JP6457582B2 - Galantamine-containing pharmaceutical composition, method for inhibiting galantamine bitterness in pharmaceutical composition, and galantamine bitterness inhibitor - Google Patents

Description

  The present invention relates to a galantamine-containing pharmaceutical composition, a method for suppressing the bitter taste of galantamine in the pharmaceutical composition, and an agent for suppressing the bitter taste of 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 that is effective and effective in suppressing the progression of dementia symptoms in mild and moderate Alzheimer's dementia.

As preparations containing galantamine hydrobromide as an active ingredient, film-coated tablets, orally disintegrating tablets and product forms for internal use are marketed with the product name “Reminil”.
Among the various dosage forms, it is considered that the orally disintegrating tablet is particularly significant because the preparation target is mainly elderly people and the caregiver has a lot of medication assistance.

  However, galantamine is a bitter component, and when taking the drug product, it can be bitter when disintegrating in the oral cavity, or if bitterness remains in the oral cavity after swallowing the tablet, it can lead to worsening compliance. There is a problem. Therefore, there is a demand for preparations with improved dosing properties.

In the reminyl 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 is performed to measure improvement in bitterness. Yes.
However, these proposals have a problem that it cannot be said that the bitter taste of galantamine can be sufficiently suppressed.

  Therefore, there is a strong demand for further development of a technology that can suppress the bitter taste of galantamine.

JP 2012-188364 A

  An object of the present invention is to solve the above-described problems and achieve the following objects. That is, the present invention relates to a galantamine-containing pharmaceutical composition excellent in the inhibitory effect of galantamine bitterness at the time of disintegration and / or aftertaste of the pharmaceutical composition, a galantamine bitterness suppressing method in a pharmaceutical composition, and a galantamine bitterness inhibitor The purpose is to provide.

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

  According to the present invention, the galantamine-containing pharmaceutical composition is capable of solving the above-described problems and achieving the object, and having an excellent inhibitory effect on the bitter taste of galantamine at the time of disintegration and / or aftertaste of the pharmaceutical composition. And a method for suppressing the bitter taste of galantamine in a pharmaceutical composition and a bitterness inhibitor of galantamine can be provided.

(Galantamine-containing pharmaceutical composition)
The galantamine-containing pharmaceutical composition of the present invention contains at least galantamine and at least one sweetener selected from the group consisting of sucralose, acesulfame potassium, stevia, and thaumatin, and further contains other components as necessary. .

<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, a 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.

<Sweetener>
The sweetener contains at least one selected from the group consisting of sucralose, acesulfame potassium, stevia, and thaumatin, and may further contain other sweeteners as necessary. These may be used individually by 1 type and may use 2 or more types together.
Among these, the group consisting of sucralose, stevia, and thaumatin in that the bitter taste of galantamine can be further suppressed, and further, the decrease 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 when the sweetener is used in combination include sucralose and stevia, sucralose and stevia and thaumatin, sucralose and thaumatin, acesulfame potassium and stevia.

  As the sweetening agent, those produced by a known method may be used, or commercially available products may be used.

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

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

  The amount of each sweetener when two or more sweeteners are used is not particularly limited and may be appropriately selected depending on the intended purpose.

<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 usually used in the pharmaceutical field can be appropriately selected according to the purpose. Examples include excipients, binders, lubricants, surfactants, sweeteners, flavoring agents, fragrances, fluidizers, colorants, stabilizers, pH adjusters, and coating agents. These may be used individually by 1 type and may use 2 or more types together.
As other components in the galantamine-containing pharmaceutical composition, those produced by a known method may be used, 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 depending on the intended purpose. Examples thereof include 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 individually by 1 type and may use 2 or more types together.
Among these, it is preferable that at least any one of mannitol and lactose is included in that the decrease in stability of galantamine due to the influence of high temperature and high humidity can be improved. For these, mannitol may be used alone, lactose may be used alone, or both may be used in combination.

