KR20200061244A - Varenicline free base-containing sustained release pharmaceutical formulation and preparation method thereof - Google Patents

Abstract

The present invention relates to: a pharmaceutical composition containing a varenicline free base and an antioxidant carrier; and an oral sustained-release formulation in which the composition is formulated. The formulation of the present invention controls a drug release speed by a sustained-release matrix drug delivery system to exhibit continuous absorption when being administered to the human body, and can improve patient compliance. The formulation of the present invention is the formulation having excellent stability with reduced impurity content.

Description

A sustained-release preparation containing varenicline free base and a method for preparing the same {Varenicline free base-containing sustained release pharmaceutical formulation and preparation method thereof}

The present invention relates to a sustained-release sustained-release preparation containing varenicline and a method for preparing the same, and more particularly, to a sustained-release sustained-release preparation comprising varenicline free base and a method for manufacturing the same. .

Varenicline acts as a partial agonist on 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 binding, and rather to relieve nicotine craving and withdrawal symptoms during smoking cessation by releasing a small amount of dopamine, so it is mainly used as a smoking cessation aid.

Champix® is a commercially available product. Side effects such as nausea, sleep disorders (nightmares, strange dreams, etc.), constipation, bloating, and vomiting are known as common side effects. In particular, nausea is temporary, but in some patients, it is difficult to continue taking the drug, and problems such as nausea persist. In clinical trials, these symptoms increased in a dose-dependent manner, and to solve this, the drug was taken through dose titration. First, 0.5 mg of varenicline was taken once a day for 3 days. Then, from 4 to 7 days, 0.5 mg is taken twice a day. After 12 weeks, as a varenicline, taking 1.0 mg twice a day to maintain effective blood levels and alleviating withdrawal symptoms, there is a disadvantage that medication compliance is remarkably reduced due to this complex dosing method.

The formulation containing varenicline as an active ingredient may be included in the sustained-release pharmaceutical composition in the form of additionally combining varenicline, which is an active ingredient generally exhibiting medicinal properties, with a salt that helps to activate and formulate the drug.

As a free base form, an acid addition salt of L-tartrate salt is known in Korean Patent Registration No. 10-0551184 as a prior art that improves the stability or solubility problem of varenicline, which is a solid-state humidity stability , It has been suggested in the form of improving the high formulation compatibility and solubility with excipients. In addition, in Korean Patent Publication No. 2016-0126697, oxalate hydrate, which improved excellent thermal stability, is presented, and in Korean Patent No. 10-1724301, salicylate, which improves moisture and thermal stability, is presented. It is. In addition, Korean Patent Publication No. 2017-083509 discloses various acid addition salts (Tartrate, Salicylate, Sulphate, Fumarate, Oxalate, Hydrochloride, Hydrobromide, Citrate, Maleate, Succinate, Phosphate, Tosylate, Base, Mesylate, Etc,.) has been suggested, but the prior art contains a varenicline and its salt as a main ingredient, while improving stability and improving drug convenience while improving oral convenience. No mention.

In order to solve the above problems, the present invention is to provide a sustained-release oral solid preparation comprising a varenicline free base as an active ingredient.

The present invention is also intended to provide a pharmaceutical formulation with improved stability by suppressing the production of impurities and the like by adding an antioxidant carrier in a sustained-release oral solid preparation containing a varenicline free base, and a method for manufacturing the same.

In addition, the present invention is to provide a pharmaceutical composition with improved medication convenience and compliance by controlling the rate of drug release.

The inventors of the present invention intend to propose a new stabilization method capable of suppressing the amount of impurities produced by the interaction between the free base and the excipient.

The present invention also provides a sustained release oral pharmaceutical composition capable of sustained absorption over a long period of time.

The present invention provides a pharmaceutical composition comprising a varenicline free base and an antioxidant carrier.

As used herein, "barenicline" may include a compound having a structure represented by Formula 1 below.

The inventors of the present invention have confirmed that the free base of varenicline is very unstable, unlike the salt of varenicline, and sought a method to improve stability to complete the present invention.

