JP2018177706A - Galanthamine-containing pharmaceutical composition, and method for inhibiting bitterness of galanthamine in pharmaceutical composition, and agent for inhibiting bitterness of galanthamine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a galanthamine-containing pharmaceutical composition having an excellent effect of inhibiting the bitterness of galanthamine either at the time of breakdown of a pharmaceutical composition or in its aftertaste, and a method for inhibiting the bitterness of galanthamine in a pharmaceutical composition, and an agent for inhibiting the bitterness of galanthamine.SOLUTION: A galanthamine-containing pharmaceutical composition contains galanthamine, and a sweetness agent. The sweetness agent contains at least one selected from the group consisting of sucralose, acesulfame potassium, stevia, and thaumatin.SELECTED DRAWING: None

Description

  The present invention relates to a galantamine-containing pharmaceutical composition, a method for suppressing bitterness of galantamine in the pharmaceutical composition, and a bitterness inhibitor for galantamine.

Galantamine is a compound represented by the following structural formula (chemical name: (4aS, 6R, 8aS) -4a, 5, 9, 10, 11, 12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [ 3a, 3, 2-ef] [2] benzazepin-6-ol). At present, galantamine hydrobromide, which is a salt of galantamine, is used as an active ingredient of a preparation having efficacy and effect of suppressing the progression of dementia symptoms in mild and moderate Alzheimer's disease.

As formulations containing galantamine hydrobromide as an active ingredient, dosage forms of film-coated tablets, orally disintegrating tablets, and internal solutions having a product name of "reminil" have been marketed.
Among the various dosage forms, the orally disintegrating tablet is considered to be particularly significant, because the preparation is mainly for the elderly and the care aid by the caregiver is large.

  However, galantamine is a component that exhibits a bitter taste, and when taking the preparation, feeling bitter when disintegrated in the oral cavity or that bitter taste remains in the oral cavity after swallowing a tablet may lead to deterioration in medication compliance. There is a problem of Therefore, there is a need for a preparation with improved drugability.

In the above-mentioned Reminil orally disintegrating tablet proposed so far and the orally disintegrating tablet described in Patent Document 1, aspartame is added to add sweetness to the preparation and masking, thereby measuring improvement in bitter taste There is.
However, these proposals have a problem that it can not be said that the bitter taste of galantamine can be sufficiently suppressed.

  Therefore, there is a strong demand for further development of technology capable of suppressing the bitter taste of galantamine.

JP, 2012-188364, A

  An object of the present invention is to solve the above-mentioned problems in the prior art and to achieve the following objects. That is, the present invention provides a galantamine-containing pharmaceutical composition excellent in the bitter taste suppressing effect of galantamine on at least one of disintegration and aftertaste of the pharmaceutical composition, a bitter taste suppressing method of galantamine in the pharmaceutical composition, and a bitter taste suppressing agent of galantamine. Intended to provide.

