JP5155524B2 - Liquid pharmaceutical preparation for oral administration contained in a container equipped with a discharge device - Google Patents

Description

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

  At present, various liquid preparations are marketed 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 drugs for nasal administration (for example, Patent Document 5), and external drugs for pharyngeal diseases (for example, patents). Used as reference 6).

  Liquid pharmaceutical preparations for oral administration are marketed as “internal liquids” or “syrups”, but since they are liquids, the dosage tends to be inaccurate, and a separate measuring cup is required for measurement when taking. In addition, the measurement of the liquid agent and the cleaning of the cup after use are cumbersome and burden the patient.

Furthermore, when it is necessary to carry the internal liquid for taking several times a day, there is a risk of leakage of the liquid when carried, and a sanitary problem due to contamination of the measuring cup.
JP-A-8-193023 Japanese Patent Laid-Open No. 10-265369 JP 2000-273050 A Japanese Patent Laid-Open No. 2003-206242 JP-A-11-171762 Japanese Patent Laid-Open No. 10-259124

  An object of the present invention is to provide a liquid pharmaceutical preparation for oral administration that reduces the burden on the patient in order to reduce the burden on the patient and enables safe dosing.

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 contained in a container provided with a discharge device, and is administered by direct non-contact injection from the discharge device 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 moves against the elastic force when discharging the liquid pharmaceutical preparation. The liquid pharmaceutical preparation is provided, which is a discharge device including a valve member in an open state.

  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 has a cylindrical piston at the lower end portion, and is urged upward from 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 the depression of the stem, and the content liquid passes through the upper valve. The liquid defined above is configured to be discharged from the outlet of the discharge portion provided above the stem and to suck up the liquid in the container through the lower valve and into the cylinder by the rise of the stem. A pharmaceutical formulation is provided.

  According to another aspect of the present invention, for oral administration, which is contained in a container provided with a discharge device and is administered by direct non-contact injection from the discharge device on or around the tongue in the oral cavity. A liquid pharmaceutical preparation, wherein the discharge device includes a pressing head that is mounted on a pump in which the stem 2 is erected so as to be pushed in an upward biased state, and the pressing head is fitted to the upper end of the stem 2 8 is suspended from the lower surface of the top plate 9, and a mounting cylinder member 3 is provided in which a sliding cylinder 10 communicating with the inside of the stem 2 is erected above the top plate 9, and is fitted to the outer periphery of the sliding cylinder 10 so as to be able to slide down. A valve chamber having a spout 21 at the tip is provided above the combined cylinder 16 and the main body 4 is provided so as to be able to be pushed down with respect to the mounting cylinder member, and the rear outer periphery is slidable on the valve chamber periphery. Engulfed in the forward biased state The upper end is linked to the valve member 6 which closes the port 21 and defines a flow path from the communication port 19 communicating with the inside of the cylinder to the jet port 21, and the rear end portion of the valve member 6, and the lower end portion A liquid medicine as defined above, comprising: an abutment member 7 pivotally attached to the main body so as to be swingable so that the valve member is pulled out rearward when the main body is pressed against the mounting cylinder member. A formulation is provided.

  Examples of the discharge device according to the present invention include a so-called trigger-type discharge device, a so-called push pump-type discharge device, and the like. For example, JP-A-2002-326054, JP-A-2001-171764, and JP-A-2004. -359242, JP-A-2004-359241, JP-A-2004-359238, JP-A-2004-352343, JP-A-2004-352333, etc. can be used. .

  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 it difficult to remove. The fitting 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.

  As one aspect of the side surface, a first ratchet in which a fitting portion of a container mouth neck portion and a mounting cap of a discharge device has external teeth formed on an outer peripheral surface of the container mouth neck portion forming an inner layer of the fitting portion. 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, An annular fitting portion configured to prevent rotation in a direction of loosening screwing of the container neck and the mounting cap may be used. That is, the inner teeth and the outer teeth have a shape that allows rotation in a direction in which the mounting cap and the neck of the container mouth are tightened but does not allow rotation in a loosening direction. Further, in the annular coupling portion, the tooth surface on the side that comes into contact with and presses against 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 may be inclined in a state of being advanced toward the direction of the rotational force (or the opposite direction) as compared to the base of the tooth.

