JPH0459723A - Intraoral patch type film preparation - Google Patents

Abstract

PURPOSE:To obtain a film preparation directly bondable to an intraoral affected part, having proper durability, comprising a water-soluble polymer film containing pharmaceutical activity. CONSTITUTION:A compound having pharmaceutical activity, especially percutaneously absorbable active component, is added to a water-soluble polymer (e.g. hydroxypropyl cellulose or hydroxypropylmethyl cellulose), which is made into a film by casting method or rolling method to give an intraoral patch type film preparation. The thickness of polymer film is 0.20-0.30mm, preferably 0.24-0.26mm. By providing at least one surface of the film with an adjusting layer, a film preparation having a controlled amount of active ingredient released is obtained. Gelatin, guar gum, etc., is used as the adjusting layer for the purpose of adjusting water permeability and polyvinyl acetal diethylaminoacetate is used for adjusting pH dependence.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is applied to the oral cavity, and is used to treat diseases that occur in the oral cavity.
For example, the present invention relates to membrane preparations suitable for treatment of stomatitis and other oral treatments.

[Conventional technology]

A typical oral disease is so-called stomatitis. The causes of stomatitis are diverse, including those caused by trauma and those caused by medical factors, but all of them cause ulcers and, in many cases, inflammation, resulting in severe pain.

Treatment of these oral diseases is done at the same time as treating the underlying disease.
Alternatively, the affected area in the oral cavity may be treated first as symptomatic treatment.

Conventionally, gargles, drops, troches, and ointments have been mainly used to treat such oral diseases.

Sublingual drugs are also used to treat angina pectoris.

[Problem to be solved by the invention]

However, gargles lack long-lasting properties, and drops and lozenges only last for a short time until they dissolve, and they do not take into account the protection of the affected area. moreover,
With these conventional therapeutic agents, the amount that acts on the affected area is extremely small, and most of the active ingredients are excreted or swallowed, so none of them are preferable from the standpoint of efficiency. Ointments are excellent in terms of local treatment, but they require a large amount of application, which reduces the effective amount, and they do not last very long. Sublingual preparations are also not sufficient in terms of foreign body sensation and persistence.

One of the objects of the present invention is that it can be applied directly to the affected area in the oral cavity,
The object of the present invention is to provide a membrane preparation with appropriate durability.

Another object of the present invention is to provide a membrane preparation that can control the amount of active ingredient released.

[Means to solve the problem]

The oral adhesive membrane preparation of the present invention is made of a water-soluble polymer film containing a pharmacologically active compound (hereinafter referred to as pharmacologically active ingredient).

Furthermore, by providing a layer that can adjust the release of pharmacologically active ingredients on at least one surface of the film, sustained release properties can be enhanced or the release time of different types of pharmacologically active ingredients can be controlled. I can do it.

[For production]

The membrane preparation of the present invention basically consists of a water-soluble polymer film containing a pharmacologically active ingredient.

The use of water-soluble polymers in pharmaceutical preparations is well known and is widely used as coatings for granules and tablets, capsules for capsules, and the like. However, a film-like material that itself serves as a base material containing a pharmacologically active ingredient is not known.

According to the membrane preparation of the present invention, since it is in the form of a film, it is possible to cover the affected area and protect it from the outside world. Furthermore, since a water-soluble polymer is used, the pharmacologically active ingredients will be eluted by saliva and the like, and the film itself will eventually dissolve. If hydroxypropyl cellulose or the like is used as the water-soluble polymer, it becomes sticky due to moisture during the day, so it can be easily applied directly to the affected area.

In addition, when a layer that can adjust the release of the pharmacologically active ingredient is provided on at least one surface of the water-soluble polymer film containing the pharmacologically active ingredient, it is possible to easily control the sustained release of the pharmacologically active ingredient, and to adjust the pH, etc. It becomes possible to adjust the release amount by changing the environment.

〔Example〕

Oral diseases that are typical examples of diseases targeted by the present invention include various stomatitis such as aphthous stomatitis, periodontitis, glossitis, infectious stomatitis, and tonsillitis.

Therefore, various pharmacologically active ingredients used in the targeted therapy of these diseases can be used in the present invention, but active ingredients that can also be absorbed transdermally are particularly preferred. Specific examples include, but are not limited to, various anti-inflammatory agents or anti-inflammatory analgesics for diseases accompanied by inflammation, such as azulene-based compounds such as sodium azulene sulfonate and guaiazulene, ibuprofen, and aspirin. isn't it. Furthermore, for bacterial diseases, various antibacterial agents and antibiotics such as tetracycline, tetracycline hydrochloride, fradiomycin sulfate, acetylkitamycin, and chlorhexidine hydrochloride can be used, but the drugs are not limited to these. In addition, nitroglycerin, isosorbide nitrate, and the like can be used as angina therapeutic agents.

