WO2012148225A2

WO2012148225A2 - Sustained-release pharmaceutical composition comprising donepezil or pharmaceutically acceptable salt thereof having improved dissolution stability and method for manufacturing the same

Info

Publication number: WO2012148225A2
Application number: PCT/KR2012/003304
Authority: WO
Inventors: Sang-Joon Lee; Kwan-Young Chang; Jae-Soon Ahn; Jae-Min Cho; Kyoung-Un Kang; Hyun-Joo Lee
Original assignee: BIO PHARMARTIS Co Ltd
Current assignee: BIO PHARMARTIS Co Ltd
Priority date: 2011-04-29
Filing date: 2012-04-27
Publication date: 2012-11-01
Anticipated expiration: 2013-10-29
Also published as: WO2012148225A3; KR20120122558A

Abstract

The present invention relates to a sustained-release formulation comprising donepezil or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a sustained-release pharmaceutical composition comprising donepezil or a pharmaceutically acceptable salt thereof, and one or more sustained-release bases selected from the group consisting of polyvinyl acetate and fatty acid ester, and a preparation method thereof.

Description

[DESCRIPTION]

[Invention Title]

Sustained-release pharmaceutical composition comprising donepezil or pharmaceutically acceptable salt thereof having improved dissolution stability and method for manufacturing the same

[Technical Field]

The present invention relates to a sustained-release formulation comprising donepezil or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a sustained-release pharmaceutical composition comprising donepezil or a pharmaceutically acceptable salt thereof, and one or more sustained-release bases selected from the group consisting of polyvinyl acetate and fatty acid ester, and a preparation method thereof. [Background Art]

Donepezil is a compound with a chemical name of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl)methyl]piperidine, and donepezil or a salt thereof (e.g., hydrochloride thereof) is known to be a useful drug for the prevention and treatment of senile dementia, in particular, Alzheimer's diseases (EP Patent No. 296,560 and US Patent No. 4,895,841). This drug is administered at an initial dose of 5 mg per day, which can be increased to 10 mg per day after 4-6 weeks, in the form of oral solid formulations such as film-coated tablets, capsules, and granules.

Currently, there is a need of sustained-release formulations which slowly release donepezil or the salt thereof in the body to maintain a plasma level of the active ingredient and to improve patient compliance through reduced dose frequency. These sustained-release formulations are expected to solve the problems that a pharmaceutical composition including donepezil or the salt thereof shows reduced stability due to variation in release rate of active ingredients over time and thus storage time is shortened. The design of sustained-release formulations is also encountered with problems of a reduction in sustained-release function due to the initial burst-out or dose-dumping of the drug and a Lag-phase due to retardation of drug release at the desired time. To avoid these problems, the formulations should be designed with selection of sustained-release bases, considering characteristics of active ingredients.

Regarding the sustained-release formulations of donepezil, Korean Patent No. 0904602 discloses a matrix type sustained-release formulation including donepezil or a salt thereof and one or more enteric polymers. The present inventors prepared sustained-release formulations according to the above constitution and stored them at 40°C and 75% relative humidity for a long period of time, and then they performed dissolution studies. Unfortunately, they found that the dissolution rate was greatly reduced. Further, the dissolution studies under food intake showed that sustained-release of donepezil hydrochloride could not be achieved due to the degradation of matrix tablet.

[Disclosure]

[Technical Problem]

Accordingly, the present inventors have made many efforts to prepare a sustained-release formulation including donepezil, which maintains dissolution stability during long-term storage and exhibits a suitable dissolution profile even under food intake. As a result, the present inventors found that excellent dissolution stability can be obtained by using one or more sustained-release bases selected from the group consisting of polyvinyl acetate and fatty acid ester, thereby completing the present invention.

[Technical Solution]

An object of the present invention is to provide a sustained-release pharmaceutical composition comprising donepezil or a pharmaceutically acceptable salt thereof; and one or more sustained-release bases selected from the group consisting of polyvinyl acetate and fatty acid ester.

