WO2007116915A1 - Liquid drug preparation for oral administration packaged in a container having discharge unit - Google Patents

Abstract

[PROBLEMS] To provide a liquid drug preparation for oral preparation by which the labor at drug-taking can be saved to thereby reduce patient burden and which enables safe drug-taking. [MEANS FOR SOLVING PROBLEMS] A liquid drug preparation for oral preparation which is packaged in a container having a discharge unit and administered via direct discharge from the discharge unit onto the tongue or the vicinity thereof in the oral cavity without any contact, wherein the discharge unit is provided with a valve member which is elastically biased so as to close the discharge hole for the liquid drug preparation and migrates against the elastic force at the point of discharging the liquid drug preparation so as to open the discharge hole.

Description

 Liquid pharmaceutical preparation for oral administration contained in a container equipped with a discharge device

 [0001] The present invention relates to a liquid pharmaceutical preparation for oral administration contained in a container equipped with a discharge device.

 Background art

 [0002] At present, various liquid preparations are promoted as pharmaceuticals and are actually sold. These liquid preparations include, for example, oral drugs for oral administration (for example, Patent Documents 1 to 4), nasal sprays for nasal administration (for example, Patent Document 5), and external drugs for pharyngeal diseases (for example, Patent Document 6).

ヽる。 [0003] Liquid pharmaceutical preparations for oral administration are commercially available as "internal liquids" and "syrups"! However, since it is a liquid, the dose is inaccurate and a separate measuring cup is required for weighing when taking it immediately. Also, measuring the liquid and washing the cup after use is cumbersome and

Speak.

 [0004] Furthermore, if it is necessary to carry an internal solution to take multiple times a day, there is a risk of leakage of the liquid when it is carried, and sanitary problems due to contamination of the measuring cup.

 Patent Document 1: JP-A-8-193023

 Patent Document 2: Japanese Patent Laid-Open No. 10-265369

 Patent Document 3: Japanese Patent Laid-Open No. 2000-273050

 Patent Document 4: Japanese Patent Laid-Open No. 2003-206242

 Patent Document 5: Japanese Patent Laid-Open No. 11 171762

 Patent Document 6: JP-A-10-259124

 Disclosure of the invention

 Problems to be solved by the invention

[0005] An object of the present invention is to provide a liquid pharmaceutical formulation for oral administration that reduces the burden on patients and reduces the burden on patients and enables safe medication. Means for solving the problem

 [0006] The present inventor has intensively studied to solve the above problems and completed the present invention.

 According to one aspect of the present invention, for oral administration, which is accommodated in a container provided with a discharge device, and is administered by direct non-contact injection of the discharge device force on or around the tongue in the oral cavity. A liquid pharmaceutical preparation, wherein the discharge device is energized by an elastic force so as to close the jet outlet of the liquid pharmaceutical preparation, and is moved to pile up the elastic force when the liquid pharmaceutical preparation is discharged. The liquid pharmaceutical preparation is provided, which is a discharge device provided with a valve member.

 [0007] According to another aspect of the present invention, the discharge device includes a pump, and the pump has a cylinder suspended in the container and a cylindrical piston at the lower end, and is biased upward from the inside of the cylinder. The stem is raised, and the pressure of the liquid stored in the internal space between the upper valve on the stem side and the lower valve on the cylinder side is increased by pushing down the stem, and the content liquid is It is configured to pass through the upper valve and be discharged from a jet outlet of a discharge portion provided above the stem, and to raise the stem, suck the liquid in the container through the lower valve and suck it into the cylinder. An already defined liquid pharmaceutical formulation is provided.

[0008] According to another aspect of the present invention, the medicine is contained in a container provided with a discharge device, and is administered by direct non-contact injection of the discharge device force on or around the tongue in the oral cavity. A liquid pharmaceutical preparation for oral administration, wherein the discharge device comprises a pressing head that is attached to a pump with the stem 2 standing upright so as to be able to be pushed in an upward biased state, and the pressing head has an upper end of the stem 2 The mounting cylinder 8 fitted to the top plate 9 is suspended from the lower surface of the top plate 9, and the sliding cylinder 10 communicating with the inside of the stem 2 is erected above the top plate 9 and the sliding cylinder 10 Provided above the cylinder 16 that is slidably fitted on the outer periphery is provided with a valve chamber having a spout 21 at the tip, and is provided so as to be able to be pressed down against the mounting cylinder member, and the valve chamber The rear outer periphery is slidably fitted to the jet nozzle 2 in the forward biased state. 1 is closed, and the upper end is linked to the valve member 6 and the rear end portion of the valve member 6 that define a flow path from the communication port 19 that communicates with the inside of the cylinder to the jet port 21, and the lower end portion is The valve member is pulled back when the main body is pressed against the mounting cylinder member. An already defined liquid pharmaceutical formulation is provided comprising a heel member 7 pivotally attached to the body so as to be able to swing.

 [0009] Examples of the discharge device in the present invention include a so-called trigger-type discharge device, V, a so-called push pump-type discharge device, and the like. For example, JP 2002-326054 A, JP No. 2001-171764, No. 2004-359242, No. 2004-359241, No. 2004-359238, No. 2004-352343, No. 2004-352333, etc. Can use the discharge device

[0010] In one aspect of the present invention, for example, the discharge device may be attached to the mouth and neck of the container by fitting, and the fitting may be performed in a manner that makes the fitting difficult to remove. The mating mode is considered to contribute to prevention of breakage of the container during transportation and carrying and prevention of accidental ingestion of the liquid pharmaceutical preparation of the present invention.

