JPS6347687B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to sustained release preparations, and more specifically,
A sustained-release preparation for oral mucosa that easily adheres to the oral mucosa for a long time, has a constant elution of drug into saliva per unit time, and lasts for a long time, allowing efficient treatment. Regarding. (Relationship with Prior Art) In the past, pharmaceutical studies to improve the durability of the therapeutic effects of drugs have mainly been conducted on internally administered drugs. However, in these preparations,
Sustained-release preparations using other sites have disadvantages such as difficulty in retaining the drug in the absorption site for a long time, being easily metabolized by the liver, and being easily degraded by gastric acid. The need for this has been pointed out. On the other hand, for the purpose of oral administration, oral preparations, troches, sublingual tablets, oral ointments, and the like are known. However, conventional buccal tablets, lozenges, and sublingual tablets have a strong foreign body sensation, and patients who use them tend to have an urge to chew or swallow them, making it difficult to keep them in the mouth for a long time. Ta. In addition, oral ointments do not require chewing or swallowing, but have the disadvantage that it is difficult to adjust the dosage. In an attempt to improve the above-mentioned drawbacks of oral dosage forms, for example,
No. 54-38168, Japanese Patent Publication No. 58-7605, etc., propose new dosage forms that adhere to the oral mucosa. Japanese Patent Publication No. 54-38168 describes a formulation in which a therapeutic drug is contained in a mixture of sodium polyacrylate and an excipient, but this formulation has insufficient adhesion and easily peels off, and lacks sustained release performance. Due to its inferiority, it is not suitable for continuous treatment. On the other hand, the special public service in 1978-
Publication No. 7605 discloses a dosage form for oral mucosa that combines hydroxypropylcellulose and polyacrylic acid or a pharmaceutically acceptable salt thereof,
Although this method is improved compared to the above-mentioned method, it cannot be said to be sufficient particularly in terms of adhesion. (Objective of the Invention) In view of the above-mentioned drawbacks of conventional dosage forms, the object of the present invention is to provide a drug that easily adheres to the oral mucosa, does not peel off during normal activities such as eating, drinking, and talking, and does not cause a foreign body sensation. The object of the present invention is to provide a new type of sustained-release preparation for application to the oral mucosa, in which the elution of the drug into saliva continues for a long period of time. (Description of Structure of the Invention) As a result of intensive efforts to obtain the above-mentioned target formulation, the present inventors discovered a layer () that moderately retards the elution of the drug and a layer () that highly retards the elution of the drug, which consists of specific components. It has been found that this objective can be achieved with a formulation consisting of two layers. That is, the present invention is based on the layer ()
and a layer (), wherein the layer () is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salts, and alternating copolymers of maleic anhydride and methyl vinyl ether. One or more polymer components and a drug are essential components, and if necessary, one or more selected from the group consisting of excipients, lubricants, binders, and flavoring agents may be added. and the polymer component accounts for 20% by weight or more based on the total composition of the layer (), and the layer () contains polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salts, maleic anhydride and methyl One or more polymer components (A) selected from the group consisting of alternating copolymers of vinyl ethers and one or two selected from the group consisting of polyacrylic acid and pharmaceutically acceptable salts thereof. The above polymer component (B) and drug are essential components, and one or more selected from the group consisting of excipients, lubricants, binders, and flavoring agents may be added as necessary. , the weight ratio of polymer component (A) and polymer component (B) is 5:95 to 95:
This is a sustained-release formulation for oral mucosa application, characterized by the following: The layer () contains one or more polymer components selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salts, alternating copolymers of maleic anhydride and methyl vinyl ether, and a drug. is an essential component, and the effect of moderately delaying the release of the drug is brought about by the polymer component. In this layer, in addition to the above-mentioned polymer components and drugs, one or two selected from the group consisting of excipients, lubricants, binders, and flavoring agents may be contained as needed.
However, in order to appropriately retard the elution of the drug, it is necessary that the above-mentioned polymer component accounts for 20% by weight or more of the total composition in the () layer. This is because the above polymer component is 20
If it is less than % by weight, the drug elutes too quickly and even if it is combined with a layer that highly retards drug elution, elution at a constant rate over a long period of time cannot be achieved. On the other hand, the layer (2) contains one or more polymer components (A) selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, and its pharmaceutically acceptable salts, and polyacrylic acid and its pharmaceutically acceptable salts. The essential constituents are one or more polymer components (B) selected from the group consisting of salts acceptable to The effect of highly delayed drug release is brought about by the combination of the polymer component (A) and polymer component (B). Polymer component (A) alone does not have a sufficient release retardation effect, and component (B) alone exhibits a sufficient release retardation effect, but the swelling property is too strong, resulting in a strong foreign body sensation. From this point of view, it is necessary that the weight ratio of polymer component (A) and polymer component (B) be 5:95 to 95:5. In addition, one or more selected from the group consisting of excipients, lubricants, binders, and flavoring agents may be added to the layer () if necessary, but the effect may be sufficiently enhanced. In order to demonstrate
Additives other than (A), (B), and (C) are 20% of the total composition in the () layer.
