The present invention relates to plasters containing 4-biphenylyl acetic acid (general name: FELBINAC; hereinafter simply referred as to “BPAA”), and more particularly, to analgesic and anti-inflammatory external plasters in which BPAA is dissolved into an aqueous hot melted type adhesive base material comprising a styrene-isoprene-styrene block copolymer, an adhesive resin, an antioxidant, lanolin, and water as essential components.
BPAA is a pharmacologically active agent that is widely used in various external preparations, such as ointments, lotions, and aqueous plasters (cataplasm), for the purposes of relieving pain and alleviating inflammation in various disease conditions, including osteoarthritis, muscle- and fascia-related lumbago, periarthritis humeroscapularis, tendinitis, tenosynovitis, peritendinitis, external humeral epicondylitis (such as tennis elbow), sore muscle, and post-traumatic swelling and pain.
Among these external preparations, ointments and lotions have been considered less suitable for administration of BPAA continuously and in constant dosages and are also thought to be inconvenient since they may stick elsewhere other than the intended application site, and may sometimes soil the clothes at the time of administration. On the other hand, an aqueous plaster, though not associated with these problems, has a low adhesiveness and thus requires fixing means such as a strip of surgical tape so that it stays on flextion parts such as elbows and knees.
Non-aqueous adhesives are also known, including those that use natural or synthetic rubber as a base material and plasters that make use of adhesive base material using acrylate adhesive base. This type of plaster has a strong adhesiveness and is thought to overcome the drawbacks of aqueous plasters. Thus, much effort has been put into development of external preparations of various drugs using such plasters.
However, the low solubility of BPAA makes it difficult to dissolve BPAA directly in adhesive base material. BPAA is readily soluble in dimethylacetamide, less soluble in acetone, ethanol, glacial acetic acid, and ether, and hardly soluble in water. BPAA is also hardly soluble in polyols, glycols, and esters, which are commonly used as a solvent for drugs in preparation of external plasters.
For this reason, attempts have been made to use various solubilizers to dissolve BPAA. For example, Japanese Patent Laid-Open Publication No. Hei 4-321624 discloses a technique in which crotamiton is used as a solubilizer for BPAA. Nonetheless, the use of crotamiton as a solubilizer to help dissolve BPAA has achieved a solubility of at most about 7%. Also, the solubility achieved by the aforementioned aqueous plaster, which uses diisopropanolamine as the solubilizer, is not more than about 11%. Thus, it has been difficult heretofore, even with the help of a solubilizer, to obtain a hot melted type adhesive base material that contains BPAA in an amount sufficient to allow it to exert desired pharmacological effects.
In aqueous plasters containing BPAA, BPAA is solubilized by first dissolving diisopropanolamine in water so that it becomes ionized and then adding BPAA to the solution, thus facilitating dissolving of BPAA in the solution. Though possible, adoption of this technique in producing non-aqueous adhesives containing BPAA, for example, solvent adhesives, which require a drying process, or hot melted type adhesive base materials, which require exposure to high temperature, may result in evaporation of moisture and thus crystallization of BPAA in the adhesive base.
A surfactant may also be used as a component of the hot melted type adhesive base material in order to facilitate mixing of water. This approach, however, may cause skin irritation and thus is not favorable.
Aside from the above-described approaches, a water-absorbable or water-soluble high molecular compound is thought to enable the adhesive material to absorb water. One disadvantage of this approach is that moisture evaporates when the temperature is raised to melt the successive adhesive in continuous production. As a result, the high molecular compound crystallizes and forms unwanted particles in the adhesive base. Moreover, water is surrounded by the high molecular compound which is presented in the adhesive base material, and this prevents diffusion of BPAA in the adhesive preparation, and as a result, the efficiency of drug utilization is lowered.
Accordingly, it is an objective of the present invention to provide an aqueous hot melted type adhesive base material containing BPAA that overcomes the above-identified problems. This adhesive base material contains constant amounts of BPAA and exhibits a good releasability of the drug from the adhesive, thereby enhancing bioavailability of the drug.
