized in that 10 to 45% by weight relative to the total weight of the formulation, oral sustained release formulation.
According to claim 1, wherein the matrix polymer is hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer, xanthan gum, alginic acid, and any one or more selected from the group consisting of gelatinized starch, oral sustained release formulation. .
The method of claim 7, wherein the matrix polymer of the formulation is any one or more selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropyl cellulose, carbomer, xanthan gum, alginic acid, and gelatinized starch,

The matrix polymer is characterized in that 3 to 75% by weight relative to the total weight of the formulation, oral sustained release formulation.
The method of claim 7, wherein the matrix polymer of the formulation is any one or more selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropyl cellulose, carbomer, xanthan gum, alginic acid, and gelatinized starch,

The matrix polymer is 3 to 75% by weight based on the total weight of the formulation,

The matrix polymer is 2% dissolved in purified water at room temperature 20 ℃, characterized in that the viscosity measured by the U.S. pharmacopey viscosity measurement method is 500 to 400,000 mPaS, oral sustained release formulation.
According to claim 7, wherein the formulation comprises hydroxypropylmethylcellulose and carbomer as a matrix polymer, the matrix polymer is included 10 to 45% by weight relative to the total weight of the formulation,

The mixing ratio of hydroxypropylmethylcellulose and carbomer is a weight ratio of hydroxypropylmethylcellulose: carbomer is 1: 0.2 to 1.5, oral sustained-release preparation.
The oral sustained release preparation of claim 1, wherein the preparation further comprises a swelling control polymer.
The method of claim 11, wherein the swelling control polymer is polyvinylacetate, polyvinylacetate-polyvinylpyrrolidone, polyvinylpyrrolidone, poly (vinylpyrrolidone-vinylacetate) copolymer, crospovidone, ethylcellulose, Oral sustained release formulation, characterized in that any one or more selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and mixtures thereof.
The method of claim 1, wherein the formulation comprises hydroxypropylmethylcellulose and carbomer as a matrix polymer, the matrix polymer is 10 to 45% by weight relative to the total weight of the formulation, the hydroxypropylmethylcellulose and carbomer The mixing ratio of hydroxypropylmethylcellulose: carbomer is 1: 0.2 to 1.5 by weight,

The formulation is characterized in that it further comprises polyvinylpyrrolidone, oral sustained release formulation.
The oral sustained release preparation of claim 1, wherein the preparation further comprises a diluent.
The oral sustained release preparation according to claim 14, wherein the diluent is microcrystalline cellulose.
The formulation of claim 15, wherein the formulation comprises (a) 0.1-2.5% by weight of varenicline or a pharmaceutically acceptable salt thereof, relative to the total weight of the formulation,

(b) 10 to 45 weight percent hydroxypropylmethylcellulose, carbomer or mixtures thereof, relative to the total weight of the formulation,

(c) oral sustained release preparation, characterized in that it comprises 40 to 80% by weight of microcrystalline cellulose relative to the total weight of the preparation.
The method of claim 16, wherein the formulation is

Polyvinylacetate, polyvinylacetate-polyvinylpyrrolidone, polyvinylpyrrolidone, poly (vinylpyrrolidone-vinylacetate) copolymer, crospovidone, ethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxy Oral sustained release formulation, characterized in that it further comprises 1 to 20% by weight of any one selected from the group consisting of propylmethylcellulose phthalate, and mixtures thereof.
An oral sustained release preparation for once-daily administration, characterized in that the formulation contains varenicline or a pharmaceutically acceptable salt thereof, characterized by a sustained release matrix system comprising a matrix polymer: When the release of varenicline or its pharmaceutically acceptable salts was eluted under the condition of 900 ± 0.01 N HCl in a basket test at 37 ± 0.5, 100 rpm,

An oral sustained release preparation characterized by eluting at 10-50% per hour, less than 80% at 2 hours, or 90% at 16 hours.
The method of claim 18, wherein the oral sustained release formulation is

Barreniclin free base containing 0.1 to 10% by weight based on the total weight of the formulation,

Hydroxypropylmethylcellulose and carbomer are included as a matrix polymer, the matrix polymer is contained 10 to 45% by weight relative to the total weight of the formulation, the mixing ratio of the hydroxypropylmethylcellulose and carbomer is hydroxypropylmethylcellulose Carbomer has a weight ratio of 1: 0.2 to 1.5,

The formulation is characterized in that it comprises 40 to 80% by weight of microcrystalline cellulose relative to the total weight of the formulation, oral sustained release formulation.