  As an example of the ejection device in the present invention, for example, an ejection device having a pressing head described in JP-A-2004-834 can be cited (see FIGS. 4 to 7). The pressing head is a pressing head that is mounted on a pump in which the stem 2 is erected so as to be able to be pushed in an upward biased state, and the mounting cylinder 8 that is fitted to the upper end of the stem 2 is suspended from the lower surface of the top plate 9. A spray cylinder 10 communicating with the inside of the stem 2 is installed above the top plate 9 and a cylinder 16 is fitted to the outer periphery of the slide cylinder 10 so as to be slidably lowered. The main body 4 is provided with a valve chamber having an outlet 21 open, and can be pushed down with respect to the mounting cylinder member. The outer periphery of the rear portion is slidably fitted to the periphery of the valve chamber, and sprayed in a forward biased state. The upper end is linked to the valve member 6 that closes the outlet 21 and defines a flow path from the communication port 19 that communicates with the inside of the cylinder to the jet port 21, and the rear end portion of the valve member 6, and the lower end portion. Is in contact with and locked to the top surface of the top plate 9 and mounted. And a lever member 7 which is pivotally attached to the pivotable body as withdrawing the valve member during the pressing of the body to the rear with respect to member. In the pressing head, the valve member 6 urged forward by the coil spring 26 always urges the linking portion of the upper portion of the vertical plate portion 28 of the eaves member 7 forward. 3 top plate 9 pushes up the inclined plate portion 29 to rotate the collar member 7, and the valve material portion 6 is pulled backward against the forward biasing force of the coil spring 26, and a flow path for the liquid agent is secured. . In the present invention, the use of the discharge device including the pressing head described above prevents deterioration due to the chemical solution not being brought into contact with the outside air, improves hygiene due to dripping, and improves the quantification of the chemical solution by improving the cutting of the chemical solution. It is preferable from the viewpoint.

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 the mounting cylinder 8 that is fitted to the upper end of the stem 2 is a top plate. 9 A mounting cylinder that is vertically suspended from the lower surface, has 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 to the outer periphery of the sliding cylinder 10 so as to be able to slide down are suspended from the lower surface of the horizontal cylinder 15 projecting from the front portion of the peripheral wall 14a with a front end and a space around the front end. In addition, the main body 4 that is engaged with the outer surface of the locking plate so that the inner wall both sides of the peripheral wall 14a cannot rotate and can be moved up and down, and the tubular shape that is fitted to the horizontal cylinder 15 and has the spout 21 opened at the tip. From the front surface of the rear wall 15a of the horizontal cylinder 15 The outer periphery of the seal cylinder 18 is slidably fitted to the inner periphery of the seal cylinder 18, the outlet 21 is closed in the forward biased state, and the flow path from the communication port 19 communicating with the cylinder to the outlet 21 is formed. The upper end is linked to the valve member 6 formed and the rear end portion of the valve member 6 projecting rearward through the window hole 17 of the horizontal cylinder rear wall 15a, and the lower end portion is brought into contact with the upper surface of the top plate 9. And a flange member 7 pivotally attached to the main body so that the valve member is swingable so that the valve member can be pulled out rearward when the main body is pressed against the mounting cylinder member. You may have the structure characterized by being smaller than drag. Thereby, not only the head can be pushed down easily, but also the chemical solution is ejected after the ejection port is opened, and it is possible to reliably eject the liquid to an appropriate part in the oral cavity.

When the cover portion 14 is pushed down in the pressing head, 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 pivots rearward so that the valve member 6 is moved to the coil spring 26. The nozzle 21 is moved backward against the resilience of the nozzle, and the spout 21 is opened. 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 connection port 19 to the outside through the flow outlet 21 through the flow path. At that time, the interval between the valve member serving as the flow path and the jet outlet 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. 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 rate of the discharged chemical liquid and the particle diameter of the droplets can be controlled.

  The liquid pharmaceutical preparation of the present invention is a liquid preparation having the advantage that it can be taken in a dose that is measured easily and accurately. Furthermore, the preparation of the present invention does not require water and can be safely taken, and is quickly delivered to the absorption site of the active ingredient after taking and exhibits a desired medicinal effect.

