JP6615978B2 - Oral patch - Google Patents

Description

The present invention relates to an intraoral patch.
This application claims priority on February 25, 2016 based on Japanese Patent Application No. 2016-34513 for which it applied to Japan, and uses the content for it here.

Conventionally, various intraoral patches are known (for example, refer to Patent Document 1).
When saliva infiltrates into the oral patch and the oral patch gradually disintegrates, the drug contained in the oral patch is released into the saliva. The drug released into the saliva is absorbed into the patient's body through the gastrointestinal tract and other mucous membranes.

International Publication No. 2014/192918

  Since the intraoral patch adheres to the oral cavity and is not easily swallowed, the drug is gradually released due to the infiltration of saliva, and is therefore suitable for applications in which the drug is released over a long period of time. The release of drugs from the oral patch is affected by the patient's salivary secretion. For example, since saliva secretion decreases during sleep, saliva is less likely to infiltrate the oral patch, and drug release may vary.

  This invention is made | formed in view of the situation mentioned above, Comprising: It aims at providing the intraoral patch which can discharge | release a medicine stably even if saliva secretion falls.

The present invention has a drug layer containing a drug and an infiltration promoter, and an adhesion layer containing an adhesion-imparting component to the mucous membrane and fixed to the drug layer, and the drug layer is the infiltration promoter As an intraoral patch containing only D-sorbitol and containing neither xylitol nor erythritol .

  The infiltration promoter may contain an osmotic pressure regulator having an osmotic pressure at 20 ° C. of 1000 mOsm / kg or more and 2000 mOsm / kg or less.

  The content of the infiltration promoter in the drug layer may be 20% by mass or more and 70% by mass or less.

  The drug may be an ultra-short-acting sleep inducer.

  The drug layer may contain at least one of an excipient and a binder.

  The adhesion layer may contain at least one of an excipient and a binder.

  The adhesion imparting component may contain at least one of povidone and carboxyvinyl polymer.

  According to the present invention, since the infiltration promoter allows saliva to infiltrate into the drug layer, the saliva can be retained in the drug layer, so that the drug can be stably released even when saliva secretion decreases. .

It is a perspective view which shows an example of the dosage form of the intraoral patch which concerns on one Embodiment of this invention. It is a top view of the chamber used in the experiment example using the intraoral patch of the embodiment. It is a photograph which shows the infiltration state of the water | moisture content to the drug layer in the experiment example. It is a photograph which shows the infiltration state of the water | moisture content to the drug layer in another experiment example using the intraoral patch of the embodiment. It is a photograph which shows the infiltration state of the water | moisture content to the drug layer in a comparative example. It is a graph which shows the result of an example of an experiment. It is a graph which shows the result of an example of an experiment.

An embodiment of the present invention will be described. FIG. 1 is a perspective view showing an example of the dosage form of the intraoral patch of the present embodiment.
The intraoral patch of the present embodiment is a drug that is used by being stuck in the oral cavity.
As shown in FIG. 1, the dosage form of the intraoral patch 1 is a tablet, and in particular, a multilayer tablet having an adhesive layer 3 that can adhere to the oral cavity. The shape of the intraoral patch 1 is, for example, a disc shape. As an example, the oral patch 1 has a diameter of 6 mm to 12 mm and a total thickness of 1 mm to 6 mm.

  The intraoral patch 1 has a drug layer 2 and an adhesion layer 3.

The drug layer 2 contains a drug and an infiltration promoter.
The type of drug is not particularly limited. For example, an ultrashort-acting sleep induction agent or a short-acting sleep induction agent may be contained in the drug layer 2 of the present embodiment as a drug. Examples of ultra-short-acting sleep-inducing agents are zolpidem (N, N, 6-Trimethyl-2- (4-methylphenyl) imidazo [1,2-α] pyridine-3-acetamide), triazolam, zopiclone, and S Examples include zopiclone. Examples of the short-acting sleep induction agent include protizolam, lormetazopam, rilmagaphone and the like.
Zolpidem may be a base educt or an acid addition salt.
For example, the acid added to zolpidem is selected from known medically acceptable acids. For example, an inorganic acid such as hydrochloric acid or nitric acid may be used as the acid added to zolpidem.
In addition, as acids added to zolpidem, organic acids such as (hemi) tartaric acid, (hemi) succinic acid, (hemi) fumaric acid, (hemi) maleic acid, malic acid, lactic acid, citric acid, and (hemi) adipic acid May be used.
In this embodiment, the zolpidem acid addition salt is preferably a tartaric acid addition salt or a hemitartaric acid addition salt. In this embodiment, the drug layer 2 contains zolpidem tartrate (N, N, 6-Trimethyl-2- (4-methylphenyl) imidazo [1,2-α] -pyridine-3-acetamide hemi- (2R) as a drug. , 3R) -tartrate) in a predetermined amount of 2 mg to 8 mg. The content of the drug in the drug layer 2 may be appropriately set in consideration of a desired drug effect.

