EP3086777A1 - Racecadotril compositions - Google Patents

Racecadotril compositions

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Withdrawn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)
French (fr)
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.)
Kenvue Brands LLC
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/en
Withdrawn legal-status Critical Current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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Emergency Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (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

A lipid composition comprising racecadotril, at least one surfactant and a lipid.

Description

.. i .. TITLE
RACECADOTRIL COMPOSITIONS
BACKGROUND OF THE INVENTION
Field of the In vention
[0001] 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.
Related Background Art
[0002] 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.
[0003] 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.
[0004] 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.
[0005] Additionally, racecadotril is a pharmaceutical active ingredient that exhibits poor solubility and poor oral bioavailability. Presently, racecadotril is available in solid oral dosage forms. SUMMARY OF THE INVENTION
[0006] The present invention is directed to a microemuision composition comprising racecadotril, at least one surfactant and a lipid.
[0007] In one embodiment, 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.
[0008] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0009] As used herein, a "microemuision" refers to a liquid mixture of a lipid, water and at feast one surfactant, A microemuision is characterized by its clear, thermodyiiamically stable, and isotropic appearance.
[0010] As used herein, "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. less than 0.2 wt.% based on the total wt.% of racecadotril when stored at 3 months and 40°C. In another embodiment, 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. In one embodiment, 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.
[0011] As used herein, "self-niicroemulsifying drug delivery systems" (SMEDDS) are mixtures of oils, surfactants, and sometimes cosoivents. 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. For 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.
[0012] The present invention is a microemulsion composition comprising racecadotril, at least one surfactant, and a lipid.
[0013] Various studies have shown racecadotril to be efficacious in reducing the symptoms of diarrhea. One benefit of using racecadotril over other remedies is that racecadotril has been shown to have fewer side effects such as post-treatment constipation.
[0014] Racecadotril has low water solubility, of about 10 micrograms/ml at room
temperature conditions. In the inventive composition, the racecadotril may be solubilized in the microemulsion.
[0015] 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. Preferably, 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. In one embodiment, the racecadotril is about 4.0 wt.% to about 24,0 wt.% per 100 ml of the emulsion
composition. In another embodiment, the racecadotril is about 4.0 wt.% to about 18.0 wt.% per 100 ml of the emulsion composition. In yet another embodiment, the racecadotril is about 4.0 wt.% to about 12.0 wt.% per 100 ml of the emulsion composition. In still yet another embodiment, the racecadotril is about 4.0 wt.% to about 10.0 wt.% per 100 ml of the emulsion composition. [001 ] 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,
[0017] 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. 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.
[0018] 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
(CREMOPHO EL, CREMOPHOR ELP), Polyoxyi 40 hydrogenated castor oil (Cremophor RH 40), Polyoxyi 60 hydrogenated castor oil (CREMOPHOR RH 60), Polysorbate 20 ('TWEEN 20), Polysorbate 80 ('TWEEN 80), d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), Solutol HS-15, Sorbitan monooleate (SPAN 20), PEG 300 caprylic/capric glycerides (SOFTIGEN 767), PEG 400 caprylic/capric glycerides (LABRASOL), PEG 300 oleic glycerides (LABRAFIL M-1944CS), Polyoxyi 35 Castor oil (ETOCAS 35), Glyceryl Capr late (Mono- and Diglycerides) (IMWITOR), PEG 300 linoleic glycerides (LABRAFIL M-2125CS), Polyoxyi 8 stearate (PEG 400 monosterate), Polyoxyi 40 stearate (PEG 1750 monosterate), Peppermint oil, and combinations thereof.