The means for solving the problems are as follows. That is,
<1> contains galantamine and a sweetener,
The galantamine-containing pharmaceutical composition is characterized in that the sweetening agent contains at least one selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin.
<2> The galantamine-containing pharmaceutical composition according to <1>, wherein the sweetening agent comprises at least one selected from the group consisting of sucralose, stevia, and thaumatin.
It is a galantamine containing pharmaceutical composition in any one of said <1> to <2> which is a <3> orally disintegrating tablet.
<4> The galantamine-containing pharmaceutical composition according to any one of <1> to <3>, further comprising at least one of mannitol and lactose, and at least one of polyvinyl alcohol and polyvinyl pyrrolidone.
<5> The galantamine-containing pharmaceutical composition according to <4>, wherein a total amount of at least one of mannitol and lactose is 7 parts by mass to 99 parts by mass with respect to 1 part by mass of the galantamine.
The total amount of at least any one of <6> said polyvinyl alcohol and polyvinyl pyrrolidone is 0.001 mass part-5 mass parts with respect to 1 mass part of said galantamine to either of said <4> to <5> It is a galantamine containing pharmaceutical composition as described.
It is a galantamine containing pharmaceutical composition in any one of said <1> to <6> which does not contain a <7> disintegrant.
<8> including the step of contacting galantamine with a sweetener,
The method for suppressing bitterness of galantamine in a pharmaceutical composition, wherein the sweetening agent contains at least one selected from the group consisting of sucralose, acesulfame potassium, stevia, and thaumatin.
<9> The method according to <8>, wherein the sweetening agent comprises at least one selected from the group consisting of sucralose, stevia, and thaumatin.
<10> The method for suppressing bitterness of galantamine in the pharmaceutical composition according to any one of <8> to <9>, wherein the pharmaceutical composition is an orally disintegrating tablet.
<11> The galantamine in the pharmaceutical composition according to any one of <8> to <10>, further comprising the step of contacting galantamine, at least one of mannitol and lactose, and at least one of polyvinyl alcohol and polyvinyl pyrrolidone. Bitterness suppression method.
<12> The method for suppressing bitterness of galantamine in the pharmaceutical composition according to <11>, wherein at least one of the mannitol and lactose is used in a total of 7 parts by mass to 99 parts by mass with respect to 1 part by mass of the galantamine It is.
<13> In any one of <11> to <12>, at least one of the polyvinyl alcohol and polyvinyl pyrrolidone is used in a total amount of 0.001 parts by mass to 5 parts by mass with respect to 1 part by mass of the galantamine. It is the bitterness suppression method of galantamine in the pharmaceutical composition as described.
<14> The pharmaceutical composition is a method for suppressing bitter taste of galantamine in the pharmaceutical composition according to any of <8> to <13>, wherein the pharmaceutical composition does not contain a disintegrant.
<15> It is used for the pharmaceutical composition containing galantamine,
It is a bitter taste inhibitor of galantamine in a pharmaceutical composition comprising at least one sweetener selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin.
<16> The bitter taste inhibitor of galantamine in the pharmaceutical composition according to <15>, wherein the sweetening agent contains at least one selected from the group consisting of sucralose, stevia, and thaumatin.
<17> The bitter taste inhibitor for galantamine in the pharmaceutical composition according to any one of <15> to <16>, which is an orally disintegrating tablet.
<18> A bitter taste inhibitor of galantamine in the pharmaceutical composition according to any one of <15> to <17>, further comprising at least one of mannitol and lactose, and at least one of polyvinyl alcohol and polyvinyl pyrrolidone. .
<19> The pharmaceutical composition according to <18>, wherein the total amount of at least one of mannitol and lactose is 7 parts by mass to 99 parts by mass with respect to 1 part by mass of the galantamine. It is a bitter taste inhibitor of galantamine.
<20> The <18> to <19> are mixed so that the total amount of at least one of the polyvinyl alcohol and the polyvinyl pyrrolidone is 0.001 parts by mass to 5 parts by mass with respect to 1 part by mass of the galantamine. It is a bitterness inhibitor of galantamine in the pharmaceutical composition in any one of <>.
<21> The pharmaceutical composition is a bitter taste inhibitor of galantamine in the pharmaceutical composition according to any one of <15> to <20> which does not contain a disintegrant.

  According to the present invention, the galantamine-containing pharmaceutical composition can solve the above-mentioned various problems in the prior art and achieve the above-mentioned object, and is excellent in the bitter taste suppressing effect of galantamine in at least one of collapse and aftertaste of the pharmaceutical composition. And a method for suppressing bitter taste of galantamine in a pharmaceutical composition, and a bitter taste inhibitor of galantamine.

(Galantamine-containing pharmaceutical composition)
The galantamine-containing pharmaceutical composition of the present invention comprises at least galantamine and at least one sweetening agent selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin, and optionally further components. .

<Galantamine>
The galantamine is a compound represented by the following structural formula (chemical name: (4aS, 6R, 8aS) -4a, 5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a, 3, 2-ef] [2] benzazepin-6-ol). The galantamine may be in the form of a salt. There is no restriction | limiting in particular as a form of the said salt, According to the objective, it can select suitably, For example, galantamine hydrobromide etc. are mentioned.
As the galantamine, one produced by a known method may be used, or a commercially available product may be used.

  There is no restriction | limiting in particular as content in the said galantamine containing pharmaceutical composition of the said galantamine, According to the objective, it can select suitably, For example, 1 mass%-10 mass% etc. are mentioned as galantamine.

Sweeteners
The sweetening agent contains at least one selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin, and may further contain other sweetening agents as required. These may be used alone or in combination of two or more.
Among these, the group consisting of sucralose, stevia, and thaumatin in that the bitter taste of galantamine can be further suppressed, and further, the reduction in tablet hardness can be prevented even when stored under high temperature and high humidity conditions. It is preferable to contain at least one selected from

  Specific examples of the combined use of the above-mentioned sweeteners include sucralose and stevia, sucralose and stevia and thaumatin, sucralose and thaumatin, acesulfame potassium and stevia and the like.

  The sweetening agent may be one produced by a known method, or a commercially available product.

