WO2015100241A1 - Racecadotril liquid compositions - Google Patents
Racecadotril liquid compositions Download PDFInfo
- Publication number
- WO2015100241A1 WO2015100241A1 PCT/US2014/071906 US2014071906W WO2015100241A1 WO 2015100241 A1 WO2015100241 A1 WO 2015100241A1 US 2014071906 W US2014071906 W US 2014071906W WO 2015100241 A1 WO2015100241 A1 WO 2015100241A1
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- WO
- WIPO (PCT)
- Prior art keywords
- liquid composition
- racecadotril
- dosage form
- active ingredient
- composition
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 98
- 229960002281 racecadotril Drugs 0.000 title claims abstract description 71
- 108700040249 racecadotril Proteins 0.000 title claims abstract description 71
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- 239000007788 liquid Substances 0.000 title claims abstract description 61
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- OOYIOIOOWUGAHD-UHFFFAOYSA-L disodium;2',4',5',7'-tetrabromo-4,5,6,7-tetrachloro-3-oxospiro[2-benzofuran-1,9'-xanthene]-3',6'-diolate Chemical compound [Na+].[Na+].O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(Br)=C([O-])C(Br)=C1OC1=C(Br)C([O-])=C(Br)C=C21 OOYIOIOOWUGAHD-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229940037395 electrolytes Drugs 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- IINNWAYUJNWZRM-UHFFFAOYSA-L erythrosin B Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 IINNWAYUJNWZRM-UHFFFAOYSA-L 0.000 description 1
- 235000012732 erythrosine Nutrition 0.000 description 1
- 239000004174 erythrosine Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 235000019240 fast green FCF Nutrition 0.000 description 1
- 235000021149 fatty food Nutrition 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- WDPIZEKLJKBSOZ-UHFFFAOYSA-M green s Chemical compound [Na+].C1=CC(N(C)C)=CC=C1C(C=1C2=CC=C(C=C2C=C(C=1O)S([O-])(=O)=O)S([O-])(=O)=O)=C1C=CC(=[N+](C)C)C=C1 WDPIZEKLJKBSOZ-UHFFFAOYSA-M 0.000 description 1
- 239000008123 high-intensity sweetener Substances 0.000 description 1
- 235000012738 indigotine Nutrition 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical class [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 229940125722 laxative agent Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000000978 natural dye Substances 0.000 description 1
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 235000012736 patent blue V Nutrition 0.000 description 1
- 239000004177 patent blue V Substances 0.000 description 1
- DHAHKSQXIXFZJB-UHFFFAOYSA-O patent blue V Chemical compound C1=CC(N(CC)CC)=CC=C1C(C=1C(=CC(=C(O)C=1)S(O)(=O)=O)S(O)(=O)=O)=C1C=CC(=[N+](CC)CC)C=C1 DHAHKSQXIXFZJB-UHFFFAOYSA-O 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000012731 ponceau 4R Nutrition 0.000 description 1
- 239000004175 ponceau 4R Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 235000012739 red 2G Nutrition 0.000 description 1
- 239000004180 red 2G Substances 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- GSFNWGKBQZDYCL-UHFFFAOYSA-N sodium 2-(3-hydroxy-5-sulfo-1H-indol-2-yl)-3-oxoindole-5-sulfonic acid Chemical compound [Na+].Oc1c([nH]c2ccc(cc12)S(O)(=O)=O)C1=Nc2ccc(cc2C1=O)S(O)(=O)=O GSFNWGKBQZDYCL-UHFFFAOYSA-N 0.000 description 1
- KVMUSGMZFRRCAS-UHFFFAOYSA-N sodium;5-oxo-1-(4-sulfophenyl)-4-[(4-sulfophenyl)diazenyl]-4h-pyrazole-3-carboxylic acid Chemical compound [Na+].OC(=O)C1=NN(C=2C=CC(=CC=2)S(O)(=O)=O)C(=O)C1N=NC1=CC=C(S(O)(=O)=O)C=C1 KVMUSGMZFRRCAS-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000021259 spicy food Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 235000012751 sunset yellow FCF Nutrition 0.000 description 1
- 239000004173 sunset yellow FCF Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 235000012756 tartrazine Nutrition 0.000 description 1
- 239000004149 tartrazine Substances 0.000 description 1