Note that these pharmacologically active ingredients may be used alone or in combination of two or more types as far as permissible, and the amount thereof is adjusted within a permissible range.

The basic form of the membrane preparation of the present invention is a film containing a pharmacologically active ingredient in a water-soluble polymer. The water-soluble polymer used may be one that is non-toxic.

The "water-soluble polymer" in the present invention is not limited to those that dissolve in water, but also includes those that gel or swell by absorbing water. Therefore, sustained release can also be controlled by selecting the solubility of the water-soluble polymer. Examples of water-soluble polymers include, but are not limited to, one or more of hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC). Especially HPC and H
PMC and the like are preferable because they become sticky when they come into contact with water, so they can be easily applied to the oral mucosa and the like.

A water-soluble polymer film containing a pharmacologically active ingredient can be obtained, for example, by mixing a pharmacologically active ingredient into a solution of a water-soluble polymer and forming the mixture into a film.

The solvent may be appropriately selected depending on the type of water-soluble polymer and pharmacologically active ingredient, but one or more of water, ethyl alcohol, acetone, etc., are preferably used. When HPC is used as the water-soluble polymer, a mixed solvent of water and isopropanol is preferred. Casting method, rolling method, roller method, etc. are adopted as a method for forming a film.

The basic form of the membrane preparation of the present invention thus obtained is shown in FIG. 1a. Note that both FIG. 1 and FIG. 2, which will be described later, are schematic cross-sectional views of embodiments of the membrane preparation of the present invention, with the right side of the page being the intraoral mucosa side and the left side of the page being the intraoral space side.

Figure 1a shows a basic embodiment of a water-soluble polymer film (3) containing a pharmacologically active ingredient, in which a water-soluble polymer film (1) contains one or more pharmacologically active ingredients (2). be.

The embodiment shown in FIG. 1b has a two-layer structure of water-soluble polymer films (3a) and (3b) containing pharmacologically active ingredients. The water-soluble polymer films (la), (tb) and pharmacologically active ingredients (2a), (2b) may be of the same type or different types, respectively. For example, even if the pharmacologically active ingredients are of the same type, the release amount can be adjusted by using different types of water-soluble polymers. Furthermore, even if the water-soluble polymers are of the same type, the therapeutic effect can be improved if the pharmacologically active ingredients are of different types, such as an anti-inflammatory agent and an antibiotic. Of course, they can also be of different types.

Figure 1c shows a water-soluble polymer film containing pharmacologically active ingredients (3
This is an embodiment in which an intermediate layer (4) is placed between a) and (3b). As the intermediate layer, a water-insoluble film, polyvinyl acetal diethylaminoacetate (AEA),
Hydroxypropyl methylcellulose phthalate (HP
MCP), aminoalkyl methacrylate copolymer E (Eudragit E), aminoalkyl methacrylate copolymer R9 (Eudragit-R8), hydroxypropyl methylcellulose acetate succinate (HPMCAS), etc. When using a water-soluble film, pharmacologically active ingredients can be added. It has the effect of slow release.

FIG. 1d shows an embodiment of the embodiment shown in FIG. 1a in which an outer covering layer (5) is provided on the intraoral space side. When the outer covering layer (5) is made of a water-insoluble or slightly water-soluble film, it is possible to suppress the elution of the pharmacologically active ingredient into the oral cavity, and it is possible to concentrate it in the affected area, and its sustainability is also improved. An overcoat layer may also be provided in the embodiment shown in Figures 1b, lc or the following Figure 1e. This outer covering layer is, for example, HPMC.

Eudragitto R8SHPMCAS etc. can be used. Moreover, this embodiment exhibits particularly excellent effects when using transdermally absorbable pharmacologically active ingredients.

This is not particularly necessary if a water-soluble polymer that immediately becomes sticky upon contact with water is used, but if the water-soluble polymer does not become self-adhesive due to moisture, as shown in Figure 1e. An adhesive layer (6) may be provided on the mucous membrane side. The adhesive layer (6) basically only needs to be adhesive to the affected area and permeable to pharmacologically active ingredients; for example, the adhesive water-soluble polymer described above may be used as is. As the adhesive layer, in addition to the above-mentioned adhesive water-soluble polymer,
Examples include one or more of gelatin and gum arabic. Further, the adhesive layer can be similarly provided in other embodiments other than that shown in FIG. 1a.

