WO2007116916A1 - Liquid drug preparation for oral administration - 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.

Description

 Specification

 Liquid pharmaceutical formulation for oral administration

 Technical field

 [0001] The present invention relates to a liquid pharmaceutical preparation for oral administration.

 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. That is, according to one aspect of the present invention, there is provided a liquid pharmaceutical preparation for oral administration accommodated in a container provided with a discharge device, which is non-contact from the discharge device on or around the tongue in the oral cavity. The liquid pharmaceutical formulation is provided for administration by direct injection. Here, on or around the tongue includes, for example, dentition, gingiva, sputum, and the floor of the mouth, and by injecting into the area and taking the medicine, liquid droplets of liquid preparations into the trachea and lungs Inflow is prevented and safe oral administration is possible. Preferably, the liquid pharmaceutical formulation of the present invention is administered by injection onto the tongue.

 [0007] 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 droplet can be adjusted by selecting the nozzle of the discharge device, the configuration of the liquid agent flow path near the injection port, or the configuration of the discharge device such as the length of the pushing stroke.

[0009] The viscosity of the liquid pharmaceutical preparation of the present invention is not particularly limited, but the viewpoint of the rapid delivery of the active ingredient to the absorption site (such as the small intestine) of the active ingredient after the dispensing device force, and 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)). [0010] The active ingredient applicable to the liquid pharmaceutical preparation of the present invention is not particularly limited as long as it is a liquid pharmaceutical preparation for oral administration. 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 ingredients is provided. In another embodiment of the present invention, the active ingredient is codine phosphate, dihydrocodine phosphate, dextromethorphan hydrobromide, dl-methylephedrine hydrochloride, guaifenesin, potassium guaiacol sulfonate, lysozyme chloride, malein There is provided an already defined liquid pharmaceutical formulation further comprising one or more selected from acid chlorfelamin and anhydrous caffeine.

[0011] According to one aspect of the present invention, a liquid pharmaceutical preparation for oral administration which contains one or more selected from codine phosphate and dihydrocodein phosphate as an active ingredient and is contained in a container equipped with a discharge device The liquid pharmaceutical preparation is provided by being directly injected in a non-contact manner onto or around the tongue in the oral cavity. In this aspect, the liquid pharmaceutical preparation of the present invention includes, for example, as an additional active ingredient, bronchodilators, expectorants, antiphlogistics, antipyretic analgesics, antihistamines, bactericides, caffeine, gastric mucosa protective agents. It may contain one or more selected from herbal ingredients and antitussives and vitamins. According to another embodiment of this aspect, the liquid pharmaceutical formulation of the present invention comprises dl-methylephedrine hydrochloride, guaifenesin, potassium guaiacol sulfonate, lysozyme chloride, chlorfelamine maleate, and anhydrous caffeine as additional active ingredients. Inca selected

Including one or more types.

[0012] 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 White sucrose granules, honey, simple syrup, lactose, glucose, maltose, maltose, man-toll, starch, sorbitol, caramel, aspartame, stevia extract, kanzo , Licorice extract, xylitol, brown sugar, liquid sugar, fructose, fructose glucose liquid sugar, saccharin

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

[0013] Among the above sweeteners, the masking agent is used in the present invention from the viewpoint of masking unpleasant taste derived from the active ingredient and preventing the generation of solids when the product is stored for a long period of time. Sweeteners' flavoring agents are selected, for example, asunameme, saccharin sodium power 1 or more; stevia, caramel, kanzo power 1 or more selected; and sugar alcohol (sorbitol, maltose, maltose, mannitol, xylitol), glycerin One or more combinations selected from may be used.

[0014] In the present invention, the antitussive agent includes, for example, 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.

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, amphetamine, methamphetamine, methoxyphenamine, orciprenaline, chlorprenalin, isoproterenol, donomine, dobutamine, isoprenaline, salbutamol, terbutaline, hex Soprenalin, allobuteronole, fenoteronore, pro force tellonore, pinolebuteronore, talenbuteronore, mabuteronore, formoterol, salmeterol, etc., xanthine derivatives (e.g., aminophylline, diprofiline, theophylline, proxyphylline, proxytin, xanthine) , Theopromin, pentoxifylline, etc.) or salts thereof, anticholinergic agents (eg, dalla-equis, belladonna alkaloids, belladonna total alkaloids, belladonna extract, rotokis, etc.) and parasympatholytic agents (eg, isopropamide iodide, iprato mouthpium) One or more of which forces are also selected can be used, such as plutonium, plutonium, oxytropium, etc.). Preferably, bronchodilators include β-adrenergic receptor stimulants (eg, trimethquinol hydrochloride, methoxyphenamine hydrochloride, methylephedrine hydrochloride) and xanthine derivatives (eg, aminophylline, diprofylline, theophylline, proxyphylline). Selected

One or more can be used.

