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US20060121067A1 - Menthol-containing preparation - Google Patents

Menthol-containing preparation Download PDF

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Publication number
US20060121067A1
US20060121067A1 US10/559,731 US55973105A US2006121067A1 US 20060121067 A1 US20060121067 A1 US 20060121067A1 US 55973105 A US55973105 A US 55973105A US 2006121067 A1 US2006121067 A1 US 2006121067A1
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Prior art keywords
menthol
formulation
weight
containing formulation
formulation according
Prior art date
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Abandoned
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US10/559,731
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English (en)
Inventor
Tomonori Hamawaki
Yosuke Kataoka
Takako Isoda
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Nihon Pharmaceutical Co Ltd
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Individual
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Assigned to NIHON PHARMACEUTICAL CO., LTD. reassignment NIHON PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HAMAWAKI, TOMONORI, ISODA, TAKAKO, KATAOKA, YOSUKE
Publication of US20060121067A1 publication Critical patent/US20060121067A1/en
Priority to US12/458,876 priority Critical patent/US7993635B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/273—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the upper alimentary canal, e.g. oesophagoscopes, gastroscopes
    • A61B1/2736—Gastroscopes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/31—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the rectum, e.g. proctoscopes, sigmoidoscopes, colonoscopes

Definitions

  • the present invention relates to an L-menthol-containing formulation for inhibiting smooth muscle contraction or peristalsis, particularly a formulation for inhibiting digestive tract contraction, which remains stable over a long time, exhibits high light transmittance, and produces little foam when sprayed at a target area to inhibit contraction to facilitate observation of the area in endoscopic examination of the digestive tract etc.
  • scopolamine butylbromide As a contraction inhibitor for endoscopic examination of the digestive tract, an anti-cholinergic agent scopolamine butylbromide (Trade name: Buscopan Injection, Nippon Boehringer Ingelheim Co., Ltd.) or glucagon has conventionally been prescribed.
  • scopolamine butylbromide is contraindicated in a patient with glaucoma, prostatic hypertrophy, or arrhythmia, and glucagon has some problems including its very weak effect in inhibition of digestive tract contraction.
  • Scopolamine butylbromide has to be injected immediately before or during the examination because it is to be injected intravenously or intramuscularly.
  • some of the formulations may cause disorder of accommodation or vertigo after administration, so that the person who received administration of such a formulation for the examination should refrain for example from driving a car for a while after completion of the examination.
  • the conventional methods disclosed include a method in which peppermint oil and water are mixed by stirring and allowed to stand at room temperature for 24 hours and only the transparent portion after elimination of the oily component floating on the surface of the water is used, and a method in which after mixing by stirring and standing at room temperature for 24 hours, an aqueous layer is filtered to remove an oily component before use.
  • the formulations produced by these methods have a risk of loss of the volatile peppermint oil by evaporation while standing at room temperature for a long time, and thus have a problem that the content of peppermint oil at the time of administration to a patient may be inconstant or indefinite.
  • the present inventors succeeded in development of a smooth muscle contraction inhibitor formulation or a digestive tract contraction inhibitor formulation containing L-menthol which remains stable for a long time and transparent by emulsifying L-menthol and a fat or oil with a surfactant, and filed an application for patent.
  • This inhibitor formulation required a relatively high content of the surfactant for transparency so that foaming occurred during filling the formulation into a container or during spraying through a tube to the affected area for endoscopic examination, and the foam made observation of the affected area difficult.
  • development of an L-menthol-containing digestive tract contraction inhibitor formulation that has good transparency, namely high light transmittance, and is less foamy and remains stable for a long time has ardently been desired.
  • an L-menthol-containing formulation for inhibiting smooth muscle contraction, especially for inhibiting digestive tract contraction that remains stable for a long time, exhibits highly light transmittance, and hardly causes foaming during filling into a container or administration to a target region the inventors have found that an L-menthol-containing formulation that hardly causes foaming during filling or use of the formulation, is good in transmittance, and remains stable for a long time can be obtained by addition of a small amount of an antifoaming agent to a mixture of L-menthol, a surfactant and water, and making the average particle size of the emulsion particles less than 100 nm, and finally have accomplished the present invention.
