JP2011016781A - Film-like formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a film-like formulation for oral administration which contains ketotifen fumarate as a drug ingredient, is excellent in the stability of the ketotifen fumarate, and in which unpleasant taste can not be easily sensed.SOLUTION: The film-like formulation for oral administration which is formed of an edible water-soluble film base in the shape of a film having 1-3,000 μm thickness, comprises ketotifen fumarate, and 0.7-3.6 g of a glycyrrhizic acid salt based on 1 g of ketotifen fumarate.

Description

  The present invention relates to a film-form preparation, and particularly to a film-form preparation for oral administration containing ketotifen fumarate as a drug component.

  Ketotifen fumarate has antihistaminic activity and bronchial smooth muscle dilation effect, and is widely used as a therapeutic and preventive agent for skin diseases such as allergic rhinitis, bronchial asthma, eczema / urticaria / skin pruritus. Yes. As a dosage form of a preparation containing ketotifen fumarate, capsules, tablets, dry syrups, ophthalmic solutions and nasal solutions are generally used.

  By the way, in recent years, there has been an increasing demand for preparations that facilitate oral administration of drug components even for those who have difficulty swallowing. In particular, as the aging of society tends to increase, the number of people whose swallowing function has declined due to aging tends to increase. Therefore, even those who are easy to disintegrate or dissolve in the oral cavity and are difficult to swallow things are easy to take However, there is a strong demand. The prevalence of allergic diseases such as hay fever is increasing year by year, and atopic dermatitis is more common in infants and cutaneous pruritus is more common in older people, so ketotifen fumarate is also swallowed. There is a demand for preparations that are easy for anyone to take, including those with low functions.

  The present inventors have been researching various edible films, such as lamination of a plurality of films having different functions, strength, solubility, stability, and technologies based on these researches. Taking advantage of this accumulation, a edible water-soluble film is further incorporated with a pharmaceutical ingredient, and a film-form preparation that rapidly disintegrates or dissolves in the oral cavity and has practical strength is proposed (see Patent Document 1). .

  However, when a film-form preparation containing ketotifen fumarate is tried to be produced by a method similar to the conventional method, there is a problem that the stability is lacking.

  In the case of a film-form preparation that rapidly disintegrates or dissolves in the oral cavity, the taste is also felt quickly on the tongue, and in the case of a film-form preparation, since the surface area in contact with the tongue is large, it is easy to feel the taste. There is a strong demand for an unpleasant taste compared to swallowed dosage forms.

  Therefore, in view of the above circumstances, the present invention provides a film-form preparation for oral administration which contains ketotifen fumarate as a drug component, is excellent in stability of ketotifen fumarate, and does not feel an unpleasant taste. It is to be an issue.

  In order to solve the above problems, a film-form preparation according to the present invention is a film-form preparation for oral administration formed into a film having a thickness of 1 μm to 3000 μm by an edible and water-soluble film base. , Ketotifen fumarate, and 0.7 to 3.6 g of glycyrrhizinate with respect to 1 g of ketotifen fumarate ".

  As “ketotifen fumarate”, those listed in the Japanese Pharmacopoeia can be used. Examples of the “glycyrrhizinate” include dipotassium glycyrrhizinate, disodium glycyrrhizinate, and diammonium glycyrrhizinate.

  The “thickness” of the film-form preparation of the present invention can be set within a range of 1 μm to 3000 μm. However, when emphasis is placed on ease of handling and production efficiency, it is preferably set to 10 μm to 1000 μm. When emphasizing solubility or disintegration, 5 μm to 500 μm is preferable, and 10 μm to 500 μm is more preferable because it satisfies both requirements.

  “Film base” refers to a material that has film-forming ability and forms the base of a film in a film-form preparation. The film base is considered not to affect the stability of ketotifen fumarate, and those commonly used in the pharmaceutical field can be used, but the film preparation does not have an unpleasant taste. For this purpose, a film base having substantially no taste is desirable. For example, “edible and water-soluble film base” includes gelatin, pectin, arabinoxylan, sodium alginate, carrageenan, xanthan gum, guar gum, pullulan, hypromellose, hydroxypropylcellulose, water-soluble hydroxyethylcellulose, methylcellulose, carboxymethylcellulose. Polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol and the like can be used.

