JP6548809B2 - Method for producing oral patch - Google Patents

Description

The present invention relates to a method for producing an intraoral patch.
Priority is claimed on Japanese Patent Application No. 2016-034522, filed Feb. 25, 2016, the content of which is incorporated herein by reference.

  Conventionally, a preparation (oral patch) to be used by sticking on the oral mucosa is widely used. For example, Patent Document 1 discloses, as an intraoral patch, a tablet which is composed of two layers of a drug layer and an adhesive layer and is attached to a mucous membrane in the oral cavity such as the palate.

  Such a two-layered tablet (laminated tablet) can be manufactured using a known laminated tableting machine. First, the first layer powder is filled in a die and lightly compressed by upper and lower punches. Subsequently, the second layer powder is piled up on top of the compressed first layer powder in a mortar and lightly compressed by upper and lower punches. Finally, the compressed first layer powder and second layer powder are strongly compressed by the upper and lower punches to obtain a bilayer tablet.

Japanese Patent No. 5775970

  In the intraoral patch described in Patent Document 1, an elution control component for sustained elution of the drug is compounded in a proportion of 10% by mass or more in the drug layer which is the first layer, and in the adhesive layer which is the second layer. The adhesion component for adhering the preparation to the oral mucosa is blended at a ratio of 25 to 75% by mass. Here, the elution control component is, for example, hydroxypropyl cellulose or hypromellose. The adhesion component is, for example, carmellose sodium or povidone.

  Hydroxypropyl cellulose and hypromellose which are elution controlling components are powders having good moldability, while carmellose sodium and povidone which are adhering components are powders having poor moldability. For this reason, the formability of the first layer of tableting powder differs from that of the second layer of tableting powder. In the production of a two-layer tablet, if the formability of each layer is different, compression molding of each layer works predominantly to weaken the adhesive force at the interface between the two layers, and delamination tends to occur.

  The present invention has been made in view of the above-described circumstances, and an object thereof is to provide a method for producing an intraoral patch capable of reducing the occurrence of delamination between a drug layer and an adhesive layer. Do.

According to one aspect of the present invention, a method for producing an intraoral patch comprises: adhesion comprising a drug layer containing hydroxypropyl cellulose as a drug release controlling agent , a carboxyalkyl cellulose salt as an adhesive , and polyvinyl pyrrolidone A method for producing an intraoral patch comprising a layer, wherein the first layer powder constituting the drug layer is filled in a die of a tableting machine, and the first layer powder is 0.2 to 1.2 kN Compressed at a tableting pressure to form the drug layer, and the second layer powder constituting the adhesive layer is loaded on the drug layer in the die, and the drug layer and the second layer powder are And compressing at a tableting pressure of 0 to 26 kN to form the adhesive layer, and compressing the drug layer and the adhesive layer at a tableting pressure of 7.5 to 26 kN.

  In the above-mentioned method for producing an intraoral patch, the diameter of the intraoral patch in which the drug layer and the adhesive layer are compressed at a tableting pressure of 7.5 to 26 kN is the thickness of the intraoral patch. It may be four times or more.

  According to the method for producing the intraoral patch, the occurrence of delamination between the drug layer and the adhesive layer can be reduced.

It is a figure which shows the manufacturing method of the intraoral patch concerning one Embodiment of this invention.

  Hereinafter, an embodiment of the present invention will be described.

  First, the intraoral patch according to the present embodiment will be described. The intraoral patch comprises a drug layer and an adhesive layer.

  The drug layer contains a drug release controlling agent consisting of at least one selected from the group consisting of hydroxyalkyl alkyl cellulose, hydroxypropyl cellulose, sodium carboxyalkyl cellulose, ethyl cellulose, hydrogenated castor oil, and sucrose fatty acid ester. The compounding amount of the drug release controlling agent is not particularly limited as long as it can delay elution of the drug from the drug layer or disintegration of the drug layer. Preferably, the content of the drug release controlling agent is 10% by mass or more based on the total mass of the components of the drug layer.

