JPS6323964B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an oral or nasal preparation comprising a mucoadhesive coating layer that adheres to the oral or nasal mucosa and coats a drug layer, and a drug layer that efficiently supplies the drug through the mucous membrane. More specifically, in the mucoadhesive coating layer that adheres to the oral or nasal mucosa and covers and protects the drug layer, the layer is made of lower alkyl or lower hydroxyalkyl ether of cellulose and an acrylic acid polymer or a pharmaceutically acceptable salt thereof. ,
It is characterized by unevenly distributing a drug layer for efficiently supplying the drug through the mucous membrane, which is made of an ointment base containing a drug and a surfactant that are not absorbed or hardly substantially absorbed by normal oral administration. The present invention relates to oral or nasal mucosal adhesive preparations. Conventionally, when the mucous membrane of the oral cavity or nasal cavity is the site of disease, it is quite natural to administer drugs such as ointments and liquids to the mucous membrane; There are only a few examples, such as sublingual nitroglycerin tablets. Although it is said that the oral or nasal mucosa is a relatively efficient site for drug absorption, the structure of the drug
In addition to the difficulty of absorption due to its nature, there was no means to keep the drug in the mucosal area for the necessary time;
In other words, this is thought to be because in conventional ointments and liquid preparations, the amount of drug that flows out or is swallowed after administration is much larger than the amount of drug that is absorbed. This is the object of the present invention. In other words, there is no need to intentionally absorb drugs that are easily absorbed through the oral mucosa or nasal mucosa during normal oral administration; The object is to provide a means for absorption through mucous membranes or nasal mucosa. As mentioned above, insulin can be cited as a typical drug that is hardly or substantially absorbed by normal oral administration. Until now, the only practical method of administering insulin has been injection, and diabetic patients are forced to take daily subcutaneous injections, which is said to cause great mental and physical pain. It is being said. Injectables with long-lasting efficacy have been developed based on the origins of insulin and the formation of complexes with metal salts and other proteins, reducing the number of injections. As a result, frequent injections are about to be administered. In this way, insulin injections can cause local allergic reactions, lipodystrophy, eczema, anaphylaxis, etc., in addition to the mental and physical pain caused by daily injections or multiple injections a day. There may be cases where For this reason, research into dosage forms other than injections has been actively conducted for insulin preparations, including suppositories, nasal preparations,
Inhalants, eye drops, oral sublingual tablets, etc. are being researched, but none of these methods have been put to practical use as they are still unsatisfactory. For example, as an oral insulin agent, W/O (so-called micellar insulin) contains microscopic water droplets containing insulin in microscopic fat droplets with a diameter of 0.6 to 2 μm, and these microscopic oil droplets are further made into an aqueous suspension. /W-type insulin preparations are known. Since this micellar insulin preparation is an orally administered drug, it has the advantage of being easy to handle, but on the other hand, the stability of micellar insulin itself is low, making it difficult to store for a long period of time, and its absorption is limited by food intake. It has the disadvantage that it is easily influenced by the physiological conditions of the digestive tract, such as the presence or absence of gastrointestinal tract, and its absorption efficiency is also not fully satisfactory. Furthermore, the present inventors are not aware of any report that insulin is substantially absorbed from the oral mucosa. The present inventors have developed a non-injectable insulin preparation that not only has excellent stability and storage stability, but also has a simple administration method and is capable of efficiently absorbing insulin through the oral or nasal mucosa. As a result of intensive research with the aim of obtaining a mucosal adhesive consisting of a lower alkyl or lower hydroxyalkyl ether of cellulose and an acrylic acid polymer or a pharmaceutically acceptable salt thereof, which has adhesive properties to oral mucosa or nasal mucosa. In preparations in which a drug layer consisting of an ointment base such as cacao butter containing insulin and a surfactant is unevenly distributed in a sexual coating layer, the drug layer may be in contact with or in close proximity to the oral mucosa or nasal mucosa. Insulin is efficiently absorbed through the oral or nasal mucosa by administering it to the patient, and is