KR20200034293A - Varenicline formulation for controlled-release - Google Patents

Abstract

The present invention is a core containing varenicline or a pharmaceutically acceptable salt thereof as an active ingredient; And a controlled release layer comprising a plurality of active ingredient eluting materials having different dissolution levels formed on the core, wherein the controlled release layer comprises a first coating layer comprising a first active ingredient eluting material, and a second coating layer. It comprises a second coating layer comprising an active ingredient eluting material, the first coating layer is formed between the core and the second coating layer, the content ratio of the core and the first coating layer and the second coating layer is 60 to 80 : 1 to 10: Provides a varenicline formulation for controlled release in a weight ratio of 10 to 40 and a method for manufacturing the same.

Description

Varenicline formulation for controlled release {Varenicline formulation for controlled-release}

The present invention relates to a varenicline formulation for controlled release and a method for manufacturing the same.

Varenicline having the structure of Formula 1 is compound name 5,8,14-triazatetracyclo [10.3.1.0 ^2,11 .0 ^4,9 ] -hexadeca-2 (11), 3, 5,7,9-pentaene is a compound that is a drug that modulates the function of a choline receptor by binding to a nerve nicotinic acetylcholine receptor.

[Formula 1]

Varenicline is an inflammatory bowel disease such as ulcerative colitis, necrotosis, Crohn's disease, irritable bowel syndrome, spastic muscular dystonia, chronic pain, acute pain, celiac sprue, appendicitis, vasoconstriction, anxiety, panic disorder , Depression, bipolar disorder, autism, sleep disorder, parallax syndrome, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, hyperphagia, anorexia, obesity, cardiac arrhythmia, gastric hypersecretion, ulcers, chromocytoma Dependence and addiction to progressive supranuclear palsy, nicotine, alcohol, benzodiazepines, barbiturates, opioids or cocaine, headache, migraine, stroke, traumatic brain injury (TBI), obsessive compulsive disorder (OCD), psychosis, Huntington's chorea, delayed Dyskinesia, hyperactivity disorder, reading disorder, schizophrenia, multiple infarction dementia, age-related cognitive decline, epilepsy including epileptic seizure epilepsy, Alzheimer's senile dementia, Parkinson's disease, Uiryeok deficit hyperactivity disorder (ADHD) and can be used in the treatment of Tourette's syndrome.

Formally, salts are developed to meet physicochemical criteria such as good solubility, good stability, and processability into tablet formulations. The pharmaceutically acceptable salt of varenicline may be used without any limitation as long as it is commonly used in the art, and metal salts such as varenicline tartrate, oxalate, succinate, hydrochloride, sodium salt, potassium salt, calcium salt, etc. Or it may be an ammonium salt. For example, the salt of varenicline is oxalate. Varenicline, or a pharmaceutically acceptable salt thereof, is useful for modulating the function of choline receptors by binding to neuron nicotinic acetylcholine specific receptor sites. Thus, varenicline or a pharmaceutically acceptable salt thereof can be usefully used to treat, prevent or ameliorate dependence and addiction to nicotine or tobacco products.

However, a tablet formulation containing varenicline or a pharmaceutically acceptable salt thereof has a small ratio of the main component to its weight, and is a formulation that differs greatly in stability depending on the mixing of granules and the particle size of the main component when tableting. In addition, it shows a decrease in stability in the state of exposure to moisture, and thus, it is an important formulation for formulation management and moisture management in varenicline oxalate-containing compositions.

Varenicline or chamber fixes a commercially available product containing a pharmaceutically acceptable salt thereof (Champix ^®, Pfizer) or Chan ticks (Chantix ^®, Pfizer) has, and uses of this product, the dose bar for 3 days Day Replenishing Clean 0.5 mg is taken once a day, and from 4 to 7 days, 0.5 mg is taken twice a day. Thereafter, by taking 1.0 mg of varenicline twice a day until the 12th week, the effective blood level is maintained and the withdrawal symptoms are relieved.

To overcome this, the development of a sustained release agent was required, and related technologies are disclosed in prior patent documents 1 to 3.

On the other hand, in the case of a matrix sustained-release formulation that is conventionally performed in the art, it has a large effect on the dissolution of varenicline at a low dose depending on the ratio of the polymer and other excipients. In addition, if the selection of the excipient is not correct because the varenicline is a BCS class I drug with a very high solubility in pharmacological properties, the drug may become eroded or swelled quickly, resulting in a large surface area. There is a problem that it is not delayed release and is released quickly (see precedent patent document 4).

Patent Document 1: WO 99/35131 (released on July 15, 1999) Patent Literature 2: Korean Patent Publication No. 2016-0126696 (released on Nov. 02, 2016) Patent Document 3: WO 2003/045437 (published on June 5, 2003) Patent Literature 4: Korean Patent Publication No. 2018-0058644 (published on June 1, 2018)

In order to solve the above problems, the present inventors proceeded to develop a sustained-release formulation using a release mechanism with a low production and low influence on the release of a low-dose drug by an excipient, as compared to a sustained-release tablet of a matrix type. Came to completion.

That is, one object of the present invention is to provide a varenicline preparation for controlled release containing varenicline or a pharmaceutically acceptable salt thereof as an active ingredient and exhibiting a sustained release pattern.

Another object of the present invention is to provide a method for preparing a varenicline formulation for controlled release that exhibits a sustained release pattern through control of a manufacturing process.

One aspect of the present invention, a core containing varenicline or a pharmaceutically acceptable salt thereof as an active ingredient; And a controlled release layer comprising a plurality of active ingredient elutable materials having different dissolution levels for the active ingredient formed on the core, wherein the controlled release layer comprises a first coating layer comprising a first active ingredient elutable material. And, a second coating layer comprising a second active ingredient eluting material, wherein the first coating layer is formed between the core and the second coating layer, and the content ratio of the core and the first coating layer and the second coating layer Provides a varenicline formulation for controlled release in a weight ratio of 60 to 80: 1 to 10: 10 to 40.

Another aspect of the present invention, a core containing a varenicline (varenicline) or a pharmaceutically acceptable salt as an active ingredient, a first coating layer comprising a first active ingredient eluting substance, and a second active ingredient elution A second coating layer comprising a sex material, the first coating layer is formed between the core and the second coating layer, the second active ingredient of the second coating layer eluent material, ethyl cellulose (a) and A bicomponent mixture of hydroxypropylcellulose (b) or a bicomponent mixture of ethylcellulose (a) and hydroxypropylmethylcellulose (b '), wherein the content ratio of the core and the first coating layer and the second coating layer is 60 to 80 : 1 to 10: a weight ratio of 10 to 40, the blending ratio of the binary mixture ((a) :( b) or (a) :( b ')) is 2.5: 1 to 1.7: 1 (w / w) Provides a sustained-release capsule.

