JP4916894B2 - Film-form preparation and method for producing film-form preparation - Google Patents

Description

  The present invention relates to a film-form preparation and a method for producing the film-form preparation, and particularly to a film-form preparation that is dissolved in the oral cavity and orally administered with a drug and a method for producing the film-form preparation.

  In recent years, awareness of edible films made from natural polysaccharides and proteins has increased, and attempts have been made to develop film-like products having various uses in various fields. Examples thereof include mouth fresheners, dental hygiene films, packaging materials such as food inner bags, tapes for bundling foods such as dry noodles, food decoration chips, cosmetic packs, and pharmaceutical coating materials. The present inventors have also conducted research and development on various edible films, such as lamination of a plurality of films having different strengths, solubility, component stability, and different functions. (For example, Patent Documents 1 and 2).

JP 2004-248665 A JP 2005-112957 A

  Taking advantage of the accumulation of technology based on research and development on edible films as described above, aging can be achieved by adding pharmaceutical ingredients to the edible film so that it can be dissolved in the oral cavity and administered orally. It is expected to be an easy-to-use preparation for people and children whose swallowing function has been reduced due to illness or disease. In particular, since the number of people with difficulty in swallowing tends to increase with the progress of aging, development of film-form preparations is strongly demanded also in the medical field. For practical use, the film-form preparation is required to have both rapid disintegration property in the oral cavity and practical strength with no handling problems.

  Therefore, in view of the above circumstances, the present invention has an object to provide a film-form preparation having a practical strength with no problem in handling as well as rapid disintegration in the oral cavity, and a method for producing the film-form preparation It is what.

  In order to solve the above-mentioned problems, the film-form preparation according to the present invention is a film-form preparation that is dissolved in the oral cavity and orally administered with a drug, an edible water-soluble film-forming agent, Containing low-substituted hydroxypropylcellulose having a degree of substitution of 0.05 to 1.0 ".

The “drug” is a medical drug containing a pharmaceutical ingredient, and is not particularly limited, but the following drugs A to P can be exemplified.
A. Non-steroidal anti-inflammatory agents such as acetaminophen, aspirin, ibuprofen, ketoprofen, diflunisal, fenoprofen calcium, naproxen, tolmethylene sodium, indomethacin;
B. Antibacterial agents such as triclosan, cetylpyridinium chloride, domifane bromide, quaternary ammonium salts, zinc compounds, sanguinarine, fluoride, alkidine, octonidine, EDTA;
C. Antitussives such as benzonate, calamiphen edicylate, menthol, dextromeltfan hydrobromide, clofenocyanol hydrochloride;
D. Decongestants such as pseudoephedrine hydrochloride, phenylephrine, phenylpropanolamine, pseudoephedrine sulfate;
E. Brompheniramine maleate, chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate, dexchlorpheniramine maleate, diphenhydramine hydrochloride, diphenylpyramine hydrochloride, azatadine maleate, diphenhydramine citrate, doxylamine succinate, promethazine hydrochloride, malein Antihistamines such as acid pyrilamine, tripelenamine citrate, tripelenamine hydrochloride, triprolidine hydrochloride, acribastine, loratadine, brompheniramine, dexbrompheniramine;
F. Expectorants such as guaifenesin, tocone, potassium iodide, hydrated terpine;
G. Antidiarrheal agent such as loperamide;
H. H ₂ -antagonists such as famotidine, lantidine;
I. Proton pump inhibitors such as omeprazole, lansoprazole;
J. et al. General non-selective CNS sedatives such as fatty alcohols, barbital acids;
K. Common non-selective CNS stimulants such as caffeine nicotine, strychnine, picrotoxin, pentyleneterazole;
L. Phenyldantoin, phenobarbital, pyrimidone, carbamazepine, ethosuximide, methosuximide, fencesuximide, trimetadione, diazepam, benzodiazepic acid, phenacelide, phenetride, acetazolamide, sulthiam, bromide, and so on. Drugs to do;
M.M. Antiparkinsonian drugs such as lepotopa and amantadine;
N. Narcotic analgesics such as morphine, heroin, hydromorphone, methopone, oxymorephone, levorphanol, codeine, hydrocodone, oxycodone, nalolphine, naloxone, naltoxone;
O. Antipyretic analgesics such as salicylate, phenylptazone, indomethacin, phenacetin;
P. Psychiatric drugs such as chlorpromazine, metotriprazine, haloperidol, clozapine, reserpine, imiplan, tranylcypromine, lithium phenelzine.