 [0011] As one aspect of the side surface, the fitting portion of the container mouth neck portion and the mounting cap of the discharge device includes a first portion in which external teeth are formed on the outer peripheral surface of the container mouth neck portion forming an inner layer of the fitting portion. A first ratchet and a second ratchet that forms inner teeth on the inner peripheral surface of the mounting cap that forms the outer layer and meshes with the first ratchet, the first ratchet and the second ratchet The ratchet may be an annular fitting portion configured to prevent rotation in a direction in which the container neck and neck portion and the mounting cap are loosened. That is, the inner teeth and the outer teeth have a shape that allows rotation in the direction in which the screwing of the attachment cap and the container mouth neck is tightened but does not allow rotation in the loosening direction. . Further, in the annular coupling portion, the tooth surface on the side that contacts and presses when the rotational force in the direction in which the screwing between the mounting cap and the container neck is loosened is perpendicular to the rotational force. The tip of the tooth tip side may be inclined to the forward direction in the direction of the rotational force (or the opposite direction) as compared with the tooth base side.

[0012] Examples of the discharge device in the present invention include a discharge device having a pressing head described in JP-A-2004-834 (see FIGS. 4 to 7). The pressing head is a pressing head that is attached to a pump in which the stem 2 is erected so that it can be pushed in an upward biased state, and a mounting cylinder 8 that is fitted to the upper end of the stem 2 is suspended from the bottom surface of the top plate 9. Stem (2) A sliding cylinder (10) communicating with the inside of the top cylinder (9) is mounted on the top of the mounting cylinder member (3), and the sliding cylinder (10) is slidably fitted to the outer periphery of the cylinder (16) and is jetted to the tip above the cylinder (16). A main body 4 provided with a valve chamber having an outlet 21 open and capable of being pushed down with respect to the mounting cylinder member, and a rear outer periphery slidably fitted to the valve chamber outer periphery, and in a forward biased state The upper end is linked to the rear end of the valve member 6 and the rear end of the valve member 6 which closes the outlet 21 and defines a flow path from the communication port 19 communicating with the inside of the cylinder to the outlet 21. And a flange member 7 pivotally attached to the main body so that the valve member can be pulled out rearward when the main body is pressed against the mounting cylinder member. In the press-down head, the valve member 6 biased forward by the coil spring 26 always biases the upper portion of the vertical plate portion 28 of the flange member 7 forward, and is mounted by pushing down the main body 4. The top plate 9 of the cylindrical member 3 pushes up the inclined plate portion 29 and rotates the flange member 7, and the valve member portion 6 is pulled out against the front biasing force of the coil spring 26, so that a fluid flow path is secured. It is done. In the present invention, the use of the discharge device including the pressing head described above prevents the chemical liquid from coming into contact with the outside air, prevents deterioration due to the liquid being left in contact with the outside air, and improves the hygiene due to the dripping and the chemical liquid quantification by improving the chemical liquid. The improvement viewpoint power is also preferable.

 In one embodiment of the pressing head, the pressing force of the main body against the stem 2 is configured to be smaller than the pressing force of the stem itself.

In one aspect of the present invention, the pressing head is a pressing head that is mounted on a pump in which the stem 2 is erected so that it can be pushed in an upward biased state, and a mounting cylinder 8 that is fitted to the upper end of the stem 2 is attached to the top plate. 9 A mounting cylinder that is suspended from the bottom surface, and is provided with a sliding cylinder 10 that communicates with the inside of the stem 2 erected above the top plate 9 and a locking plate 12 that extends vertically on both sides of the top plate 9 The cylinder 3 fitted to the member 3 and the sliding cylinder 10 so as to be slidable and descendable on the outer periphery of the sliding cylinder 10 is suspended from the lower surface of the horizontal cylinder 15 projecting from the front of the peripheral wall 14a with a front end opened and a space around it. A main body 4 that is engaged with the outer surface of the locking plate so that both sides of the inner surface of the peripheral wall 14a cannot rotate and move up and down, and a cylinder that is fitted to the horizontal cylinder 15 and has an outlet 21 at the tip. -Shaped jetting member 5 and the rear wall 15a of the horizontal cylinder 15 and the seal cylinder 18 projecting from the front surface. It causes slidably fitted to and closing the ejection port 21 in the forward forcing state, one 且 valve member 6 made defining a flow path to the ejection port 21 than the communication opening 19 communicating with the cylinder And the valve member 6 protruding rearward through the window hole 17 of the horizontal cylinder rear wall 15a, the upper end is linked to the rear end portion, the lower end portion is brought into contact with and locked to the upper surface of the top plate 9, and And a flange member 7 pivotally attached to the main body so that the valve member can be pulled out backward when the main body is pressed against the mounting cylinder member, and the main body's pressing resistance against the stem 2 is smaller than the pressing resistance of the stem itself You may have the structure characterized by this. As a result, the chemical liquid is ejected after opening the spout, which makes it easy to push down the head, and can be reliably ejected to an appropriate part in the oral cavity.

