WO2013110812A1 - Composition in the form of a gel capsule comprising ginger powder and a coating agent - Google Patents

Description

 COMPOSITION IN THE FORM OF A GELULE COMPRISING GINGER POWDER AND A COATING AGENT

The present invention relates to a composition containing ginger powder, associated with an excipient, its method of preparation, and its use for the treatment or prevention of nausea and / or vomiting and / or heartburn, lifts acids, and / or gastroesophageal reflux, preferably in the pregnant woman, especially as a dietary supplement.

Traditional use, and more recently published scientific studies, have shown that ginger or ginger preparations have the property of alleviating or even suppressing digestive disorders such as nausea and vomiting (see Borrelli et al Obstetrics and Gynecology 2005, 105, No. 4, 849-856). The exact mechanism of action of ginger is not definitively confirmed, but it is very likely that it induces a local action on gastric motility and a central action in the central nervous system (see White et al American Family Physician 2007 , 75, No. 1, 1689-1691).

Ginger contains many components with a strong taste and smell, including a volatile fraction, the main components of which are Gingerols and Shogaols. However, this odor is difficult to withstand by some people and can be a nuisance, especially in people with nausea.

In addition, ginger has a rapid antiemetic action when it comes into contact with the stomach, particularly through the interaction of the stomach wall with the volatile components mentioned above (see Bryer et al Journal of Midwifery). and Women's Health, 2005, 50, No. 1, el-e3). It therefore seems important to obtain a dosage form that both masks the smell of ginger while allowing a quick release in the stomach of the ginger powder.

Typically, the daily effective dose is 1 g divided into four daily administrations of 250 mg (see White et al American Family Physician 2007, 75 No. 11, 1689-1691).

The object of the present invention is therefore to provide patients in need of this treatment, an oral composition for the daily administration of an effective dose of ginger powder, for example a dose of 250 mg per intake of said powder.

However, it is not conceivable to develop a filling composition comprising the dose of 250 mg of ginger powder in a presentation intended for oral administration of capsules of size 00 (volume 0.91 ml) or 000 (volume 1.34 ml). ) for example. Indeed, before this type of capsules, nauseated patients, especially pregnant women, are discouraged from following the treatment because they feel discomfort and have difficulty swallowing the capsule.

The technical problem to be solved for obtaining a dosage form for oral administration of a composition based on ginger powder intended for the treatment of nausea, in particular in pregnant women, is therefore antithetical, since it is necessary at the same time to mask taste of the ginger root and increase the stability of the ginger powder, which involves the use of a large amount of excipient as described in the prior art, and minimize the amount of excipient since it is it is preferable to obtain a capsule of typically size 1 comprising a quantity of ginger root that is large enough for an effective treatment (for example 250 mg).

The present invention therefore proposes to solve this problem. In a completely unexpected manner, the inventors have shown that it is possible to obtain a filling composition comprising ginger powder associated with excipients comprising an effective amount of ginger powder, typically 250 mg, and which can be contained in a capsule easy to swallow for a nauseated patient, particularly a pregnant woman.

This filling composition can therefore be used, for example, to fill capsules of size 1 (useful volume 0.49 ml) allowing the administration of a unit dose of ginger powder. This size is below the avalability limit. It makes it possible to avoid difficulties in swallowing the capsule and to improve the observance of the treatment, which makes it possible to relieve more effectively people suffering from digestive disorders such as nausea and vomiting. It is also conceivable to use capsules of size 0 (useful volume 0.68 mL) in certain particular cases.

The present invention thus relates to a composition in the form of a capsule containing a filling composition comprising, by weight relative to the total weight of the filling composition: 94 to 99.95% of ginger powder, and

0.05 to 3% of at least one polysaccharide water-soluble polymeric coating agent.

Advantageously, such a composition comprises between 220 mg and 280 mg of coated ginger powder. In one embodiment, the present invention provides a capsule composition containing a fill composition comprising, by weight based on the total weight of the fill composition:

95 to 99.5% of ginger powder, and

0.5 to 2% of at least one polysaccharide-type water-soluble polymeric coating agent.

By "filling composition" according to the invention is meant the composition that will be contained in the capsule in the final oral composition. "Capsule" according to the invention means hard shell capsules. Indeed this type of capsule makes it possible to exert compression during the filling of the capsule with the filling composition.

