JP2017500355A - Racecadotril composition - Google Patents

Abstract

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

Description

  The present invention relates to lipid-based microemulsion compositions. More specifically, the present invention relates to a lipid-based microemulsion composition containing a pharmaceutically active ingredient and a method for producing the composition.

  Diarrhea is an intestinal disease characterized by increased frequency of watery stool excretion. Diarrhea can arise from a variety of causes, including bacterial or virus-induced diarrhea. Food intolerance caused by ingestion of foods such as allergies or foods high in fat or spices may cause diarrhea. Food poisoning can also lead to diarrhea. In some cases, diarrhea can be a symptom of other conditions and diseases.

  Diarrhea is a symptom of bowel or other physical dysfunction. A variety of prescription and non-prescription dispensing products can be taken for relief. However, many of these products provide relief with some side effects.

  Racecadotril is also used to treat diarrhea. Racecadotril reduces (i) hypersecretion of water and electrolytes into the intestinal lumen, (ii) incidence and duration of acute diarrhea, and (iii) diarrhea related symptoms.

  In addition, racecadotril is an active pharmaceutical ingredient that exhibits poor solubility and low oral bioavailability. Currently, racecadotril is available in a solid oral dosage form.

  The present invention relates to a microemulsion composition comprising racecadotril, at least one surfactant, and a lipid.

  In one embodiment, the microemulsion composition of the present invention comprises about 0.01 wt.% To about 24.0 wt.% Racecadotril, a total of about 1 wt.% To about 95 wt. From 0.01 wt% to about 60 wt% lipid, each wt% based on 100 mL of the composition.

  The invention also encompasses a method of treating a subject having diarrhea, comprising the step of orally administering to the subject a composition comprising racecadotril, at least one surfactant, and a lipid.

  As used herein, “microemulsion” refers to a liquid mixture of lipid, water and at least one surfactant. Microemulsions are characterized by a transparent, thermodynamically stable and isotropic appearance.

  As used herein, “stable” refers to a composition that is transparent to the naked eye and is substantially free of chemical degradation, substantial discoloration, turbidity or oily droplets of racecadotril. Phase separation should not be observed for at least about 3 months at 40 ° C. in any of the aqueous and / or non-aqueous components. More preferably, phase separation should not be observed at 40 ° C. for at least about 6 months in any of the aqueous and / or non-aqueous components. In one embodiment, the total chemical degradation product of racecadotril is less than 0.5 weight percent (% by weight), for example 0.2%, when stored at 40 ° C. for 3 months, based on the total weight percent of racecadotril. Must be less than wt%. In another embodiment, the total chemical degradation product of racecadotril, when stored at 40 ° C. for 6 months, is less than 0.5 weight percent (% by weight), for example, 0.1% based on the total weight percent of racecadotril. It must be less than 2% by weight. The percent degradation product is determined in the HPLC chromatogram by calculating the% peak area of the degradation product peak area relative to the peak area of the racecadotril peak. In one embodiment, the total chemical degradation product of racecadotril is less than 0.5%, eg, less than 0.2%, of racecadotril, based on the total percent of racecadotril, when stored at 40 ° C. for 3 months. is there.

  As used herein, a “self-microemulsifying drug delivery system” (SMEDDS) is a mixture of oil, surfactant, and optionally a co-solvent. SMEDDS can be used in system formulations to improve oral absorption of highly lipophilic compounds. SMEDDS spontaneously emulsifies with gentle agitation when introduced into the aqueous phase to produce a fine oil-in-water emulsion. Drugs in SMEDDS occur with small droplet sizes and show increased solubility and permeability. SMEDDS may be formulated for use in liquid or solid form. For solid use, the solid is packaged into capsules or tablets. Liquid filled or semi-solid filled capsules are preferred dosage forms for certain consumers because of speed perception, appearance of the pharmaceutical composition and ease of swallowing.

  The present invention is a microemulsion composition comprising racecadotril, at least one surfactant, and a lipid.

  Various studies have shown that racecadotril is effective in reducing the symptoms of diarrhea. One benefit of using racecadotril over other therapies is that racecadotril has been shown to have fewer side effects such as constipation after treatment.

