Field of the Invention

[0001] The present invention relates to liquid compositions. More particularly, the present invention relates to liquid compositions containing racecadotril and the method of making said compositions.

Related Background Art

[0002] Diarrhea is an intestinal disorder that is characterized by an increase in the frequency of watery bowel movements. It may result from a variety of causes including bacteria or viral induced diarrhea. Food intolerance caused by allergy or the consumption of foods such as fatty or spicy foods may result in diarrhea. Food poisoning may also lead to diarrhea. In some instances, diarrhea may be a symptom of other conditions and diseases.

[0003] Diarrhea is symptomatic of an intestinal or other bodily function disorder. Various prescription and nonprescription products can be taken for relief. However, many of these products provide relief with some side effects.

[0004] Racecadotril is also used in the treatment of diarrhea. It reduces (i) hypersecretion of water and electro lytes into the intestinal lumen, (ii) the incidence and duration of acute diarrhea and (iii) diarrhea-associated symptoms.

[0005] Presently, racecadotril is available in solid oral dosage forms. SUMMARY OF THE INVENTION

[0006] The present invention is directed to a liquid composition comprising racecadotril and cyciodextrin.

[0007] In one embodiment, the inventive composition comprises about 0.01 wt.% to about 24.0 wt.% racecadotril and about 1 wt.% to about 95 wt.% of a cyciodextrin, wherein each wt.% is based upon 100 ml of the composition.

[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 and cyciodextrin.

DETAILED DESCRIPTION OF THE INVENTION

[0009] As used herein, "stable" refers to a liquid composition substantially free of chemical degradation of racecadotril or substantial color change. In one embodiment, the total chemical degradant products of racecadotril should be less than 0.2 percent by weight (wt.%), e.g. less than 0.1 w t.% based on the total wt.% of racecadotril when stored at 3 months and 40°C. In another embodiment, the total chemical degradant products of racecadotri l should be less than 0.2 percent by weight (wt.%), e.g. less than 0.1 wt.% based on the total wt.% of racecadotril when stored at 6 months and 40°C.

[0010] 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] The present invention is a liquid composition comprising racecadotril and cyciodextrin.

[0012] Racecadotril' s efficacy in reducing the symptoms of diarrhea have been demonstrated in various studies. One of the benefits of using racecadotril over other remedies is that in comparative trials racecadotril was shown to have fewer adverse events such as post-treatment constipation,

[0013] In the present invention, the racecadotril is included in a stable liquid composition.

[0014] Racecadotril is a. compound with low water solubility, making it difficult to formulate into liquid compositions. However, oral liquid compositions are the most preferred dosage form for administering medications to the pediatric population.

[0015] In one embodiment, a. RS racemic form of racecadotril is used. In another embodiment, a. R form of racecadotril is used.

[0016] Racecadotril is included in the liquid composition in an amount from about 0.01 grams to about 0.5 grams per 100 ml of the liquid composition. Preferably, the racecadotril is about 0.05 grams to about 0.4 grams, and more preferably, about, 0.1 grams to about 0.3 grams per 100 ml of the liquid composition. In one embodiment, the racecadotril is about 0.25 grams per 100 ml of liquid composition,

[0017] In one embodiment, the viscosity of the liquid composition is from about 1 to about 500 centipoise at room temperature (25° C) measured using a Brookfield Viscometer,

[0018] The pH of the liquid composition is from about I to about 6, Preferably, the pH is about 3 to about 5. More preferably, the pH is about 4.5.

[0019] In one embodiment, a buffering system may be included to maintain the pH at the value or in the desired range. The buffer may be a citrate, an acetate, a phosphate, or mixtures thereof. Preferably, an acetate buffer is used.

[0020] In one embodiment the racecadotril is dissolved into the liquid composition.

[0021] Cyclodextrins are compounds used in a wide variety of products, which include pharmaceutical, food, consumer and chemical products. They are synthesized from starch via an enzymatic reaction.

[0022] Suitable cyclodextrins include, for example, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydro xypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, or mixtures thereof.

