JP2010095446A - Film-shaped preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a film-shaped preparation for oral administration that comprises sodium picosulfate as a medicinal ingredient and is excellent in stability of sodium picosulfate. <P>SOLUTION: The film-shaped preparation for oral administration comprises sodium picosulfate, hypromellose, hydroxypropyl cellulose and a compound whose aqueous solution is alkaline and is formed in a film shape, and an aqueous solution of a total volume of 100 ml containing 1 g of the dry mass of the preparation dissolved in water has a pH within the range of 7-9. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

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

  Picosulfate sodium has a laxative effect by promoting peristaltic movement of the large intestine and inhibiting water absorption, and is hardly absorbed in the stomach and small intestine, acting on the intestinal mucosa and having few side effects. It is widely used as a defecation aid after surgery, a defecation facilitator after administration of contrast medium (barium sulfate), and an intestinal contents exclusion agent before surgery or before colon examination. As a dosage form of a preparation containing sodium picosulfate, a liquid, a tablet, a syrup, a dry syrup, a granule and a capsule 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 inventors of the present invention have been researching various edible films such as lamination of a plurality of films having strength, solubility, stability, and different functions (for example, Patent Document 1, Patent Document 2), taking advantage of the accumulation of technology based on these studies, a edible water-soluble film further contains a medicinal ingredient, and rapidly disintegrates or dissolves in the oral cavity and has a practical strength. It has proposed about a formulation (refer patent document 3). And, picosulfate sodium, which is widely used for the above-mentioned applications and often administered to people with low swallowing function such as sick people and elderly people, has a high significance as a preparation that rapidly disintegrates or dissolves in the oral cavity. It is a drug component.

JP 2004-248665 A JP 2005-112957 A JP 2008-169138 A

  However, when picosulfate sodium was tried to be contained in an edible water-soluble film, there was a problem that it lacked stability and decomposed in a short period of time.

  Therefore, in view of the above circumstances, an object of the present invention is to provide a film-form preparation for oral administration which contains picosulfate sodium as a drug component and is excellent in stability of picosulfate sodium.

  In order to solve the above-mentioned problems, the film-form preparation according to the present invention is a film-form preparation for oral administration, which contains sodium picosulfate, hypromellose, hydroxypropylcellulose, and an aqueous solution containing an alkaline compound. The pH of an aqueous solution of 100 milliliters in total, which is formed into a film and has a dry mass of 1 gram dissolved in water, is 7-9. "

  In the present invention, the “film form” refers to a thin film form having a thickness of 5 μm to 500 μm.

  “Hypromellose (formerly Japanese Pharmacopoeia“ Hydroxypropylmethylcellulose ”) has 1828, 2208, 2906, and 2910 substitution types, and any of those commonly used in the pharmaceutical field may be used. it can. For example, as the substitution degree type 2910, METROSE 60SH-15 (viscosity 15 mPa · s), 60SH-25 (viscosity 25 mPa · s), 60SH-50 (viscosity 50 mPa · s), 60SH-100 (viscosity 100 mPa · s) manufactured by Shin-Etsu Chemical Co., Ltd. S), 60SH-400 (viscosity 400 mPa · s), 60SH-1500 (viscosity 1500 mPa · s), 60SH-4000 (viscosity 4000 mPa · s), 60SH-10000 (viscosity 10000 mPa · s), substitution degree type 2906 , Shinetsu Chemical Industries METROSE 65SH-50 (viscosity 50 mPa · s), 65SH-400 (viscosity 400 mPa · s), 65SH-1500 (viscosity 1500 mPa · s), 65SH-4000 (viscosity 4000 mPa · s), 65SH-15000 ( Viscosity 1 As the substitution degree type 2208, METROSE 90SH-100SR (viscosity 100 mPa · s), 90SH-4000SR (viscosity 4000 mPa · s), 90SH-15000SR (viscosity 15000 mPa · s), etc. available from Shin-Etsu Chemical Co., Ltd. can be used. It is. The viscosity is the viscosity of a 2% aqueous solution at 20 ° C. specified by the Japanese Pharmacopoeia, and the same applies hereinafter.