  • the invention relates to:
  • An L-menthol-containing formulation for inhibiting smooth muscle contraction which comprises L-menthol, a surfactant, and an antifoaming agent and which is an emulsion with an average particle size of less than 100 nm;
  • the L-menthol employed in the invention is not particularly limited as to its origin, being generally a main component of peppermint oil.
  • Peppermint oil is obtained by steam distillation of a plant for example of Mentha piperita or Mentha arvensis and contains 30% or more by weight of L-menthol.
  • the L-menthol-containing material employed may be peppermint oil or mentha oil as it is, but highly purified L-menthol obtained for example by fractional distillation of peppermint oil or mentha oil can also be employed preferably. More preferably L-menthol of a purity of 90% or more by weight is employed. Recently L-menthol is produced also by synthesis. In any way the one in compliance with the Japanese Pharmacopoeia standard of L-menthol is preferable.
  • L-menthol is present in an amount of 0.01 to 5.0% by weight, preferably 0.1 to 3.0% by weight, and more preferably 0.3 to 1.5% by weight based on the entire weight of the formulation.
  • the antifoaming agent employed in the invention is not limited particularly as long as it is an antifoaming agent that can be employed in a pharmaceutical product, and a mixture of two or more antifoaming agents may be used. Silicone antifoaming agents are preferable, agents of the polydimethylsiloxane series are particularly preferable, and polydimethylsiloxane-silicone dioxide mixture is more preferable.
  • the amount of the antifoaming agent employed in the invention is usually 0.0001 to 0.01% by weight, preferably 0.0005 to 0.007% by weight, and more preferably 0.0007 to 0.005% by weight based on the entire formulation.
  • the surfactant employed in the invention is not limited particularly as long as it is a surfactant that can be employed in a pharmaceutical product, and a mixture of two or more surfactants may be used.
  • the amount of the surfactant is usually 0.1 to 10% by weight, preferably 0.5 to 5% by weight based on the entire formulation.
  • the surfactant of the invention preferably contains at least polyoxyethylene hydrogenated caster oil.
  • the amount of polyoxyethylene hydrogenated caster oil, when contained, is usually 1 to 3% by weight, preferably 1.5 to 2.5% by weight based on the entire formulation.
  • Sucrose fatty acid ester and polysorbate may be used preferably, and polysorbate 80 etc. can be used particularly preferably.
  • surfactants that can be employed in pharmaceutical products, such as edible nonionic surfactants and ionic surfactants, may be employed alone or in combination thereof.
  • a formulation of the present invention can be obtained by stirring water that contains the above-mentioned L-menthol, surfactant, and antifoaming agent, and, if necessary, also the fat or oil, with heating, or by heating the mixture after mixing by stirring.
  • Antifoaming effect of the emulsion thus obtained as a smooth muscle contraction inhibitor formulation of the invention was evaluated based on the time for disappearance of foam after 1-minute shaking of 20 mL of a sample in a 30-mL glass bottle of 33 mm in diameter in a shaker (170 shakes/min, stroke: 40 mm).
  • the time for disappearance of foam of the formulation of the invention is preferably not more than 3 minutes, more preferably not more than 30 seconds, and particularly preferably not more than 20 seconds.
  • the average particle size of the emulsion as a smooth muscle contraction inhibitor formulation of the invention is less than 100 nm, preferably not more than 70 nm, more preferably not more than 50 nm, and particularly preferably not more than 30 nm.
  • the average particle size of the emulsion was determined by placing a few drops of the sample in a 10-mm cell and adding distilled water to obtain a sample solution, followed by measurement using a light scattering photometer (ELS8000, OTSUKA ELECTRONICS CO., LTD).
  • the emulsion obtained in the invention is a clear or slightly turbid liquid with foaming suppressed and thus is free of problems mentioned above.
  • the light transmittance of the formulation of the invention is preferably 50% or more and particularly preferably 70% or more.
  • the light transmittance was measured by placing a sample in a 10-mm cell using a double beam spectrophotometer Model U-2001 (HITACHI, LTD.) at 900 nm as a measurement wavelength.
  • the formulation of the invention can be obtained by means of a known emulsification or solubilization.
  • a preferred method is one of those listed below, to which it is not limited.
  • L-menthol is dissolved in a fat or oil.
  • the dissolution may be conducted at room temperature or with warming.
  • the resultant uniform mixture of the L-menthol and the fat or oil is added to water containing a surfactant which has been dispersed well by stirring for example with a stirrer such as homomixer, and the mixture is stirred thoroughly using a stirrer such as a homomixer.