The antioxidant carrier included in one embodiment of the present invention is a carrier having a function of protecting varenicline (particularly, varenicline free base) from heat, humidity and oxidation reaction, and is closely mixed with or closed to varenicline. It means a substance that coexists in space and delays or inhibits the oxidation of varenicline. The anti-oxidant carrier of the present invention is not limited as long as it is a substance having antioxidant or antioxidant synergistic properties, for example, tocopherol and esters thereof, ascorbic acid, ascorbyl palitate, tartaric acid, 2,5-dihardoxy benzoic acid , Butylhydroxytoluene, butylhydroxyanisole and propyl gallate.

The antioxidant carrier is in the group consisting of tocopherol and its esters, ascorbic acid, ascorbyl palletite, tartaric acid, 2,5-dihardoxy benzoic acid, butylhydroxytoluene, butylhydroxyanisole and propyl gallate It may be one or more selected. Preferably, the antioxidant carrier may be tartaric acid, propyl gallate, or a mixture thereof, especially considering compatibility with a varenicline free base.

In another embodiment of the present invention provides a pharmaceutical formulation in which the pharmaceutical composition is formulated, preferably an oral sustained release formulation.

The present invention provides a formulation containing improved varenic free base, which has improved stability and is capable of sustained release. The present invention provides a pharmaceutical formulation that improves the convenience of administration by oral administration once a day through a formulation containing varenicline, an antioxidant carrier, and a matrix polymer.

One embodiment of the present invention provides a pharmaceutical preparation comprising a varenicline free base as an active ingredient, a sustained release matrix polymer, a diluent, and a lubricant.

In one embodiment of the present invention, it may be composed of one to two or more polymer combinations to construct a sustained-release matrix system using a matrix polymer, in which case it may be necessary to maintain the structure through gelling in solution phase. . In particular, the matrix for application to varenicline requires fine composition control, because the dosage of the salt allowed for varenicline is small, so the dosage is small and the proportion of polymers and other excipients is relatively high in the prescription, which is greatly affected by them. . In addition, in the case of varenicline or a pharmaceutically acceptable salt thereof, the difference in solubility in water is large depending on the form of the acid addition salt. It is necessary to control the phenomenon that the swelling occurs largely and the surface area is wide, so that drug release is not delayed. In order to solve this, it is necessary to select the type and ratio of the polymer that does not undergo erosion, and at the same time, the polymer capable of properly controlling the degree of swelling It is necessary to use .

The sustained-release matrix polymer is hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carbomer, xanthan gum, alginic acid, luxury starch, carboxymethyl cellulose, polyethylene oxide, propylene glycol alginate, methacrylic acid-acrylic acid ethyl Polymer, dimethylaminoethyl methacrylate-methacrylic acid methyl copolymer, methacrylate-methacrylate trimethylammonium ethyl copolymer, methacrylic acid-ethyl acrylate copolymer, dimethylaminoethyl methacrylate-methacrylic acid Ester copolymers or mixtures thereof, preferably hydroxypropylmethylcellulose, carbomer or mixtures thereof. The matrix polymer may include 3 to 75% by weight, preferably 5 to 50% by weight, preferably 10 to 45% by weight based on the total weight of the formulation. The sustained release effect of the present invention in the above content range may be excellent. The matrix polymer may be dissolved in purified water at 20°C in 2% by weight and have a viscosity value of 1,000 to 200,000 mPaS measured by the United States Pharmacopoeia viscosity measurement method.

When the matrix polymer is dissolved at 2% by weight in purified water at room temperature (20°C), according to a process viscosity measurement method such as NF/EP/JP, 1,000 to 200,000 mPaS, preferably 3,000 to 200,000 mPaS, more preferably It may have a viscosity of 3,500 to 200,000 mPaS, and the viscosity may be appropriately adjusted within the above range according to a desired drug release rate, or two or more different viscosity polymers may be mixed and 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.