Another object of the present invention is to provide a preparation method of the sustained-release pharmaceutical composition. [Advantageous Effects]

The sustained-release formulation of the present invention effectively controls the release rate of donepezil or a pharmaceutically acceptable salt thereof so as to maintain the plasma level of active ingredients and to reduce the frequency of administration for the improvement of patient compliance, thereby exhibiting therapeutic or prophylactic effects on the target diseases. In particular, the sustained-release formulation of the present invention exhibits a suitable dissolution profile even under food intake and no changes in dissolution rate during long-term storage of 4 months, that is, it exhibits remarkably improved dissolution stability under various dissolution conditions.

[Description of Drawings]

FIG. 1 is a graph showing a time-dependent dissolution profile immediately after preparation of the donepezil hydrochloride sustained-release tablet of Example 1 ;

FIG. 2 is a graph showing a time-dependent dissolution profile immediately after preparation of the donepezil hydrochloride sustained-release tablet of Comparative Example 2;

FIG. 3 is a graph showing a time-dependent dissolution profile at 4 months after preparation of the donepezil hydrochloride sustained-release tablet of Example 1; and

FIG. 4 is a graph showing a time-dependent dissolution profile at 4 months after preparation of the donepezil hydrochloride sustained-release tablet of Comparative Example 1.

[Best Mode]

In one aspect to achieve the above objects, the present invention relates to a sustained-release pharmaceutical composition comprising donepezil or a pharmaceutically acceptable salt thereof; and one or more sustained-release bases selected from the group consisting of polyvinyl acetate and fatty acid ester.

As used herein, the term "donepezil" refers a compound with a chemical name of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl)methyl]piperidine, and the following Chemical Formula:

As used herein, the term "donepezil" also includes all types of donepezil, for example, an amorphous form of donepezil or a crystalline polymorphous form such as crystalline donepezil, a hydrate form, an anhydride form, or a solvate form.

As used herein, the term "pharmaceutically acceptable salt of thereof is not particularly limited, as long as it forms an addition salt of donepezil, for example, hydrochloride, oxalate, hydrobromide, sulfate, nitrate, phosphate, maleate, fumarate, methanesulfonate, benzenesulfonate, or toluenesulfonate thereof. Donepezil hydrochloride is preferred.

In the present invention, donepezil or the acceptable salt thereof may be included in an amount of approximately 2 to 20% by weight, and preferably approximately 7 to 15% by weight, based on the total weight of the composition.

The sustained-release pharmaceutical composition of the present invention includes one or more selected from the group consisting of polyvinyl acetate and fatty acid ester as a sustained-release base. In the present invention, the sustained-release base may be included in an amount of approximately 10 to 80% by weight, preferably approximately 20 to 60% by weight, and more preferably approximately 25 to 50% by weight, based on the total weight of the composition. If the content of the sustained-release base is less than 10% by weight, the sustained release function is reduced, and thus dose dumping of the active ingredient may occur. If the content of the sustained-release base is more than 80% by weight, drug diffusion may be reduced to decrease the dissolution rate.

In the present invention, if polyvinyl acetate is used as the sustained-release base, polyvinyl acetate may be used alone or a mixture of polyvinylpyrrolidone and polyvinyl acetate may be used. For example, commercially available Kollidon®SR (BASF, German) may be used, but it is not limited thereto. This mixture of polyvinylpyrrolidone and polyvinyl acetate is a mixture of the compounds that are insoluble and soluble in gastric or intestinal fluid. Preferably, the mixture may include polyvinylpyrrolidone and polyvinyl acetate at a weight ratio of 8 : 1 to 2.

The polymer mixture of polyvinyl acetate and polyvinylpyrrolidone used in the present invention functions to support materials for the formation of solid formulation and to form pores within the formulations in water after a predetermined time. In addition, the polymer mixture of polyvinyl acetate and polyvinylpyrrolidone is allowed to exhibit a predetermined release pattern irrespective of pH change and a sustained-release even left in water for a long time, and thus it is a very important component for the sustained-release of donepezil.

