CN105848643A - Racecadotril compositions - Google Patents

Abstract

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

Description

Racecadotril Composition

technical field

The present invention relates to lipid-based microemulsion compositions. More specifically, the present invention relates to lipid-based microemulsion compositions comprising pharmaceutically active ingredients and methods of preparing said compositions.

Background technique

Diarrhea is an intestinal disorder characterized by increased frequency of watery stools. Diarrhea can be caused by a variety of causes, including diarrhea caused by bacteria or viruses. Food intolerances caused by allergies or eating foods such as fatty or spicy foods can cause diarrhea. Food poisoning can also cause diarrhea. In some cases, diarrhea may be a symptom of other conditions and diseases.

Diarrhea is a symptom of a disease of the bowel or other bodily functions. There are a variety of prescription and over-the-counter products that can be used to relieve pain. However, many of these products have side effects while relieving the pain.

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

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

Contents of the invention

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

In one embodiment, the microemulsion compositions of the present invention comprise from about 0.01% to about 24.0% by weight of racecadotril, in total from about 1% to about 95% by weight of surfactants, and from about 0.01% to about 95% by weight of surfactants, and from about 0.01% to about About 60% by weight of lipids, where each % by weight is based on 100 mL of the composition.

The 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

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

As used herein, "stable" means that the composition is clear to the naked eye and is substantially free of chemical degradation, substantial color change, turbidity, or oily globules of racecadotril. No phase separation occurs in the aqueous and/or non-aqueous components for at least about 3 months at 40°C. More preferably, no phase separation occurs in the aqueous and/or non-aqueous components for at least about 6 months at 40°C. In one embodiment, the total chemical degradation products of racecadotril should be less than 0.5 wt%, such as less than 0.2 wt%, based on the total wt% of racecadotril, when stored at 40°C for three months %. In another embodiment, the total chemical degradation products of racecadotril should be less than 0.5% by weight, such as less than 0.2% by weight, based on the total weight % of racecadotril, after storage for six months at 40°C. weight%. The percentage of degradation product was determined by calculating the peak area % of the degradation product peak area in the HPLC chromatogram relative to the peak area of the racecadotril peak. In one embodiment, the total chemical degradation products of racecadotril should be less than 0.5% of racecadotril based on the total % of racecadotril when stored at 40°C for 3 months, e.g. Less than 0.2%.

As used herein, "self-microemulsifying drug delivery systems" (SMEDDS) are mixtures of oils, surfactants and sometimes co-solvents. SMEDDS can be used in formulation systems to improve the oral absorption of highly lipophilic compounds. When introduced into the aqueous phase, SMEDDS spontaneously emulsifies using gentle agitation to produce a fine oil-in-water emulsion. Drugs in SMEDDS appear as small droplet sizes and exhibit increased solubility and permeability. SMEDDS can be formulated for use in liquid or solid form. When used in solid form, the solid is enclosed in a capsule or tablet. Liquid-filled or semi-solid-filled capsules are preferred dosage forms by some consumers due to the perception of speed, visual 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 racecadotril over other drugs is that racecadotril has been shown to have fewer side effects, such as post-treatment constipation.

Racecadotril has a low water solubility of about 10 μg/ml at room temperature. In the compositions of the present invention, racecadotril may be dissolved in the microemulsion.

Racecadotril is included in the microemulsion composition in an amount of about 0.01% to about 24.0% by weight per 100 ml of the emulsion composition. Preferably, racecadotril is from about 0.01% to about 18.0% by weight per 100ml of the emulsion composition, more preferably from about 0.01% to about 12.0% by weight, and even more preferably about 0.01% to about 10.0% by weight. In one embodiment, racecadotril is present at about 4.0% to about 24.0% by weight per 100 ml of the emulsion composition. In another embodiment, racecadotril is present at about 4.0% to about 18.0% by weight per 100 ml of the emulsion composition. In yet another embodiment, the racecadotril is from about 4.0% to about 12.0% by weight per 100 ml of the emulsion composition. In yet another embodiment, racecadotril is present at about 4.0% to about 10.0% by weight per 100 ml of the emulsion composition.