One embodiment of the present invention includes a hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer, xanthan gum, alginic acid, and a matrix polymer selected from the group consisting of gelatinous starch, and the matrix polymer is the total weight of the formulation Compared to 10 to 45% by weight, the mixing ratio of the hydroxypropylmethylcellulose and carbomer may provide a pharmaceutical formulation having a weight ratio of hydroxypropylmethylcellulose:carbomer of 1:0.2 to 1.5.

Diluents can be prepared by being included in the preparation of the sustained-release preparations 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.

The pharmaceutically acceptable additives are referenced in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington 6 edition and previous editions, which are incorporated herein by reference.

The pharmaceutical formulation may be formulated by a dry granulation method.

In one embodiment of the present invention, a formulation containing a varenicline free base, characterized by a sustained-release matrix system comprising a matrix polymer, is an oral sustained-release preparation for once-daily administration having the following characteristics: , When the total release of varenicline is 37℃±0.5℃, in the experiment of dissolution under the condition of 900 ml of 0.01 N HCl in a basket test method of 100 rpm, 10 to 50% in 1 hour, 80 in 2 hours It provides an oral sustained-release preparation, characterized in that it is eluted at less than 90% and more than 90% in 16 hours.

Another embodiment of the present invention can provide a sustained-release preparation for oral use, coated with a coating base containing both titanium dioxide and lecithin, including a varenicline free base as an active ingredient. The coating base material comprising titanium dioxide and lecithin may preferably be an Opadry AMB 80W41101 green coating base material.

The content of the total coating component may include 0.5 to 10% by weight of the total composition of the tablet, preferably 1 to 6% by weight, preferably 2 to 4% by weight. When the content is in the above range, while the coating effect of uncoated tablets is excellent, the antioxidant effect is excellent.

In one embodiment of the present invention, oral sustained release preparations containing varenicline free base may be provided in a container containing a deoxidizing agent. One embodiment of the present invention can provide a packaging method of a formulation containing a varenicline free base, which is stored in a container containing an oxygen scavenger.

The deoxidant is present in the container packaging state together with the varenicline-containing agent in an enclosed space, and is not limited as long as it is a substance having the effect of reducing the generation of impurities due to the oxidation reaction of the active ingredient by removing residual residue in the container, but is not limited. For example, iron is used as the inorganic system, and the organic system may be one or more substances selected from the group consisting of ascorbic acid and catechol components. In particular, by adding a deoxidizing agent in the packaging container state, since oxygen is removed from the outside over a long period of time or chemically removed by itself by any reaction, the removal rate of oxygen is very high, so it can maintain a state close to oxygen free for a long time. Can greatly contribute to the improvement of long-term storage stability

The deoxidizing agent may include iron as an inorganic system, ascorbic acid, catechol or a mixture thereof as the organic system, or may include both the inorganic system and the organic system.

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 comprises 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. 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 necessarily 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 pharmaceutical composition according to the present invention may be formulated into oral dosage forms, specifically, tablets, hard capsules, soft capsules, granules, powders, etc., preferably tablets and hard capsules.

Hard capsules and tablets according to the invention, in addition to varenicline and its salts and antioxidant carriers and hydrophilic polymers, may further include pharmaceutically acceptable additives such as diluents, disintegrants, adsorbents, lubricants, binders, etc. have.

Oral sustained-release preparations of the present invention are standard techniques and manufacturing methods generally known in the art (e.g., Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form, Mark Gibson, Informa Healthcare, 2009 ). It can be prepared by dry granulation, for example, varenicline, one or more diluents and one or more matrix polymers, and one or more binders are mixed together with a lubricant. Before mixing, each component or mixture itself may be passed through a mesh screen, for example, a 290-1000 μm mesh screen. The lubricant can also be sieved and mixing is continued until a homogeneous mixture is added to the mixture. 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. After further mixing, it is compressed into tablets.

In addition, the pharmaceutical composition of the present invention can be prepared using a wet granulation method. For example, after mixing varenicline or its salt with one or more diluents and one or more matrix polymers with a lubricant, granulation is performed by adding a binder solution in which the binder is dissolved in a solvent for pharmaceutical class 3 such as purified water or ethanol. Sour, wet granules are dried and sized. Residues of excipients, lubricants and lubricants are added to the milled granules and the resulting homogeneous mixture is compressed into tablets after mixing. Dry mixing and wet granulation methods can be modified by techniques and manufacturing methods known in the art, including the order of addition of ingredients and mixing prior to their screening and compression into tablets.