It is preferably less than % by weight. Furthermore, the layer () has strong adhesion to the oral mucosa due to the presence of both the adhesive polymer components (A) and (B). The polymer components used in the above () and () layers, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salts,
Alternating copolymers of maleic anhydride and methyl vinyl ether can be used as long as they do not affect their physicochemical properties.
This also includes two or more copolymers with one or more other monomers. In order not to affect the physicochemical properties, the copolymerization ratio of other monomers should be 30 mol%.
The following is desirable. The pharmaceutically acceptable salts herein include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, ammonium salts, and the like. In the case of other polymer components used in the () layer, polyacrylic acid and its pharmaceutically acceptable salts, these include homopolymers and copolymers of two or more elements with one or more other monomers, respectively. Since it does not affect the physicochemical properties of the homopolymer, other monomers are included in the copolymer.
It is preferable that the amount of copolymerization is 30 mol% or less. As suitable examples, commercially available products such as Carbopol 934, Carbopol 940, Carbopol 941, etc. can be used. The oral mucosal sustained-release preparation provided by the present invention can be prepared from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salts, and alternating copolymers of maleic anhydride and methyl vinyl ether. One or more selected polymeric components and a therapeutically effective drug, and if necessary, one type of lubricant, binder, excipient, or flavoring agent to improve appearance or odor. Or mix two or more of them thoroughly to form a homogeneous mixture, punch appropriate amounts of these,
After molding the () layer by direct pressure molding using a die and press or by pressure molding through an appropriate granulation process, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and pharmaceutically acceptable thereof are formed. one or more polymer components selected from the group consisting of a salt, an alternating copolymer of maleic anhydride and methyl vinyl ether;
(A), one or more polymer components selected from the group consisting of polyacrylic acid and pharmaceutically acceptable salts thereof (B), a drug (C), and, if necessary, a lubricant. , a binder, an excipient, and a flavoring agent, or a mixture of two or more of them can be placed on the () layer and further applied. Another method for producing the sustained-release formulation for oral mucosa provided by the present invention is to separately dissolve the components constituting each of the layers () and () in an appropriate solvent, and then
Two-layer tablets are formed by casting, drying, forming into a thin film, and bonding with a suitable adhesive, moistening with water or other solvent and pressing, or pressing using heat. can be obtained. The drug contained in the preparation of the present invention may be any drug for treating oral diseases, dental diseases, or systemic diseases, such as analgesic anti-inflammatory agents such as indomethacin and ibuprofen, and oral disinfectants such as chlorhexidine hydrochloride and hexylresorcinol. , enzymes such as lysozyme chloride, dextranase, kallikrein, anti-anginal drugs such as nitroglycerin, isosorbide dinitrate, nifedipine, anti-asthmatic drugs such as sodium cromoglycate, antibiotics such as penicillin, erythromycin, sulfathiazole, nitrofurazone. Chemotherapy agents such as, local anesthetics such as benzocaine, inotropes such as digitalis, digoxin, antitussive expectorants such as codeine phosphate, isoproterenol hydrochloride, gastrointestinal drugs such as azulene, vitamin U, diphenhydra hydrochloride In addition to antihistamines such as minol, chlorpheniramine maleate, anti-inflammatory steroids such as prednisolone and triamcinolone, hemostatic agents, sex hormones, sedatives, and anti-malignant tumor drugs. Examples of lubricants that may be used as necessary include talc, stearic acid and its salts, and waxes, and examples of binders include starch, dextrin, tragacanth, gelatin,
Excipients include starch, crystalline cellulose, dextrin, lactose, mannitol, sorbitol, anhydrous calcium phosphate, etc., and flavoring agents include citric acid, fumaric acid, tartaric acid, menthol, citrus. Examples include fragrances and the like. Application of the preparation of the present invention to patients is not particularly limited, and the () layer side may be applied to the gums, inner cheek, or mucous membrane of the oral cavity for local treatment. It is done as follows. The () layer side of the preparation of the present invention also has adhesive properties to mucous membranes due to the presence of the adhesive polymer, but when this is applied, for example, to the outside of the gums with the () layer side adhered,
() The layer side may adhere to the buccal mucosa, but this does not pose any problem. (Effects of the Invention) As described above, the present invention has two layers: a layer that moderately retards drug release () and a layer that highly retards drug release ().