  Examples of the “edible water-soluble film-forming agent” include hypromellose (formerly Japanese Pharmacopoeia “hydroxypropylmethylcellulose”), which is a cellulose derivative (CHPMC) in which cellulose is etherified with a methyl group and a hydroxypropyl group, and cellulose. Hydroxypropyl cellulose (HPC) which is a cellulose derivative etherified with a hydroxypropyl group can be suitably used. In any case, those prescribed in the 15th revision Japanese Pharmacopoeia can be used.

  “Low-substituted hydroxypropyl cellulose” is a low-substituted hydroxypropyl ether of cellulose, in which the hydroxy group of the cellulose glucose ring is partially substituted with a hydroxypropoxy group (the hydrogen atom of the hydroxy group is a hydroxypropyl group). Is replaced). Here, “degree of molar substitution” refers to the average number of moles of hydroxypropoxy groups per anhydroglucose unit. This degree of molar substitution can be measured based on the Japanese Pharmacopoeia. As the low-substituted hydroxypropyl cellulose, for example, LH11, LH33, LH21, LH22, LH31, LH32, LH33 manufactured by Shin-Etsu Chemical Co., Ltd. or LODICEL (trade name) LDC-L, LDC-H are preferably used. be able to.

  The film-form preparation of the present invention can contain other components in addition to the drug, the film forming agent, and the low-substituted hydroxypropylcellulose. For example, crystalline cellulose, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, crospovidone, and the like can be used as general-purpose disintegrants listed in the Japanese Pharmacopoeia and pharmaceutical additive standards. Further, if desired, a slight amount of sweeteners, fragrances, coloring agents and the like may be contained.

  Cellulose is insoluble in water, but it has the property of swelling in water when the hydroxyl group of the glucose ring is partially substituted with a hydroxypropoxy group, and it becomes water-soluble when further substitution proceeds. Its properties vary greatly depending on the degree of molar substitution. The present inventors generally add low-substituted hydroxypropylcellulose having a molar substitution degree of 0.05 to 1.0 with a decrease in strength when attempting to increase the disintegration of the preparation. Thus, it was found that the disintegration property of the film containing the drug can be improved while suppressing a decrease in the strength of the film.

  Therefore, according to the present invention, according to the present invention, it is possible to obtain a film-form preparation having a practical strength with no problem in handling as well as rapid disintegration in the oral cavity while containing a drug. .

  In addition, the film-form preparation according to the present invention can be “the low-substituted hydroxypropylcellulose has a number average value of the minor axis of particles of 1 μm to 20 μm”.

  The low-substituted hydroxypropylcellulose particles have a structure in which fibrous primary particles are gathered in a bundle. The particle diameter of such particles can be determined by analyzing the image of an observation image using an optical microscope, a polarizing microscope, an electron microscope, or the like, so that the longer particle diameter (major axis) and the shorter particle diameter (minor axis). ) And can be evaluated by statistically processing each.

  The present inventors produce a film-form preparation having suitable strength by adding a low-substituted hydroxypropyl cellulose having a number average value of the minor axis of particles of 1 to 20 μm, more preferably 1 to 10 μm. I found out that I can. Such a low-substituted hydroxypropyl cellulose having a particle size can be obtained, for example, by dispersing untreated low-substituted hydroxypropyl cellulose in water and grinding it by applying a shearing force. Grinding with shear force (hereinafter referred to as “shear milling”) should be performed using a vibrating ball mill, colloid mill, homomixer, propeller homogenizer, ultrasonic homogenizer, high pressure homogenizer, milling mill, etc. Can do. In particular, shear grinding is preferred in which the dispersion liquid is jetted and collided from two directions at high pressure, or the jetted water dispersion liquid is collided with the collision plate.

  With the above configuration, according to the present invention, a film-form preparation having suitable strength can be obtained by controlling the particle size of the low-substituted hydroxypropylcellulose to be added.

  Furthermore, the film-form preparation according to the present invention may be "the low-substituted hydroxypropylcellulose is contained in an amount of 1.5 to 4.5 wt% with respect to the total weight of the film-form preparation". .