  The infiltration promoter is contained in the drug layer 2 in order to promote saliva infiltration into the drug layer 2. The infiltration promoter includes an osmotic pressure adjusting agent for adjusting the osmotic pressure of the drug layer 2 in a state where the intraoral patch 1 of the present embodiment is attached to the oral cavity. Examples of the osmotic pressure regulator that serves as an infiltration promoter include erythritol and D-sorbitol. That is, the drug layer 2 in the present embodiment may include at least one of erythritol and D-sorbitol.

  The osmotic pressure regulator that can be used as an infiltration promoter is not limited to the above, and may be a substance that has an osmotic pressure at 20 ° C. of 1000 mOsm / kg or more and 2000 mOsm / kg or less.

The content of the invasion promoter in the drug layer 2 defines the drug release rate. The higher the content of the infiltration promoter in the drug layer 2, the more the drug release is promoted. This is because the amount of saliva infiltrating into the drug layer 2 increases as the content of the infiltration promoter increases.
The content of the infiltration promoter in the drug layer 2 defines the time during which the medicinal effect of the oral patch 1 of the present embodiment is maintained. In the present embodiment, the content of the infiltration promoter in the drug layer 2 is a predetermined content in the range of 20% by mass to 70% by mass.

  The infiltration promoter is a drug layer that contains liquid (saliva) necessary for disintegration of the drug layer 2 by taking saliva into the drug layer 2 in a state where the oral patch 1 is attached to the oral cavity. Hold at 2. That is, in the present embodiment, the infiltration promoter contained in the drug layer 2 is an osmotic pressure regulator, so that in the state where saliva has infiltrated into the drug layer 2, the inside of the drug layer 2 is more than the outside of the drug layer 2. Is kept high, and saliva further infiltrates into the drug layer 2. Further, the drug layer 2 is gradually disintegrated from the outside by dissolving the drug and other components in the saliva retained in the drug layer 2.

  The drug layer 2 may contain at least one of an excipient and a binder in addition to the drug and the infiltration promoter. Furthermore, the drug layer 2 may contain other components as necessary.

For example, the drug layer 2 may contain crystalline cellulose, lactose, lactose hydrate, aminoalkyl methacrylate copolymer, waxes, purified shellac and the like as excipients. For example, when crystalline cellulose and lactose are included in the drug layer 2 as excipients, the disintegration is excellent.
The compounding ratio of crystalline cellulose and lactose is preferably 1.5: 1 to 2: 1 by mass ratio. Moreover, it is preferable that lactose is a hydrate.
The content of the excipient in the drug layer 2 is a predetermined content in the range of 67% by mass to 87% by mass.

In addition, for example, the drug layer 2 includes povidone (polyvinylpyrrolidone), crospovidone, carmellose or a sodium salt thereof, croscarmellose or a sodium salt thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, carboxy as a binder. Vinyl polymers, starches, starch derivatives and the like may be included. Of these, povidone, croscarmellose, and sodium salt of croscarmellose are particularly preferred as the binder.
The povidone contained in the binder preferably has a K value of about 90 (grade K-90).

  In addition to the above-described excipients and binders, the drug layer 2 is composed of other components that control the release of the drug, additional bioactive components, stabilizers, colorants, lubricants, in addition to the drug and the infiltration promoter. An agent or the like may be contained.

  The adhesion layer 3 contains a component (adhesion imparting component) that provides adhesion to the mucous membrane when moisture (saliva) infiltrates.

The adhesion layer 3 may also contain povidone (polyvinylpyrrolidone), carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose or a sodium salt thereof, starch, starch derivatives and the like as adhesion imparting components. Good. Of these, the combination of povidone and carboxyvinyl polymer can obtain particularly good adhesion due to wettability by hydrophilic povidone and swelling by carboxyvinyl polymer following movement to the oral mucosa. .
Moreover, it is preferable that the povidone contained in the adhesion layer 3 as an adhesion imparting component has a K value of about 90 (grade is K-90).
The compounding ratio of povidone and carboxyvinyl polymer is preferably 2: 3 by mass ratio. Moreover, it is preferable that lactose is a hydrate.
The content of the adhesion-imparting component in the adhesion layer 3 is set based on the time required for the adhesion layer 3 to adhere to the oral mucosa. The content of the adhesion-imparting component in the adhesion layer 3 is preferably, for example, 50% by mass of the entire adhesion layer 3.