  • a further ultrasonic treatment or use of a high-pressure emulsifier may be employed additionally to ensure uniform and fine particles of the emulsion.
  • the emulsion thus prepared is autoclaved at 115° C. for 30 minutes.
  • a formulation is prepared by the method described above, and stored at 60° C. or a higher temperature for about 1 week instead of the autoclave sterilization.
  • a surfactant is added to water and dispersed using a stirrer such as a homomixer, and thereafter L-menthol and a fat or oil are added, and the mixture is stirred at about 80° C. for about 10 minutes with a homomixer.
  • a fat or oil can be used.
  • the fat or oil to be used is not particularly limited as far as it is a pharmaceutically acceptable fat or oil, but preferably a middle-chain fatty acid triglyceride (MCT) or a long-chain fatty acid triglyceride (LCT) such as soybean oil, olive oil, and coconut oil can be used.
  • MCT middle-chain fatty acid triglyceride
  • LCT long-chain fatty acid triglyceride
  • MCT that can be used includes those with C6- to C12-fatty acid moiety, and a mixture of those with different carbon numbers can be used (for example, ‘Panasate 800’ manufactured by NOF Corporation, ‘Coconad RK’ manufactured by KAO Corporation).
  • the fat or oil can be used as a solvent for L-menthol, where 0.5- to 10-fold weight, preferably 1- to 5-fold weight, of the fat or oil can be used per weight of L-menthol.
  • the fat or oil is used in an amount usually of 0.1 to 5% by weight, preferably 0.5 to 3% by weight, based on the weight of the entire emulsion.
  • the contraction inhibitory formulation containing a fat or oil may be prepared by stirring L-menthol, a fat or oil, a surfactant, and water containing an antifoaming agent, and heating while stirring, or heating after stirring can produce a more stable formulation.
  • Heat treatment can be accomplished by a method which is not limited specifically, and it is acceptable to heat an L-menthol-containing emulsion, which contains L-menthol, a fat or oil, a surfactant, and an antifoaming agent, at any stage during the course of manufacturing.
  • Examples of the heat treatment may be a procedure in which emulsification of the mixture is performed for example with a homomixer under a heating condition, in which emulsification of the mixture is performed using a high pressure emulsifier under a heating condition, in which the emulsion is filled in a container which is then sterilized by heating, in which the emulsion is filled in a container which is then stored at a high temperature, or in which the emulsification is performed under a heating condition followed by sterilization also under a heating condition.
  • Heating time may vary depending on the stirring condition, and it is desirable to maintain the heating condition for 1 minute to 14 days, preferably for 5 minutes to 6 hours.
  • the heating temperature may be 60° C. or higher, preferably 70° C. to 130° C., especially preferably 80° C. to 121° C. A satisfactory result is obtained when heating sterilization is performed under the heating condition usually employed for an ordinary fat emulsion (110 to 121° C.).
  • Another active ingredient a thickening agent, a stabilizer, a preservative, etc. may be added appropriately as needed.
  • the thickening agent may be carrageenan, methyl cellulose, carboxymethyl cellulose, guar gum, pectin, or the like. Addition of the thickening agent can adjust the falling-down rate of the formulation sprayed inside the digestive tract to a desirable rate.
  • the amount of the thickening agent to be added may vary according to the type of the thickening agent and is usually selected from the range from 0.01 to 5% by weight.
  • the stabilizer may be sodium edetate and the preservative may be sorbic acid, benzalkonium chloride, a parabene, or the like, in a suitable amount.
  • the L-menthol-containing formulation of the invention is sprayed directly onto the target area, for example the inner side of the digestive tract, via a sprayer or an endoscopic forceps guide, in laparotomic or endoscopic surgery of the digestive tract, in endoscopic examination of the digestive tract, or in any medical care that requires inhibition of the digestive tract contraction.
  • a sprayer or an endoscopic forceps guide it is desirable to fill the unit dose of the emulsion that has been prepared as described above into an extrusive vessel such as a pre-filled syringe.
  • the product of the invention can be filled and stored in a container such as a vial or ampoule.
  • the formulation of the invention remains stable even after storage for a long term.
  • the average particle size of the emulsion does not exceed 100 nm and the light transmittance does not become below 50% after storage at 25° C. for 1 month.
  • the formulation for inhibiting smooth muscle contraction, the emulsion of the invention remains stable over a long time, exhibits a high light transmittance, and causes little foam during filling in a container or in use, namely in administration. Therefore the formulation is useful as a contraction inhibitor to be used particularly in endoscopic examination of the digestive tract.
  • FIG. 1 shows the percent change of peristaltic contraction wave area of the body of stomach of dog in Experimental Example 2.