  The total content of at least one sweetener selected from the group consisting of sucralose, acesulfame potassium, stevia, and thaumatin in the galantamine-containing pharmaceutical composition is not particularly limited, and may be appropriately selected according to the purpose. However, 0.001% by mass to 10% by mass is preferable, 0.005% by mass to 7% by mass is more preferable, and 0.01% by mass to 5% by mass is particularly preferable. It is advantageous at the point which the bitterness inhibitory effect of galantamine is more excellent in it being in the said preferable range.

  The amount of at least one sweetening agent selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin relative to galantamine is not particularly limited and may be appropriately selected depending on the purpose, The total amount is preferably 0.0001 parts by mass to 2 parts by mass, more preferably 0.0005 parts by mass to 1 part by mass, and particularly preferably 0.001 parts by mass to 0.7 parts by mass with respect to 1 part by mass of the galantamine. It is advantageous at the point which the bitterness inhibitory effect of galantamine is more excellent in it being in the said preferable range.

  There is no restriction | limiting in particular as quantity of each sweetening agent in the case of using 2 or more types of said sweetening agents, According to the objective, it can select suitably.

<Other ingredients>
The other components in the galantamine-containing pharmaceutical composition are not particularly limited as long as the effects of the present invention are not impaired, and additives commonly used in the pharmaceutical field can be appropriately selected according to the purpose, for example, Excipients, binders, lubricants, surfactants, sweeteners, flavoring agents, flavors, fluidizers, colorants, stabilizers, pH adjusters, coating agents and the like can be mentioned. These may be used alone or in combination of two or more.
The other components in the galantamine-containing pharmaceutical composition may be manufactured by known methods, or commercially available products may be used.
There is no restriction | limiting in particular as content in the said galantamine containing pharmaceutical composition of the said other component, According to the objective, it can select suitably.

-Excipient-
The excipient is not particularly limited and may be appropriately selected according to the purpose. For example, mannitol (hereinafter sometimes referred to as "D-mannitol"), lactose, corn starch, sucrose, erythritol, talc , Purified gelatin, hydroxypropyl starch, calcium silicate and the like. These may be used alone or in combination of two or more.
Among these, it is preferable to include at least one of mannitol and lactose in that the decrease in stability of galantamine due to the effects of high temperature and high humidity can be improved. Among these, mannitol may be used alone, lactose may be used alone, or both may be used in combination.

  As said mannitol, what was manufactured by the well-known method may be used, and a commercial item may be used.

  The lactose may be anhydrate or a hydrate. The lactose may be one produced by a known method or a commercially available product.

  The amount of mannitol or lactose in at least one of mannitol and lactose is not particularly limited, and can be appropriately selected depending on the purpose.

  There is no restriction | limiting in particular as a total content in the said galantamine containing pharmaceutical composition of the said mannitol and lactose, Although it can select suitably according to the objective, 70 mass%-99 mass% are preferable, 75 % By mass to 98% by mass is more preferable, and 85% by mass to 98% by mass is particularly preferable. Within the preferred range, it is advantageous in that the decrease in stability of galantamine due to the effects of high temperature and high humidity can be further improved.

  The amount of at least one of the mannitol and lactose to the galantamine is not particularly limited and may be appropriately selected according to the purpose, but the total amount is 7 parts by mass to 99 parts by mass with respect to 1 part by mass of the galantamine. A mass part is preferable, 7.5 mass parts-66 mass parts are more preferable, 8.5 mass parts-49 mass parts are especially preferable. If the amount of at least one of the mannitol and lactose for the galantamine is within the preferred range, it is advantageous in that the reduction in stability of galantamine due to the effects of high temperature and high humidity can be further improved.

-Binder-
There is no restriction | limiting in particular as said binder, According to the objective, it can select suitably, For example, polyvinyl alcohol, polyvinyl pyrrolidone, a hypromellose, a hydroxypropyl cellulose etc. are mentioned. These may be used alone or in combination of two or more.
Among these, it is preferable to include at least one of polyvinyl alcohol and polyvinyl pyrrolidone from the viewpoint of being able to improve the decrease in stability of galantamine due to the effects of high temperature and high humidity. Among these, polyvinyl alcohol may be used alone, polyvinyl pyrrolidone may be used alone, or both may be used in combination.

The polyvinyl alcohol is a polymer obtained by saponifying polyvinyl acetate.
As the average degree of polymerization and the degree of saponification of the polyvinyl alcohol, the average degree of polymerization and the degree of saponification can be appropriately adjusted by appropriately adjusting vinyl acetate as a raw material.

  There is no restriction | limiting in particular as an average polymerization degree of the said polyvinyl alcohol, Although it can select suitably according to the objective, 200-3,500 are preferable and 300-2,200 are more preferable. The average degree of polymerization can be measured according to JIS K 6726.

