JPH01299228A - Filmy percutaneous absorption preparation - Google Patents

Abstract

PURPOSE:To obtain a filmy percutaneous absorption preparation having an initial swelling rate in a specific range, releasing an active ingredient and absorbing the ingredient in organisms by absorption of sweat in pasting to exodermis, useful for treating mental diseases, containing polyvinyl alcohol and haloperidol. CONSTITUTION:A filmy percutaneous absorption preparation containing haloperidol consisting of polyvinyl alcohol, a water-soluble hydrocarbon and haloperidol. The preparation has 0.01-0.20sec<-1> initial swelling rate in water at 32 deg.C. When polyvinyl alcohol having 500-2,400 average polymerization degree is used as the polyvinyl alcohol, after application to exodermis, the preparation is fast stuck to exodermis by wetting such as sweating and improves percutaneous absorption such as excellent adhesivity to skin for many hours. The polyvinyl alcohol used has preferably >=88mol% degree of saponification.

Description

Detailed Description of the Invention (a) Industrial Field of Application The present invention releases haloperidol at the application site by applying it to the outer skin, and further allows the haloperidol to be absorbed into the body to treat mental disorders, etc. The present invention relates to a film-like transdermal absorption preparation for the purpose of carrying out this invention.

(b) Conventional technology In recent years, transdermal administration, in which drugs are administered through the skin, has been used as a method of administering drugs into living bodies. Because of its superiority, the preparation of transdermal formulations for various drugs is being considered.

■Drugs are gradually absorbed into the body through the skin, resulting in sustained pharmacological effects.

■Drugs can be administered and the dosage can be accurately controlled by an extremely simple fabrication of pasting and repeating.

■ Administer fI by peeling the preparation from the skin! !
You can simply cancel it.

■In the case of oral administration, absorbed drugs pass through the portal vein and liver and undergo primary metabolism before being distributed throughout the body, but drugs absorbed through the skin directly enter the bloodstream and are distributed throughout the body, causing gastrointestinal disorders. The burden on the liver is reduced. In addition, the efficiency of drug utilization is increased because the administered drug is not degraded by tlY-transforming enzyme or metabolized by the liver, and even drugs that show little efficacy orally, such as hormones, can be effective without injection. I can do it.

In addition, ointments, patch preparations, tape preparations, and the like have been developed as dosage forms for transdermal administration. However, with ointments, it is difficult to apply a certain amount accurately, and since they are sticky, they may stain clothing.

In addition, delta-shaped patch preparations containing water-soluble polymers such as polyacrylates and gelatin as main ingredients have also been developed, and are used as poultices because they cause less irritation when removed from the skin. However, this patch preparation contains a large amount of water,
Because of this, the drug content may be hydrolyzed during storage, leading to a decrease in the drug content or evaporation of the water content.

On the other hand, tape-type preparations in which drugs are contained in adhesive substances such as natural rubber or synthetic rubber have also been developed. but,
While these sticky substances exhibit good adhesion to dry skin surfaces, they are extremely adhesive to moist surfaces that exude bodily fluids, such as injured skin, or to skin surfaces that are heavily sweating. It is difficult to apply, and even if it is adhered, it will peel off immediately after application.
Since it fell off, it could not be said to be an optimal patch preparation.

Furthermore, in recent years, many transdermal absorption preparations of nitroglycerin have been developed, and in particular, trini-F roglycerin and low molecular weight partially hydrolyzed polyvinyl alcohol, as shown in Japanese Patent Publication No. 58-501078, and high molecular weight and A polymer diffusion matrix consisting of substantially completely hydrolyzed polyvinyl alcohol and glycerin can be kept in close contact with the skin surface for a long period of time, allowing sustained drug release, and can be said to be a preferred formulation for transdermal absorption. . However, the formulation disclosed in Japanese Patent Publication No. 58-501078 is a fluid gel or a fixed-dimensional solid gel, and has the same problems as the above-mentioned ointments and gel preparations.

On the other hand, as a film preparation, there is a transdermal absorption preparation using a polyamino acid film shown in Japanese Patent Publication No. 52-33169, but in the case of a preparation, oils, fats, waxes, etc. Transdermal absorbability is improved by adding one or more of polyoxyalkylene glycol and polyoxyalkylene glycol. However, when these additives are used, problems arise such as skin irritation and drug stability.