  As used herein, “on or around the tongue” includes, for example, dentition, gingiva, cheeks, and the floor of the mouth. Inflow to the lung is prevented, and safe oral administration is possible. Preferably, the liquid pharmaceutical formulation of the present invention is administered by injection onto the tongue.

According to another aspect of the present invention, there is provided an already defined liquid pharmaceutical formulation wherein the pressing head has a pressing force of the body against the stem 2 that is less than the pressing force of the stem itself.
5. The liquid according to claim 3, wherein the pressing head includes a mounting cylinder member 3 formed by extending locking plates 12 extending vertically on both sides of the top plate 9. A pharmaceutical formulation is provided.

  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 not only due to the prevention of dripping by the valve member that closes the jet port, but also because the valve member that closes the jet port is biased by elastic force, the timing of closing the valve at the end of injection. It is thought that the fact that the liquid is constant and the chemical liquid is pushed out by the biasing also contributes to the improvement of the quantitativeness.

  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 a pharmaceutical preparation, and is a solution, suspension, emulsion or dispersion. It may be. 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 in a proportion 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, and more preferably 0.3 to 1 mL. Moreover, it is preferable that the particles of the droplets at the time of ejection have a certain particle diameter or more from the viewpoint of preventing inflow into the trachea and lungs. The particle diameter of the droplet may be, for example, 100 to 5500 μm, preferably 100 to 3600 μm, and more preferably 100 to 1600 μm. The particle diameter of the droplet can be adjusted by selecting the nozzle of the discharge device or by configuring the liquid agent flow path near the injection port.

  The viscosity of the liquid pharmaceutical preparation of the present invention is not particularly limited, but is 0.8 to 500 cP, for example, from the viewpoint of quantitative measurement of dosage from the discharge device and rapid delivery of the active ingredient to the absorption site (such as the small intestine) after the dosage. 0.9 to 100 cP, more preferably 1.00 to 50.0 cP, still more preferably 1.00 to 25 cP, and still more preferably 1.00 to 2.5 cP (digital viscometer DV-II + (Brook Measured with a UL adapter under the conditions of 25 ° C.).

  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 drugs, digestive drugs, live colonic bacteria ingredients, antidiarrheals, constipation drugs, vitamins, nourishing tonics, circulatory organs An already defined liquid pharmaceutical formulation is provided comprising one or more selected from pharmaceuticals, herbal medicines and herbal ingredients. In another embodiment of the present invention, as an active ingredient, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, dl-methylephedrine hydrochloride, guaifenesin, potassium guaiacol sulfonate, lysozyme chloride, chlorpheniramine maleate, And an already defined liquid pharmaceutical formulation further comprising one or more selected from and anhydrous caffeine.

  According to one aspect of the present invention, it is contained in a container equipped with a discharge device, contains one or more selected from codeine phosphate and dihydrocodeine phosphate as an active ingredient, and is provided on or around the tongue in the oral cavity. A liquid pharmaceutical preparation for oral administration that is administered by being directly injected in a non-contact manner from a discharge device, wherein the discharge device is biased by an elastic force so as to close a spout of the liquid pharmaceutical preparation, An already defined liquid pharmaceutical formulation is provided, which is a dispensing device comprising a valve member that opens against the elastic force during ejection of the liquid pharmaceutical formulation to open the jet port. 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, It may contain one or more ingredients selected from herbal medicine 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, chlorpheniramine maleate, and anhydrous caffeine as additional active ingredients 1 or more types selected from may further be included.

  According to another aspect of the present invention there is provided a liquid pharmaceutical formulation as defined above comprising one or more flavoring or sweetening agents. In one embodiment of this aspect, the corrigent or sweetener comprises: amateur, reduced maltose water candy, glycine, dipotassium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, fructose liquid sugar, glucose water candy, sucrose spherical granules Honey, simple syrup, lactose, glucose, maltose, maltose, mannitol, water candy, sorbitol, caramel, aspartame, stevia extract, licorice, licorice extract, xylitol, brown sugar, liquid sugar, fructose, fructose glucose liquid sugar, saccharin, It may be one or more selected from saccharin sodium, sucrose, and glycerin.