  As the drug to be contained in the drug layer, a bactericidal agent for oral cavity, an agent for removing bad breath (deodorant), an anti-inflammatory agent, an agent for treating periodontal disease and the like can be used. In addition to the above-mentioned components, the drug layer may be a pH regulator, a refreshing agent such as 1-menthol, a sweetener, a flavoring agent, a coloring agent, an adsorbent, a stabilizer, a flavoring agent (flavoring agent), etc. You may contain the component.

  The adhesive layer usually contains an adhesive as a component adhering to the oral mucosa. The adhesion layer is selected from the group consisting of carboxyalkyl cellulose, carboxyalkyl cellulose salt, alginic acid, alginate, poly (N-vinyl lactam), polyvinyl alcohol, hydroxypropyl cellulose, carboxy vinyl polymer, pullulan and pregelatinized starch as an adhesive. It contains at least one selected. Preferably, the adhesion layer contains carboxyalkyl cellulose or a carboxyalkyl cellulose salt and polyvinyl pyrrolidone as an adhesion agent. The content of the adhesive is preferably 25 to 75% by mass based on the total mass of the adhesion layer component.

  The intraoral patch according to the present embodiment is a tablet, and is a bilayer tablet (laminated tablet) comprising two layers of a drug layer and an adhesive layer. The intraoral patch is formed in a thin disk shape having a substantially circular outer periphery, and the front and back surfaces thereof are both formed flat. The thickness of the intraoral patch is, for example, 1.0 to 2.5 mm, preferably 1.5 to 2.0 mm. Among them, the thickness of the drug layer, which is the first layer, is 0.67 to 1.67 mm, and the thickness of the adhesion layer, which is the second layer, is 0.33 to 0.83 mm. Moreover, the diameter of the intraoral patch is, for example, 5 to 15 mm, preferably 7 to 10 mm.

  The intraoral patch according to the present embodiment is preferably formed as thin as possible in consideration of the ease of application to the intraoral area and the small amount of discomfort when applied. When such a shape is represented by the ratio of diameter to thickness (diameter / thickness), it is approximately 4 or more.

  The drug layer and adhesive layer of the tablet further contain an excipient such as lactose hydrate, a binder such as microcrystalline cellulose, and a component commonly used in tablets such as a lubricant such as stearate and talc. It may be done.

  Next, the manufacturing method of the intraoral patch concerning this embodiment is demonstrated. FIG. 1 is a view showing a method of manufacturing the intraoral patch 30 according to the present embodiment. (A)-(e) of FIG. 1 have shown each process of tableting.

  First, the first layer powder 10 constituting the drug layer 11 and the second layer powder 20 constituting the adhesive layer 21 are prepared. The respective components of the drug layer 11 are weighed and mixed based on a predetermined blending ratio, to obtain a first layer powder 10 which is a tableting powder for the first layer. Moreover, about the adhesion layer 21, each component is measured based on a predetermined | prescribed mixture ratio, and it mixes, and it is set as the 2nd layer powder 20 which is a tableting powder for 2nd layers. The first layer powder 10 and the second layer powder 20 are set in the hopper of the tableting machine 1 respectively.

  Next, tableting of the first layer powder 10 and the second layer powder 20 is performed by the tableting machine 1. First, the first layer powder 10 is filled into the die 2 from the hopper of the tableting machine 1 (see FIG. 1A). The first layer powder 10 is compressed at a tableting pressure (first tableting pressure) of 0.2 to 1.2 kN by the upper punch 3 and the lower punch 4 of the tableting machine 1 to form the drug layer 11 (Fig. 1 (b)). Next, the second layer powder 20 is filled from the hopper of the tablet press 1 onto the drug layer 11 in the die 2 (see FIG. 1 (c)). The second layer powder 20 is compressed at a tableting pressure (second tableting pressure) of 6.0 to 26 kN by the upper punch 3 and the lower punch 4 to form the adhesive layer 21 (see FIG. 1 (d)). Then, the drug layer 11 and the adhesion layer 21 are compressed by the upper punch 3 and the lower punch 4 at a tableting pressure (third tableting pressure) of 7.5 to 26 kN. Thus, the intraoral patch 30 can be produced (see FIG. 1 (e)).

