JPH0438726B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to an oral drug, particularly a sustained-release oral drug, which is used by being attached to the oral mucosa (cheeks and gums in the mouth). The oral drug of the present invention is produced by attaching a drug (for example, a cardiotonic drug, a blood pressure lowering drug, a sex hormone, etc.) to the oral mucosa and releasing the drug uniformly and continuously over a long period of time. Drugs can be absorbed through mucous membranes or the gastrointestinal tract. PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION Certain drugs are known for use in application to the oral mucosa. For example, there are several types of oral preparations that allow drugs to be absorbed through the oral mucosa and exert their systemic effects. One example is sublingual tablets. This is used for drugs that are expected to have an immediate effect, such as nitroglycerin, but since the tablet cannot be kept under the tongue for a long time, for example, PWArmstrong has reported [Circulation 59 , 585 (1979)], it is not an agent that can provide long-lasting effects. In addition, there are drugs commonly known as buccal preparations (for example, tablets held between the cheek and gums) that act on drugs in the oral cavity for a relatively long period of time. By adjusting the disintegration time of the tablet, this buccal agent can be expected to have a sustained effect that cannot be obtained with sublingual tablets. However, for example, reports such as JGHardy (JGHardy)
J.Pharm Pharmacol 34 , 91 (1982)
However, there are problems with the disintegration time of tablets, such as the method of administration and the fact that the disintegration time of the tablets is not constant among the individuals to whom it is administered. This is because the disintegration time of the tablet can easily vary depending on the secretion of Daeki, and when activities such as talking or eating are involved, the tablet cannot be stably held at the administration site. Additionally, a lateral tablet has been proposed in which the tablet is administered into the upper anterior gums. T.Futaki
Examples include the administration agent reported by et al. (Otolaryngology Clinic 72 , 1059 (1983)) and the administration agent in which the disintegration time of the tablet is controlled as described in Japanese Patent Application Laid-open No. 58-21007. These tablets are administered by focusing on the fact that the upper anterior gums, which are the administration site, secrete far less Daeki than the back gums and move less when talking or eating. To,
The disintegration time of the tablet is more stable than that of the above-mentioned tablets, and the retention of the tablet at the administration site is not significantly impaired by activities such as talking or eating. However, even with these administration agents, if the tablet is kept in the oral cavity for a longer period of time, the tablet disintegrates and drips from the administration site, which interferes with conversation and eating. In addition, as a backlash agent, for example, JP-A-Sho
As described in Japanese Patent No. 58-213709, there are adhesive patches that adhere to the gums. However, with any one of the formulations listed here, it is not possible to quantitatively release the drug into the oral cavity over a particularly long period of time and maintain constant drug absorption over a long period of time. Means for Solving the Problems The present inventors obtain an oral drug that is excellent in keeping the drug attached to the oral cavity for a long period of time, and is capable of maintaining quantitative drug release over a long period of time. As a result of extensive research, we have found that drugs can be sandwiched between a film containing a sticky polymer material that can adhere to the inner surface of the oral cavity for a long time, and a film made of a polymer material that is not easily broken down by water. The present inventors have discovered that a preparation in which one or more holes are made in at least one side of the film can satisfy the above object, and have completed the present invention. That is, the present invention provides (1) an intraoral drug comprising a film that does not break down with water, a film that adheres to the inner surface of the oral cavity, and a drug, and having one or more holes in at least one of the films; and ( 2) A film that does not break down with water, a film that adheres to the inner surface of the oral cavity, and a drug, with one or more holes in at least one side of the film, and the exposed part of the drug is covered with a water-disintegrable substance. Concerning oral drugs. Since the oral drug of the present invention releases the drug at a constant release rate over a long period of time, there is no need for frequent administration of the drug. Furthermore, when the drug of the present invention is adhesively administered to the inner surface of the oral cavity (for example, the outer surface of the anterior gums), even if the drug is left for a long time, the drug does not spread to the lips or drip down.