Another aspect of the present invention, preparing an active amount of varenicline or a pharmaceutically acceptable salt thereof, and dry granules of a pharmaceutical additive as an active ingredient; Sieving the dry granules and adding a disintegrant and a lubricant to mix; Tableting the mixture in the form of a multi-unit spheroidal tablet (MUST) to form a core; And applying a solution for controlled release containing an eluent to the surface of the core and forming a controlled release layer, wherein the controlled release layer is separable comprising a first active ingredient eluent in the core. Forming a first coating layer by coating a coating solution; Coating a sustained-release coating solution containing a second active ingredient eluting material on the first coating layer and obtaining a sustained-release coated formulation with a second coating layer; And filling the sustained-release coated formulation into a capsule base to form a capsule, thereby providing a method for manufacturing a varenicline formulation for controlled release.

The controlled release varenicline preparation according to an aspect of the present invention enables sustained drug absorption in vivo through a sustained release pattern of a pharmacologically active ingredient, and improves medication compliance without side effects even when taken once a day. You can.

1 is a schematic diagram of a sustained-release capsule 100, which is a sustained-release coating layer mini-tablet (MUST, 110) according to an embodiment of the present invention.
FIG. 2 is a line chart showing the dissolution profile of the sustained release capsule 100 of Examples 1 to 4 of the present invention using the USP device 2 paddle method.
Figure 3 is a line chart showing the dissolution profile of the capsules of Comparative Examples 1 to 9 of the present invention.
Figure 4 is a line chart showing the dissolution profile of the sustained-release capsule 100 of Examples 1 to 4 of the present invention using the USP device 2 paddle method, depending on the rotational speed.

One embodiment of the present invention relates to a varenicline formulation for controlled release containing varenicline or a pharmaceutically acceptable salt thereof as an active ingredient. An exemplary aspect chamber fix (Champix ^®, Pfizer) and comparison to be sustained drug absorption is possible and to improve the medication compliance, without side effects in doses once daily in a living body over a sustained release pattern of the pharmacologically active ingredient Provided is a multi-particle controlled release system.

Justice

Unless otherwise defined, all terms used in the present invention have the same meaning as commonly understood by those skilled in the art.

In one example, the terms “controlled release” and “sustained release” as used in the present invention have conventional meanings understood by those skilled in the art and include, by way of non-limiting example, controlled release of a drug from a dosage form over a long period of time. . For example, in some embodiments, a controlled release or sustained release formulation is one that has a substantially longer release rate than that of a comparable immediate release form. The two terms can be used interchangeably.

As used herein, the term “pharmaceutically acceptable salt” refers to salts that are biologically or otherwise undesirable and retain the biological effectiveness and properties of the compounds of the preferred embodiment. In many cases, the compounds of the preferred embodiments are capable of forming acids and / or bases due to the presence of amino and / or carboxyl groups or similar groups. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid , p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed of inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; Ammonium, potassium, sodium, calcium and magnesium salts are particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., specifically isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.

In some aspects, the "varenicline-based" may refer to a varenicline-based or pharmaceutically acceptable salt thereof, for example, varenicline tartrate, varenicline salicylate, varenicline sulfate, bar Lenicline Fumarate, Barenicline Oxalate, Barenicline Hydrochloride, Barenicline Hydrobromide, Barenicline Citrate, Barenicline Malate, Barenicline Succinate, Barenicline Phosphate, Barenicline Tosyl It may be at least one selected from the group consisting of a rate, a varenicline base, and a varicline mesylate. Specifically, it may refer to oxalate hydrate. It has the following chemical structure. Oxalate monohydrate is more preferred.

[Formula 2]

[In the above formula, n is 0.5 to 3.]

In some further aspects, the “barenicline or a pharmaceutically acceptable salt thereof” may be in the form of dry granules. The angle of repose of the granules may be within about 40 °.

The term “Multi-Unit Spheroidal Tablet (MUST)” can be a mini tablet in a spherical or near spherical shape. The mini tablet may be a tablet having a small size. The mini tablet may have a diameter of about 1 mm to about 10 mm, about 1 mm to about 8 mm, about 1 mm to about 6 mm, about 1 mm to about 4 mm, or about 1.5 mm to about 3 mm.

The term “core” can be used interchangeably with the term “core”. The core may include a pharmacologically active ingredient varenicline or a pharmaceutically acceptable salt thereof.

In some aspects, the dissolution test can be performed by USP paddle method. The dissolution test can be performed in the presence of an artificial medium. The artificial intestinal fluid may have a pH of about 6.5 to about 7.0, or about 6.7 to about 6.9. The dissolution test may be performed at a speed of 100 to 150 revolutions per minute (rpm). The dissolution test may be performed at about 30 ° C to about 40 ° C, about 32 ° C to about 40 ° C, about 34 ° C to about 40 ° C, about 36 ° C to about 40 ° C, or about 37 ° C.

In the controlled release varenicline formulation, 70% or more within about 12 hours and 90% or more within about 18 hours of active ingredient may be eluted during the dissolution test.

As used herein, “subject” is a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or bird, such as a chicken, as well as any other spine. Means an animal or an invertebrate.

“Treatment” as used in the present invention means administering a pharmaceutical composition / formulation for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" means reducing the likelihood of developing a disease in a patient by treating a patient who is not yet suffering from, but is at risk of, or at risk of becoming a disease. The term "therapeutic treatment" means administering a therapeutic agent to a patient who is already suffering from the disease.

The compositions or formulations described herein are preferably provided in unit dosage form. As used herein, "unit dosage form" is a composition / formulation containing an amount of a compound suitable for administration to an animal, preferably a mammalian subject, in a single dose, according to appropriate medical practice. However, a single or unit dosage form preparation does not mean that the dosage form is administered once a day or once per course of treatment, or that the unit dosage form contains all doses to be administered at one time. The dosage form is considered to be administered once, twice, three times or more per day, and may be administered multiple times during the course of treatment, even if single administration is not specifically excluded. In addition, multiple unit dosage forms can be administered at substantially the same time to achieve the intended total amount (e.g., two or more tablets can be swallowed by the patient to achieve a complete dose). Those skilled in the art will recognize that the formulation does not specifically consider the entire course of treatment, and the decision is made by those skilled in the art of treatment rather than formulation.