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

  The lactose may be an anhydride or a hydrate. What was manufactured by the well-known method may be used for the said lactose, and a commercial item may be used for it.

  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.

  The total content of the galanthamine-containing pharmaceutical composition of at least one of mannitol and lactose is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 70% by mass to 99% by mass, The mass% is more preferably 98 mass%, and particularly preferably 85 mass% to 98 mass%. Within the preferable range, it is advantageous in that the decrease in stability of galantamine due to the influence of high temperature and high humidity can be further improved.

  Moreover, there is no restriction | limiting in particular as the quantity with respect to the said galantamine of at least any one of the said mannitol and lactose, Although it can select suitably according to the objective, A total of 7 mass parts -99 with respect to the said galantamine 1 mass part. Mass parts are preferable, 7.5 parts by mass to 66 parts by mass are more preferable, and 8.5 parts by mass to 49 parts by mass are particularly preferable. When the amount of at least one of the mannitol and lactose in the galantamine is within the preferable range, it is advantageous in that the decrease in the stability of galantamine due to the influence 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, hypromellose, hydroxypropyl cellulose, etc. are mentioned. These may be used individually by 1 type and may use 2 or more types together.
Among these, it is preferable to contain at least one of polyvinyl alcohol and polyvinyl pyrrolidone in that the decrease in stability of galantamine due to the influence of high temperature and high humidity can be improved. In these, polyvinyl alcohol may be used alone, polyvinylpyrrolidone 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 degree of polymerization 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, the saponification degree is preferably 78 mol% to 96 mol% (partially saponified product), 97 mol% or more (completely saponified product), and particularly preferably 78 mol% to 96 mol% (partially saponified product). The saponification degree can be measured according to JIS K 6726.

  As the polyvinyl alcohol, one produced by a known method may be used, or a commercially available product 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, 000-60,000 is particularly preferred. The weight average molecular weight can be measured by a light scattering measurement method.

  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 polyvinylpyrrolidone in at least any one of the said polyvinyl alcohol and polyvinylpyrrolidone, 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 at least any one of the said polyvinyl alcohol and polyvinylpyrrolidone, Although it can select suitably according to the objective, 0.01 mass%-5 mass% Is preferable, 0.05 mass%-3 mass% is more preferable, 0.1 mass%-2 mass% is especially preferable. Within the preferable range, it is advantageous in that the decrease in stability of galantamine due to the influence of high temperature and high humidity can be further improved.

  Further, the amount of at least one of the polyvinyl alcohol and polyvinyl pyrrolidone with respect to the galantamine is not particularly limited and may be appropriately selected depending on the purpose, but it is 0.001 in total with respect to 1 part by mass of the galantamine. Mass parts to 5 parts by mass are preferable, 0.005 parts to 3 parts by mass are more preferable, and 0.01 parts to 2 parts by mass are particularly preferable. Within the preferable range, it is advantageous in that the decrease in stability of galantamine due to the influence of high temperature and high humidity can be further improved.

  The mass ratio between at least one of the polyvinyl alcohol and polyvinyl pyrrolidone and at least one of the mannitol and lactose is not particularly limited and may be appropriately selected depending on the intended purpose. Any total amount: The total amount of at least one of mannitol and lactose is preferably 1:14 to 1: 9,900, more preferably 1:25 to 1: 1,960, and 1:42 to 1: 980 is particularly preferred. Within the preferable range, it is advantageous in that the decrease in stability of galantamine due to the influence 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 intended purpose. For example, magnesium stearate, calcium stearate, talc, hydrogenated oil, white beeswax, carnauba wax, polyethylene glycol 6000, sodium stearyl fumarate And stearic acid. These may be used individually by 1 type and may use 2 or more types together.
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 does not contain a disintegrant.

