HK1208178B - Racecadotril lipid compositions - Google Patents

Description

Racecadotril lipid compositions

Background

Technical Field

The present invention relates to a microemulsion composition based on lipids. More particularly, the present invention relates to a lipid-based microemulsion composition comprising a pharmaceutically active ingredient and a process for preparing said composition.

Related background Art

Dysentery is an intestinal disease characterized by an increase in the frequency of watery stools. It may be caused by a variety of causes, including bacterial or viral induced dysentery. Food intolerance caused by allergies or food consumption such as greasy or spicy foods may lead to diarrhea. Food poisoning may also lead to diarrhea. In some cases, diarrhea may be a symptom of other conditions and diseases.

Dysentery is a symptom of intestinal or other body function disorders. Various prescription and over-the-counter products can be taken for relief. However, many of these products provide relief with some side effects.

Racecadotril is also used for the treatment of dysentery. It reduces (i) excessive water and electrolytes secretion into the intestinal lumen, (ii) the incidence and duration of acute diarrhea and (iii) symptoms associated with diarrhea.

In addition, racecadotril is a pharmaceutically active substance ingredient exhibiting poor solubility and poor oral bioavailability. Currently, racecadotril is used in solid oral dosage forms.

Disclosure of Invention

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

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

The invention also includes a method for treating a subject suffering from 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 of racecadotril, substantial color change, turbidity, or oily globules. No phase separation should be observed in the aqueous and/or non-aqueous components for at least about 3 months at 40 ℃. More preferably, no phase separation should be observed in the aqueous and/or non-aqueous components for at least about 6 months at 40 ℃. 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 weight% (wt%) of racecadotril when stored at 40 ℃ for 3 months. In another 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 weight% (wt%) of racecadotril when stored at 40 ℃ for 6 months. The percentage of degradation products was determined by calculating the% peak area of the degradation product peak area relative to the peak area of the racecadotril peak in the HPLC chromatogram. In one embodiment, the total chemical degradation products of racecadotril should be less than 0.5% of racecadotril, such as less than 0.2%, based on the total% of racecadotril when stored at 40 ℃ for 3 months.

As used herein, a "self-microemulsifying drug delivery system" (SMEDDS) is a mixture of oil, surfactant, and sometimes a cosolvent. SMEDDS can be used in formulation systems to improve oral absorption of highly lipophilic compounds. When introduced into the aqueous phase, SMEDDS spontaneously emulsifies using mild agitation to produce a fine oil-in-water emulsion. The drug in SMEDDS appears in small droplet sizes and exhibits increased dissolution and permeability. SMEDDS can be formulated for liquid or solid use. For solid use, the solid is encapsulated in a capsule or tablet. Liquid-filled or semi-solid filled capsules are some consumer preferred dosage forms due to 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 effectively reduces the symptoms of diarrhea. One benefit of using racecadotril over other drugs is that racecadotril appears to have fewer side effects, such as post-treatment constipation.

Racecadotril has low aqueous solubility, about 10 micrograms/mL at room temperature. In the composition of the invention, racecadotril is soluble in the microemulsion.

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

The microemulsion composition of the present invention comprises at least one surfactant. The surfactant can be, for example, a nonionic surfactant, a cationic surfactant, an anionic surfactant, 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, aid in the formation of oil-water droplets. Surfactants are amphiphilic in nature and are capable of dissolving or solubilizing relatively high amounts of hydrophobic drug compounds.