  Racecadotril has a low water solubility of about 10 micrograms / mL at room temperature conditions. In the composition of the present invention, racecadotril may be solubilized in a microemulsion.

  Racecadotril is included in the microemulsion composition in an amount of about 0.01 wt% to about 24.0 wt% per 100 mL of the emulsion composition. Preferably, racecadotril is about 0.01 wt.% To about 18.0 wt.%, More preferably about 0.01 wt.% To about 12.0 wt.%, Even more preferably, the emulsion composition per 100 mL of the emulsion composition. About 0.01 wt% to about 10.0 wt% per 100 mL. In one embodiment, the racecadotril is about 4.0% to about 24.0% by weight per 100 mL of the emulsion composition. In another embodiment, the racecadotril is about 4.0% to about 18.0% by weight per 100 mL of the emulsion composition. In yet another embodiment, the racecadotril is about 4.0% to about 12.0% by weight per 100 mL of the emulsion composition. In yet another embodiment, the racecadotril is about 4.0% to about 10.0% by weight per 100 mL of the emulsion composition.

  The microemulsion composition of the present invention includes at least one surfactant. The surfactant may be, for example, a nonionic surfactant, a cationic surfactant, an anionic surfactant, or a mixture thereof.

  Suitable surfactants include, for example, water-insoluble surfactants having a hydrophilic-lipophilic balance (HLB) value of less than 12, and water-soluble surfactants having an HLB value of more than 12. Surfactants with high HLB and hydrophilicity help to form oil-water droplets. Surfactants are amphiphilic in nature and can dissolve or solubilize relatively large amounts of hydrophobic drug compositions.

  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, phospholipid, Hydrogenated soybean phosphatidylcholine (HSPC), distearoylphosphatidylglycerol (DSPG), L-α-dimyristoylphosphatidylcholine (DMPC), L-α-dimyristoylphosphatidylglycerol (DMPG), polyoxyl 35 castor oil (CREMOPHOR EL, CREMOPHOR ELP) Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), Polyoxyl 60 hydrogenated castor oil (CREMOPHOR RH 60), Resorbate 20 (TWEEN 20), polysorbate 80 (TWEEN 80), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), Solutol HS-15, sorbitan monooleate (SPAN 20), PEG 300 caprylic acid / capric glyceride ( SOFTIGEN 767), PEG 400 caprylic / capric glycerides (LABRASOL), PEG 300 oleic glycerides (LABRAFIL M-1944CS), polyoxyl 35 castor oil (ETOCAS 35), glyceryl caprylate (mono and diglycerides) (IMWITOR), PEG 300 linoleic acid glyceride (LABRAFIL M-2125CS), polyoxyl 8 stearate (PEG 400 Roh stearate), polyoxyl 40 stearate (PEG 1750 monostearate), peppermint oil, and combinations thereof.

  In addition, suitable surfactants include, for example, polyoxyethylene derivatives of sorbitan monolaurate such as polysorbate, caprylcaproyl macrogol glyceride, polyglycolized glyceride and the like.

  In one embodiment, the surfactant is a combination of polyoxyl 35 castor oil and glyceryl caprylate (mono and diglycerides) NF.

  In the compositions of the present invention, the total weight percent of surfactant is from about 1% to about 95% by weight per 100 mL of microemulsion composition. Preferably, the surfactant is from about 25% to about 95%, more preferably from about 30% to about 90% by weight per 100 mL of the microemulsion composition. In one embodiment, the surfactant is about 45% to about 95% by weight per 100 mL of microemulsion composition.

  Lipids are another essential component of the composition of the present invention. Lipids help solubilize racecadotril and also facilitate the self-emulsification process. Suitable lipids may include, for example, vegetable oils (modified and / or hydrolyzed), long and medium chain triglycerides having different degrees of saturation, and combinations thereof.

  In addition, lipophilic and water-insoluble monoglycerides, diglycerides, and / or triglyceride emulsifiers (fats and oils) (available from Abitec Corporation, sold under the trade name CAPMUL®) are used as lipids. Also good. For example, beeswax, oleic acid, soybean fatty acid, d-α-tocopherol (vitamin E), corn 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 oil, medium chain triglyceride, caprylic / capric acid triglyceride derived from coconut oil, palm seed oil, and combinations thereof It is.