The envelopes of the capsules according to the invention are preferably based on gelatin or any other polymer other than gelatin, such as, for example, hydroxypropylmethylcellulose, by methods well known to those skilled in the art.

The capsules according to the invention are advantageously of size 1, possibly of size 0 in certain particular cases, although size 1 is preferable. Advantageously, the envelope of the capsule consists of hydroxypropylmethylcellulose. This polymer is indeed water-soluble. In addition, this polymer is a polysaccharide of plant origin, which makes it possible to avoid the absorption of products of animal origin by the patients who wish to avoid it.

The capsule according to the invention is intended for oral administration. The capsule is swallowed directly by the patient as is, with water for comfort.

Preferably, the ginger powder according to the invention is a powder of ginger rhizome, more commonly called ginger root. Ginger powder is well known to those skilled in the art. It is preferably from organic farming, to minimize the amount of toxic residues, especially for the fetus. It can be obtained by methods well known to those skilled in the art. The ginger powder preferably has a content of 6-Shogaol of the order of 0.2 to 0.5% by weight, and / or a content of 6-gingerol of 0.3 to 1.3% by weight, and / or a content of 8- gingerol of 0.05 to 0.3% by weight, and / or a gingerol content of 0.10 to 0.5% by weight, based on the total weight of the powder.

Advantageously, the coating agent is pharmaceutically or nutraceutically acceptable. By "pharmaceutically or nutraceutically acceptable" is meant within the meaning of the present invention that the product, here the excipient, is compatible with a pharmaceutical or nutraceutical use of the compound, that is, that is, it is not toxic to humans when used in a pharmaceutical or nutraceutical composition.

The polysaccharide water-soluble polymeric coating agents are preferably selected from the group consisting of gum arabic and hydroxypropyl methylcellulose and mixtures thereof. Preferably, when the coating agent according to the invention is hydroxypropylmethylcellulose, it is chosen from hydroxypropylmethylcelluloses of low molecular weight, less than 10,000 Daltons, preferably less than 1,000 Daltons.

In one embodiment, the polysaccharide water-soluble polymeric coating agent is gum arabic.

According to one particular characteristic of the invention, the composition further comprises an anti-caking or lubricating agent, preferably with a content of 0.5% to 3% by weight relative to the total weight of the filling composition.

Examples of anti-caking or lubricating agents include talc, colloidal silica, magnesium stearate. The anti-caking agent or lubricant has the role of preventing the powder from forming clumps during transport and filling of the capsule.

According to the present invention, the percentages are expressed as percentages by weight (w / w) relative to the total weight of the filling composition. In a preferred embodiment, the filling composition according to the invention comprises, based on the total weight of the filling composition, from 94 to 99.95% (w / w), for example from 95 to 99.5%, of ginger and 0.05 to 3%) (w / w), for example 0.5 to 2%, gum arabic and / or hydroxypropyl methylcellulose. In one embodiment, the filling composition according to the present invention comprises between 95.5 and 99.5% (w / w) of ginger powder and between 0.5 and 1.5% (w / w) of coating agent such as gum arabic and or hydroxypropyl methylcellulose. According to one embodiment of the invention, the filling composition comprises between 98 and 99.5% (w / w) of ginger powder and between 0.5 and 1.5% (w / w) of gum arabic.

The composition according to the invention can be used to produce unit administration doses each comprising the amount of ginger powder that is to be administered to a patient (for example 250 mg).

The compositions according to the invention preferably allow the oral administration of a quantity of ginger powder of between 220 mg and 280 mg, preferably between 240 mg and 260 mg, even more preferably equal to 250 mg, in a single dose ( for example a capsule). Preferentially, the compositions according to the invention thus comprise between 220 mg and 280 mg, preferably 250 mg of ginger powder per unit (capsule).

Advantageously, the compositions according to the invention are nutraceutical or pharmaceutical. Particularly advantageously, such compositions are used for the treatment and / or prevention of nausea and / or vomiting, particularly in pregnant women. They can also be used in patients undergoing chemotherapy who are suffering from or are likely to experience nausea and / or vomiting. In another embodiment of the invention, said compositions are used for the treatment and / or prevention of heartburn, acid reflux and / or gastroesophageal reflux, particularly in pregnant women.

The present invention also relates to a process for preparing the composition according to the present invention.