  “Hydroxypropyl cellulose” is generally divided into 3.0 to 5.9 mPa · s, 6.0 to 10.0 mPa · s, 150 to 400 mPa · s, and 1000 to 4000 mPa · s depending on the viscosity. Any of those generally used in the pharmaceutical field can be used. For example, Nippon Soda HPC-SL (viscosity 3.0 to 5.9 mPa · s), HPC-L (viscosity 6.0 to 10.0 mPa · s), HPC-M (viscosity 150 to 400 mPa · s), HPC -H (viscosity 1000 to 4000 mPa · s) or the like can be used.

  As the “compound in which the aqueous solution shows alkalinity”, those generally used in the pharmaceutical field or those recognized as food additives can be used. Sodium bicarbonate, sodium hydroxide, hydroxide Examples include potassium, sodium carbonate, potassium carbonate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate.

  “PH” is a value measured according to the pH measurement method defined in the Japanese Pharmacopoeia.

  The present inventors comprise a film-form preparation with the above-mentioned raw materials, and disintegrate or dissolve at a practical rate by saliva in the oral cavity by adjusting the pH of the aqueous solution of the film-form preparation to a range of 7-9. The present inventors have found that a film-form preparation in which picosulfate sodium does not decompose even when stored for a long period of time can be obtained. And when the aqueous solution of a film-form preparation became smaller than pH 7, it turned out that stability of picosulfate sodium falls remarkably. Further, when the pH of the aqueous solution of the film-form preparation is larger than 9, it is considered that some people may feel a tingling irritation in the oral mucosa when disintegrated or dissolved by the saliva in the oral cavity. Therefore, according to the present invention, it is possible to provide a film-form preparation that contains picosulfate sodium as a drug component and is excellent in stability of picosulfate sodium and easy to take.

  The film-form preparation of the present invention may contain an appropriate amount of additives such as a plasticizer, an excipient, an emulsifier, a sweetener, a flavoring agent, a coloring agent, 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, popidone, carmellose sodium, ethyl cellulose, partially pregelatinized starch, pregelatinized starch, gum arabic, sodium alginate, dextrin, gelatin, pullulan, polyvinyl alcohol, methylcellulose, carboxy Vinyl polymer, etc. as emulsifier, sodium lauryl sulfate, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene hard Castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, etc. Citric acid, tartaric acid, malic acid, ascorbic acid, etc. as flavoring agents, food coloring, edible lake coloring, iron sesquioxide, yellow iron sesquioxide, etc. as coloring agents, fennel oil, orange oil, chamomile oil as flavoring agents , Spearmint oil, cinnamon oil, clove oil, peppermint oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil, rose oil, roman chamomile oil, etc. as preservatives, benzoic acid, sodium benzoate, benzyl benzoate, It can be used ethyl oxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate and the like. These additives can be used alone or in combination.

  As described above, as an effect of the present invention, a film-form preparation for oral administration containing picosulfate sodium as a drug component and excellent in the stability of picosulfate sodium can be provided.

  Hereinafter, the film-form preparation which is the best embodiment of the present invention will be described.

  The film-form preparation of the present embodiment is a film-form preparation for oral administration, and is formed into a film form containing sodium picosulfate sodium, hypromellose, hydroxypropylcellulose, and an aqueous compound containing an alkali, and dried. The pH of an aqueous solution of 100 milliliters in total of 1 gram dissolved in water is 7-9. Here, in this embodiment, sodium hydrogen carbonate or sodium hydroxide is used as a compound in which the aqueous solution exhibits alkalinity.

  In addition, the film-form preparation of the present embodiment comprises a mixed solution preparation step of preparing a mixed solution containing picosulfate sodium, hypromellose, hydroxypropulose cellulose, and sodium bicarbonate or sodium hydroxide, and the mixed solution as a base film. A casting process for casting on, a drying process for drying the cast mixed liquid to form a film, a peeling process for peeling the formed film-form preparation from the base film, and a film-form preparation of a predetermined size It can manufacture by the manufacturing method which comprises the cutting process cut | disconnected in.