  Lipids are included in the composition in an amount of about 0.01% to about 60% by weight per 100 mL of the emulsion composition. Preferably, the lipid is about 0.01% to about 50% by weight. In another embodiment, the lipid is from about 1% to about 20% by weight per 100 mL of emulsion composition, more preferably from about 1% to about 15% by weight, even more preferably, per 100 mL of emulsion composition. From about 1% to about 10% by weight per 100 mL of the emulsion composition. In one particular embodiment, the lipid is about 1% to about 2% by weight per 100 mL of the emulsion composition.

  It is desirable to minimize the amount of water in the composition. The amount of water in the composition will be determined primarily by the water content of each component included in the composition. In one embodiment, the water content of the composition is less than about 3.5% by weight, based on the total weight% of the composition. In another embodiment, the water content of the composition is less than about 2.5% by weight, based on the total weight% of the composition. In yet another embodiment, the water content of the composition is less than about 0.5% by weight, based on the total weight% of the composition. In yet another embodiment, the water content of the composition is less than about 0.2% by weight, based on the total weight% of the composition.

  Optionally, various components may be included in the emulsion composition of the present invention.

  Any colorant suitable for use in food or pharmaceutical products may be used in the present invention. Typical colorants include, for example, azo dyes, quinopthalone dyes, triphenylmethane dyes, xanthene dyes, indigoid dyes, iron oxides, iron hydroxides, titanium dioxide, natural dyes, and mixtures thereof. Can be mentioned. More specifically, suitable colorants include Patent Blue V, Acid Brilliant Green BS, Red 2G, Azorubin, 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, carotene, antyhocyanines, turmeric, cochineal extract, clorophyllin, canthaxanthin, caramel, betanin, and mixtures thereof.

  Similarly, flavoring agents may be included in the emulsion composition of the present invention. The amount of flavoring agent added to the composition depends on the desired taste characteristics.

  Compositions include fragrances; sweeteners such as sucralose, sorbitol, high fructose corn syrup, sugar; viscosity modifiers such as xanthan gum; preservatives such as sodium benzoate NF; buffers such as citric acid and / or sodium chloride; Or other components or components, such as a mixture thereof, may be included.

  The emulsion composition of the present invention may be made by any method known to those skilled in the art as long as the desired composition is obtained.

  Suitable methods include, for example, a method in which the components are combined in a mixing kettle, where the components may be added continuously or in any manner as long as the intended result is achieved. May be. Furthermore, the mixing action should be sufficient to incorporate each component into the composition.

  The primary means of assessing emulsion stability is based on analytical decomposition analysis. The efficiency of self-emulsification can be estimated by emulsification rate, droplet size distribution and turbidity measurement.

  Furthermore, stability may be evaluated by measuring the turbidity of the emulsion. This evaluation helps to determine whether the emulsion reaches equilibrium in a quick and reproducible time.

  Stability is also assessed by checking for supersaturation (precipitation). The test is performed by placing 1 mL of the formulation in a beaker containing 250 mL of 0.1 N HCL. If a precipitate is formed, the system is supersaturated.

  In one embodiment of the 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 plurality of microgel beads containing the microemulsion composition. In yet another embodiment, the microemulsion composition is administered in a hard gelatin capsule containing the microemulsion composition. When the microemulsion composition is contained in a hard gelatin capsule, the hard gelatin capsule may be band-fixed. In yet another embodiment, the microemulsion composition is administered in a suppository or enema containing the microemulsion composition.

  Optionally, the microemulsion composition of the present invention comprises a second active ingredient. In one embodiment, the second active ingredient is a digestible health active ingredient. Non-limiting examples include laxatives, antacids, proton pump inhibitors, antigas agents, antiemetics, H2 blockers, or second antidiarrheal agents.

  In one embodiment, the second active ingredient is incorporated into the microemulsion matrix. In another embodiment, the second active ingredient is present in a separate portion of the dosage form composition that 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.

  In one embodiment, the microemulsion composition of the present invention comprises about 8.0% to about 10.0% by weight racecadotril, and a total of about 88% to about 91% by weight surfactant, about 1%. % To about 2% by weight of lipid, each weight% based on 100 mL of composition.