  Further, the adhesion layer 3 may contain at least one of an excipient and a binder in addition to the adhesion imparting component. Furthermore, the adhesion layer 3 may contain other components as necessary.

For example, the adhesion layer 3 may contain maltitol, crystalline cellulose, lactose, starch, dextrin, sucrose and the like as an excipient.
A combination of maltitol and crystalline cellulose is preferable because maltitol is non-cariogenic and has an appropriate cooling sensation, and crystalline cellulose improves adhesion to the oral mucosa due to a water-conducting effect.
The blending ratio of maltitol and crystalline cellulose is preferably 3: 2 by mass ratio.
Moreover, it is preferable that lactose is a hydrate.
The content of the excipient in the adhesion layer 3 is preferably, for example, 50% by mass of the entire adhesion layer 3.

  For example, the drug layer 2 may contain povidone (polyvinylpyrrolidone) as a binder.

The outline of the manufacturing method of the intraoral patch 1 of this embodiment is demonstrated.
The intraoral patch 1 of this embodiment can be manufactured using the well-known tableting apparatus which can manufacture a two-layer laminated tablet. At the time of manufacturing the oral patch 1 of the present embodiment, first, the components of the drug layer 2 are tableted with the first tableting pressure, and then the components of the adhesive layer 3 are laminated on the drug layer 2. Tablet with the second tableting pressure. At this time, the second tableting pressure is greater than the first tableting pressure. As an example, the first tableting pressure is a predetermined pressure of 50N to 150N, and the second tableting pressure is a predetermined pressure of 300N to 1000N. By such two-stage tableting, the oral patch 1 of this embodiment is produced as a tablet having a hardness of about 20N to 70N.

The effect | action of the intraoral patch 1 of this embodiment is demonstrated.
The intraoral patch 1 of this embodiment is used by being affixed to the oral mucosa such as the tongue belly (back of the tongue), for example. At this time, by bringing the adhesion layer 3 into contact with the mucous membrane, saliva infiltrates into the adhesion layer 3, and the adhesion layer 3 is fixed to the mucosa. In a state where the oral patch 1 of the present embodiment is fixed to the oral mucosa, when saliva comes into contact with the oral patch 1, part of the saliva contacts the infiltration promoter and infiltrates into the drug layer 2. . Thereby, the drug layer 2 gradually collapses. Further, the drug and other components contained in the drug layer 2 are dissolved or dispersed in saliva. Even when the supply of saliva to the vicinity of the intraoral patch 1 is reduced because the drug layer 2 contains an infiltration promoter, saliva necessary for the collapse of the drug layer 2 is contained in the drug layer 2. Retained. For this reason, even if the supply of saliva decreases due to going to bed after taking, etc., the amount of drug released from the drug layer 2 is unlikely to decrease.

In the intraoral patch 1 of this embodiment, the release of the drug from the drug layer 2 is not easily affected by the increase or decrease of the saliva secretion amount, and is not easily interrupted even when the saliva secretion amount is reduced. That is, the intraoral patch 1 of this embodiment can maintain a medicinal effect suitably even if saliva secretion falls.
Zolpidem tartrate exemplified in this embodiment is an ultra-short-acting sleep-inducing agent, and may become awakened when the medicinal properties are cut off during sleep. In the intraoral patch 1 of this embodiment, the release of zolpidem tartrate from the drug layer 2 continues even during sleep when the saliva secretion amount decreases. For this reason, the medicinal effect can be suitably maintained during sleep, and the medicinal effect can be quickly lost after the drug layer 2 is completely disintegrated by the infiltration of saliva. As a result, according to the intraoral patch 1 of this embodiment containing zolpidem tartrate in the drug layer 2 as an example of an ultra-short-acting sleep-inducing agent, it is surely effective during sleep time of a preset length. It is possible to control the release of the drug so as to maintain the sleepiness and leave no sleepiness after waking up.

