EP3086777A1 - Compositions de racécadotril - Google Patents

Compositions de racécadotril

Info

Publication number
EP3086777A1
EP3086777A1 EP14833428.7A EP14833428A EP3086777A1 EP 3086777 A1 EP3086777 A1 EP 3086777A1 EP 14833428 A EP14833428 A EP 14833428A EP 3086777 A1 EP3086777 A1 EP 3086777A1
Authority
EP
European Patent Office
Prior art keywords
composition
dosage form
racecadotril
lipid
surfactant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14833428.7A
Other languages
German (de)
English (en)
Inventor
Der-Yang Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Johnson and Johnson Consumer Inc
Original Assignee
Johnson and Johnson Consumer Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US14/138,309 external-priority patent/US9801819B2/en
Application filed by Johnson and Johnson Consumer Inc filed Critical Johnson and Johnson Consumer Inc
Publication of EP3086777A1 publication Critical patent/EP3086777A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K47/44—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to lipid based microemuision compositions. More particularly, the present invention relates to lipid based microemuision compositions containing a pharmaceutical active ingredient and the method of making said compositions.
  • Diarrhea is an intestinal disorder that is characterized by an increase in the frequency of watery bowel movements. It may resul t from a variety of causes including bacteria or viral induced diarrhea. Food intolerance caused by allergy or the consumption of foods such as fatty or spicy foods may result in diarrhea. Food poisoning may also lead to diarrhea. In some instances, diarrhea may be a symptom of other conditions and diseases.
  • Diarrhea is symptomatic of an intestinal or other bodily function disorder.
  • Various prescription and nonprescription products can be taken for relief. Howe ver, many of these products provide relief with some side effects.
  • Racecadotril is also used in the treatment of diarrhea. I t reduces (i) hypersecretion of water and electrolytes into the intestinal lumen, (ii) the incidence and duration of acute diarrhea and (Hi) diarrhea- associated symptoms.
  • racecadotril is a pharmaceutical active ingredient that exhibits poor solubility and poor oral bioavailability.
  • racecadotril is available in solid oral dosage forms.
  • the present invention is directed to a microemuision composition
  • a microemuision composition comprising racecadotril, at least one surfactant and a lipid.
  • the inventive microemuision composition comprises about 0.01 wt.% to about 24.0 wt.% racecadotril, about 1 wt.% to about 95 wt.% of surfactant in total, and about 0.01 wt.% to about 60 wt.% lipid, wherein each wt.% is based upon 100 ml of the composition.
  • the present invention also includes a method for treating a subject experiencing diarrhea comprising the step of orally administering to the subject a composition comprising racecadotril, at least one surfactant, and a lipid.
  • microemuision refers to a liquid mixture of a lipid, water and at least one surfactant, A microemuision is characterized by its clear, thermodyiiamically stable, and isotropic appearance.
  • stable refers to a composition that is clear to the naked eye and substantially free of chemical degradation of racecadotril, substantial color change, turbidity or oily globules. No phase separation should be observed in either aqueous and/or nonaqueous components for at least about 3 months at 40°C. More preferably, no phase separation should be observed in either aqueous and/or non-aqueous components for at least about 6 months at 40°C. In one embodiment, the total chemical degradant products of racecadotril should be less than 0.5 percent by weight ( wt.%), e.g.
  • the total chemical degradant products of racecadotril should be less than 0.5 percent by- weight ( wt.%), e.g., less than 0.2 wt.% based on the total wt.% of racecadotril when stored at 6 months and 40°C.
  • the percent degradation products are determined by calculating the % peak area of the degradation product peak areas relative to the peak areas of the Racecadotril peaks in the HPLC chromatograms.
  • the total chemical degradant products of racecadotril should be less than 0.5 % of racecadotril, e.g. less than 0.2 % based on of the total % of racecadotril when stored at 3 months and 40°C.
  • SMEDDS self-niicroemulsifying drug delivery systems
  • SMEDDS are mixtures of oils, surfactants, and sometimes cosfects. SMEDDS can be used for formulating systems to improve the oral absorption of highly lipophilic compounds.
  • SMEDDS emulsify spontaneously using gentle agitation to produce fine oil-in-water emulsions when introduced into an aqueous phase.
  • a drug in an SMEDDS appears in a small droplet size and exhibits increased dissolution and permeability.