Controlled release formulation

One embodiment of the present invention relates to a varenicline preparation for controlled release comprising varenicline or a pharmaceutically acceptable salt thereof as an active ingredient in a core, and when administered orally, the formulation is controlled release of the active ingredient Have a profile In some embodiments, the varenicline formulation for controlled release comprises a core containing varenicline or a pharmaceutically acceptable salt thereof as an active ingredient, and a plurality of different elution degrees for the active ingredient formed on the core are different. It includes a controlled-release layer containing an active ingredient eluting substance, The controlled release layer includes a first coating layer comprising a first active ingredient eluting material, and a second coating layer comprising a second active ingredient eluting material, wherein the first coating layer comprises the core and the second It is formed between the coating layers and provides a sustained release controlled release profile.

1 is a schematic diagram of a sustained-release capsule 100, which is a sustained-release coating layer mini-tablet (MUST, 110) according to an embodiment of the present invention. Referring to Figure 1, the controlled release varenicline formulation 100 of the present invention is provided in the form of a sustained release capsule as an example, the sustained release capsule is a core, and a first coating layer surrounding the core (terminal endothelium) It is composed of a multi-coating structure of a second coating layer (which is used interchangeably with the term western coating layer) surrounding the first coating layer).

In this embodiment of the invention, the core may comprise one or more selected from mini-tablets, pellets and tablets in the form of a Multi-Unit Spheroidal Tablet (MUST), in some such embodiments, active It may be in the form of a multi-unit spheroidal tablet (MUST) containing varenicline or a pharmaceutically acceptable salt as an ingredient. The multi-dose spherical tablet (MUST) type of mini-tablet is preferable because it can minimize the effect on local drug concentration because the GI passage time and release profile are less volatile and the drug load is further dispersed.

In this embodiment of the present invention, the content ratio of the core and the first coating layer and the second coating layer is, for example, 60 to 80: 1 to 10: 10 to 40 by weight, or 75 to 82: 3 to 5: 15 to 15 It may be a weight ratio of 20. Optimizing the sustained release pattern in which the second coating layer dissolves primarily in the content range, and secondly, the first coating layer is combined with water molecules penetrating the second coating layer to elute the active ingredient contained in the core. Can be provided.

In addition, the first active ingredient eluting substance is a substance eluted under the same pH condition as the body, and the second active ingredient eluting substance is eluted than the first active substance eluting substance under the same pH condition in the body. It is preferably a slow material.

The first active ingredient eluting material of the first coating layer satisfying the above-described conditions is, for example, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropyl cellulose (HPC) -L), starch (Starch), gelatin (gelatin), ethyl cellulose (EC), and any combination thereof. In some such embodiments, the first active ingredient eluent may be hydroxypropylmethylcellulose or hydroxypropylcellulose.

In addition, the second active ingredient eluent material of the second coating layer satisfying the above-described conditions, for example, hydroxypropyl methyl cellulose (hydorxyprophyl methylcellulose, HPMC), hydroxypropyl cellulose (hydroxypropyl cellulose, HPC), hydroxyethyl Cellulose (hydroxyethyl cellulose, HEC), ethylcellulose (EC), pregelatinized starch, carboxymethylcellulose, polyethylene oxide, propylene glycol alginate, methacrylic acid Copolymer S (Eudragit S-100), methacrylic acid copolymer L (Eudragit L-100), methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer or any of these Two or more kinds may be selected from the group consisting of a combination of. In some such embodiments, the second active ingredient eluable material of the second coating layer may be a binary mixture of ethylcellulose and hydroxypropylcellulose, or a binary mixture of ethylcellulose and hydroxypropylmethylcellulose. . In one embodiment, the binary component mixture may include ethylcellulose and a mixture of hydroxypropylcellulose or hydroxypropylmethylcellulose in a weight ratio of 2.5: 1 to 1.7: 1 to provide a desired dissolution rate. desirable.

The first active ingredient eluent material of the first coating layer used in the present invention and the second active ingredient eluent material of the second coating layer are, for example, greater than 1: 2.76 to 1: 4.34 by weight It may be, in particular, may have a weight ratio of 1: 3.16 to 1: 3.95. In the above range, it is more preferable to be able to provide a varenicline preparation which is a controlled release form of at least once daily administration and exhibits medication compliance.

The core used in the present invention is a diluent, disintegrant, binder, lubricant, surfactant, anti-oxidant, preservative, and stable It may further include one or more excipients selected from the group consisting of a stabilizer.

The diluent is selected from the group consisting of mannitol, microcrystalline cellulose, hydrate, cellulose and its derivatives, dibasic or tribasic calcium phosphate, erythritol, low-substituted hydroxypropyl cellulose, pregelatinized starch, sorbitol and xylitol. It may be more than a species. For example, the diluents are microcrystalline cellulose and lactose hydrate. The content of each diluent may be about 1% to about 80% by weight, about 10% to about 70% by weight, or about 20% to about 60% by weight relative to the core.

The disintegrant may be at least one selected from the group consisting of croscarmellose sodium, corn starch, crospovidone, low-substituted hydroxypropylcellulose, and pregelatinized starch. For example, the disintegrant is croscarmellose sodium. The content of the disintegrant may be about 1% to about 20% by weight, about 5% to about 15% by weight, or about 7% to about 10% by weight relative to the core.

The binder is hydroxypropyl cellulose (HPC), copovidone (copolymer of vinylpyrrolidone with other vinyl derivatives), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (polyvinyl pyrrolidone, povidone), pregelatinized starch, and low-substituted hydroxypropyl cellulose. For example, the binder is HPC. The content of the binder may be about 1% to about 30% by weight, about 1% to about 20% by weight, or about 1 to about 10% by weight relative to the core.

The lubricant may be at least one selected from the group consisting of sodium stearyl fumarate, magnesium stearate, talc, polyethylene glycol, calcium behenate, calcium stearate, and hydrogenated castor oil. For example, the lubricant is sodium stearyl fumarate. The lubricant content may be from about 1% to about 30% by weight, from about 1% to about 20% by weight, or from about 1 to about 10% by weight relative to the core.

The second coating layer used in the present invention may include a plasticizer so as to provide flexibility of film coating and serve to prevent a disadvantage of peeling off of the coating film. The plasticizer is not limited as long as it is a material used in the art, and for example, triethyl citrate may be used. The plasticizer is 10 to 50% (w / w), 15 to 25% (w / w), or 16 to 21% (w) based on the weight of the second active ingredient eluting substance in the second coating layer / w). Within this range, it is possible to suitably provide the flexibility and the anti-peeling effect of the coating without affecting the sustained release effect of the second coating layer.

