EP3086777A1

EP3086777A1 - Racecadotril compositions

Info

Publication number: EP3086777A1
Application number: EP14833428.7A
Authority: EP
Inventors: Der-Yang Lee
Original assignee: Johnson and Johnson Consumer Inc
Current assignee: Johnson and Johnson Consumer Inc
Priority date: 2013-12-23
Filing date: 2014-12-22
Publication date: 2016-11-02
Also published as: JP2017500355A; CN105848643A

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.