Furthermore, Japanese Patent Application Laid-open No. 58-32816 describes a contraceptive film preparation using polyvinyl alcohol, but this preparation is intended to be dissolved in the vagina. If the film is used for a long time, it will dissolve and stain clothes, like ointments and the like.

On the other hand, haloperidol is a major tranquilizer of the butyrophenone family and is a drug used to treat mental illnesses such as schizophrenia and depression, and is currently commercially available in tablets, powders, injections, and other formulations.

(e) Problems to be Solved by the Invention As mentioned above, in transdermal absorption systems that aim to administer drugs transdermally into living bodies, adhesive substances are used as a patch base as in the past. The preparation used had poor adhesion to wet surfaces; on the other hand, when a patch using a patch base with strong adhesive force to wet surfaces was applied to the damaged skin surface, the adhesive force caused the adhesive force to deteriorate when the preparation was removed. There are various problems such as the risk of re-damaging the damaged skin surface, and there is a strong demand for the development of transdermal absorption preparations that eliminate these problems.

Furthermore, formulations containing haloperidol, such as tablets, powders, and injections, have not always had excellent compliance due to the characteristics of the disease and dosage form.

Furthermore, in recent years, pharmacological elucidation of haloperidol has shown that haloperidol has an antiemetic effect (CURRENT TIIERA).
PEUT[CRESEARCH”Vol, 15.No.
9) and alleviation of cancer pain (“Treatment”’tjS Vol. 63, No. 1)
No. 1) No. 11 It has become clear that However, when administered to cancer patients, simultaneous administration with commercially available preparations has been difficult due to side effects caused by administration of anticancer drugs.

For this reason, there is a strong desire to develop a formulation that improves the compliance of haloperidol formulations and can also be administered to loyal users.

The present invention was made in view of these circumstances,
Although it has almost no adhesion to the outer skin when dry, it adheres to the outer skin due to moisture such as perspiration, has excellent skin adhesion for a long time, is flexible and does not cause any discomfort, and has an active adhesive that uses body fluids such as sweat. The purpose of the present invention is to provide a film-like transdermal absorption preparation that can be used for sealed treatment and improve the transdermal absorption of haloperidol.

(d) Means for Solving the Problems In order to achieve the above object, the film-form transdermal absorption preparation of the present invention is a film-form preparation made of polyvinyl alcohol containing haloperidol, which is made of polyvinyl alcohol and haloperidol, and comprises: The film-like preparation has an initial DfI velocity of 0.01-1 in water at a temperature of 32°C.
It is characterized by being 0.20 sec −'.

The polyvinyl alcohol used in the present invention is a type of water-soluble commercial molecular substance, and has shape-retaining properties. Even when absorbed, it remains in a swollen state, improving flexibility but having low solubility.

The polyvinyl alcohol film-form preparation containing haloperidol of the present invention increases the adhesion to the outer skin due to improved flexibility during water absorption, and also enables active occlusion therapy (OCT) by using the film in a body fluid-absorbing state. It is possible to improve the absorption of the drug.

The above-mentioned polyvinyl alcohol is used to form the film of the film-like transdermal absorption preparation of the present invention, and the polyvinyl alcohol has various absorption rates of body fluids, that is, water absorption rates, depending on its degree of saponification, degree of polymerization, and film formation conditions. They can be obtained by varying the amount, and these may be used alone or in combination of two or more.

Incidentally, since polyvinyl alcohol films absorb water while swelling in water, there is a close relationship between changes in swelling degree and water absorption rate.

In the present invention, the above-mentioned polyvinyl alcohol is used and haloperidol is added thereto to form a film-like preparation. In order to improve the drug absorption of this film-like preparation, the adhesion between the preparation and the outer skin is improved. In order to obtain a film or mucous preparation with good adhesion to the skin, the temperature of the film preparation must be 32°C.
The initial swelling speed in water is 0.01~0.20s
Preferably it is ec-1.

The initial swelling rate here refers to a film preparation made of polyvinyl alcohol containing haloperidol with a thickness of approximately 40 μm, which is immersed in distilled water at a temperature of 32°C, and the degree of swelling of the film preparation is plotted against the immersion time. This graph shows the "slope" from immediately after immersion to 20 seconds after immersion.