The microemulsion compositions of the present invention comprise at least one surfactant. Surfactants can be, for example, nonionic surfactants, cationic surfactants, anionic surfactants, or mixtures 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 greater than 12. Surfactants with high HLB and hydrophilicity facilitate the formation of oil-water droplets. Surfactants are amphiphilic in nature and are capable of dissolving or solubilizing relatively high levels of hydrophobic drug compounds.

Non-limiting examples include: Tween, Dimethylacetamide (DMA), Dimethylsulfoxide (DMSO), Ethanol, Glycerol, N-Methyl-2-pyrrolidone (NMP), PEG 300, PEG 400, Porol Sham 407, Propylene Glycol, Phospholipids, Hydrogenated Soybean Phosphatidylcholine (HSPC), Distearoylphosphatidylglyceride (DSPG), L-α-Dimyristoylphosphatidylcholine (DMPC), L-α- Dimyristoylphosphatidylglyceride (DMPG), polyethylene glycol 35 castor oil (CREMOPHOR EL, CREMOPHOR ELP), polyethylene glycol 40 hydrogenated castor oil (Cremophor RH 40), polyethylene glycol 60 hydrogenated castor oil ( CREMOPHOR RH 60), Polysorbate 20 (TWEEN 20), Polysorbate 80 (TWEEN 80), d-alpha-Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS), Solutol HS-15, Dehydrated Sorbitan Oleate (SPAN 20), PEG 300 Caprylic/Capric Glycerides (SOFTIGEN 767), PEG 400 Caprylic/Capric Glycerides (LABRASOL), PEG 300 Olein Glycerides (LABRAFIL M-1944CS), Polyethylene Glycol 35 Castor Oil (ETOCAS 35), Caprylic Glycerides (Mono- and Diglycerides) (IMWITOR), PEG 300 Glyceryl Linoleate (LABRAFIL M-2125CS), Macrogol 8 Stearate ( PEG 400 monostearate), polyethylene glycol 40 stearate (PEG 1750 monostearate), peppermint oil, and combinations thereof.

Additionally, suitable surfactants include, for example, polyethylene glycol derivatives of sorbitan laurate such as polysorbates, macrogol caprylate caprylate, pegylated glycerides, and the like.

In one embodiment, the surfactant is a combination of polyethylene glycol 35 castor oil and caprylic acid (mono- and diglycerides) NF.

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

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

In addition, lipophilic and water-insoluble monoglyceride, diglyceride and/or triglyceride emulsifiers (fats and oils) (available from Abitec under the trade name sold) can be used as lipids. For example, beeswax, oleic acid, soybean fatty acid, d-alpha-tocopherol (vitamin E), corn oil mono-di-triglycerides, medium-chain (C8/C10) mono- and diglycerides, long-chain glycerol 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 Triglycerides, Caprylic/Capric Acid from Coconut Oil triglycerides, palm seed oil, and combinations thereof.

The lipid is included in the composition in an amount of about 0.01% to about 60% by weight per 100ml of the emulsion composition. Preferably, the lipid is from about 0.01% to about 50% by weight. In another embodiment, the lipid is from about 1% to about 20% by weight per 100ml of the emulsion composition, more preferably from about 1% to about 15% by weight per 100ml of the emulsion composition, and even more preferably From about 1% to about 10% by weight per 100ml of emulsion composition. In a specific embodiment, the lipid is present at 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 water content of the composition will primarily be determined by the water content of each component contained in the composition. In one embodiment, the composition has a moisture content of less than about 3.5% by weight, based on the total weight % of the composition. In another embodiment, the composition has a moisture content of less than about 2.5% by weight, based on the total weight % of the composition. In yet another embodiment, the composition has a moisture content of less than about 0.5% by weight, based on the total weight % of the composition. In yet another embodiment, the composition has a water content of less than about 0.2% by weight, based on the total weight % of the composition.

Optionally, various ingredients may be included in the emulsion compositions 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, quinophthalone dyes, triphenylmethane dyes, xanthene-based dyes, indigo-based 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, Azorubin, Carmine 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, bright black BN, carbon black, iron oxide black, iron oxide red, oxidation Iron yellow, titanium dioxide, riboflavin, carotene, anthocyanin, turmeric, cochineal extract, chlorophyll, canthaxanthin, caramel, betaine and mixtures thereof.

