JPS6130516A - Mucosa adhesive pharmaceutical - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, having a mucosa-bonding adhesive layer containing an alginic acid ester and a chemical on a base material, and improved adhesive property to mucosa of the oral cavity and good supporting property of the chemical without natural peeling, and excellent for a base of a sustained release mucosa absorption pharmaceutical. CONSTITUTION:A mucosa adhesive pharmaceutical obtained by dissolving an ester of alginic acid, preferably a 4-20C higher aliphatic alcohol ester of alginic acid, e.g. n-butyl alginate or n-octyl alginate, and a chemical, e.g. corticosteroid, anesthetic agent or antihistaminic agent, in water, and applying the resultant solution onto a base material. The pharmaceutical is characterized in that the alginic acid ester is used as an adhesive in the mucosa adhesive layer on the base material. The alginic acid ester is an adhesive having improved mucosa bonding property with little swelling deformation by moisture.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field of the Invention The present invention relates to a preparation for mucoadhesion, and more particularly, to a preparation for mucoadhesion, which has improved mucoadhesive properties using an ester of alginic acid as an adhesive and is less swollen by moisture. This invention relates to preparations for mucoadhesion.

Technical background of the invention Oral administration (tablets, powders, capsules,
granules, etc.), injections (injectables for skin, subcutaneous, muscular, intravenous, etc.), skin (ointments, creams, poultices, tapes, etc.), oral cavity (lozenges, sublingual tablets,
However, recently, transdermal administration of systemic agents for the purpose of sustained absorption has been actively studied.

However, since the basic function of the skin is to prevent foreign substances from entering from the outside world, there are limits to how they can be absorbed through the skin. In the case of administration, it is limited to those with strong side effects or those that are metabolized by the liver and for which oral administration is not effective. In addition, skin disorders have become a major problem. Therefore, we attempted to effectively administer drugs using mucous membranes, especially oral mucosa, which is easy to apply.

Conventional technology Conventional 1 Oral preparations include local anesthetic-containing ointments for anesthesia of the gums, corticosteroid-containing ointments as a treatment for aphthae, patches, and systemic agents for use during attacks of angina pectoris. There are sublingual nitroglycerin tablets that can be used, but ointments have the disadvantage of flowing out with saliva and affecting areas other than those needed, and sublingual tablets have a quick action, but the disadvantage is that the effect is not long-lasting. was there. One of the reasons for this is that there is no suitable adhesive for areas that are constantly wet with saliva, such as the oral mucosa.

Conventionally, various adhesives have been known as oral mucosal adhesives. For example, JP-A-56-100714 discloses cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose, polyacrylic acid, and salts of polyacrylic acid. Also, JP-A-5
No. 8-213709 discloses polyvinyl alcohol,
Gelatin, agar, starch, xanthan gum, gum arabic, gum tragacanth, gum karaya, echo gum, locust bean gum, sodium alginate, pectin, cell, rose derivative, methyl vinyl ester, polyvinylpyrrolidone, carboxyvinyl polymer, casein, albumin, Chitin, sodium polyacrylate, etc. are shown. Furthermore, JP-A-58-59910
The publication describes cellulose derivatives, acrylic acid polymers or copolymers or salts thereof, polyvinyl alcohol, polyalkylene glycols, polyvinylpyrrolidone, hydroxypropyl starch, alginic acid or salts thereof, polysaccharides such as gum tragacanth or derivatives thereof, gelatin,
Collagen or those modified with succinic acid, phthalic anhydride, etc. are shown. However,
These adhesives have advantages and disadvantages, and to date no satisfactory adhesive for mucosa has been obtained. For example, there have been problems such as insufficient adhesion, or even if adhesiveness is good, swelling due to moisture is large and the swelling force causes the adhesive to peel off.

OBJECTS OF THE INVENTION An object of the present invention is to provide a preparation for mucoadhesion using an adhesive that has excellent mucoadhesive properties and is less susceptible to swelling and deformation due to moisture.