By the way, the degree of swelling is generally expressed based on a weight ratio or a volume ratio.
The degree of swelling in this case is expressed on a weight ratio basis.

If the initial swelling rate is less than 0.01 sec-', the film-like preparation will absorb body fluids slowly, making it difficult to release haloperidol efficiently, and it will take time for the film-like preparation to soften, making it difficult to apply the adhesive. The sense of discomfort will remain for a long time. On the other hand, if the initial swelling rate exceeds O', 20 sec-', the film-like preparation will dissolve within a short time after application, resulting in a state similar to that of an ointment or the like.

In addition, in the above-mentioned film preparation made of polyvinyl alcohol containing haloperidol, the content of haloperidol is desirably in the range of 0.001 to 30% by weight, particularly 0.05 to 20% by weight, considering the medicinal efficacy and economical efficiency. .

Further, the thickness of the above-mentioned film-form preparation is not particularly limited, but is preferably 10 to 100 μm from the viewpoints of falling off due to fraying of clothes, etc., and economical efficiency.

In the film-form transdermal absorption preparation of the present invention, by using polyvinyl alcohol with an average degree of polymerization of 500 to 2400, after application to the outer skin, it adheres to the outer skin due to moisture such as sweating, and has long-term skin WJ adhesion. In addition, it is flexible and does not cause any discomfort, and it is possible to perform active sealing treatment using body fluids such as sweat, further improving the percutaneous absorption of haloperidol.

If you use a product with an average degree of polymerization of less than 500, it will be easily soluble in water even if you change the film forming conditions, so if it is attached to the skin for a long time, the polyvinyl alcohol will dissolve on the skin and it will be in the same state as an ointment. This will stain your clothes, etc., and on the other hand,
When the average degree of polymerization exceeds 2400, the rate of water permeation into the film-like preparation is slow, making it difficult to efficiently supply haloperidol onto the skin.

In the film-form transdermal absorption preparation of the present invention, polyvinyl alcohol has a saponification degree of 88 mo/% or more, especially one with an average polymerization degree of 500 to 2400, and has a saponification degree of 88 mo/% or more.
It is preferable to use mot'% or more for the reasons described below.

If a saponification degree of less than 88 mo1% is used, it is easily soluble in water even if the film forming conditions are changed, so if it is attached to the skin for a long time, the polyvinylflucol will dissolve on the skin, which is the same as a cartilage agent. This will result in staining your clothes etc.

The film-like transdermal absorption preparation of the present invention can be produced, for example, by dissolving polyvinyl alcohol in distilled water, adding and mixing haloperidol thereto, and then rapidly casting and drying to form a film. In this case, the drying temperature is preferably in the range of 80-120°C;
If the drying temperature is below 0°C, the degree of crystallinity of polyvinyl alcohol is low, and if it is attached to the skin for a long time, the film itself will dissolve on the skin surface, causing the same problem as emollients. When the temperature exceeds 120°C, the crystallinity of polyvinyl alcohol increases and the initial swelling rate decreases, which slows down the absorption of body fluids and takes time for it to adhere to the skin surface, which reduces the time it takes for haloperidol to be absorbed in an effective amount. I don't like this because it causes delays.

According to this manufacturing method, it is possible to easily obtain a very thin film, but the thickness of the film is not particularly limited, but it is recommended to be 10 to 100 μm from the viewpoint of preventing it from falling off due to wear on clothes, etc., and from the economical viewpoint. preferable.

When applying the film-like transdermal absorption preparation of this invention, it can be applied directly to the moist part of the skin, but if necessary, it may be fixed with adhesive tape from the back side to the dry skin. It is.

(e) Effect The film-form transdermal absorption preparation of the present invention is a film-form preparation consisting of haloperidol and polyvinyl alcohol, which is a water-soluble polymer substance, and when this preparation is used on the outer skin, it absorbs body fluids such as sweating and swells. It adheres closely to the skin surface and efficiently supplies haloperidol from the skin surface into the body. In other words, the film skeleton of this film-like transdermal absorption preparation is composed of polyvinyl alcohol, and when it is applied to the outer skin, sweat is absorbed between the polyvinyl alcohol molecules due to perspiration. By doing so, the adhesion of the film to the skin becomes extremely good, and the stratum corneum of the skin, which is mainly composed of keratin, swells, thereby having the effect of improving the transdermal absorption of haloperidol. In addition, this film-like transdermal absorption preparation can be applied well to moist skin surfaces, and even if it is applied to an injured site, it will not reinjure the injured skin when it is peeled off. The reason for this is that this film-like transdermal absorption preparation has good adhesion over a long period of time and can also be removed from the skin surface with a weak peeling force when removed. It is understood that this is because the polyvinyl alcohol constituting the film-like transdermal absorption preparation conforms to the shape of the skin surface to which it is applied, rather than adhesion due to the adhesive force of adhesive substances.