Similarly, flavoring agents may be included in the emulsion composition. The amount of flavoring agent added to the composition depends on the desired mouthfeel profile.

The composition may contain other ingredients or components such as: flavoring agents; sweeteners such as sucralose, sorbitol, high fructose corn syrup, sugar, etc.; viscosity modifiers such as xanthan gum; preservatives such as benzene Sodium formate NF, buffers such as citric acid and/or sodium chloride; or mixtures thereof.

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

Suitable methods include combining each ingredient, for example in a mixing tank, wherein the ingredients may be added continuously or in any manner so long as the desired result is achieved. Furthermore, the mixing operation should be sufficient to incorporate each ingredient into the composition.

The main method for evaluating the stability of emulsions is based on analytical degradation analysis. The efficiency of self-emulsification can be estimated by determining the emulsification rate, droplet size distribution and turbidity measurements.

Additionally, stability can be assessed by measuring the turbidity of the emulsion. This evaluation helps determine whether the emulsion reaches equilibrium quickly and within a reproducible time.

Stability was also assessed by checking supersaturation (precipitation). Testing was performed by placing 1 ml of the formulation in a beaker with 250 ml of 0.1N HCL. If a precipitate forms, the system is supersaturated.

In one embodiment of the invention, the microemulsion composition is administered as an encapsulated emulsion for direct oral consumption. In another embodiment, the microemulsion composition is administered in the form of an oral soft gelatin capsule comprising the microemulsion composition. In yet another embodiment, the microemulsion composition is applied in the form of a plurality of microgel beads comprising the microemulsion composition. In yet another embodiment, the microemulsion composition is administered in the form of a hard gelatin capsule comprising the microemulsion composition. When the microemulsion composition is contained in a hard gelatin capsule, the hard gelatin capsule may be in the form of a ribbon. In yet another embodiment, the microemulsion composition is administered in the form of a suppository or enema comprising the microemulsion composition.

Optionally, the microemulsion compositions of the present invention comprise 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, antigas agents, antiemetics, H2 blockers, secondary antidiarrheals.

In one embodiment, the second active ingredient is incorporated into the microemulsion base. In another embodiment, the second active ingredient is present in another portion of the dosage form composition separate from the microemulsion composition. In yet another embodiment, the second active ingredient is microencapsulated.

Suitable antigas 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 of racecadotril, a total of about 88% to about 91% by weight of surfactant, and about 1% to about 1% by weight. About 2% by weight of lipid, where each % by weight is based on 100 mL of the composition.

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

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

The microemulsion compositions of the present invention can 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 yet another embodiment, the microemulsion composition is delivered in a hard shell dosage form. In yet another embodiment, a tablet dosage form is used to deliver the microemulsion composition.

Furthermore, 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 samples were placed in a temperature-controlled chamber at 25°C during the measurement. Immediately prior to the measurement, instrument performance was checked using a nominal 100 nm polystyrene latex (PSL) size standard in 10 mM NaCl solution. Count rates for these measurements ranged from 1 million to 3 million counts per second. Each measurement lasts one minute. The resulting data were analyzed using cumulant techniques.

Also, the droplet size was measured on a Nicomp 380 Nano Particle Size Analyzer by Dynamic Light Scattering (DLS) at the Particle Size Analyzer (PSS) with a 90 degree scattering angle. All measurements were performed at 23°C. After the instrument has warmed up, it can be challenging to check the accuracy of the instrument with NIST-traceable standards (ie, polystyrene latex). Scattering intensities were determined between 150 kHz and 500 kHz during sample measurements lasting 15 minutes. The resulting data were analyzed using cumulant techniques.

The present invention also includes a method of 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.