Structure of the Invention The present invention is a mucoadhesive preparation having a mucoadhesive adhesive layer containing an alginic acid ester and a drug on a base material.

The components of the present invention will be explained in detail below.

(Support for mucosal adhesive) Supports used in the present invention include collagen, paper, nonwoven fabric, cloth, polyethylene film, polypropylene film, polyvinyl chloride film, polyvinylidene chloride film, polyethylene terephthalate film, nylon film, Polyurethane films, foams and laminates thereof are used.

(Adhesive) In the present invention, an alginic acid ester is used as an adhesive for the mucoadhesive layer on the substrate.

Preferably, as the alginic acid ester, a higher aliphatic alcohol ester having 4 to 20 carbon atoms of alginic acid is used, such as n-butyl alginate, n-alginate
-octyl, n-dodecyl alginate, n-alginate
Octadecyl etc. are used.

The thickness of the adhesive layer does not need to be specifically determined, but generally speaking, it can be set to a thickness of 5 to 60 μm, and further 10 to 60 μm.
A thickness of ~40 μm is preferred.

(Drug) The drug used in this invention can be dissolved or dispersed in alginate and absorbed through the mucous membrane.
For example, corticosteroids.

Anesthetics, antihistamines, antibacterial substances, antifungal agents, analgesic anti-inflammatory agents, keratin emollients, vitamins, antihypertensive agents, antibiotics,
These include central nervous system agents, vasodilators, sedatives, antispasmodics, sex hormones, and antidiabetic agents.

The appropriate amount of these drugs is selected to obtain the desired treatment or administration effect depending on the type of drug.

To give specific examples, examples of corticosteroids include prednisolone acetate, prednisolone, hydrocortisone acetate, dexamethacin, fluocinolone acetonide, betamethasone, beclometazone propionate, fludroxycortide, fluocinonide, and the like.

Anesthetics include pensicaine, lidocaine, and ethyl aminobenzoate; antihistamines include diphenhydramine hydrochloride and chlorpheniramine maleate; antibacterial agents include benzalkonium chloride and nitrofurazone; and antifungal agents include Nicecutin. , undecylenic acid, etc., and analgesic anti-inflammatory agents include methyl salicylate, indomethacin, diclofenac sodium, flurbiprofen, etc.

In addition, examples of keratin softeners include salicylic acid and vitamin A. In addition, antihypertensive agents such as reserpine and clonidine as systemic adjuvants, erythromycin, chloramphenicol, cephalexin, tetracycline,
Examples include antibiotics such as penicillin, central nervous system agents such as palpyrate, diazempam, nitrazepam, and chlorpromazine, and vasodilators such as nitroglycerin and isosorbite nitrate.

(Other additives) In the present invention, especially when the drug is not sufficiently soluble in the adhesive film, about 10% by weight of a mucosal absorption enhancer such as isopropyl myristate or isoprobilalate may be added as necessary. May be added.

(Production method) A method for producing the adhesive preparation of the present invention will be described below.

When the drug is water-soluble, the alginate alkyl ester and the drug are dissolved in water, the resulting solution is applied onto the substrate, and the water is evaporated to form the finished product.

When the drug is poorly soluble in water, it can be dissolved in isopropyl myristate, isoprobilalate, etc.
This is emulsified in an aqueous solution of alginate alkyl ester.
disperse and apply the suspension thus obtained on a substrate,
The water is evaporated to form the finished product.

EXAMPLES The present invention will be described in more detail with reference to Examples below, but the present invention is not limited thereto.

Example 1 Sodium alginate 20g, n-octyl bromide 21
g was added to 200 g of tetrahydrofuran, and the mixture was heated to 90° C. for 8 hours in an autoclave.

After cooling, the reaction product was poured into n-hexane of about 1000 mΩ, and the precipitate was washed, filtered, and dried to obtain 30 g of n-octyl alginate. Next, the obtained n-octyl alginate Log was dissolved in 100 g of water, 0.1 g of Twin 80 was added as a nonionic surfactant, and 10 g of a 4% aqueous solution of lidocaine hydrochloride was added and stirred well. This solution was applied onto a polyurethane film with a thickness of 100 μm, and the coating amount after drying was 20 g/rr? It was applied and freeze-dried. This product was punched into a square shape with a diameter of 1.13 cm and stored in an aluminum pack.

One sheet (1d) of this product contains 0.08ml/g of lidocaine hydrochloride.

When the placebo of this product (not containing lidocaine hydrochloride) was applied to the gums, it showed extremely good adhesion and did not peel off naturally for 3 days. Additionally, when this product was applied to the gums, a feeling of numbness was felt, which lasted for approximately 1 hour until removed.

Example 2 Sodium alginate 20g, n-dodecyl bromide 27
．． 5g was added to 200g of toluene, and 10g was added to 200g of toluene.
The mixture was stirred at 0°C for 8 hours. After the reaction, cool and reduce the contents to about 10
Pour into n-hexane of 00+aQ, wash the precipitate, filter and dry, and add n-dodecyl alginate 34
I got g.

Next, 100g of the obtained n-dodecyl alginate log
0.1 g of Twin 80 and 0.5 g of diclofenac sodium were added and stirred well to dissolve. This solution was applied to the polyethylene terephthalate surface of a laminate in which a 10 μm thick polyethylene terephthalate film was laminated to a 200 μm thick polyethylene foam at a dry coating weight of 20 g/nf, and freeze-dried.

This product has a diameter of 1. ．． A 13 cm circular shape was punched out and stored in an aluminum bag.

One sheet of this product (la&) contains 0.1 mg of diclofenac sodium.

When a placebo of this product (not containing diclofenac sodium) was applied to the gums, it showed extremely good adhesion and did not peel off naturally for three days. In addition, when crystals were applied to the gums of teeth suffering from toothache,
The toothache was well suppressed during application.

Example 3 20 g of sodium alginate and 36 g of n-octadecyl bromide were added to 200 g of toluene, and the mixture was heated for 10 g in a nitrogen stream.
The mixture was stirred at 0°C for 8 hours. After the reaction, the contents were reduced to about 1000a
k1 into n-hexane, wash the precipitate, filter,
It was dried to obtain 36 g of n-octadecyl algin.

Next, 1°g of the obtained n-octadecyl alginate was dissolved in 100wfi of water, and further 0.1g of Twin 8° was dissolved.
In addition, 1 g of isopropyl myristate containing 0.04 g of beclomethasone dipropionate was added and dispersed by stirring. The coating amount after drying this solution is 44g/rrr
It was applied onto the skin-forming surface of the polyurethane foam so as to have the following properties, freeze-dried, punched into a circular shape with a diameter of 1.13 cm, and stored in an aluminum bag. One crystal (lti) contains 8 μg of beclomethasone diprobionate.

The crystal placebo (not containing beclomethasone dipropionate) adhered well to the oral mucosa and did not peel off spontaneously for 3 days.

Furthermore, when the crystal was adhered to the gums for 2 hours and then removed, pallor due to anemic spots caused by the corticosteroid was observed on the applied area.

Comparative Example 1 A mucoadhesive film piece (adhesive film coating amount: 20 g/rrr) was prepared using hydroxypropylcellulose in the same manner as in Example 1 and using a drug-free 100 μm polyurethane support.

When the crystal was applied to the gums in the same way, the mucoadhesive film at the edge began to swell in about 30 minutes, and within a few hours the thickness had increased to several 1.
It became crown-shaped and swollen to 0 times its original size and spontaneously detached within 24 hours.

Effects of the Invention The preparation for oral mucosa adhesion according to the present invention has excellent adhesion to the surface of the oral mucosa, does not peel off naturally even after long-term application, and has good drug retention properties, so it can be used as a sustained-release mucosal agent. Excellent as a base for absorption preparations.

Claims (1)

[Claims] A mucoadhesive preparation having a mucoadhesive adhesive layer containing an alginic acid ester and a drug on a base material.