  • FIG. 2 shows the percent change of peristaltic contraction wave area of the pyloric part of stomach of dog in Experimental Example 2.
  • the solid line with the marks ⁇ indicates a graph for the composition in Example 7, and the dotted line with the marks X indicates a graph of the untreated case.
  • sucrose fatty acid ester Surfhope J1616, Mitsubishi-Kagaku Foods Corporation
  • polyoxyethylene hydrogenated caster oil 60 36.0 g
  • MCT Coconad RK, Kao Corporation
  • L-menthol that was in compliance with the Japanese Pharmacopoeia standard (L-Menthol, The SUZUKI Menthol CO., LTD.) and the polydimethylsiloxane-silicone dioxide mixture fluid, followed by emulsification with a homomixer at a liquid temperature of 80° C.
  • Water was added to this liquid to make the entire volume 2000 mL to give a desired emulsion.
  • the average particle size of this emulsion was 28.5 nm with the light transmittance of 96.09%.
  • sucrose fatty acid ester Surfhope J1616, Mitsubishi-Kagaku Foods Corporation
  • HCO-60 NIKKOL HCO-60, Nikko Chemicals Co., Ltd.
  • MCT Coconad RK, Kao Corporation
  • a mixture of 4.0 g of Tween 80 (Rheodol TW-O120V, KAO Corporation) and 0.10 g of a polydimethylsiloxane-silicone dioxide (KS-66, Shin-Etsu Chemical Co., Ltd.) were added to 200 mL of water, followed by emulsification with a homomixer (liquid temperature: 60° C.) to give a polydimethylsiloxane-silicone dioxide mixture fluid.
  • L-menthol 1.12 g of L-menthol that was in compliance with the Japanese Pharmacopoeia standard (L-menthol, The SUZUKI Menthol CO., LTD.) and 2.8 g of MCT (Coconad RK, Kao Corporation) were mixed and dissolved in a water bath at 60° C. to give an L-menthol solution.
  • L-menthol The SUZUKI Menthol CO., LTD.
  • MCT Coconad RK, Kao Corporation
  • Example 1 Average particle Average particle size Light transmittance Example or size at initial Light transmittance after storage for 1 month at after storage for 1 month Time for disappearing Comparative Example (nm) at initial (%) 25° C.(nm) at 25° C.(%) of foams
  • Example 1 28.5 96.09 33.7 93.80 4 sec.
  • Example 2 28.8 94.68 34.4 92.46 4 sec.
  • Example 3 27.7 93.72 37.6 90.11 4 sec.
  • Example 4 27.6 95.75 31.0 94.11 3 sec.
  • Example 5 26.3 94.16 30.7 91.82 3 sec.
  • Example 6 27.2 92.58 32.5 98.62 3 sec.
  • Example 7 23.2 97.34 25.9 96.16 6 sec. Comparative 30.3 97.48 — — 6.5 hr
  • Example 1 As evident from Table 1, all of the formulations obtained in Examples of the invention had an average particle size as about 1.2-fold large as the initial particle size not only immediately after formulation but also even after storage at 25° C. for 1 month, with a light transmittance of 95% or more of the initial value, and foam disappeared in a very short time, the time for disappearance being 6 seconds or less. In contrast the average particle size and the initial light transmittance of the emulsion obtained in Comparative Example 1 were not very different from those of the emulsions obtained in Examples, but 6 hours and 30 minutes was required for disappearance of foam.
  • Atropine sulfate as a pre-anesthetic medication was intravenously injected followed by intravenous injection of thiopental sodium for induction of anesthesia.
  • An intratracheal tube was inserted and fixed.
  • a mixture gas of nitrous oxide and oxygen was blown into.
  • Isoflurane was sent via the isoflurane vaporizer.
  • the concentration of isoflurane was elevated gradually from 0.5% for maintenance anesthesia.
  • the anesthetized dog was laparotomized at the median line, and a strain gauge force transducer (SGT) was fixed in the body of stomach and at the pyloric part of stomach according to the conventional procedure.
  • SGT strain gauge force transducer
  • Example 7 Ten minutes after completion of IMC (inter-digestive migrating contraction), erythromycin at 6 mg/animal was intravenously administered to induce peristaltic movement of the stomach. Ten more minutes later, 10 ml of the formulation of Example 7 which had been stored at 25° C. for 1 month was administered via a stomach catheter into the body of stomach or to the pyloric part of stomach, and contraction was recorded. Contraction-inhibiting effect was evaluated from the percent change of the wave area at every 10 minutes after administration of the formulation. The results are shown in FIG. 1 and FIG. 2 . As a control, the percent change of the wave area without treatment was also determined.
  • the contraction inhibitor formulation of the invention when sprayed on the body or the pyloric part of the stomach after induction of contraction by administration of erythromycin, inhibited significantly more strongly as compared with the untreated stomach. No foam appeared in endoscopy after spraying of the contraction inhibitor formulation, with no disturbance for observation of the area.
  • the L-menthol-containing formulation for inhibiting smooth muscle contraction of the invention remains stable for a long time after preparation, exhibits a high light transmittance, and hardly causes foaming when administered into the digestive tract, and thus can be used favorably for endoscopic examination of the digestive tract such as esophagus, stomach, small intestine, large intestine, and rectum.