  Among the above sweeteners / flavoring agents, masking of unpleasant tastes derived from the active ingredients and sweeteners / flavoring agents used in the present invention from the viewpoint of preventing generation of solids when the preparation is stored for a long period of time. The agent is, for example, one or more selected from aspartame, sodium saccharin; one or more selected from stevia, caramel, licorice; and one or more combinations selected from sugar alcohol (sorbitol, maltose, maltose, mannitol, xylitol), glycerin It may be.

  In the present invention, the antitussive agent includes, for example, codeine phosphate, dihydrocodeine phosphate, hydrocodone, hydromorphone, methadone, morphine, oxymethebanol, aloclamide hydrochloride, cloperastine hydrochloride, pentoxyberine citrate, tipipedin citrate, dibutate sodium , Dextromethorphan hydrobromide, dextromethorphan phenolphthalic acid, tipepidine hibenzate, cloperastine fendizoate, noscapine, maou, nantenjitsu, clofedanol, levopropoxyphene, hominoben, oxerazine, pentoxyberine, benproberine, dimemorphan One or more selected from dibutate, eprazinone, carbetapentane, isoaminyl and the like can be used. Preferably, the antitussive agent includes codeine phosphate, dihydrocodeine phosphate, aloclamide hydrochloride, cloperastine hydrochloride, pentoxyberine citrate, tipepidine citrate, dibutate sodium, dextromethorphan hydrobromide, dextromethorphan phenolphthalein. One or more selected from acids, tipepidine hibenzate, cloperastine fendizoate, noscapine, mao and nantenjitsu may be used.

  In the present invention, bronchodilators include, for example, α-adrenergic receptor stimulators (for example, phenylpropanolamine, pseudoephedrine, phenylephrine, norepinephrine, methoxamine, naphazoline, xylometazoline, clonidine, etc.), β-adrenergic receptor stimulators ( For example, trimethquinol hydrochloride, methoxyphenamine hydrochloride, dl-methylephedrine hydrochloride, tyramine, ephedrine, methylephedrine saccharinate, amphetamine, methamphetamine, methoxyphenamine, orciprenaline, chlorprenalin, isoproterenol, dopamine, dobutamine, Isoprenaline, salbutamol, terbutaline, hexoprenalin, tulobuterol, fenoterol, procaterol, pyrbuterol, cre Nbuterol, mabuterol, formoterol, salmeterol, etc.), xanthine derivatives (eg, aminophylline, diprofilin, theophylline, proxyphylline, xanthine, theobromine, pentoxyphyllin, etc.) or salts thereof, anticholinergic agents (eg, datsura extract, belladonna alkaloid, belladonna total) One or more components selected from alkaloids, belladonna extracts, funnel extracts, etc.) and parasympathetic blockers (eg, isopropamide iodide, ipratropium, flurtropium, oxitropium, etc.) can be used. Preferably, the bronchodilator is selected from β-adrenergic receptor stimulants (eg, trimethquinol hydrochloride, methoxyphenamine hydrochloride, methylephedrine hydrochloride) and xanthine derivatives (eg, aminophylline, diprofylline, theophylline, proxyphylline). One or more of the above may be used.

  In the present invention, as an expectorant, for example, ammonium chloride, 1-menthol, ammonia fennel, lysozyme chloride, ethylcysteine hydrochloride, methylcysteine hydrochloride, potassium guaiacolsulfonate, guaifenesin, potassium cresolsulfonate, bromhexine hydrochloride, hydrochloric acid One or more selected from ambroxol, L-carbocysteine, and fudostein can be used. Preferably, the expectorant is at least one selected from ammonium chloride, l-menthol, ammonia fennel, lysozyme chloride, ethylcysteine hydrochloride, methylcysteine hydrochloride, potassium guaiacol sulfonate, guaifenesin, potassium cresolsulfonate, and the like. Can be used.

  In the present invention, the anti-inflammatory agent may be one or more selected from lysozyme chloride, glycyrrhizic acid, dipotassium glycyrrhizinate, sodium azulene sulfonate, and the like.