Excellent compatibility during administration. Furthermore, the rate at which water is absorbed through the film with pores, the drug gradually disintegrates, and the drug is released into the oral cavity through the pores depends on factors such as mouth movements during conversation and eating, and the amount of Daeki secreted. As a result, a stable, unaffected and consistent release rate is achieved. In addition to controlling the drug release rate by additives mixed with the drug (e.g., excipients such as microcrystalline cellulose and hydroxypropyl cellulose), the release rate is also controlled by the size and number of pores in the film. It has the excellent feature of being able to be adjusted as desired. A specific example of the oral drug of the present invention is shown in Fig. 1 (the drug consists of a thin circular tablet, and the water-indestructible film that protects the tablet is in contact with the tablet surface at the outer diameter of the tablet). Oral medicine with one pore smaller than Figure 3 (The drug consists of a thin circular tablet, and the water-indestructible film that protects the tablet has a hole that is smaller than the outside diameter of the tablet at the contact area with the tablet surface. (oral drugs) with multiple small pores.
Among these, the intraoral drug shown in FIG. 1 is particularly preferred. The drug of the present invention can be used, for example, as a tablet prepared by a conventional method by containing the drug in a commonly used excipient, a wax molded body, or a drug support band on which the drug is adsorbed. Furthermore, it can be used as a pharmaceutical composition consisting of two layers, a non-adhesive and disintegrating layer and an adhesive layer, and at least one of which contains a drug. The shape of the drug may be circular, oval, square, oblong (rectangular), etc., and the thickness of the drug is preferably thin. For example, in the case of a circle, the diameter is 2
mm to 15 mm, if oval, the major axis is 5 mm to 15 mm
In the case of a square, the length is about 2 mm to 20 mm, and in the case of an oblong, the short axis is 2 mm to 5 mm.
Preferably, the diameter is about 4 mm to 20 mm, and the major axis is about 4 mm to 20 mm. The weight of the drug is usually about 5mg to 300mg
Those within the range of are used. The oral drug of the present invention is a preparation for adhesive administration to the inner surface of the oral cavity, and in order to eliminate the feeling of a foreign body at the administration site, it is preferable to set the weight of the drug so that the thickness and external shape of the drug are as small as possible. . Examples of the water-resistant film used in the present invention include films made of polymeric substances such as polyethylene, vinyl chloride, polyester, nylon, polypropylene, vinylon, cellophane, ethylene monovinyl acetate copolymer, and other flexible films. plastic film and shellac, ethyl cellulose, propyl cellulose, Eudragit R, cellulose acetate phthalate, hydroxypropyl cellulose phthalate, polyvinyl alcohol phthalate,
Examples include common enteric films such as styrene maleic anhydride copolymer. The shape of the film is the same as or larger than the drug, for example, if it is circular, the diameter is 20 mm or less, and if it is oblong, the short axis is 15 mm or less and the long axis is 25 mm or less. used. The thickness of the film used is in the range of 0.005 to 0.50 mm. Preferably, a thin one (in the range of 0.005 to 0.01 mm) is used. The adhesive film used in the present invention must have the function of supporting the shape of the film and the function of adhering to the inner surface of the oral cavity for a long period of time. A suitable film is one in which the surface of the above-mentioned water-indestructible film is coated with an adhesive polymer substance that allows the drug to adhere to the inner surface of the oral cavity for a long period of time. Suitable adhesive polymeric substances include natural rubber, polyacrylic acid and adhesives based on esters thereof, which are harmless to humans and mammals even if ingested. The shape of the film must be the same as or larger than the size of the drug to be preserved; if it is circular, the diameter is 20 mm or less; if it is oblong, the short axis is 15 mm or less and the long axis is 25 mm or less. used in Film thickness is 0.005
Used in the range of ~0.50mm. Preferably, a thin one (0.005 to 0.010 mm) is used. A hole is made in one or both of the film that retains the drug, that is, the film that does not break down with water, or the adhesive film, and the drug is brought into contact with the fluid, and the drug is released little by little into the oral cavity. The number of holes in the film may be one or more than two. When the number of pores in the film is one, the diameter of the pore is smaller than the diameter or length if the drug is circular or square, and smaller than the major axis and the length of the pore if the drug is oval or oblong. The area used is 10% or more of the area of the top surface of the tablet.