  More specifically, in the mixed solution preparation step, picosulfate sodium, hypromellose, hydroxypropyl cellulose, sodium hydrogen carbonate or sodium hydroxide, and an additive are mixed and stirred with water or an organic solvent to obtain 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 suitably 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 result of having examined stability about the film-form preparation with a different composition is shown, and the grounds which made the film-form preparation of this embodiment the said structure are demonstrated. The examination was conducted by producing film-form preparations for the plurality of compositions shown in Tables 1 to 4. In any of Tables 1 to 4, the numerical value of each component is the mass (g) per 100 g of the film-form preparation.

  In each composition, HPT-SL and HPC-L made by Nippon Soda were used as hydroxypropylcellulose, and MRTROSE 60SH-4000 made by Shin-Etsu Chemical Co., Ltd. was used as hypromellose. In the production, first, the raw material (a) in the table was mixed and stirred using purified water as a solvent to prepare a pre-preparation solution a. On the other hand, the raw material of (b) in the table was mixed and stirred using absolute ethanol as a solvent to prepare Preliminary Solution b. Next, the pre-preparation liquid a and the pre-preparation liquid b were mixed and stirred, and defoamed to obtain a mixed liquid. The mixed solution was cast and dried by the above method to obtain a film-form preparation having a thickness of about 100 μm.

  The obtained film-form preparation was cut into a size of 20 mm × 15 mm, and a pH measurement and a stability test were performed by the following methods.

<PH measurement>
The pH of the aqueous solution when 1 gram of the film-form preparation after constant weight is dissolved in water to make the total amount 100 ml is measured using a pH meter in accordance with the pH measurement method which is a general test method of the Japanese Pharmacopoeia. did.
<Stability test (severe test)>
Store in a thermostatic bath at a high temperature of 60 ° C, measure the content of picosulfate sodium after one month, and calculate the residual rate from the measurement result and the content of picosulfate sodium before the test. As an indicator of stability. The content of sodium picosulfate was measured using liquid chromatography.

  About composition A-composition F of Table 1, the residual rate in a stability test and pH of the aqueous solution of a film-form preparation are collectively shown in FIG. Here, the composition shown in Table 1 is obtained by changing the amount of addition using sodium bicarbonate as a compound in which the aqueous solution exhibits alkalinity. As is clear from FIG. 1, compositions D, E, and F showed a high residual rate of 95% or more with almost no decomposition even under severe conditions. And in the composition E and the composition F in which the addition amount of sodium hydrogencarbonate is large and the pH exceeds 8, the residual rate was almost 100%. On the other hand, the composition A to which no sodium hydrogen carbonate was added had a pH of about 6.3 and a low residual rate. Moreover, although composition B and composition C to which the amount of added sodium bicarbonate is small, the residual ratio is increased as compared with composition A, but the residual ratio is about 80% in composition B and in composition C. This was about 87%, which was insufficient as the stability of the preparation.

  Next, with respect to the composition G to the composition J in Table 2 and the composition P to the composition T in Table 3, the residual ratio in the stability test and the measurement results of the pH of the aqueous solution of the film-form preparation are shown in FIGS. 3 shows. Here, also in the compositions of Tables 2 and 3, the aqueous solution used sodium bicarbonate as a compound showing alkalinity, and the amount of addition was changed, but the difference from the composition of Table 1 was hydroxypropyl. It is the point which uses only HPC-L (made by Nippon Soda) as a cellulose, the point which does not add the propylene glycol as a plasticizer, and the point which adds food coloring. In addition, in the composition of Table 3, the mixing ratio of picosulfate sodium with respect to all the composition components is twice that of the compositions of Tables 1 and 2.

  As apparent from FIGS. 2 and 3, the compositions G and P to which no sodium hydrogen carbonate was added had pH values of about 6.5 and about 6.7, respectively, while the residual rate was low, whereas sodium hydrogen carbonate. In the other composition to which is added, a high residual ratio of 95% or more was shown. In particular, in the compositions I and J and the compositions R, S, and T with a large amount of sodium hydrogen carbonate added, the residual rate was almost 100%.