 In the present invention, the expectorants include, for example, ammonium chloride, 1 menthol, ammonia, wikial, lysozyme chloride, ethyl cystine hydrochloride, methyl cystine 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-molybdenum, 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.

 [0017] In the present invention, as the anti-inflammatory agent, one or more selected from lysozyme chloride, glycyrrhizic acid, dipotassium glycyrrhizinate, sodium azulene sulfonate and the like can be used.

 [0018] In the present invention, as the antipyretic analgesic, for example, one or more selected from force such as acetaminophen, ibuprofen, aspirin, ethenzamide and the like can be used.

In the present invention, the antihistamines include, for example, isothipenzil hydrochloride, iproheptin hydrochloride, dipheterol hydrochloride, diphenylpyrroline hydrochloride, diphenhydramine hydrochloride, triprolidine hydrochloride, triberenamine hydrochloride, tonsylamine hydrochloride, phenetazine hydrochloride, and methazine hydrochloride. , Diphenhydramine salicylate, carbinoxamine diphenol disulfonate, Almemazine tartrate, diphenhydramine tannate, phenetazine tannate, diferruleline teuroate, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorfelamine maleate, d-chlorfelamine maleate and phosphoric acid One or more selected forces such as dipheterol can be used.

[0019] In the present invention, as the fungicide, for example, one or more kinds selected from local fungicides such as salt cetylpyridium, decalyl chloride and chlorhexidine hydrochloride may be used.

 In the present invention, as the caffeine, for example, one or more selected from powers 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.

 [0021] In the present invention, as the neurostimulant, for example, one or more selected from caffeine, anhydrous caffeine, caffeine benzoate and the like 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.

[0022] In the present invention, as the hypnotic sedative, one or more kinds selected from, for example, bromoreryl urea, allyl isopropylacetyl urea, diphenhydramine hydrochloride and the like may be used.

 [0023] In the present invention, as the blood circulation improving agent, for example, one or more selected from force 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. In the present invention, as the antipruritic agent, for example, one or more kinds 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.

 [0025] 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.

[0026] In the present invention, as the live intestinal bacterium 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.

[0027] In the present invention, as a constipation therapeutic agent, for example, one or more kinds of which power is also selected such as sennoside, senna, daio, Brantagovabata seed 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.

[0028] In the present invention, as the nourishing tonic, for example, one or more selected from power such as taurine, calcium pantothenate, nicotinamide, etc. 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.

 [0029] In the present invention, as the traditional Chinese medicine, for example, one or more kinds, for which power is selected, such as kakkonto, kazuka detoxification water, etc. can be used.

In the present invention, herbal medicine components include, for example, ziryu, sansoonin, ohhi, onji, kandu, kikiyou, kiyounin, shazenshi, shazenso, sexan, senega, tokon, baimo, azajak, wiki, ougon, caronin, kehi, go, Gomin, Saishin, Zion, Jiakou, Shajin, Shokiyo, Sohakuhi, Soyo, Chikusenjin, Chin One or more species, such as pi, carrots, buttermonds, and roe, can be selected.

[0030] Examples of combinations of active ingredients in the liquid pharmaceutical preparation of the present invention include the following:

 Dihydrocodine phosphate and potassium guaiacol sulfonate;

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

 Dihydrocodine phosphate and potassium guaiacol sulfonate;

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

 Dextromethorphan hydrobromide, guaifenesin and chlorpheniramine maleate.

 [0031] 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.

 [0032] [Table 1]

すなわち、本発明の 1つの側面によれば、有効成分として、上記表 1に示す成分を 含む、既に定義された液体医薬製剤が提供される。 [0034] 本発明の液体医薬組成物は、任意成分として、矯味剤、甘味剤、防腐剤、矯臭剤、 希釈剤、可溶化剤、 PH調整剤、粘度調整剤、着色剤、安定化剤、界面活性剤、懸 濁剤、抗酸化剤、清涼化剤、着香剤、香料などの添加剤を含んでいてもよい。

That is, according to one aspect of the present invention, there is provided an already defined liquid pharmaceutical preparation containing the components shown in Table 1 as an active ingredient. [0034] The liquid pharmaceutical composition of the present invention comprises, 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.

 [0035] 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. , 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.

 [0036] The daily 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. 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.

 [0037] 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.

[0038] Since the liquid pharmaceutical preparation of the present invention has the effect of eliminating complexity at the time of taking and reducing the burden on the patient in frequent administration, the present invention can take two or more times a day. Suitable for such drugs. The number of doses of the liquid pharmaceutical preparation of the present invention is, for example, 1 to 6 times a day, Preferably, it may be 4 to 6 times.