In the above manufacturing method, 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 to the naked portion. 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 present invention can improve the stability of the sustained-release preparation of varenicline free base in which stability is particularly a problem.

It can increase the stability of varenicline free base and reduce the amount of related substances.

The present invention is to provide a sustained release oral solid preparation containing a varenicline free base as an active ingredient.

The present invention can also provide a pharmaceutical formulation with improved stability by suppressing the production of impurities and the like by adding an antioxidant carrier in a sustained-release oral solid preparation containing varenicline free base.

The present invention can provide a pharmaceutical composition with improved medication convenience and compliance by controlling the rate of drug release.

The present invention can propose a new stabilization method that can suppress the amount of impurities generated by the interaction between the free base and the excipient.

The present invention can provide a sustained release oral pharmaceutical composition capable of sustained absorption over a long period of time.

Figure 1 shows the dissolution pattern of the formulation containing the antioxidant carrier (Comparative Example 1) and the formulation containing the antioxidant carrier (Examples 1 and 2).
Figure 2 shows the results confirming the amount of related substances generated in the product (Example 3) and the product (Comparative Example 3) containing no deoxidizer.
Figure 3 shows the results confirming the amount of the related substances generated by the formulation prepared by the dry granulation method (Example 4) and the wet granulation method (Comparative Example 4).

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.

[Dissolution test]

The formulation formulated below was tested for elution by the Korean Pharmacopoeia 10th revision dissolution test method. The elution method used a basket method, the stirring speed was 100 rpm, and the elution temperature was performed at 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 (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 at that time.

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 ℃

Manufacturing example  One. Bareniclin Free base  Contain As an antioxidant carrier  Preparation of sustained-release matrix containing antioxidants

A sustained-release matrix tablet containing a varenicline free base and containing an antioxidant as an antioxidant carrier was prepared according to the composition table in Table 1 below. Varenicline, microcrystalline cellulose, hydroxypropyl methylcellulose, carbomer, light anhydrous silicic acid, and antioxidants were filtered and mixed with No. 30 sieve, then added with magnesium stearate to make a slug using a sweeper, and then No. 25 body The granules were assembled using to prepare dry granules, and then, after the final mixing of the extra fluidizing agent and the lubricant, the tablets were compressed.

Classification ingredient Comparative Example 1 Comparative Example 2 Example 1 Example 2 Content (mg) Content (mg) Content (mg) Content (mg) Pharmacologically active ingredient Barenicline free base 2.0 2.0 2.0 2.0 Matrix polymer Hydroxypropylmethylcellulose (2208 K200M) 20.0 20.0 20.0 20.0 Carbopol 71G® 20.0 20.0 20.0 20.0 Water-insoluble diluent Microcrystalline cellulose
(PH 102) 155.0 150.0 150.0 154.0 Antioxidant Tartaric acid - - 5.0 - Profile gallate - - - 1.0 Citric acid - 5.0 - - Fluidizing agent Light anhydrous silicic acid 1.0 1.0 1.0 1.0 Lubricant Magnesium stearate 2.0 2.0 2.0 2.0 Tablet total weight 200.0 200.0 200.0 200.0

Dissolution experiment was conducted using the formulation having the composition of Table 1. As can be seen from the results of the dissolution test in Table 2 below, even if the antioxidant carrier was included, there was no change in dissolution, and it was suitable for use as an oral sustained-release preparation.