SUMMARY OF THE INVENTION
The present invention has been devised to overcome the above-described problems and provides in one aspect an analgesic and anti-inflammatory external plaster containing 4-biphenylyl acetic acid as active ingredient, wherein 4-biphenylyl acetic acid is dissolved into an aqueous hot melted type adhesive base material comprising styrene-isoprene-styrene block copolymer, an adhesive resin, an antioxidant, lanolin, and water as essential components of said adhesive base material.
More specifically, the present invention provides an analgesic and anti-inflammatory external plaster containing BPAA, obtainable through the process comprising the steps of melting and kneading a styrene-isoprene-styrene block copolymer, an adhesive resin, an antioxidant, lanolin, and a softener to form an adhesive base material; adding water and an aqueous solution of BPAA to the adhesive base material at a temperature of 80 to 100° C., while stirring, to form an adhesive base material containing BPAA; coating said base material on a liner; laminating the liner to a backing; and cutting the resulting backing to a desired size.
In one preferred embodiment of the present invention, the analgesic and anti-inflammatory plaster for external use containing BPAA contains water in an amount of 0.1 to 30%.
In a further aspect, the present invention provides an analgesic and anti-inflammatory external plaster containing BPAA in which BPAA is dissolved into the above-described aqueous hot melted type adhesive base material in a stable manner.
In summary, what is characteristic of the present invention resides in the use of the aqueous hot melted type adhesive base material that contains a styrene-isoprene-styrene block copolymer, an adhesive resin, an antioxidant, lanolin and water as essential components. The plaster obtained by dissolving BPAA in such aqueous hot melted type adhesive base material has an enhanced drug stability as well as an enhanced drug releasability over time and thus overcomes the aforementioned drawbacks of the conventional art.
BEST MODE FOR CARRYING OUT THE INVENTION
An external plaster in accordance with the present invention will now be described in detail with the emphasis on the types and the amounts of the components contained.
Styrene-isoprene-styrene block copolymer (hereinafter referred simply as to “SIS”) for use in the plaster of the present invention is synthetic rubber to form the basic component of the adhesive base material and has ratio of styrene/rubber as 14/86. While adhesive base materials containing SIS are normally produced by melting at temperatures of 120 to 160° C., it is essential to design the production process of the aqueous hot melted type adhesive base material of the present invention so that the components are kneaded and mixed at 80 to 100° C. in order to permit mixing of water.
It is thus preferred that the amount of SIS to be used is from 10 to 30% (as measured in % by weight with respect to the total weight of the adhesive preparation containing BPAA. All of the numbers expressed in percentages appear in the following description are calculated in the same manner.), more preferably from 15 to 25%. If the amount is less than 10%, the cohesion of the adhesive material is lost and it tends to remain on the surface to which it is applied after the plaster has been removed. In comparison, if the amount exceeds 30%, the adhesive base material becomes hard, making kneading and mixing of the adhesive base material difficult. As a result, the adhesion of the base material is reduced.
Adhesion resin for use in the plaster of the present invention may be any of the following resin materials: aromatic resins such as Petrosin® (manufactured by MITSUI PETROCHEMICAL INDUSTRIES, Ltd.) and Hiresin® (manufactured by TOHO OIL Co., Ltd.); aliphatic resins such as Escorez® (manufactured by TONEN OIL Co., LTD.) and Quintone® (manufactured by NIPPON ZEON Corporation); alicyclic petroleum resins; rosin resins; rosin ester resins; and terpene resins.
The amount of the adhesive resin to be used is preferably from 15 to 35%, and more preferably from 20 to 30%. If the amount is less than 15%, then the adhesive base material can hardly exhibit the adhesion, and the cohesion of the adhesive base material is reduced. As a result, the base material tends to remain on the surface to which it is applied after the plaster has been removed. In comparison, if the amount exceeds 35%, the adhesive base material becomes hard, making kneading and mixing of the adhesive difficult. As a result, the adhesiveness of the base material is reduced.
Antioxidant for use in the plaster of the present invention is contained for the purpose of preventing the adhesive base material from undergoing deterioration due to oxidation during mixing and storage of the adhesive base material. Examples of the antioxidant include dibutylhydroxytoluene, pentaerythrityl-tetrakis [3-(3,5-di-t-butyl-4-hydroxyphenyl)]propionate, and tocopherol acetate. Preferably, these antioxidants are added in an amount of 0.1 to 2%.
