JPH0366612A - Ointment in mouth - Google Patents

Abstract

PURPOSE:To obtain an ointment in the mouth having excellent adhesion for many hours by blending an oily base with a compound capable of forming a complex thereof with a polyacrylic acid or a salt thereof. CONSTITUTION:An oily base is blended with a compound capable of forming a complex thereof with a polyacrylic acid or a salt thereof, namely one or more of chitosan, polyvinyl pyrrolidone and polyvalent metallic salt and optionally an excipient, a surfactant, a solubilizer, etc., and pharmaceutically manufactured to give the objective substance. The objective substance contains 1-30% polyacrylic acid, 1-40% chitosan, 1-40% polyvinyl pyrrolidone or 0.01-30% polyvalent metallic salt. By the formation of the complex, the ointment itself is made into an insolubilized film, which can prevent elimination of the base, make a sustained release of drug and the objective substance can be administered without feeling of physical disorder like an ointment in the mouth molded into tablets or a lamellar state.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to an ointment with excellent adhesion in the oral cavity, and more specifically, an ointment containing a compound that forms a complex with polyacrylic acid or its salts in the base. By doing.

The present invention relates to an oral ointment that absorbs moisture in the oral cavity, forms a complex, becomes insolubilized and stably adheres for a long period of time, and gradually releases the drug contained therein to exert its medicinal effect.

(Prior Art) Attempts have been made for a long time to treat mucosal diseases such as stomatitis by adhering drugs to the mucous membranes in the oral cavity, or to absorb drugs through the oral mucosa. Generally known oral preparations include buccal preparations, troches, sublingual tablets, tablet and sheet-type adhesive preparations, and ointments.

For example, JP-A No. 54-41320 discloses an oral mucosa-adhesive sustained-release preparation comprising hydroxypropyl cellulose, polyacrylic acid or its salts, and a drug. The formulation preferably comprises hydroxypropylcellulose having a 2% aqueous solution viscosity (at 20°C) of particularly 1000 to 4000 centipoise, a pH of 1 to 7.5°, a polyacrylic acid having a 0.2% aqueous solution viscosity (at 25°C) of in particular 3600 to 16500 centipoise. It is a tablet-shaped preparation consisting of a drug or its salts and a drug.

Further, JP-A-57-118511 discloses an oral mucosa-adhesive sustained release preparation containing hydroxypropyl cellulose and a drug. This is hydroxypropylcellulose, preferably having a 2% aqueous solution viscosity of 1000
These are formulations such as powders, fine granules, granules, tablets, etc., which consist of an intimate mixture of the drug and the drug. However, in these preparations described in this publication, water-soluble polymer compounds such as polyacrylic acid or its salts and hydroxypropyl cellulose absorb saliva, etc., swell and adhere to mucous membranes, and if they absorb more water than their capacity, they will be short-lived. There is a drawback that the base dissolves over time or spreads into the mouth and is washed away. In addition, because the dosage forms are powders, fine granules, granules, tablets, etc., the administration site is limited, and it can be used on the oral mucosa, which has a complex structure, and for the protection of inflamed areas such as stomatitis.
It is not suitable for treatment, and this type of dosage form has drawbacks such as the sensation of a foreign body in the oral cavity.

Furthermore, in JP-A-59-181218, the average molecular weight is 30.
Orally administered preparations containing more than 10,000 polyethylene oxide and a drug have been disclosed. This is also similar to the above-mentioned formulation, in which polyethylene oxide absorbs saliva and adheres to it, and it also has the disadvantage that it will wash away if it absorbs more water than it can.

JP-A No. 60-237018 discloses an adhesive, long-lasting adhesive, and sustained-release adhesive in the oral cavity, which is obtained by containing 20% or more of a carboxyvinyl polymer in the total composition, a glue or a thickener, and a drug. Compositions are disclosed. However, this is also made by mixing water-soluble polymer compounds and drugs such as carboxymethyl cellulose, sodium alginate, methyl cellulose, tragacanth gum, and xanthan gum and molding them into small plate shapes, spherical, conical, and elliptical shapes, which absorb water quickly. This is a formulation that utilizes the combination of a polymer and a poorly soluble carboxyvinyl polymer to compensate for the drawbacks of each, and as in the present invention, after applying the ointment to the oral mucosa, it absorbs water and forms an insoluble complex. Some tablet-shaped adhesive preparations such as 0 and above have weak adhesion and lack novelty compared to those that are applied to the skin, but they have the drawbacks mentioned above, and the adhesion area can be adjusted freely. It cannot be removed and is physically easy to detach.