superior not only in its stability and preservation, but also in that the administration method is simple and blood sugar levels can be easily maintained. The present invention was achieved based on the discovery that such a preparation can be applied to drugs other than insulin that are not absorbed or are hardly substantially absorbed by normal oral administration. That is, the present invention provides that the present invention is not absorbed or almost substantially absorbed into a mucoadhesive coating layer consisting of a lower alkyl or lower hydroxyalkyl ether of cellulose and an acrylic acid polymer or a pharmaceutically acceptable salt thereof. This is an oral or nasal mucoadhesive preparation characterized by having a unevenly distributed drug layer consisting of an ointment base containing a drug that is not absorbed by the patient and a surfactant. The mucoadhesive coating layer of this agent consists of lower alkyl or lower hydroxyalkyl ether of cellulose and acrylic acid polymer or a pharmaceutically acceptable salt thereof, as detailed later, and its purpose is to: The purpose is to keep the drug layer in contact with the mucous membrane for a necessary period of time and fix it so that it will not run off or be swallowed. Furthermore, the drug layer of this drug consists of an ointment base containing a drug and a surfactant, as will be explained in detail later, and its purpose is to melt or soften it with body temperature to ensure that the drug is delivered to the mucous membranes. The aim is to improve drug absorption by using a surfactant at the same time. That is, the oral mucosa or nasal mucosa-adhesive preparation provided by the present invention has a mucoadhesive coating layer consisting of a lower alkyl or lower hydroxyalkyl ether of cellulose and an acrylic acid polymer or a pharmaceutically acceptable salt thereof. , which consists of an unevenly distributed drug layer consisting of an ointment base containing a drug that is not absorbed or hardly substantially absorbed by normal oral administration and a surfactant. Ointment bases used in the drug layer include cacao butter, palm oil, palm oil, coconut oil, lard, oils and fats mainly composed of triglycerides such as uitepsol, waxes such as lanolin and reduced lanolin,
Hydrocarbons such as petrolatum, squalene, squalane, capric acid, lauric acid, stearic acid,
Medium- and long-chain fatty acids such as oleic acid, higher alcohols such as lauryl alcohol, cetanol, stearyl alcohol, and oleyl alcohol, polyhydric alcohols such as propylene glycol, polyethylene glycol, and glycerin, butyl stearate, dilauryl malonate, and glycerin. Preferred examples include esters such as monoester and glycerin diester. Among these, lipophilic bases such as cacao butter, uitepsol, and glycerin ester are particularly preferably used. Surfactants used in the drug layer include glycerin fatty acid mono- or diesters such as glyceryl monocaprylate, glyceryl monomyristate, glyceryl oleate, glyceryl monostearate, acetylated glyceryl monostearate, and other sorbitan fatty acid esters. polyoxyethylene alkyl amines and aliphatic amides such as polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene stearylamine, polyoxyoleic acid amide, sodium laurate , sodium stearyl sulfate, triethanolamine lauryl sulfate, alkyl sulfate salts and polyoxyethylene alkyl ether sulfate salts such as triethanolamine lauryl sulfate, triethanolamine lauryl ether sulfate, sodium lauroyl sarcosine, benzalkonium chloride, betaine lauryl dimethylamino acetate , pyridoxine dipalmitate, nitrogen-containing and amino acid derivatives such as addition reaction products of amino acids with aldehydes, ketones, and keto acids, substituted fatty acid esters such as ascorbic acid fatty acid ester, pantothenic acid ester, sodium glycocholate, ursodeoxycol Cholic acid and its salts such as sodium chloride, saponins such as Senegin, Kikyo saponin, osteodin, and lily of the valley saponin, and phospholipids such as lecithin can be used.
Among these, cholates, saponins, glycerin esters, polyhydric alcohol esters,
Amino acid derivatives are preferably used. In addition, there is no need to intentionally administer drugs to the oral cavity or nasal mucosa that are easily absorbed by normal oral administration, unless the drug is used for local treatment of the oral cavity or nasal mucosa. Drugs that are not absorbed or are substantially poorly absorbed include insulin, angiotensin, vasopressin, protirelin, gonadotropin-releasing hormone, corticotropin, prolactin, thyrotropin, luteinizing hormone,
Examples include polypeptide hormones such as calcitonin, parathylin, glycagon, gastrin, and secretin, mucoplasms such as heparin and chondroitin sulfate, prostaglandins, and oil-soluble vitamins. The amounts of these ointment bases, surfactants, and drugs to be used cannot be generalized depending on the type of drug, but for example, 150 mg of lower alkyl or lower hydroxyalkyl ether of cellulose is mixed with 50 mg of acrylic acid polymer.