In the process according to the present invention, the coating of the ginger powder is carried out according to the so-called "fluidized air bed" method, optionally preceded by a step of debacterization of the ginger powder. This technique of fluidized air bed consists of suspending a powder in a hot air stream and spraying a polymer solution over the powder. The droplets of polymer solution will be deposited on the powder particles, and the temperature of the air flow will allow a virtually immediate evaporation of the solvent, allowing a polymer deposition on the surface of the particles.

Since the water-soluble polysaccharide polymeric coating agent is water-soluble, the solvent used to form the polymer solution is preferably water.

The concentration of the polysaccharide water-soluble polymeric coating agent in the spray solution is typically from 0.1 to 10% by weight, preferably 1% by weight of the total solution. Preferably, the concentration of the solution is chosen so that the viscosity of this solution is about 5 mPa / s. In addition, the temperature of the solution is advantageously between 25 and 65 ° C, even more advantageously, it is 45 ° C. In a preferred embodiment of the invention, the ginger powder is heated at a temperature between 30 ° C and 50 ° C, preferably between 40 ° C and 50 ° C, for the implementation of the step coating by the so-called "fluidized air bed" technique. This embodiment allows a better coating of the powder with the polysaccharide-type water-soluble polymeric coating agent. In this embodiment, the flow rate of the solution comprising the coating agent is between 200 g. min ^-1 and 1000 g min ^-1 , preferably between 500 g. min ^-1 and 1500 g min ^-1 and the spray pressure of said solution is advantageously between 1 and 3 bar, more advantageously it is about 2 bar.

The drying time is advantageously between 10 and 30 min, while the cooling time of the powder is preferably between 10 and 30 min.

In general, those skilled in the art can adapt these different parameters according to each other from the provided forks so as to obtain a coating for implementing the invention. Pregnant women are a population with special risks. It is indeed important that pregnant women are not exposed to certain disease-causing pathogens, such as listeriosis or toxoplasmosis, for example. It is therefore preferable that the method comprises a step of debacterization of the filling composition prior to encapsulation. The conditions for carrying out the debacterization step are well known to those skilled in the art, and include, for example, the heating of the powder for a short time in an oven, in a fluidized air bed or on a worm heating. The operating temperature is preferably between 50 ° C and 80 ° C. An alternative method consists in wetting the powder with a water-ethanol mixture followed by a drying step, however the temperatures and drying times necessary for the complete evaporation of the water can, under certain conditions, lead to losses of active substances.

The ginger powder coated according to the invention is thus subjected to a moderate temperature which makes it possible not to degrade the volatile active ginger molecules while advantageously proceeding to the debacterization of said coated ginger powder.

The present invention further relates to the use of a composition as a dietary supplement. Preferably, it is intended for non-therapeutic treatment and / or prevention of nausea and / or vomiting, particularly in pregnant women, in order to relieve the patient of certain discomfort caused by nausea.

Patients taking chemotherapy are also prone to nausea and / or vomiting, which is caused by chemotherapy treatments. It is the same for patients following radiation therapy. Patients who have undergone anesthesia may also have postoperative nausea and / or vomiting.

For these patients, the problem is the same as for pregnant women: mask the taste of the ginger root while using a sufficiently small dosage form, such as a size 1 capsule, so that the nauseated patient is not put off at the time of taking the capsule. The compositions according to the invention can therefore also be used as a dietary supplement for the treatment and / or prevention of nausea and / or vomiting in patients following chemotherapy. The compositions may also be used in patients undergoing radiotherapy, or in patients having undergone anesthesia.

In addition to pregnancy and the conditions mentioned above, motion sickness can also cause nausea and / or vomiting. Thus, the compositions according to the invention may also be useful in the prevention of nausea and / or vomiting caused by motion sickness, particularly in children, who may experience some difficulty and / or apprehension to swallow a capsule. of size 00 for example. In this case, the capsules according to the invention are particularly suitable.

In cases where nausea and / or vomiting are very common, they can cause weight loss and impact the patient's health. The present invention therefore further relates to a composition according to the present invention for use as a herbal medicament.

In particular, it relates to a composition according to the present invention for its use in the treatment and / or prevention of nausea, in particular in pregnant women. The compositions according to the invention for their use in the treatment and / or prevention of nausea are also advantageously used in patients following chemotherapy. It is also advantageous to use them in patients undergoing radiotherapy, or in patients having undergone anesthesia.