Furthermore, it is preferable that the center of the hole coincides with the center of the tablet. When the number of holes is plural, the diameter of the holes is smaller than the outer diameter of the tablet;
The number of holes is arbitrary. Further, it is preferable that the pores are uniformly distributed in the area where the film and the tablet surface contact each other. The pores of the film may be covered with a water-disintegrating substance (eg, gelatin, lactose, fructose, starch, hydroxypropyl cellulose, etc.). The oral drug of the present invention is produced by a method known per se. For example, the drug may be held in a film that does not break down with water and a film that is adhesive to the inner surface of the oral cavity, and holes are made in at least one of the films, or a drug may be held in a film that does not break down with water and a film that is adhesive to the inner surface of the oral cavity. It is manufactured by making holes and then holding the drug in the film. The pores (exposed portions of the drug) of the resulting oral drug may be further covered with a water-disintegrating substance, or a porous film previously covered with a water-disintegrating substance may be used. In the composition of the drug according to the present invention, when the drug consists of a tablet or a wax molded body, excipients used in the composition of ordinary tablets or suppositories are used. In addition, additives that mask the bitter taste of drugs in the oral cavity or additives that provide a refreshing sensation can also be used. The excipients include lactose, fructose, microcrystalline cellulose, starch, gelatin, polyvinylpyrrolidone, polyacrylic acid resin, hydroxypropyl cellulose,
Hydroxypropyl methylcellulose, carbo wax, fatty acids, fatty acid esters, vegetable oils, or mixtures of two or more thereof are used. Further, the manufacturing method thereof follows a known tablet manufacturing method or suppository manufacturing method. on the other hand,
Apart from this, if the drug consists of a drug support to which the drug is adsorbed, the support may be a polymer film or fibrous material as long as it easily adsorbs the drug. Good too. Examples of the drug used in the present invention include pharmaceuticals for treating oral diseases or systemic diseases. More specifically, examples include the following: Local anesthetics such as lidocaine, procaine hydrochloride, tetracaine hydrochloride, benzocaine, and zipcaine hydrochloride; nitroglycerin, mononitroisosorbit, dinitroisosorbit, molsidomine,
Cardiac drugs such as papaverine hydrochloride, dipyridamole, prenylamine lactate, and nifedipine; antiarrhythmic drugs such as alprenolol hydrochloride and pindolol; N
-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-N-(indan-2-yl)glycine hydrochloride, reserpine,
Antihypertensive drugs such as clonidine hydrochloride, trichlormethiazide, dihydroergocristine methanesulfonate, and captopril; bronchodilators such as isopreterenol hydrochloride and salbutamol sulfate;
Analgesic and anti-inflammatory drugs such as acetaminophen, phenacetin, aspirin, aminopyrine, sulpirin, phenylbutazone, mefenamic acid, flufenamic acid, ibufenac, ipprofen, indomethacin, colchicine, probenecid; alpha-chymotoprednisone, prednisolone, triamcinolone acetonide, dexatazone, pentamethasone Anti-inflammatory steroids such as; testosterone,
Sex hormones such as methyltestosterone, progesterone, oxendrone, chlormadinone acetate, norethindrone, and ethinyl estradiol; antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate; tetracycline hydrochloride, leucomycin, fradiomycin, penicillin and their Antibiotic bactericidal agents such as derivatives, cephalosporin derivatives, and erythromycin; Chemotherapy agents such as sulfathiazole and nitrofurazone; Antitussive expectorants such as codeine phosphate; Oral disinfectants such as chlorhexidine hydrochloride, hexylresorcinol, dequalinium chloride, ethacridine, and azulene. Drugs: Gastrointestinal drugs such as pepstatin, phenovaline, and butamine U; enzymes such as lysozyme chloride, dextranase, and serratioprotease; other hemostatic agents, hypoglycemic agents, and sedatives. Among these drugs, there are drugs whose blood concentration must be maintained for a long period of time to produce their pharmacological effects, or drugs whose effects are difficult to obtain when administered orally (i.e., drugs that are not absorbed from the gastrointestinal tract when administered orally). , drugs that pass through the liver after entering the blood, but are decomposed in the liver, etc.) are more preferably blended. For example, these drugs include drugs such as coronary vasodilators such as nitroglycerin and dinitroisosorbit; and sex hormones such as testosterone, methyltestosterone, progesterone, oxendrone, norethindrone, and ethinyl estradiol. Although the proportion of these drugs in the composition cannot be determined unconditionally because the required amount varies depending on the type of drug, it is generally preferable that the proportion of these drugs be 80% or less in the tablet. When administering the oral drug of the present invention intraorally,
The bioavailability of the drug is several to several tens of times higher than when administered orally, so the daily dose per adult can be a fraction of that of oral administration, and the number of administrations is once to a few times a day. About 2 times is enough. For example, for the treatment and prevention of hypertension, N-[N-(1-(S)
-ethoxycarbonyl-3-phenylpropyl)
-L-alanyl]-N-(indan-2-yl)glycine hydrochloride or dinitrosorbite as a pharmacologically active ingredient per adult per day at 1 to 2 doses of 5 to 100 mg.