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

Example 1

Concentrated racecadotril lipid composition: for use in liquid-filled gelatin capsules

Table 1: Racecadotril Lipid Based Composition Percentage of Composition: Triglyceride Type 1

1: yes 35 USP/NF, EP, JP are commercially available from CRODA Healthcare

2: yes 988USP/NF, EP, JP purchased from CREMER

3: yes 810N (caprylic/capric triglyceride; 70:30/C8:C10) USP/NF, EP, JP commercially available from CRHMER

Table 2: Racecadotril lipid-based composition as a percentage of composition: triglyceride type 2

1: yes 35 USP/NF, EP, JP are commercially available from CRODA Healthcare

2: yes 988USP/NF, EP, JP purchased from CREMER

3: yes 812N (caprylic/capric triglyceride; 60:40/C8:C10) USP/NF, EP, JP commercially available from CRHMER

Using the materials in Table 1 and Table 2, the following mixing steps were taken to form the microemulsion. A total of 6 mixtures comprising 3 ratios were prepared, where each mixture was prepared using MIGLYOL 810N (Table 1) and MIGLYOL 812N (Table 2).

Step 1: In a suitable container, mix polyethylene glycol 35 castor oil ( 35), glyceryl caprylate ( 988) and medium chain triglycerides ( 810N & 812N) were prepared as three separate mixtures in the following weight ratios: 88:10:2 (Ratio 1), 58:40:2 (Ratio 2) and 30:68:2 (Ratio 3).

Step 2: Mix the mixture from Step 1 using a vortex mixer.

Step 3: Use a vortex mixer to slowly add racecadotril to the mixture from step 2 and mix for 5 minutes.

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

Stability of racecadotril lipid formulations

The chemical stability of the formulation prepared in Embodiment 1 was tested for degradation of racecadotril when stored in sealed vials at 40° C. for 40.1 weeks and is shown in Table 3.

Table 3: Stability data for lipid-based formulations :

Preparation 1, Preparation 3, Preparation 5

Preparation 2, Preparation 4, Preparation 6

No Impurity A, Thiofene or Impurity E in Formulation 1, Formulation 2, Formulation 3, Formulation 4, Formulation 5, Formulation 6

ND: not detected

Preparations :

1.88% Ultra Refined Etocas 35, 10% Imwitor 988, 2% Miglyol 810N (ratio 1)

2.88% Ultra Refined Etocas 35, 10% Imwitor 988, 2% Miglyol 812N (Ratio 1)

3.58% Ultra Refined Etocas 35, 40% Imwitor 988, 2% Miglyol 810N (Ratio 2)

4.58% Ultra Refined Etocas 35, 40% Imwitor 988, 2% Miglyol 812N (ratio 2)

5. 30% ultra-refined Etocas 35, 68% Imwitor 988, 2% Miglyol 810N (ratio 3)

6. 30% ultra-refined Etocas 35, 68% Imwitor 988, 2% Miglyol 812N (ratio 3)

ND – not detected

Ingredients :

A. Ultra-refined Etocas 35 (NF, EP, JP):

Made by CRODA Health Care

PEG 35 castor oil

HLB value 14

B.Imwitor 988: medium chain partial glycerides

Made by CREMER

Glyceryl Caprylate (Monoglycerides and Diglycerides)

Melting point about 25°C

HLB value 4

C.Imwitor 742: medium chain partial glycerides

Made by CREMER

Caprylic/Capric Glycerides

Melting point about 25°C

HLB value 3-4

D. Miglyol: medium chain triglycerides (MCT oil, fractionated coconut oil)

Made by CREMER

Caprylic (C8)/Capric (ClO) Triglyceride

810N-70: 30C8/C10 blend

812N-60: 40C8/C10 blend

Conversions based on density of various formulations :

Formulation 1/Formulation 2: 1.042 g/ml

Formulation 3/Formulation 4: 1.028g/ml

Formulation 5/Formulation 6: 1.016 g/ml

Moisture content (% w/w) :

preparation Moisture content (% w/w) 1 0.02 2 0.02 3 0.08 4 0.08 5 0.13 6 0.13 7 0.09 8 0.09 9 0.10 10 0.10

Example 2

Concentrated racecadotril lipid composition: for use in liquid-filled gelatin capsules

Table 4 :