  • SMEDDS may be formulated for liquid or solid use.
  • the solids are packaged in capsules or tablets.
  • Liquid filled or semi-solid filled capsules are a preferred dosage form by certain consumers, due to the perception of speed, visual appearance of the drug composition and ease of swallowing.
  • the present invention is a microemulsion composition comprising racecadotril, at least one surfactant, and a lipid.
  • racecadotril has been shown to have fewer side effects such as post-treatment constipation.
  • Racecadotril has low water solubility, of about 10 micrograms/ml at room
  • the racecadotril may be solubilized in the microemulsion.
  • Racecadotril is included in the microemulsion composition in an amount from about 0.01 wt.% to about 24.0 wt.% per 100 ml of the emulsion composition.
  • the racecadotril is about 0.01 wt.% to about 18,0 wt.%, and more preferably, about 0.01 wt.% to about 12,0 wt.% per 100 ml of the emulsion composition, and even more preferably, about 0,01 wt.% to about 10.0 wt.% per 100 ml of the emulsion composition.
  • the racecadotril is about 4.0 wt.% to about 24,0 wt.% per 100 ml of the emulsion
  • the inventive microemulsion composition includes at least one surfactant.
  • the surfactant may be, for example, a nonionic surfactant, cationic surfactant, anionic surfactant, or mixtures thereof,
  • Suitable surfactants include, for example, water-insoluble surfactants having a hydrophilic-lipophific balance (HLB) value less than 12 and water-soluble surfactants having a HLB value greater than 12.
  • HLB hydrophilic-lipophific balance
  • surfactants that have a high HLB and hydrophilicity aid the formation of oil-water droplets.
  • the surfactants are amphiphilic in nature and are capable of dissolving or soiubilizing relatively high amounts of hydrophobic drag compounds.
  • Non-limiting examples include, Tween, Dimethylacetamide (DMA), Dimethyl sulfoxide (DMSO), Ethanol, Glycerin, N-methyl-2-pyrrolidone (NMP), PEG 300, PEG 400, Poloxamer 407, Propylene glycol, Phospholipids, Hydrogenated soy phosphatidylcholine (HSPC), Distearoylphosphatidylglyceroi (DSPG), L-a-dimyristoylphosphatidylcholine (DMPC), L-a-dimyristoylphosphatidyiglycerol (DMPG), Polyoxyi 35 castor oil
  • suitable surfactants include, for example, poiyoxyethyiene derivative of sorbitan monolaurate such as polysorbate, caprylcaproyl macrogol glycerides, polyglycoiyzed glycerides, and the like.
  • the surfactant is a combination of polyoxyi 35 castor oil and glyceryl caprvlate (mono- and diglycerides) NF.
  • the total weight percent of surfactant(s) is from about 1 wt.% to about 95 wt.% per 100 ml of the microemulsion composition.
  • the surfactant is about 25 wt.% to about 95 wt.%, and more preferably, about 30 wt.% to about 90 wt.% per 100 ml of the microemulsion composition.
  • the surfactant is about 45 wt.% to about 95 wt.% per 100 ml of the microemulsion composition.
  • a lipid is another essential component of the inventive composition. The lipid aids in solubilizing the racecadotril and also facilitates the self-emulsification process. Suitable lipids include, for example, vegetable oils (modified and/or hydrolyzed), long-chain triglycerides and medium-chain triglycerides having different degrees of saturation, and combinations thereof may be used.
  • monoglyceride, diglyceride, and/or triglyceride emulsifiers that are lipophilic and insoluble in water (available from Abitec Corporation, sold under the tradename CAPMUL®) may be used as the lipid.
  • triglyceride emulsifiers fats and oils
  • lipid for example, Beeswax, Oleic acid, Soy fatty acids, d-a-tocopherol (Vitamin E), Com oil mono-di-tridiglycerides, Medium chain (C8/C10) mono- and diglycerides. Long-chain triglycerides, Castor oil, Corn oil, Cottonseed oil, Olive oil, Peanut oil. Peppermint oil, Safflower oil, Sesame oil, Soybean oil,
  • Hydrogenated soybean oil Hydrogenated vegetable oils, Medium-chain triglycerides, Capryiic/capric triglycerides derived from coconut oil, palm seed oil, and combinations thereof.
  • the lipid is included in the composition in an amount from about 0.01 wt.% to about 60 wt.% per 100 ml of the emulsion composition.
  • the lipid is about 0.01 wt.% to about 50 wt.%.
  • the lipid is about 1 wt.% to about 20 wt.% per 100 mi of the emulsion composition, more preferably, about 1 wt.% to about 15 wt.% per 100 ml of the emulsion composition, and even more preferably, about I wt.% to about 10 wt.% per 100 mi of the emulsion composition.
  • the lipid is from about i wt.% to about 2 wt.% per 100 ml of the emulsion composition.
  • the amount of water in the composition will be largely determined by the water content of each component that is included in the composition.
  • the water content of the composition is less than about 3.5 wt.% based on the total wt.% of the composition.