In the above-described pressing head, when the cover portion 14 is pressed down, the main body 4 is lowered with respect to the mounting cylinder member 3. At this time, the lower end portion of the flange member 7 is pushed up to the upper surface of the top plate 9 of the mounting cylinder member 3 and pivots about the pivot shaft 32, and the upper end portion thereof pivots rearward so that the valve member 6 is coiled. Pile to the repulsive force and move backward, and the spout 21 opens. Next, the stem 2 descends, and as the stem descends, the liquid in the pump passes through the cylinder 16 from the stem 2 and is ejected from the ejection port 21 to the outside through the communication port 19 through the flow path. At that time, the distance between the valve member serving as the flow path and the ejection port is, for example, 0.1 to 1 mm, and the cross-sectional area of the flow path of the chemical liquid at the time of ejection is, for example, 0.1 to 3.5 mm ² . There may be. Based on a known technique related to the discharge device, the discharge amount of the liquid agent and the cross-sectional area of the flow path can be adjusted, and thereby the flow speed of the discharged chemical liquid and the particle diameter of the droplets can be controlled.

 [0015] The liquid pharmaceutical preparation of the present invention is a liquid preparation having the advantage that it can be used in a simple and accurate dose. Furthermore, the preparation of the present invention does not require water and can be safely taken, and is quickly delivered to the active ingredient absorption site after taking to exhibit a desired medicinal effect.

 In the present specification, “on or around the tongue” includes, for example, a dentition, gums, heels, and the floor of the mouth. Infiltration of droplets into the trachea and lungs is prevented, and safe oral administration is possible. Preferably, the liquid pharmaceutical formulation of the present invention is administered by injection onto the tongue.

[0017] According to another aspect of the present invention, there is provided a liquid pharmaceutical formulation as defined above, wherein the pressing head has a pressing force of the body against the stem 2 smaller than the pressing force of the stem itself. According to another aspect of the present invention, the pressing head extends vertically on both sides of the top plate 9. The liquid pharmaceutical preparation according to claim 3 or 4, further comprising a mounting cylinder member 3 formed by extending a locking plate 12 to be provided.

 [0018] The variation in the injection amount of the liquid pharmaceutical preparation of the present invention is, for example, ± 15% or less, preferably ± 13% or less, and ± 10% or less. Thereby, an appropriate amount of the physiologically active substance contained in the liquid pharmaceutical preparation can be easily taken. This is because the valve member that closes the spout just by preventing the dripping by the valve member that closes the spout is energized by the elastic force, so the timing of closing the valve at the end of injection is It is considered that the fact that it is constant and the chemical solution is pushed out by the biasing will also contribute to the improvement of quantitativeness.

 [0019] The liquid pharmaceutical preparation of the present invention is a liquid pharmaceutical composition containing a solvent (for example, water, ethanol, glycerin, propylene glycol) that can be used as a component of the pharmaceutical preparation, and includes a solution, a suspension, It may be an emulsion or dispersion. As one embodiment of the above aspect of the present invention, the liquid pharmaceutical preparation of the present invention may be an aqueous liquid preparation, for example, an aqueous solution. Examples of water that can be used in the present invention include, for example, Japanese Pharmacopoeia purified water, and can be contained at a ratio of, for example, 10 to 99% by weight, preferably 45 to 98% by weight, based on the entire preparation.

 In the present invention, the injection amount from the discharge device by one injection is, for example, 0.03 to 3 mL, preferably 0.1 to 2 mL, more preferably 0.3 to LmL. In addition, it is preferable that the particles of the droplets at the time of ejection have a particle diameter that exceeds a certain level in terms of preventing inflow into the trachea and lungs. The particle diameter of the droplet may be, for example, 100 to 5500 111, preferably 100 to 3600 μm, more preferably 100 to 1600 μm. The particle size of the droplets can be adjusted by selecting the nozzle of the discharge device or by configuring the liquid agent flow path near the injection port.

 [0021] The viscosity of the liquid pharmaceutical preparation of the present invention is not particularly limited. However, the dispensing power of the dispensing device is quantitative, and the viewpoint power for prompt delivery to the absorption site (such as the small intestine) of the active ingredient after the administration is 0. 8 to 500 cP, preferably 0.9 to: LOOcP, more preferably 1.00 to 50. OcP, more preferably 1.00 to 25 cP, and even more preferably 1.00 to 2.5 cP (digital viscosity) (Measured with a UL adapter at 25 ° C using a total DV— DV + (Brookfield)).

[0022] The active ingredient applicable to the liquid pharmaceutical preparation of the present invention is a liquid pharmaceutical preparation for oral administration. If it is, it will not specifically limit. In one embodiment of the present invention, as an active ingredient, an antitussive, bronchodilator, expectorant, antiphlogistic, antipyretic analgesic, antihistamine, antibacterial agent, caffeine, gastric mucosal protective agent, neurostimulant, antistimulant, Plasmin drugs, hypnotic sedatives, blood circulation improving drugs, hemostatic drugs, antipruritic drugs, analgesic antispasmodic drugs, stomachic medicines, digestive drugs, live intestinal components, antidiarrheal drugs, anti-constipation drugs, vitamins, nourishing tonics, circulatory organs Selected from medicines, herbal medicines and herbal ingredients

An already defined liquid pharmaceutical formulation comprising one or more is provided. In another embodiment of the present invention, as an active ingredient, codin phosphate, dihydrocodine phosphate, dextromethorphan hydrobromide, dl-methylephedrine hydrochloride, guaifenesin, potassium guaiacol sulfonate, lysozyme chloride, maleic acid Provided is an already defined liquid pharmaceutical formulation further comprising chlorfelamin and one or more selected from anhydrous caffeine.