  Hereinafter, the present invention will be further described by way of examples, but the present invention is not limited thereto.

Example 1
In this example, the sizes of the first tableting pressure and the second tableting pressure were changed, and the ranges of the first tableting pressure and the second tableting pressure in which the delamination could be reduced were examined.

(Sample formation procedure)
The magnitude | sizes of the 1st tableting pressure and the 2nd tableting pressure were changed, and the tablet of the intraoral patch of sample number A1-A60 was manufactured. First, with respect to the drug layer, each component shown in Table 1 was weighed based on each blending ratio, and mixed to obtain a first layer powder. Similarly, with respect to the adhesive layer, the respective components shown in Table 1 were weighed based on the respective blending proportions and mixed to obtain a second layer powder. The first layer powder and the second layer powder were set in a tableting machine, and tableting was performed according to the process shown in FIG.

  First, 80 mg of the first layer powder was filled in a die and compressed at a first tableting pressure of each sample number shown in Table 2 to form a drug layer. Next, 40 mg of the second layer powder was filled in a die and compressed at a second tableting pressure of each sample number shown in Table 2 to form an adhesive layer. The drug layer and the adhesion layer were then compressed at a third tableting pressure of 18.5 kN. The third tableting pressure is constant regardless of the sample number. Thereby, a tablet (sample number A1 to A60) of an intra-oral patch comprising a diameter of 8 mm, a drug layer thickness of 1.3 mm, and an adhesive layer thickness of 0.6 mm was produced.

(Evaluation method)
With reference to the “test method for testing the friability of tablets” described in the reference information of the 16th Amended Japanese Pharmacopoeia, put the number of tablets corresponding to the above into a drum in an amount equivalent to as much as 6.5 g. It was made to rotate at 300 rpm at 25 rpm. After the end of rotation, the mass percentage of the tablet not delaminated to the initial mass was calculated. This mass percentage was evaluated based on the following evaluation criteria.
○: The proportion of tablets that did not delaminate is 95% or more. ×: The proportion of tablets that did not delaminate is less than 95%.

(Evaluation results)
The evaluation results for each sample number are shown in Table 2. As shown in Table 2, when the first tableting pressure was 1.4 kN or more, the evaluation criteria were not satisfied regardless of the magnitude of the second tableting pressure. When the first tableting pressure was 1.0 to 1.2 kN, the degree of delamination changed in accordance with the magnitude of the second tableting pressure. When the first tableting pressure was 0.8 kN or less, the evaluation criteria were satisfied regardless of the magnitude of the second tableting pressure.

  When the first tableting pressure is 0 kN, the second layer powder is stacked without compression molding the first layer powder, so the layer interface between the first layer and the second layer in the two-layer tablet is disturbed. It will This condition is not suitable as a production condition because this is undesirable in appearance. Moreover, the second tableting pressure has an upper limit of 26 kN due to the pressure tolerance limit of the punch of the tableting machine.

  From the above results, as an appropriate tableting pressure range, the first tableting pressure is 0.2 to 1.2 kN, the second tableting pressure is 5 to 26 kN, and the third tableting pressure is 18.5 kN.

Example 2
In the present example, the sizes of the second tableting pressure and the third tableting pressure were changed, and the range of the second tableting pressure and the third tableting pressure in which the delamination could be reduced was examined using the friability as an index.

(Sample formation procedure)
The magnitude | sizes of the 2nd tableting pressure and the 3rd tableting pressure were changed, and the tablet of the intraoral patch of sample number B1-B7 was manufactured. First, with regard to the drug layer, each component shown in Table 3 was weighed based on each blending ratio and mixed to obtain a first layer powder. Similarly, with respect to the adhesive layer, the respective components shown in Table 3 were weighed based on the respective blending proportions and mixed to obtain a second layer powder. The first layer powder and the second layer powder were set in a tableting machine, and tableting was performed according to the process shown in FIG.