Also, as a sheet-form preparation, JP-A-60-11630.60
No. 11631 discloses an oral sheet-like preparation that can be administered systemically or locally, consisting of a drug layer containing an acrylic acid polymer, sodium carboxymethylcellulose, and a drug, and a support containing an acrylic acid polymer, sodium carboxymethylcellulose, glycerin, and a metal salt. JP-A-61-30516 discloses a mucoadhesive sheet-like preparation having a mucoadhesive layer containing an alginate ester and a drug on a base. However, these sheet preparations also have advantages and disadvantages.

For example, a satisfactory preparation for oral mucosa adhesion has not yet been obtained due to problems such as insufficient adhesion, easy detachment due to swelling with water even if adhesion is sufficient, and complicated manufacturing process.

Furthermore, oral ointments made by mixing beeswax, plastibase, etc. with pectin, gelatin, sodium carboxymethylcellulose, etc. have been applied, but the adhesion to the oral mucosa is insufficient and a satisfactory product has not yet been obtained. . As a method to improve this drawback, JP-A No. 51-38412 discloses an oral preparation using a mixture of sodium polyacrylate, an excipient, and a drug as an ointment or buccal preparation, and JP-A No. 54-35212 discloses an oral preparation using vaseline. , an emulsifying base for mucous membranes containing sterols, higher aliphatic alcohols and active agents is also disclosed in JP-A-56-139415.
In this issue, a gel-like dental analgesic agent for external use, which is a mixture of a neutralized carboxyvinyl polymer and a drug, is also published.
No. 206534 discloses an oral drug base containing a specific amount of pectin of 150 mesh or more.

However, if only sodium polyacrylate, pectin, etc. are blended, although the initial adhesion is good, the water-soluble polymer compound swells, dissolves, and is washed away, resulting in poor sustainability.

Furthermore, emulsifying bases are inferior in adhesion and durability even when compared to those containing water-soluble polymer compounds. Furthermore, gel-like dental analgesics using neutralized carboxyvinyl polymers have similarly weak adhesive strength, making it difficult to apply them to oral adhesive preparations.

(Problems to be Solved by the Invention) Most of the above-mentioned oral preparations adhere to the mucous membranes due to their ability to absorb moisture from the oral mucosa, and as time passes, their ability to absorb moisture decreases and they swell. There are problems such as dissolution and desorption, that is, the adhesion time is short and the adhesion force is weak. Showa 5
7-118511, JP 58-206534, JP 59-181218), by simply combining two or more water-soluble polymer compounds, the dissolution time is delayed and the adhesion time is extended. It's not too much (Unexamined Japanese Patent Application Publication No. 1973)
2-70009, JP 54-41320, JP 60-116630, JP 60-116631,
(Japanese Patent Application Laid-open No. 60-237018), it is a preparation that is simply a gel base commonly found in external preparations adapted for oral use (
JP-A No. 56-139415), all of them are inferior in novelty, adhesion, and durability, and no fundamental improvement has been made. Therefore, there is currently a strong demand for mucoadhesive preparations with excellent properties.

(Means for Solving the Problems) As a result of intensive research, the present inventors have found that, unlike the above-mentioned prior art, a compound that forms a complex with polyacrylic acid or its salts blended into a base is We have succeeded in providing a new oral ointment that uses a new adhesive method to strongly adhere to the oral mucosa while absorbing moisture and forming an insoluble complex. In other words, by forming a complex, the ointment base itself becomes an insolubilized film, and as the base does not swell or dissolve as in the past, detachment can be prevented, and the drug is gradually released through the insolubilized film. By doing so, we succeeded in providing sustained release properties.

The oral ointment of the present invention is a wire metal product containing polyacrylic acid or its salts and one or more of chitosan, polyvinylpyrrolidone, and polyvalent metal salts in an oily base, and optionally excipients, When a surfactant and a poorly soluble drug are added, a solubilizer can be added.

The polyacrylic acid or its salts used in the present invention can be of any molecular weight, but in order to adjust the rate at which the ointment absorbs water on the oral mucosa and adheres to the mucous membrane to form a complex. Regarding polyvinylpyrrolidone, a molecular weight of 1,000,000 to 1,500,000 is particularly preferable, and chitosan of any molecular weight can be used as a compound forming a complex with polyacrylic acid or its salts, but a molecular weight of 100,000 to 200,000 is particularly preferable. The same applies, and those having an average molecular weight of 40,000 are particularly preferred. Any divalent to trivalent polyvalent metal salt can be used, but magnesium salts, aluminum salts, and calcium salts are particularly preferred.