  In another embodiment, the microemulsion composition of the present invention comprises from about 0.01% to about 24.0% by weight racecadotril, and in total from about 1% to about 95% by weight surfactant, 0.01 wt% to about 60 wt% lipid, each wt% based on 100 mL of the composition.

  In yet another embodiment, the microemulsion composition of the present invention comprises from about 3.0% to about 7.0% by weight racecadotril and a total of about 40% to about 53% by weight surfactant, About 40 wt% to about 53 wt% lipid, each wt% based on 100 mL of the composition.

  The microemulsion composition of the present invention may be delivered by 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 yet another embodiment, the microemulsion composition is delivered in a hard shell dosage form. In yet another embodiment, tablet dosage forms are used for delivery of the microemulsion composition.

  In addition, the droplet size of the composition of the present invention was measured by dynamic light scattering (DLS) at a scattering angle of 90 degrees using a Horiba SZ-100 Nanoparticle Size Analyzer. The sample was kept at 25 ° C. in a temperature control chamber during the measurement. Immediately prior to measurement, instrument performance was tested using a nominal 100 nm polyester latex (PSL) size standard in 10 mM NaCl. Count rates for these measurements ranged from 1 million to 3 million counts / second. Each measurement was performed for 1 minute. Data was analyzed using the cumulant method.

  Droplet size was also measured at 90 ° scattering angle by Dynamic Light Scattering (DLS) on a Nicomp 380 Nanoparticulate Size Analyzer at Particle Sizing Systems (PSS). All measurements were performed at 23 ° C. After warm-up operation, the instrument was challenged with NIST traceable standards (ie, polystyrene latex) and inspected for accuracy. During sample measurement, a scattering intensity of 150-500 kHz was targeted and continued for 15 minutes. Data was analyzed using the cumulant method.

  The invention also encompasses a method of treating a subject having diarrhea, comprising the step of orally administering to the subject a composition comprising racecadotril, at least one surfactant, and a lipid.

  The following examples are provided to further illustrate the compositions and methods of this invention. It should be understood that the invention is not limited to the described embodiments.

Example 1
Concentrated racecadotril lipid composition: for liquid-filled gelatin capsules

１：ＣＲＯＤＡ ＨｅａｌｔｈｃａｒｅからＥＴＯＣＡＳ（登録商標）３５ ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている
２：ＣＲＥＭＥＲからＩＭＷＩＴＯＲ（登録商標）９８８ ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている
３：ＣＲＥＭＥＲからＭＩＧＬＹＯＬ（登録商標）８１０Ｎ（カプリル酸／カプリン酸トリグリセリド；７０：３０／Ｃ８：Ｃ１０）ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている

1: CRODA Healthcare is commercially available as ETOCAS (registered trademark) 35 USP / NF, EP, JP 2: CREMER is commercially available as IMWITOR (registered trademark) 988 USP / NF, EP, JP is commercially available 3: CREMER is MIGLYOL (Registered trademark) 810N (caprylic acid / capric acid triglyceride; 70: 30 / C8: C10) marketed as USP / NF, EP, JP

１：ＣＲＯＤＡ ＨｅａｌｔｈｃａｒｅからＥＴＯＣＡＳ（登録商標）３５ ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている
２：ＣＲＥＭＥＲからＩＭＷＩＴＯＲ（登録商標）９８８ ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている
３：ＣＲＥＭＥＲからＭＩＧＬＹＯＬ（登録商標）８１２Ｎ（カプリル酸／カプリン酸トリグリセリド；６０：４０／Ｃ８：Ｃ１０）ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている

1: CRODA Healthcare is commercially available as ETOCAS (registered trademark) 35 USP / NF, EP, JP 2: CREMER is commercially available as IMWITOR (registered trademark) 988 USP / NF, EP, JP is commercially available 3: CREMER is MIGLYOL (Registered trademark) 812N (caprylic acid / capric acid triglyceride; 60: 40 / C8: C10) commercially available as USP / NF, EP, JP

  Using the materials in Tables 1 and 2, the following mixing steps were performed to form microemulsions. Three ratios were prepared using MIGLYOL 810N (Table 1) and MIGLYOL 812N (Table 2), respectively, for a total of six mixtures.