Non-limiting examples include, Tween (Tween), Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), ethanol, glycerol, N-methyl-2-pyrrolidone (NMP), PEG300, PEG400, poloxamer 407, propylene glycol, phospholipids, Hydrogenated Soybean Phosphatidylcholine (HSPC), distearoyl phosphatidylglycerol (DSPG), L- α -dimyristoyl phosphatidylcholine (DMPC), L- α -dimyristoyl phosphatidylglycerol (DMPG), polyoxyethylene 35 castor oil (CREMOPHOR EL, CREMOPHOR ELP), polyoxyethylene 40 hydrogenated castor oil (CREMOPHOR RH 40), polyoxyethylene 60 hydrogenated castor oil (CREMPHOR RH60), polysorbate 20(TWEEN 20), polysorbate 80(TWEEN 80), d- α -tocopheryl polyethylene glycol 1000 succinate (TPTPTPP), Solutol HS-15, Sorbitan monooleate (SPAN 20), PEG300 glyceryl caprylate/caprate (SOFTIGEN767), PEG400 glyceryl caprylate/caprate (LABRASOL), PEG300 glyceryl oleate (LABRAFIL-1944 CS), polyoxyethylene 35 castor oil (ETOCAS 35), glyceryl caprylate (mono-and diglycerides) (IMWITOR), PEG300 glyceryl linoleate (LABRAFIL M-2125CS), polyoxyethylene 8 stearate (PEG 400 monostearate), polyoxyethylene 40 stearate (PEG 1750 monostearate), peppermint oil, and combinations thereof.

In addition, suitable surfactants include, for example, polyoxyethylene derivatives of sorbitan monolaurate, such as polysorbates, caprylocaproyl macrogolglycerides, pegylated glycerides (polyglycolized glycerides), and the like.

In one embodiment, the surfactant is a combination of polyoxyethylene 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 weight percent to about 95 weight percent per 100mL of the emulsion composition. Preferably, the surfactant is from about 25% to about 95% by weight, and even more preferably, from about 30% to about 90% by weight, per 100mL of the emulsion composition. In one embodiment, the surfactant is about 45% to about 95% by weight per 100mL of the emulsion composition.

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

Furthermore, lipophilic andwater-insoluble mono-, di-and/or triglyceride emulsifiers (fats and oils) (available from Abitec under the trade name Abitec;)Sold) can be used as a lipid, for example, beeswax, oleic acid, soy fatty acids, d- α -tocopherol (vitamin E), corn oil mono-di-triglycerol, 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 vegetable oil, medium chain triglycerides, caprylic/capric triglycerides derived from coconut oil, palm seed oil, and combinations thereof.

The lipid is included in the composition in an amount of about 0.01 wt% to about 60 wt% per 100mL of the emulsion composition. Preferably, the lipid is from about 0.01% to about 50% by weight per 100mL of the emulsion composition. In another embodiment, the lipid is from about 1% to about 20%, more preferably, from about 1% to about 15%, and even more preferably, from about 1% to about 10% by weight per 100mL of the emulsion composition. In one embodiment, the lipid is about 1% to about 2% by weight per 100mL 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% by weight 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 another embodiment, the water content of the composition is less than about 0.5% by weight, based on the total% by weight of the composition. In another embodiment, the water content of the composition is less than about 0.2 wt% based on the total wt% of the composition.

Optionally, a variety of ingredients may be included in the emulsion compositions of the present invention.

Any colorant suitable for use in food or pharmaceutical products can be used in the present invention. Typical colorants include, for example, azo dyes, quinolinone (quinophthalone) dyes, triphenylmethane dyes, xanthene dyes, indigo dyes, iron oxide, iron hydroxide, 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, 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, brilliant black BN, carbon black, iron oxide red, iron oxide yellow, titanium dioxide, riboflavin, carotene, anthocyanins (antyhocyanines), turmeric, cochineal extract, chlorophyll (clorophyllin), canthaxanthin, caramel, betanin, and mixtures thereof.

Similarly, flavors may be included in the emulsion compositions. The amount of flavor added to the composition depends on the desired mouthfeel characteristics.

The composition may contain other ingredients or components, such as fragrances; sweeteners such as sucralose, sorbitol, high fructose corn syrup, sugar, and the like; viscosity modifiers, such as xanthan gum; preservatives, such as sodium benzoate NF, buffers, such as citric acid and/or sodium chloride; or mixtures thereof.