As the polyacrylic acid or its salts in the present invention, it is possible to use not only polyacrylic acid alone, but also metal salts such as sodium polyacrylate, and copolymers of vinyl ether methacrylate heptanomer and acrylic acid. It is.

Preferred oil bases include petrolatum, gelled hydrocarbons [trade name: Plastibase (manufactured by Squibb)], gelled glycerin fatty acid ester [trade name: Miglyol Gel (manufactured by Dynamic Nobel)], hydrogenated lanolin, etc. .

When applied to the oral mucosa, the oral ointment prepared by these methods quickly absorbs moisture on the mucous membrane, forms an insoluble complex on the mucosa, and gradually releases the drug contained therein.

Polyacrylic acid or its salts included in the present invention are 1 to
30%, chitosan 1 to 40%, polyvinylpyrrolidone 1 to 40%, polyvalent metal salt 0.01 to 30%, more preferably polyacrylic acid or its salts 3
~20%, chitosan from 2 to 25%, polyvinylpyrrolidone from 5 to 25%, and polyvalent metal salt from 0.05 to 30%. In addition, the blending ratio of the compound capable of forming a complex to polyacrylic acid or its salts is 1:0.1 to chitosan.
5, more preferably 1:0.3-3, polyvinylpyrrolidone preferably 1:0.1-10, 180.5-5
is even more preferable. Polyvalent metal salt is 1:0.01~3
is preferable, and 1:0.05-3 is more preferable.

Furthermore, the oral ointment of the present invention may contain excipients, surfactants, solubilizing agents, etc. as necessary, and excipients include crystalline cellulose, kaolin, dextrin, lactose, gelatin, pectin, silicic anhydride, Examples include methylcellulose. Examples of the surfactant include sorbitan fatty acid ester, decaglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, and mixtures thereof. Further, examples of dissolving agents for poorly soluble drugs include polyhydric alcohols and polyhydric alcohol medium chain fatty acid esters.

The drug used in the present invention may be any drug that can be applied to mucous membranes or inflamed areas of mucous membranes and can be expected to have systemic or local therapeutic and preventive effects. Examples include lidocaine, dibucaine hydrochloride, and tetracaine hydrochloride. local anesthetics such as chlorhexidine hydrochloride, oral disinfectants such as cetylpyridinium chloride, anti-inflammatory drugs such as azulene, indomethacin, ibuprofen, mefenamic acid, anti-inflammatory analgesics, prednisolone, dexamethasone, dexamethasone acetate, triamcinolone acetonide, etc. Examples include anti-inflammatory steroids, methalyzine hydrochloride, cymenhydrinate, and other antiseptics.

(Example) The present invention will be explained in more detail with reference to Examples below.

Example 1 74.5 g of Plastibase was added with polyacrylic acid [Power-Bopol 941 (manufactured by Gutdrich Chemical Co., Ltd.)] Log,
Polyvinylpyrrolidone (average molecular weight = 40000) 1
0 g, polyethylene glycol (average molecular weight: 40
0) and 0.5 g of water-soluble azulene were added and mixed well to obtain 100 g of oral ointment.

Example 2 59.5 g of Plastibase, 8 g of polyacrylic acid [Hibisfuco-105 (manufactured by Wako Tsumugi Kogyo Co., Ltd.)] and chitosan (
Average molecular weight: 200,000) 12g, crystalline cellulose 15g,
5 g of polyethylene glycol (average molecular weight: 400) and 0.5 g of water-soluble azulene were added and mixed well to obtain 100 g of oral ointment.

Example 3 59.5 g of Plastibase and 115 g of polyacrylic acid [Cyber-Bopol 941 (manufactured by Gutdrich Chemical Co., Ltd.)]
Add 20 g of magnesium aluminate metasilicate, 5 g of polyethylene glycol (average molecular weight: 400) and 0.5 g of water-soluble azulene and mix well to make oral ointment 10 g.
Obtained 0g.

Example 4 67.5 g of Plastibase and 113 g of polyacrylic acid [Crypto-Bopol 941 (manufactured by Gutdrich Chemical Co., Ltd.)]
Chitosan (average molecular weight = 200,000) 9g, dextrin 5
g, polyethylene glycol (average molecular weight: 400) 5
g and 0.5 g of cetylpyridinium chloride were added and mixed well to obtain 100 g of oral ointment.