  • the water content of the composition is less than about 2.5 wt.% based on the total wt.% of the composition.
  • the water content of the composition is less than about 0.5 wt.% based on the total wt.% of the composition.
  • the water content of the composition is less than about 0.2 wt.% based on the total wt.% of the composition.
  • a variety of ingredients may be included in the emulsion composition of the present invention.
  • Any coloring agent suitable for use in a food or pharmaceutical product may be used in the present invention.
  • Typical coloring agents include, for example, azo dyes, quinopthalone dyes, triphenylmeihane dyes, xanthene dyes, indigoid dyes, iron oxides, iron hydroxides, titanium dioxide, natural dyes, and mixtures thereof.
  • suitable colorants include, but are not limited to patent blue V, acid brilliant green BS, red 2G, azorubine, ponceau 4R, amaranth, D&C red 33, D&C red 22, D&C red 26, D&C red 28, D&C yellow 10, FD&C yellow 5, FD&C yellow 6, FD&C red 3, FD&C red 40, FD&C blue 1 , FD&C blue 2, FD&C green 3, brilliant black ⁇ , carbon black, iron oxide black, iron oxide red, iron oxide yellow, titanium dioxide, riboflavin, carotenes, antyhocyanines, turmeric, cochineal extract, clorophyllin, canthaxanthin, caramel, betanin, and mixtures thereof.
  • a flavor may be included in the emulsion composition.
  • the amount of flavor added to the composition is dependent upon the desired taste characteristics.
  • the composition may contain other ingredients or components, such as aromas; sweeteners such as sucralose, sorbitol, high fructose corn syrup, sugar, and the like; viscosity modifiers such as xantban gum; preservatives such as sodium benzoate NF, buffers such as citric acid and/or sodium chloride; or mixtures thereof.
  • sweeteners such as sucralose, sorbitol, high fructose corn syrup, sugar, and the like
  • viscosity modifiers such as xantban gum
  • preservatives such as sodium benzoate NF, buffers such as citric acid and/or sodium chloride; or mixtures thereof.
  • the emul sion composition of the present invention may be made by any method known to those skilled in the art so long as it results in the desired composition.
  • Suitable methods include, for example, combining each ingredient in a mixing kettle, where the ingredients may be added sequentially or in any manner so long as the intended result is achieved. Moreover, the mixing action should be sufficient to incorporate each ingredient into the composition.
  • the primary means of assessing the stability of the emulsion is based on analytical degradation analysis.
  • the efficiency of seJf-emuisificatton could be estimated by determining the rate of emufsification, droplet-size distribution and turbidity measurements,
  • stability may be evaluated by measuring the turbidity of the emulsion. This evaluation helps to determine whether the emulsion reaches equilibrium quickly and in a reproducible time.
  • the microemulsion composition is administered as a packaged emulsion for direct oral consumption.
  • the microemulsion composition is administered in an oral soft gelatin capsule containing the microemulsion composition.
  • the microemulsion composition is administered in a multiple of microgel beads containing the microemulsion composition.
  • the microemulsion composition is administered in a hard gelatin capsule containing the microemulsion composition. When the microemulsion composition is contained in the hard gelatin capsule, the hard gelatin capsule may be banded.
  • the microemulstion composition is administered in a suppository or enema containing the microemulsion composition.
  • the microemulsion composition of the present invention comprises a second active ingredient.
  • the second active ingredient is a digestive health active ingredient.
  • Non-limiting examples include, for example, laxatives, antacids, proton pump inhibitors, anti-gas agents, antiemetics, H2 blockers, or a second antidiarrheal agent.
  • the second active ingredient is incorporated into the second active ingredient
  • the second active ingredient is present in another portion of the dosage for m composition which is separate from the microemulsion composition. In yet another embodiment, the second active ingredient is microencapsulated.
  • Suitable anti-gas agents include, but are not limited to simethicone.
  • Suitable additional antidiarrheal agents include, but are not limited to loperamide.
  • the inventive microemulsion composition includes about 8.0 wt.% to about 10.0 wt.% racecadotril, about 88 wt.% to about 91 wt.% of surfactant in total, about 1 wt.% to about 2 wt.% lipid, wherein each wt.% is based upon 100 ml of the composition.