1: yes USP/NF, EP, JP are commercially available from CREMER

2: yes 810N (caprylic/capric triglyceride; 70:30/C8:C10) USP/NF, EP, JP commercially available from CRHMER

3: yes 812N (caprylic/capric triglyceride; 60:40/C8:C10) USP/NF, EP, JP commercially available from CRHMER

Table 5 :

1: Can IMWITOR USP/NF, EP, JP are commercially available from CREMER

2: yes 810N (caprylic/capric triglyceride; 70:30/C8:C10) USP/NF, EP, JP commercially available from CRHMER

3: yes 812N (caprylic/capric triglyceride; 60:40/C8:C10) USP/NF, EP, JP commercially available from CRHMER

Test method :

Sample preparation: (in acetonitrile)

1. Pipette 1ml of racecadotril lipid solution into a 100ml volumetric flask (V.F.)

2. Dilute to a certain volume with acetonitrile. If necessary, add about 20 ml of dimethylacetamide.

3. If necessary, further dilute the sample solution to about 0.1 mg/mL with acetonitrile.

sample analysis

A reference standard (0.1 mg/mL racecadotril in acetonitrile) and samples were injected onto a suitable HPLC system under conditions similar to those suggested below. Parameters can be modified to optimize chromatography.

The determination of racecadotril was determined using the comparison of the peak area of racecadotril of the sample solution with the peak area of racecadotril of the standard solution. Degradation product content was determined by % peak area relative to the racecadotril chromatographic peak.

Chromatographic separation conditions (European Pharmacopoeia racecadotril method) :

Gradient table :

time (min) flow rate %A %B initial 1.0 60 40 5 1.0 60 40 25 1.0 20 80 35 1.0 20 80 36 1.0 60 40 45 1.0 60 40

Mobile phase A: phosphate buffer, pH2.5 (buffer preparation: dissolve 1g potassium dihydrogen phosphate in water, use phosphoric acid to adjust the pH to 2.5, and dilute to 1000ml with water)

Mobile phase B: 100% acetonitrile

Example 3

Racecadotril Lipid Composition: Droplet Size

step

Droplet size was measured on a Horiba SZ-100 nanoparticle size analyzer by dynamic light scattering (DLS) at a scattering angle of 90 degrees. The samples were placed in a temperature-controlled chamber at 25°C during the measurement. Immediately prior to the measurement, instrument performance was checked using a nominal 100 nm polystyrene latex (PSL) size standard in 10 mM NaCl solution. Count rates for these measurements ranged from 1 million to 3 million counts per second. Each measurement lasts one minute. The resulting data were analyzed using cumulant techniques.

Solubility and droplet size of lipid-based formulations

** Preparation 1, Preparation 3, Preparation 5

** Preparation 2, Preparation 4, Preparation 6

*Measured by dynamic light scattering (DLS) using a Horiba SZ-100 nanoparticle size analyzer, the average of three measurements (n=3)

1 General procedure: Combine 0.08 g of each formulation and 15 mL of 0.1 N HCl and vortex to mix

2 Calculated based on a density of 1.042g/mL

3 Calculated based on a density of 1.028g/mL

4 Calculated based on a density of 1.016g/mL

5 The concentration of racecadotril is about 0.53mg/mL

6 The concentration of racecadotril is about 0.55mg/mL

7 The concentration of racecadotril is about 0.44mg/mL

8 The concentration of racecadotril is about 0.60 mg/mL

9 The concentration of racecadotril is about 0.43mg/mL

10 The concentration of racecadotril is about 0.46 mg/mL

**For formulation see Example 1

Also, the droplet size was measured on a Nicomp 380 Nano Particle Size Analyzer by Dynamic Light Scattering (DLS) at the Particle Size Analyzer (PSS) with a 90 degree scattering angle. All measurements were performed at 23°C. After the instrument has warmed up, it can be challenging to check the accuracy of the instrument with NIST-traceable standards (ie, polystyrene latex). Scattering intensities were determined between 150 kHz and 500 kHz during sample measurements lasting 15 minutes. The resulting data were analyzed using cumulant techniques.