  The present inventors have found that the addition of a low-substituted hydroxypropylcellulose within the above range of content is particularly suitable for improving disintegration while suppressing a decrease in strength. With the above configuration, according to the present invention, it is possible to obtain a film-form preparation having excellent disintegration and suitable strength.

  In addition, the film-form preparation according to the present invention is “the water-soluble film-forming agent is contained in an amount of 7 to 12% by weight based on the total weight of the film-form preparation, and the low-substituted hydroxypropylcellulose is a film-form preparation. It may be contained from 1.5% to 6% by weight relative to the total weight.

  In order to improve the disintegration, it is effective for the inventors to reduce the content of the film-forming agent, and with the addition of low-substituted hydroxypropylcellulose, the content of the film-forming agent is reduced. It has been found that a decrease in film strength can be suppressed, and that there is a suitable range for the content of the film-forming agent and the low-substituted hydroxypropylcellulose.

  With the above configuration, according to the present invention, it is possible to obtain a film-form preparation that is further excellent in disintegration while suppressing a decrease in film strength.

  Next, the method for producing a film-form preparation according to the present invention is “a method for producing a film-form preparation which is dissolved in the oral cavity and orally administers a drug, and has a low molar substitution degree of 0.05 to 1.0. A shear grinding step of shearing and grinding an aqueous dispersion in which hydroxypropylcellulose having a degree of substitution is dispersed in water; and an aqueous solution of the sheared and ground aqueous dispersion, a drug, and an edible water-soluble film-forming agent. A mixed liquid preparation step of preparing a mixed liquid containing, and a casting step of casting the mixed liquid on a base surface ”.

  The “shear milling” can be performed by the method described above. Further, the “base surface” is a surface from which a “mixed solution” that is a stock solution of a film-form preparation is cast on the upper surface thereof, and is a surface from which a film is formed. For example, a mirror-polished stainless steel belt, A drum or a plastic film fixed on a smooth surface can be used as a base surface. And a film-form preparation can be obtained by drying the liquid mixture cast on the base surface together with the base surface, and peeling from the base surface.

  With the above configuration, according to the present invention, the low-substituted hydroxypropylcellulose dispersed in water is sheared and ground to reduce the particle size of the low-substituted hydroxypropylcellulose, and the low-substituted swelled in water The particles of hydroxypropylcellulose can be uniformly dispersed in water. Then, in the state of the shear-milled aqueous dispersion, the low-substituted hydroxypropyl cellulose is mixed with an aqueous solution of a water-soluble film-forming agent, a drug, etc. A uniformly dispersed film-form preparation can be obtained. Thereby, the above-mentioned excellent properties of practical strength and quick disintegration are uniformly provided, and a film-form preparation having a constant quality can be produced.

  As described above, as an effect of the present invention, it is possible to provide a film-form preparation having a practical strength with no problem in handling as well as a rapid disintegration property in the oral cavity, and a method for producing the film-form preparation. it can.

  Hereinafter, the film-form preparation which is the best embodiment of the present invention and the method for producing the film-form preparation will be described with reference to FIGS. Here, FIG. 1 shows the relationship between the content of low-substituted hydroxypropyl cellulose substituted with crystalline cellulose, (a) disintegration, and (b) tensile strength, for an example of the film-form preparation of this embodiment. FIG. 2 is a graph showing the relationship between the content of low-substituted hydroxypropylcellulose substituted with hypromellose, (a) disintegration, and (b) tensile strength for an example of the film-form preparation of this embodiment. 3 is a graph showing the relationship between the hypromellose content and the tensile strength of the film-form preparation of FIGS. 1 and 2, and FIG. 4 is a process showing the method for producing the film-form preparation of this embodiment. FIG. 5 is a graph showing the relationship between the content of acetaminophen, (a) disintegration, and (b) tensile strength, and FIG. 6 shows a partially pregelatinized starch as the disintegrant. (A) disintegrating time, and (b) is a graph showing the change in tensile strength.

  The film-form preparation of this embodiment is a film-form preparation in which the drug is orally administered after being dissolved in the oral cavity, and the drug, the edible water-soluble film-forming agent, and the molar substitution degree is 0.05 to 1. 0 low-substituted hydroxypropyl cellulose (hereinafter simply referred to as “L-HPC”). Moreover, in this embodiment, the disintegrating agent and the sweetener, fragrance | flavor, coloring agent, etc. as other components are contained.