Preferably, the mixture of polyvinyl acetate and polyvinylpyrrolidone may further include a surfactant that functions as an auxiliary wetting agent. Examples of the surfactant may include sodium lauryl sulfate or derivatives thereof, poloxamer or derivatives thereof, a variety of polysorbates (e.g., polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate and polyoxy sorbitan monostearate), and sorbitan ester, but are not limited thereto. Preferably, it may include sodium lauryl sulfate. Addition of the surfactant enhances the wetting effect and solubilization, when polyvinyl acetate and polyvinylpyrrolidone are contacted with gastric or intestinal fluid. In the specific Example of the present invention, a mixture of polyvinyl acetate and polyvinylpyrrolidone (Kollidon®SR, BASF, Germany) consisting of 80% by weight of polyvinyl acetate, 19% by weight of polyvinylpyrrolidone, 0.8% by weight of sodium lauryl sulfate, and 0.2% by weight of colloidal silica was used.

In the present invention, fatty acid ester as the sustained-release base may include glyceryl behenate, hydrogenated castor oils (cutina®), stearyl, cetostearyl or cetylalcohol, mono-, di-, and tri-glycerides such as glyceryl palmitostearate or glyceryl monooleate, and solid paraffin, preferably glyceryl behenate, but is not limited thereto. For example, the glyceryl behenate under the trade name of COMPRITOL® 888 ATO may be used, and this compound allows control of matrix permeability.

As the sustained-release base of the present invention, polyvinyl acetate and/or fatty acid ester exhibit(s) predetermined release patterns under various pH conditions, and can be prepared by direct compression, dry or wet granulation, melt granulation or the like, and minimize(s) burst-out effect in the initial period of release, and exhibit(s) excellent durability under physicochemical conditions. In addition, polyvinyl acetate and fatty acid ester are able to maintain stability under high humidity condition, because they are hydrophobic.

The sustained-release pharmaceutical composition of the present invention may further include a release controlling agent. In the present invention, the release controlling agent may be included in an amount of approximately 0.1 to 50% by weight, and preferably approximately 5 to 30% by weight, based on the total weight of the composition.

Generally, the matrix tablet is disadvantageous in that its dissolution rate is lower in the late stage than in the initial stage of dissolution and thus drug release does not completely occur. Therefore, the present inventors could obtain a dissolution profile in the late stage similar to that in the initial stage by using the release controlling agent such as carboxymethylethylcellulose or methacrylic acid-acrylic acid ethyl copolymer.

The sustained-release pharmaceutical composition of the present invention is characterized in that it exhibits a dissolution rate of 20 to 40% at 2 hr, 40 to 60% at 4 hr, and 80% or higher at 10 hr for the effective once-daily administration of donepezil or the salt thereof (see Table 4 of Experimental Example).

Further, the sustained-release pharmaceutical composition of the present invention is characterized in that it maintains dissolution stability without great variation in dissolution rate even after long-term storage. According to the specific Example of the present invention, when the sustained-release formulation of the present invention was stored at 40°C and 75% relative humidity for 4 months and its dissolution was measured according to the second method of the Korean Pharmacopoeia (paddle method), changes in dissolution rate was hardly observed. However, the conventional formulation that was prepared by wet granulation using ethyl cellulose as the sustained-release base showed a greatly reduced dissolution rate.

Further, the sustained-release pharmaceutical composition of the present invention is characterized in that it shows bioequivalence in the dissolution test under food intake. According to the specific Example of the present invention, when the dissolution test of the sustained-release formulation was performed under in vitro conditions similar to the gastrointestinal tract environment, changes in dissolution rate was hardly observed. However, the conventional formulation that was prepared using ethyl cellulose as the sustained-release base showed an abrupt dissolution change at the initial stage.

These results show that the sustained-release pharmaceutical composition of the present invention exhibits excellent dissolution stability under various environments such as long-term storage and food intake.