(Experimental example 1)
An experimental example for illustrating the action of the oral patch of the present embodiment in a state where the amount of saliva secreted in the oral cavity is reduced is shown below.
FIG. 2 is a schematic diagram illustrating a configuration of a chamber used in Experimental Example 1. FIG. 3 is a photograph showing the state of water infiltration into the drug layer in Experimental Example 1. Each photograph shown in FIG. 3 is a photograph of the intraoral patch taken 5 minutes, 10 minutes, 20 minutes, 30 minutes, and 50 minutes after supplying purified water to the chamber. In each photograph in FIG. 3, the upper row is an oral patch containing maltitol in the drug layer, the middle row is an oral patch containing D-sorbitol in the drug layer, and the lower row is erythritol in the drug layer. It is an intraoral patch containing.

  In Experimental Example 1, a chamber was used in which the state of lack of water (saliva) necessary for the collapse of the drug layer of the oral patch was used. As shown in FIG. 2, the chamber 10 in this experimental example has a filter paper 12 disposed on the bottom surface of a container 11. Using this chamber 10, the intraoral patch of this embodiment is placed so that the adhesive layer is in contact with the filter paper 12, and purified water is soaked into the filter paper 12, thereby purifying the oral patch through the filter paper. Water was infiltrated. The amount of purified water is such that the filter paper 12 is immersed in the chamber 10. The purified water was supplied from the periphery of the filter paper 12 to the filter paper 12 so that the purified water was not directly applied to the intraoral patch.

  As examples of intraoral patches, three types of invasion promoters (Experimental Example 1-1: Maltitol, Experimental Example 1-2: D-sorbitol, Experimental Example 1-3: Erythritol) Three each were used. These experimental examples are intended to show the difference in the infiltration aspect of purified water due to the difference in the type of invasion promoter, and the oral patch used in this experimental example is the above-mentioned zolpidem tartrate in the drug layer. It is a placebo not included. Table 1 shows the composition of the drug layer in each experimental example. The numbers listed in Table 1 are mass%.

  The composition of the adhesion layer in Experimental Examples 1-1 to 1-3 is excipient: 50% by mass (maltitol: 30% by mass, crystalline cellulose: 20% by mass), adhesion imparting component: 50% by mass (carboxyvinyl) Polymer: 30% by mass, povidone K-90F: 20% by mass).

  After 5 minutes, 10 minutes, 20 minutes, 30 minutes, and 50 minutes from the time when purified water was supplied to the chamber 10, water infiltration into the oral patch on the filter paper 12 was observed. Water infiltration is visualized by a colorant (blue No. 1) contained in the oral patch.

  As shown in FIG. 3, in Experimental Example 1-1 containing erythritol as an infiltration promoter in the drug layer, purified water completely infiltrated into all three oral patches in 20 minutes from the addition of purified water, The infiltration of purified water was the fastest among the three experimental examples. In Experimental Example 1-2 containing D-sorbitol in the drug layer, purified water completely infiltrated into all three oral patches in 30 minutes from the addition of purified water. In Experimental Example 1-3 containing maltitol in the drug layer, purified water completely infiltrated into all three oral patches in 50 minutes from the addition of purified water.

(Experimental example 2)
Next, Experimental Example 2 is shown as an experimental example of the amount of drug released from the drug layer.
In Experimental Example 2, using the oral patches of Experimental Examples 2-1 to 2-5 and Comparative Example 2-1 each having a drug layer having the composition shown in Table 2, the time course and drug release amount Show the relationship.

  The composition of the adhesion layer was the same as in Experimental Example 1 above.

  In Experimental Example 2, the adhesive layer of each oral patch was brought into contact with a Franz cell membrane (filter paper), and the first oral solution (pH 1.2) was used as the dissolution test solution. The drug was released from the drug layer. At 15, 30, 60, 120, 180, 300, and 420 minutes from the start of the test, a part of the dissolution test solution was collected and the drug concentration was measured by HPLC.

  FIG. 4 is a photograph showing the state of the oral patch on the membrane (filter paper) at the point of 15 minutes from the start of the test. When comparing Experimental Example 2-3 containing 40% by mass of erythritol (FIG. 4A) and Comparative Example 2-1 containing 40% by mass of maltitol as an infiltration promoter (FIG. 4B), Experimental Example 2 containing erythritol -3 infiltrated the dissolution test solution more rapidly than Comparative Example 2-1 containing maltitol.

  FIG. 5 is a graph showing the results of measuring the cumulative dissolution amount of the drug from the start of the test to 180 minutes in Experimental Example 2-3 and Comparative Example 2-1. In FIG. 5, the horizontal axis represents the elapsed time (min) from the start of the dissolution test, and the vertical axis represents the cumulative dissolution amount (mg) of the drug.