Example 5 30 g of Plastibase, 36.5 g of Vaseline, and polyacrylic acid [Hibisukuko-105 (manufactured by Wako Tsumugi Kogyo Co., Ltd.)]
Log, polyvinylpyrrolidone (average molecular weight: 400
00) 13 g, crystalline cellulose 5 g, polysorbate 80 2 g, polyethylene glycol (average molecular weight:
400) and 0.5 g of lidocaine hydrochloride were added and mixed well to obtain 100 g of oral ointment.

Example 6 63.98 g of petrolatum, 111 g of polyacrylic acid [Carbopol 941 (manufactured by Gutdrich Chemical Co., Ltd.)] 15 g of aluminum stearate, 5 g of lactose, polyoxyethylene hydrogenated castor oil [Nitsukol HCO-60 (manufactured by Nikko Chemical Co., Ltd.)] )], 3 g of sorbitan monocaprylate [Cefsol 418 (manufactured by Nikko Chemical Co., Ltd.)] and 0.025 g of dexamethasone were added and mixed well to obtain 100 g of oral ointment.

Example 7 20 g of sodium polyacrylate, 25 g of magnesium aluminate metasilicate, 2 g of polyethylene glycol (average molecular weight: 400) and 0.5 g of indomethacin were added to 52.5 g of Plastibase (manufactured by Squibb),
Mix well to obtain a long oral ointment.

Reference example 1 44.5 g of Plastibase, 6 g of pectin, 1.0 g of gelatin, 3 g of sodium carboxymethyl cellulose
4g, polyethylene glycol (average molecular weight: 400)
5 g and 0.5 g of water-soluble azulene were added and mixed well to obtain 100 g of oral ointment of Reference Example 1.

Reference example 2 56g of Vaseline, 8.5g of Plastibase and 2 parts of pectin
0 g, polyvinyl alcohol 10 g, polyethylene glycol (average molecular weight: 400) 5 g, and water-soluble azulene 0.5 g were added and mixed well to obtain 100 g of oral ointment of Reference Example 2.

Reference Example 3 To 84.5 g of Plastibase were added polyacrylic acid [Hibisfuco-105 (manufactured by Wako Tsumugi Kogyo)] Log, 5 g of polyethylene glycol (average molecular weight, 400), and 0.5 g of water-soluble azulene, and mixed well. 100 g of oral ointment of Reference Example 3 was obtained.

In order to evaluate the obtained oral ointment, an adhesion test and a drug release test were conducted.

Test Example 1 10% of the oral ointment of Examples 1, 2 and Reference Examples 1, 2.3
The adhesive was applied to the oral mucosa of a human panel to investigate the adhesion stability. The results are shown in Table 1.

Table 1 Test Example 2 A diurnal dissolution test method in which 5 g of each of the ointments of Examples 1, 2.3 and Reference Examples 1 and 2 was filled into a cellulose tube, and purified water was used as the release liquid. The operation was performed according to the second method (paddle method), and the amount of water-soluble azulene released was measured. The results were as shown in FIG.

Effects of the Invention As described above, the oral ointment of the present invention maintains excellent adhesion to the complex-shaped oral mucosa for a long time, provides a sustained drug release effect, and can be molded into tablets, plates, etc. It is an extremely useful preparation with features not seen in conventional oral preparations, such as the ability to be administered without any discomfort, and its practical value is extremely high.

[Brief explanation of drawings]

FIG. 1 shows the release test results of Experiments 1 and 2.3 and Reference Examples 1 and 2 containing water-soluble azulene, and sustained release over a long period of time was confirmed. In FIG. 1, 10- indicates Example 1. -・- is Example 2.
-Δ- indicates Example 3, -X- indicates Reference Example 1, and -■- indicates Reference Example 2.

Claims (5)

[Claims] (1) A mouth ointment characterized by blending a compound capable of forming a complex with polyacrylic acid or its salts in an oily base. (2) The oral ointment according to claim 1, wherein the compound forming a complex with polyacrylic acid or a salt thereof is a metal compound. (3) The oral ointment according to claim 1, wherein the compound that forms a complex with polyacrylic acid or its salts is a polymer compound. (4) The oral ointment according to claim 2, wherein the metal salt comprises a di- or trivalent polyvalent metal ion. (5) The oral ointment according to claim 3, wherein the polymer compound comprises one or both of chitosan and polyvinylpyrrolidone.