The controlled release varenicline formulation of the present invention is in a single unit dosage form or two or more unit dosage forms. In some embodiments, the unit dosage form is a tablet, capsule, pill, pellet, free flowing powder or liquid. In some such embodiments, the capsule base of the capsule (corresponding to reference numeral 120 in FIG. 1) is selected from the group consisting of gelatin, hypromellose, pullulan, polyvinyl alcohol, and any combination thereof.

The capsule base 120 of the capsule may be a hard capsule, or any hard capsule that can be commonly used in the art. The base of the hard capsule may be selected from, for example, gelatin, hypromellose, pullulan (NP caps TM, etc., Capsugel), polyvinyl alcohol, and any combination thereof, but is not limited thereto. .

The capsule base 120 is a hard capsule may be a capsule of a conventional size used in the art. Depending on the size of the capsule, capsule sizes of various lakes are commonly used, but large capsules such as 00 capsules (capsule cap diameter 8.5mm, capsule length 23.3mm) are taken by patients with small body size, such as the elderly or small children. There is an uncomfortable disadvantage to, and the portability may also deteriorate due to the increase in volume. In some embodiments, the capsule base 120 may use capsules No. 0, No. 1, No. 2, No. 3, or No. 4 in consideration of the mass limit of tablets or granules filled in capsules, for example. , More specifically, No. 1, No. 2, or No. 3 capsules may be used.

According to this further embodiment of the present invention, a core containing varenicline or a pharmaceutically acceptable salt as an active ingredient, a first coating layer comprising a first active ingredient eluting substance, and a second A second coating layer comprising an active ingredient eluent material, the first coating layer is formed between the core and the second coating layer, the second active ingredient eluent material of the second coating layer, ethyl cellulose ( a) and hydroxypropylcellulose (b) or hydroxypropylmethylcellulose (b ') as a binary component mixture, wherein the content ratio of the core and the first coating layer and the second coating layer is 60 to 80: 1 to 10: 10 to 40 weight ratio, the blending ratio of the binary mixture ((a) :( b) or (a) :( b ')) is 2.5: 1 to 1.7: 1 (w / w), to provide a sustained-release capsule. You can.

The sustained-release capsules, as described above, the content ratio of the core and the first coating layer and the second coating layer may be a weight ratio of 75 to 82: 3 to 5: 15 to 20.

The sustained-release capsule has a weight ratio of a first active ingredient eluent material of the first coating layer and a second active ingredient elution material of the second coating layer of greater than 1: 2.76 to less than 1: 4.34, or 1 Having a weight ratio of: 3.16 to 1: 3.95 is more preferable because it can provide a varenicline preparation that is a controlled release form of at least once daily administration and exhibits medication compliance.

Manufacturing method

In another embodiment of the present invention, an effective amount of varenicline or a pharmaceutically acceptable salt thereof is included in the core as an active ingredient, and the core is a controlled release layer comprising a plurality of active ingredient eluting materials having different degrees of dissolution. Wrapped, wherein the control release layer comprises a first coating layer comprising a first active ingredient eluent material, and a second coating layer comprising a second active ingredient eluent material, the first coating layer comprising the core By preparing a multi-coating formulation (corresponding to reference numeral 110 in FIG. 1) formed between the second coating layers, sustained-release controlled release is provided with medicament compliance without side effects. In some such embodiments, the preparation method comprises the steps of preparing an effective amount of varenicline or a pharmaceutically acceptable salt thereof, and dry granules of a pharmaceutical additive as an active ingredient; Sieving the dry granules and adding a disintegrant and a lubricant to mix; Tableting the mixture in the form of a multi-unit spheroidal tablet (MUST) to form a core; And applying a solution for controlled release containing an eluent to the surface of the core and forming a controlled release layer, wherein the controlled release layer is separable comprising a first active ingredient eluent in the core. Forming a first coating layer by coating a coating solution; Coating a sustained-release coating solution containing a second active ingredient eluting material on the first coating layer and obtaining a sustained-release coated formulation with a second coating layer; And filling the sustained-release coated formulation into a capsule base (corresponding to reference numeral 120 in FIG. 1) to form a capsule.

In some implementations, the step of obtaining the core comprises: (a) mixing varenicline or a pharmaceutically acceptable salt thereof with a diluent, binder and lubricant; (b) dry granulating the mixture of step (a); And (c) mixing the dry granules of step (b) by adding a disintegrant and a lubricant, and tableting the resulting mixture to obtain mini-tablets or tablets, but is not limited thereto.

The first coating layer formed on the core can block the interaction between the core and the second coating layer, and does not inhibit the release of the active ingredient in the core when the second coating layer collapses after administration of the sustained-release capsule 100. To prevent this, any biocompatible hydrophilic polymer eluting at the same pH condition as the body can be contained as the first active ingredient eluting substance (coating base). According to this embodiment, it is possible to provide a first coating layer using a separable coating liquid, such a separable coating liquid, for example, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), low At least one first active ingredient eluent selected from the group consisting of substituted hydroxypropyl cellulose (HPC-L), starch, gelatin, ethylcellulose (EC), and any combinations thereof. It may be an aqueous solution containing. In one embodiment, the separable coating solution may include hydroxypropyl methylcellulose or hydroxypropylcellulose as the first active ingredient eluting material.

The second coating layer formed on the first coating layer, the substance having a dissolution characteristic relatively slow dissolution rate than the first active ingredient eluting substance at the same pH conditions in the body as the second active ingredient eluent substance ( Coating base), for example, hydroxypropyl methylcellulose (hydorxyprophyl methylcellulose, HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (hydroxyethyl cellulose, HEC), ethyl cellulose ( Ethylcellulose, EC), pregelatinized starch, carboxymethylcellulose, polyethylene oxide, Propylene Glycol Alginate, Methacrylic acid copolymer S, (Eudragit S-100), Methacrylic acid copolymer L (Eudragit L-100), methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl methacrylate-methacryl Ester copolymer or a mixture thereof. As a specific example, ethylcellulose, hydroxypropylmethylcellulose, or mixtures thereof can be used.

As the second active ingredient eluent material, it is preferable to use a binary mixture of ethyl cellulose and hydroxypropyl methyl cellulose or a binary mixture of ethyl cellulose and hydroxypropyl cellulose, wherein ethyl cellulose has a fast dissolution rate. Components that can be provided, and hydroxypropylmethylcellulose and hydroxypropylcellulose are components capable of providing a slow dissolution rate, respectively, and can provide desired controlled release by appropriately adjusting the mixing ratio between them.