  Step 1: In a suitable container, mix a mixture of polyoxyl 35 castor oil (ETOCAS® 35), glyceryl caprylate (IMWITOR® 988) and medium chain triglycerides (MIGLYOL® 810N and 812N). Were prepared as three separate mixtures of the following weight ratios. 88: 10: 2 (ratio 1), 58: 40: 2 (ratio 2), and 30: 68: 2 (ratio 3).

  Step 2: The mixture obtained in Step 1 was mixed using a vortex mixer.

  Step 3: Using a vortex mixer, racecadotril was slowly added to the mixture obtained in step 2 and mixed for 5 minutes.

  Step 4: The mixture obtained in Step 3 was placed in a laboratory shaker and mixed for 36 hours until a clear solution was formed.

The stability of the racecadotril lipid formulation The chemical stability of the formulation prepared in Example 1 was tested for racecadotril degradation when stored in a sealed bottle at 40 ° C for 40.1 weeks. The results are shown in Table 3.

  Impurity A, thiorphan, or impurity E was not present in Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, and Formula 6.

ND: not detectable
1.88% Super Refined Etocas 35, 10% Imwitor 988, 2% Miglyol 810N (ratio 1)
2.88% Super Refined Etocas 35, 10% Imwitter 988, 2% Miglyol 812N (ratio 1)
3.58% Super Refined Etocas 35, 40% Imwitter 988, 2% Miglyol 810N (ratio 2)
4.58% Super Refined Etocas 35, 40% Imwitter 988, 2% Miglyol 812N (ratio 2)
5. 30% Super Refined Etocas 35, 68% Imwitter 988, 2% Miglyol 810N (ratio 3)
6. 30% Super Refined Etocas 35, 68% Imwitter 988, 2% Miglyol 812N (ratio 3)
ND-not detectable

component:
A. Super Refined Etocas 35 (NF, EP, JP):
CRODA Health Care polyoxyl 35 castor oil HLB value 14
B. Imwriter 988: Medium-chain partial glycerides Made by CREMER Glyceryl caprylate (mono and diglycerides)
Melting point about 25 ° C
HLB value 4
C. Imwriter 742: Medium-chain partial glyceride Made by CREMER Caprylic acid / Capric glyceride Melting point: about 25 ° C
HLB value 3-4
D. Miglyol: medium chain triglyceride (MCT oil, functionalized coconut oil)
Caprelic acid (C8) / capric acid (C10) triglyceride 810N-70: 30 C8 / C10 blend 812N-60: 40 C8 / C10 blend

Conversion based on the density of each recipe:
Formula 1 / Formulation 2: 1.042 g / mL
Formula 3 / Formulation 4: 1.028 g / mL
Formula 5 / Formulation 6: 1.016 g / mL

(Example 2)
Concentrated racecadotril lipid composition: for liquid-filled gelatin capsules

１：ＣＲＥＭＥＲからＩＭＷＩＴＯＲ ７４２（登録商標）ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている
２：ＣＲＥＭＥＲからＭＩＧＬＹＯＬ（登録商標）８１０Ｎ（カプリル酸／カプリン酸トリグリセリド；７０：３０／Ｃ８：Ｃ１０）ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている
３：ＣＲＥＭＥＲからＭＩＧＬＹＯＬ（登録商標）８１２Ｎ（カプリル酸／カプリン酸トリグリセリド；６０：４０／Ｃ８：Ｃ１０）ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている

1: Commercially available from CREMER as IMWITOR 742® USP / NF, EP, JP 2: from CREMER MIGLYOL® 810N (caprylic / capric triglyceride; 70: 30 / C8: C10) USP / Commercially available as NF, EP, JP 3: Commercially available from CREMER as MIGLYOL® 812N (caprylic acid / capric acid triglyceride; 60: 40 / C8: C10) USP / NF, EP, JP

１：ＣＲＥＭＥＲからＩＭＷＩＴＯＲ ９８８（登録商標）ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている
２：ＣＲＥＭＥＲからＭＩＧＬＹＯＬ（登録商標）８１０Ｎ（カプリル酸／カプリン酸トリグリセリド；７０：３０／Ｃ８：Ｃ１０）ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている
３：ＣＲＥＭＥＲからＭＩＧＬＹＯＬ（登録商標）８１２Ｎ（カプリル酸／カプリン酸トリグリセリド；６０：４０／Ｃ８：Ｃ１０）ＵＳＰ／ＮＦ、ＥＰ、ＪＰとして市販されている