<Dosage form>
The dosage form of the galantamine-containing pharmaceutical composition is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include tablets, granules such as uncoated tablets, orally disintegrating tablets, chewable tablets, and film-coated tablets. Is mentioned. Among these, an orally disintegrating tablet is preferable.
The galantamine-containing pharmaceutical composition is preferably a wet tablet.
There is no restriction | limiting in particular as a shape of a tablet, a structure, and a magnitude | size, 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 tableting method, a dry granule compression method, a wet granule compression method, and a wet tableting method may be mentioned.

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

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

Specific examples of the wet granule compression method include compression molding of granules obtained by extrusion granulation method, fluidized bed granulation method, stirring granulation method and the like.
The method and conditions of the extrusion granulation method, fluidized bed granulation method, and stirring granulation method are not particularly limited, and known methods and conditions can be appropriately selected according to the purpose.

There is no restriction | limiting in particular as the tableting method 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.

Further, the production method when the galantamine-containing pharmaceutical composition of the present invention is a wet tablet is not particularly limited and can be appropriately selected according to the purpose. For example, the galantamine, the sucralose, acesulfame potassium, After mixing at least one sweetener selected from the group consisting of stevia and thaumatin and the other ingredients as necessary, a kneading solvent is added and kneaded, and the resulting wet powder is compressed. A method of molding is mentioned.
The wet powder may be compression molded as it is, or may be compression molded after wet granulation to obtain 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 suppressing the bitter taste of galantamine at the time of disintegration of the pharmaceutical composition and / or aftertaste.

(Method for inhibiting bitter taste of galantamine in a pharmaceutical composition)
The method for suppressing the bitter taste of galantamine in the pharmaceutical composition of the present invention includes at least a sweetener contact step, and further includes other steps as necessary.
The method of the present invention may be referred to as a step of contacting galantamine, at least one of mannitol and lactose, and at least one of polyvinyl alcohol and polyvinylpyrrolidone (hereinafter referred to as “contact step of mannitol etc.”) as the other step. ) Is preferably included.

<Sweet agent contact process>
The sweetener contact step is a step of bringing galantamine into contact with at least one sweetener selected from the group consisting of sucralose, acesulfame potassium, stevia, and thaumatin.
In the contacting step, other components other than at least one sweetener selected from the group consisting of the galantamine, the sucralose, acesulfame potassium, stevia, and thaumatin may be present.

-Galantamine-
The galantamine is the same as that described in the item <galantamine> of the galantamine-containing pharmaceutical composition of the present invention described above.

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

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

-Contact-
The contact method is not particularly limited and may be appropriately selected depending on the purpose. For example, the contact may be performed by the method described in the <Production method> section of the galantamine-containing pharmaceutical composition of the present invention described above. The method etc. are mentioned.

<Other processes>
There is no restriction | limiting in particular as said other process, unless the effect of this invention is impaired, It can select suitably according to the objective, For example, contact processes, such as the said mannitol, etc. are mentioned.
The contact method in the contact step such as mannitol is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include the same method as in the sweetener contact step.

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

  According to the method for suppressing the bitter taste of galantamine in the pharmaceutical composition of the present invention, the bitter taste of galantamine at the time of disintegration of the pharmaceutical composition and / or aftertaste can be suppressed.

(Galantamine bitterness inhibitor in pharmaceutical composition)
The galantamine bitterness inhibitor 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 other components as necessary.

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

<Other ingredients>
The other components are the same as those described in the item <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 pharmaceutical composition is the same as that described in the item <Dosage form> of the galantamine-containing pharmaceutical composition of the present invention described above, and the preferred embodiment is also the same.

There is no restriction | limiting in particular as a usage method of the bitterness inhibitor of galantamine in the said pharmaceutical composition, According to the objective, it can select suitably, For example, the method of making it contact with the said galantamine etc. are mentioned.
The contact method is not particularly limited and may be appropriately selected depending on the purpose. For example, the contact may be performed by the method described in the <Production method> section of the galantamine-containing pharmaceutical composition of the present invention described above. The method etc. are mentioned.