  There is no restriction | limiting in particular as a saponification degree of the said polyvinyl alcohol, Although it can select suitably according to the objective, 65 mol% or more is preferable and 78 mol% or more is more preferable. Among these, 78 mol% to 96 mol% (partial saponification), 97 mol% or more (complete saponification) are more preferable, and 78 mol% to 96 mol% (partial saponification) are particularly preferable. In addition, as said saponification degree, it can measure according to JISK6726.

  As said polyvinyl alcohol, what was manufactured by the well-known method may be used, and a commercial item may be used.

  The polyvinyl pyrrolidone is a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone.

  There is no restriction | limiting in particular as a weight average molecular weight of the said polyvinylpyrrolidone, Although it can select suitably according to the objective, 10,000-400,000 are preferable, 10,000-60,000 are more preferable, 20,000. 000 to 60,000 are particularly preferred. The weight average molecular weight can be measured by light scattering measurement.

  As the polyvinyl pyrrolidone, one produced by a known method may be used, or a commercially available product may be used.

  There is no restriction | limiting in particular as content of polyvinyl alcohol or polyvinyl pyrrolidone in at least any one of the said polyvinyl alcohol and polyvinyl pyrrolidone, According to the objective, it can select suitably.

  There is no restriction | limiting in particular as total content in the said galantamine containing pharmaceutical composition of the said polyvinyl alcohol and polyvinyl pyrrolidone, Although it can select suitably according to the objective, 0.01 mass%-5 mass% Is preferable, 0.05 to 3% by mass is more preferable, and 0.1 to 2% by mass is particularly preferable. Within the preferred range, it is advantageous in that the decrease in stability of galantamine due to the effects of high temperature and high humidity can be further improved.

  The amount of at least one of the polyvinyl alcohol and polyvinyl pyrrolidone relative to the galantamine is not particularly limited and may be appropriately selected depending on the purpose, but the total amount is 0.001 parts by mass with respect to 1 part by mass of the galantamine. The parts by mass to 5 parts by mass are preferable, the parts by mass to 0.005 parts by mass are more preferable, and the parts by mass to 0.01 parts by mass are particularly preferable. Within the preferred range, it is advantageous in that the decrease in stability of galantamine due to the effects of high temperature and high humidity can be further improved.

  The mass ratio of at least one of the polyvinyl alcohol and polyvinyl pyrrolidone to at least one of the mannitol and lactose is not particularly limited and may be appropriately selected according to the purpose. However, at least one of the polyvinyl alcohol and polyvinyl pyrrolidone is selected. Any total amount: The total amount of at least one of the above-mentioned mannitol and lactose is preferably 1:14 to 1: 9,900, more preferably 1:25 to 1: 1,960, 1:42 to 1: 980 is particularly preferred. Within the preferred range, it is advantageous in that the decrease in stability of galantamine due to the effects of high temperature and high humidity can be further improved.

-Lubricant-
The lubricant is not particularly limited and may be appropriately selected depending on the purpose. For example, magnesium stearate, calcium stearate, talc, hydrogenated oil, white beeswax, carnauba wax, polyethylene glycol 6000, stearyl sodium fumarate And stearic acid. These may be used alone or in combination of two or more.
There is no restriction | limiting in particular as content in the said galantamine containing pharmaceutical composition of the said lubricant, According to the objective, it can select suitably.

  The galantamine-containing pharmaceutical composition preferably contains no disintegrant.

<Dosage form>
There is no restriction | limiting in particular as a dosage form of the said galantamine containing pharmaceutical composition, According to the objective, it can select suitably, For example, tablets, such as an uncoated tablet, an orally disintegrating tablet, a chewable tablet, a film coating tablet, granules etc. Can be mentioned. Among these, orally disintegrating tablets are preferred.
Further, the galantamine-containing pharmaceutical composition is preferably a wet tablet.
There is no restriction | limiting in particular as a shape, a structure, and a size of the said tablet, According to the objective, it can select suitably.

<Manufacturing method>
There is no restriction | limiting in particular as a manufacturing method of the said galantamine containing pharmaceutical composition, A well-known method can be suitably selected according to the objective.
For example, as a manufacturing method in the case of manufacturing a tablet as the galantamine containing pharmaceutical composition, a direct compression method, a dry granular compression method, a wet granular compression method, a wet compression method can be mentioned.

  Specific examples of the direct compression method include the galantamine, the at least one sweetener selected from the group consisting of the sucralose, acesulfame potassium, stevia, and thaumatin, and the other components as necessary. The method of mixing and compression-molding the said mixture is mentioned.