- GMMAPXRGRVJYJY-UHFFFAOYSA-J tetrasodium 4-acetamido-5-hydroxy-6-[[7-sulfonato-4-[(4-sulfonatophenyl)diazenyl]naphthalen-1-yl]diazenyl]naphthalene-1,7-disulfonate Chemical compound [Na+].[Na+].[Na+].[Na+].OC1=C2C(NC(=O)C)=CC=C(S([O-])(=O)=O)C2=CC(S([O-])(=O)=O)=C1N=NC(C1=CC(=CC=C11)S([O-])(=O)=O)=CC=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 GMMAPXRGRVJYJY-UHFFFAOYSA-J 0.000 description 1
- AAAQKTZKLRYKHR-UHFFFAOYSA-N triphenylmethane Chemical compound C1=CC=CC=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 AAAQKTZKLRYKHR-UHFFFAOYSA-N 0.000 description 1
- SWGJCIMEBVHMTA-UHFFFAOYSA-K trisodium;6-oxido-4-sulfo-5-[(4-sulfonatonaphthalen-1-yl)diazenyl]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N=NC3=C4C(=CC(=CC4=CC=C3O)S([O-])(=O)=O)S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 SWGJCIMEBVHMTA-UHFFFAOYSA-K 0.000 description 1
- 235000013976 turmeric Nutrition 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000001018 xanthene dye Substances 0.000 description 1
Classifications
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- 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
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- 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
- A61K31/695—Silicon compounds
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
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- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
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- 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 liquid compositions. More particularly, the present invention relates to liquid compositions containing racecadotril 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 result 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. However, many of these products provide relief with some side effects.
- Racecadotril is also used in the treatment of diarrhea. It reduces (i) hypersecretion of water and electro lytes into the intestinal lumen, (ii) the incidence and duration of acute diarrhea and (iii) diarrhea-associated symptoms.
- racecadotril is available in solid oral dosage forms.
- the present invention is directed to a liquid composition comprising racecadotril and cyciodextrin.
- the inventive composition comprises about 0.01 wt.% to about 24.0 wt.% racecadotril and about 1 wt.% to about 95 wt.% of a cyciodextrin, 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 and cyciodextrin.
- stable refers to a liquid composition substantially free of chemical degradation of racecadotril or substantial color change.
- the total chemical degradant products of racecadotril should be less than 0.2 percent by weight (wt.%), e.g. less than 0.1 w t.% based on the total wt.% of racecadotril when stored at 3 months and 40°C.
- the total chemical degradant products of racecadotri l should be less than 0.2 percent by weight (wt.%), e.g. less than 0.1 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.
- the present invention is a liquid composition comprising racecadotril and cyciodextrin.
- Racecadotril' s efficacy in reducing the symptoms of diarrhea have been demonstrated in various studies.
- One of the benefits of using racecadotril over other remedies is that in comparative trials racecadotril was shown to have fewer adverse events such as post-treatment constipation,
- the racecadotril is included in a stable liquid composition.
- Racecadotril is a. compound with low water solubility, making it difficult to formulate into liquid compositions.
- oral liquid compositions are the most preferred dosage form for administering medications to the pediatric population.
- a. RS racemic form of racecadotril is used. In another embodiment, a. R form of racecadotril is used.
- Racecadotril is included in the liquid composition in an amount from about 0.01 grams to about 0.5 grams per 100 ml of the liquid composition.
- the racecadotril is about 0.05 grams to about 0.4 grams, and more preferably, about, 0.1 grams to about 0.3 grams per 100 ml of the liquid composition.