  The inventors of the present invention can stabilize ketotifen fumarate by adding glycyrrhizinate to a film containing ketotifen fumarate at a ratio of 0.7 g or more with respect to 1 g of ketotifen fumarate. It was found that long-term storage is possible.

  On the other hand, in addition to improving the stability of ketotifen fumarate, the present invention has the problem of not having an unpleasant taste, which is required because the dosage form of the preparation is a film. That is, since a water-soluble film is easily dissolved or disintegrated by saliva in the oral cavity, the taste tends to spread quickly on the tongue. In the case of a film-form preparation, the surface area in contact with the tongue is large and the taste is easy to feel. In addition, glycyrrhizinate is a component contained in licorice and has a peculiar sweet taste, and this taste is generally not preferred as an unpleasant sweetness.

  Here, in the formulation field, when the taste of the component is not preferable, a flavoring agent or a sweetening agent is often added. This is to try to conceal an unpleasant taste with a stronger taste, so that it tends to be deeper and the composition becomes complicated. On the other hand, the present inventors do not add any other component, but by setting the ratio of glycyrrhizinate to 1 g of ketotifen fumarate to 0.7 g to 3.6 g, The present inventors have found that a film-form preparation that hardly feels an unpleasant taste can be realized without impairing the effect of enhancing stability.

  Therefore, according to the present invention configured as described above, even a person with a low swallowing function is easy to take, and stably contains ketotifen fumarate as a drug component, and can be rapidly dissolved or disintegrated in the oral cavity. Thus, it is possible to provide a film-form preparation that hardly feels an unpleasant taste.

  The film-form preparation of the present invention may contain an appropriate amount of additives such as a plasticizer, an excipient, an emulsifier, a colorant, a fragrance, and an antiseptic in addition to the above-described configuration. For example, as a plasticizer, macrogol, glycerin, propylene glycol and the like, as an excipient, mannitol, lactose, fructose, sucrose, glucose, trehalose and other sugars, corn starch, potato starch, wheat starch and other starches, Celluloses such as crystalline cellulose, powdered cellulose, talc, titanium oxide, carmellose sodium, ethyl cellulose, partially pregelatinized starch, pregelatinized starch, gum arabic, sodium alginate, dextrin, gelatin, pullulan, polyvinyl alcohol, methylcellulose, carboxyvinyl polymer As an emulsifier, sodium lauryl sulfate, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil Polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, etc. as coloring agent, food coloring, edible lake coloring, iron sesquioxide, yellow iron sesquioxide, etc. as fragrance, fennel oil, orange oil, chamomile oil, spearmint oil , Cinnamon oil, clove oil, mint oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil, rose oil, roman chamomile oil, etc. as preservatives, benzoic acid, sodium benzoate, benzyl benzoate, ethyl paraoxybenzoate Butyl paraoxybenzoate, propyl paraoxybenzoate, and the like can be used. These additives can be used alone or in combination.

  In addition, the present invention can realize a film-form preparation that does not feel an unpleasant taste without adding a sweetening agent or a flavoring agent as described above. Is not to be excluded. For example, aspartame, acesulfame potassium, saccharin, saccharin sodium, stevia, thaumatin, sucralose, etc. can be used as sweeteners, and citric acid, tartaric acid, malic acid, ascorbic acid, etc. can be used alone or in combination. It is.

  The film-form preparation according to the present invention may contain “hypromellose and / or hydroxypropylcellulose as the film base”.

  “Hypromellose” includes 2910, 2906, and 2208 substitution types, and any of those commonly used in the pharmaceutical field can be used. For example, the substitution degree type 2910 includes METOLOSE 60SH-50 (viscosity 50 mPa · s), 60SH-4000 (viscosity 4000 mPa · s), 60SH-10000 (viscosity 10000 mPa · s), Shin-Etsu Chemical TC-5E (manufactured by Shin-Etsu Chemical). Viscosity 3.0 mPa · s), TC-5M (viscosity 4.5 mPa · s), TC-5R (viscosity 6.0 mPa · s), TC-5S (viscosity 15.0 mPa · s), substitution degree type 2906 METOLOSE 65SH-50 (viscosity 50 mPa · s), 65SH-400 (viscosity 400 mPa · s), 65SH-1500 (viscosity 1500 mPa · s), 65SH-4000 (viscosity 4000 mPa · s), substitution degree type 2208 Is METOLOSE SR 90SH-100 made by Shin-Etsu Chemical ( Degree 100 mPa · s), 90SH-4000 (viscosity 4000 mPa · s), 90SH-15000 (viscosity 15000 mPa · s), 90SH-100000 (viscosity 100000 mPa · s), Shin-Etsu Chemical SB-4 (viscosity 4.0 mPa · s) Etc. can be used. The viscosity is the viscosity of a 2% aqueous solution at 20 ° C. specified by the Japanese Pharmacopoeia, and the same applies hereinafter.