In the film-like transdermal absorption preparation of the present invention, by using polyvinyl alcohol with an average weight of 500 to 2400, it has excellent shape retention and water absorption, and when applied to the outer skin, sweating etc. Due to the moisture of the haloperidol, it comes into close contact with the outer skin, and active sealing treatment can be performed using body fluids such as sweat, which has the effect of further improving the transdermal absorption of haloperidol.

In the film-form transdermal absorption preparation of the present invention, by using polyvinyl alcohol with a saponification degree of 88 moi'% or more, it has excellent shape retention and water absorption;
Moreover, after being applied to the outer skin, it adheres to the outer skin due to moisture such as perspiration, and the state of close contact lasts for a long time. Furthermore, active sealing treatment using body fluids such as sweat can be performed, so haloperidol can be used without treatment. It has the effect of further improving skin absorption.

(r) Examples Next, examples of the present invention will be described in detail together with comparative examples.

Example 1 Polyvinyl alcohol 15% (saponification degree 99.6 moN%, average degree of polymerization 1700) Distilled water 85% by weight After the above raw materials were made into a solution, haloperidol was added in an amount of 5% by weight based on the solid content. After thoroughly stirring this solution, it was cast onto a polyester film and 1
After drying for 5 minutes, the film-like transdermal absorption gJI of the present invention
I got M.

The content of haloperidol in this preparation is 210 μg/a
m2 (initial swelling rate 0.08 sec −')
.

Example 2 Polyvinyl alcohol 15111% (saponification degree 88mof%, average polymerization degree 1700) Distilled water
85% by weight 1% After the above raw materials were brought into a solution state, haloperidol was added in an amount of 5% by weight based on the solid content. This solution was sufficiently stirred, cast onto a polyester film, and dried for 15 minutes in a dry oven at a temperature of 100°C to obtain a film-like transdermal absorption preparation of the present invention.

The content of haloperidol in this formulation is 208μbi/C
It was duck 2 (initial swelling rate 0.14 sec −')
.

Example 3 Polyvinyl alcohol 20% by weight (degree of saponification 98.5moZ%, average degree of polymerization 500) Distilled water
80% by weight After the above raw materials were made into a solution state, haloperidol was added in an amount of 5% by weight based on the solid content. This solution was sufficiently stirred, cast onto a polyester film, and dried for 15 minutes in a dry oven at a temperature of 100°C to obtain a film-like transdermal absorption preparation of the present invention.

The content of haloperidol in this preparation is 212μg/c
m2 (initial swelling rate 0.13 sec-').

Example 4 Polyvinyl alcohol 10 fifi% (degree of saponification 98.51io1%, average degree of polymerization 2400) Distilled water 90% by weight After the above raw materials were made into a solution, haloperidol was added in an amount of 5% by weight based on the solid content. This solution was thoroughly stirred, cast onto a polyester film, and dried for 1 hour at a temperature of 100"C.
It was dried for 5 minutes to obtain a film-like transdermal absorption preparation of the present invention.

The content of haloperidol in this preparation is 210μg/c
m" (initial swelling rate 0.04 sec -')
.

Comparative Example 1 Polyvinyl alcohol 20% by weight (degree of saponification 78.5mol1%, average degree of polymerization 500) Distilled water
80% by weight After the above raw materials were made into a solution state, haloperidol was added in an amount of 5% by weight based on the solid content. This solution was thoroughly stirred, cast onto a polyester film, and dried for 15 minutes in a drying oven at a temperature of 100°C to obtain a film containing haloperidol.

The content of haloperidol in this film is 200μg
/cm2 (initial swelling rate 0.32se
c-1).