The multilayer membrane preparations shown in FIGS. 1b to 1e may be prepared by forming the films constituting each layer and then bonding them together, or by further casting on the first layer film.

The thickness of the water-soluble polymer film containing a pharmacologically active ingredient varies depending on the type of water-soluble polymer, the content of the pharmacologically active ingredient, the drying temperature, etc., but is usually 0.20 to 0.30. It is 0.26 mm. In addition, the thickness of the entire membrane preparation is usually 0.3 to 0.5 fins, preferably 0.34 to 40 mra, taking into consideration foreign body sensation during use, pharmacologically active ingredients, and film stability. .

The present invention further relates to a membrane preparation in which an adjustment layer for adjusting the release of a pharmacologically active ingredient is provided on one or both sides of a water-soluble polymer film containing a pharmacologically active ingredient.

Embodiments of membrane preparations having such a release-modifying layer are described in Sections 2a to 2a.
The description will be made based on FIG. 20, but the invention is not limited to these embodiments.

Figure 2a shows a water-soluble polymer film containing pharmacologically active ingredients (3
) is a basic embodiment in which a release regulating layer (7) is provided on the oral mucosal side.

The adjustment function of the release adjustment layer (7) is not only the function of adjusting the release amount using differences in water permeability and dissolution rate in water.
It has functions such as adjusting the release amount in response to changes in pH.

Such an adjustment layer is formed from a polymeric substance, and the former adjustment function is achieved by adjusting its water permeability by adjusting the molecular weight, adjusting the type and amount of hydrophilic groups, adjusting the layer thickness, etc. can. The latter function of adjusting the release amount by pH is presumed to be due to the pH dependence of the solubility of the adjustment layer.

For adjusting the water permeability, for example, in addition to the water-soluble polymers described above, gelatin, guar gum, etc. can be used.

Examples of pH-dependent adjustment layers include AEA and HPM.
CP, Eudragitto E, methacrylic acid copolymer (Eudragitto), etc.
The pH responsiveness can also be adjusted by mixing more than one species.

For example, in the case of a membrane preparation containing an azulene-based anti-inflammatory agent in RPC, the release amount is not pH dependent;
layer increases the release at pH 1, while HPM
When a CP layer is provided, the amount released at pH 7 increases.

When AEA and HP)4CP are mixed, sustained release with lag time occurs at pH 1, pH 5, and pH 7 depending on the mixing ratio.

The reason for this is presumed to be that AEA has the property of dissolving on the acidic side and HPMCP has the property of dissolving on the alkaline side, and that this is due to the interaction between these same polymer films.

The release adjustment layer may be formed by directly coating a raw polymer solution on a water-soluble polymer film containing a pharmacologically active ingredient, or it may be formed into a film by a separate casting method or the like and then formed into a film by RPC.
They may be bonded together using a solution or the like. Furthermore, the pH dependence may also be affected by the solvent during layer formation. Examples of the solvent include, but are not limited to, ethanol, acetone, and isopropanol.

The thickness of the release regulating layer is usually 0.10 to 0.20 mm, preferably 0.15 to 0.20 mm.

Fig. 2b shows an embodiment in which an adhesive layer (6) is provided on the release regulating layer (7), and Fig. 2c shows an embodiment in which an adhesive layer (6) is provided on the release regulating layer (7), and Fig. 2c shows an embodiment in which a water-soluble polymer film (3) containing a pharmacologically active ingredient has the same or different release properties on both sides of the water-soluble polymer film (3) containing a pharmacologically active ingredient. This is an embodiment in which adjustment layers (7a) and (7b) are provided, and an adhesive layer (6) is further provided on the mucous membrane side. The adjustment layer (7a) on the intraoral space side may be an outer covering layer as shown in FIG. 1d, and the adjustment layer is not limited to a single layer, but may be a multilayer of the same or different types, or an intermediate layer as shown in FIG. 1c. It may also be used as

Although preferred embodiments of the membrane preparation of the present invention have been described above, the present invention also includes embodiments other than these.

EXAMPLES Next, the present invention will be described in detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 RPC was added to a 1:1 (weight ratio) mixed solvent of water/isopropanol and thoroughly mixed to obtain a 5% HPC solution. 2.5 g of sodium acid] was dissolved. The obtained azulene-dissolved HPC solution 401 was poured into a container made of tetrafluoroethylene with a diameter of 8 CIl, and dried at room temperature to form an azulene-containing RPC film with a thickness of 0.25 mm (
A membrane preparation A) was prepared.