The specific mixing ratio may be, for example, a ratio of 2.5: 1 to 1.7: 1 (w / w). When the ratio is lower than the above ratio, relatively rapid release may occur, and thus it may be difficult to exhibit a sustained release property required as a second active ingredient eluable material. In addition, when the ratio is higher than the above ratio, the proportion of the ethyl cellulose which is an insoluble component increases, and drug release may be excessively delayed. Therefore, there is a concern that the bioavailability may be lowered due to excretion without complete release of the drug.

In this specification, the core on which the second coating layer (the sustained-release coating layer) is formed on the first coating layer (the endothelial coating layer) is also referred to as a “core with a controlled release coating layer (western mini-tablet, 110)”. It is preferable that the sustained-release coating liquid providing the second coating layer contains the second active ingredient eluting substance within a range of 68 to 90% by weight based on the total weight of the sustained-release coating liquid. More preferably, the sustained-release coating solution contains a mixture of ethylcellulose and hydroxypropylmethylcellulose described above.

The details of the method for manufacturing the varenicline formulation for controlled release according to this aspect can be appropriately used by any person skilled in the art using any method known in the art. That is, when the core of the sustained-release coating layer of the sustained-release capsule (corresponding to reference numeral 100 in FIG. 1) is a mini-tablet or tablet, it may be prepared by a direct compression method or an indirect compression method, and the indirect compression method is It can be prepared using dry granules or wet granules. In addition, the step of coating the endothelial coating layer and the sustained-release coating layer on the mini-tablet or tablet may be applied to any coating method of coating the mini-tablet or tablet, and may be coated using, for example, a fluid bed coater.

Dissolution test

Varenicline formulation for controlled release according to the present invention, for example, the above-mentioned sustained-release capsules (corresponding to reference numeral 100 in FIG. 1), in the dissolution test having the same conditions as in the body, dissolution in artificial intestinal fluid between pH 6.7 and 6.9 Disclosed, 10% or more is released for 2 hours after the start of the dissolution test, 40% or less at 4 hours, and after 12 hours, 70% or more and 90% or more after 18 hours may be released.

In some embodiments, the varenicline formulation for controlled release according to the present invention, for example, the above-mentioned sustained-release capsule 100 is 100 rpm, 37 ± 0.5 ° C. according to the United States Pharmacopeia (USP) second method paddle method 10% or more for 2 hours, 40% or less for 4 hours, 70% or more after 12 hours, and 90% or more of the active ingredient may be eluted at 18 hours in artificial intestinal fluid having a pH of 6.7-6.9 (see FIGS. 2 to 3). .

Therefore, the varenicline formulation for controlled release according to the present invention, for example, the sustained-release capsule 100, exhibits a sustained-release pattern without change in elution with time, and thus has a sufficient bioavailability and duration, and thus, the frequency of administration. It can be used effectively while reducing.

The controlled release varenicline preparation, for example, the sustained-release capsule 100, contains the varenicline or a pharmaceutically acceptable salt thereof as the active ingredient, and thus the active ingredient is known to be effective or will be newly revealed in the future. It can be used for the treatment or prevention of any indication that may be. Thus, in one embodiment, the sustained-release capsule 100 may be useful for treating, preventing or improving dependence and addiction to nicotine or tobacco products. In one embodiment, the sustained-release capsule 100 may be administered at least once a day. In some further embodiments, the pharmaceutical formulation is for once daily administration. In a further embodiment, the sustained-release capsule 100 may be a smoking cessation adjuvant.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention and the scope of the present invention is not limited thereto.

[Example]

Preparation Example 1: Formation of a core containing barenicline oxalate and a first coating layer (endothelial coating layer)

The composition of the MUST core containing barenicline oxalate was mixed with barenicline oxalate, microcrystalline cellulose, lactose hydrate and hydroxypropylcellulose in an empty blender according to the composition shown in Table 1 below, mixed for 30 minutes, and then magnesium stearate. After adding and mixing for 5 minutes, it was put into a roller compactor, and the granules obtained by dry granulation were sieved through a 20 mesh circular body. After mixing the sizing powder and croscarmellose sodium, the mixture was finally mixed with magnesium stearate.

Then, 10 tablets of mini tablets having a hardness of about 1 to 2 kp and a weight of 7.5 mg per tablet were tableted with a MUST punch having a diameter of 2.0 mm to form a MUST.

core ingredient weight
(mg / 10 tablets) weight (%) Dry granules
(Compacting) Barenicline oxalate monohydrate 3.02 4.0 Microcrystalline cellulose 19.00 25.3 Lactose hydrate 42.48 56.6 Hydroxypropylcellulose 2.50 3.3 Magnesium stearate 1.00 1.3 mix Croscarmellose sodium 6.00 8.0 Magnesium stearate 1.00 1.3 Sum 75.0 100.0

The prepared mini-tablets (corresponding to the core) were coated with a separable coating solution having a composition of 1 elution layer (endothelial coating layer) in Table 2 below in a fluid bed coater to obtain an endothelial coating mini-tablet having a weight of 7.88 mg per tablet.

ingredient weight
(mg / 10 tablets) weight (%) Separability
Coating solution Hydroxypropylmethylcellulose
(First active ingredient eluting substance) 3.8 4.82 Purified water (Suitable) - Sum 78.8 100.0

Preparation Example 2: Examples 1 to 4 and Comparative Examples 2 to 9

Preparation of the second coating layer (western coating layer) -forming mini-tablets

According to the composition of the second coating layer (western coating layer) of Tables 3 and 4 below in the fluidized bed granulator, the second coating layer of Examples 1 to 4 and Comparative Examples 2 to 9 was coated by coating on the endothelial coating minitablet of Preparation Example 1 Coating layer) to form a mini-tablet (western mini-tablets, corresponding to the reference numeral 110 of Figure 1) was prepared.

First, in Examples 1 to 4, a mixture of ethylcellulose and hydroxypropylcellulose was coated in the proportion of the composition of the second coating layer (western coating layer) in Table 3 below, and 15-20% (w based on the weight of the endothelial coating minitablet) / w).

ingredient Weight (mg / 10 Tablet) Example 1 Example 2 Example 3 Example 4 Ethylcellulose (7cPs)
(Second active ingredient elutable substance-1) 8.0 8.6 7.6 10.0 Hydroxypropylcellulose 2910 (second active ingredient eluent-2) 4.0 3.4 4.4 5.0 Triethyl citrate 2.5 2.5 2.5 2.5 ethanol (Suitable) (Suitable) (Suitable) (Suitable) Purified water (Suitable) (Suitable) (Suitable) (Suitable) Sum 14.5 14.5 14.5 17.5

On the other hand, Comparative Example 1 is a commercial product containing varenicline (Chmpix® 1mg), Comparative Examples 2 and 3 were prepared as a sustained coating base using ethylcellulose alone and hydroxypropylcellulose alone, respectively.