  In addition, as shown in FIG. 4, the method for producing the film-form preparation of the present embodiment shears an aqueous dispersion in which low-substituted hydroxypropylcellulose having a molar substitution degree of 0.05 to 1.0 is dispersed in water. A shear grinding step S1 for grinding, a mixed solution preparation step S2 for preparing a mixed solution containing an aqueous solution of an edible water-soluble film-forming agent, a drug, a disintegrant, and a shear-milled aqueous dispersion, and a mixed solution A casting step S3 for casting on the base surface, a drying step S4 for drying the cast mixed liquid, and a peeling step S5 for peeling the film-form preparation formed by drying the mixed liquid from the base surface. It has.

  More specifically, in the shear grinding step S1, first, L-HPC is dispersed in water to obtain an aqueous dispersion. Here, the concentration of L-HPC in the aqueous dispersion is desirably 0.5 to 10% by weight, and more desirably 2 to 8% by weight. If the concentration is higher than this, the viscosity after shear grinding increases, making it difficult to cast the mixed solution in the casting step S3. Conversely, if the concentration is lower than this, in the mixed solution preparing step S2. This is because the amount of the dispersion after shearing and grinding added for a predetermined formulation increases, and the time required for drying the film in the drying step S4 increases. The concentration of L-HPC in the aqueous dispersion of this embodiment was set to 5% by weight.

  Moreover, the particle diameter of L-HPC before shear grinding is preferably 20 to 60 μm as an average particle diameter measured with a laser diffraction particle size distribution analyzer. This is because if the average particle size is too small, the dispersibility in water decreases due to aggregation, making shear milling difficult, and if the average particle size is too large, the energy and time required for sufficient shear milling are required. This is because of the increase. In addition, the average particle diameter by said laser diffraction type particle size distribution measuring apparatus is a value measured without distinguishing the major axis and minor axis of the fibrous particle | grains of L-HPC.

  In this embodiment, the average particle diameter of L-HPC after shear grinding is measured by measuring the major axis and minor axis of 200 or more L-HPC particles using an observation image of 200 times by an optical microscope. Obtained as an average value. For image analysis, REGULUS image processing inspection apparatus Ver. 1.1.33 was used. As a result, in the L-HPC particles in which the fibrous primary particles were bundled, the fibers were peeled along the longitudinal direction by shear grinding, and the minor axis was reduced to 1 to 10 μm. In addition, such an image analysis can be performed using a wet particle shape measuring device FPIA-3000S manufactured by Sysmex.

  Next, a drug, an aqueous solution of a film-forming agent, a disintegrant and other components are dissolved or dispersed in water or an organic solvent (step S2 ′), and the liquid and the shear-milled dispersion are given a predetermined formulation. The resulting mixture is mixed and degassed to prepare a mixed solution (mixed solution preparing step S2).

  Thereafter, the base film (PP, made of PET) is fixed to a smooth plane to form a base surface, and the prepared mixed solution is uniformly coated on the base surface (casting step S3). Since the thickness of the film depends on the concentration, viscosity, and coating speed of the raw material solution, the film thickness is appropriately adjusted so as to have a desired thickness.

  The base film coated with the mixed solution is placed in a warm air dryer in which convection is created and maintained at 40 to 50 ° C. for about 5 minutes, and the coating layer is dried to form a film-form preparation (drying step S4). Then, the base film is peeled off (peeling step S5).

  By the above method, a film-form preparation having a thickness of 50 to 100 μm, which is the same as that of a normal edible film, can be obtained after drying.

  The obtained film-form preparation was cut into a size of about 3 cm × 2 cm and subjected to each test. The test performed the disintegration test, the measurement of film strength, and the electron microscope observation of the film surface about the film-form preparation of each prescription. The method is shown below. In addition, although the mass of one film-form preparation cut | disconnected differs with prescriptions, it was 35-50 mg.

<Disintegration test>
One film-form preparation was floated and allowed to stand in purified water at room temperature (20 to 25 ° C.) placed in a petri dish, and the time required until the collapse was visually recognized from the moment of floating was measured. Furthermore, in order to correct variations in the weight of the film, the value divided by the weight of the film, that is, the disintegration time per unit weight (sec / mg) was used as an indicator of disintegration. In addition, about each prescription mentioned later, it measured about 3-5 film-form preparations, respectively, and used the average value.
<Measurement of film strength>
The stress until breakage due to tension was measured with a rheometer (manufactured by Rheotech, RT-2010-JW type), and divided by the cross-sectional area of the film. In addition, about each prescription, it measured about 3-5 film-form preparations, respectively, and used the average value.
<Electron microscope observation>
Using a scanning electron microscope (manufactured by JEOL, JSM-T330 type), the film surface was observed.