Administer in divided doses. In the present invention, the rate of drug release into the oral cavity is determined by the size of the pores in the film for the drug to absorb water, disintegrate, and release the drug, that is, the area of the pores and the rate at which the drug absorbs water. Determined by the nature of the collapse. Generally, when a drug is in the form of a tablet, the disintegration time of the drug will be faster if more lactose is used in the tablet composition, and slower if more water-soluble polymers such as hydroxypropyl cellulose are used in the tablet composition.
By varying the formulation of such compositions, the rate of drug release can be controlled. As detailed above, the long-acting oral preparation of the present invention is an excellent preparation that can be suitably used in the oral cavity and provides a long-lasting drug effect. EXAMPLES The present invention will be explained in further detail by way of Examples below.
Note that percentages used in examples, etc. are weight percentages unless otherwise specified.
shows. Example 1 4 g of dinitroisosorbit lactose powder (quadruple powder), 6 g of lactose, 10 g of hydroxypropyl cellulose (HPC-L) and a trace amount of magnesium stearate were mixed, and the mixture was 100 mg.
was compressed using a mortar with a diameter of 8 mm and a punch with one side flat and the other rounded to obtain tablets. This is a circular polyethylene film (0.02 mm thick) with a diameter of 15 mm, which has a circular hole with a diameter of 6.5 mm in the center, and an ethylene-vinyl acetate copolymer (acetic acid content of 14 mm).
%) with a diameter of 15 mm (thickness 0.04
mm) and a polyacrylic acid adhesive was applied to the surface of the vinyl acetate copolymer film to obtain a sustained-release (sustained-release) oral drug of dinitroisosorbitol. Example 2 4 g of dinitroisosorbit lactose powder (quadruple powder), 1 g of hydroxypropyl cellulose (HPC-L) and a trace amount of magnesium stearate were mixed, and 25 mg of the mixture was placed in a mortar with a diameter of 5 mm and one side of which was flat. The other one is compressed with a Sumimaru pestle,
Got the tablets. This is a circular polyethylene film (thickness 0.02mm) with a diameter of 10mm, with the diameter
Covered with a film with 3.5 mm circular holes and a 10 mm diameter circular film (thickness 0.04 mm) made of ethylene vinyl acetate copolymer (acetic acid content 14%).
By applying a polyacrylic acid adhesive to the surface of an ethylene-vinyl acetate copolymer film, a long-acting oral drug of dinitroisosorbit was obtained. Example 3 4 g of nitroglycerin lactose powder (10x powder)
and hydroxypropyl cellulose (HPC-L)
4 g and a small amount of magnesium stearate were mixed, 100 mg of the mixture was made into tablets by the method shown in Example 1, and the resulting tablets were further covered with a film to obtain a long-acting oral drug of nitroglycerin. Example 4 The diameter of the nitroglycerin tablet obtained in Example 3 was
15mm circular cellophane film (thickness 0.02mm)
A film with a plurality of circular holes with a diameter of 1 mm and a grid pattern of 1 mm x 1 mm, and a circular film made of ethyl cellulose (thickness
A long-lasting intraoral drug containing nitroglycerin was obtained by sandwiching and covering the sample between films coated with a polyacrylic acid adhesive (0.04 mm). Example 5 N-[N-(1-(S)-ethoxycarbonyl-3
-Phenylpropyl)-L-alanyl]-N-(indan-2-yl)glycine hydrochloride (5 g) and α-cyclodextrin (12 g), further mixed with 2 g of hydroxypropyl cellulose (HPC-L) and a trace amount of magnesium stearate, the mixture
A tablet of 100 mg was produced by the method shown in Example 1, and a film (thickness 0.02 mm) made of cellulose acetate phthalate was used instead of the polyethylene film shown in Example 1, and the other methods were the same as in Example 1. A film was coated in exactly the same manner and N-[N-(1-(S)-ethoxycarbonyl-
3-phenylpropyl)-L-alanyl]-N-
A long-acting oral drug of (indan-2-yl)glycine hydrochloride was obtained. Example 6 N-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L- obtained in Example 5
100 mg of a mixture of alanyl]-N-(indan-2-yl)glycine hydrochloride was made into tablets by the method shown in Example 4, and the resulting tablets were covered with a film to form N-[N-(1-( S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-N
- A long-acting oral drug of (indan-2-yl)glycine hydrochloride was obtained. Example 7 Molsidomine 1g, Carbowax (PEG-
6000), 6 g of stearic acid, 7 g of lactose, and a trace amount of magnesium stearate were mixed, and 100 mg of the mixture was made into tablets by the method shown in Example 1.