  As the “hydroxypropylcellulose”, any of those generally used in the pharmaceutical field can be used. For example, Nippon Soda HPC-SSL (viscosity 2.0 to 2.9 mPa · s), HPC-SL (viscosity 3.0 to 5.9 mPa · s), HPC-L (viscosity 6.0 to 10.0 mPa · s) s), HPC-M (viscosity 150 to 400 mPa · s), HPC-H (viscosity 1000 to 4000 mPa · s), and the like can be used.

  Hypromellose and / or hydroxypropyl cellulose are both excellent in film-forming ability, and the formed film is highly water-soluble. Therefore, they are suitable as the film base of the film-form preparation of the present invention that exhibits the above-mentioned effects.

  In addition, the 13th revised Japanese pharmacopoeia states that hydroxypropylcellulose is "white to yellowish white powder with no odor and taste", and the 14th revised Japanese pharmacopoeia describes hydroxypropylmethylcellulose. (Formerly known as hypromellose), "Hypromellose and hydroxypropyl as white to yellowish white powder or granules with no odor or slightly unique odor and no taste" Since cellulose does not have any taste, it is suitable as a film base for the film-form preparation of the present invention that does not have an unpleasant taste.

  As described above, as an effect of the present invention, to provide a film-form preparation for oral administration that contains ketotifen fumarate as a drug component, has excellent stability of ketotifen fumarate, and does not feel an unpleasant taste. Can do.

It is a graph which shows the relationship between the addition amount of a dipotassium glycyrrhizinate, and the residual rate of a ketotifen fumarate about the composition of Table 1. FIG. It is a graph which shows the relationship between the addition amount of dipotassium glycyrrhizinate and the residual rate of ketotifen fumarate about the composition of Table 2.

  Hereinafter, the film-form preparation which is one embodiment of the present invention will be described. The film-form preparation of this embodiment is a film-form preparation for oral administration formed into a film form having a thickness of 1 μm to 3000 μm with an edible and water-soluble film base, and includes ketotifen fumarate and ketotifen fumarate It contains 0.7 to 3.6 g of glycyrrhizinate with respect to 1 g of acid salt. Moreover, in this embodiment, hypromellose and / or hydroxypropylcellulose are contained as a film base.

  Here, the film-form preparation of this embodiment comprises a mixed solution preparation step of preparing a mixed solution containing ketotifen fumarate, hypromellose and / or hydroxypropellulose, and glycyrrhizinate, and the mixed solution on the base film. The casting process for casting, the drying process for drying the cast mixed liquid to form a film, the peeling process for peeling the formed film-form preparation from the base film, and the film-form preparation being cut into a predetermined size It can manufacture by the manufacturing method which comprises the cutting process to perform.

  In more detail, in the mixed solution preparation step, ketotifen fumarate, hypromellose and / or hydroxypropyl cellulose, glycyrrhizinate, and appropriate additives are mixed and stirred with water or an organic solvent to prepare a solution or suspension. Prepare a turbid solution and defoaming to prepare a mixture.

  In the casting process, the base film is fixed on a smooth plane, and the prepared mixed solution is uniformly coated on the base film. Here, the base film is a film constituting a surface that becomes a prototype for forming a film by casting a mixed solution, which is a stock solution of a film-form preparation, on the upper surface thereof, for example, a mirror-polished stainless steel belt A plastic film such as polyethylene terephthalate or polypropylene fixed on a smooth surface such as a drum or a drum can be used. In addition, since the thickness of a film-form preparation is dependent on the density | concentration of a liquid mixture, a viscosity, and a coating speed, it adjusts so that it may become desired thickness.