The donepezil-containing sustained-release pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive. The pharmaceutically acceptable additive refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. The additive may promote the manufacture, compressibility, appearance, and taste of the preparation. For example, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, bases, adsorbents, flavor enhancers, binders, suspending agents, cross-linking agents, antioxidants, polishing agents, flavors, flavor enhancers, dyes, coating agents, wetting agents, humectants, fillers, antifoaming agents, refreshing agents, masticatory substances, antistatic agents, colorants, sugar coating agents, isotonizing agents, softeners, emulsifying agents, adhesives, thickeners, blowing agents, pH regulating agents, excipients, dispersing agents, disintegrants, waterproof agents, antiseptic agents, preservatives, solubilizing agents, solvents, plasticizers or the like may be added, if necessary.

Specific examples of the additive may include refined white sugar, glucose, trehalose, lactose, maltose, mannitol, sorbitol, xylitol, erythritol, sodium saccharin, aspartame, acesulfame potassium, sucralose, licorice extract, stevia extract, momordica extract, corn starch, potato starch, wheat starch, sodium hydro gencarbonate, sodium chloride, crystalline cellulose, methyl cellulose, ethyl cellulose, hypromellose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, hypromellose phthalic acid ester, cellulose acetate phthalate, dextrin, pregelatinized starch, Arabica gum, tragacanth, gelatin, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyyinyl polymer, magnesium stearate, talc, hydrogenated vegetable oil, macrogol, polyoxyethylene hydrogenated castor oil 60, hydrated silicon dioxide, silicone oil, agar, shellac, glycerin, essential oil, water soluble food colors, yellow ferric oxide, yellow ferric oxide diiron trioxide, iron sesquioxide, brown ferric oxide, black ferric oxide, titanium dioxide, lake dye, benzoic acid, sodium benzoate, paraoxybenzoate, polysorbate 80, fatty acid ester of glycerin, white beeswax, medium-chain triglyceride, ascorbic acid, tocopherol, sodium thiosulfate, sodium edetate, citrus fruit flavor such as orange or lemon, coffee flavor, chocolate flavor, yogurt flavor, milk flavor, plant oils such as lemon oil, peppermint oil, spearmint oil, and spice oil. However, there are no particular limitations, as long as it is pharmaceutically available.

The sustained-release formulation of the present invention is not particularly limited, as long as it is an oral formulation. It may be formulated in a form of tablet, powder, granule, capsule, or pellet, and preferably a matrix-type formulation. In the matrix-type sustained-release formulation, the drug and the sustained-release base are uniformly distributed. Thus, it is easily prepared, and advantageous in terms of size reduction. If necessary, film coating of the matrix-type sustained-release formulation may be performed.

The particular mode of administration and the dosage of the sustained-release formulation of the present invention may be selected by the attending physician taking into account the particulars of the patient, especially age, weight, life style, symptom level, etc. Preferably, the sustained-release formulation of the present invention may be provided in a form suitable for once-daily administration, in order to maintain the plasma level of active ingredients and to reduce the frequency of administration for the improvement of patient compliance.

The donepezil-containing sustained-release formulation of the present invention may be used for the prevention and treatment of senile dementia, in particular, Alzheimer's diseases.

In another aspect, the present invention relates to a preparation method for the sustained-release pharmaceutical composition including donepezil or the salt thereof.

Specifically, the present invention relates to a preparation method of the sustained-release pharmaceutical composition, including the steps of:

(a) blending donepezil or the pharmaceutically acceptable salt thereof; and one or more sustained-release bases selected from the group consisting of polyvinyl acetate and fatty acid ester; and

(b) compression-molding the mixture.

In the preferred embodiment, a pharmaceutically acceptable additive may be blended therewith at the same time in step (a). For example, one or more of a lubricant, a filler, a diluent, a binder, and a disintegrant may be included, and other commonly used desiccant, sweetener, or moisture absorbent may be included.

A process of granulating the mixture, for example, wet granulation, dry granulation, fluidized-bed granulation, compression granulation, or spray drying granulation, may be further included before the compression molding process. Alternatively, compression molding may be performed using a compressor by direct compression after the blending process. The blending and compression-molding processes may be performed according to the typical methods in pharmaceutics.