  Hereinafter, Examples 1 to 7 of the present embodiment will be described in comparison with a control example. Here, a case where hypromellose (hereinafter referred to as “HPMC”) is used as the edible water-soluble film forming agent and crystalline cellulose is used as the disintegrant is exemplified. As HPMC, Metroze (trade name) 60SH-50 manufactured by Shin-Etsu Chemical Co., Ltd. was used, but the same 60SH, 90SH, and 65SH can also be suitably used. As crystalline cellulose, Ceraos (trade name) manufactured by Asahi Kasei was used.

The ratio of each component in the following formulations is% by weight with respect to the total weight of the film-form preparation, and is a numerical value as a solid content.
<Control example>
The control example is a formulation that does not contain L-HPC and is determined based on the composition of the basic edible film. Acetaminophen 10.0%, HPMC 11.5%, crystalline cellulose 63. 2% and the remaining 15.3% were used as other ingredients such as sweeteners.

The film-form preparation obtained by the formulation of the control example has a tensile strength of 10 MPa or more which is considered to be a practical strength with no handling problems, but the disintegration time per unit weight is as long as about 0.74 sec / mg. The solubility in the inside is not good. Below, it is evaluated whether the film-form preparations of each Example have the same tensile strength as the film-form preparations of the control examples, and whether the disintegration time per unit weight can be shortened compared to the control examples. .
<Example 1 to Example 3>
L-HPC was added so that the content ratios relative to the total weight of the film-form preparation were 1.5%, 3.0%, and 6.0%, respectively. Those reduced from the prescription were referred to as Example 1, Example 2, and Example 3, respectively. The formulations of these examples are shown in Table 1 along with the control examples. As L-HPC, L-HPC having a molar substitution degree of 0.3 (LH-21 manufactured by Shin-Etsu Chemical Co., Ltd.) was used.

  The results of the disintegration test for the film-form preparations of Examples 1 to 3 are shown in FIG. Moreover, the measurement result of tensile strength is similarly shown in FIG.1 (b) with a control example. As is clear from the figure, replacing a small amount of crystalline cellulose as a disintegrant with L-HPC shortened the time required to disintegrate and improved disintegration, but increased the amount replaced with L-HPC. With this, the disintegration property gradually decreased, and the disintegration property when the content of L-HPC was 6% (Example 3) decreased to a value close to that of the control example. On the other hand, the tensile strength was increased by replacing crystalline cellulose with L-HPC, but no dependency on the L-HPC content was observed. From the above results, by replacing a part of crystalline cellulose as a disintegrant with L-HPC, disintegration can be improved without affecting the strength of the film, but the amount of substitution with L-HPC is small. The effect was high in the case of a small amount, and it was considered that the content of L-HPC did not exceed 6%.

<Example 4 to Example 7>
L-HPC was added so that the content ratios with respect to the total weight of the film-form preparation were 1.5%, 3.0%, 4.5%, and 6.0%, respectively, and the content ratio of HPMC Were reduced from the prescription of the control example as Example 4, Example 5, Example 6, and Example 7, respectively. The formulations of these examples are shown in Table 2 along with the above control examples. As L-HPC, L-HPC having a molar substitution degree of 0.3 (LH-21 manufactured by Shin-Etsu Chemical Co., Ltd.) was used.

  The result of the disintegration test for the film-form preparations of Examples 4 to 7 is shown in FIG. As is apparent from the figure, the disintegration was greatly improved by replacing a part of HPMC with L-HPC. This improvement in disintegration was much greater than in the above case where crystalline cellulose was replaced with L-HPC. That is, the disintegration time per unit weight of the film-form preparation is shortened to about ½ by replacing 1.5% HPMC with L-HPC, and about 1 by replacing 3.0 to 4.5%. Reduced to / 4. In addition, when looking at the average disintegration time of one film-form preparation, it is about 40 seconds in the control example, whereas in the case of 3.0 to 4.5% L-HPC, it is extremely 8 to 11 seconds. It was a short time.