  First, 80 mg of the first layer powder was filled in a die and compressed at a first tableting pressure of 1.0 kN to form a drug layer. The first tableting pressure is constant regardless of the sample number. Next, 40 mg of the second layer powder was filled in a die and compressed at a second tableting pressure of each sample number shown in Table 4 to form an adhesive layer. Then, the drug layer and the adhesion layer were compressed at the third tableting pressure of each sample number shown in Table 4. Thereby, tablets (sample numbers B1 to B7) of the intraoral patch consisting of two layers each having a diameter of 8 mm, a drug layer thickness of 1.3 mm, and an adhesive layer thickness of 0.6 mm were produced.

(Evaluation method)
The friability (mass percentage of the reduced mass relative to the initial mass) was measured according to the “table friability test method” described in the reference information of the 16th revised Japanese Pharmacopoeia. Delamination was evaluated based on the following evaluation criteria by using the degree of friability as an index.
○: Abrasion degree is 3.0% or less ×: Abrasion degree exceeds 3.0%

(Evaluation results)
The evaluation results for each sample number are shown in Table 4. As shown in Table 4, delamination was reduced as the second and third tableting pressures increased. The upper limit of the second tableting pressure and the third tableting pressure is 26 kN due to the pressure tolerance limit of the punch of the tablet press.

  From the above results, as a suitable tableting pressure range, the first tableting pressure is 1.0 kN, the second tableting pressure is 6.0 to 26 kN, and the third tableting pressure is 7.5 to 26 kN.

  From the results of Example 1 and Example 2 described above, the first tableting pressure is 0.2 to 1.2 kN, the second tableting pressure is 6.0 to 26 kN, and the third is a suitable tableting pressure range. The tableting pressure is 7.5 to 26 kN.

  In addition, the tablets produced in Example 1 and Example 2 described above have a diameter of 8 mm and a thickness of 1.9 mm (sum of 1.3 mm thickness of drug layer and 0.6 mm thickness of adhesion layer) . Thus, even if it is a thin disc-like double-layered tablet having a diameter of 4 times or more with respect to its thickness, a tablet which is less likely to cause delamination by applying the method for producing an intraoral patch according to the embodiment described above. Can be suitably produced.

  The preferred embodiments of the present invention have been described above, but the present invention is not limited to these embodiments. Additions, omissions, substitutions, and other modifications of the configuration are possible without departing from the spirit of the present invention.

  According to the method for producing the intraoral patch according to the above embodiment, the occurrence of delamination between the drug layer and the adhesive layer can be reduced.

1 tableting machine 2 mills 3 upper punch 4 lower punch 10 first layer powder 11 drug layer 20 second layer powder 21 adhesion layer 30 intraoral patch

Claims (3)

A method for producing an intraoral patch comprising a drug layer containing hydroxypropyl cellulose as a drug release controlling agent, and an adhesion layer containing a carboxyalkyl cellulose salt and polyvinyl pyrrolidone as an adhesion agent,
Filling the first layer powder constituting the drug layer into a die of a tableting machine;
The first layer powder is compressed at a tableting pressure of 0.2 to 1.2 kN to form the drug layer,
Filling the second layer powder constituting the adhesive layer on the drug layer in the die;
The drug layer and the second layer powder are compressed at a tableting pressure of 6.0 to 26 kN to form the adhesive layer,
A method for producing an intraoral patch, wherein the drug layer and the adhesive layer are compressed at a tableting pressure of 7.5 to 26 kN.   The tableting pressure value of the second layer powder is 1/2 or more of the tableting pressure value when the drug layer and the adhesive layer are compressed.
  The manufacturing method of the intraoral patch of Claim 1. It is a manufacturing method of the intraoral patch according to claim 1;
The diameter of the intraoral patch in which the drug layer and the adhesive layer are compressed at a tableting pressure of 7.5 to 26 kN is four times or more the thickness of the intraoral patch. Production of intraoral patch Method.

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