Comparative Example 2 Hydroxypropylcellulose 5wt 1% (Nippon Soi1! Co., Ltd.!! IIPC-11) Ethanol
95% by weight After the above raw materials were brought into a solution state, haloperidol was added in an amount of 5% by weight based on the solid content. This solution was thoroughly stirred and applied on a polyester film for 10 minutes in a drying oven at a temperature of 100°C.
After drying for minutes, a haloperidol-containing film was obtained.

The content of haloperidol in this film is 210μg
/cm” (dissolved immediately after immersion in water).

Comparative Example 3 Haloperidol was added to polyvinyl acetate (Nippon Gosei Co., Ltd.!! Gosenil M35-Y-8.35% methanol solution) in an amount of 5% by weight based on the solid content. This solution was thoroughly stirred, cast onto a release-treated polyester film, and dried for 10 minutes in a drying layer at a temperature of 100°C to obtain a haloperidol-containing film.

The content of haloperidol in this film is 212μs
/cm2 (initial swelling rate <0.01see-'
).

Comparative Example 4 The formulation obtained in Example 1 was further dried at a temperature of 160° C. for 5 minutes to obtain a haloperidol-containing film. The content of haloperidol was 210 μg/cex2 (
initial swelling rate 0.24 sec −').

The film-like transdermal absorption preparations obtained in Examples 1 to 4 and Comparative Examples 1 to 4 were cut into pieces of 3 cw x 3 am, fixed on all sides with medical adhesive tape, and applied to the back of a human for 24 hours.

The adhesion state to the skin 5 hours after the start of the test, the adhesion ia rate to the skin when removed 24 hours later, and the skin [f1 line rate] of loberidol in the film after 24 hours of application. @1 Shown in table.

(Margin below) Table 151 Note> The skin transfer rate (%) of haloperidol in tjss1 was determined under the conditions shown below.

That is, haloperidol in the film preparation applied for 24 hours was quantified, and the skin transfer rate of haloperidol was calculated from the residual amount using the following formula.

-B Skin transfer rate (%) = -person- x 100 A... Amount of haloperidol in unapplied film preparation B
... Haloperidol amount (g) in the film-form preparation of patch i Effect of the invention The film-form transdermal absorption preparation of the present invention is a haloperidol-containing polyvinyl alcohol film-form preparation consisting of polyvinyl alcohol and haloperidol, The film-like preparation has an initial swelling rate of o, oi to 0,20 sec-' in water at a temperature of 32°C, and although it has almost no adhesion to the outer skin when dry, it does not absorb perspiration. Transdermal absorption of haloperidol is possible because it adheres closely to the outer skin due to moisture, has excellent long-term adhesion to the skin, is flexible and causes little discomfort, and can be actively sealed using body fluids such as sweat. It has the effect of improving sex.

Furthermore, this film-like transdermal absorption preparation can be applied to moist skin surfaces or damaged areas, and even when applied to the damaged area, it has the effect of not reinjuring the damaged skin when it is peeled off.

In the film-form transdermal absorption preparation of the present invention, by using polyvinyl alcohol with an average degree of polymerization of 500 to 2400, after application to the outer skin, it adheres to the outer skin due to moisture such as sweating, and the adhesion state remains for a long time. In addition, it is soft and causes very little discomfort, and furthermore, active sealing treatment using body fluids such as sweat can be performed, which has the effect of further improving the transdermal absorption of haloperidol.

In the film-like transdermal absorption preparation of the present invention, by using polyvinyl alcohol with a saponification degree of 88SO1% or more, it has excellent shape retention and water absorption properties, and furthermore, after application to the outer skin, sweating etc. Due to the moisture, it comes into close contact with the outer skin and remains in close contact for a long time, and active sealing treatment using body fluids such as sweat can be performed, which has the effect of further improving the transdermal absorption of haloperidol. It is.

Claims (3)

[Claims] (1) A haloperidol-containing polyvinyl alcohol film-form preparation consisting of polyvinyl alcohol and haloperidol, which film-form preparation has an initial swelling rate of 0.5 in water at a temperature of 32°C. 1. A film-like transdermal absorption preparation, characterized in that the absorption time is 01 to 0.20 sec^-^1. (2) Average degree of polymerization of polyvinyl alcohol is 500-2
400. The film-like transdermal absorption preparation according to claim 1. (3) The film-shaped transdermal absorption preparation according to claim 1 or 2, wherein the degree of saponification of the polyvinyl alcohol is 88 mol% or more.