  According to the galantamine bitterness inhibitor in the pharmaceutical composition of the present invention, the bitter taste of galantamine at the time of disintegration of the pharmaceutical composition and / or aftertaste can be suppressed.

  Hereinafter, although this invention is demonstrated more concretely based on a test example, this invention is not limited to these test examples.

(Test Example 1)
As shown in the following Table 1, galantamine hydrobromide (manufactured by Scinopharm), lactose hydrate (Pharmacatose 125M, manufactured by DFE Pharma), and any of the following sweeteners were weighed and 3 L Using a mechanom mill (Okada Seiko Co., Ltd.), mixing was performed at 600 rpm for 2 minutes to obtain a mixture.
[Sweetener]
・ Sucralose (manufactured by Saneigen FFI Co., Ltd.)
Acesulfame potassium (Sanet (registered trademark), manufactured by Fi Nutrition Co., Ltd.)
・ Stevia (Stevi MZ, manufactured by Maruzen Pharmaceutical Co., Ltd.)
・ Dipotassium glycyrrhizinate (manufactured by Nippon Paper Chemicals Co., Ltd.)
・ Somachin (Sun Sweet, Saneigen FFI Co., Ltd.)
・ Aspartame (Ajinomoto KK Aspartame, Ajinomoto Healthy Supply Co., Ltd.)

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

The wet powder was tableted using a tableting machine for wet tablets (EMT-18 and ETD-18, manufactured by Sankyo Seisakusho Co., Ltd.), 7.0 mm in diameter and 110 mg tablets (tablet 1) -1 to 1-6) were obtained. Table 1 below shows the prescription per tablet.
The molding and drying conditions were as follows.
・ Tablet molding pressure: 15kgf
・ Molding bowl ・ ・ ・ Diameter 7.0mm, WR bowl ・ Drying temperature ・ ・ ・ 85 ℃

<Test>
-Sensory test-
About each tablet obtained above, the sensory test was done as follows.
The tablet was included in the mouth, and (A) at the time of disintegration in the oral cavity and (B) after disintegration, the bitterness intensity felt in the aftertaste remaining in the oral cavity after the tablet was discharged was evaluated.
In the evaluation, “−” indicates that the bitterness is not particularly felt, and “+” indicates the strength of the bitterness. That is, the stronger the bitterness, the greater the number of “+”. The results are shown in Table 1 below.

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

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

-Appearance-
The appearance of (i) the initial product of each tablet obtained above and (iii) the stored product stored for 1 month under the conditions of 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 sweetener exhibits white-pale yellow. Therefore, in Table 1 below, tablets having the same appearance as the tablets not containing the sweetener are indicated as “−”, and changes in the tablets having a clear change in color change or physical properties are described.

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

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

  Regarding tablet hardness, when acesulfame potassium was used, a decrease in hardness was observed when stored under severe conditions ((ii) stored for 2 weeks at 50 ° C. and 90% relative humidity).

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

(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 when the sweetness intensity of sugar is 1.

Therefore, each tablet (tablets 2-1 to 2-6) was produced 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 sweetness intensity was equivalent. . The prescription is shown in Table 2-2 below.
Moreover, the result of having conducted each test similarly to Test Example 1 is also shown in Table 2-2 below.

  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 least one of the aftertaste and (B) aftertaste, the bitterness intensity was reduced, and the bitterness was improved.

  As a result of the disintegration test, it was confirmed that disintegration of the tablets using dipotassium glycyrrhizinate was slower than other tablets.

  Regarding tablet hardness, when acesulfame potassium was used, a decrease in hardness was observed when stored under severe conditions ((ii) stored for 2 weeks at 50 ° C. and 90% relative humidity).

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

  From the results of Test Examples 1 and 2, by using sucralose, acesulfame potassium, stevia, or thaumatin as a sweetener, the bitter taste of galantamine can be masked as compared with conventionally used aspartame, and the bitter taste is further reduced. Confirmed to do.