- the racecadotril is about 0.25 grams per 100 ml of liquid composition
- the viscosity of the liquid composition is from about 1 to about 500 centipoise at room temperature (25° C) measured using a Brookfield Viscometer,
- the pH of the liquid composition is from about I to about 6, Preferably, the pH is about 3 to about 5. More preferably, the pH is about 4.5.
- a buffering system may be included to maintain the pH at the value or in the desired range.
- the buffer may be a citrate, an acetate, a phosphate, or mixtures thereof.
- an acetate buffer is used.
- racecadotril is dissolved into the liquid composition.
- Cyclodextrins are compounds used in a wide variety of products, which include pharmaceutical, food, consumer and chemical products. They are synthesized from starch via an enzymatic reaction.
- Suitable cyclodextrins include, for example, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydro xypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, or mixtures thereof.
- the cyclodextrin is hydroxypropyl-beta-cyclodextrin.
- One source of hydroxypropyi-beta-cyclodextrin is CAVASOL W7 available from International Speciality Products Corporation (ISP).
- the cyciodextrin is a sulfobutyl ether derivative of ⁇ - cyciodextrin, sold under the tradename CAPTISOL available from Captisol,
- the cyciodextrin is included in the composition in an amount from about 1 grams to about 70 grams per 100 ml of the liquid composition.
- the cyciodextrin is about 5 grams to about 60 grams, and more preferably, about 5 grams to about 50 grams per 100 ml of the liquid composition,
- the cyciodextrin is from about 40 grams to about 60 grams per 100 ml of the liquid composition.
- the cyciodextrin is from about 15 grams to about, 30 grams per 100 ml of the liquid composition.
- the liquid composition also has water.
- Water is the solvent that, fills the gap after all other components have been added.
- the amo unt of water that is included varies because the water is added to bring the composition up to a desired volume amount.
- propylene glycol may be included in the liquid composition.
- Propylene glycol has many uses, such as for example a moisturizer in food and medicines, and as a solvent for food colorings and flavorings. It is a colorless, nearly odorless, clear, viscous liquid with a faintly sweet taste, hygroscopic and miscible with water, acetone, and chloroform.
- Any coloring agent suitable for use in a food or pharmaceutical product may be used in the present inventive composition.
- Typical coloring agents include, for example, azo dyes, quinopthalone dyes, triphenylmethane 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 BN, 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 liquid composition. The amount of flavor added to the composition will be dependent upon the desired taste characteristics.
- composition may contain other ingredients or components, such as aromas;
- sweeteners such as, sorbitol, high fructose corn syrup, sugar, and high intensity sweeteners such as sucralose, aspartame and saccharine and the like: viscosity modifiers such as xanthan gum; preservatives such as sodium benzoate NF, buffers such as citric acid and/or sodium chloride; surfactants such as polysorbate 80 a.nd/or sodium iauryl sulfate or mixtures thereof.
- viscosity modifiers such as xanthan gum
- preservatives such as sodium benzoate NF, buffers such as citric acid and/or sodium chloride
- surfactants such as polysorbate 80 a.nd/or sodium iauryl sulfate or mixtures thereof.
- the inventive liquid composition includes about 0,1 wt.% to about 0.3 wt.% racecadotril and about 40 wt.% to about 65 wt.% cyclodextrin, wherein each wt.% is based upon 100 ml of the composition.
- the inventive liquid composition includes about 0.1 wt.% to about 0.3 wt.% racecadotril and about 10 wt.% to about 40 wt.% cyclodextrin, wherein each wt.% is based upon 100 ml of the composition.
- the solubility of the racecadotril in the inventive composition is about 1.5 to about 4.0
- liquid 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 ma ner so long as the intended result is achieved. Moreover, the mixing action should be sufficient to incorporate each ingredient into the composition.
- the liquid of the present invention comprises a second active ingredient.
- the second active ingredient may be, for example, present in a suspended state, or may be solubilizecl in the liquid composition.
- the second active ingredient is a digestive health active ingredient may be, for example, laxatives, antacids, proton pump inhibitors, anti-gas agents, antiemetics, H2 blockers, a second antidiarrheal agent, and the like.