In addition, Comparative Example 3 is a coating using hydroxypropyl cellulose corresponding to the hydroxymethylpropyl cellulose and replaceable biocompatible polymers used in forming the first coating layer (endothelial coating layer) in Preparation Example 1, resulting in It corresponds to the experimental example in which only the first coating layer (endothelial coating layer) was formed in the invention.

Furthermore, in Comparative Examples 4 to 9, samples were prepared by varying the ratio of a mixed coating agent (a second active ingredient eluting substance) of ethyl cellulose and hydroxypropyl cellulose to an endothelial coated minitablet.

ingredient Weight (mg / 10 tablets) Comparative Example 2 Comparative example
3 Comparative Example 4 Comparative example
5 Comparative Example 6 Comparative example
7 Comparative Example 8 Comparative example
9 Ethyl cellulose
(7cPs)
(Second active ingredient elutable substance-1) 12.0 - 9.0 8.7 7.4 6.0 7.0 11.0 Hydroxypropylcellulose 2910 (second active ingredient eluent-2) - 12.0 3.0 3.3 4.6 6.0 3.5 5.5 Triethyl citrate (plasticizer) 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 ethanol (Suitable) (Suitable) (Suitable) (Suitable) (Suitable) (Suitable) (Suitable) (Suitable) Purified water (Suitable) (Suitable) (Suitable) (Suitable) (Suitable) (Suitable) (Suitable) (Suitable) Sum 14.5 14.5 14.5 14.5 14.5 14.5 13.0 19.0

Preparation Example 3: Preparation of sustained-release capsules

Preparation of a sustained release capsule containing a second coating layer (western coating layer) -forming minitablet

Each of 10 tablets of the sustained-release mini-tablets of Examples 1 to 4 and Comparative Example 2 (corresponding to symbol 110 in FIG. 1) was filled into gelatin hard capsules 2 (corresponding to symbol 120 in FIG. 1), respectively, of which the main agent was gelatin. Thus, a sustained-release capsule (containing 2 mg as varenicline, corresponding to 100 in FIG. 1) was prepared.

Preparation Example 4: Preparation of sustained-release capsules according to capsule type

The sustained-release capsules (the sign of Fig. 1) in the same manner as in Preparation Example 3, except that the main base of the hard capsule (corresponding to the sign 120 of Fig. 1) was filled into the hypromellose capsules, respectively. 100). In addition, the sustained-release capsules (corresponding to the symbol 100 in FIG. 1) in the same manner as in Preparation Example 3, except that the main base of the hard capsule (corresponding to the reference numeral 120 in FIG. 1) is respectively filled in the fluran capsule, which is flurane. ) Were prepared respectively.

Furthermore, in the gelatin hard capsule of Preparation Example 3, the capsule base of the hard capsule (corresponding to reference numeral 120 in FIG. 1) was replaced with hypromellose and pullulan, respectively, to prepare the hypromellose capsule of Preparation Example 4, or The dissolution rate of the same or similar degree was confirmed for the pullulan capsule. For reference, in the case of immediate release, disintegration time is different for each hard capsule (for example, about 5 minutes for gelatin capsules, about 7 minutes for flurane capsules, and about 10 minutes for hypromellose capsules). It will be insane, but in this experiment, since these hard capsules provide a sustained release pattern showing an elution rate of 10% or less even at 1 hour of release, it is inferred that the effect of the type of capsule is small.

Test Example 1: Test for dissolution rate of sustained-release capsules

Conditions described below using capsules (corresponding to symbol 100 in FIG. 1) containing sustained-release mini-tablets (corresponding to symbol 110 in FIG. 1) of Examples 1 to 4 and Comparative Examples 2 to 9 according to Preparation Example 3 The dissolution rate of varenicline oxalate was measured over time. In Comparative Example 1, 1 mg and 2 tablets were added to match the dose.

-Dissolution conditions-

Eluent: Artificial intestinal fluid 900 mL (pH 6.8)

Device: USP paddle method, 100 rpm

Temperature: 37 ℃

Dissolution time: 1, 2, 4, 8, 12, 18 hours

-Analysis conditions-

Equipment used: HPLC (Hitachi 5000 series, Japan)

Detector: Ultraviolet absorption photometer (measurement wavelength: 235 nm)

Column: a column filled with a silica gel for liquid chromatography with a particle diameter of 5 μm in a stainless steel pipe having an inner diameter of about 4.60 mm and a length of about 15 cm.

Mobile phase-0.1% trifluoroacetic acid: methanol: acetonitrile = 8: 1: 1 (v / v / v)

Flow rate: 1.0 mL / min

Column temperature: 25 ℃

The dissolution rate measurement results are shown in Tables 5 to 6 and Figures 2 to 3 below. In addition, the first active material eluent material for forming the first coating layer (endothelial coating layer) of Table 2 and the second active material eluent material for forming the second coating layer (western coating layer) of Table 3 The content ratio was calculated and summarized together in Tables 5 and 6.

Dissolution rate (%) Example 1 Example 2 Example 3 Example 4 First: weight ratio of the second substance 1: 3.16 1: 3.16 1: 3.16 1: 3.95 Hour (hr) Average Deviation Average Deviation Average Deviation Average Deviation One 4.5 0.9 3.1 3.2 6.3 2.1 2.1 1.5 2 12.0 2.9 11.9 4.3 18.3 4.3 10.9 3.9 4 28.3 4.8 25.6 5.9 34.1 4.6 24.8 6.1 8 56.1 2.1 50.7 3.0 60.3 2.2 50.0 3.6 12 77.9 1.0 74.6 2.0 82.3 1.0 71.9 2.1 18 98.1 1.0 95.6 1.0 101.3 0.5 94.1 1.2

According to the results of Tables 5 and 2, Examples 1 to 4 are 10% or more at 2 hours, 40% or less at 4 hours, 70% or more at 12 hours, 90 at the end of 18 hours in artificial intestinal fluid (pH6.8). It was confirmed that the sustained-release pattern for release of more than% varenicline.