Time (hr) Comparative Example 1 Example 1 Example 2 0 0.0 0.0 0.0 0.5 23.5 19.1 18.5 One 33.9 30.1 28.3 2 48.2 45.6 42.9 4 68.3 66.6 63.7 8 89.2 89.2 85.9 10 93.9 93.9 91.7 12 96.7 96.1 94.8 16 98.5 98.1 97.9

HDPE Bottles were packaged for Comparative Examples 1 and 2 and Examples 1 and 2, and stored in a harsh environment (60° C.) to measure the amount of impurities at the beginning and after 2 weeks. The results are shown in Table 3 below. It can be seen that the amount of total impurities and individual impurities in Examples 1 and 2 was improved by more than 2 times as compared to Comparative Example 1 in which no antioxidant was added as an antioxidant carrier. In addition, as can be seen from the results in Table 3, Examples 1 and 2 significantly reduced the impurity content compared to (Comparative Example 2) when citric acid, which is well known as an antioxidant, was used.

Time points Comparative Example 1 Comparative Example 2 Example 1 Example 2 Total Impurity (%) Single Max Impurity (%)
RRT 1.83 Total Impurity (%) Single Max Impurity (%)
RRT 1.83 Total Impurity (%) Single Max Impurity (%)
RRT 1.83 Total Impurity (%) Single Max Impurity (%)
RRT 1.83 Initial 0.08 0.03 0.14 0.06 0.15 0.06 0.15 0.06 60℃, 1 week 0.39 0.39 0.57 0.46 0.24 0.17 0.24 0.17 60℃, 2 weeks 0.66 0.60 1.00 0.88 0.36 0.27 0.38 0.25

Manufacturing example  2. Coating formulation compatibility test

As a result of conducting a formulation compatibility test for each component of the coating composition and composition widely used in the pharmaceutical industry with the varenicline organic base as an active ingredient, it was found that the blending compatibility with the varenicline organic base was unintentionally different for each coating agent. As a coating agent, various products marketed as Opadry ^® by Colorcon Korea were used. The results are as shown in Table 4 below, and it was confirmed that the formulation compatibility of the Opadry AMB 80W41101 green coating base of the Opadry AMB series containing titanium dioxide and lecithin and the varenicline free base was excellent. In the case of the rest of the coating agent, it was confirmed that an effect of increasing the decomposition of the active ingredient appeared.

Ingredients Mixing ratio
(Active ingredient: Additive) Early 60℃, 1 week Total Impurity
(%) Single Max Impurity
(%)
RRT 1.83 Total Impurity
(%) Single Max Impurity
(%)
RRT 1.83 Barenicline free base One 0.03 0.00 0.04 0.00 + Opadry I 03B90547 BLUE 1:5 0.00 0.00 0.33 0.24 + Opadry I 03K12415 Yellow 1:5 0.00 0.00 2.32 0.23 + Opadry II 85F150004 Red 1:5 0.03 0.00 0.20 0.16 + Opadry AMB 80W41101 GREEN 1:5 0.04 0.00 0.08 0.04 + Polyethylene glycol 400 1:1 0.20 0.16 52.00 33.00 + Titanium dioxide 1:1 0.03 0.00 0.04 0.00

As can be seen from Table 4, when using Opadry AMB 80W41101 GREEN, it can be seen that the generation of related substances was the lowest. In addition, unlike the varenicline free base, in the case of a preparation containing varenicline tartrate or varenicline oxalate, the above formulation did not show a pattern, and similar results were used with any Opadry.

Manufacturing example  3. Bareniclin Free base  Contain As an antioxidant carrier Courage Deoxidizer  Western matrix manufacturing including

A sustained-release matrix tablet containing varenicline free base was prepared according to the composition table in Table 5 below. Varenicline, microcrystalline cellulose, hydroxypropyl methylcellulose, carbomer, light anhydrous silicic acid, and antioxidants were filtered and mixed with No. 30 sieve, then added with magnesium stearate to make a slug using a sweeper, and then No. 25 body The granules were assembled using to prepare dry granules, and then, after the final mixing of the extra fluidizing agent and the lubricant, the tablets were compressed. As a coating agent, an Opadry AMB (Anti-moisture barrier)-based coating composition was used, and a coating solution was prepared by homogeneously dispersing the coating solution on the surface of a tablet in a coating machine and drying it. After filling this with 30 tablets of 40 ml HDPE bottle, the self-reactive oxygen absorber (H-type) commercially available from Lipmen Co., Ltd. as a deoxidizing agent was placed in a container and covered with a cap to seal it. It was prepared and prepared in Comparative Example 3 sealed without containing an oxygen scavenger.