 [0039] 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.

 As the discharge device that can be used in the present invention, a discharge device that is capable of measuring a dose of a liquid pharmaceutical preparation with a substantially constant discharge amount at one time is used. In addition, as the discharge device, a device having a function capable of directly injecting a liquid pharmaceutical preparation on or around the tongue in the oral cavity without contact is used. As long as it has the above function, a discharge device that can be used in the present invention is not particularly limited, and a so-called push pump type discharge device, a so-called trigger type discharge device, and the like can be used.

 [0040] According to one aspect of the present invention, there is provided an already defined liquid pharmaceutical formulation, wherein the discharge device is a push pump type discharge device. Here, the push pump type discharge device includes, for example, a cylinder suspended in a container, and a stem that has a cylindrical piston at the lower end and is urged upward from the cylinder, By pushing down the stem, 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 increases, and the liquid passes through the upper valve and is provided above the stem. It may be a discharge device that is discharged from the outlet of the push-down head and configured to suck up the liquid in the container through the lower valve and into the cylinder by raising the stem. In the discharge device, the particle size of the liquid droplet at the time of liquid injection can be adjusted by the shape of the flow path of the liquid agent at the jet nozzle. As long as the function of properly injecting the liquid into the oral cavity is ensured, the discharge device in the present invention may be a spray type.

[0041] The ejection device according to the present invention may be configured such that the ejection port of the ejection device is closed by a valve member, and the ejection port is opened by the movement of the valve member when the medicine is injected. Good. According to one aspect of the present invention related to this, it is accommodated in a container equipped with a push pump type discharge device, and is directly injected in a non-contact manner onto or around the tongue in the oral cavity. A liquid pharmaceutical formulation for oral administration that is already defined, wherein the discharge device is energized by an elastic force so as to occlude the jet port of the liquid pharmaceutical formulation. Sometimes by staking the elastic force and moving There is also provided the liquid pharmaceutical preparation, which is a discharge device including a valve member that opens the spout.

 [0042] Examples of the discharge device in the present invention include a so-called push-bump type discharge device which is widely used. For example, Japanese Utility Model Publication No. 58-9358, Japanese Utility Model Application Publication No. 2-95562, No. 5-13563, JP-A 8-169462, JP-A 9-15 5254, JP-A 2002-326044, JP-A 2001-171764, JP-A 2-004-359242, It is possible to use discharge devices disclosed in Japanese Unexamined Patent Publication Nos. 2004-359241, 2004-359238, 2004-352343, 2004-352333, and the like.

 [0043] 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.

 [0044] As one aspect of the side surface, the fitting portion of the container neck of the container and the mounting cap of the discharge device includes an outer tooth formed on the outer peripheral surface of the container neck of the container forming the 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.

[0045] 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. Accordingly, the mounting cylinder 8 fitted to the upper end of the stem 2 is suspended from the bottom surface of the top plate 9 and the mounting cylinder member 3 is formed by standing the sliding cylinder 10 communicating with the inside of the stem 2 above the top plate 9; A main body provided with a valve chamber having a spout 21 opened at the tip above the cylinder 16 fitted to the outer periphery of the sliding cylinder 10 so as to be slidable and capable of being pushed down with respect to the mounting cylinder member. 4 and a flow passage extending from the communication port 19 communicating with the inside of the cylinder to the jet port 21 while the rear outer circumference is slidably fitted to the valve chamber circumference, and the jet port 21 is closed 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, the lower end is brought into contact with and locked to the upper surface of the top plate 9, and the valve member is pressed when the main body is pressed against the mounting cylinder member And a saddle member 7 pivotally attached to the main body so as to be swingable so as to be pulled out rearward. In the press-down head, the valve member 6 biased forward by the coil spring 26 always biases the upper part 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 deterioration due to the chemical solution not coming into contact with the outside air, improves hygiene due to dripping, and improves the quantification of the chemical solution by improving the chemical solution. The viewpoint power is also preferable.

 [0046] A liquid pharmaceutical formulation for oral administration which is contained in a container equipped with the discharge device of the present invention and is administered by direct non-contact injection of the discharge device force on or around the tongue in the oral cavity. The ejection device is biased by an elastic force so as to close the ejection port of the liquid pharmaceutical preparation, and is moved into an elastic state when the liquid pharmaceutical formulation is ejected to move to open the ejection port. The liquid pharmaceutical preparation, which is a discharge device including a valve member.