  In the drying process, for example, the mixed solution is made into a film by drying the cast solution together with the base film by convection of air with adjusted temperature and humidity and irradiation of far infrared rays, thereby obtaining a film-form preparation. Can do. Note that the order of the peeling process and the cutting process may be reversed, or the producer may be configured not to perform the peeling process. For example, the film-form preparation can be stored in a state of being attached to the base film, and the film-form preparation can be peeled off from the base film at the time of taking.

  Next, the reason why the film-form preparation of this embodiment is configured as described above will be described. First, the result of having examined stability about the film-form preparation from which a composition differs is shown. Examination of stability was performed by producing a film-form preparation for a plurality of compositions shown in Tables 1 and 2. In both Tables 1 and 2, the numerical value of each component indicates mass (g).

  In each composition, HPC-L made by Nippon Soda was used as the hydroxypropyl cellulose, and METOLOSE 60SH-4000 made by Shin-Etsu Chemical was used as the hypromellose.

Prepare a liquid mixture as described above for each composition, cast the liquid mixture and dry the film-form preparation with a thickness of about 100 μm, cut into a size of 20 mm × 15 mm, and stability by the following method A test was conducted.
<Stability test (severe test)>
Store in a thermostatic bath at a high temperature of 60 ° C., measure the ketotifen fumarate content after one month, and determine the residual rate (%) from the measurement results and the ketotifen fumarate content before the test ) Was calculated as a stability index. The ketotifen fumarate content was measured using liquid chromatography.

  About the film-form preparation of composition R1, S1-S3 of Table 1, the residual rate of totifen fumarate by a stability test is shown in FIG. Here, compositions S1 to S3 are cases where dipotassium glycyrrhizinate is added as a stabilizer for ketotifen fumarate and the amount added is increased, and composition R1 is a composition for control that does not contain glycyrrhizinate. is there.

  As is clear from FIG. 1, in composition R1, the residual ratio of ketotifen fumarate was about 90%, but in compositions S1 to S3, the residual ratio increased with an increase in the amount of dipotassium glycyrrhizinate. Further, in FIG. 1, the residual ratio of each sample is on the curve swollen upward, and by interpolation and extrapolation, the mass of ketotifen fumarate is about 2.5 g of dipotassium glycyrrhizinate per gram of ketotifen fumarate. If the mass of dipotassium glycyrrhizinate per gram of ketotifen fumarate is in the range of at least 1 to 8 g, a residual ratio of ketotifen fumarate of 97% or more can be obtained. Can read that. Moreover, if the mass of dipotassium glycyrrhizinate per 1 g of ketotifen fumarate is in the range of 0.5 to 8 g, it can be read that a residual ratio of ketotifen fumarate of 93% or more is obtained.

  Regarding the film-form preparations having the compositions R2, S4 to S6 in Table 2, the residual ratio of ketotifen fumarate by the stability test is shown in FIG. Here, compositions S4 to S6 are cases where dipotassium glycyrrhizinate is added as a stabilizer for ketotifen fumarate and the amount added is increased, and composition R2 is a composition for control that does not contain glycyrrhizinate. is there. The composition in Table 2 differs from the composition in Table 1 in that sodium lauryl sulfate is added as an emulsifier and macrogol 6000 is added as a plasticizer.

  As is apparent from FIG. 2, the residual ratio of ketotifen fumarate was about 89% in composition R2, but the residual ratio increased with an increase in the amount of dipotassium glycyrrhizinate in compositions S4 to S6. The increase in the residual rate is more gradual than in the case of the composition of Table 1 shown in FIG. 1, but this is presumed to be due to the influence of the added surfactant and plasticizer. However, the residual rate of each sample in FIG. 2 is on a slightly swollen curve, and by interpolation and extrapolation, if the mass of dipotassium glycyrrhizinate per gram of ketotifen fumarate is 1 g or more, It can be read that a residual ratio of ketotifen fumarate of 95% or more is obtained. Further, it can be read that a residual ratio of ketotifen fumarate of 93% or more can be obtained when the mass of dipotassium glycyrrhizinate per 1 g of ketotifen fumarate is 0.7 g or more.