  • the inventive microemulsion composition includes about 0.01 wt.% to about 24.0 wt.% racecadotril, about 1 wt.% to about 95 wt.% of surfactant in total, about 0.01 wt.% to about 60 wt.% lipid, wherein each wt.% is based upon 100 ml of the composition.
  • the inventive microemulsion composition includes about 3.0 wt.% to about 7.0 wt.% racecadotril, about 40 wt.% to about 53 wt.% of surfactant in total, about 40 wt.% to about 53 wt.% lipid, wherein each wt.% is based upon 100 ml of the composition.
  • the inventive microemulsion composition may be delivered in any suitable delivery system.
  • the microemulsion composition is delivered orally.
  • the microemulsion composition is delivered in a soft shell dosage form.
  • the microemulsion composition is delivered in a hard shell dosage form.
  • a tablet dosage form is used to deliver the microemulsion composition.
  • the droplet size of the inventive composition was measured using a Horiba SZ- 100 Nanoparticle Size Analyzer by dynamic light scattering (DLS) at a scattering angle of 90 degrees. Samples were kept in a temperature control chamber at 25°C during measurement. Immediately prior to measurement the instrument performance was checked with a nominal 100 nm polystyrene latex (PSL) size standard in 10 mM NaCl. Count rates for these measurements ranged from 1 million to 3 million counts per second. The measurements were performed for one minute each. Data were analyzed using the cumulant technique.
  • DLS dynamic light scattering
  • the droplet size was also measured on a Nicomp 380 Nanoparticle Size Anaiyzer by dynamic light scattering (DLS) with a scattering angle of 90 degrees at Particle Sizing Systems (PSS), All measurements were performed at 23"C. After warming up, the instrument was challenged with a NIST traceable standard (i.e., polystyrene latex) to check for accuracy. A scattering intensity of 150-500 kHz was targeted during sample
  • the present invention also includes a method for treating a subject experiencing diarrhea comprising the step of orally administering to the subject a composition comprising racecadotril, at least one surfactant, and a lipid,
  • Table 1 Racecadotril Lipid Based Composition as a percentage of the composition: Triglyceride Type 1
  • Triglycerides 60:40/C8:C10 USP/NF, EP, JP
  • Step 1 In a suitable vessel, a mixture of the Polyoxyl 35 Castor oil (ETOCAS ⁇ 35), Glyceryl Caprylate (IMWITOR® 988) and Medium Chain triglycerides (MIGLYOL® 810N & 8 I2N) was prepared in three separate mixtures in the following weight ratios: 88: 10:2 (Ratio 1), 58:40:2 (Ratio 2), and 30:68:2 (Ratio 3) .
  • ETOCAS ⁇ 35 Polyoxyl 35 Castor oil
  • IMWITOR® 988 Glyceryl Caprylate
  • MIGLYOL® 810N & 8 I2N Medium Chain triglycerides
  • Step 2 The mixture(s) from Step 1 were mixed utilizing a vortex mixer.
  • Step 3 The Racecadotril was slowly added to the mixture(s) from Step 2 utilizing the vortex mixer, and mixed for 5 minutes.
  • Step 4 The mixture from Step 3 was placed into a laboratory shaker and mixed for 36 hours until a clear solution was formed. cecadotnl Lipid r ormulation
  • MIGLYOL® 810N Capr lic/Capric Triglycerides
  • MiGLYOLiSj 812 Caprylic/Capric Triglycerides
  • MIGLYOL® 810 Caprylic/Capric Triglycerides
  • MIGLYOL® 812N Caprylic/Capric Triglycerides
  • Inject reference standards O. I mg/mL of Racecadotril in Acetonitrile
  • Sample onto a suitable HPLC system under conditions similar to those suggested below. Parameters may be modified to optimize chromatography.
  • Racecadotril Determine the assay of Racecadotril using the Racecadotril peak areas of the sample solutions under iest in comparison with the Racecadotril peak areas of the standard solution.
  • the degradation products levels are determined by % peak area relative to the Racecadotril peak. hromatographie conditions (European Pharmacopoeia Racecadotril met
  • the droplet size was measured on a Horiba SZ- 100 Nanoparticie Size Analyzer by dynamic light scattermg (DLS) at a scattering angle of 90 degrees. During measurement, samples were kept in a temperature control chamber at 25 C. immediately prior to measurement the instrument performance was checked with a nominal 100 nm polystyrene latex (PSL) size standard in 10 mM NaCl. Count rates for these measurements ranged from 1 million to 3 million counts per second. The measurements were performed for one minute each. Data were analyzed using the cumulant technique.
  • DLS dynamic light scattermg
  • the droplet size was also measured on a Nicomp 380 Nanoparticle Size Analyzer by dynamic light scattering (DLS) with a scattering angle of 90 degrees at Particle Sizing Systems (PSS). Ail measurements were performed at 23°C. After warmthing up, the instrament was challenged with a NIST traceable standard (i.e., polystyrene latex) to check for accuracy. A scattering intensity of 150-500 kHz was targeied during sample