 [0047] 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 member 3 and the cylinder 16 fitted so as to be able to slide down on the outer periphery of the sliding cylinder 10 are It is suspended from the lower surface of the horizontal tube 15 that is open at the front end of the wall 14a and has a space around it, and engages 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. Main body 4, a cylindrical jetting member 5 fitted to the horizontal cylinder 15 and having an outlet 21 opened at the tip, and a rear wall 15a of the horizontal cylinder 15 and a seal cylinder 18 projecting from the front surface The outer periphery of the rear part is slidably fitted to the periphery, the outlet 21 is closed in a forward biased state, and a flow path from the communication port 19 communicating with the inside of the cylinder to the outlet 21 is defined. The upper end is linked to the valve member 6 and the rear end portion of the valve member 6 protruding rearward through the window hole 17 of the horizontal cylinder rear wall 15a, and the lower end portion is brought into contact with and locked to the upper surface of the top plate 9 And a collar member 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 7 And the pressing resistance of the main body against the stem 2 is smaller than the pressing resistance of the stem itself. 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.

 [0049] The liquid pharmaceutical preparation of the present invention is a liquid preparation having an advantage that a dose measured in a simple and accurate manner can be taken. 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.

Example [0050] In the following, the power for explaining 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.

 [0051] 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.

 [0052] Further, the viscosity of each liquid was measured with a UL adapter using a digital viscometer DV-II + (manufactured by Brookfield) under the conditions of V and 25 ° C.

[0053] [Table 2]

[0054] Decorative I9

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

[0055] dihydrocodine phosphate 280mg

Potassium guaiacol sulfonate 2500mg Aspartame 180mg

 Glycerin 16g

 Propylene glycolate 480mg

 Caramenore 330mg

 Sweet potato extract 150mg

 Stevia 170mg

 D—sorbitol 2000mg

 Sodium benzoate 140mg

 ,

 Antiseptic

 pH adjuster

 Yuri

 ,

 Perfume Yuri

 Purified water alone.

 A doo

 O 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]

[0057] 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.

 [0058] 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 3% by weight or less quenate aqueous solution with a jet nebulizer (NE-C16, manufactured by OMRON). 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 subjects in one group. 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.

[0059] 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 2 groups (n = 6), 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 to which the drug solution of Example 9 was administered, a significant decrease in the number of coughs was confirmed, and it was confirmed that the main absorption site in the living body of the pharmaceutical composition according to the present invention was the digestive tract after the stomach.

 Brief Description of Drawings

 [0060] 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 Cylinder, 11: Guide cylinder, 12: Locking plate, 13: Engaging groove, 14: Cover part, 14a: Perimeter wall, 14a: Top wall, 15: Horizontal cylinder, 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 flange 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 protrusion 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: Mating / detaching prevention structure, 102: Container neck and neck, 103: Mounting cap, 104: External teeth, 105: Internal teeth, 106: Surface

Claims

The scope of the claims  [I] A liquid pharmaceutical preparation for oral administration contained in a container equipped with a discharge device, which is administered by direct non-contact injection of the discharge device force on or around the tongue in the oral cavity Said liquid pharmaceutical formulation.  [2] The liquid pharmaceutical preparation according to claim 1, which is an aqueous liquid preparation.  [3] The liquid pharmaceutical preparation according to claim 1 or 2, wherein an injection amount of one injection by the discharge device is 0.03 to 3 mL. [4] The liquid pharmaceutical preparation according to any one of claims 1 to 3, wherein the droplet diameter upon ejection is 100 to 5500 μm.  [5] The liquid pharmaceutical formulation according to claims 1 to 4, wherein the viscosity at 25 ° C is 0.8 to 500 cP.  [6] As active ingredients, antitussives, bronchodilators, expectorants, antiphlogistics, antipyretic analgesics, antihistamines, bactericides, caffeine, gastric mucosa 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 6. The liquid pharmaceutical preparation according to any one of claims 1 to 5, comprising one or more selected from herbal ingredients.  [7] The liquid pharmaceutical preparation according to any one of claims 1 to 6, which comprises one or more flavoring agents or sweetening agents.  [8] Sorbitol, caramel, aspartame, stevia extract, licorice, licorice extract Glycine, xylitol, erythritol, brown sugar, liquid sugar, fructose, fructose liquid sugar, fructose grape sugar liquid sugar, saccharin, sodium saccharin, sucrose, trehalose, glycerin, including at least one selected from claims 1 to 7. Any one of the liquid pharmaceutical preparations according to 1.  [9] The liquid pharmaceutical preparation according to any one of claims 1 to 8, which has a single dose power of 0.5 to 5 mL.  [10] The liquid pharmaceutical preparation according to any one of claims 1 to 9, wherein the daily dose is 1.5 to 18 mL.  [II] The liquid pharmaceutical preparation according to any one of claims 1 to 10, which is taken at least twice a day. [12] The discharge device is a push-pump type discharge device. The liquid pharmaceutical formulation as described.  The liquid pharmaceutical preparation according to any one of claims 1 to L1, wherein the discharge device is a trigger-type discharge device.