  [Composition D in Table 1, Composition H in Table 2, Composition Q in Table 3], [Composition E in Table 1, Composition I in Table 2, Composition R in Table 3], and [Composition F in Table 1] The composition J in Table 2 and the composition S in Table 3 have the same blending ratio of sodium hydrogen carbonate with respect to all the composition components in each combination, but each combination showed substantially the same pH and the residual ratio was similar. . Therefore, if the ratio of sodium hydrogen carbonate is equal, there is no effect on pH even if there are differences in other conditions such as the presence or absence of addition of plasticizer and the viscosity of hydroxypropyl cellulose. Was considered to be similar.

  For composition L to composition N in Table 4, the measurement results of the residual ratio in the stability test and the pH of the aqueous solution of the film-form preparation are shown in FIG. Here, the composition of Table 4 is based on the composition G as in the composition of Table 2, but the aqueous solution uses sodium hydroxide instead of sodium bicarbonate as a compound showing alkalinity. It is different from the composition.

  As is apparent from FIG. 4, the composition L to composition N to which sodium hydroxide is added shows a high residual ratio of 95% or more. In particular, the residual ratio is high in compositions M and N with a large amount of sodium bicarbonate added. It was almost 100%.

  From the above test results, it was considered that the residual rate of the film-form preparation is related to the pH of the aqueous solution and does not depend on whether the aqueous solution is alkaline or sodium hydroxide. Then, about the whole composition of Table 1-Table 4, the relationship of pH of the aqueous solution of a film-form formulation and a residual rate is put together in FIG. As can be seen from FIG. 5, the change in the residual ratio with respect to the pH draws a curve that swells upward (shown in the figure, a two-dot chain line). In addition, when the pH is in the range of 7 to 8, the residual rate increases as the pH increases, and in the range of pH of 8 to 9, the residual rate is almost 100%. Further, from the above curve, it was considered that if the pH is 7 or more, the residual rate can be 95% or higher (see the dashed line in the figure), and at least up to pH 9 can be maintained. And when pH is larger than 9, when a film-form preparation disintegrates or dissolves by saliva in the oral cavity, there is a possibility that some people may feel a tingling irritation in the mucous membrane in the oral cavity. Therefore, the pH of the aqueous solution of the film-form preparation should be in the range of 7 to 9, and the more desirable range was considered to be pH 8 to 9 in which the residual rate is almost 100%.

  FIG. 5 summarizes all the compositions in Tables 1 to 4, and the measurement points of each composition are distributed on a substantially single curve. From this, the stability of picosulfate sodium mainly depends on the pH, and if the pH is the same, even if the types and blending ratios of other components are different, the stability is considered to be the same. It was.

  Next, in order to know the blending ratio of sodium hydrogen carbonate required for obtaining a film-form preparation having an aqueous solution pH of 7 to 9, sodium hydrogen carbonate with respect to all the components in each composition of Tables 1 to 3 The relationship between the ratio (mass%) and the pH of the aqueous solution of the film-form preparation is collectively shown in FIG. As can be seen from FIG. 6, in the composition in the present embodiment, the ratio of sodium hydrogen carbonate to the total composition components and the pH of the aqueous solution of the film-form preparation are in a substantially linear relationship within this range. The ingredients were considered to have little effect on the pH value. And the ratio of sodium hydrogen carbonate with respect to all the composition components shall be 0.15-0.6 mass%, pH of aqueous solution is the range of 7-9, and the residual rate of picosulfate sodium is 95% or more It was thought that a film-form preparation with high stability could be produced. Moreover, by making the ratio of sodium hydrogen carbonate with respect to all the composition components 0.35 to 0.6% by mass, a film-form preparation having a pH of 8 to 9, which is a more desirable range, in which the residual rate is almost 100% can be produced. It was considered.