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition lipidique comprenant du racécadotril, au moins un tensioactif et un lipide.
EP14833428.7A 2013-12-23 2014-12-22 Compositions de racécadotril Withdrawn EP3086777A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14/138,309 US9801819B2 (en) 2012-06-28 2013-12-23 Racecadotril compositions
PCT/US2014/071887 WO2015100234A1 (fr) 2013-03-15 2014-12-22 Compositions de racécadotril

Publications (1)

Publication Number Publication Date
EP3086777A1 true EP3086777A1 (fr) 2016-11-02

Family

ID=56989639

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14833428.7A Withdrawn EP3086777A1 (fr) 2013-12-23 2014-12-22 Compositions de racécadotril

Country Status (3)

Country Link
EP (1) EP3086777A1 (fr)
JP (1) JP2017500355A (fr)
CN (1) CN105848643A (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019165420A1 (fr) * 2018-02-26 2019-08-29 R.P. Scherer Technologies, Llc Forme posologique pharmaceutique pour une émulsion de siméthicone et de lopéramide

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU756752B2 (en) * 1998-04-01 2003-01-23 Skyepharma Canada Inc. Anticancer compositions
EP1498122A1 (fr) * 2003-07-18 2005-01-19 Aventis Pharma S.A. Systèmes semi-solides contenant des dérivés d'azétidine
GB0402679D0 (en) * 2004-02-06 2004-03-10 Novartis Ag Organic compounds
FR2900823B1 (fr) * 2006-05-15 2009-02-13 Bioprojet Soc Civ Ile Nouvelle forme d'administration du racecadotril.
CN101264065A (zh) * 2008-04-18 2008-09-17 盐城苏海制药有限公司 消旋卡多曲滴丸及其制备方法
EP2462922A1 (fr) * 2010-12-10 2012-06-13 Bioprojet Nouvelle forme d'administration pour inhibiteurs de l'enképhalinase
CN102133168B (zh) * 2011-03-18 2012-05-02 汤广武 一种美容面膜及其制备方法
US9801819B2 (en) * 2012-06-28 2017-10-31 Johnson & Johnson Consumer Inc. Racecadotril compositions

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CN105848643A (zh) 2016-08-10
JP2017500355A (ja) 2017-01-05

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