The composition according to the present invention may be administered in combination, simultaneously, separately or spread over time, with another drug or dietary supplement for use in the treatment of nausea, particularly in pregnant women. Heartburn, acid reflux, and / or gastroesophageal reflux disease (GERD) are often associated with nausea and / or vomiting, especially during pregnancy. Because of its action on gastric motility, ginger seems particularly suitable for relieving patients suffering from these ailments. Thus, in a particular embodiment, the present invention relates to a composition according to the present invention for its use in the treatment and / or prevention of heartburn, acid reflux, and / or gastroesophageal reflux disease (GERD). ), especially in pregnant women, or in patients undergoing chemotherapy, radiotherapy or having undergone anesthesia. In a preferred embodiment, the present invention relates to a composition comprising:

a first composition as defined above, and especially in the form of a capsule containing a filling composition comprising, by weight relative to the total weight of the filling composition 94 to 99.95% of ginger powder, and 0.05 to 3% of at least one polysaccharide water-soluble polymeric coating agent; said composition advantageously comprising between 220 mg and 280 mg of ginger powder coated according to the invention, and

a second composition comprising at least one drug or dietary supplement intended for use in the treatment of heartburn, acid reflux, and / or gastroesophageal reflux, as a combination product for simultaneous, separate or spread use over time in the treatment and / or prevention of heartburn, acid reflux, and / or gastroesophageal reflux, especially in pregnant women.

Indeed, it has been fortuitously observed that the simultaneous taking of the composition according to the invention and a second composition comprising a drug or food supplement for use in the treatment of heartburn, acid reflux, and / or gastroesophageal reflux provoked a synergy of beneficial activity. By drug or food supplement for use in the treatment of heartburn, acid reflux, and / or gastroesophageal reflux, is meant for example antacids, alginates, H2 antihistamines, and inhibitors of the pump. protons, or their mixtures. Antacids include, in particular, aluminum, magnesium and calcium salts - such as magnesium hydroxide, calcium carbonate - or mixtures thereof, such as, for example, hydrotalcite (aluminum and magnesium salt). Alginates include in particular alginic acid or sodium alginate. Examples of H2 antihistamines are famotidine and cimetidine. Proton pump inhibitors include pantoprazole, omeprazole and esomeprazole.

Preferably, the taking of the two compositions by the patient is simultaneous.

The number of times the combination product is taken can vary from 2 to 6 per day, i.e., the first and second compositions are typically administered orally 2 to 6 times daily. In a particularly preferred embodiment, the second composition intended for use in the treatment of heartburn, acid reflux, and / or gastroesophageal reflux comprises at least one drug or dietary supplement selected from alginic acid. or sodium alginate, alone or in admixture with an antacid. Advantageously, the antacid is an agent releasing carbon dioxide, in particular calcium carbonate, calcium bicarbonate, sodium carbonate and sodium bicarbonate.

In this embodiment, the first composition advantageously comprises 250 mg of coated ginger powder according to the invention, and the second composition comprises, for example, 400 mg of alginic acid or of sodium alginate and 200 mg of a releasing agent. carbon dioxide, especially sodium bicarbonate. Legend of figures:

Figure 1: Diagram comparing the size of the different existing capsules (from size 000 to size 5). The size of the capsules (in mm) is given on the y-axis. The volume is also specified.

The invention is illustrated by the examples below, which are not limiting. Examples

Example 1 Preparation of Capsules According to the Invention

1. Coating process The coating of the ginger powder is carried out according to the so-called "fluidized air bed" method. This technique involves suspending a powder in a hot air stream and spraying a polymer solution over the powder. The droplets of polymer solution will be deposited on the powder particles and the temperature of the air flow will allow almost immediate evaporation of the solvent, allowing the polymer deposition on the surface of the particles.

Optimal parameters are as follows: Polymer Solvent: Water Polymer Solution Concentration: 1% Polymer Solution Temperature: 45 ° C Powder Temperature: 47 ° C

Solution flow: 500 g / min Spray pressure: 2 bar Drying time: 20 min Cooling time: 15 min 2. Put in capsule

Tests have been carried out with gum arabic (GA). The density obtained as a function of the amount of gum arabic used is presented in Table 1 below.