Lanolin for use in the plaster of the present invention is also called “wool fat” and is purified and collected when secretions of sheep are washed off of wool. Lanolin is a cholesterin fat that does not lose its ointment-like viscosity even when added with 2 to 3 times as much water and is readily soluble in ether, chloroform, petroleum, benzine, or the like.
What is characteristic of the plaster of the present invention resides in the use of lanolin as a component of the adhesive base material for the plaster. Lanoline is blended to serve not only to retain moisture in the adhesive base material but also as a softener of the adhesive base material.
The amount of lanolin to be used is determined based on the balance between the amount of water and the amounts of other oils and fats and the softeners such as liquid rubbers. Preferably, the amount of lanolin is from 5 to 40% and more preferably from 10 to 30%. Lanolin contained in an amount less than 5% is insufficient for stable retention of water, whereas when contained in an amount greater than 40%, it makes the adhesive base material unfavorably sticky.
Water is contained for the purposes of dissolving BPAA and providing the base material with a sense of “cooling effect”. The amount of water is determined based on the balance between the amount of the active ingredient and the amount of lanolin and is preferably from 0.1 to 30% and more preferably from 0.3 to 20%. If the amount of water is less than 0.1%, it becomes difficult not only to dissolve BPAA in the base material but also to provide the “cooling effect” to the plaster. In comparison, the adhesive preparation can hardly have required properties if the amount of water exceeds 30%.
The plaster of the present invention may optionally contain a solubilizer for BPAA, including amines and crotamiton. Examples of amine include monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, and triisopropanolamine. The amount of amine to be contained is preferably in the range from 1 to 15%.
In addition, the plaster of the present invention may further contain a softener for the purpose of providing the adhesive base material with a proper plasticity. Aside from the above-described lanolin component, examples of the softener include liquid rubbers, liquid paraffin, and fatty acid esters including isopropyl myristate. The amount of the softener to be used is preferably from 5 to 50% and more preferably from 10 to 45%.
Less than 5% of the softener is insufficient to provide sufficient plasticity to the adhesive base material. In such a case, the base material becomes too hard to be spread. In comparison, the softener, if contained in an amount exceeding 50%, makes the adhesive base material unfavorably sticky and brings about unfavorable situations such as the base material remaining on the surface to which it is applied after the plaster has been removed, or the base material coming out from the edges of the backing.
The amount of BPAA for serving as the active ingredient in the plaster of the present invention is preferably from 0.5 to 8% and more preferably from 2 to 6%. The amount of BPAA that is less than 0.5% is insufficient to elicit pharmacological effects of BPAA, whereas if the amount exceeds 8%, unfavorable situations arise, such as crystallizing of BPAA.
Aside from the above-described components, the adhesive base material of the present invention may contain a pharmaceutically acceptable absorption enhancer, refrigerant, preservative, bactericide, pigment and other pharmaceutically acceptable agents as desired.
Using the above-described adhesive components, the plaster of the present invention can be manufactured, for example, through the following process.
For example, SIS, the adhesive resin, the antioxidant, lanolin, and the softener are melted, mixed, and kneaded in a kneader heated to about 150° C. to obtain the adhesive base material, which is then cooled to 80 to 100° C. by air or water.
Subsequently, warm water, together with a BPAA solution (aqueous) to serve as the active ingredient solution, is added gradually to the adhesive base material under stirring. The resulting adhesive base material is spread on the liner to a predetermined thickness, and then, laminated with the backing. Then, the backing thus obtained is cut into desired size to produce the plaster of the present invention.
Alternatively, the adhesive base material may be prepared in a separate container and is stored into block forms. A required amount of the block forms is then melted at 80 to 100° C. and mixed with water and the active ingredient solution.
If the temperature of the adhesive base material exceeds 100° C. during addition of the aqueous solution of the active ingredient and water, water is brought to boiling and evaporates, and as a result, the amount of water in the plaster is significantly reduced. In comparison, if the temperature is lower than 80° C., the adhesive base material becomes so viscous that it is difficult to stir the mixture during the addition of the aqueous solution of the active ingredient. This prevents uniform dispersion of the active ingredient.