As a specific example of the dry granular compression method, there is mentioned a method of compressing and molding the granules obtained by the roller compression method or the like.
There is no restriction | limiting in particular as a method and conditions of the said roller compression method, A well-known method and conditions can be suitably selected according to the objective.

As a specific example of the said wet-granule compression method, the method of compression-molding the granule obtained by the extrusion granulation method, a fluidized bed granulation method, the stirring granulation method etc. is mentioned.
There is no restriction | limiting in particular as a method and conditions of the said extrusion granulation method, a fluidized-bed granulation method, and a stirring granulation method, A well-known method and conditions can be suitably selected according to the objective.

There is no restriction | limiting in particular as a method of tableting in manufacture of the said tablet, A well-known method can be suitably selected according to the objective, For example, the method of using a rotary type tableting machine, etc. are mentioned.
There is no restriction | limiting in particular as conditions for the said tableting, According to the objective, it can select suitably.

In addition, the method for producing the galantamine-containing pharmaceutical composition of the present invention is not particularly limited and may be appropriately selected according to the purpose without particular limitation. For example, the galantamine, the sucralose, the acesulfame potassium, After mixing at least one type of sweetener selected from the group consisting of stevia and thaumatin with the above-mentioned other components as required, a mixing solvent is added and the mixture is mixed, and the obtained wet powder is compressed. The method of shape | molding is mentioned.
The wet powder may be compression molded as it is or may be compression molded after being wet granulated to form a granulated product.
There is no restriction | limiting in particular as a method and conditions of the said mixing, kneading | mixing, and compression molding, A well-known method and conditions can be suitably selected according to the objective.

  The galantamine-containing pharmaceutical composition of the present invention is excellent in the bitter taste suppressive effect of galantamine on at least one of decay time and aftertaste of the pharmaceutical composition.

(Method for suppressing bitter taste of galantamine in pharmaceutical composition)
The method for suppressing bitter taste of galantamine in the pharmaceutical composition of the present invention at least includes a sweetener contact step, and further includes other steps as necessary.
In the method of the present invention, as the other step, a step of contacting galantamine, at least one of mannitol and lactose, and at least one of polyvinyl alcohol and polyvinyl pyrrolidone (hereinafter referred to as "contacting step with mannitol etc." Is preferred.

Sweetener Contact Step
The sweetening agent contacting step is a step of bringing galantamine into contact with at least one sweetening agent selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin.
At the said contact process, other components other than the at least 1 sort (s) of sweetener selected from the group which consists of said galantamine, said sucralose, acesulfame potassium, stevia, and thaumatin may exist.

-Galantamine-
The said galantamine is the same as what was described in the item of <galantamine> of the galantamine containing pharmaceutical composition of this invention mentioned above.

-Sweetener-
The at least one sweetening agent selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin is the same as that described in the <sweetener> of the galantamine-containing pharmaceutical composition of the present invention described above. Preferred embodiments are also the same.

-Other ingredients-
The other components are the same as those described in the section <Other components> of the galantamine-containing pharmaceutical composition of the present invention described above, and preferred embodiments are also the same.

-Contact-
There is no restriction | limiting in particular as the method of the said contact, According to the objective, it can select suitably, For example, it is made to contact by the method described in the item of <manufacturing method> of the galantamine containing pharmaceutical composition of this invention mentioned above. Methods etc.

<Other process>
The other steps are not particularly limited as long as the effects of the present invention are not impaired, and may be appropriately selected according to the purpose. Examples thereof include the above-mentioned contacting step of mannitol and the like.
There is no restriction | limiting in particular as a method of the contact in the said mannitol etc. contact process, According to the objective, it can select suitably, For example, the method similar to the said sweetener contact process etc. are mentioned.

  The dosage form of the above-mentioned pharmaceutical composition is the same as that described in the item of <Formulation> of the galantamine-containing pharmaceutical composition of the present invention described above, and the preferred embodiments are also the same.

  According to the method for suppressing bitter taste of galantamine in the pharmaceutical composition of the present invention, it is possible to suppress the bitter taste of galantamine at the time of disintegration and / or aftertaste of the pharmaceutical composition.

(Bitter taste inhibitor of galantamine in pharmaceutical composition)
The bitter taste inhibitor of galantamine in the pharmaceutical composition of the present invention is used in a pharmaceutical composition containing galantamine, and is at least one sweetener selected from the group consisting of sucralose, acesulfame potassium, stevia, and thaumatin. And at least one other component as needed.

Sweeteners
The at least one sweetening agent selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin is the same as that described in the <sweetener> of the galantamine-containing pharmaceutical composition of the present invention described above. Preferred embodiments are also the same.