In the present invention, as the antipyretic analgesic, for example, one or more selected from acetaminophen, ibuprofen, aspirin, etenzaamide and the like can be used.
In the present invention, examples of the antihistamine include isothipentyl hydrochloride, iproheptin hydrochloride, dipheterol hydrochloride, diphenylpyralin hydrochloride, diphenhydramine hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, diphenhydramine salicylate, diphenyldisulfonic acid Select from carbinoxamine, alimemazine tartrate, diphenhydramine tannate, phenetazine tannate, diphenylpyraline teocrate, promethazine methylene disalicylate, carbinoxamine maleate, chlorpheniramine maleate, chlorpheniramine maleate and dipheterol phosphate One or more of the above may be used.

  In the present invention, as the fungicide, for example, one or more selected from local fungicides such as cetylpyridinium chloride, decalinium chloride and chlorhexidine hydrochloride can be used.

In the present invention, as the caffeine, for example, one or more selected from sodium benzoate caffeine, caffeine and anhydrous caffeine can be used.
In the present invention, examples of the gastric mucosa protective agent include aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, and dry aluminum hydroxide gel. , Aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / potassium aluminum sulfate coprecipitation product 1 type or more selected from the thing, magnesium carbonate, magnesium metasilicate aluminate, etc. may be used.

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.

  In the present invention, as the hypnotic sedative, for example, one or more selected from bromvalerylurea, allylisopropylacetylurea, diphenhydramine hydrochloride and the like can be used.

In the present invention, as the blood circulation improving drug, for example, one or more selected from inositol hexanicotinate can be used.
In the present invention, as the hemostatic agent, for example, one or more selected from tranexamic acid, sodium carbazochrome sulfonate and the like can be used.

In the present invention, as the antipruritic agent, for example, one or more selected from diphenidol hydrochloride, scopolamine hydrobromide and the like can be used.
In the present invention, as the analgesic and antispasmodic agent, for example, one or more selected from ethyl aminobenzoate, methylbenactidium bromide, butylscopolamine bromide, funnel extract and the like can be used.

In the present invention, as the stomachic medicine, for example, one or more selected from Keihi, Owaku, Showa, assembly and the like can be used.
In the present invention, as the digestive agent, for example, one or more selected from ursodeoxycholic acid, fat digestive enzyme, starch digestive enzyme and the like can be used.

In the present invention, for example, one or more selected from lactic acid bacteria powder, bifidobacteria, butyric acid powder, etc. can be used as the live intestinal bacteria component.
In the present invention, as an antidiarrheal agent, for example, one or more selected from loperamide hydrochloride, albumin tannate, bismuth subgallate and the like can be used.

In the present invention, as the constipation therapeutic agent, for example, one or more selected from sennoside, senna, daiou, plantago obata seeds and the like can be used.
In the present invention, as the vitamin agent, for example, one or more selected from tocopherol acetate, ascorbic acid, thiamine, pyridoxine, cyanocobalamin and the like can be used.

In the present invention, as a nourishing tonic, for example, one or more selected from 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 from ubidecarenone, carrot, and agate can be used.

In the present invention, as the traditional Chinese medicine, for example, one or more selected from kakkonto, kazuku detoxified water, etc. can be used.
In the present invention, the herbal medicine components include, for example, jellyfish, sunflower nin, spruce, onji, licorice, kyoukyo, kyounin, shazenshi, shazenso, sekisan, senega, tokon, baimo, asenyaku, fennel, oxon, caronine, cinnamon, gooh, gomin One or more selected from Saishin, Zion, Muskok, Shajin, Shoyo, Sakuhakuhi, Soyou, Chikutsujinjin, Chimpi, Carrot, Bakumondo and Hange can be used.