[0023] According to one aspect of the present invention, containing one or more selected from codin phosphate and dihydrocodeine phosphate as active ingredients, contained in a container equipped with a discharge device, on the tongue in the oral cavity or A liquid pharmaceutical formulation for oral administration administered by direct injection in a non-contact manner around the discharge device force, wherein the discharge device is elastic so as to close the jet port of the liquid pharmaceutical formulation. An already defined liquid pharmaceutical formulation is provided which is a dispensing device comprising a valve member that is energized and moves against the elastic force during ejection of the liquid pharmaceutical formulation to open the spout. In this aspect, the liquid pharmaceutical preparation of the present invention includes, for example, a bronchodilator, expectorant, antiphlogistic, antipyretic analgesic, antihistamine, antibacterial agent, caffeine, gastric mucosa protective agent as an additional active ingredient. Herbal ingredients and antitussives, vitamins may contain one or more selected ingredients. According to another embodiment of this aspect, the liquid pharmaceutical formulation of the present invention comprises, as additional active ingredients, dl-methyl ephedrine hydrochloride, guaifenesin, potassium guaiacol sulfonate, lysozyme chloride, chlorfelamine maleate, and It should also contain one or more types of anhydrous caffeine selected.

[0024] According to another aspect of the present invention, there is provided an already defined liquid pharmaceutical formulation comprising one or more flavoring or sweetening agents. In one embodiment of this aspect, the corrigent or sweetener comprises amatya, reduced maltose starch, glycine, dipotassium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, fructose sugar, glucose water Enter Sucrose spherical granules, honey, simple syrup, lactose, glucose, maltose, maltose, man-toll, starch, sorbitol, caramel, aspartame, stevia extract, licorice, licorice extract, xylitol, brown sugar, liquid sugar, fructose, Fructose dextrose liquid sugar, saccharin

, Saccharin sodium, sucrose, glycerin power may also be selected.

[0025] Among the above sweeteners, the masking agent is used in the present invention from the viewpoint of masking an unpleasant taste derived from the active ingredient and preventing generation of solids when the preparation is stored for a long period of time. Sweeteners' taste-masking agents are selected, for example, asunameme, saccharin sodium power 1 or more; stevia, caramel, kanzo power 1 or more selected; and sugar alcohols (sorbitol, maltose, maltose, mannitol, xylitol), glycerin One or more combinations selected from may be used.

[0026] In the present invention, examples of the antitussive include codine phosphate, dihydrocodine phosphate, hydrocodone, hydromorphone, methadone, morphine, oximetebanol, aloclamide hydrochloride, cloperastine hydrochloride, pentoxyberine citrate, ken Tipepidine acid, dibutanato sodium, dextromethorphan hydrobromide, dextromethorphan phenol phthalic acid, tipepidine hibenzate, cloperastine fendizoate, nospin, maou, nantenjit, clofedanol, levopropoxy One or more force-selected ones such as phen, hominoben, oxerazine, pentoxyberine, benproberine, dimemorphane, dibutate, eprazinone, carbetapentane and isoamyl can be used. Preferably, the antitussive agent is codin phosphate, dihydrocodine phosphate, aloclamide hydrochloride, cloperastine hydrochloride, pentoxyberine citrate, tipepidine citrate, sodium dibutate, dextromethorphan hydrobromide, One or more selected from dextromethorphan phenol phthalic acid, tipepidine hibenzate, cloperastine fendizoate, noss force pin, maou and nantenji can be used.

[0027] In the present invention, examples of bronchodilators include ex-adrenergic receptor stimulators.

(E.g., phenol propanolamine, pseudoephedrine, phe-ephedrine, norpinephrine, methoxamine, naphazoline, xylometazoline, clozine, etc.), β-adrenergic receptor stimulators (e.g. trimethquinol hydrochloride, methoxyphenamine hydrochloride) Dl-methylephedrine hydrochloride, tyramine, ephedrine, methylephedrine saccharinate, amphetami , Methamphetamine, methoxyphenamine, olciprenaline, chlorprenalin, isoproterenol, donomine, dobutamine, isoprenaline, salbutamol, terbutaline, hexoprenaline, allobuterinore, fenoteronole, protellonore, pinolebuteronore, sauce ), Xanthine derivatives (for example, aminophylline, diprophyrin, theophylline, proxyphylline, xanthine, theopromine, pentoxyphyllin) or salts thereof, anticholinergic agents (for example, dallee) Kisses, belladonna alkaloids, belladonna total alkaloids, belladonna extract, rotokiss, etc.) and parasympatholytic agents (eg, isopropamide iodide, i Rato port Piumu, Frankfurt port Piumu, at least one component force is also selected etc.) Okishitoropiumu may be used. Preferably, bronchodilators include β-adrenergic receptor stimulants (eg, trimethquinol hydrochloride, methoxyphenamine hydrochloride, methylephedrine hydrochloride) and xanthine derivatives (eg, aminophylline, diprofylline, theophylline, proxyphylline). One or more selected may be used.

 [0028] In the present invention, as an expectorant, for example, ammonium chloride, 1 menthol, ammonia, wikial, lysozyme chloride, ethyristine hydrochloride, methylcystine hydrochloride, potassium guaiacol sulfonate, guaifenesin, crezo-one One or more selected forces may be used, such as potassium sulfonate, bromhexine hydrochloride, ambroquinol hydrochloride, L carbocystine, and hoodine. Preferably, the expectorants include salt amylum, 1-menthol, ammonia 'wikial, lysozyme chloride, ethyristine hydrochloride, methylcystine hydrochloride, potassium guaiacol sulfonate, guaifenesin and potassium cresolol sulfonate. One or more selected can be used.