[0023] In one embodiment, the cyclodextrin is hydroxypropyl-beta-cyclodextrin. One source of hydroxypropyi-beta-cyclodextrin is CAVASOL W7 available from International Speciality Products Corporation (ISP). [0024] In another embodiment, the cyciodextrin is a sulfobutyl ether derivative of β- cyciodextrin, sold under the tradename CAPTISOL available from Captisol,

[0025] The cyciodextrin is included in the composition in an amount from about 1 grams to about 70 grams per 100 ml of the liquid composition. Preferably, the cyciodextrin is about 5 grams to about 60 grams, and more preferably, about 5 grams to about 50 grams per 100 ml of the liquid composition,

[0026] In one embodiment, the cyciodextrin is from about 40 grams to about 60 grams per 100 ml of the liquid composition.

[0027] In another embodiment, the cyciodextrin is from about 15 grams to about, 30 grams per 100 ml of the liquid composition.

[0028] The liquid composition also has water. Water is the solvent that, fills the gap after all other components have been added. The amo unt of water that is included varies because the water is added to bring the composition up to a desired volume amount.

[0029] Optionally, a variety of ingredients may be included in the liquid composition of the present invention.

[0030] For example, propylene glycol may be included in the liquid composition. Propylene glycol has many uses, such as for example a moisturizer in food and medicines, and as a solvent for food colorings and flavorings. It is a colorless, nearly odorless, clear, viscous liquid with a faintly sweet taste, hygroscopic and miscible with water, acetone, and chloroform.

[0031] Any coloring agent suitable for use in a food or pharmaceutical product may be used in the present inventive composition. Typical coloring agents include, for example, azo dyes, quinopthalone dyes, triphenylmethane dyes, xanthene dyes, indigoid dyes, iron oxides, iron hydroxides, titanium dioxide, natural dyes, and mixtures thereof. 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 BN, carbon black, iron oxide black, iron oxide red, iron oxide yellow, titanium dioxide, riboflavin, carotenes, antyhocyanines, turmeric, cochineal extract, clorophyllin, canthaxanthin, caramel, betanin, and mixtures thereof. [0032] Similarly, a flavor may be included in the liquid composition. The amount of flavor added to the composition will be dependent upon the desired taste characteristics.

[0033] The composition may contain other ingredients or components, such as aromas;

sweeteners such as, sorbitol, high fructose corn syrup, sugar, and high intensity sweeteners such as sucralose, aspartame and saccharine and the like: viscosity modifiers such as xanthan gum; preservatives such as sodium benzoate NF, buffers such as citric acid and/or sodium chloride; surfactants such as polysorbate 80 a.nd/or sodium iauryl sulfate or mixtures thereof.

[0034] In one embodiment, the inventive liquid composition includes about 0,1 wt.% to about 0.3 wt.% racecadotril and about 40 wt.% to about 65 wt.% cyclodextrin, wherein each wt.% is based upon 100 ml of the composition.

[0035] In another embodiment, the inventive liquid composition includes about 0.1 wt.% to about 0.3 wt.% racecadotril and about 10 wt.% to about 40 wt.% cyclodextrin, wherein each wt.% is based upon 100 ml of the composition.

[0036] The solubility of the racecadotril in the inventive composition is about 1.5 to about 4.0

[0037] The liquid composition of the present invention may be made by any method known to those skilled in the art so long as it results in the desired composition.

[0038] Suitable methods include, for example, combining each ingredient in a mixing kettle, where the ingredients may be added sequentially or in any ma ner so long as the intended result is achieved. Moreover, the mixing action should be sufficient to incorporate each ingredient into the composition.

[0039] In one embodiment the liquid of the present invention comprises a second active ingredient. The second active ingredient may be, for example, present in a suspended state, or may be solubilizecl in the liquid composition. In one embodiment, the second active ingredient is a digestive health active ingredient may be, for example, laxatives, antacids, proton pump inhibitors, anti-gas agents, antiemetics, H2 blockers, a second antidiarrheal agent, and the like. In one embodiment, the second active ingredient is microencapsulated.