A sustained-release preparation for oral mucosa application consisting of layers, which releases the drug at a constant rate over a long period of time, easily adheres to the oral mucosa, and does not easily peel off during normal activities such as eating, drinking, and talking. This is a new type of sustained-release preparation that does not give any foreign body sensation. The most important feature of the formulation of the present invention is that the elution rate of the drug into saliva is sustained over a long period of time, and it is expected that the therapeutic efficiency of the drug can be greatly improved. The second feature of the formulation of the present invention is that it easily adheres to the oral mucosa, and its adhesive properties last for 4 to 24 hours.
It is about sustaining. Moreover, this adhesiveness is due to drinking,
It is not affected by daily oral movements such as smoking, drinking coffee, eating, and talking. The third feature of the formulation of the present invention is that the molded article swells with saliva in the mouth and becomes extremely soft, so there is almost no foreign body sensation. The fourth feature of the formulation of the present invention is that since the dosage is determined in advance at the time of molding, there is no variation among individuals unlike in ointments. The fifth feature of the formulation of the present invention is that adhesion and persistence can be adjusted at will by changing the composition of the layer that moderately retards the elution of the drug () and the layer that retards the elution of the drug highly. Moreover, by adjusting the ratio of the amounts of the () layer and () layer, the optimum sustained release performance depending on the drug can be arbitrarily obtained. The excellent sustained release properties of the preparation of the present invention allow it to be absorbed through the oral mucosa, and when applied to drugs used for systemic therapy, it exhibits an excellent function of maintaining blood drug concentration at a constant level for a long period of time. Excellent characteristics can only be imparted by a formulation consisting of two layers () and () of a specific composition, and cannot be achieved with a formulation consisting of a single layer. (Examples) Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto. In the examples, parts or % simply indicate parts by weight or % by weight. Test method 1 Adhesion test to mucous membrane using mouse peritoneum This will be explained using FIGS. 14 and 15. First, track field type tablets 6 made of various compositions prepared in the same manner as shown in Example 1 below.
A stainless steel hook 7 was fixed to the plate using adhesive. Next, the back side of the mouse peritoneum 5 was fixed on a 9 cm ² square acrylic plate 2 using adhesive, placed on the support plate 1 with hooks, the packing 3 and the fixing plate 4 were stacked, and the four corners were fixed with screws 8. The surface of the peritoneum 5 was moistened with a small amount of water, the previously prepared tablet with a hook was placed thereon, and a load of 1700 g was applied for 1 minute to adhere the tablet to the peritoneum 5 of the mouse. Next, after fixing the tablet side hook 7 to the upper chuck of the thread tension tester and the support plate 1 side hook to the lower chuck, fill the mouse peritoneum with water and pull the support plate side hook to apply a load that causes the peritoneum and the tablet to separate. The thread tension tester tensilon
The adhesive strength of the tablets in the wet state was measured by UTM/. Test method 2 Adhesion to oral mucosa and foreign body sensation test by subjects Similar tablets of various compositions (however, in this test, 5 parts of indomethacin sodium was excluded) were prepared according to the method of Example 1 described below. In order to observe the adhesion to human oral mucosa and the degree of foreign body sensation, tablets were attached to the outer gums of the upper molars of 24 subjects and observed. Observations were made by evaluating adhesion in terms of time until peeling, and by evaluating the degree of foreign body sensation using a questionnaire after the test was completed.
In addition, in order to examine the effects of drinking coffee and eating, the subjects were made to behave according to the following time schedule.

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Claims (1)

[Claims] 1 Consisting of at least two layers, layer () and layer (), where the layer () is made of polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salt, and an alternating copolymer of maleic anhydride and methyl vinyl ether. The essential constituents include one or more polymer components selected from the group and a drug, and optionally one or two selected from the group consisting of excipients, lubricants, binders, and flavoring agents. and the polymer component accounts for 20% by weight or more based on the total composition of the layer (), and the layer () contains polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salts, anhydrous One or more polymer components (A) selected from the group consisting of alternating copolymers of maleic acid and methyl vinyl ether, and one selected from the group consisting of polyacrylic acid and pharmaceutically acceptable salts thereof. The essential components are a species or two or more polymer components (B) and a drug, and if necessary, excipients,
One or more selected from the group consisting of a lubricant, a binder, and a flavoring agent are added, and the weight ratio of the polymer component (A) and the polymer component (B) is 5:95 to 95.
A sustained-release formulation for oral mucosa application, characterized by a ratio of 95:5.