The obtained tablets were covered with a film according to the method shown in Example 5 to obtain a long-acting oral drug of molsidomine. Example 8 A small amount of magnesium stearate was mixed into the granules obtained by wet granulating 5 g of oxendrone, 5 g of lactose, and 3 g of hydroxypropyl cellulose (HPC-L), and then dried, and 130 mg of the mixture was mixed with a granule with a short diameter of 6.
Tablets were obtained by compression using an oblong-shaped mortar with a diameter of 12 mm and a punch with one side flat and the other violet round. This is made of oblong-shaped ethyl cellulose film (thickness 0.02 mm) with a short axis of 15 mm and a long axis of 20 mm.
It is covered with a film (thickness 0.04 mm) consisting of a film with an oblong-shaped hole with a minor axis of 4 mm and a major axis of 10 mm in the center and an oblong-shaped ethyl cellulose with a minor axis of 15 mm and a major axis of 20 mm, and polyacrylic acid adhesive is attached to the ethyl cellulose. By applying the agent, a long-acting oral drug of oxendrone was obtained. Example 9 A melt of Witepsol W-35 containing 5% dinitroisosorbit was placed in a molding machine and cooled.
A circular molded body with a weight of 100 mg and a diameter of 8 mm was obtained. Furthermore, by coating the film with a film according to the method shown in Example 4, a long-acting oral drug of dinitroisosorbit was obtained. Example 10 A circular drug weighing 50 mg and having a diameter of 8 mm was obtained from an ethylcellulose film containing 10% nitroglycerin. Furthermore, by coating it with a film in the manner shown in Example 4, a long-acting oral drug of dinitroisosorbit was obtained. Example 11 The exposed portion of the dinitroisosorbit oral drug obtained in Example 10 was covered with hydroxypropyl cellulose (HPC-L) to obtain a dinitroisosorbit long-acting oral drug. Effects of the present invention Experimental examples are shown below to explain the effects of the present invention in detail. Experimental Example 1 As a comparative control, both the tablets coated with polyacrylic acid adhesive used in Examples 1 and 8 and the drug of the present invention obtained in Examples 1 and 8 were tested on humans. Administer into the gums,
The disintegration time of both formulations in the oral cavity and the presence or absence of deformation, spreading, and sagging of the drug at the administration site during disintegration were investigated. The results are shown in Table 1.

【table】

[Table] As is clear from Table 1, the drug of the present invention can remain at the administration site for about 10 hours. Furthermore, there is no spreading or sagging of the drug during disintegration, and it can be said that the formulation has significantly improved compatibility during administration. Experimental Example 2 The long-acting oral preparation of dinitroisosorbit obtained in Examples 1 and 2 was administered to the upper gums of beagle dogs, and the concentration of dinitroisosorbit in blood was measured by gas chromatography (column; 3%
SP-2401, chromosorb W
(AWDMCS) 100-120 mesh, column temperature;
Measurement was performed at 140°C, detector: ECD detector, _N2 gas flow rate: 60ml/min. As a control, a commercially available oral tablet of dinitroisosorbit (20 mg tablet) was orally administered (Figure 5). As a result, any of the long-acting oral drugs of the present invention has a high blood concentration of dinitroisosorbitol.