A mucoadhesive coating layer was prepared from mg, 50 mg of cocoa butter,
A drug layer is prepared from 5 mg of sodium glycocholate and 10 mg of drug. A drug layer consisting of an ointment base containing a surfactant and a drug is produced by adding the surfactant and drug to the ointment base and melt-mixing the mixture in a conventional manner. The lower alkyl or lower hydroxyalkyl ether of cellulose used in the mucoadhesive coating layer in the present invention is a cellulose derivative in which a plurality of hydroxyl groups of cellulose are at least partially etherified. The number of ether groups does not necessarily have to be one, and the cellulose ether may have two or more types of ether groups in its molecule, for example, having both a lower alkyl group and a lower hydroxyalkyl group. Here, "lower alkyl" means an alkyl group having 5 or less carbon atoms, preferably 3 or less carbon atoms. Examples of the lower alkyl or lower hydroxyalkyl ether of cellulose include methylcellulose, ethylcellulose, propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Among these, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose is particularly preferably used. These cellulose ethers can be used alone or with 2
It is also possible to use a mixture of more than one species. The cellulose ether may have any molecular weight and any degree of ether substitution, and any commercially available cellulose ether may be used. As the cellulose ether in the present invention, for example, the viscosity of a 2% aqueous solution at 20°C is 3 to
100,000 centiboise, more preferably 3 to 10,000
Those having centivoise, particularly preferably 6 to 6000 centivoise, are preferably used. Further, as the cellulose ether in the present invention, for example, those having an ether substitution degree of 0.1 to 6.0,
In particular, those of 0.4 to 4.6 are preferably used. The degree of ether substitution refers to the amount of 1 that constitutes cellulose.
Per glucose unit, it refers to the average number of ether groups for the three hydroxyl groups that one unit has. In the present invention, the acrylic acid polymer used for the mucoadhesive coating layer includes not only acrylic acid homopolymers but also acrylic acid and allyl sucrose, methyl acrylate, methacrylic acid, etc., as commercially available products. Examples include copolymers with acids, methyl methacrylate, hydroxyethyl methacrylate, styrene, or vinyl type ether monomers such as methyl vinyl ether, either singly or in mixtures of two or more. This copolymerization ratio can be changed within a range that maintains the water solubility or water swelling property of the copolymer, and also ensures that the formulation of the present invention maintains adhesiveness or non-irritating properties to the oral or nasal mucosa. limited to such a range. It is usually about 20 mol% or less. Also, for example, commercially available polyacrylic acid and some other amount (usually less than about 20% by weight)
Mixtures of acrylic acid with water-soluble polymers (eg, polymethacrylic acid or its salts, polyethylene glycol) can also be used as the acrylic acid polymer in the present invention. Pharmaceutically acceptable salts of polyacrylic acid in the present invention include its Na salt, K
Alkali metal salts such as salts or ammonium salts are preferred, and any degree of neutralization may be used. Polyacrylic acid or a pharmaceutically acceptable salt thereof can be used with any molecular weight, but preferably the polyacrylic acid has a concentration of 0.2% as polyacrylic acid and has a pH of 7 to 7.5.