[0040] Suitable anti-gas agents include but are not limited to simethicone.

[0041] Suitable additional antidiarrheal agents include but are not limited to loperamide. [0042] The inventive liquid composition may be delivered in any suitable delivery system. For example, in one embodiment, the liquid composition is delivered orally. In another embodiment, the composition is a liquid oral dosage form. In still another embodiment, a soft shell solid dosage form is used to deliver the liquid composition. In still yet another embodiment, a hard shell solid dosage form is used to deliver the liquid composition. In still yet another

embodiment, a tablet dosage form is used to deliver the liquid composition.

[0043] The present invention also includes a method for treating a subject experiencing diarrhea comprising the step of orally administering to the subject a composition comprising racecadotril and cyclodextrin.

[0044] 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.

[0045] The composition for an oral racecadotril liquid is shown in Table 1. Utilizing the materials in Table 1 , the following mixing steps were used:

[0046] Step 1 : A solution of was formed by mixing the purified water and hydroxvpropyl beta- cyciodextrin in a suitable vessel with a laboratory mixer.

[0047] Step 2: The racecadotril was added to the solution in Step 1 and mixed in a laboratory shaker for at least 12 hours and a clear solution was formed.

[0048] Step 3: The citric acid, sorbitol solution, high fractose com syrup, and sodium chloride was mixed to form a solution and mixed using a laboratory mixer until dissolved.

[0049] Step 4: A separate mixture was prepared by mixing the flavor into the polyethylene glycol 400 in a suitable vessel. This mixture was then mixed with the solution from Step 3 and diluted to volume with purified water. 0050] Table 1 : Racecadotril Oral Liquid Composition (2.5 mg/g)

1 : Commercially available from the ISP as CAVASOL W7

EXAMPLE 2: Concentrated Racecadotril Aqueous composition

Three formulations of racecadotril in an aqueous buffer of acetate were prepared and three formulations of racecadotril in an aqueous buffer of citrate were prepared. These formulations were prepared utilizing a mixture of racecadotril in the Sulfobutyl ether derivative of β- cyciodextrin (Captisol®) and are shown in Table 2.

Table 2: Racecadotril Sulfobutyl Ether Derivative of β-cyelodextrin Based Aqueous Compositions Solvent System Actual Composition

Racecadotril Acetate Racecad¬

Capiisol Acetate by Assay Captisel Acetate Captisol Buffer otril

Lot # (w/v) Buffer (ml) (mg/mL) (8) Buffer (mL) j (w/w%) (w/w%) (w/ %)

Formula 1 60% 100 2.62 59.9972 _ 5_4_._0_ J 5 __2_._4__9__ 47.25 0.26

Form tila 3 70% 100 2.41 70.0018 40.58 0,24

Formula 5 78% 100 2.26 80.0035 54.6 j 59.30 40,47 0.23

Solvent System Actual Composition

Actual

Racecadotril Citrate Racecad¬

Captisol Citrate by Assay Captisol Citrate Captisol Buffer otril

List # (w/v) Buffer (mg/mL) (g) Buffer (mL) (w/w%) (w/w%) (w/w%)

Fo rmtila 2 60% 100 2.43 60.0120 66.0 47.51 52.25 0.24

Fo rmtila 4 69% 100 2.39 70.0016 62.6 j 52,90 46,86 0.24

Formula 6 80% 50 1.92 39.9954 33.0 j 54.69 45.12 0.19

Utilizing the materials in TABLE 2, the following mixing steps were taken to form the solutions.

Step 1 : in a suitable glass bottle, the Captisol ^4, were weighed, mixed and prepared as 60%, 70% and 78% in pH 4.5 acetate buffers, respectively (Formulae 1, 3 and 5). Also, the Captisol ^® were weighed and prepared as 60%, 69% and 80% in pH 4.5 citrate buffers, respectively (Formulae 2, and 6).

Step 2: The pH of each bottle was adjusted to pH 4.5 with either glacial acetic acid (17.4 M) or citric acid (3 M).