Dissolution rate (%) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 First: weight ratio of the second substance - 1: 3.16 1: 3.16 1: 3.16 1: 3.16 1: 3.16 1: 3.16 1: 2.76 1: 4.34 Hour (hr) Average Deviation Average Deviation Average Deviation Average Deviation Average Deviation Average Deviation Average Deviation Average Deviation Average Deviation One 98.9 1.0 0.0 3.1 90.9 2.1 0.0 2.4 1.5 1.6 15.9 1.7 69.1 1.3 20.9 2.2 0.0 2.0 2 99.0 0.9 0.0 4.5 100.3 4.7 3.8 3.3 7.9 3.5 30.5 4.6 84.3 2.9 40.7 3.0 1.4 4.6 4 100.3 1.0 1.3 3.3 100.1 1.3 4.8 4.7 18.0 4.6 55.4 3.1 97.7 3.4 65.7 3.1 3.2 3.0 8 - - 3.2 3 - - 9.8 2.4 37.8 3.1 95.6 2.0 98.2 1.0 99.7 1.5 7.4 2.8 12 - - 6.7 3.9 - - 17.4 2.2 52.6 2.0 99.6 1.0 98.6 0.9 101.2 1.8 15.1 1.9

According to the results of Tables 6 and 3, in Comparative Example 1, it was confirmed that the elution was completed after 1 hour due to the rapid dissolution pattern.

In addition, the second active ingredient of the second coating layer was only used twice as the first active ingredient eluent material by using the first active ingredient eluent material equivalent to the first coating layer (hydroxypropylcellulose) alone. In the case of Comparative Example 3, which was considered as an unused experiment, the eluent showed a fast dissolution rate but could not confirm the sustained release profile. Therefore, in the present invention, when only the first coating layer is formed and a separate second coating layer is not formed using a specific second active ingredient eluent material, the technical problem of sustained release to be solved in the present invention cannot be effectively provided. Was confirmed.

On the other hand, even when the second active ingredient eluent is used, Comparative Example 2 in which only ethyl cellulose is used, Comparative Examples 4 to 5 in which the ratio of ethyl cellulose and hydroxypropyl cellulose is greater than 2.5: 1 (w / w), and coating In Comparative Example 9 having a high ratio, a low dissolution rate was confirmed. In addition, in the case of Comparative Examples 6 to 7, in which the ratio of ethyl cellulose and hydroxypropyl cellulose was less than 1.7: 1 (w / w), and Comparative Example 8 with a low coating ratio, it was possible to confirm dissolution rates faster than the target elution pattern, respectively.

Furthermore, from the results of Table 5 and Table 6, the weight ratio of the first active ingredient elutable material and the second active ingredient elutable material is greater than 1: 2.76 to 1: 4.34 or less, especially 1: 3.16 to It was confirmed that having a weight ratio of 1: 3.95 is a controlled release form of at least once daily administration and can provide a varenicline preparation that exhibits medication compliance.

Test Example 2: Western capsule dissolution rate test: by rotation speed

Conditions described below using each capsule (corresponding to symbol 100 in FIG. 1) containing the sustained-release mini-tablets of Examples 1 to 4 and Comparative Examples 2 to 9 (corresponding to symbol 110 in FIG. 1) according to Preparation Example 3 The dissolution rate of varenicline oxalate according to the rotational speed over time was measured.

-Dissolution conditions-

Eluent: Artificial intestinal fluid 900 mL (pH 6.8)

Device: USP paddle method, 150 rpm

Temperature L 37 ℃

Dissolution time: 1, 2, 4, 8, 12, 18 hours

The dissolution rate measurement results are shown in Tables 7 and 4 below.

Dissolution rate (%) Example 1 Example 2 Example 3 Example 4 Hour (hr) Average Deviation Average Deviation Average Deviation Average Deviation One 5.0 1.0 4.1 2.1 7.3 1.1 3.1 1.5 2 13.6 1.9 10.9 4.1 20.1 4.3 10.5 2.9 4 30.7 1.4 26.8 3.9 35.8 1.5 25.1 3.1 8 55.9 1.0 52.1 2.1 60.3 1.1 51.7 3.0 12 75.9 0.6 76.6 1.0 83.3 0.5 73.4 2.0 18 100.5 0.7 98.7 0.6 100.1 0.5 96.1 0.9

Through the results of Tables 7 and 4, it was confirmed that the sustained pattern was maintained even though the rotational speed was increased from 100 rpm to 150 rpm. For reference, in a sustained-release formulation having a delayed-release characteristic, it is not preferable if there is a change in the dissolution pattern according to the rotational speed, but the sustained-release capsule in the present invention was able to secure a target dissolution pattern without a change in the dissolution rate according to the rotational speed.

In addition, various additional experiments were conducted as follows, and the results and related theories were summarized.

<Experiment related to the formation of the second coating layer directly on the core (non-forming of the first coating layer)>

In Example 1, the first coating layer (endothelial coating layer) was not formed, and the second coating layer (Western coating layer) of Preparation Example 2 was directly formed on the core. The pattern could not be confirmed.

This is when the second active ingredient eluent material of the second coating layer (western coating layer) without the first coating layer (endothelial coating layer) is in direct contact with the drug contained in the core, the second active ingredient eluent material and the core It is inferred that the stability of the drug was not secured by the drug-to-drug interaction.

<Experimental example of matrix polymer use>

In order to prepare for the sustained-release pattern provided in an experiment for providing a sustained-release preparation using a matrix polymer, Barney was used as an active ingredient in <Test Example 8> of the aforementioned prior patent document 4 (Korean Patent Publication No. 2018-0058644). Preparation of a sustained-release matrix using a matrix polymer (hydroxypropylmethylcellulose) containing clean or a salt thereof, was referred.

Specifically, the sustained-release dissolution pattern of the preceding document <Test Example 8> , and the dissolution pattern experimental data (Example 8-1 in Table 24), and the results of Table 5 related to Example 1 of the present invention presented above In Table 8, the results were summarized together to prepare.

time
(hr) Dissolution rate (%) Example 1 of Table 5 Example 8-1 in Table 24 of the prior literature One 4.5 ± 0.9 25.1 2 12.0 ± 2.9 38.0 4 28.3 ± 4.8 - 5 - 62.8 8 56.1 ± 2.1 - 10 - 85.6 12 77.9 ± 1.0 - 16 - 97.1 18 98.1 ± 1.0 - 20 - 99.3

According to the above Table 8, in Example 1 according to the present invention, a slow sustained release pattern could be confirmed before 12 hours, in particular, at 1 to 8 hours at the beginning of administration, and specifically, an emission rate of less than 60% was also observed at 8 hours of administration. Looked.

On the other hand, in Example 8-1 of the prior literature, the dissolution pattern of more than 60% is already shown at the beginning of administration at 1 to 8 hours, especially at 5 hours of administration, which is required to provide sustained release when applied as a matrix polymer. It was confirmed that it still did not provide a gentle release pattern at the beginning of administration.