Examples of combinations of active ingredients in the liquid pharmaceutical formulation of the present invention include the following:
Dihydrocodeine phosphate and potassium guaiacol sulfonate;
Dihydrocodeine phosphate, guaifenesin and chlorpheniramine maleate;
Codeine phosphate, dl-methylephedrine hydrochloride and chlorpheniramine maleate;
Dextromethorphan hydrobromide, guaifenesin and chlorpheniramine maleate;
Dihydrocodeine phosphate and potassium guaiacol sulfonate;
Dihydrocodeine phosphate, guaifenesin and chlorpheniramine maleate;
Codeine phosphate, dl-methylephedrine hydrochloride and chlorpheniramine maleate; and dextromethorphan hydrobromide, guaifenesin and chlorpheniramine maleate.

  The liquid preparation of the present invention is used as a medicine for oral administration, for example, as a general cold medicine, cough, oral rhinitis, antipyretic analgesic, gastrointestinal medicine, antidiarrheal, motion sickness preventive or alleviating agent. be able to. For example, Table 1 below shows an example of prescription of active ingredients 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.

  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 active ingredients.

  The liquid pharmaceutical composition of the present invention comprises, as optional ingredients, a flavoring agent, sweetener, preservative, flavoring agent, diluent, solubilizer, pH adjustor, viscosity modifier, colorant, stabilizer, surfactant. In addition, additives such as suspending agents, antioxidants, cooling agents, flavoring agents, and fragrances may be included.

  In one aspect of the invention, there is provided an already defined liquid pharmaceutical formulation comprising one or more flavoring or sweetening agents. The taste-masking agent and sweetening agent used in the present invention are not particularly limited, and for example, a taste-masking agent and a sweetening agent usually used in pharmaceutical preparations can be used. Specific examples of the corrigent and sweetener include fructose, glucose liquid sugar, sucrose, caramel, aspartame, neotame, stevia extract, licorice extract, brown sugar, saccharin sodium, sorbitol, and sugar alcohols (eg, mannitol, xylose, xylitol, erythritol). , Maltitol and lactitol) 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 compounding quantity of the sweetening agent and flavoring agent contained in the liquid pharmaceutical formulation of this invention is 2-95 weight%, for example, Preferably it is 2-50 weight%, More preferably, it is 2-23 weight%.

  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 during 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. .

  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 doses per day, 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 to a normal oral liquid pharmaceutical preparation.

  Since the liquid pharmaceutical preparation of the present invention has the effect of eliminating the complexity at the time of taking and reducing the burden on the patient in frequent administration, the present invention is suitable for a drug having two or more daily doses. Is suitable. The number of doses of the liquid pharmaceutical preparation of the present invention may be, for example, once to 6 times a day, preferably 4 to 6 times a day.

  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 can be used.

  EXAMPLES Hereinafter, although the preferable Example of this invention is described in detail, this invention is not limited to these Examples. The percentage values shown below represent weight percentages unless otherwise specified.

Examples 1-8
In accordance with the formulation shown in Table 2 below, solutions of Examples 1 to 8 containing active ingredients as cough oral administration solutions were prepared. The numerical value in a table | surface represents g. The total amount of each formulation was 100 mL, and distilled water was used as the balance. The obtained liquid agent was filled in a container with a discharge device (SP500LR shut-off nozzle, purchased from Yoshino Kogyo Co., Ltd.), and the injection amount and the particle size at the time of injection were measured. In addition, the particle size at the time of injection measured the particle size distribution in the distance of about 10 cm from the injection nozzle using the particle size distribution measuring device LDSA-2400 type (made by Tohnichi Computer Applications Co., Ltd.).

  Furthermore, the viscosity of each liquid agent was measured with a UL adapter under the condition of 25 ° C. using a digital viscometer DV-II + (manufactured by Brookfield).

Example 9
A liquid pharmaceutical preparation was prepared based on the following prescription and filled into a container with a push pump type discharge device (with an opening / closing valve of a spout, SP500LR shut-off nozzle, purchased from Yoshino Industrial Co., Ltd.).

Dihydrocodeine phosphate 280mg
Potassium guaiacol sulfonate 2500mg
Aspartame 180mg
Glycerin 16g
Propylene glycol 480mg
Caramel 330mg
Licorice extract 150mg
Stevia 170mg
D-sorbitol 2000mg
Sodium benzoate 140mg
Preservative appropriate amount pH adjuster appropriate amount Fragrance appropriate amount
100 mL of purified water remaining
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). In addition, the amount of chemical | medical solution discharged per time (g) was measured and the volume (mL) of the chemical | medical solution discharged from the specific gravity (1.05) of the chemical | medical solution was converted. The results are shown in Table 3.