  As shown in FIG. 5, when comparing Experimental Example 2-3 containing 40% by mass of erythritol as an infiltration promoter and Comparative Example 2-1 containing 40% by mass of maltitol as an infiltration promoter, erythritol promoted infiltration. Experimental Example 2-3 contained as an agent has a larger amount of drug elution than Comparative Example 2-1 containing maltitol. That is, by containing erythritol as an infiltration promoter in the drug layer, elution of the drug is promoted more than when maltitol is contained. In addition, whether the infiltration promoter is erythritol or maltitol, the drug elution amount per unit time can be considered to be substantially constant in each case.

FIG. 6 shows the results of measuring the cumulative dissolution amount of the drug from the start of the test to 420 minutes in Experimental Example 2-1 to Experimental Example 2-5, which have different erythritol contents, and Comparative Example 2-1 not containing erythritol. It is a graph to show. In FIG. 6, the horizontal axis represents the elapsed time (min) from the start of the dissolution test, and the vertical axis represents the cumulative dissolution amount (mg) of the drug.
As shown in FIG. 6, the higher the erythritol content in the drug layer, the greater the cumulative elution amount of the drug. As shown in FIG. 6, when the erythritol content in the drug layer is in the range of 20% by mass to 66% by mass, the amount of drug released per unit time is substantially constant in each case.

(Experimental example 3)
Next, Experimental example 3 is shown as an experimental example about the sensory test in the oral cavity of the intraoral patch of this embodiment.
In Experimental Example 3, a placebo tablet having the composition shown in Table 3 below was prepared as an example of the oral patch of the present embodiment, and the oral patch was applied to the subject's tongue before going to bed (around 22:00). Then, the undissolved state of the oral patch at the time of getting up the next morning (around 7 o'clock) was evaluated. For the evaluation of the undissolved state, the subject himself / herself must select one closest to the undissolved state of his / her oral patch from a score of 0 to 5 (see Table 4 below) corresponding to the degree of undissolved. Went by.

  The composition of the adhesion layer was the same as in Experimental Example 1 above.

  The results of the sensory test are shown in Table 5 below.

  As shown in Table 5, Experimental Examples 3-2, 3-4, 3-5, and 3-7 containing erythritol or D-sorbitol as an infiltration promoter in the drug layer were compared with other experimental examples. The average score was low, that is, there was little undissolved residue when waking up.

  In addition, although not shown in the drawing, the oral adhesive patch in which triazolam, zopiclone, or eszopiclone was used instead of zolpidem tartrate (the above experimental examples 2-1, 2-2, 2-3, 2-4, respectively) , 2-5, and Comparative Example 2-1) were prepared, and the dissolution test was performed in the same manner as in Experimental Example 2 described above. In the oral patch containing these drugs, zolpidem tartrate was also added. The behavior similar to that of the intraoral patch contained was shown.

  The embodiment and each experimental example of the present invention have been described in detail with reference to the drawings. However, the specific configuration is not limited to the embodiment and the experimental example, and the scope of the present invention is not deviated. Design changes are also included.

  The present invention can be suitably applied to an intraoral patch.

1 Oral patch 2 Drug layer 3 Adhesive layer

Claims (7)

A drug layer containing a drug and an infiltration promoter;
An adhesive layer containing an adhesion-imparting component to the mucous membrane and fixed to the drug layer;
Have
The drug layer is
Containing only D-sorbitol as the infiltration promoter,
Contains neither xylitol nor erythritol,
Oral patch. The intraoral patch according to claim 1, wherein the infiltration promoter includes an osmotic pressure regulator having an osmotic pressure at 20 ° C of 1000 mOsm / kg or more and 2000 mOsm / kg or less. The intraoral patch according to claim 1 or 2 , wherein the content of the infiltration promoter in the drug layer is 20 mass% or more and 70 mass% or less. The intraoral patch according to any one of claims 1 to 3 , wherein the drug is an ultrashort-acting sleep induction agent. The intraoral patch according to any one of claims 1 to 4 , wherein the drug layer contains at least one of an excipient and a binder. The intraoral patch according to any one of claims 1 to 5 , wherein the adhesion layer contains at least one of an excipient and a binder. The intraoral patch according to any one of claims 1 to 6 , wherein the adhesion-imparting component contains at least one of povidone and carboxyvinyl polymer.