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

Suitable methods include, for example, mixing each ingredient in a mixing kettle, wherein the ingredients may be added sequentially or in any manner so long as the desired result is achieved. In addition, the mixing action should be sufficient to incorporate each ingredient into the composition.

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

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

Stability was also assessed by checking for supersaturation (precipitation). The test was performed by placing 1mL of the formulation in a beaker with 250mL of 0.1 NHCL. 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 an oral soft gelatin capsule containing the microemulsion composition. In another embodiment, the microemulsion composition is administered as a plurality of microgel beads comprising the microemulsion composition. In 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 banded. In another embodiment, the microemulsion composition is administered in a suppository or enema formulation comprising 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 digestive health active ingredient. Non-limiting examples include, for example, a laxative, an antacid, a proton pump inhibitor, an antiasthmatic, an antiemetic, an H2 blocker, or a second antidiarrheal agent.

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 form composition that is separate from the microemulsion composition. In 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 from about 8.0 wt% to about 10.0 wt% racecadotril, from about 88 wt% to about 91 wt% total surfactant, from about 1 wt% to about 2 wt% lipid, wherein each wt% is based on 100mL of the composition.

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

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

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

The invention also includes a method for treating a subject suffering from 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 the present invention. It is to be understood that the invention is not limited to the described examples.

Example 1

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

Table 1: compositions based on racecadotril lipids asThe percentage of the composition is as follows: triglyceride type 1

1: can be used for35USP/NF, EP, JP are commercially available from Croda Healthcare

2: can be used for988USP/NF, EP, JP commercially available from CREMER

3: can be used for810N (caprylic/capric triglyceride; 70:30/C8: C10) USP/NF, EP, JP commercially available from CREMER

Table 2: composition based on racecadotril lipid as percentage of the composition: triglyceride type 2

1: can be used for35USP/NF, EP, JP are commercially available from Croda Healthcare

2: can be used for988USP/NF, EP, JP commercially available from CREMER

3: can be used for812N (caprylic/capric triglyceride; 60:40/C8: C10) USP/NF, EP, JP commercially available from CREMER

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

Step 1: polyoxyethylene 35 Castor oil (I) was prepared in three separate mixtures in the following weight ratios in a suitable vessel35) Caprylic acid glyceride (A)988) And medium chain triglycerides (810N&812N): 88:10:2 (ratio 1), 58:40:2 (ratio 2), and 30:68:2 (ratio 3).

Step 2: the mixture from step 1 was mixed using a vortex mixer.

And step 3: racecadotril was added slowly to the mixture from step 2 using a vortex mixer and mixed for 5 minutes.

And 4, 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 formulations prepared in example 1 were tested for chemical stability against racecadotril degradation when stored in sealed bottles at 40 ℃ for 3 months and are shown in table 3.

*: preparation:

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

2.88% superfinished Etocas 35, 10% Imwitor 988, 2% Miglyol 812N (ratio 1)

3.58% superfinished Etocas 35, 40% Imwitor 988, 2% Miglyol 810N (ratio 2)

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

5.30% superfinished 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

The components:

A. ultra-refined Etocas 35(NF, EP, JP): HLB value of Polyoxyethylene 35 Castor oil 14 manufactured by CRODA Health Care

Imwitor 988: production of glyceryl caprylate (mono-and diglycerides) from CREMER medium chain partial glycerides melting Point-25 ℃ HLB value of 4

C.imwitor 742: the melting point of caprylic/capric glyceride prepared from CREMER (medium chain partial glyceride) is 3-4 ℃ and the HLB value is 25 DEG C

Miglyol: medium chain Triglycerides (MCT oil, fractionated coconut oil) caprylic (C8)/capric (C10) triglycerides 810N-70:30C8/C10 blend 812N-60:40C8/C10 blend made by CREMER