(Test Example 3)
Each tablet (Tablets 3-1 to 3-2) was produced 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.
Further, a sensory test was conducted in the same manner as in Test Example 1. The results are shown in Table 3 below.

  As shown in Table 3, the bitterness of the preparation was improved even when a sweetener whose effect was recognized in Test Examples 1 and 2 was used in combination.

(Test Example 4)
<Manufacture of tablet 4-1>
As shown in Table 4 below, galantamine hydrobromide (manufactured by Scinopharm), lactose hydrate (Pharmacatose 125M, manufactured by DFE Pharma), and sucralose (manufactured by Saneigen FFI Co., Ltd.) ) And weighed for 2 minutes at 600 rpm using a 3 L Mechanomyl (Okada Seiko Co., Ltd.) to obtain a mixture.

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

The wet powder was tableted using a tableting machine for wet tablets (EMT-18 and ETD-18, manufactured by Sankyo Seisakusho Co., Ltd.), 7.0 mm in diameter and 110 mg tablets per tablet (tablet 4 -1) was obtained. The prescription per tablet is shown in Table 4 below.
The molding and drying conditions were as follows.
・ Tablet molding pressure: 15kgf
・ Molding bowl ・ ・ ・ Diameter 7.0mm, WR bowl ・ Drying temperature ・ ・ ・ 85 ℃

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

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

  24 water-ethanol mixed solvent (mass ratio: water: ethanol = 7: 3) in which 2.2 g of polyvinylpyrrolidone (Kollidon 30 (weight average molecular weight: 50,000), manufactured by BASF) was dissolved in the mixture was 24. .2g was added and kneaded for 2 minutes to obtain a wet powder.

  A tablet 4-3 was produced using a wet tableting machine in the same manner as in the production of the tablet 4-1, except that the wet powder was used. The prescription per tablet is shown in Table 4 below.

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

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

<Test>
In the same manner as in Test Example 1, each test was performed on tablets 4-1 to 4-4. The results are shown in Table 4.

  As shown in Table 4, even when the excipient and the binder were changed, the bitterness of the preparation was improved. Further, among the excipients or binders used in the above test examples, the disintegration property, tablet hardness, and appearance were equivalent.

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 dosing properties. Therefore, it can contribute to improvement of patient compliance and suppression of deterioration of dementia symptoms.

Claims (6)

Including galantamine, a sweetener , at least one of mannitol and lactose, and at least one of polyvinyl alcohol and polyvinylpyrrolidone ,
The sweetener contains at least one selected from the group consisting of sucralose, acesulfame potassium, stevia, and thaumatin;
A pharmaceutical composition containing galantamine, which is an orally disintegrating tablet.   The galantamine-containing pharmaceutical composition according to claim 1, wherein the sweetening agent contains at least one selected from the group consisting of sucralose, stevia, and thaumatin. 3. The galantamine-containing pharmaceutical composition according to claim 1, wherein a total amount of at least one of the 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 1 to 3, wherein a total amount of at least one of the polyvinyl alcohol and polyvinyl pyrrolidone is 0.001 to 5 parts by mass with respect to 1 part by mass of the galantamine. object. A step of contacting galantamine, a sweetener, at least one of mannitol and lactose, and at least one of polyvinyl alcohol and polyvinylpyrrolidone,
The sweetener contains at least one selected from the group consisting of sucralose, acesulfame potassium, stevia, and thaumatin, and a method for suppressing the bitter taste of galantamine in an orally disintegrating tablet, Used for orally disintegrating tablets containing galantamine,
An oral cavity comprising at least one sweetener selected from the group consisting of sucralose, acesulfame potassium, stevia and thaumatin, at least one of mannitol and lactose, and at least one of polyvinyl alcohol and polyvinyl pyrrolidone Bitter taste inhibitor of galantamine in internally disintegrating tablets.