[Mode for Invention] Hereinafter, the present invention will be described in detail with reference to Examples. However, the following examples are for illustrative purposes only, and the invention is not intended to be limited by these Examples.

Examples 1 to 10. Preparation of donepezil-containing sustained-release formulations

According to the ingredients and contents of the following Tables 1 and 2, donepezil-containing sustained-release formulations were prepared in a form of tablet (unit: mg).

Specifically, donepezil hydrochloride, polyvinyl acetate, glyceryl behenate, methacrylic acid-acrylic acid ethyl copolymer (Eudragit® LI 00-55), carboxymethylethylcellulose, hydrated lactose and hydroxypropylcellulose were prepared according to the contents of the following Tables 1 and 2, passed through a 30-mesh sieve, and then blended therewith. The mixture was lubricated with magnesium stearate. The lubricated mixture was compressed using a roller compactor (TF-Labo, Freund), and milled using an oscillator (AR402, Erweka) to give dry granules. The dry granules were compressed to give 200 mg of tablet, and the tablet was coated with Opadry® 85F665007 to prepare a final coating tablet. [Table 1]

Magnesium stearate 1 1 1 1 1 1

Opadry® 85F665007 8 8 8 8 8 8

Total 208 208 208 208 208 208

[Table 2]

Comparative Examples 1 and 2. Preparation of donepezil-containing sustained-release formulations

The comparative formulations were prepared according to Korean Patent No. 0904602. According to the ingredients and contents of the following Table 3, donepezil-containing sustained-release formulations were prepared in a form of tablet (unit: mg).

Specifically, donepezil hydrochloride, Ethocel 10FP (ethyl cellulose), methacrylic acid-acrylic acid ethyl copolymer and lactose were prepared according the contents of the following Table 3, and blended in a stirring granulator. An aqueous solution of hydroxypropylcellulose dissolved in a suitable amount of purified water was added to the mixture, followed by wet granulation. The granules were dried by heating using a dryer, followed by granulation. Magnesium stearate was added to the granules, and mixed with each other, and the mixture was compressed using a rotary compressor to give a tablet with a diameter of 8 mm, containing 23 mg of donepezil hydrochloride in 200 mg. Aqueous film coating of the obtained tablet was performed using hydroxypropylmethylcellulose to give a film-coated tablet.

[Table 3]

. means quantity sufficient.

Experimental Example 1. Dissolution test immediately after tablet preparation

Dissolution tests were performed immediately after preparation of donepezil hydrochloride sustained-release tablets of Examples and Comparative Examples. The dissolution test was performed using 900 ml of phosphate buffer (pH 6.8) as a medium at 37°C and a paddle rotation speed of 50 rpm according to the second method of the Korean Pharmacopoeia (paddle method) so as to examine the dissolution profile of each tablet. The results are shown in Tables 4 and 5 (unit: % by weight).

56.6 58.4 60.5 57.5 39.6 37.6 56.0 56.6 52.1 47.4

73.0 72.8 77.1 73.8 50.0 44.9 66.1 74.5 59.6 68.7

85.0 86.9 88.8 85.5 58.3 53.5 71.5 85.0 71.5 83.5

93.4 95.7 97.1 95.6 65.7 62.3 75.2 97.2 76.5 96.7

[Table 5]

Experimental Example 2. Dissolution test immediately and at 4 months after tablet preparation

Dissolution tests were performed immediately and at 4 months after preparation of donepezil hydrochloride sustained-release tablets of Examples 1 and 4, and Comparative Example 2. Each tablet was stored at 40°C and 75% relative humidity for 4 months. The dissolution test was performed using 900 ml of phosphate buffer (pH 6.8) as a medium at 37°C and a paddle rotation speed of 50 rpm according to the second method of the Korean Pharmacopoeia (paddle method) so as to examine the dissolution profile of each tablet. The results are shown in Table 6 and FIGs. 1 and 2 (unit: % by weight). [Table 6]

As shown in Table 6, the tablets of Examples 1 and 4, prepared by dry granulation using hydrophobic polymers, showed no changes in the dissolution rate even after 4 months. On the contrary, the tablet of Comparative Example 2, prepared using ethylcellulose as the sustained-release base, showed a greatly reduced dissolution rate after 4 months.