  From this, it was confirmed that the effect of increasing the residual ratio of ketotifen fumarate by adding dipotassium glycyrrhizinate can be sufficiently obtained even if the addition of an emulsifier or a plasticizer is slightly reduced. It was. Here, in the production of a film-form preparation, the addition of an emulsifier makes it easier to prepare a mixed solution that is a stock solution of the film. In addition, the addition of a plasticizer is effective in order to make the produced film flexible and have a good mouthfeel, and are less likely to crack or break. Therefore, even if an emulsifier or a plasticizer is added, the ability to increase the residual ratio of ketotifen fumarate by adding dipotassium glycyrrhizinate is very significant for a preparation having a film form.

  Considering the examination results for the film-form preparations having the compositions shown in Tables 1 and 2, the residual ratio of ketotifen fumarate can be obtained by adding dipotassium glycyrrhizinate at a rate of 1 to 8 g per 1 g of ketotifen fumarate. A high rate of 95% or more can be achieved. Further, by adding dipotassium glycyrrhizinate at a rate of 0.7 to 8 g per 1 g of ketotifen fumarate, a residual ratio of ketotifen fumarate of 93% can be ensured.

Next, the examination result about the taste of a fill-form preparation is shown. The examination was conducted by orally administering the film-form preparations R1, S1 to S4 having the above composition to three subjects A, B, and C, and evaluating the impression of taste at that time. The results are shown in Table 3. Here, the taste was evaluated in the following three stages.
“○” Does not feel an unpleasant taste or hardly.
“△” feels slightly unpleasant taste, but acceptable.
“X” feels unpleasant taste and unacceptable.

  As shown in Table 3, if the ratio of dipotassium glycyrrhizinate per 1 g of ketotifen fumarate is 3.6 g or less, it does not taste unacceptable or acceptable for most people, and 1.5 g or less If so, it was thought that the unpleasant taste was acceptable or acceptable for a percentage of all.

  Unlike the other film-form preparations R1, S1 to S3, the film-form preparation S4 contains sodium lauryl sulfate as an emulsifier and macrogol 6000 as a plasticizer, but is not added with dipotassium glycyrrhizinate. Similar to the film-form preparation R1, it did not feel an unpleasant taste or hardly felt it. From this, it was considered that sodium lauryl sulfate and macrogol 6000 do not affect the taste of the film-form preparation.

  Considering the above-mentioned results of the study on the stability and the results of the study on the taste, if the ratio of dipotassium glycyrrhizinate per 1 g of ketotifen fumarate is 0.7 to 3.6 g, the remaining ketotifen fumarate remains. It was thought that 93% of the rate could be secured and that most people did not feel an unpleasant taste. And when importance is attached to the stability of ketotifen fumarate, the ratio of dipotassium glycyrrhizinate per gram of ketotifen fumarate is 1 to 3.6 g. When importance is attached to the taste, glycyrrhizin per gram of ketotifen fumarate is important. It was considered desirable for the ratio of dipotassium acid to be 0.7-1.5 g. Furthermore, if the ratio of dipotassium glycyrrhizinate per gram of ketotifen fumarate is 1 to 1.5 g, high stability of 95% or more of residual ratio of ketotifen fumarate and a proportion of people who can say all It was considered that a film-form preparation having both of the effects of not feeling unpleasant taste could be realized.

  The present invention has been described with reference to the preferred embodiments. However, the present invention is not limited to the above-described embodiments, and various improvements can be made without departing from the spirit of the present invention as described below. And design changes are possible.

  For example, the case where dipotassium glycyrrhizinate is used as the glycyrrhizinate is exemplified above, but it is considered that the same effect can be obtained even when sodium salt or ammonium salt is used. In such a case, the above-mentioned numerical range expressing the desirable range as the addition amount of dipotassium glycyrrhizinate as the mass per gram of ketotifen fumarate cannot be applied as it is, but the dipotassium glycyrrhizinate is not applicable. Since the molecular weight is as large as about 899, it is considered that the above numerical range can be applied even if the kind of salt is different from potassium salt, sodium salt or ammonium salt.

JP 2008-169138 A

Claims (2)

A film-form preparation for oral administration formed into a film having a thickness of 1 μm to 3000 μm by an edible and water-soluble film base,
Ketotifen fumarate,
A film-form preparation comprising glycyrrhizinate at a ratio of 0.7 g to 3.6 g with respect to 1 g of ketotifen fumarate. The film-form preparation according to claim 1, comprising hypromellose and / or hydroxypropylcellulose as the film base.

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