In an aqueous solution of its sodium salt showing 25.0±0.5
Those exhibiting a viscosity of 360 to 165,000 centipoise, preferably 3,600 to 16,500 centipoise when measured at °C are preferably used. The acrylic acid polymer or its pharmaceutically acceptable salt in the present invention can be used alone or in combination of two or more. In the present invention, it is preferable to use cellulose ether and an acrylic acid polymer or a pharmaceutically acceptable salt thereof in combination because they have sufficient adhesion to mucous membranes and are less irritating to the oral and nasal mucosa. . In addition to the above-mentioned cellulose ether, acrylic acid polymer, or pharmaceutically acceptable salt thereof, known lubricants, binders, excipients, colorants, flavoring agents, preservatives, etc. may be added as necessary. Type 1 or 2
It may contain more than one species. Examples of lubricants include talc, stearic acid and its salts, waxes, etc.; binders include starch, dextrin, tragacanth, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.; excipients include starch, crystals, etc. Cellulose, dextrin, lactose, mannitol, sorbitol, anhydrous calcium phosphate, etc.; Examples of flavoring agents include citric acid, fumaric acid, tartaric acid, menthol, citrus flavoring, etc. The preparation of the present invention has a drug layer consisting of an ointment base containing the above drug and a surfactant, and a drug layer consisting of a lower alkyl or lower hydroxyalkyl ether of cellulose and an acrylic acid polymer or a pharmaceutically acceptable salt thereof. It is unevenly distributed in the mucoadhesive coating layer. The uneven distribution here means that when the preparation of the present invention is administered by adhering to the oral or nasal mucosa, the drug layer is
It means that it is not in the center of the preparation, but in contact with or in close proximity to the oral or nasal mucosa. Specific examples of dosage forms of such preparations are as shown in A to C of the attached FIG. 1. Among these dosage forms, the first
As shown in A in the figure, a drug layer consisting of an ointment base, a surfactant, and a drug is preferably distributed unevenly on the surface of the preparation. For example, a preferred form of the preparation, such as A in Figure 1, is obtained by compressing and molding the powder for the mucoadhesive coating layer using an upper punch having a convex portion and a lower punch having a flat surface. It can be manufactured by manufacturing a tablet having a molten drug layer and pouring a molten drug layer into the recessed portion of the tablet. Alternatively, if the drug layer has a certain degree of hardness, it can also be produced by compression molding together with the powder for the coating layer. In this way, an ointment base containing a drug such as insulin and a surfactant is mixed into a mucoadhesive coating consisting of a lower alkyl or lower hydroxyalkyl ether of cellulose and an acrylic acid polymer or a pharmaceutically acceptable salt thereof. By creating a preparation that adheres to the mucosa of the oral cavity or nasal cavity, which is unevenly distributed, it becomes possible to absorb drugs such as insulin through the mucous membrane of the oral cavity or nasal cavity, which has been considered difficult in the past. It makes it extremely easy to administer drugs that are difficult to administer orally, and it not only has excellent storage stability and stability, but also has a simple administration method and is excellent as a formulation that allows the drug to be absorbed efficiently. It is something that Hereinafter, the present invention will be explained in detail with reference to Examples. Example In the center, cocoa butter, sodium glycocholate, and insulin (Sigma Co., Ltd. 26.8IV/mg) were melted and mixed in the proportions shown in Table 1, left at room temperature, and then compressed and molded. Add a mixed base of hydroxypropyl cellulose (HPC) and carbopol (CP) (1:2) to the tablet and press it into a tablet.
A formulation as shown in FIG. 1A was prepared. This was adhered to the oral mucosa of fasted beagle dogs (5 dogs), and changes in blood sugar levels were examined up to 6 hours later. The results are shown in Table 2 and Figure 2. Comparative Example A formulation was prepared in the same manner as in the example without using sodium glycocholate, and changes in blood sugar levels were examined. The results are shown in Table 2 and Figure 2.

【table】

【table】 [Brief explanation of the drawing]

FIG. 1 shows a cross-sectional view and a front view of the oral mucosa or nasal mucosa-adhesive preparation of the present invention,
FIG. 2 is a graph showing changes in blood sugar levels when using the preparation.

Claims (1)

[Scope of Claims] 1. In the mucoadhesive coating layer consisting of a lower alkyl or lower hydroxyalkyl ether of cellulose and an acrylic acid polymer or a pharmaceutically acceptable salt thereof, it is not or hardly absorbed by normal oral administration. 1. An oral mucosa or nasal mucosa-adhesive preparation characterized by unevenly distributing a drug layer consisting of an ointment base containing a drug and a surfactant that are not substantially absorbed. 2. The oral mucosa- or nasal mucosa-adhesive preparation according to claim 1, wherein the drug layer consisting of an ointment base containing a drug and a surfactant is unevenly distributed so as to be exposed on the surface of the preparation. 3. The oral mucosa- or nasal mucosa-adhesive preparation according to claim 1 or 2, wherein the drug in the drug layer is insulin. 4. Any one of claims 1 to 3, wherein the surfactant is selected from the group consisting of cholates, saponins, glycerin esters, polyhydric alcohol esters, and amino acid derivatives. The oral mucosa- or nasal mucosa-adhesive preparation described in . 5. Claims 1 to 5, wherein the ointment base is selected from the group consisting of oils and fats, waxes, hydrocarbons, higher fatty acids, higher alcohols, polyhydric alcohols, and glycerin esters. The oral mucosa- or nasal mucosa-adhesive preparation according to any one of item 4.