1: Commercially available from CREMER as IMWITOR 988® USP / NF, EP, JP 2: CREMER® MIGLYOL® 810N (caprylic / capric triglyceride; 70: 30 / C8: C10) USP / Commercially available as NF, EP, JP 3: Commercially available from CREMER as MIGLYOL® 812N (caprylic acid / capric acid triglyceride; 60: 40 / C8: C10) USP / NF, EP, JP

Test method:
Sample preparation: (in acetonitrile)
Pipette 1.1 mL of racecadotril lipid solution into a 100 mL volumetric flask (VF).
2. Dilute to full volume with acetonitrile. If necessary, add approximately 20 mL of dimethylacetamide.
3. If necessary, further dilute the sample solution with acetonitrile to about 0.1 mg / mL.

Sample analysis A reference standard (0.1 mg / mL racecadotril in acetonitrile) and a sample are injected into a suitable HPLC system under conditions similar to those described below. The parameters may be changed to optimize the chromatography.

  The racecadotril peak area of the sample solution under test is compared to the racecadotril peak area of the standard solution to determine the concentration of racecadotril. The percentage of degradation products is determined by the% peak area relative to the racecadotril peak.

  Mobile phase A: phosphate buffer, pH 2.5 (buffer preparation: 1 g potassium dihydrogen phosphate dissolved in water, adjusted to pH 2.5 with phosphoric acid and diluted to 1000 mL with water)

  Mobile phase B: 100% acetonitrile

(Example 3)
Racecadotril lipid composition: Droplet size Procedure Droplet size was measured on a Horiba SZ-100 Nanoparticle Size Analyzer with dynamic light scattering (DLS) at a scattering angle of 90 degrees. During the measurement, the sample was kept at 25 ° C. in a temperature control chamber. Immediately prior to measurement, instrument performance was tested using 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 / second. Each measurement was performed for 1 minute. Data was analyzed using the cumulant method.

  Solubility and droplet size for lipid-based formulations

^＊Ｈｏｒｉｂａ ＳＺ−１００ Ｎａｎｏｐａｒｔｉｃｌｅ Ｓｉｚｅ Ａｎａｌｙｚｅｒを用いて動的光散乱（ＤＬＳ）により測定、３回の測定の平均（ｎ＝３）
^１一般的な手順：０．０８ｇの各製剤と１５ｍＬの０．１Ｎ ＨＣｌとを組み合わせ、渦撹拌により混合した。
^２密度１．０４２ｇ／ｍＬに基づいて計算
^３密度１．０２８ｇ／ｍＬに基づいて計算
^４密度１．０１６ｇ／ｍＬに基づいて計算
^５ラセカドトリルの濃度約０．５３ｍｇ／ｍＬ
^６ラセカドトリルの濃度約０．５５ｍｇ／ｍＬ
^７ラセカドトリルの濃度約０．４４ｍｇ／ｍＬ
^８ラセカドトリルの濃度約０．６０ｍｇ／ｍＬ
^９ラセカドトリルの濃度約０．４３ｍｇ／ｍＬ
^１０ラセカドトリルの濃度約０．４６ｍｇ／ｍＬ
^＊＊処方に関しては実施例１を参照

^* Measured by dynamic light scattering (DLS) using Horiba SZ-100 Nanoparticulate Size Analyzer, average of 3 measurements (n = 3)
¹ General procedure: 0.08 g of each formulation was combined with 15 mL of 0.1 N HCl and mixed by vortexing.
Calculated based on ² density 1.042 g / mL
³ Calculated based on 1.028 g / mL density
⁴ Calculated based on 1.016 g / mL density
Concentration of ⁵ racecadotril about 0.53 mg / mL
Concentration of ⁶ racecadotril about 0.55 mg / mL
Concentration of ⁷ racecadotril about 0.44 mg / mL
Concentration of ⁸ racecadotril about 0.60 mg / mL
Concentration of ⁹ racecadotril about 0.43 mg / mL
Concentration of ¹⁰ racecadotril about 0.46 mg / mL
^** See Example 1 for prescription

  The droplet size was also measured at 90 ° scattering angle by Dynamic Light Scattering (DLS) on a Nicomp 380 Nanoparticulate Size Analyzer at Particle Sizing Systems (PSS). All measurements were performed at 23 ° C. After warm-up operation, the instrument was challenged with NIST traceable standards (ie, polystyrene latex) and inspected for accuracy. During sample measurement, a scattering intensity of 150-500 kHz was targeted and continued for 15 minutes. Data was analyzed using the cumulant method.