- 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 liquid composition may be delivered in any suitable delivery system.
- the liquid composition is delivered orally.
- the composition is a liquid oral dosage form.
- a soft shell solid dosage form is used to deliver the liquid composition.
- a hard shell solid dosage form is used to deliver the liquid composition.
- a tablet dosage form is used to deliver the liquid 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 and cyclodextrin.
- composition for an oral racecadotril liquid is shown in Table 1. Utilizing the materials in Table 1 , the following mixing steps were used:
- Step 1 A solution of was formed by mixing the purified water and hydroxvpropyl beta- cyciodextrin in a suitable vessel with a laboratory mixer.
- Step 2 The racecadotril was added to the solution in Step 1 and mixed in a laboratory shaker for at least 12 hours and a clear solution was formed.
- Step 3 The citric acid, sorbitol solution, high fractose com syrup, and sodium chloride was mixed to form a solution and mixed using a laboratory mixer until dissolved.
- Step 4 A separate mixture was prepared by mixing the flavor into the polyethylene glycol 400 in a suitable vessel. This mixture was then mixed with the solution from Step 3 and diluted to volume with purified water.
- Table 1 Racecadotril Oral Liquid Composition (2.5 mg/g)
- racecadotril in an aqueous buffer of acetate Three formulations of racecadotril in an aqueous buffer of acetate were prepared and three formulations of racecadotril in an aqueous buffer of citrate were prepared. These formulations were prepared utilizing a mixture of racecadotril in the Sulfobutyl ether derivative of ⁇ - cyciodextrin (Captisol®) and are shown in Table 2.
- Table 2 Racecadotril Sulfobutyl Ether Derivative of ⁇ -cyelodextrin Based Aqueous Compositions Solvent System Actual Composition
- Step 1 in a suitable glass bottle, the Captisol 4, were weighed, mixed and prepared as 60%, 70% and 78% in pH 4.5 acetate buffers, respectively (Formulae 1, 3 and 5). Also, the Captisol ® were weighed and prepared as 60%, 69% and 80% in pH 4.5 citrate buffers, respectively (Formulae 2, and 6).
- Step 2 The pH of each bottle was adjusted to pH 4.5 with either glacial acetic acid (17.4 M) or citric acid (3 M).
- Step 3 The Racecadotril was slowly added to each bottle in Step 2, utilizing the vortex mixer to mix for 5 minutes, and then placed each bottle into a. laboratory shaker and mixed for 24 hours until a solution was formed.
- racecadotril was tested at room temperature and at room temperature
- racecadotril is unstable after 12 hours. Moreover, at I week, racecadotril is present at less than 1 %.
- the assay of Racecadotril is determined by using the external standard injected.