Example 2 AEA was dissolved in ethanol to prepare a 5% solution.

This solution 4011 was cast into an AEA film having a thickness of 0.12 mm in the same manner as in Example 1.

This AEA film was adhered to one side of an azulene-containing RPC film prepared in the same manner as in Example 1 from a 5% RPC solution to produce a multilayer film preparation (referred to as film preparation B).

Example 3 HPMCP was dissolved in acetone to form a 5% solution. This solution 4011 was cast in the same manner as in Example 1 to form an HPMCP film with a thickness of 0.12 mm. This HPMCP film was adhered to an azulene-containing RPC film in the same manner as in Example 2 to produce a multilayer film preparation (referred to as film preparation C).

Example 4 AEA solution prepared in Example 2 and H prepared in Example 3
A mixed solution was prepared by mixing PMCP solution at a ratio of 2:1, 1:1, and 1:2 (all weight ratios), and Example 1
Cast molding was performed in the same manner as above to obtain a film thickness of 0.
A 12 mm thick EM-HPMCP mixed film was produced. Each of these mixed films was adhered to an azulene-containing RPC film in the same manner as in Example 2 to produce a multilayer film preparation.

In addition, the mixture ratio of AEA/HPMCP of 2=1 is called a membrane preparation, the mixture ratio of 1:1 is called a membrane preparation E1, and the mixture ratio of 1:2 is called a membrane preparation F.

Test Example 1 An azulene release test was conducted using a dissolution test apparatus containing C1ark Lubs buffer 5001f in a beaker equipped with a paddle type stirrer.

1 co of membrane preparations A to F obtained in Examples 1 to 4, respectively.
Attach the test piece cut at the + angle to the wall of the dissolution test device using double-sided tape, and set the liquid temperature to 37℃ and the paddle rotation speed to 100℃.
The amount of azulene released was observed over time at rpIl, pH 7.0. In addition, for membrane preparations B-D, the release side and the wall surface of the device were pasted together with double-sided tape.

The results are shown in Figure 3 (membrane formulation A) and Figure 4 (membrane formulation B-F).
).

Test Example 2 The pH of the Clark-Lapus buffer was changed to 1.0 and 5.0, and the amount of azulene released was observed over time in the same manner as in Test Example 1.

The results are shown in Figure 5 (pH 1, o) and Figure 6 (pH 5, 0).
).

[Effects of the Invention] When using the membrane preparation of the present invention, not only can the pharmacologically active ingredient be delivered directly to the affected area in the oral cavity, but also its release amount can be controlled. Furthermore, the affected area can be protected.

[Brief explanation of drawings]

1a to 18 and 2a to 20 are schematic cross-sectional views of embodiments of the membrane preparation of the present invention, FIGS. 3 and 4 are graphs showing changes over time in the amount of azulene released in Test Example 1, and FIG. The figure and FIG. 6 are graphs showing changes over time in the amount of azulene released in Test Example 2. (Main symbols in the drawings) (1): Water-soluble polymer film (z: Pharmacologically active ingredient (3): Water-soluble polymer film containing pharmacologically active ingredient (Sword: Release control layer 7'1d, Figure 7'1b) 1C Figure 71d Figure O] e Figure 3 Figure ×: Membrane preparation A Figure 2a Figure 2b Figure 2C Figure 4 Figure 0.11ψ milling B Polishing 3 17S C ■, Membrane membrane D O1 Membrane formulation E ・Membrane Δ1] J1・5 times ×: Membrane preparation A B: Membrane preparation B Membrane preparation C ■: Membrane preparation D O9 membrane preparation E 0. Membrane preparation F Year 6 ×: Membrane preparation A Oral membrane preparation B Membrane preparation C ■ Membrane preparation D O3 membrane 17s E ・: Membrane preparation F

Claims (1)

[Scope of Claims] 1. An intraorally adhesive membrane preparation comprising a water-soluble polymer film containing a pharmacologically active compound. 2. An intraorally adhesive membrane preparation comprising a release regulating layer for a pharmacologically active ingredient on at least one surface of the film according to claim 1. 3. An adhesive membrane preparation for the treatment of oral diseases consisting of a hydroxypropyl cellulose film containing an azulene anti-inflammatory agent. 4. An adhesive film preparation for treating oral diseases, comprising a layer of polyvinyl acetal diethylaminoacetate and/or hydroxypropyl methylcellulose phthalate on at least one surface of the film according to claim 3.