** Preparation 1, Preparation 3, Preparation 5

** Preparation 2, Preparation 4, Preparation 6

*Measured by dynamic light scattering (DLS) using a Nicomp 380 nanometer particle size analyzer.

1 General procedure: For formulations 1 and 3, combine 0.2 mL of formulation and 4.8 mL of 0.1N HCl, and mix; for formulations 2 and 4, combine 0.1 mL of formulation and 4.9 mL of 0.1N HCl, and mix; For formulations 5 and 6, combine 0.1 mL of formulation and 4.9 mL of 0.1 N HCl, mix well, then add 2.5 mL of the diluent to 2.5 mL of 0.1 N HCl.

2 Calculated based on a density of 1.042g/mL

3 Calculated based on a density of 1.028g/mL

4 Calculated based on a density of 1.016g/mL

5 The concentration of racecadotril is about 3.84mg/mL

6 The concentration of racecadotril is about 3.72mg/mL

7 The concentration of racecadotril is about 0.83mg/mL

8 The concentration of racecadotril is about 1.89mg/mL

9 The concentration of racecadotril is about 1.80 mg/mL

10 The concentration of racecadotril is about 0.83mg/mL

**For formulation see Example 1

While the invention has been described in conjunction with specific embodiments of the invention, it will be evident that various changes, modifications and variations can be made without departing from the inventive concepts disclosed herein. Accordingly, this document is intended to cover all such changes, modifications and variations that come within the true and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are hereby incorporated by reference in their entirety.

Claims (16)

1. a compositions, comprises:

Racecadotril；At least one surfactant, wherein said surfactant is selected from poly- Ethylene glycol 35 Oleum Ricini, glycerol caprylate (monoglyceride and diglyceride) and their group Close；And lipoid, wherein said lipoid is medium chain triglyceride.

Compositions the most according to claim 1, wherein said compositions is self-emulsifying systems.

Compositions the most according to claim 1, wherein said compositions stablizes about 40 at 40 DEG C Week.

Compositions the most according to claim 1, at least one surfactant wherein said is with often A total of about 1 weight % of the described emulsion compositions of 100mL exists to the amount of about 95 weight %.

Compositions the most according to claim 1, wherein said lipoid is with the described emulsion of every 100mL About 0.01 weight % of compositions exists to the amount of about 60 weight %.

Compositions the most according to claim 1, also comprises group optional selecting free the following to form Composition: preservative, sweeting agent, viscosity modifier, coloring agent, aromatic, flavoring agent and Their mixture.

Compositions the most according to claim 1, also comprises group optional selecting free the following to form Composition: citric acid, sodium benzoate, sucralose, flavoring agent and their mixture.

8. comprising a dosage form for compositions according to claim 1, wherein said dosage form is soft shell agent Type, duricrust dosage form or Tabules.

Compositions the most according to claim 1, wherein said compositions has based on described compositions The total moisture content of less than about 3.5 weight % of gross weight meter.

Compositions the most according to claim 1, is also included as the second of digestive health active component and lives Property composition.

11. 1 kinds of compositionss, including:

The racecadotril of about 0.01 weight % to about 24.0 weight %；

A total of about 1 weight % is to the surfactant of about 95 weight %；With

The lipoid of about 0.01 weight % to about 60 weight %；

Wherein each weight % compositions based on 100mL meter.

12. 1 kinds of dosage forms comprising compositions according to claim 15, wherein said dosage form is soft shell Dosage form, duricrust dosage form or Tabules.

13. compositionss according to claim 15, wherein said compositions stablizes about 40 at 40 DEG C Week.

14. 1 kinds of compositionss, including:

The racecadotril of about 3.0 weight % to about 7.0 weight %；

A total of about 40 weight % are to the surfactant of about 53 weight %；With

The lipoid of about 40 weight % to about 53 weight %；

Wherein each weight % compositions based on 100mL meter.

15. 1 kinds of dosage forms comprising compositions according to claim 18, wherein said dosage form is soft shell Dosage form, duricrust dosage form or Tabules.

16. 1 kinds, for the method treating person under inspection diarrhoea occur, are administered orally including described person under inspection The step of compositions according to claim 1.