Step 3: The Racecadotril was slowly added to each bottle in Step 2, utilizing the vortex mixer to mix for 5 minutes, and then placed each bottle into a. laboratory shaker and mixed for 24 hours until a solution was formed.

Stability of Racecadotril in Aqueous Solutions

For comparative purposes, the stability of racecadotril was tested at room temperature and at

40°C. Time Racecadotril (%) in Racecadotril (%) in

Water at Room Water at 40°C

Temperature (%)

Initial 74,88 78.88

12 Hours 44.9 N/A

1 Week 1.0 0

2 Weeks 0.0 0.2

3 Weeks N/A N/A

These results show that at room temperatore and at 40°C conditions, racecadotril is unstable after 12 hours. Moreover, at I week, racecadotril is present at less than 1 %.

Stability of Racecadotril in Buffer Solutions

For comparative purposes, the stability of racecadotril was analyzed when solubilized in pH 4.5 Acetate buffer and pH 4.5 Citrate buffer (Table 4).

Table 4: Stability of Racecadotril in Buffer

Time Racecadotril in pH 4.5 Racecadotril in pH 4.5

Acetate Buffer at 40°C (% Citrate Buffer at 40°C

Racecadotril) (% Racecadotril)

Initial 99.86 99.74

12 Hours 99.69 99.63

1 Week 96.7 95.3

2 Weeks 93.3 91.2

3 Weeks 91.5 89.0

4 Weeks 88.0 85.4 The data shows at 40°C and 4 weeks that although the stability is somewhat compromised, it is more stable in a buffer than in water. The data, also demo strates that racecadotril is more soluble in buffer than in water.

Sjabij^

Formulations of racecadotril in beta-hydro xypropyl-cyclodextrin were evaluated (Table 5).

Table 5: Stability of Racecadotril in Beta-Hydroxypropyl-Cyelodextrin (Beta-HPCD)

The data shows that, the stability is similar to that in buffers alone, but higher solubility was achieved utilizing the Beta-HPCD.

Stabilitv of Racecadotril in Sirifobutyl Ether Derivative of β-cyclodextrin ¹ Solution The stability of samples prepared above in Example 2 utilizing Sulfobutyl ether derivative of β- cyciodextrin (Captisol®) solutions was analyzed. The data is shown in Table 6.

TABLE 6: Stability Data of Racecadotril in Sulfobutyl Ether Derivative of β-cyclodextrin based

Aqueous S @ 40°C)

Formula 1 , Formula 3, Formula 5

ormula 2, Formula 4, Formula 6

Machine error due to inseparable integration between two peaks

Captisol ^® 60%w/w in 1.5 Acetate Buffer

Captisol ^® 60%w/w in 1.5 Citrate Buffer

Captisol ^® 70%w/w in 1.5 Acetate Buffer

Captisol ^® 69%w/w in 1.5 Citrate Buffer

Captisol ^® 78%w/w in 1.5 Acetate Buffer

Captisol ^® 80%w/w in 1.5 Citrate Buffer Sample preparation:

1. Pipet 1 mL of Racecadotril solution into a l OOn L volumetric flask (V.F.)

2. Dilute to volume with the same buffer used in the solution preparation.

3. Further dilute the sample solution to about 0.1 mg mL if necessary.

Sample Analysis

Inject standards (0.1 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.

The assay of Racecadotril is determined by using the external standard injected. The degradation products levels are determined by % peak area relative to the Racecadotril peak. mc conditions .buro ean riiaraiaco oesa Kaceeac

Gradient Table:

Mobil Phase A: Phosphate buffer, pH 2.5 (Buffer prep: dissolve l g of potassium dihydrogen phosphate in water, adjust to pH 2.5 with phosphoric acid, dilute to lOOOmL with water) Mobil Phase B: 100% Acetonitrile

Stability of Racecadotril in Beta-Hydroxypropyl-Cyclodextrin (Beta-HPCD) at 40°C

[0051] 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 such changes, modifications, and variations that fail 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.