<Other ingredients>
The other components are the same as those described in the section <Other components> of the galantamine-containing pharmaceutical composition of the present invention described above, and preferred embodiments are also the same.

  The dosage form of the above-mentioned pharmaceutical composition is the same as that described in the item of <Formulation> of the galantamine-containing pharmaceutical composition of the present invention described above, and the preferred embodiments are also the same.

There is no restriction | limiting in particular as a usage method of the bitter taste inhibitor of galantamine in the said pharmaceutical composition, According to the objective, it can select suitably, For example, the method of making said galantamine contact etc. are mentioned.
There is no restriction | limiting in particular as the method of the said contact, According to the objective, it can select suitably, For example, it is made to contact by the method described in the item of <manufacturing method> of the galantamine containing pharmaceutical composition of this invention mentioned above. Methods etc.

  The bitter taste inhibitor of galantamine in the pharmaceutical composition of the present invention can suppress the bitter taste of galantamine at the time of disintegration and / or aftertaste of the pharmaceutical composition.

  Hereinafter, the present invention will be more specifically described based on test examples, but the present invention is not limited to these test examples.

(Test Example 1)
Measure 3 liters of galantamine hydrobromide (Scinopharm), lactose hydrate (Pharmatose 125M, DFE Pharma), and any of the following sweeteners as shown in Table 1 below: The mixture was mixed for 2 minutes at 600 rpm using a mechano mill (manufactured by Okada Seiko Co., Ltd.) to obtain a mixture.
[Sweetening agent]
・ Sucralose (made by San-Ei Gen FFI Co., Ltd.)
・ Acesulfame potassium (SANET (registered trademark), made by Fi Nutrition Inc.)
Stevia (Stevi MZ, manufactured by Maruzen Pharmaceutical Co., Ltd.)
-Dipotassium glycyrrhizinate (manufactured by Nippon Paper Chemicals Co., Ltd.)
・ Somatin (Sun Suite, manufactured by San-Ei Gen F. F. I. Ltd.)
Aspartame (Ajinomoto KK Aspartame, made by Ajinomoto Healthy Supply Co., Ltd.)

  Water-ethanol mixed in which 1.1 g of polyvinyl alcohol (Gosenol EG-03P (polyvinyl alcohol partial saponification; degree of saponification 86.5 mol% to 89.0 mol%), manufactured by Japan Synthetic Chemical Industry Co., Ltd.) is dissolved in the above mixture 23.1 g of a solvent (mass ratio: water: ethanol = 7: 3) was added, and the mixture was kneaded for 2 minutes to obtain a wet powder.

The wet powder is tableted using a tablet making machine for wet making (EMT-18 and ETD-18, manufactured by Sanko Seisakusho Co., Ltd.), and a tablet of 7.0 mm in diameter and 110 mg per tablet (Tablet 1 -1 to 1-6) were obtained. The formulation per tablet is shown in Table 1 below.
The conditions for molding and drying were as follows.
・ Tablet molding pressure ・ ・ ・ 15kgf
・ Molding rod ・ ・ ・ Diameter 7.0mm, WR 杵 ・ Drying temperature ・ ・ ・ 85 ° C

<Test>
-Sensory test-
The sensory test was performed about each tablet obtained above as follows.
A tablet was included in the mouth, and at the time of disintegration in (A) oral cavity and (B) disintegration, sensory evaluation was performed on the intensity of bitter taste felt in the aftertaste which remains in the oral cavity after exhaling the tablet.
The said evaluation made "-" the thing which does not feel bitterness in particular, and represented the strength of bitterness by the number of "+". That is, as the bitterness is stronger, the number of "+" is more represented. The results are shown in Table 1 below.

-Collapse test-
The (i) initial product of each tablet obtained above and (ii) the stored product stored at 50 ° C. and 90% relative humidity for 2 weeks are disintegrated using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.) The time was measured. In the test described above, a disintegration test was conducted visually for 6 tablets of each sample without using a stopper, and the time until the disintegration of all the tablets was confirmed was recorded. The results are shown in Table 1 below.

-Tablet hardness-
Load cell type tablet hardness meter portable checker PC-30 type ((i) initial product of each tablet obtained above and (ii) stored product stored for 2 weeks at 50 ° C and 90% relative humidity. It measured using Okada Seiko Co., Ltd. product). The results are shown in Table 1 below.