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US10/559,731 2003-06-30 2004-06-28 Menthol-containing preparation Abandoned US20060121067A1 (en)

Priority Applications (1)

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US12/458,876 US7993635B2 (en) 2003-06-30 2009-07-27 Menthol-containing formulation

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JP2003186493 2003-06-30
JP2003-186493 2003-06-30
PCT/JP2004/009096 WO2005000361A1 (fr) 2003-06-30 2004-06-28 Preparation contenant du menthol

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US12/458,876 Expired - Lifetime US7993635B2 (en) 2003-06-30 2009-07-27 Menthol-containing formulation

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US (2) US20060121067A1 (fr)
EP (2) EP2311444B1 (fr)
JP (1) JP4459167B2 (fr)
KR (1) KR100985131B1 (fr)
CN (2) CN1893982B (fr)
AT (1) ATE538779T1 (fr)
ES (2) ES2390162T3 (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
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US20090275795A1 (en) * 2008-05-02 2009-11-05 Zassi Medical Evolutions, Inc. Continent ostomy system with chemical neuromuscular control
US20130204086A1 (en) * 2007-08-08 2013-08-08 Given Imaging Ltd. Method for clearing a body lumen environment

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2014211953B2 (en) * 2013-02-01 2018-08-02 Ddrops Company Liquid menthol compositions
JP7300995B2 (ja) * 2017-11-01 2023-06-30 武田薬品工業株式会社 医薬組成物、医薬組成物の安定化方法、及び医薬組成物の保存安定性を評価する方法
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HK1098683A1 (en) 2007-07-27
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US7993635B2 (en) 2011-08-09
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JPWO2005000361A1 (ja) 2006-10-19
CN1893982A (zh) 2007-01-10
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KR100985131B1 (ko) 2010-10-05
KR20060032604A (ko) 2006-04-17
ES2379876T3 (es) 2012-05-04
JP4459167B2 (ja) 2010-04-28
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CN102038963A (zh) 2011-05-04

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