  In addition, when L-HPC was 6.0% (Example 7), disintegration did not occur in the film-form preparation. Here, even in a formulation containing 6.0% L-HPC, such a phenomenon was not observed in the above case (Example 3) in which the crystalline cellulose was substituted, and therefore no collapse occurred. This was not due to the inclusion of 6.0% L-HPC, but was attributed to the decrease in the HPMC content. From these facts, disintegration can be greatly improved by replacing part of HPMC with L-HPC, but there is a lower limit to the content of HPMC that can be reduced by replacing with L-HPC. It was suggested that the value was between the content in Example 7 and the content in Example 6, that is, 5.5 to 7.0%.

  Next, the measurement result of the tensile strength about Example 4 thru | or Example 7 is shown in FIG.2 (b) with a control example. As is apparent from the figure, the tensile strength was increased by replacing 1.5% of L-HPC with HPMC, but the strength was gradually decreased when the content of L-HPC was further increased.

  Here, the relationship between the HPMC content and the tensile strength is shown in FIG. 3 together with the results of Examples 1 to 3. As is clear from this figure, when the L-HPC content is 1.5 to 0.6%, there is an approximately linear relationship between the tensile strength and the HPMC content. It can be seen that the film strength also decreases as the HPMC content decreases, regardless of the content of crystalline or the content of crystalline cellulose. This is considered to be because HPMC has the largest contribution to the film strength since it is a base that forms the center of film formation. And it was thought that the fall of the film strength accompanying the fall of the content rate of HPMC can be suppressed by shifting to the side where film strength is large by addition of L-HPC.

  Furthermore, referring to the relationship between the content of HPMC and the tensile strength, the content of the film forming agent is reduced as much as possible while ensuring the content of the film forming agent capable of exhibiting an acceptable strength for handling. Thus, it was considered that a film-form preparation having both excellent disintegration property and practical strength could be designed. For example, while adding L-HPC and ensuring a content of at least 7.0% for HPMC, the film strength is maintained at the same level as that of the control example, and is about 1/4 that of the control example. A film-form preparation having disintegrability can be obtained (Example 6). Alternatively, by securing a content of about 10% for HPMC, it is possible to obtain a film-form preparation having a strength higher than that of the control example and having a good disintegration property of about 1/2 of that of the control example. (Example 4).

  As shown above, according to the present embodiment, by containing 1.5 to 6% of L-HPC with respect to the total weight and substituting with part of the crystalline cellulose, the film strength is improved along with the disintegration. Was able to improve. Further, when the content of L-HPC is 1.5 to 4.5%, HPMC as a film forming agent is replaced even when the added L-HPC is replaced with crystalline cellulose as a disintegrant. Even in this case, it was possible to suppress disintegration of the film and improve disintegration.

  Furthermore, in order to increase the disintegration property of the film-form preparation, it is extremely effective to reduce the content of HPMC as a film forming agent, but there is a lower limit to the extent that the content of HPMC can be reduced. By ensuring at least 7% content, the content of L-HPC was in the range of 1.5 to 6%, and the decrease in film strength was suppressed, and the disintegration property could be remarkably improved.

  In addition, generally, when a drug is to be contained, the film tends to be thick. In this embodiment, the film contains a drug and is as thin as 50 to 100 μm, which is as thin as a conventional edible film. Thus, it was possible to produce a film-form preparation that is easy to take even for a sick person, an elderly person, a child, and the like who have a feeling of foreign matter in the oral cavity and have a low swallowing function.

  Although the case where the content rate of the acetaminophen as a chemical | medical agent was 10% was shown above, next, it shows about the influence which the content rate of acetaminophen exerts on the disintegration property and film strength of a film-form preparation. Table 3 shows the prescriptions of Example 8 and Example 9 in which the content of acetaminophen was increased from the control example to 20% and 30%, respectively, together with the control example.

  The results of the disintegration test and the tensile strength test for Example 8 and Example 9 are shown in FIG. 5A and FIG. As apparent from FIG. 5 (b), the tensile strength increased as the acetaminophen content increased. This was thought to be because the drug particles acted as excipients and contributed to the formation of the film.