-Appearance-
The appearance of the (i) initial product of each tablet obtained above and (iii) the stored product stored for 1 month at 50 ° C. and 90% relative humidity was visually observed. The results are shown in Table 1 below.
In addition, the tablet which does not contain the said sweetening agent is exhibiting white-pale yellow. Therefore, in Table 1 below, a tablet having the same appearance as that of the tablet containing no sweetening agent was described as "-", and the change was described for a tablet that had discoloration or a clear change in physical properties.

  As shown in Table 1, as a result of the sensory test, in the case of using the conventionally used aspartame, a strong bitter taste was felt at (A) at the time of collapse and at (B) aftertaste. On the other hand, when using acesulfame potassium or dipotassium glycyrrhizinate, (B) aftertaste was as strong as aspartame but bitterness at the time of (A) collapse was slightly improved. . In addition, when using sucralose, stevia or thaumatin, the bitterness intensity is reduced at both the (A) collapse time and (B) aftertaste, as compared with the case where aspartame is used, and the bitterness is improved. It was

  Moreover, as a result of the disintegration test, it was confirmed that all the tablets disintegrated within 30 seconds.

  With regard to tablet hardness, in the case of using acesulfame potassium, a decrease in hardness was observed when stored under severe conditions ((ii) stored for 2 weeks under conditions of 50 ° C., relative humidity 90%).

  With regard to the appearance of the tablet, in the case of using acesulfame potassium, the tablet becomes brittle when stored under severe conditions ((iii) stored at 50 ° C., 90% relative humidity for 1 month), and in the bag Some things were broken. When somatin is used, (i) the initial product is light brown due to the color tone derived from thaumatin, and when stored under severe conditions ((iii) stored at 50 ° C, 90% relative humidity for 1 month ) Turned to yellowish color. When aspartame was used, it turned yellow when stored under severe conditions ((iii) stored at 50 ° C., 90% relative humidity for 1 month).

(Test Example 2)
It is known that the sweetness intensity of each sweetener used in Test Example 1 is as shown in Table 2-1 below, where the sweetness intensity of sugar is 1.

Therefore, each tablet (tablets 2-1 to 2-6) was manufactured in the same manner as in Test Example 1 except that the amount of each sweetener in Test Example 1 was changed so that the intensity of sweetness was equal. . The formulations are shown in Table 2-2 below.
Moreover, it carried out similarly to Experiment 1, and the result of having done each test is also shown in following Table 2-2.

  As shown in Table 2-2, in the case of using sucralose, acesulfame potassium, stevia or thaumatin as compared with the case of using dipotassium glycyrrhizinate or conventionally used aspartame as a result of the sensory test, (A) At the time of collapse and / or (B) aftertaste, the intensity of the bitter taste was reduced and the bitter taste was improved.

  As a result of the disintegration test, it was confirmed that the tablet using dipotassium glycyrrhizinate was disintegrated more slowly than the other tablets.

  With regard to tablet hardness, in the case of using acesulfame potassium, a decrease in hardness was observed when stored under severe conditions ((ii) stored for 2 weeks under conditions of 50 ° C., relative humidity 90%).

  With regard to the appearance of the tablet, in the case of using acesulfame potassium, the tablet becomes brittle when stored under severe conditions ((iii) stored at 50 ° C., 90% relative humidity for 1 month), and in the bag Some things were broken. When aspartame was used, it turned yellow when stored under severe conditions ((iii) stored at 50 ° C., 90% relative humidity for 1 month).

  From the results of Test Examples 1 and 2, by using sucralose, acesulfame potassium, stevia or thaumatin as a sweetener, it is possible to mask the bitter taste of galantamine as compared with the conventionally used aspartame, and the bitter taste is further reduced. It was confirmed to do.

(Test Example 3)
Each tablet (tablets 3-1 to 3-2) was manufactured in the same manner as in Test Example 1 except that the formulation in Test Example 1 was changed as shown in Table 3 below.
Moreover, it carried out similarly to Experiment 1, and performed the sensory test. The results are shown in Table 3 below.

  As shown in Table 3, the bitter taste of the preparation was improved even when a combination of sweeteners for which effects were observed in Test Examples 1 and 2 was used.

(Test Example 4)
<Manufacture of tablet 4-1>
Galantamine hydrobromide (manufactured by Scinopharm), lactose hydrate (Pharmatose 125M, manufactured by DFE Pharma), and sucralose (manufactured by San-Ei Gen F.F.I. Co., Ltd.) as prescribed in Table 4 below. ) And mixed for 2 minutes at 600 rpm using a 3 L mechanomill (manufactured by Okada Seiko Co., Ltd.) to obtain a mixture.