  A decrease in the discharge amount was confirmed for the first discharge after storage, but no particular effect was observed for the subsequent discharges, and the total amount of the three discharges was in the range of 1.5 mL ± 10% of the specified amount Was confirmed to be within.

Test example 1
Drugs Exp Clin Res JN, vol. No. 18 7 The following tests were conducted with reference to p303-309 (1992). A group of non-smokers who are healthy males who are capable of causing 10 or more coughs when inhaled with 3% by weight or less citric acid aqueous solution with a jet nebulizer (NE-C16, manufactured by OMRON). The subjects were divided into the subjects of this study (each group n = 6). By filling a container with a discharge device equipped with a shut-off nozzle with the liquid pharmaceutical preparation of the formulation of Example 9, and injecting 1.5 mL (for 3 pushes) onto the tongue of one group of subjects or its peripheral part Administered. The other group of subjects received physiological saline in the same manner. Thirty minutes after the administration, a subject was caused to cough with an aqueous citric acid solution using a jet nebulizer, and the number of coughs was counted (45 seconds). The results are shown in FIG. 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 desired drug effect was rapidly (about 30 minutes) manifested by the injection of the liquid pharmaceutical preparation on the tongue and the surrounding area. It was done.

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 put in a body holder, and an ultrasonic nebulizer was used from the front of the container according to the method of Kohrogi et al., “J. Clin. Invest. Vol. 82, pp. 2063-2068 (1988)”. Then, 0.3 mol / L citric acid was sprayed for 15 minutes to induce coughing. The change in internal pressure in the body holder for 15 minutes was recorded on a recorder as a cough curve, and the number of coughs was counted (15 minutes). The results are shown in FIG. 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 absorption site in vivo of the pharmaceutical composition according to the present invention was the gastrointestinal tract after the stomach.

It is a graph which shows an example of the test result for confirming the medicinal effect as a cough medicine internal use liquid of the medicine of the present invention. It is a graph which shows an example of the test result for confirming the medicinal effect as a cough medicine internal use liquid of the medicine of the present invention. It is a cross-sectional view which shows the removal prevention structure of the fitting part (screwing part) of the mounting | wearing cap of a container mouth neck part and discharge device used for this invention. It is a longitudinal cross-sectional view which shows an example of the pressing head used for the discharge apparatus used for the pharmaceutical composition of this invention. It is a longitudinal cross-sectional view which follows the AA line of FIG. It is a cross-sectional view which follows the BB line of FIG. It is a perspective view of the collar member used for the above-mentioned pressing head. It is a longitudinal cross-sectional view which shows another example of the pressing head of the discharge apparatus used for the pharmaceutical composition of this invention. It is a longitudinal cross-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: Fence 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: Communication port, 20: Engagement ridge, 21: Spout, 22: Annular projection, 23: Rib, 24: Skirt-shaped part, 25: Reverse skirt-shaped part, 26: Horizontal A coil spring interposed between the front surface of the rear wall 15a of the cylinder 15 and the branching portion of the skirt-like portion 24 to urge the valve member 6 forward, 27: an annular recess for engaging the flange member, 28: vertical plate portion, 29: bifurcated Inclined plate portion, 30: Notch portion provided at the center of the upper end portion of the vertical plate portion 28, 31: Front face on the upper rear portion of the rear surface of the vertical plate portion 28 Rectangular concave part 32: Pivoting shaft projecting on both sides of the refracting part 33: A pair of bearings vertically suspended from the rear lower part of the mounting plate 34, 34: Mounting fitted directly under the horizontal cylinder 15 Plate: 36: Locking protrusion 36 projecting on the inner periphery of the peripheral wall 14a, 37: Seal portion, 38: Communication hole, 39: Large outer diameter portion, 40: Small outer diameter portion, 41: From the front surface of the horizontal cylinder rear wall 15a Projecting fitting cylinder, 101: fitting / detaching prevention structure, 102: container neck and neck, 103: mounting cap, 104: external teeth, 105: internal teeth, 106: surface