 [0029] In the present invention, as the anti-inflammatory agent, one or more selected from the group consisting of lysozyme chloride, glycyrrhizic acid, dipotassium glycyrrhizinate and sodium azulene sulfonate can be used.

 [0030] In the present invention, as the antipyretic analgesic, for example, one or more selected from force such as acetaminophen, ibuprofen, aspirin, ethenzamide can be used.

In the present invention, examples of the antihistamine include, for example, isothipenzil hydrochloride, iproheptin hydrochloride, dipheterol hydrochloride, diphenylpyrroline hydrochloride, diphenhydramine hydrochloride, salt Triprolysine acid, triberenamine hydrochloride, tondiammine hydrochloride, phenetazine hydrochloride, methazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, phenetazine tannate, diphenylrubin One or more selected from the group such as promethazine methylene disalicylate, carbinoxamin maleate, dl-chlorfelamine maleate, d-chlorfelamine maleate and dipheterol phosphate can be used.

[0031] In the present invention, as the fungicide, for example, one or more selected from the group consisting of local fungicides such as salt cetylpyridium, decalium chloride and chlorhexidine hydrochloride may be used.

 [0032] In the present invention, as the caffeine, for example, one or more selected from power such as sodium benzoate caffeine, strength fein and anhydrous caffeine can be used.

 In the present invention, the gastric mucosa protective agent includes, for example, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxy aluminum, amino acetate, hydroxyaluminum gel, and dry water. Acid-aluminum gel, aluminum hydroxide-magnesium carbonate mixed dry gel, hydroxide-aluminum-sodium bicarbonate co-precipitation product, hydroxide-aluminum hydroxide, calcium carbonate-magnesium carbonate co-precipitation product, One or more selected from the group consisting of a coprecipitation product of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate and magnesium aluminate metasilicate may be used.

 [0033] In the present invention, as the neurostimulant, for example, one or more selected from power such as caffeine, anhydrous caffeine, and caffeine benzoate can be used.

 In the present invention, as the antiplasmin drug, for example, one or more selected from tranexamic acid, aminocaproic acid and the like can be used.

[0034] In the present invention, as the hypnotic sedative, one or more selected from, for example, bromide reryl urea, allyl isopropyl acetyl urea, diphenhydramine hydrochloride and the like may be used.

[0035] In the present invention, as the blood circulation improving drug, for example, one or more selected from power such as inositol hexanicotinate can be used. In the present invention, as the hemostatic agent, for example, one or more selected from the group consisting of tranexamic acid and sodium carbazochrome sulfonate can be used.

[0036] In the present invention, as the antipruritic agent, for example, one or more selected from force such as diphedol hydrochloride and scopolamine hydrobromide can be used.

 In the present invention, as the analgesic and antispasmodic agent, for example, one or more selected from the group consisting of ethyl aminobenzoate, methylbenactidium bromide, butylscopolamine bromide, funnel extract and the like can be used.

 [0037] In the present invention, as the stomachic medicine, for example, one or more selected from powers such as Keihi, Obata, Shokyo, and sempri can be used.

 In the present invention, as the digestive agent, for example, one or more selected from the group consisting of ursodesoxycholic acid, fat digestive enzyme, starch digestive enzyme and the like can be used.

[0038] In the present invention, as the intestinal viable bacteria component, for example, one or more kinds selected from lactic acid bacteria powder, bifidobacteria, butyric acid bacteria powder and the like can be used.

 In the present invention, as an antidiarrheal agent, for example, one or more selected from oral peramide hydrochloride, albumin tannate, bismuth subgallate and the like can be used.

[0039] In the present invention, as a constipation therapeutic agent, for example, one or more kinds selected for power such as sennoside, senna, daio, Brantago obata seeds can be used.

 In the present invention, as the vitamin agent, for example, one or more selected from the strengths such as tocopherol acetate, ascorbic acid, thiamine, pyridoxine, cyanobalamine may be used.

[0040] In the present invention, as the nourishing tonic, for example, one or more selected from power such as taurine, calcium pantothenate, nicotinamide and the like can be used.

 In the present invention, as the circulatory organ agent, for example, one or more selected by force such as ubidecarenone, carrot, and agate can be used.

[0041] In the present invention, as the Chinese herbal medicine, for example, one or more selected from powers such as Kakkonto and Kazuka Detoxin can be used.

In the present invention, herbal medicine components include, for example, ziryu, sansoonin, ohhi, onji, licorice, kikiyou, kiyounin, shazenshi, shazensou, sexane, senega, tokon. , Baimo, asenjak, wiki, gon, caronine, kehi, goo, gomin, saishin, zion, jiakou, shajin, shokiyo, sohakuhi, soyou, chiksendin, chimney, carrot, batmondou and roe, nge, etc. One or more can be used.

[0042] Examples of combinations of active ingredients in the liquid pharmaceutical preparation of the present invention include the following:

 Dihydrocodeine phosphate and potassium guaiacol sulfonate;

 Dihydrocodeine phosphate, guaifenesin and chlorfelamin maleate; codin phosphate, dl-methylephedrine hydrochloride and chlorfelamin maleate; dextromethorphan hydrobromide, guaifenesin and chlorfelamin maleate;

 Dihydrocodeine phosphate and potassium guaiacol sulfonate;

 Dihydrocodeine phosphate, guaifenesin and chlorfelamin maleate; codin phosphate, dl-methylephedrine hydrochloride and chlorfelamin maleate; and

 Dextromethorphan hydrobromide, guaifenesin and chlorferramine maleate.