- the degradation products levels are determined by % peak area relative to the Racecadotril peak. mc conditions .buro ean riiaraiaco oesa Kabobc
- Mobil Phase A Phosphate buffer, pH 2.5 (Buffer prep: dissolve l g of potassium dihydrogen phosphate in water, adjust to pH 2.5 with phosphoric acid, dilute to lOOOmL with water)
- Mobil Phase B 100% Acetonitrile
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CA2934756A CA2934756A1 (en) | 2013-03-15 | 2014-12-22 | Racecadotril liquid compositions |
RU2016130051A RU2016130051A (en) | 2013-03-15 | 2014-12-22 | LIQUID COMPOSITIONS RACECADOTRIL |
CN201480070556.6A CN105873582A (en) | 2013-03-15 | 2014-12-22 | Racecadotril liquid compositions |
JP2016542153A JP2017500357A (en) | 2013-03-15 | 2014-12-22 | Racecadotril liquid composition |
EP14828106.6A EP3089744A1 (en) | 2013-03-15 | 2014-12-22 | Racecadotril liquid compositions |
KR1020167019829A KR20160096199A (en) | 2013-03-15 | 2014-12-22 | Racecadotril liquid compositions |
MX2016008389A MX2016008389A (en) | 2013-03-15 | 2014-12-22 | Racecadotril liquid compositions. |
AU2014370034A AU2014370034A1 (en) | 2013-03-15 | 2014-12-22 | Racecadotril liquid compositions |
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US14/138,272 US9114171B2 (en) | 2012-06-28 | 2013-12-23 | Racecadotril liquid compositions |
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PCT/US2014/071906 WO2015100241A1 (en) | 2013-03-15 | 2014-12-22 | Racecadotril liquid compositions |
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US9801819B2 (en) | 2012-06-28 | 2017-10-31 | Johnson & Johnson Consumer Inc. | Racecadotril compositions |
KR20150023876A (en) | 2012-06-28 | 2015-03-05 | 맥네일-피피씨, 인코포레이티드 | Racecadotril lipid compositions |
US9114171B2 (en) | 2012-06-28 | 2015-08-25 | Mcneil-Ppc, Inc. | Racecadotril liquid compositions |
EP2866802B1 (en) | 2012-06-28 | 2016-07-27 | Johnson & Johnson Consumer Inc. | Racecadotril liquid compositions |
BR102017016550A2 (en) | 2017-08-01 | 2019-03-19 | Lisis Rojo Gomes | USE OF STEROAL GLUCOSIDES, PHARMACEUTICAL FORMULATIONS, USE OF FURCRAEA PLANT EXTRACTS, PROCESSING OF FURCRAEA PLANT EXTRACTS AND SKIN DISTURBANCE METHOD METHOD |
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WO2014005021A1 (en) * | 2012-06-28 | 2014-01-03 | Mcneil-Ppc, Inc. | Racecadotril liquid compositions |
WO2014150651A1 (en) * | 2013-03-15 | 2014-09-25 | Mcneil-Ppc, Inc. | Racecadotril liquid compositions |
WO2014150660A1 (en) * | 2013-03-15 | 2014-09-25 | Mcneil-Ppc, Inc. | Racecadotril lipid compositions |
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FR2673105B1 (en) * | 1991-02-26 | 1995-01-13 | Bioprojet Soc Civ | NOVEL PHARMACEUTICAL COMPOSITIONS, ESPECIALLY FOR THE TREATMENT OF FUNCTIONAL COLOPATHIES, AND METHODS OF PREPARING COMPOSITIONS AND MEDICAMENTS, ESPECIALLY FOR THE TREATMENT OF THESE CONDITIONS. |
GB9316580D0 (en) * | 1993-08-10 | 1993-09-29 | Smithkline Beecham Plc | Pharmaceutical composition |
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BRPI0509592A (en) * | 2004-05-06 | 2007-09-25 | Cydex Inc | flavored formulations containing sulfoalkyl ether sertraline and cyclodextrin |
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WO2014005021A1 (en) * | 2012-06-28 | 2014-01-03 | Mcneil-Ppc, Inc. | Racecadotril liquid compositions |
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MX2016008389A (en) | 2017-01-11 |
US9114171B2 (en) | 2015-08-25 |
JP2017500357A (en) | 2017-01-05 |
CN105873582A (en) | 2016-08-17 |
BR112015022940A2 (en) | 2017-07-18 |
IL241040A0 (en) | 2015-11-30 |
RU2016130051A3 (en) | 2018-06-15 |
US20140271831A1 (en) | 2014-09-18 |
AU2014370034A1 (en) | 2016-07-07 |
CA2907186A1 (en) | 2014-09-25 |
RU2016130051A (en) | 2018-01-30 |
AU2014235724A1 (en) | 2015-09-24 |
US20140274948A1 (en) | 2014-09-18 |
EP3089744A1 (en) | 2016-11-09 |
PH12015502061A1 (en) | 2016-01-25 |
CA2934756A1 (en) | 2015-07-02 |
WO2014150651A1 (en) | 2014-09-25 |
KR20160096199A (en) | 2016-08-12 |
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