^＊Ｎｉｃｏｍｐ ３８０ Ｎａｎｏｐａｒｔｉｃｌｅ Ｓｉｚｅ Ａｎａｌｙｚｅｒを用いて、動的光散乱（ＤＬＳ）により測定。
^１一般的な手順：処方１及び３の場合、０．２ｍＬの製剤と４．８ｍＬの０．１Ｎ ＨＣｌとを組み合わせて混合し；処方２及び４の場合、０．１ｍＬの製剤と４．９ｍＬの０．１Ｎ ＨＣｌとを組み合わせて混合し、処方５及び６の場合、０．１ｍＬの製剤と４．９ｍＬの０．１Ｎ ＨＣｌとを組み合わせて混合した後、２．５ｍＬの希釈物を２．５ｍＬの０．１Ｎ ＨＣｌに加えた。
^２密度１．０４２ｇ／ｍＬに基づいて計算
^３密度１．０２８ｇ／ｍＬに基づいて計算
^４密度１．０１６ｇ／ｍＬに基づいて計算
^５ラセカドトリルの濃度約３．８４ｍｇ／ｍＬ
^６ラセカドトリルの濃度約３．７２ｍｇ／ｍＬ
^７ラセカドトリルの濃度約０．８３ｍｇ／ｍＬ
^８ラセカドトリルの濃度約１．８９ｍｇ／ｍＬ
^９ラセカドトリルの濃度約１．８０ｍｇ／ｍＬ
^１０ラセカドトリルの濃度約０．８３ｍｇ／ｍＬ
^＊＊処方に関しては実施例１を参照

^* Measured by dynamic light scattering (DLS) using a Nicomp 380 Nanoparticle Size Analyzer.
¹ General Procedure: For Formulations 1 and 3, 0.2 mL of formulation and 4.8 mL of 0.1 N HCl are combined and mixed; for Formulations 2 and 4, 0.1 mL of formulation and 4.9 mL 0.1N HCl in combination, and for Formulations 5 and 6, 0.1 mL of the formulation and 4.9 mL of 0.1N HCl are combined and mixed, followed by 2.5 mL of the dilution. Added to 5 mL of 0.1 N HCl.
Calculated based on ² density 1.042 g / mL
³ Calculated based on 1.028 g / mL density
⁴ Calculated based on 1.016 g / mL density
Concentration of ⁵ racecadotril about 3.84 mg / mL
Concentration of ⁶ racecadotril about 3.72 mg / mL
Concentration of ⁷ racecadotril about 0.83 mg / mL
Concentration of ⁸ racecadotril about 1.89 mg / mL
Concentration of ⁹ racecadotril about 1.80 mg / mL
Concentration of ¹⁰ racecadotril about 0.83 mg / mL
^** See Example 1 for prescription

  While the invention has been described with reference to specific embodiments thereof, many changes, modifications, and variations can be made without departing from the novel concepts disclosed herein. It is clear. Accordingly, all such changes, modifications, and variations are intended to be included 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.

Embodiment
(1) a composition comprising:
Racecadotril, at least one surfactant, selected from polyoxyl 35 castor oil, glyceryl caprylate (mono and diglycerides), and combinations thereof, and lipids that are medium chain triglycerides ,Composition.
(2) A composition according to embodiment 1, wherein the composition is a self-emulsifying system.
(3) The composition of embodiment 1, wherein the composition is stable at 40 ° C. for about 40 weeks.
(4) The composition of embodiment 1, wherein the at least one surfactant is present in a total amount of about 1% to about 95% by weight per 100 mL of the emulsion composition.
(5) The composition of embodiment 1, wherein the lipid is present in an amount of about 0.01% to about 60% by weight per 100 mL of the emulsion composition.