 [0043] The liquid preparation of the present invention is used as a pharmaceutical for oral administration, and includes, for example, general cold medicine, cough, rhinitis, antipyretic analgesics, gastrointestinal drugs, antidiarrheals, motion sickness preventives or palliatives, etc. Can be used as For example, Table 1 below shows examples of active ingredient prescriptions when the present invention is used as a general cold medicine. The active ingredients shown in Table 1 can be used as a solution in an appropriately selected solvent.

 [0044] [Table 1] Table 1. Formulation Example (g)

 ① ②

 Acetaminophen 3.3 3.3

 Chlorpheniramine maleate 0.028 0.028

 Dihydrocodine phosphate 0.089 ―

 dMethylephedrine hydrochloride 0.22 0.22

 Anhydrous caffeine 0.28 0.28

Tipepidine citrate ― 0.22 [0045] That is, according to one aspect of the present invention, there is provided an already defined liquid pharmaceutical preparation comprising the components shown in Table 1 as an active ingredient.

 [0046] The liquid pharmaceutical composition of the present invention includes, as optional ingredients, a flavoring agent, sweetening agent, preservative, flavoring agent, diluent, solubilizer, PH regulator, viscosity modifier, colorant, stabilizer, It may contain additives such as surfactants, suspension agents, antioxidants, cooling agents, flavoring agents, and fragrances.

 [0047] In one embodiment of the present invention there is provided a liquid pharmaceutical formulation as defined above comprising one or more flavoring or sweetening agents. The corrigent and sweetener used in the present invention are not particularly limited, and for example, the corrigent and sweetener usually used in pharmaceutical preparations can be used. Specific examples of flavoring and sweetening agents include fructose, glucose liquid sugar, sucrose, strength lamella, aspartame, neotame, stevia extract, licorice extract, brown sugar, saccharin sodium, sorbitol, and sugar alcohols (e.g., mantol, xylo , Xylitol, erythritol, maltitol and latathitol) and glycerin. Preferably, one or more, preferably two or more selected from aspartame, neotame, stevia extract, licorice extract, brown sugar, sodium saccharin, caramel and sorbitol can be used as a corrigent or sweetener. The blending amount of the sweetener and the flavoring agent contained in the liquid pharmaceutical preparation of the present invention is, for example, 2 to 95% by weight, preferably 2 to 50% by weight, more preferably 2 to 23% by weight.

 [0048] The daily dose in the liquid preparation of the present invention is not particularly limited, and may be appropriately determined according to the daily dose of the active ingredient contained in the liquid preparation. From the viewpoint of the number of administrations per day and convenience at the time of administration, the daily dose may be, for example, 1.5 to 18 mL, preferably 3.0 to 15 mL, more preferably 6.0 to 9 mL. Good.

 [0049] The single dose in the liquid preparation of the present invention is not particularly limited, and can be appropriately determined according to the daily dose of the active ingredient contained in the liquid preparation, the number of daily doses, and the like. From the viewpoint of the number of administrations per day and safety at the time of taking, it may be, for example, 0.5 to 5 mL, preferably 0.75 to 3 mL, and more preferably 1.0 to 2 mL. According to the present invention, since the ingestion is performed safely and reliably, the necessary amount of the active ingredient can be ingested in a small amount compared with a normal oral liquid pharmaceutical preparation.

[0050] The liquid pharmaceutical formulation of the present invention eliminates complications during administration, and causes negative effects on patients during frequent administration. Since it has the effect of reducing the burden, the present invention is suitable for a drug whose daily dose is 2 times or more. The number of doses of the liquid pharmaceutical preparation of the present invention may be, for example, 1 to 6 times a day, preferably 4 to 6 times a day.

[0051] The container used in the present invention is not particularly limited as long as it is normally used as a container for a liquid pharmaceutical preparation, and for example, a brown light-shielding glass container or the like may be used.

 Example

 [0052] Hereinafter, the power to explain the preferred embodiments of the present invention in more detail. The present invention is not limited to these embodiments. The percentage values shown below represent weight percentages unless otherwise specified.

 [0053] Examples 1-8

 According to the formulation shown in Table 2 below, solutions of Examples 1 to 8 containing an active ingredient as a cough medication solution were prepared. The numbers in the table represent g. The total amount of each formulation was lOOmL, and distilled water was used as the balance. The obtained liquid was filled in a container equipped with a discharge device (SP500LR shutoff nozzle, purchased from Yoshino Kogyo Co., Ltd.), and the injection amount and the particle size at the time of injection were measured. The particle size at the time of jetting was measured using a particle size distribution analyzer LDSA-2400 (manufactured by Tohnichi Computer Applications Co., Ltd.), and the jet port force was measured at a distance of about 10 cm.

 [0054] Further, the viscosity of each liquid agent was measured with a UL adapter using a digital viscometer DV-II + (manufactured by Brookfield) under the conditions of V and 25 ° C.

[0055] [Table 2]

[0056] Decoration 19

 A liquid pharmaceutical preparation was prepared based on the following prescription and filled into a container with a push pump type discharge device (with a spout valve on the spout, SP500LR shutoff nozzle, purchased from Yoshino Kogyo Co., Ltd.).