Classification ingredient Comparative Example 3 Example 3 Content (mg) Content (mg) Pharmacologically active ingredient Barenicline free base 2.0 2.0 Matrix polymer Hydroxypropylmethylcellulose (2208 K200M) 25.0 25.0 Carbopol 71G® 20.0 20.0 Water-insoluble diluent Microcrystalline cellulose
(PH 102) 150.0 150.0 Fluidizing agent Light anhydrous silicic acid 1.0 1.0 Lubricant Magnesium stearate 2.0 2.0 Total weight 200.0 200.0 Coating Opadry AMB 80W41101 8.0 8.0 Total weight of coated tablets 208.0 208.0 Packing container HDPE bottle (40ml) HDPE bottle
(40ml) Deoxidizer Not included Oxygen absorber H-type, 1 packet

For Comparative Examples 3 and 3, HDPE bottles were 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 6 and FIG. 2 below. It can be seen that compared to Comparative Example 3 in which no oxygen scavenger was added, the amount of total impurities and individual impurities in Example 3 was improved four times or more.

Time points Comparative Example 3 Example 3 Total Impurity (%) Single Max Impurity (%)
RRT 1.83 Total Impurity (%) Single Max Impurity (%)
RRT 1.83 Initial 0.03 0.00 0.03 0.00 7days 1.89 1.29 0.52 0.32

Manufacturing example  4. Bareniclin  Or a method for preparing a sustained release matrix containing a salt thereof

A sustained-release matrix tablet containing varenicline or a salt thereof was prepared according to the composition table shown in Table 7 below. In the case of Comparative Example 4, barenicline, 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. It was tabletted after lubricating by adding hydroxypropyl methylcellulose, carbomer, extra light anhydrous silicic acid and magnesium stearate to the drafted wet granules. In contrast, in the case of Example 4, after preparing the dry granules as in Example 1, final tableting was performed to prepare a sustained release matrix.

Classification ingredient Comparative Example 4 Example 4 Content (mg) Content (mg) Pharmacologically active ingredient Barenicline free base 2.0 2.0 Matrix polymer Hydroxypropylmethylcellulose (2208 K200M) 30.0 30.0 Carbopol 71G® 20.0 20.0 Water-insoluble diluent Microcrystalline cellulose
(PH 102) 138.0 145.0 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

In addition, for Comparative Examples 4 and 4, the amount of impurities was measured immediately after the preparation was completed, and the results are shown in Table 8 and FIG. 3 below. In comparison with Comparative Example 4, it was confirmed that the amount of impurities disappeared immediately after preparation in Example 4, and the dry granulation method was adopted in Example 4, and a binding solvent was used in Comparative Example 4, and the amount of impurities in the manufacturing process was It was confirmed that it increased significantly.

Time points Comparative Example 4 Example 4 Total Impurity (%) Single Max Impurity (%)
RRT 1.83 Total Impurity (%) Single Max Impurity (%)
RRT 1.83 Initial 1.54 1.19 0.00 0.00

Claims (23)