[0019] Additionally, suitable surfactants include, for example, poiyoxyethyiene derivative of sorbitan monolaurate such as polysorbate, caprylcaproyl macrogol glycerides, polyglycoiyzed glycerides, and the like.
[0020] In one embodiment, the surfactant is a combination of polyoxyi 35 castor oil and glyceryl caprvlate (mono- and diglycerides) NF.
[0021] In the inventive composition, the total weight percent of surfactant(s) is from about 1 wt.% to about 95 wt.% per 100 ml of the microemulsion composition. Preferably, 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. In one embodiment, the surfactant is about 45 wt.% to about 95 wt.% per 100 ml of the microemulsion composition. [0022] 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.
[0023] In addition, monoglyceride, diglyceride, and/or triglyceride emulsifiers (fats and oils) that are lipophilic and insoluble in water (available from Abitec Corporation, sold under the tradename CAPMUL®) may be used as the 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.
[0024] 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. Preferably, the lipid is about 0.01 wt.% to about 50 wt.%. In another embodiment, 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. In one particular embodiment, the lipid is from about i wt.% to about 2 wt.% per 100 ml of the emulsion composition.
[0025] It is desirable to minimize the amount of water in the 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. In one embodiment, the water content of the composition is less than about 3.5 wt.% based on the total wt.% of the composition. In another embodiment, the water content of the composition is less than about 2.5 wt.% based on the total wt.% of the composition. In yet another embodiment, the water content of the composition is less than about 0.5 wt.% based on the total wt.% of the composition. In still yet another embodiment, the water content of the composition is less than about 0.2 wt.% based on the total wt.% of the composition.
[0026] Optionally, a variety of ingredients may be included in the emulsion composition of the present invention. [0027] 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. More specifically, 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 Ή, 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.
[0028] Similarly, a flavor may be included in the emulsion composition. The amount of flavor added to the composition is dependent upon the desired taste characteristics.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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,
[0033] In addition, 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.
[0034] Stability is also evaluated by checking for oversaturation (precipitation). The test is performed by placing 1 ml of formulation in a beaker with 250 ml of 0.1 N HCL. If a precipitation is formed, then the system is oversaiurated. [0035] In one embodiment of the present invention, the microemulsion composition is administered as a packaged emulsion for direct oral consumption. In another embodiment, the microemulsion composition is administered in an oral soft gelatin capsule containing the microemulsion composition. In yet another embodiment the microemulsion composition is administered in a multiple of microgel beads containing the microemulsion composition. In still yet another embodiment 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. In still yet another embodiment, the microemulstion composition is administered in a suppository or enema containing the microemulsion composition.
[0036] Optionally, the microemulsion composition of the present invention comprises a second active ingredient. In one embodiment 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.
[0037] In one embodiment, the second active ingredient is incorporated into the
microemulsion matrix. In another embodiment, 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.
[0038] Suitable anti-gas agents include, but are not limited to simethicone.
[0039] Suitable additional antidiarrheal agents include, but are not limited to loperamide.
[0040] In one embodiment, 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.