[0057] Dihydrocodine phosphate 280mg

Potassium guaiacol sulfonate 2500mg Aspartame 180mg

 Glycerin 16g

 Propylene glycolate 480mg

 Caramel 330mg

 Sweet potato extract 150mg

 Stevia 170mg

 D—sorbitol 2000mg

 Sodium benzoate 140mg

 Preservative appropriate amount

 pH adjuster

 Perfume

 A

 O doo B I lOOmL

 The preparation was stored for 1 month under accelerated test conditions (temperature 40 ± 1 ° C, humidity 75 ± 5% RH), and the discharge amount before and after storage was measured and compared (n = 6). The discharge volume was measured as the volume of chemical liquid (g) discharged at one time, and the volume (mL) of the chemical liquid discharged from the specific gravity (1.05) of the chemical liquid was converted. The results are shown in Table 3.

[Table 3]

[0059] The force at which a decrease in the discharge amount was confirmed for the first discharge after storage No particular effect was observed for the subsequent discharges, and the total amount of the three discharges was 1.5 mL ± 10% of the specified amount It was confirmed that it was within the range.

[0060] Test Example 1

The following tests were conducted with reference to Drugs Exp Clin Res skin vol. 18 No. 7 p303-309 (1992). From non-smokers who are healthy males, select a person who can cause more than 10 coughs when inhaled with a jet type nebulizer (NE-C16, manufactured by OMRON) of 3% by weight or less quenate aqueous solution. Divided into 2 groups, the subjects in this study (n = 6 in each group). A container with a discharge device equipped with a shirt-off nozzle is filled with the liquid pharmaceutical preparation of Example 9. 1.5 mL (3 pushes) was administered by injection onto or around the tongue of one group of subjects. The other group of subjects received saline in the same manner. Thirty minutes after administration, the subject was caused to cough by using a jet nebulizer, and the number of coughs was counted (45 seconds). The results are shown in Figure 1. In the group to which the drug solution of Example 9 was administered, a significant decrease in the number of coughs was confirmed, and the desired drug effect appeared quickly (approximately 30 minutes) by injection of the liquid pharmaceutical preparation on the tongue and its surroundings. confirmed.

[0061] Test Example 2

 Guinea pig Hartley males (5 weeks old) were used for the study after acclimation for 1 week. Guinea pigs were divided into two groups (n = 6), and the chemical solution of Example 9 was administered to one group with a stomach tube, and physiological saline was administered to the other group as a control group. 30 minutes after administration of the test substance, the guinea pig was placed in the body-honoreder according to the method of Kohrogi et al., “J. Clin. Invest. 82, 2063-206 8 (1988)”. Using a nebulizer, 0.3 mol ZL of citrate was sprayed for 15 minutes to induce cough. The change in internal pressure in the body holder during the 15 minutes was recorded on the recorder as a cough curve, and the number of coughs was counted (15 minutes). The result is shown in figure 2. In the group administered with the drug solution of Example 9, a significant decrease in the number of coughs was confirmed, and it was confirmed that the absorption site in vivo of the pharmaceutical composition according to the present invention was the gastrointestinal tract after the stomach.

 Brief Description of Drawings

 [0062] Fig. 1 is a graph showing an example of test results for confirming the drug efficacy of the drug of the present invention as an internal cough solution.

 FIG. 2 is a graph showing an example of test results for confirming the efficacy of the drug of the present invention as a cough medication solution.

 FIG. 3 is a cross-sectional view showing a structure for preventing removal of a fitting portion (screwing portion) of a container mouth neck portion and a mounting cap of a discharge device used in the present invention.

 FIG. 4 is a longitudinal sectional view showing an example of a pressing head used in a discharge device used in the pharmaceutical composition of the present invention.

FIG. 5 is a longitudinal sectional view taken along line AA in FIG. 6 is a cross-sectional view taken along line BB in FIG.

 FIG. 7 is a perspective view of a flange member used in the pressing head.

 FIG. 8 is a longitudinal sectional view showing another example of the pressing head of the discharge device used in the pharmaceutical composition of the present invention.

 FIG. 9 is a longitudinal sectional view of FIG.

Explanation of symbols

 1: Pressing head, 2: Stem, 3: Mounting cylinder member, 4: Main body, 5, 5A: Outlet member, 6: Valve member, 7: Saddle member, 8: Mounting cylinder, 9: Top plate, 10: Sliding Tube: 11: Guide tube, 12: Locking plate, 13: Engaging groove, 14: Cover part, 14a: Perimeter wall, 14a: Top wall, 15: Horizontal tube, 15a: Rear wall, 16: Cylinder, 17 : Window hole, 18: Seal tube, 19: Contact port, 20: Engagement ridge, 21: Spout, 22: Annular projection, 23: Rib, 24: Skirt, 25: Reverse skirt, 26: Coil spring that urges the valve member 6 forward, interposed between the rear wall 15a front of the horizontal tube 15 and the branch part of the skirt-like part 24, 27: Annular recess for engaging the collar member, 28: Vertical plate part, 29: Bifurcated inclined plate part, 30: Notch part provided in the center of the upper end of the vertical plate part 28, 31: Vertical plate part 28, a concave part with a rectangular shape in the front view at the rear upper end part, 32: Projected on both sides of the refracted part Pivoting shaft, 33: A pair of bearings suspended from the rear of the lower surface of the mounting plate 34 at a predetermined interval, 34: Horizontal cylinder 15 Mounting plate fitted directly below, 36: Locking projection protruding on the inner periphery of the peripheral wall 14a 36, 37: Seal part, 38: Connection hole, 39: Large outer diameter part, 40: Small outer diameter part, 4 1: Fitting cylinder protruding from the front of the horizontal cylinder rear wall 15a, 101: Anti-fitting structure, 102: Container neck, 103: Mounting cap, 104: External teeth, 105: Internal teeth, 106: Surface