Lasted over 10 hours. Furthermore, the bioavailability ^* was 20 times higher than that of the orally administered drug. This means that
The long-acting oral formulation of dinitroisosorbit of the present invention has been shown to be able to sustain dinitroisosorbit in the blood for a longer period of time at a lower dose than an orally administered formulation. ^* Bioavailability (%) = Curve area under the blood concentration of drug after intraoral (or oral) administration (0 to 10 hours) / Area under the curve of blood concentration of drug after intravenous administration (0 to 10 hours) ×100 (The same applies to the following experimental examples) Experimental Example 3 The long-acting oral nitroglycerin drug obtained in Example 3 was administered to the upper gums of a beagle dog,
The concentration of nitroglycerin in the blood was measured by gas chromatography (under the same conditions as Experimental Example 2). As a control, 40 commercially available oral nitroglycerin tablets (0.5 mg tablets) were orally administered at once (Figure 6). As a result, the nitroglycerin in the blood of the long-acting oral nitroglycerin drug of the present invention persisted for more than 10 hours, and the bioavailability was 30 times that of the orally administered drug. This indicates that the oral nitroglycerin long-acting drug of the present invention can sustain nitroglycerin in the blood for a longer period of time with a smaller dose than an orally administered drug. Experimental Example 4 N-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L- obtained in Example 5
Alanyl]-N-(indan-2-yl)glycine hydrochloride (hereinafter abbreviated as CV-3317) and a long-acting oral drug were administered to the upper gums of a beagle dog using a polyacrylic acid adhesive. , N-[N-(1-(S)-carboxy-3-
phenylpropyl)-L-alanyl]-N-(indan-2-yl)glycine (CV-3317-
(abbreviated as COOH) concentration using high-performance liquid chromatography (packing agent, Microbond Pack Phenyl, elution solvent acetonitrile/0.1MKH ₂ PO ₄
(3:7)). CV−3317 50 as control
Tablets prepared by mixing 50 mg of hydroxypropylcellulose and 50 mg of hydroxypropyl cellulose were orally administered (Figure 7). As a result, CV-3317-COOH in the blood of the long-acting oral preparation of CV-3317 of the present invention persisted for more than 10 hours, and the bioavailability was the same as that of the oral preparation. This means that the CV of the present invention
A long-acting oral formulation of -3317 shows that CV-3317-COOH can persist in the blood for a longer period of time at the same dose as oral administration.

[Brief explanation of drawings]

Fig. 1 is a plan view of an oral drug having one hole, and Fig. 2 is a cross-sectional view of the film.
Exposed portion of tablet, adhesive film, and tablet are shown. Fig. 3 is a plan view of an oral drug having a plurality of holes, and Fig. 4 is a cross-sectional view of the film.
The exposed part of the tablet, the tablet, and the adhesive film are shown. Figure 5 shows the blood concentration curve of dinitroisosorbitum after administration to beagle dogs, and shows Example 1.
The blood concentration curve when the oral preparation of dinitrosorbit obtained in Example 2 was administered to the upper gums of a beagle dog. The blood concentration curve when administered to the gums shows the blood concentration curve when one 20 mg tablet of commercially available dinitroisosorbit was orally administered. Figure 6 is a blood concentration curve of nitroglycerin after administration to a beagle dog, and is a blood concentration curve when the oral nitroglycerin drug obtained in Example 3 was administered to the upper gums of a beagle dog. , shows the blood concentration curve when 40 commercially available nitroglycerin tablets (0.5 mg) were orally administered. Figure 7 shows N-[N
-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-N-(indan-
The active metabolite, N-[N-(1-(S)-carboxy-3-phenylpropyl)-L-alanyl]-N, after administration of 2-yl)glycine hydrochloride to beagle dogs.
-(indan-2-yl)glycine blood concentration curve, is N-[N-(1-
(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-N-(indan-2-yl)
Active metabolites, N, in the blood when an oral drug of glycine/hydrochloride is administered to the upper gums of a beagle dog.
-N-(1-(S)-carboxy-3-phenylpropyl)-L-alanine]-N-(indan-2-
The blood concentration curve of glycine is N-[N-
(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-N-(indan-2
Figure 2 shows a blood concentration curve of the above-mentioned active metabolite when a tablet prepared from 50 mg of -yl)glycine hydrochloride and 50 mg of hydroxypropyl cellulose is orally administered.

Claims (1)

[Scope of Claims] 1. An oral drug that holds a drug with a film that does not break down with water and a film that is adhesive to the inner surface of the oral cavity, and has one or more holes in at least one of the films. 2. The drug is held by a film that does not break down with water and a film that is adhesive to the inner surface of the oral cavity, one or more holes are formed in at least one side of the film, and the exposed part of the drug is covered with a water-disintegratable substance. Oral medicine.