Experimental Example 3. Dissolution test under food intake

The sustained-release tablets are required to have bioequivalence under food intake, and thus in vitro dissolution tests were performed according to the description in "M. Zahirul I. Khan. International Journal of Pharmaceutics 140(19-6) 131 143 Dissolution testing for sustained or controlled release oral dosage forms and correlation with in vivo data: challenges and opportunities" to test whether the tablets meet the bioequivalence requirements under food intake.

Specifically, the sustained-release tablet of Example 1 was dissolved in 900 ml of pH 1.2 hydrochloric acid/sodium chloride solution similar to the gastrointestinal tract environment, and the compounds shown in the following Table 5 were added to perform the time-dependent dissolution test. The results are shown in Table 7 and FIG. 3 (unit: % by weight).

[Table 7]

The sustained-release tablet of Comparative Example 1 was also dissolved in

900 ml of pH 1.2 hydrochloric acid/sodium chloride solution, and the compounds shown in the following Table 8 were added to perform the time-dependent dissolution test. The results are shown in Table 8 and FIG. 4 (unit: % by weight).

[Table 8]

In the results of dissolution studies, the tablet of Example 1 of the present invention showed a slight change in the dissolution rate under food intake, whereas the sustained-release tablet of Comparative Example 1 prepared by the conventional method showed a great change in the dissolution rate under the environment similar to the gastrointestinal tract after food intake, suggesting that the tablet prepared by using ethylcellulose as the sustained-release base according to the conventional method is degraded by foods ingested under the gastrointestinal tract environment, and thus its abrupt dissolution occurs. As such, the sustained-release formulation of the present invention exhibits very excellent dissolution stability without change in the dissolution rate even under food intake.

Claims

[CLAIMS]

[Claim 1]

A sustained-release pharmaceutical composition, comprising donepezil or a pharmaceutically acceptable salt thereof; and one or more sustained-release bases selected from the group consisting of polyvinyl acetate and fatty acid ester.

[Claim 2]

The composition according to claim 1, wherein the salt is donepezil hydrochloride.

[Claim 3]

The composition according to claim 1 , wherein the polyvinyl acetate is included in a form of mixture containing polyvinylpyrrolidone and polyvinyl acetate in a weight ratio of 8 : 1 to 2.

[Claim 4]

The composition according to claim 1, wherein the fatty acid ester is one or more selected from the group consisting of glyceryl behenate, hydrogenated castor oil, stearyl, cetostearyl or cetylalcohol, mono-, di-, or tri-glyceride, and solid paraffin.

[Claim 5]

The composition according to claim 1, wherein the sustained-release base is included in an amount of 10 to 80% by weight, based on the total weight of the composition.

[Claim 6]

The composition according to claim 1 , further comprising a release controlling agent.

[Claim 7]

The composition according to claim 6, wherein the release controlling agent includes carboxymethylethylcellulose or methacrylic acid-acrylic acid ethyl copolymer.

[Claim 8]

The composition according to claim 6, wherein the release controlling agent is included in an amount of 0.1 to 50% by weight, based on the total weight of the composition.

[Claim 9]

The composition according to claim 1, further comprising a pharmaceutically acceptable additive.

[Claim 10]

The composition according to claim 1, for the prevention and treatment of Alzheimer's diseases.

[Claim 11]

A preparation method of the sustained-release pharmaceutical composition of claim 1 , comprising the steps of:

(a) blending donepezil or a pharmaceutically acceptable salt thereof; and one or more sustained-release bases selected from the group consisting of polyvinyl acetate and fatty acid ester; and

(b) compression-molding the mixture.