  On the other hand, as shown in FIG. 5 (a), the disintegration was about the same as the case of 10% in the case of acetaminophen 20%, but when the acetaminophen was increased to 30%, the unit The disintegration time per weight was increased approximately twice, and the disintegration property was greatly reduced. This is because the increase in the concentration of acetaminophen is prominent in its hydrophobic properties, preventing water from entering the film, and also affecting the decrease in the content of crystalline cellulose as a disintegrant. It was.

  From the above, the film strength can be increased by increasing the content of acetaminophen, but the content of acetaminophen is preferably in the range of 10 to 20% in order not to deteriorate the disintegration property. It was shown that.

  Furthermore, although the case where crystalline cellulose was used as a disintegrating agent was shown above, partially pregelatinized starch can also be used. Table 4 shows the formulation of Example 10 together with the control example, in which the crystalline cellulose of the control formulation was replaced with partially pregelatinized starch.

  The results of the disintegration test and the tensile strength test for Example 10 are shown in FIG. 6 (a) and FIG. 6 (b), respectively, in comparison with the control example. As is clear from these figures, the disintegration property of the film-form preparation was improved by using partially pregelatinized starch instead of crystalline cellulose as a disintegrant. This improvement in disintegration was thought to be due to the fact that partially pregelatinized starch was superior in swelling property compared to crystalline cellulose. On the other hand, the tensile strength was lowered by using partially pregelatinized starch as a disintegrant instead of crystalline cellulose, but the practical strength of 10 MPa was maintained.

  As a result of observing the film surface with a scanning electron microscope, a more porous structure was obtained when partially pregelatinized starch was used than when crystalline cellulose was used. In addition, when crystalline cellulose was used, the shape of the particles observed on the film surface was fibrous, whereas the particles when using partially pregelatinized starch had a nearly spherical shape. It was considered that the difference in the density and particle shape of the tissue had an effect on the disintegration property and film strength of the film-form preparation.

  From the above, crystalline cellulose can be selected as a disintegrant when emphasizing strength, and partially pregelatinized starch can be selected as a disintegrating agent when emphasizing disintegration. It was considered possible to design a film-form preparation according to the degree of strength.

It is a graph which shows the relationship between the content rate of the low substituted hydroxypropyl cellulose substituted with crystalline cellulose, (a) disintegration, and (b) tensile strength about an example of the film-form preparation of this embodiment. It is a graph which shows the relationship between the content rate of the low substituted hydroxypropyl cellulose substituted with hypromellose, (a) disintegration, and (b) tensile strength about an example of the film-form preparation of this embodiment. It is a graph which shows the relationship between the content rate of hypromellose and tensile strength about the film-form preparation of FIG.1 and FIG.2. It is process drawing which shows the manufacturing method of the film-form formulation of this embodiment. It is a graph which shows the relationship between the content rate of acetaminophen, (a) disintegration, and (b) tensile strength. It is a graph which shows the change of (a) disintegration and (b) tensile strength when a disintegrating agent is partially pregelatinized starch.

Explanation of symbols

S1 Shear and grinding process S2 Mixture preparation process S3 Casting process

Claims (5)

A film-form preparation for oral administration of a drug dissolved in the oral cavity,
Drugs,
An edible water-soluble film-forming agent;
A film-form preparation comprising low-substituted hydroxypropylcellulose having a molar substitution degree of 0.05 to 1.0.   The film-form preparation according to claim 1, wherein the low-substituted hydroxypropylcellulose has a number average value of minor axis of particles of 1 µm to 20 µm.   The film-form preparation according to claim 1 or 2, wherein the low-substituted hydroxypropylcellulose is contained in an amount of 1.5 to 4.5 wt% based on the total weight of the film-form preparation. The water-soluble film-forming agent is contained in an amount of 7 to 12% by weight based on the total weight of the film-form preparation,
The film-form preparation according to claim 1 or 2, wherein the low-substituted hydroxypropylcellulose is contained in an amount of 1.5 to 6% by weight based on the total weight of the film-form preparation. A method for producing a film-form preparation for oral administration of a drug dissolved in the oral cavity,
A shear milling step of shear milling an aqueous dispersion in which a low-substituted hydroxypropyl cellulose having a molar substitution degree of 0.05 to 1.0 is dispersed in water;
A liquid mixture preparing step for preparing a liquid mixture comprising the sheared and ground aqueous dispersion, the drug, and an aqueous solution of an edible water-soluble film forming agent;
And a casting step of casting the mixed solution on a base surface.

Images