  Moreover, in order to know the compounding ratio of sodium hydroxide required for obtaining a film-form preparation having an aqueous solution pH of 7 to 9, the ratio of sodium hydroxide to the total composition components (mass%) 7) and the pH of the aqueous solution of the film-form preparation are shown in FIG. Similarly to the above, in the composition in the present embodiment, the ratio of sodium hydroxide to the total composition components and the pH of the aqueous solution of the film-form preparation are almost linear in this range, and the ratio of sodium hydroxide is 0. It is considered that a highly stable film-form preparation having a pH of the aqueous solution in the range of 7 to 9 and a residual ratio of picosulfate sodium of 95% or more can be produced by adjusting the content to 0.1 to 0.4% by mass. It was. Moreover, by making the ratio of sodium hydroxide with respect to all the composition components 0.25 to 0.4% by mass, a film-form preparation having a pH of 8 to 9, which is a more desirable range, in which the residual rate is almost 100% can be produced. It was considered.

Next, the result of having performed the elution test by the following method about each composition of Table 1 is shown.
<Dissolution test>
Based on the dissolution test (paddle method), which is a general test method of the Japanese Pharmacopoeia, using a dissolution tester, measure the elution amount of picosulfate sodium from the film-form preparation after 10 minutes, The dissolution rate was calculated from the content of sodium picosulfate before the test. Water was used as the test solution, and the rotational speed of the paddle was 50 rpm.

The results of the dissolution test were as follows, and all of them showed a practical dissolution rate in water and were considered to be easily disintegrated or dissolved by saliva in the oral cavity.
Composition A: 96%
Composition B: 98%
Composition C: 99%
Composition D: 95%
Composition E: 95%
Composition F: 93%

  As described above, the film-form preparation of the present embodiment is highly stable in picosulfate sodium and can be stored for a long period of time by adjusting the pH of the aqueous solution to be in the range of 7-9. At the same time, it is disintegrated or dissolved at a practical rate by saliva in the oral cavity, and it is difficult to feel irritation to the mucous membrane in the oral cavity and is easy to take.

  In addition, as described above, in order to adjust the pH of the film-form preparation, when sodium hydrogen carbonate is used as the alkaline compound, sodium bicarbonate is hydrolyzed to show a slight alkalinity. It is easy to finely adjust the pH of the aqueous solution to be in the range of 7-9. In addition, sodium bicarbonate is a familiar substance that is commonly used for cooking in ordinary households, such as baking soda and baking powder, so it can be included in preparations for oral administration without giving consumers a sense of resistance. Has the advantage.

  On the other hand, when sodium hydroxide is used as a compound in which the aqueous solution exhibits alkalinity, there is an advantage that the pH can be adjusted by suppressing the amount added relative to the total amount of the composition.

  Furthermore, sodium hydrogen carbonate and sodium hydroxide have extremely high solubility in water, so that they do not easily affect the moldability and plasticity of the preparation, are highly convenient in the manufacturing process, and disintegrate the manufactured preparation. It has the advantage that it does not adversely affect the properties or solubility.

It is a graph which shows the residual rate in a stability test, and pH of the aqueous solution of a film-form preparation about composition A-composition F. FIG. It is a graph which shows the residual rate in a stability test, and pH of the aqueous solution of a film-form preparation about composition G-composition J. It is a graph which shows the residual rate in a stability test, and the pH of the aqueous solution of a film-form preparation about the composition P-composition T. FIG. It is a graph which shows the residual rate in a stability test, and the pH of the aqueous solution of a film-form preparation about composition G and composition L-composition N. It is a graph which shows the relationship between pH and residual rate of the aqueous solution of a film-form preparation. It is a graph which shows the relationship between the ratio (mass%) of sodium hydrogencarbonate with respect to all the composition components, and pH of the aqueous solution of a film-form preparation. It is a graph which shows the relationship between the ratio (mass%) of sodium hydroxide with respect to all the composition components, and pH of the aqueous solution of a film-form preparation.

Claims (1)

A film-form preparation for oral administration,
Picosulfate sodium, hypromellose, hydroxypropylcellulose, and an aqueous solution containing an alkaline compound are formed into a film,
A film-form preparation characterized in that the pH of an aqueous solution of a total amount of 100 ml in which 1 g of dry mass is dissolved in water is 7-9.

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