 Table 1

It is found that the density obtained is greater than 0.5 for the tests corresponding to a percentage of gum arabic of between 0.05% and 1.5% (tests 1 to 6), and close to 0.5 for tests 12 and 13 thus allowing 250 mg Ginger powder (plus 3.75 mg GA for the 1.5% test) to be placed in a size 1 capsule.

This range of coating percentage also allows a very fast release of active in the stomach, which is almost immediate.

In terms of odor masking and asset stabilization, the best results are obtained with the compositions comprising a percentage of water-soluble excipient of between 0.5 and 1.5%. Comparative examples

Comparative tests were carried out

 hydroxypropyl methylcellulose (HPMC) and gum arabic (GA).

The density obtained as a function of the amount of HPMC or GA used is presented in Table 2 below.

 Table 2

 These tests were very satisfactory for the purposes of odor masking, asset stabilization, rapid release of the active ingredients, for the coating percentages of between 6% and 1.7%. Beyond (14% and 16%), the release of assets in the stomach is delayed.

On the other hand, the densities obtained made it necessary to use capsules of size 0 or even 00. In fact, not only was the density low, but moreover it was necessary to take into account the quantity of polymer in the final weight of coating: For example, the 11.7% coating requires filling the capsule at 279 mg (250 mg + 250 × 11.7%); tests of use with pregnant women have shown that these sizes of capsules are not bearable for the majority of women. Example 2 Stability of Ginger Powder Compounds

Ginger compositions comprising different amounts of gum arabic are stored at room temperature for 4 months. The mass percentage of volatile compounds (6-shogaol, 6-gingerol, 8-gingerol and 10-gingerol) are measured at T = 0 (T 0) and after 4 months of storage (T4 months) for the various compositions. The results are shown in Table 3 below.

 weight based on the total weight of the starting composition at time T0 Table 3 It is found that from 0.5%, the amount of volatile active compounds remains stable after 4 months of storage at room temperature.

Claims

claims 1- Composition in the form of a capsule containing a filling composition comprising, by weight relative to the total weight of the filling composition:  - 94 to 99.95% of ginger powder, and  0.05 to 3% of at least one polysaccharide water-soluble polymeric coating agent;  said composition advantageously comprising between 220 mg and 280 mg of coated ginger powder. 2- Composition according to claim 1, characterized in that the filling composition comprises 0.5 to 2% by weight of said coating agent and 95 to 99.5% by weight of ginger powder, relative to the total weight of the filling composition.  3- Composition according to any one of claims 1 or 2, characterized in that the capsule is of size 1. 4. Composition according to any one of claims 1 to 3, characterized in that the polysaccharide water-soluble polymeric coating agent is chosen from gum arabic and hydroxypropyl methylcellulose. 5. Composition according to any one of claims 1 to 4, characterized in that it comprises 250 mg of ginger powder. 6. Composition according to any one of claims 1 to 5, wherein the capsule is a capsule capsule consisting of hydroxypropylmethylcellulose. 7- Composition according to any one of claims 1 to 6, characterized in that it further comprises an anti-caking agent or lubricant, preferably with a content of 0.5% to 3% by weight relative to the total weight of the filling composition. 8- Composition according to any one of claims 1 to 7, characterized in that it is pharmaceutical or nutraceutical. 9- Composition according to any one of claims 1 to 8 for its use for the treatment and / or prevention of nausea and / or vomiting, especially in pregnant women. 10- composition according to claim 9, in patients following chemotherapy or radiotherapy, or having undergone anesthesia. 11. Composition according to any one of claims 1 to 7 for its use for the treatment and / or prevention of heartburn, acid reflux, and / or gastroesophageal reflux, especially in pregnant women. 12- Process for preparing a composition according to any one of claims 1 to 8, characterized in that the coating of the ginger powder is carried out according to the method of fluidized air bed, optionally preceded by a step of debacterization of ginger powder. 13- Composition comprising: a first composition as defined in any one of claims 1 to 7, and a second composition comprising at least one antacid, an alginate, an antihistamine H2, a proton pump inhibitor, or mixtures thereof, as a combination product for simultaneous, separate or spread use over time in the treatment and / or the prevention of heartburn, acid reflux, and / or gastroesophageal reflux, especially in pregnant women.