  Water-ethanol mixed in which 1.1 g of polyvinyl alcohol (Gosenol EG-03P (polyvinyl alcohol partial saponification; degree of saponification 86.5 mol% to 89.0 mol%), manufactured by Japan Synthetic Chemical Industry Co., Ltd.) is dissolved in the above mixture 23.1 g of a solvent (mass ratio: water: ethanol = 7: 3) was added, and the mixture was kneaded for 2 minutes to obtain a wet powder.

The wet powder is tableted using a tablet making machine for wet making (EMT-18 and ETD-18, manufactured by Sanko Seisakusho Co., Ltd.), and a tablet of 7.0 mm in diameter and 110 mg per tablet (Tablet 4 -1) was obtained. The formulation per tablet is shown in Table 4 below.
The conditions for molding and drying were as follows.
・ Tablet molding pressure ・ ・ ・ 15kgf
・ Molding rod ・ ・ ・ Diameter 7.0mm, WR 杵 ・ Drying temperature ・ ・ ・ 85 ° C

<Production of Tablet 4-2>
A tablet 4-2 is produced in the same manner as production of the tablet 4-1 except that lactose hydrate in the tablet 4-1 is replaced with D-mannitol (Mannit P, manufactured by Mitsubishi Corporation Foodtech Co., Ltd.) did. The formulation per tablet is shown in Table 4 below.

<Manufacture of tablet 4-3>
A mixture was obtained in the same manner as in the preparation of the tablet 4-1, except that the amount of lactose hydrate in the tablet 4-1 was changed to the formulation in Table 4 below.

  A water-ethanol mixed solvent (mass ratio: water: ethanol = 7: 3) in which 2.2 g of polyvinyl pyrrolidone (Kollidon 30 (weight average molecular weight: 50,000), manufactured by BASF Corp.) is dissolved is mixed with the above mixture. The mixture was added with 2 g and kneaded for 2 minutes to obtain a wet powder.

  Tablet 4-3 was manufactured using a tablet making machine for wet making in the same manner as manufacture of tablet 4-1 except that the wet powder was used. The formulation per tablet is shown in Table 4 below.

<Manufacture of tablet 4-4>
A mixture was obtained in the same manner as in the preparation of the tablet 4-3, except that lactose hydrate in the tablet 4-3 was replaced with D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Foodtech Co., Ltd.).

  A wet powder was produced in the same manner as in the preparation of the tablet 4-3 except that the above mixture was used, and a tablet 4-4 was produced using a tablet making machine for wet making. The formulation per tablet is shown in Table 4 below.

<Test>
Each test was conducted on tablets 4-1 to 4-4 in the same manner as in Test Example 1 described above. The results are shown in Table 4.

  As shown in Table 4, even when the excipients and binders were changed, the bitter taste of the preparation was improved. In addition, among the excipients or binders used in the above-mentioned Test Examples, disintegratability, tablet hardness and appearance resulted in equivalent results.

According to the present invention, since the bitter taste of galantamine can be suppressed, it is possible to provide a galantamine-containing pharmaceutical composition with improved ease of administration. Therefore, it can contribute to the improvement of the patient's medication compliance and the suppression of the deterioration of the dementia symptoms.

Claims (9)

Contains galantamine and sweeteners,
The galantamine-containing pharmaceutical composition, wherein the sweetening agent comprises at least one selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin.   The galantamine-containing pharmaceutical composition according to claim 1, wherein the sweetening agent comprises at least one selected from the group consisting of sucralose, stevia, and thaumatin.   The galantamine-containing pharmaceutical composition according to any one of claims 1 to 2, which is an orally disintegrating tablet.   The galantamine-containing pharmaceutical composition according to any one of claims 1 to 3, further comprising at least one of mannitol and lactose, and at least one of polyvinyl alcohol and polyvinyl pyrrolidone.   The galantamine-containing pharmaceutical composition according to claim 4, wherein a total amount of at least one of mannitol and lactose is 7 parts by mass to 99 parts by mass with respect to 1 part by mass of the galantamine.   The galantamine-containing pharmaceutical composition according to any one of claims 4 to 5, wherein a total amount of at least one of the polyvinyl alcohol and polyvinyl pyrrolidone is 0.001 parts by mass to 5 parts by mass with respect to 1 part by mass of the galantamine. object.   The galantamine-containing pharmaceutical composition according to any one of claims 1 to 6, which does not contain a disintegrant. Contacting galantamine with a sweetening agent,
The method for suppressing bitter taste of galantamine in a pharmaceutical composition, wherein the sweetening agent contains at least one selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin. Used in pharmaceutical compositions containing galantamine,
An agent for suppressing bitterness of galantamine in a pharmaceutical composition comprising at least one sweetener selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin.