JPS587605B2 - Sustained-release preparation and its manufacturing method - Google Patents

Description

[Detailed description of the invention] The present invention relates to sustained release formulations.

More specifically, it swells while absorbing saliva or secretions, adheres to the oral mucosa, etc., and gradually releases the drug, thus efficiently delivering the drug at a concentration sufficient to have a therapeutic effect over a long period of time. The present invention relates to a sustained-release preparation that is used by being attached to the oral cavity.

The usual method of dosing, such as administering a single dose of a drug three times a day before, between or after meals, is not clinically pharmacologically advantageous and does not allow active ingredients to be delivered over the long periods of time required for treatment. It is widely recognized that fewer doses of a drug that release only the required concentration are advantageous to both patients and clinicians.

Conventionally, various proposals have been made regarding formulations and methods for producing the same that delay the release of drugs from formulations and maintain the efficacy of drugs for a long period of time, mainly for internal use.

For example, methods to make it difficult to disintegrate by using large amounts of binders that do not have disintegration effects in the stomach or intestines, methods to coat crystals, granules, or tablets of herbal medicines with water-repellent substances such as waxes, stearin These methods include using a large amount of hydrophobic lubricant such as an acid salt, or wrapping the drug in a semipermeable membrane.

In addition to these, there are also known sustained-release or slow-release preparations in which a poorly soluble or hydrophilic polymer is mixed with a drug to gradually release the drug.

For example, Japanese Patent Publication No. 37-13092 describes an orally administered sustained-release drug consisting of a drug and a poorly soluble acid-type carboxyvinyl polymer;
No. 24 describes granules or tablets that have a sustained effect in the stomach or intestinal tract and are made of a mixture of a hydrophilic resin such as polyvinyl alcohol or polyacrylic acid and a drug.

All of these drugs exhibit a sustained release effect of the main drug in the stomach or intestinal tract, and are further described in JP-A No. 51-91314 and JP-A-Sho. There are those described in No. 51-115910 and JP-A-51-142523.

In most of these known sustained release formulations, the purpose is to provide a continuous supply of drug to compensate for the amount of drug consumed during the passage of the ingested drug through the patient's gastrointestinal tract. .

However, in most of these known sustained-release preparations, even if the drug is continuously released from the preparation for a long period of time, the drug contained in the drug is not released in the body. It is also possible that the formulation itself passes through the site of absorption or action of the drug, in which case its most advantageous properties will not be utilized.

Conventionally, as a method to compensate for these drawbacks, the preparation was made to float in the stomach (for example, Japanese Patent Application Laid-Open No. 11591/1983).
0), a method of prolonging the residence time of a preparation in the stomach by coexisting with a hydrophilic colloid or a hydrophilic polymer exhibiting high viscosity in the presence of water.

On the other hand, preparations intended for oral administration include buccal tablets, troches, sublingual tablets, and oral ointments.

However, conventional buccal preparations, lozenges, and sublingual tablets give the sensation of a foreign body in the oral cavity, and patients often end up chewing them up and swallowing them.

In addition, oral ointments made by mixing beeswax, plastibase, etc. with gelatin, pectin, sodium carboxymethyl cellulose, etc. have been manufactured, but the adhesion to the oral mucosa is insufficient, and a satisfactory product has not yet been obtained. .

As a way to improve the conventional drawbacks of these body cavity preparations,
For example, Japanese Unexamined Patent Publication No. 51-38412 discloses an oral preparation made of a mixture of crude drugs and sodium polyacrylate.

The characteristic of this preparation is that the sodium polyacrylate contained in it absorbs water and adheres to the local area, then swells and then gradually dissolves in the local area over a long period of time, causing most of the drug to disappear. It is stated that the point is that it elutes uniformly.

Furthermore, JP-A-49-133519 discloses that thermoplastic and physiologically inert polymers that are soluble in body fluids present in body cavities, such as hydroxypropylene cellulose and polyethylene glycol, are used in effective amounts. For example, intravaginally administered contraceptive formulations comprising drugs have been described.

The feature of this formulation is that the drug is gradually released as the polymer contained in it dissolves, so the polymer is such that the entire formulation dissolves within 24 hours. It is stated that.

Completely different from these conventional techniques, the present inventors have developed a method for treating oral diseases, diseases deep in the oral cavity such as the throat, and systemic diseases for which sustained drug release is expected to increase the effects. As a result of extensive research into drug compositions for treatment by chemical reactions, we found that, surprisingly, it was easy to obtain sustained-release preparations that eliminated the drawbacks of the conventional products mentioned above, as described below. The present invention has been achieved based on the discovery that

That is, the preparation provided by the present invention is expected to further increase the therapeutic effect of cellulose hydroxypropyl, polyacrylic acid, or a pharmaceutically acceptable salt thereof, and for oral diseases, diseases deep in the oral cavity, and sustained release. This is a sustained-release formulation that is applied to the oral cavity and consists of an intimate mixture of drugs for treating systemic diseases.

Therefore, the characteristics of the above-mentioned preparation provided by the present invention are as follows: 1) It absorbs saliva or secretions and adheres to the local area, and even when swollen, it has excellent local adhesion.

Therefore, the drug can be applied directly and locally at a high concentration to the diseased area in or around the oral cavity, and the preparation itself does not pass through the absorption or action site of the drug.

2) It absorbs saliva or secretions and swells, gradually releasing the drug.

That is, swelling occurs gradually due to saliva and the like, and the drug is released from the swollen portion, so that the drug can be continuously administered to the disease site or absorption site for a long period of time.

3) It does not dissolve and flow out even when saliva or secretions are absorbed, and even in a swollen state, it still exists in a similar shape to its original shape and has good shape retention.

Therefore, it does not feel like a foreign body and can withstand the occasional urge to touch it with your tongue or peel it off. In addition, there may be cases where it is necessary to urgently stop administration of certain drugs, but even in such cases, it is possible to remove the tape with fingers or tweezers, thereby avoiding danger.

4) Drug release by changing the ratio of cellulose hydroxypill and polyacrylic acid or its pharmaceutically acceptable salt, or by forming a double-layer tablet with formulation components that have normal release properties. The speed can easily be controlled to meet therapeutic objectives.

5) The preparation operation is easy, and since the molding can be carried out by pressure molding, it is advantageous from an economical point of view as well as not impairing the stability of the main drug.

Moreover, it can be formed into various forms such as granules and powders depending on the purpose.

etc.

The aforementioned Japanese Patent Application Laid-Open No. 51-38412 discloses an oral preparation containing sodium polyacrylate that has the property of locally adhering to the oral cavity and the property of swelling. According to the inventor's research, preparations consisting of sodium polyacrylate, excipients, and drugs do not necessarily have sufficient adhesion, and after swelling, they become amorphous and easily peel off and flow. , is not necessarily sufficient for efficient administration of drugs over a long period of time.

Furthermore, in the present invention, it is possible to control the release property by using both hydroxypill cellulose and polyacrylic acid, but in the above publication, only sodium polyacrylate is used. It is difficult to control water release.

Further, the above-mentioned publication only discloses that the preparation is used to treat oral diseases and absorb drugs from the oral cavity by attaching the preparation to the oral mucosa.

Furthermore, even when using, for example, the hydroxypill cellulose described in JP-A-49-133519, as described in detail below, similar to the above example, there is no effect in the oral cavity. It was found to be inappropriate as a sustained release preparation to be used by attaching it.

Unlike these, the sustained-release preparation provided by the present invention for use in the oral cavity must contain both hydroxypill cellulose and polyacrylic acid or a pharmaceutically acceptable salt thereof. This is the first time that a formulation with the above-mentioned characteristics can be obtained.

Hydroxypyl cellulose and polyacrylic acid or a pharmaceutically acceptable salt thereof are each water-soluble polymers, so when each is used alone,
As mentioned above, it disintegrates or dissolves due to secretions and flows out, so it is not suitable as a sustained-release preparation for use in the oral cavity.

However, as mentioned above, products containing both have the desirable property of swelling, but do not dissolve and flow out under normal administration conditions, and exhibit good local adhesion even when swollen. Together, it maintains its shape and continues to act effectively on the application area.

Therefore, although it is difficult to clarify the respective roles played by hydroxypropylene cellulose and polyacrylic acid or its pharmaceutically acceptable salts in the preparation for use, as far as it can be inferred, polyacrylic acid or its pharmaceutically acceptable salts balance the elution and retention of the drug in the intimately mixed component matrix of the formulation, while at the same time providing strong adhesion to the oral mucosa, Pill cellulose not only acts as a simple excipient, but also is thought to regulate the release of drugs in the matrix of the preparation, similar to polyacrylic acid and the like.

However, even though each polymer can be dissolved and dispersed individually, why does the mixture of both polymers not dissolve and disperse for a long period of time, such as 21 hours, and maintain a desired swollen form? It is not always clear whether it will hold.

In the present invention, hydroxypill cellulose is
Although any molecular weight may be used, the components of the formulation of the present invention that provide the preferred characteristics described above include 2.
A dihydric aqueous solution having a viscosity of 3 to 10,000 centipoise, more preferably 1,000 to 4,000 centipoise at 0°C is preferably used.

Further, polyacrylic acid or a pharmaceutically acceptable salt thereof may be used in any molecular weight, but preferably, the polyacrylic acid has a concentration of 0.2 as a polyacrylic acid, and An aqueous solution of its sodium salt exhibiting a pH of 7 to 7.5 and a viscosity of 360 to 165,000 centipoise, preferably 3,600 to 16,500 centipoise, when measured at 25.0±0.5°C. is preferably used.

The polyacrylic acid referred to in the present invention includes not only polyacrylic acid alone, but also commercially available polyacrylic acid containing a small amount (usually 20% by weight or less) of other water-soluble polymers, etc. You can also use the ones you have.

Furthermore, polyacrylic acid refers not only to polyacrylic acid homopolymers, but also to copolymers obtained by copolymerizing methacrylic acid, styrene, vinyl ether monomers, etc. with acrylic acid.

Naturally, this copolymerization ratio should be limited to a copolymerization ratio that can achieve the object of the present invention.

Furthermore, the pharmaceutically acceptable salt of polyacrylic acid as used in the present invention is understood to be the corresponding salt of polyacrylic acid as described above.

The ratio of cellulose and polyacrylic acid or its pharmaceutically acceptable salt contained in the preparation varies depending on the molecular weight of each or whether it is polyacrylic acid or its salt, but usually, Based on hydroxypill cellulose, it is preferable that polyacrylic acid or a pharmaceutically acceptable salt thereof be 0.1 to 10 parts by weight per 1 part by weight of hydroxypill cellulose.

Further, in the case of polyacrylic acid, it is more preferable to use 0.1 to 3.0 parts by weight per 1 part by weight of cellulose, and pharmaceutically acceptable salts of polyacrylic acid. In this case, the amount is preferably 0.5 to 3.0 parts by weight.

The difference in the preferred range between polyacrylic acid and its pharmaceutically acceptable salt is that when using a pharmaceutically acceptable salt thereof, the preferable range is different from that of polyacrylic acid. This is due to a decrease in strength during swelling.

The pharmaceutically acceptable salts of polyacrylic acid are preferably alkali metal salts such as Na salts and K salts, or ammonium salts thereof, and any degree of neutralization may be used.

The sustained-release preparation provided by the present invention to be used by adhering to the oral cavity contains hydroxypill cellulose, polyacrylic acid or a pharmaceutically acceptable salt thereof, oral diseases, deep oral diseases and sustained-release preparations. Drugs for the treatment of systemic diseases that are expected to further increase their therapeutic effects, as well as lubricants, binders, excipients, coloring agents, and flavoring agents to improve appearance or odor as necessary. one or more flavoring agents, thoroughly mixed to form an intimate mixture thereof;
If necessary, it is produced by making slugs and granulating them, or by press-molding appropriate amounts of these using punches, dies, and presses.

In this case, intimate mixing should be understood as a state where each component contained in the preparation is mixed with each other as uniformly as possible, and some components are not localized. be.

Usually, it is convenient to mix fine powders together.

In addition to tablets, the dosage form can be changed as appropriate depending on the condition of the diseased area.

Examples include dosage forms such as granules, powders, and dental cones.

Granules are made by granulating pressure-molded slugs.
Powders are also produced by further pulverizing.

The active ingredients contained in the formulation of the present invention may be pharmaceuticals for treating oral diseases, diseases deep in the oral cavity, dental diseases, systemic diseases whose therapeutic effects are expected to be further increased than conventional ones by sustained release, and veterinary drugs. For example, acetaminophen, phenacetin, aspirin, aminopyrine, sulpirin, phenylbutazone, mefenamic acid,
Analgesic and anti-inflammatory drugs such as flufenamic acid, ibufenac, ibuprofen, indomethacin, erchicine, and probenecid nat; anti-inflammatory enzymes such as alpha-chymotrypsin; anti-inflammatory steroids such as hydrocortisone, prednisone, prednisolone, triamcinolone, dexamethasone, and betamethasone; diphenhydramine hydrochloride , antihistamines such as chlorpheramine maleate; antibiotics and fungicides such as tetracycline hydrochloride, leucomycin, fradiomycin, penicillin and its derivatives, cephalosporin derivatives, and erythromycin; sulfathiazole,
Chemotherapy drugs such as nitrofurazone; local anesthetics such as benzocaine; inotropes such as digitalis and digoxin; vasodilators such as nitroglycerin and papaverine hydrochloride; antitussive expectorants such as codeine phosphate and isoproterenol hydrochloride; chlorhexidine hydrochloride Oral disinfectants such as , hexylresorcin, ethacridine; gastrointestinal drugs such as pepstatin, aprene, phenovaline and vitamin U;
Enzymes such as lysozyme chloride and dextranase; hypoglycemic drugs such as insulin; other hemostatic drugs, sex hormones, antihypertensive drugs, sedatives, and antineoplastic drugs.

In addition, examples of lubricants used as necessary include talc, stearic acid and its salts, waxes, etc., and examples of binders include starch, dextrin, tragacanth, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc. Excipients include starch, crystalline cellulose, texturin, lactose, mannitol, sorbitol, anhydrous calcium phosphate, etc.; flavoring agents include:
Examples include citric acid, fumaric acid, tartaric acid, menthol, and citrus flavor.

As described above, the preparation provided by the present invention has extremely excellent effects, but does not dissolve or flow out in the oral cavity, retains a swollen form for a relatively long period of time, and gradually releases the drug. Furthermore, it does not feel like a foreign body, resists the urge to chew it or try to peel it off with the tongue, does not interfere with everyday life such as talking, eating, and sleeping, and can be removed in an emergency. There is also the advantage that medical care such as this can be performed easily.

Hereinafter, the present invention will be explained in detail using experimental examples and examples.
The present invention is not limited to these in any way.

The experimental example is an experiment to model the characteristic properties of the sustained release preparation of the present invention.

Experimental Example 1 The following experiment revealed that the mixture of hydroxypylcellulose and polyacrylic acid used in the present invention exhibits no solubility and exhibits excellent swelling, shape retention, and adhesion. .

A predetermined amount of fine powder of cellulose and polyacrylic acid was thoroughly mixed in a mixer, and 0.5% of the total weight of magnesium stearate was added, and the resulting intimate mixture had a weight of about 90%. ~, thickness approximately 2mm, diameter 7m
A disk with a Monsanto hardness of about 20 kg was obtained.

This disk was placed on an agar gel at 37°C,
Changes in the diameter and weight of the disk were observed as indicators of swelling properties, and changes in its shape and fluidization were observed as indicators of shape retention.

The results are shown in Table 1. Also, after moistening two rubber plates lined with a steel plate with hooks with a small amount of water, sandwich the disk, apply a load of 100g for 30 seconds to attach the disk to the rubber plate, and then place the disk between the rubber plates. The container was filled with water, one hook was fixed, and a load was applied to the other hook, and the load at which the rubber plate and the disk peeled was measured, and the adhesion force of the disk in a wet state was measured.

The results are shown in Table 2.

In addition, hydroxypills molded in the same manner as above, those using cellulose alone, those using polyacrylic acid alone,
A similar test was also conducted for a product in which the ratio of sodium polyacrylate to lactose was 1:1.

The results are also shown in Table 1.2.

As is clear from the above results, when cellulose and polyacrylic acid were used together, the disk continued to expand even after a long period of time, but it did not become fluid and had good shape retention. It was found that the disk retains a similar shape to the original disk and exhibits excellent adhesion.

On the other hand, it was observed that hydroxypills containing cellulose alone and those containing sodium polyacrylate and lactose in a 1:1 ratio immediately began to partially dissolve on the agar and became fluidized in a short time.

It was observed that polyacrylic acid alone had good shape retention even if the disk continued to expand, but as described below, it disintegrated relatively quickly in the oral cavity, and the attachment site turned white. Occasionally, vesicles were observed to occur.

In addition, it was found that the weight increase rate (water absorption rate) and adhesive force of the product of the present invention increased as the polyacrylic acid content increased.

Experimental Example 2 The following experiment revealed that the drug was gradually released from the product of the present invention.

That is, a predetermined amount of hydroxypyl cell b-z, polyacrylic acid, and 4 mg of pigment (amaranth) per approximately 200 mg tablet are thoroughly mixed in a mixer, and then 1 kg of magnesium stearate is lightly mixed. Discs approximately 1.4 m thick and with a door diameter of 10.0 mm were obtained by pressure molding from the resulting intimate mixture.

This disk was placed on an agar gel at 37°C,
The amount of pigment released into agar over time is measured at a wavelength of 520 mμ.
The dye release rate (
) was measured.

The results are shown in Table 3. In addition, similar tests were conducted on disks using sucrose and lactose corresponding to lozenges molded in the same manner as above, and the results are also shown in Table 3.

As is clear from the above results, it can be seen that the product of the present invention exhibits a sustained release of pigment much slower than tablets using sucrose and lactose, which correspond to lozenges.

Furthermore, in the products of the present invention, it was found that the higher the proportion of hydroxypill cellulose, the faster the dye release rate.

In addition, the above-mentioned product of the present invention was pressed and fixed on a plastic auxiliary board slightly moistened with water, and shaken at 37°C using water as the test solution in accordance with the disintegration test method of the Ninth Edition Japanese Pharmacopoeia.
The amount of the dye released into the water was quantified by measuring the absorbance at a wavelength of 520 mμ, and the release rate (rate) of the dye was measured.

The results are shown in Table 4.

In addition, a tablet formed in the same manner as above and formed by the direct compression method, consisting of 150 parts of crystalline cellulose, 46 parts of carboxymethylcellulose calcium, 4 parts of pigment (amaranth), and 1 part of magnesium stearate, 100 parts of crystalline cellulose, 71 parts of lactose, Tablets consisting of 25 parts of calcium carboxymethylcellulose, 4 parts of pigment (amaranth), and 1 part of magnesium stearate were also fixed on one side to a plastic auxiliary board using a small amount of adhesive, and the same test as above was performed. are also shown in Table 4.

As is clear from the above results, compared to tablets made by direct compression, the product of the present invention released the pigment extremely slowly even in water, and was found to be released in a sustained manner.

In addition, 100 μ each of granules and powders with a 1:1 ratio of cellulose and polyacrylic acid prepared by pressure molding and crushing were placed on an agar gel with a diameter of 17 m.
The sample was placed in a circular shape of m and the dye release rate (correspondence) was measured.

The results are shown in Table 5. As is clear from the above results, it was observed that the release rate of granules and powders was faster than that of disks, and the smaller the particle size, the higher the release rate.

Example 1 Made in the same manner as Experimental Example 1, weight: 90~, thickness: approximately 2n
In order to determine the adhesion to the oral mucosa and disintegration in the oral cavity of the product of the present invention, which has a diameter of 7 mm, disks were attached to various locations in the oral cavity of five subjects and observed.

The results are shown in Table 6. In addition, similar tests were conducted on hydroxypills using only cellulose, polyacrylic acid only, and those with a 1:1 ratio of sodium polyacrylate and lactose. A dissolution test was conducted and the results are shown in Table 6.

As mentioned above, the product of the present invention has extremely excellent adhesion to the oral mucosa and disintegration resistance, and does not interfere with conversation, smoking, eating, sleeping, etc., except in areas that are particularly active, such as the lips. Admitted.

Moreover, no abnormality was observed in the mucous membrane at the site where the disc was attached after the test.

On the other hand, it was observed that hydroxypill cellulose alone had a slightly weak adhesive force and dissolved and flowed out in a short period of time.

In addition, although polyacrylic acid alone has strong adhesion, its strength after swelling is somewhat weak, so it disintegrates from the surface in a relatively short period of time, causing whitening of the mucous membrane at the attachment site and sometimes formation of vesicles. .

In addition, a disk made of sodium polyacrylate and lactose is
It was observed that it swelled into an irregular shape, became several times its size, was sticky, and dispersed in a relatively short period of time.

Furthermore, it was observed that commercially available lozenges dissolve in about 20 minutes during the day.

In addition, the ratio of hydroxypill cellulose containing 15 mp of tetracycline hydrochloride to polyacrylic acid is 1:1.
A disk with a thickness of about 2 mm and a diameter of 7 mm was prepared and subjected to the same test as above, and results similar to those in Table 6 were obtained.

Example 2 Cellulose and polyacrylic acid (Ca
rbopol 934) and about 450 to about 50 isoproterenol hydrochloride per disk are thoroughly mixed in a mixer, and magnesium stearate 2
ml and from the resulting intimate mixture a thickness of 3 mm,
A disk with a diameter of 10 mm was obtained.

This disk was placed on an agar gel at 37° C., and changes in diameter, weight, and drug release properties of the disk were measured.

The results are shown in FIGS. 1, 2 and 3 of the accompanying drawings.

In FIG. 1, the vertical axis represents the diameter increase rate (times), and the horizontal axis represents the time (hours) for leaving the disk on the agar gel.

Curves a, b, c and d are obtained when the ratio of cellulose to polyacrylic acid is O:1, 1:3, respectively.
, 1:1 and 3:1.

In FIG. 2, the vertical axis represents the weight increase rate (times), and the horizontal axis represents the time the disk was allowed to stand on the agar gel.

In FIG. 3, the vertical axis represents the release rate (rate) of isoproteresyl hydrochloride into agar, and the horizontal axis represents the standing time (hours) of the disk on the agar gel.

As is clear from FIGS. 1 and 2, when the ratio of polyacrylic acid is 1:1 or more, the larger the ratio of polyacrylic acid, the larger the diameter and weight of the disk, and the easier it is to swell.

In addition, it was observed that the preparation of the present invention had extremely excellent shape retention and expanded in a similar shape to the original disk.

Furthermore, as is clear from FIG. 3, it was found that the release rate of isoproterenol hydrochloride into agar was sustained and increased as the proportion of hydroxypropyl cellulose increased.

Example 3 Amounts of Hydroxypyl Cellulose and Polyacrylic Acid and Approximately 410 mg of Penzocaine per Disc
0mg and 0mg were sufficiently mixed in a mixer, 2~2~ of magnesium stearate were added, and a disk having a thickness of 2.5mm and a diameter of 10mm was formed by pressure.

This disk was placed on an agar gel at 37° C., and changes in diameter, disk weight, and penzocaine release were observed.

The results are shown in FIGS. 4, 5, and 6 of the accompanying drawings.

In FIGS. 4, 5, and 6, the vertical axes are the disk diameter increase rate (times), the disk weight increase rate (times), and the release rate of penzocaine into the agar gel (factor), respectively.

The horizontal axis represents the time the disk was allowed to stand on the agar gel.

Curves a, b, C and d are the same as above.

As is clear from FIGS. 4 and 5, the diameter and weight increase with time, and the larger the proportion of polyacrylic acid, the more the diameter and weight tend to increase.

Further, the shape of the expanded disk of the preparation of the present invention was similar to that of the original disk, and it was recognized that the shape retention property was extremely excellent.

Furthermore, as is clear from Figure 6, the release of penzocaine into the agar increased linearly over a long period of time, and it was observed that the higher the proportion of hydroxypill cellulose, the faster the release rate of penzocaine. .

Example 4 In place of isoproterenol hydrochloride in Example 2, 2 inches of triamcinolone acetonide was used per about 200 inches of disk weight, and the same procedure as in Example 2 was carried out to obtain a thickness of 1. A disk with a diameter of 4 mm and a diameter of 10.0 mm was obtained.

These disks were pressed against a slightly dampened glass surface and fixed, and then immersed in a solution with a water to ethanol ratio of 1:1 to detect doriamcinolone acetonide, which was released over time, at a wavelength of 239 mμ. The release properties of triamcinolone acetonide were investigated by quantifying the change in absorbance at .

The results are shown in FIG. 7 of the attached drawings.

In FIG. 7, the vertical axis represents the release rate (correspondence) of triamcinolone acetonide, and the horizontal axis represents the immersion time (hours).

Curves e, f, g and h have a ratio of hydroxypropylene cellulose to polyacrylic acid of 9:1, 3:1, and 1, respectively.
:1 and 1:3.

As is clear from FIG. 7, it was observed that triamcinolone acetonide was released linearly over time, and the release rate increased as the proportion of hydroxypill cellulose increased.

Example 5 In place of isoproterenol hydrochloride in Example 2, 1 portion of tetracycline hydrochloride was added per approximately 220 m9 of disc weight.
Using 8 mg, the thickness was 1.4 mm in the same manner as in Example 2.
A disk with a diameter of 10.0 mm was obtained.

These disks were fixed by pressing them against a plastic auxiliary plate slightly dampened with water, and shaken at 37°C using water as the test solution in accordance with the disintegration test method of the Japanese Pharmacopoeia. The absorbance at a wavelength of 355 mμ was measured to examine the release properties.

The results are shown in FIG. 8 of the attached drawings.

The results of Company A's lozenges tested in the same manner as above are also shown in FIG.

In FIG. 8, the vertical axis represents the release rate (correspondence) of tetracycline hydrochloride, and the horizontal axis represents the shaking time (hours).

Straight lines 1tJyk and 1 represent the ratios of hydroxypill cellulose and polyacrylic acid of 9:1, 3:1, 1:1 and 1:3, and straight line m represents Company A's lozenge.

As is clear from FIG. 8, the product of the present invention has a sustained release property, and it was observed that the release rate varied depending on the ratio of cellulose hydroxypropyl and polyacrylic acid.

However, i and j exhibit almost the same release rate.

[Brief explanation of drawings]

Figures 1, 2, and 3 of the accompanying drawings show the economic disc diameter change, disc weight change, and release rate of isoproterenol hydrochloride when a preparation containing isoproterenol hydrochloride is placed on agar gel, respectively. It represents. FIGS. 4, 5, and 6 show changes in disk diameter, changes in disk weight, and benzocaine release rate over time, respectively, when a preparation containing penzocaine was left on an agar gel. FIG. 7 shows the release rate of triamcinolone acetonide over time when a formulation containing triamcinolone acetonide was immersed in a water-ethanol solution. FIG. 8 shows the release rate of tetracycline hydrochloride over time when a formulation containing tetracycline hydrochloride is shaken in water using a disintegration tester, and the release rate of tetracycline hydrochloride from a commercially available lozenge.

Claims (1)

[Scope of Claims] 1. A sustained release preparation for use by being deposited in the oral cavity, which is comprised of an intimate mixture of hydroxypill cellulose, polyacrylic acid or a pharmaceutically acceptable salt thereof, and a drug. 2 0.1 to 1 part of polyacrylic acid or a pharmaceutically acceptable salt thereof to 1 part by weight of cellulose
The sustained-release preparation for use by being attached to the oral cavity according to claim 1, which contains 0 parts by weight. 3. Adhesive to the oral cavity according to claim 1 or 2, wherein the hydroxypill cellulose is a dihydric aqueous solution at 20° C. and exhibits a viscosity of 3 to io, ooo centipoise. sustained-release preparations for use. 4 When polyacrylic acid is measured at 25.0 ± 0.5°C with an aqueous solution of its sodium salt having a concentration of 0.2% as polyacrylic acid and a pH of 7 to 7.5, 360 The sustained-release preparation for use by being attached to the oral cavity according to any one of claims 1, 2, or 3, which exhibits a viscosity of 165,000 centipoise.