[0041] In another embodiment, 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.
[0042] In yet another embodiment, 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.
[0043] The inventive microemulsion composition may be delivered in any suitable delivery system. For example, in one embodiment, the microemulsion composition is delivered orally. In another embodiment, the microemulsion composition is delivered in a soft shell dosage form. In still another embodiment, the microemulsion composition is delivered in a hard shell dosage form. In still yet another embodiment, a tablet dosage form is used to deliver the microemulsion composition.
[0044] In addition, 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.
[0045] 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
measurement which lasted for 15 minutes. Data were analyzed using the cumulant technique, [0046] 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,
[0047] The following example is provided to further illustrate the compositions and methods of the present invention. It should be understood that the present invention is not limited to the examples described.
EXAMPLE 1
CONCENTRATED RACECADOTRIL LIPID COMPOSITION: FOR USE IN LIQUID FILLED GELATIN CAPSULE
Table 1 : Racecadotril Lipid Based Composition as a percentage of the composition: Triglyceride Type 1
1 : Commercially available from CRODA Healthcare as ETOCAS© 35 USP/'NF, EP, JP 2: Commercially available from CREMER as IMWiTOR® 988 USP/NF, EP, JP 3 : Commercially available from CREMER as MIGLYOL® 810N (Capryiic /Capric Triglycerides; 70:30/ C8:C10) USP/NF, EP, JP
Table 2: Racecadotril Lipid Based Composition as a percentage c f the compositio! i: Triglyceride Type 2
2: Commercially available from CREMER as IMWITOR® 988 USP/NF, EP, JP
3: Commercially available from CREMER as MIGLYOL® 812N (Caprylic /Capric
Triglycerides; 60:40/C8:C10) USP/NF, EP, JP
[0048] Utilizing the materials in Table 1 and Table 2, the following mixing steps were taken to form the microemufsion. A total of 6 mixtures were prepared including 3 ratios, with each prepared with MIGLYOL 810N (Table I) and MIGLYOL 812N (Table 2).
[0049] 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) .
[0050] Step 2: The mixture(s) from Step 1 were mixed utilizing a vortex mixer.
[0051] Step 3: The Racecadotril was slowly added to the mixture(s) from Step 2 utilizing the vortex mixer, and mixed for 5 minutes.
[0052] 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
[0053] The chemical stability of the formulations prepared in Example 1 was examined for racecadotril degradation when stored for 40.1 weeks at 40"C in sealed bottles, and is shown in Table 3. Table 3: Stability Data for lipM-foased Formulations;
Formula 1, Formula 3, Formula 5
Formula 2, Formula 4, Formula 6
There was no Impurity A, thiorphan, or impurity E in Form. 1, Form. 2, Form. 3, Form. 4, Form. S, Form. 6
ND: not detectable
Formula:
1, 88% Super Refined Etocas 35, 18% Imwitor 988, 2% Miglyol 810N (Ratio 1)
2, 88% Super Refined Etocas 35, 10% Imwitor 988, 2% Miglyol 812N (Ratio 1 )
3, 58% Super Refined Etocas 35, 48% Imwitor 988, 2% Miglyol 810N (Ratio 2)
4, 58% Super Refined Etocas 35, 48% Imwitor 988, 2% Miglyol 812N (Ratio 2)
5, 38% Super Refined Etocas 35, 68% Imwitor 988, 2% Miglyol 810N (Ratio 3)
6, 38% Super Refined Etocas 35, 68% Imwitor 988, 2% Miglyol 812N (Ratio 3)
ND - Not detectable Ingredient:
Super Refined Etocas 35 (NF, EP, JP):
Manufactured by CRODA Health Car
Polyoxyl 35 Castor Oil
HLB value of 14
Imwitor 988: Medium Chain Partial Glycerides
Manufactured by CREMER
Glyceryl Caprylate (Mono- and Diglycerid
Melting Point ~ 25 °C
HLB value of 4
Imwitor 742: Medium Chain Partial Giy<
Manufactured by CREMER
Captylic/Capric G lycerides
Melting Point ~ 25 °C
HLB value of 3-4
D. Miglyoi: Medium Chain Triglycerides (MCT Oils, Fractionated Coconut Oil)
Manufactured by CREMER
Capryiic (C8)/Capric (CI O) Triglycerides
8 I ON - 70:30 C8/C 10 blend
812N - 60:40 C8/C10 blend
Conversion based on the density of each formula:
Formula 1 /Formula 2: 1.042 g/mi
Formula 3/Formula 4: 1.028 g/ml
F ormula 5/Formul a 6 : 1.016 g/ml
Water Content (%w/w): Racecadotril 0.5%
Super Refined Etoeas 0-3% (EP): 0%
Super Refined Etoeas 0- 1% (JP): 0%
Imwitor 988: 0.2%
Miglyol 810N: 0.01%
Miglyol 812N: 0.01%
EXAMPLE 2