A pharmaceutical composition comprising varenicline free base and an antioxidant carrier. The method of claim 1, wherein the antioxidant carrier is tocopherol and its esters, ascorbic acid, ascorbyl paltate, tartaric acid, 2,5-dihardoxy benzoic acid, butylhydroxytoluene, butylhydroxyanisole and propyl Pharmaceutical composition, characterized in that at least one selected from the group consisting of gallate. 3. The pharmaceutical composition according to claim 2, wherein the antioxidant carrier is tartaric acid, propyl gallate, or a mixture thereof. A pharmaceutical formulation in which the composition according to claim 1 is formulated. The pharmaceutical formulation of claim 4, wherein the pharmaceutical formulation is an oral sustained release formulation. The method of claim 5, wherein the pharmaceutical formulation
Barenicline free base as an active ingredient,
A pharmaceutical formulation comprising a sustained release matrix polymer, a diluent, and a lubricant. The method of claim 5, wherein the sustained-release matrix polymer is hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carbomer, xanthan gum, alginic acid, gelatinous starch, carboxymethyl cellulose, polyethylene oxide, propylene glycol alginate, Methacrylic acid-acrylic acid ethyl polymer, methacrylic acid dimethylaminoethyl-methacrylic acid methyl copolymer, methacrylic acid ethyl-methacrylated trimethylammonium ethyl copolymer, methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl meta Pharmaceutical preparations which are acrylate-methacrylic acid ester copolymers or mixtures thereof. The pharmaceutical formulation of claim 7, wherein the sustained-release matrix polymer is hydroxypropyl methylcellulose, carbomer, or a mixture thereof. The pharmaceutical formulation of claim 6, wherein the sustained-release matrix polymer contains 5 to 50% by weight based on the total weight of the formulation. The pharmaceutical formulation of claim 6, wherein the matrix polymer is dissolved in purified water at 20°C in 2% by weight and has a viscosity value of 1,000 to 200,000 mPaS measured by the US Pharmacopoeia Viscosity Method. The method of claim 6, wherein the sustained-release matrix polymer of the formulation is any one or more selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer, xanthan gum, alginic acid, and luxury starch,
The sustained-release matrix polymer contains 10 to 45% by weight based on the total weight of the formulation,
The mixing ratio of the hydroxypropyl methylcellulose and carbomer is characterized in that the weight ratio of hydroxypropyl methyl cellulose: carbomer is 1:0.2 to 1.5, pharmaceutical preparation. The pharmaceutical formulation of claim 4, wherein the pharmaceutical formulation is formulated by a dry granulation method. A formulation containing varenicline free base, characterized by a sustained-release matrix system comprising a matrix polymer, is an oral sustained release formulation for once-daily administration having the following characteristics:
When the total release of varenicline is 37°C 0.5°C?, in the experiment of elution under the conditions of 900 N medium of 0.01 N HCl by a basket test method of 100 rpm,
Oral sustained-release preparations characterized by eluting at 10-50% per hour, less than 80% at 2 hours, and at least 90% at 16 hours. Includes free varenic base as an active ingredient,
Oral sustained-release preparations coated with a coating base comprising titanium dioxide and lecithin. The oral sustained release preparation according to claim 14, wherein the pharmaceutical preparation comprises a sustained release matrix polymer, a diluent, and a lubricant. The method of claim 15, wherein the sustained-release matrix polymer is hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carbomer, xanthan gum, alginic acid, gelatinous starch, carboxymethyl cellulose, polyethylene oxide, propylene glycol alginate, Methacrylic acid-acrylic acid ethyl polymer, methacrylic acid dimethylaminoethyl-methacrylic acid methyl copolymer, methacrylic acid ethyl-methacrylated trimethylammonium ethyl copolymer, methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl meta Oral sustained-release preparations, which are acrylate-methacrylic acid ester copolymers or mixtures thereof. According to claim 15, Oral sustained-release preparations containing the matrix polymer 10 to 45% by weight relative to the total weight of the formulation. The oral sustained release preparation according to claim 16, wherein the sustained release matrix polymer is hydroxypropyl methylcellulose, carbomer, or a mixture thereof. The oral sustained release preparation according to claim 14, wherein the oral sustained release preparation is formulated by a dry granulation method. The sustained release preparation according to claim 14, wherein the preparation further comprises an antioxidant carrier. Pharmaceutical formulation characterized in that the oral sustained-release preparation containing the varenicline free base is stored in a container containing a deoxidizing agent. A method for packaging a formulation comprising varenicline free base for storing the formulation of claim 4, 13 or 14 in a container containing a deoxidizer. 23. The method of claim 22, wherein the deoxidizing agent includes iron as an inorganic system, ascorbic acid, catechol or a mixture thereof as an organic system, or a varenicline free base containing both the inorganic system and the organic system. Packaging method of the preparation to be done.

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