On a per basisPreparationConversion of density of (a):

preparation1/Preparation2：1.042g/mL

Preparation3/Preparation4：1.028g/mL

Preparation5/Preparation6：1.016g/mL

Water content (% weight/weight):

preparation	Water content (% weight/weight)
		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: can be IMWITORUSP/NF, EP, JP are commercially available from CREMER

2: can be used for810N (caprylic/capric triglyceride; 70:30/C8: C10) USP/NF, EP, JP commercially available from CREMER

3: can be used for810N (caprylic/capric triglyceride; 60:40/C8: C10) USP/NF, EP, JP commercially available from CREMER

TABLE 5：

1: can be IMWITORUSP/NF, EP, JP are commercially available from CREMER

2: can be used for810N (caprylic/capric triglyceride; 70:30/C8: C10) USP/NF, EP, JP commercially available from CREMER

3: can be used for812N (caprylic/capric triglyceride; 60:40/C8: C10) USP/NF, EP, JP commercially available from CREMER

Test method：

Sample preparation: (in acetonitrile)

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

2. Dilute to volume with acetonitrile. About 20mL of dimethylacetamide was added if necessary.

3. The sample solution was also diluted with acetonitrile to about 0.1mg/mL if necessary.

Sample analysis

Standard standard (0.1mg/mL racecadotril in acetonitrile) and sample were injected into a suitable HPLC system under conditions similar to those suggested below. The parameters can be modified to optimize the chromatography.

The racecadotril peak area of the sample solution was used to determine the determination of racecadotril under tests comparing the racecadotril peak areas of the standard solutions. The degradation product level was determined by% peak area relative to the racecadotril peak.

Chromatographic separation conditions (European pharmacopoeia racecadotril method)：

Gradiometer：

Time (minutes)	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: dissolving 1g of monopotassium phosphate in water, adjusting pH to 2.5 with phosphoric acid, diluting to 1000mL with water)

A mobile phase B: 100% acetonitrile

Although the present 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 scope of the appended claims. All patent applications, patents, and patent publications cited herein are incorporated by reference in their entirety.

Claims (13)

1. A microemulsion composition comprising:

4.0-10.0 wt% racecadotril;

30-95 wt% of at least one surfactant, wherein the surfactant comprises polyoxyethylene 35 castor oil and glyceryl caprylate; and

1-2% by weight of a lipid;

wherein each weight percent is based on the total weight of the composition,

wherein the microemulsion composition is stable for 3 months at 40 ℃.

2. A composition according to claim 1, wherein the glyceryl caprylate is caprylic monoglyceride or caprylic diglyceride.

3. The composition of claim 1, wherein the racecadotril is present in an amount of 8-10 wt.%.

4. The composition of claim 1, wherein the at least one surfactant is present in an amount of 88-91 wt.%, based on the total weight of the composition.

5. The composition of claim 1, wherein the lipid is a triglyceride selected from the group consisting of long chain triglycerides, medium chain triglycerides, caprylic/capric triglycerides and mixtures thereof.

6. The composition of claim 1, further comprising an optional ingredient selected from the group consisting of citric acid, sodium benzoate, sucralose, and mixtures thereof.

7. 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.

8. The composition of claim 1, wherein the composition has a total water content of less than 3.5 wt.%, based on the total weight of the composition.

9. The composition of claim 1, further comprising a second active ingredient, the second active ingredient being a digestive active ingredient.

10. Use of the composition of claim 1 in the preparation of a medicament for treating a subject suffering from diarrhea, comprising the step of orally administering to the subject the composition of claim 1.

11. The composition of claim 9, wherein the digestive health state active ingredient is selected from the group consisting of: laxatives, antacids, proton pump inhibitors, antiasthmatic agents, antiemetics, H2 blockers and antidiarrheal agents.

12. The composition of claim 11, wherein the anti-gas agent is dimethicone.

13. The composition of claim 11, wherein the antidiarrheal agent is loperamide.