CONCENTRATED RACECADOTRIL LIPID COMPOSiTiON: FOR USE IN
Ingredient Formula 7 Formula 8 f%w/wV (%w/w)
Racecadotril 4.61 4.25
Glyceryl Caprylate (Mono- and Diglycerides) NF* 47.95 48.00
Medium Chain Triglycerides2 47.44
Medium Chain Triglycerides3 47.75
Total 100 100 Racecadotrii Assay (mg/mL) 46. 42.49
1 : Commercially available from CREMER. as IMWITOR 742® USP/NF, EP, JP
2: Commercially available from CREMER as MIGLYOL® 810N (Capr lic/Capric Triglycerides;
70:30/C8:CT0) USP NF, EP, JP
3: Commercially available from CREMER as MiGLYOLiSj 812 (Caprylic/Capric Triglycerides;
60:40/C8:C10) USP/NF, EP, JP
1 : Commercially available from CREMER as IMWITOR 988® USP NF, EP, JP
2: Commercially available from CREMER as MIGLYOL® 810 (Caprylic/Capric Triglycerides;
70:30/C8:C10) USP/NF, EP, JP
3: Commercially available from CREMER as MIGLYOL® 812N (Caprylic/Capric Triglycerides;
60:40/C8:CiO) USP/NF, EP, JP
Testing methods:
Sample preparation: (in Acetonitrile)
1 . Pipet 1 raL of Racecadotrii lipid solution into a 10OmL volumetric flask (V.F.)
2. Dilute to volume with Acetonitrile. Add about 20 ml. of Dimethyiacetamide if necessary.
3. Further dilute the sample solution to about 0.1 mg/mL with acetonitrile if necessary. SIS
Inject reference standards (O. I mg/mL of Racecadotril in Acetonitrile) and samples onto a suitable HPLC system under conditions similar to those suggested below. Parameters may be modified to optimize chromatography.
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
Flow rate: 1 niL/mm
Mobil Phase A: Phosphate buffer, pH 2.5 (Buffer prep: dissolve lg of potassium
dihydrogen phosphate in water, adjust to pH 2.5 with phosphoric acid, dilute to lOOOmL with water)
I: 100% Acetonitrile EXAMPLE 3
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.
Solubility and Droplet Size for lipid-based formulations
**Formula 1 , Formula 3, Formula 5
Determined by dynamic light scattering (DLS) with a Horiba SZ- 100 Nanoparticie Size Analyzer, average of three determinations (n=3)
'General procedure: O.OSg of each formulation and 15mL of O. IN HCl were combined and mixed by vortex
Calculated based on density of 1 .042 g mL
^Calculated based on density of 1 .028 g/mL 4Calculated based on density of 1.0.16 g 'mL
"Concentration of racecadotril -0.53 mg/mL
"Concentration of racecadotril -0.55 mg/mL
'Concentration of racecadotril -0.44 mg mL
"Concentration of racecadotril -0.60 mg/mL
Concentration of racecadotril -0.43 mg/mL
'" Concentration of racecadotril -0.46 mg/mL
**See Example 1 for Formula
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 wanning 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
measurement which lasted for 1 5 minutes. Data were analyzed using the cumulant technique.
**Formula 1 , Formula 3, Formula 5
Form. 1 Form. 3 Form. 5
Solubility (mg/mL) 96.0 93.1 83.4
Solubility (nig/g) 92,2 2 90.6 3 82.1 4
Droplet Size s m n ;~
17,2 5 22.9 6 56.6 7
(Z-avg Diameter) 1
Determinations (n= ) 2
**Formuia 2, Formula 4, Formula 6
Form. 2 Form. 4 Form. 6
Solubility (ing/rnL) 94.7 89,8 83.3
Solubility ί mg/'g) 90.7 2 87,7 3 82.1 4
Droplet Size ( n)
17.8 s 24.7 9 47.4 !0
(Z-avg Diameter) 1
Determinations (n= ) 1 2 2 Determined by dynamic light scattering (DLS) with a Nicomp 380 Nanoparticle Size Analyzer.
' General procedure: 0.2 mL of formulation and 4.8mL of 0.1N HQ were combined and mixed for Formula 1 and 3; 0.1 mL of formulation and 4.9 mL of 0.1N HCl were combined and mixed for Formula 2 and 4; 0.1 mL of formulation and 4.9 mL of 0. IN HCl were combined and mixed, then 2.5 mL of dilution was added to 2.5 mL of 0. IN HCl for Formula 5 and 6.
''Calculated based on density of 1.042 g/mL
"Calculated based on density of 1 ,028 g mL
Calculated based on density of 1.016 g/mL
Concentration of racecadotrii ~3.84 mg/mL
Concentration of racecadotrii -3.72 mg/mL
'Concentration of racecadotrii -0.83 mg/mL
Concentration of racecadotrii -1.89 mg/mL
Concentration, of racecadotrii -1.80 mg/mL
'Concentration of racecadotrii -0.83 mg/mL
**See Example 1 for Formula
[0054] While the invention has been described above with reference to specific embodiments thereof, it is apparent that many changes, modifications, and variations can be made without departing from the inventive concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are incorporated by reference in their entirety.