(6) The composition according to embodiment 1, further comprising an optional component selected from the group consisting of preservatives, sweeteners, viscosity modifiers, colorants, fragrances, flavoring agents, and mixtures thereof.
(7) The composition of embodiment 1, further comprising an optional ingredient selected from the group consisting of citric acid, sodium benzoate, sucralose, a flavoring agent, and mixtures thereof.
(8) A dosage form comprising the composition of embodiment 1, wherein the dosage form is a soft shell dosage form, a hard shell dosage form, or a tablet dosage form.
9. The composition of embodiment 1, wherein the composition has a total moisture content of less than about 3.5% by weight, based on the total weight of the composition.
(10) The composition according to embodiment 1, further comprising a second active ingredient which is a digestible health active ingredient.

(11) A composition comprising:
About 0.01% to about 24.0% by weight of racecadotril;
A total of about 1% to about 95% by weight of surfactants;
About 0.01 wt% to about 60 wt% lipid,
Each weight percent is a composition based on 100 mL of the composition.
(12) A dosage form comprising the composition of embodiment 11, wherein the dosage form is a soft shell dosage form, a hard shell dosage form, or a tablet dosage form.
(13) A composition according to embodiment 11, wherein the composition is stable at 40 ° C. for about 40 weeks.
(14) a composition comprising:
From about 3.0% to about 7.0% by weight racecadotril;
A total of about 40% to about 53% by weight of surfactants;
About 40 wt% to about 53 wt% lipid,
Each weight percent is a composition based on 100 mL of the composition.
(15) A dosage form comprising the composition of embodiment 14, 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 having diarrhea, comprising the step of orally administering the composition of embodiment 1 to the subject.

Claims (16)

A composition comprising:
Racecadotril, at least one surfactant, comprising a surfactant selected from polyoxyl 35 castor oil, glyceryl caprylate (mono and diglycerides), and combinations thereof, and a lipid that is a medium chain triglyceride ,Composition.   The composition of claim 1, wherein the composition is a self-emulsifying system.   The composition of claim 1, wherein the composition is stable at 40 ° C. for about 40 weeks.   The composition of claim 1, wherein the at least one surfactant is present in a total amount of about 1 wt% to about 95 wt% per 100 mL of the emulsion composition.   The composition of claim 1, wherein the lipid is present in an amount of about 0.01 wt% to about 60 wt% per 100 mL of the emulsion composition.   The composition of claim 1, further comprising an optional ingredient selected from the group consisting of preservatives, sweeteners, viscosity modifiers, colorants, fragrances, flavoring agents, and mixtures thereof.   The composition of claim 1, further comprising an optional ingredient selected from the group consisting of citric acid, sodium benzoate, sucralose, flavoring agents, and mixtures thereof.   A dosage form comprising the composition of claim 1, wherein the dosage form is a soft shell dosage form, a hard shell dosage form, or a tablet dosage form.   The composition of claim 1, wherein the composition has a total moisture content of less than about 3.5% by weight, based on the total weight of the composition.   The composition according to claim 1, further comprising a second active ingredient which is a digestive health active ingredient. A composition comprising:
About 0.01% to about 24.0% by weight of racecadotril;
A total of about 1% to about 95% by weight of surfactants;
About 0.01 wt% to about 60 wt% lipid,
Each weight percent is a composition based on 100 mL of the composition.   12. A dosage form comprising the composition of claim 11, wherein the dosage form is a soft shell dosage form, a hard shell dosage form, or a tablet dosage form.   The composition of claim 11, wherein the composition is stable at 40 ° C. for about 40 weeks. A composition comprising:
From about 3.0% to about 7.0% by weight racecadotril;
A total of about 40% to about 53% by weight of surfactants;
About 40 wt% to about 53 wt% lipid,
Each weight percent is a composition based on 100 mL of the composition.   15. A dosage form comprising the composition of claim 14, wherein the dosage form is a soft shell dosage form, a hard shell dosage form, or a tablet dosage form.   A method for treating a subject with diarrhea, comprising the step of orally administering the composition of claim 1 to the subject.