Claims

The scope of the claims  [1] A liquid pharmaceutical formulation for oral administration which is contained in a container equipped with a discharge device, and is administered by direct non-contact injection from the discharge device onto or around the tongue in the oral cavity. The discharge device is energized by an elastic force so as to close the jet port of the liquid pharmaceutical preparation, and is moved to pile up the elastic force when the liquid pharmaceutical formulation is discharged, thereby opening the jet port. The said liquid pharmaceutical formulation which is a discharge apparatus provided with a member.  [2] The discharge device includes a pump, and the pump includes a cylinder vertically suspended in the container, and a stem having a cylindrical piston at the lower end and upwardly biased to raise the internal force of the cylinder. The pressure of the liquid stored in the internal space between the upper valve on the stem side and the lower valve on the cylinder side is increased by pushing down, and the content liquid passes above the upper valve and is provided above the stem. 2. The liquid pharmaceutical preparation according to claim 1, wherein the liquid pharmaceutical preparation is configured to be discharged from a discharge port of a discharge portion and to suck up the liquid in the container through the lower valve and into the cylinder by raising the stem.  [3] The discharge device includes a pressing head that is attached to a pump that stands upright so that the stem can be pushed in an upward biased state, and the pressing head suspends a mounting cylinder that is fitted to the upper end of the stem from the bottom surface of the top plate. And at the tip of the mounting cylinder member, the sliding cylinder communicating with the inside of the stem standing above the top plate, and the upper side of the cylinder fitted to the outer periphery of the sliding cylinder so as to be able to slide down. The main body is provided with a valve chamber having an opening at the spout, and can be pushed down with respect to the mounting cylinder member, and a rear outer periphery is slidably fitted to the valve chamber periphery, and in a forward biased state. The upper end is linked to the valve member formed by closing the jet port and defining a flow path from the communication port communicating with the inside of the cylinder to the jet port, and the lower end portion of the valve member. And abut the top surface of the top plate, and , And a lever member that is pivotally swingable to the body as withdrawing the valve member during the pressing of the body rearward relative to the hollow mounting member, the liquid pharmaceutical formulation according to claim 1 or 2.  4. The liquid pharmaceutical preparation according to claim 3, wherein the pressing head has a pressing resistance of the main body against the stem smaller than that of the stem itself. [5] The liquid pharmaceutical preparation according to claim 3 or 4, wherein the pressing head includes the mounting cylinder member formed by extending a locking plate extending vertically on both sides of the top plate. [6] The first ratchet in which the fitting portion of the container mouth neck and the mounting cap of the discharge device forms an inner layer of the fitting portion, and the outer layer is formed on the outer peripheral surface of the container mouth neck, and the outer layer A second ratchet that forms internal teeth on the inner peripheral surface of the mounting cap and meshes with the first ratchet, and the first ratchet and the second ratchet are the container. The liquid pharmaceutical preparation according to any one of claims 1 to 5, wherein the liquid pharmaceutical preparation is configured to prevent rotation in a direction of loosening screwing between the mouth and neck and the mounting cap.  [7] The liquid pharmaceutical preparation according to any one of claims 1 to 6, wherein the variation in injection amount is ± 10% or less.  [8] The liquid pharmaceutical preparation according to any one of claims 1 to 7, which is an aqueous liquid preparation.  [9] The liquid pharmaceutical preparation according to any one of claims 1 to 8, wherein an injection amount by one injection by the discharge device is 0.03 to 3 mL. [10] The liquid pharmaceutical preparation according to any one of [1] to [9], wherein the particle size of the droplets upon ejection is 100 to 5500 μm.  [11] The liquid pharmaceutical preparation according to any one of claims 1 to 10, wherein the viscosity at 25 ° C is 0.8 to 500 cP. [12] Active ingredients include antitussives, bronchodilators, expectorants, antiphlogistics, antipyretic analgesics, antihistamines, bactericides, caffeine, gastric mucosal protective agents, neurostimulants, antiplasmin drugs, hypnosis Sedatives, blood circulation improving drugs, hemostatic drugs, antipruritic drugs, analgesic antispasmodic drugs, stomachic drugs, digestive drugs, live colonic fungi ingredients, antistatic drugs, anti-constipation drugs, vitamins, nourishing tonics, cardiovascular drugs, Chinese medicine The liquid pharmaceutical preparation according to any one of claims 1 to 11, comprising one or more selected from herbal medicine ingredients.  [13] The liquid pharmaceutical preparation according to any one of claims 1 to 12, comprising one or more flavoring agents or sweetening agents.  [14] Sorbitol, caramel, aspartame, stevia extract, licorice, licorice extract, glycine, xylitol, erythritol, brown sugar, liquid sugar, fructose, fructose liquid sugar, fructose glucose liquid sugar, saccharin, sodium saccharin, white sugar, trehalose, glycerin 14. The liquid pharmaceutical preparation according to any one of claims 1 to 13, comprising one or more selected. [15] The liquid according to any one of claims 1 to 14, which has a dose power of 0.5 to 5 mL. Pharmaceutical formulation.  The liquid pharmaceutical preparation according to any one of claims 1 to 15, wherein a daily dose is 1.5 to 18 mL.  The liquid pharmaceutical preparation according to any one of claims 1 to 16, which is taken twice or more per day.