Claims

WH AT IS CLAIMED:
1. Acomposition comprising:
racecadotrii, at least one surfactant, wherein the surfactant is selected from polyoxyl 35 castor oil, glyceryl capiylate (mono- and digiycerides), and combinations thereof, and a lipid, wherein the lipid is a medium chain triglyceride.
2. The composition of claim 1, wherein the composition is a self-emulsifying system.
3. The composition of claim 1, wherein the composition is stable for about 40 weeks at 40 °C.
4. The composition of claim 1 , wherein the at least one surfactant is present in an amount from about 1 wt.% to about 95 wt.% in total per 100 ml of the emulsion composition.
5. The composition of claim 1, wherein the lipid is present in an amount of from about 0.01 wt.% to about 60 wt.% per 100 ml of the emulsion composition.
6. The composition of claim 1, further comprising an optional ingredient selected from the group consisting of preservatives, sweeteners, viscosity modifiers, colors, aromas, flavors, and mixtures thereof.
7. The composition of claim 1, further comprising an optional ingredient selected from the group consisting of citric acid, sodium benzoate, sucralose, flavors and mixtures thereof.
8. A dosage form comprising the composition of claim I, wherein the dosage form is a soft shell dosage form, a hard shell dosage form, or a tablet dosage form.
9. The composition of claim 1 , wherein the composition has a total water content of less than about 3,5 wt.% based on the total weight of the composition.
10. The composition of claim 1, further comprising a second active ingredient that is a digestive health active ingredient.
1 1. A composition compnsmg:
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.
12. A dosage form comprising the composition of claim 15, wherein the dosage form is a soft shell dosage form, a hard shell dosage form, or a tablet dosage form.
13. The composition of claim 15, wherein the composition is stable for about 40 weeks at 40°C.
14. A composition comprising:
about 3.0 wt.% to about 7.0 wt.% racecadotril;
about 40 wt.% to about 53 wt.% of surfactant in total; and
about 40 wt.% to about 53 wt.% lipid;
wherein each wt.% is based upon 100 ml of the composition.
15. A dosage form comprising the composition of claim 18, wherein the dosage form is a soft shell dosage form, a hard shell dosage form, or a tablet dosage form.
16. A method for treating a subject experiencing diarrhea comprising the step of orally administering to the subject the composition comprising of claim 1.
EP14833428.7A 2013-12-23 2014-12-22 Racecadotril compositions Withdrawn EP3086777A1 (en)

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 (en) 2013-03-15 2014-12-22 Racecadotril compositions

Publications (1)

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

Family

ID=56989639

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14833428.7A Withdrawn EP3086777A1 (en) 2013-12-23 2014-12-22 Racecadotril compositions

Country Status (3)

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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112020016884A2 (en) * 2018-02-26 2020-12-15 R.P. Scherer Technologies, Llc PHARMACEUTICAL DOSAGE FORM FOR A SIMULICONE AND LOPERAMIDE EMULSION

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999049848A1 (en) * 1998-04-01 1999-10-07 Rtp Pharma Inc. Anticancer compositions
EP1498122A1 (en) * 2003-07-18 2005-01-19 Aventis Pharma S.A. Semi-solid systems containing azetidine derivatives
GB0402679D0 (en) * 2004-02-06 2004-03-10 Novartis Ag Organic compounds
FR2900823B1 (en) * 2006-05-15 2009-02-13 Bioprojet Soc Civ Ile NEW FORM OF ADMINISTRATION OF RACECADOTRIL.
CN101264065A (en) * 2008-04-18 2008-09-17 盐城苏海制药有限公司 Racecadotril dropping pill and preparation method thereof
EP2462922A1 (en) * 2010-12-10 2012-06-13 Bioprojet New form of administration of enkephalinase inhibitor
CN102133168B (en) * 2011-03-18 2012-05-02 汤广武 Beauty mask and preparation method thereof
US9801819B2 (en) * 2012-06-28 2017-10-31 Johnson & Johnson Consumer Inc. Racecadotril compositions

Also Published As

Publication number Publication date
CN105848643A (en) 2016-08-10
JP2017500355A (en) 2017-01-05

Similar Documents

Publication Publication Date Title
US9801819B2 (en) Racecadotril compositions
AU2013282413B2 (en) Racecadotril lipid compositions
CN100367951C (en) Butylphthalide Intravenous Emulsion and Its Application
EP3955894A1 (en) Self-emulsifying drug delivery systems for delivery of lipophilic compounds
JP6618488B2 (en) A stable formulation of testosterone undecanoate
US20150342882A1 (en) Methods of treatment using cadotril compositions
EP3086777A1 (en) Racecadotril compositions
KR100426346B1 (en) Pharmaceutical compositions for Hypercholesterolemia treatment using of Self Emulsifying drug delivery system
KR100524700B1 (en) Pharmaceutical compositions for Hyperlipidemia treatment using of Self Emulsifying drug delivery system
HK1208178B (en) Racecadotril lipid compositions

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20160725

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

DAX Request for extension of the european patent (deleted)
18W Application withdrawn

Effective date: 20170228