100: varenicline preparation for controlled release (ex. Sustained release capsule form)
110: Western mini tablet in which the first coating layer and the second coating layer sequentially wrap the core
120: capsule base

Claims (17)

A core containing varenicline or a pharmaceutically acceptable salt thereof as an active ingredient; And a controlled release layer comprising a plurality of active ingredient eluting materials having different dissolution levels for the active ingredient formed on the core,
The controlled release layer includes a first coating layer comprising a first active ingredient eluting material, and a second coating layer comprising a second active ingredient eluting material, wherein the first coating layer comprises the core and the second It is formed between the coating layers,
The content ratio of the core and the first coating layer and the second coating layer is a varenicline formulation for controlled release in a weight ratio of 60 to 80: 1 to 10: 10 to 40. The method according to claim 1, wherein the core is a multi-dose unit tablets (Multi-Unit Spheroidal Tablet: MUST) in the form of mini-tablets, pellets and tablets at least one selected for controlled release varenicline formulations. The method according to claim 1, The core is a multi-unit unit tablets (Multi-Unit Spheroidal Tablet: MUST) in the form of a mini-tablet, the formulation is one of capsules, pills, tablets for controlled release varenicline formulations. The method according to claim 1, The content ratio of the core and the first coating layer and the second coating layer is 75 to 82: 3 to 5: 15 to 20 weight ratio of varenicline formulation for controlled release. The method according to claim 1, wherein the first active ingredient eluting substance is a substance that elutes the active ingredient under the same pH conditions in the body, the second active ingredient eluting substance is the first activity under the same pH conditions in the body A substance that has a slower dissolution rate of the active component than a component-soluble substance,
Control to provide a sustained release pattern in which the second coating layer disintegrates primarily and the first coating layer is combined with water molecules penetrating the second coating layer to elute the active ingredient contained in the core. Varenicline formulations for release. The method according to claim 1, wherein the first active ingredient eluting material of the first coating layer is hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropyl cellulose (HPC-L) , Starch, gelatin, ethylcellulose (EC), and any one or more selected from the group consisting of a combination of varenicline formulations for controlled release. The method according to claim 1, The second active ingredient eluent material of the second coating layer is hydroxypropyl cellulose (hydorxyprophyl methylcellulose, HPMC), hydroxypropyl cellulose (hydroxypropyl cellulose, HPC), hydroxyethyl cellulose (hydroxyethyl cellulose) , HEC), ethylcellulose (EC), pregelatinized starch, carboxymethylcellulose, polyethylene oxide, propylene glycol alginate, methacrylic acid copolymer S ( Eudragit S-100), methacrylic acid copolymer L (Eudragit L-100), methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, or any combination thereof Varenicline formulation for controlled release, which is selected from two or more groups. The method according to claim 7, wherein the second active ingredient eluting material of the second coating layer is ethylcellulose and hydroxypropylcellulose or ethylcellulose and hydroxypropylmethylcellulose in a weight ratio of 2.5: 1 to 1.7: 1 Varenicline formulation for controlled release, which is a fractional mixture. The method according to claim 1, wherein the first active ingredient eluent material of the first coating layer, and the second active ingredient eluent material of the second coating layer has a weight ratio of greater than 1: 2.76 to 1: 4.34 or less. Varenicline formulations for phosphorus controlled release. The method according to any one of claims 1 to 9, wherein the active ingredient is measured by a dissolution test of the USP device 2 paddle method, 10% or more within 2 hours, 40% or less within 4 hours, 70% or more within 12 hours, A varenicline formulation for controlled release with a dissolution profile of at least 90% varenicline or pharmaceutically acceptable salt release within 18 hours. A core containing varenicline or a pharmaceutically acceptable salt as an active ingredient, a first coating layer comprising a first active ingredient eluent, and a second comprising a second active ingredient eluent It includes a coating layer, the first coating layer is formed between the core and the second coating layer,
The second active ingredient eluent material of the second coating layer is a binary mixture of ethylcellulose (a) and hydroxypropylcellulose (b) or hydroxypropylmethylcellulose (b '),
The content ratio of the core and the first coating layer and the second coating layer is a weight ratio of 60 to 80: 1 to 10: 10 to 40, and the mixing ratio of the binary mixture ((a) :( b) or (a) :( b ')) Is 2.5: 1 to 1.7: 1 (w / w), sustained-release capsules. The method according to claim 11, The content ratio of the core and the first coating layer and the second coating layer is a weight ratio of 75 to 82: 3 to 5: 15 to 20, sustained release capsules. The sustained-release capsule formulation of claim 11, wherein the first active ingredient eluent material of the first coating layer and the second active ingredient eluent material of the second coating layer have a weight ratio of 1: 3.16 to 1: 3.95. . Preparing an active amount of varenicline or a pharmaceutically acceptable salt thereof, and dry granules of a pharmaceutical additive as an active ingredient;
Sieving the dry granules and adding a disintegrant and a lubricant to mix;
Tableting the mixture in the form of a multi-unit spheroidal tablet (MUST) to form a core;
Applying a solution for controlled release containing an eluent to the surface of the core and forming a controlled release layer,
Forming a first coating layer by coating the control release layer with a separable coating solution containing a first active ingredient eluting substance on the core;
Coating a sustained-release coating solution containing a second active ingredient eluting material on the first coating layer and obtaining a sustained-release coated formulation with a second coating layer; And
A method of manufacturing a varenicline formulation for controlled release, comprising filling the sustained-release coated formulation in a capsule base to form a capsule. The method of claim 14, wherein the step of obtaining the core,
(a) mixing varenicline or a pharmaceutically acceptable salt thereof with a diluent, binder and lubricant;
(b) dry granulating the mixture of step (a); And
(c) a step of adding a disintegrant and a lubricant to the dry granules of step (b), mixing and tableting the resulting mixture to obtain mini-tablets or tablets, a method for preparing a varenicline formulation for controlled release. . The method according to claim 14, The separable coating solution, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropyl cellulose (HPC-L), starch (Starch), gelatin (gelatin) ), Ethylcellulose (EC) and any combinations thereof, using a water solution comprising at least one first active ingredient eluent selected from the group consisting of varenicline formulations for controlled release. The method according to claim 14, wherein the sustained-release coating solution, ethyl cellulose and hydroxypropyl cellulose, or a mixture of ethyl cellulose and hydroxypropyl methylcellulose from 2.5: 1 to 1.7: 1 (w / w) based on the total weight of the sustained-release coating solution. A method of preparing a varenicline formulation for controlled release, which uses a solution comprising within the range of 68 to 90% by weight.

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