Claims (12)

A liquid pharmaceutical preparation for internal use which is housed in a container provided with a discharge device and is orally administered by being directly contactlessly injected from the discharge device onto or around the tongue in the oral cavity, the discharge device Is provided with a valve member that is energized by an elastic force so as to close the jet outlet of the liquid pharmaceutical preparation, and moves against the elastic force when the liquid pharmaceutical preparation is discharged to open the jet outlet. The device has a particle size of 100 to 5500 μm at the time of ejection, and as an active ingredient, an antitussive, expectorant, anti-inflammatory agent, antipyretic analgesic, antihistamine, antiseptic, gastric mucosal protective agent, nerve excitement Drugs, antiplasmin drugs, hypnotic sedatives, blood circulation improving drugs, hemostatic drugs, antipruritic drugs, analgesic antispasmodic drugs, gastric drugs, digestive drugs, live organizing bacteria, antidiarrheal drugs, anti-constipation drugs, cardiovascular drugs, Chinese medicine and One or more selected from herbal medicine ingredients Wherein, dose of one is 0.5 to 5 ml, the liquid pharmaceutical formulation.   The discharge device includes a pump, and the pump includes a cylinder suspended in the container, and a stem that has a cylindrical piston at the lower end and is urged upward from the cylinder to push down the stem. This increases 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, and the content liquid passes through the upper valve and passes through the discharge valve provided above the stem. The liquid pharmaceutical preparation according to claim 1, wherein the liquid pharmaceutical preparation is configured to be discharged from a spout and configured to suck up the liquid in the container through the lower valve and into the cylinder by raising the stem.   The discharge device includes a pressing head that is mounted on a pump that stands upright so that the stem can be pushed in an upward biased state, and the pressing head vertically suspends a mounting cylinder fitted to the upper end of the stem from the bottom surface of the top plate. A sliding cylinder communicating with the inside of the stem is provided above the top plate, and a jet cylinder at the tip of the mounting cylinder member is fitted on the outer periphery of the sliding cylinder so as to be slidably lowered. A main body provided with an open valve chamber and capable of being pushed down with respect to the mounting cylinder member, a rear outer periphery is slidably fitted to the valve chamber periphery, and the jet outlet is configured to be forward biased. The valve member, which is closed and defines a flow path from the communication port communicating with the inside of the cylinder to the jet port, and the upper end is linked to the rear end portion of the valve member, and the lower end portion is connected to the top surface of the top plate Attached to and attached to And a lever member that is pivotally attached to the pivotable body as withdrawing the valve member during the pressing of the body to the rear with respect to member, the liquid pharmaceutical formulation according to claim 1 or 2.   The liquid pharmaceutical formulation according to claim 3, wherein the pressing head has a pressing drag of the main body against the stem that is smaller than a pressing drag of the stem itself.   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.   The fitting part of the container mouth neck and the mounting cap of the discharge device is a first ratchet in which outer teeth are formed on the outer peripheral surface of the container mouth neck part forming the inner layer of the fitting part, and the attachment forming the outer layer An inner tooth is formed on an inner peripheral surface of the cap, and a second ratchet that meshes with the first ratchet is provided, and the first ratchet and the second ratchet are connected to the container neck and the neck. The liquid pharmaceutical formulation of any one of Claims 1-5 comprised so that rotation of the direction which loosens the screwing of a cap may be prevented.   The liquid pharmaceutical formulation according to any one of claims 1 to 6, wherein the variation in injection amount is ± 10% or less.   The liquid pharmaceutical formulation of any one of Claims 1-7 which is an aqueous liquid formulation.   The liquid pharmaceutical formulation of any one of Claims 1-8 whose injection amount by one injection by the said discharge device is 0.03-3mL.   The liquid pharmaceutical formulation of Claims 1-9 whose viscosity in 25 degreeC is 0.8-500 cP. The liquid pharmaceutical formulation of any one of Claims 1-10 whose daily dose is 1.5-18 mL. The liquid pharmaceutical formulation according to any one of claims 1 to 11 , which is taken twice or more per day.

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