WO2018015353A1

WO2018015353A1 - A pharmaceutical or food supplement formulation for the treatment of intestinal constipation

Info

Publication number: WO2018015353A1
Application number: PCT/EP2017/068056
Authority: WO
Inventors: Annalisa CULZONI
Original assignee: Nathura S.P.A.
Priority date: 2016-07-18
Filing date: 2017-07-17
Publication date: 2018-01-25
Also published as: EP3484494A1; IT201600075072A1

Abstract

A composition with laxative effect which comprises a tamarind extract, a ginger extract and a buckthorn extract, as well as, possibly, a caraway extract; the buckthorn extract in a weight ratio less than or equal to 0.03 with respect to the tamarind extract; a pharmaceutical or food supplement formulation suitable for oral administration, for the treatment of constipation, comprising the above-mentioned composition and at least one pharmaceutically or nutritionally acceptable excipient is also described.

Description

TITLE: A pharmaceutical or food supplement formulation for the treatment of intestinal constipation

DESCRIPTION

Field of Application

The present invention relates to the sector of the pharmaceutical and food supplement and functional food industry.

In particular, the invention relates to a tamarind-based composition for the regulation of the gastrointestinal motility and the prevention and/ or treatment of the intestinal constipation.

Prior Art

Constipation is a disorder of the intestinal motor activity, very common particularly among industrialized countries. It is one of the most frequent gastrointestinal disorders and about 13 million Italians, including about 9 million women, suffer from it.

Constipation is essentially a disorder connected to defecation and consists in the difficulty to evacuate the intestine. Constipation occurs with a considerable reduction of the evacuation frequency and of the feces volume, abdominal pain and swelling, meteorism and difficulty to evacuate.

Constipation is a symptom rather than a disease and in most cases it is temporary and not severe.

Among the most frequent causes of constipation there are fiber deficiency in diet, insufficient physical activity, irritable colon syndrome, pregnancy, trips, dehydration and problems with intestine function.

The most frequent cause of constipation is to attribute to a fiber- deficient diet or to an excessively high fat content.

A healthy diet, with a high content of vegetables, fresh fruit, wholewheat bread and cereals, is fundamental in preventing constipation. An abundant liquid intake allows to keep soft feces, facilitating their expulsion and a constant physical activity is just as much important to maintain an adequate intestinal muscle tone.

In case the dietary and behavioral regimen are not sufficient to prevent constipation, laxatives are generally used.

Laxatives are usually classified in four categories:

- Bulk-forming laxatives, namely laxatives which increase feces volume, thereby promoting intestinal transit; among these it is possible to mention psyllium seeds, agar-agar, bran, fucus and guar gum;

Contact laxatives, that act by increasing the contractions of the intestinal wall, thereby activating the peristalsis: among these the following can be mentioned: cascara, senna, buckthorn, rhubarb, castor oil, phenolphthalein, bisacodyl and sodium picosulphate. - Emollient laxatives, that act by mixing themselves to the feces, thereby softening and lubricating them; among these it is possible to mention glycerin and liquid paraffin;

- Osmotic laxatives, that act retaining and drawing liquids from the intestine, so as to form voluminous and soft feces and to accelerate the transit thereof in the large intestine; among these it is possible to mention lactulose, mannitol, magnesium salts, sorbitol and tamarind.

Each one of the above mentioned laxative categories exhibits drawbacks. In particular, contact laxatives can cause diarrhea and abdominal cramps and their prolonged use can damage intestinal muscle function with worsening of the constipation. Emollient laxatives can interfere with the absorption of liposoluble vitamins and calcium. Osmotic laxatives, especially at high doses, can cause abdominal cramps, nausea and vomiting, as well as dehydration and renal problems. Bulk-forming laxatives are the relatively most safe but they are not always sufficient to resolve constipation and moreover, if they are taken in excessive doses, can cause meteorism and obstruction of the intestinal tract.

The Applicant conducted a research project aimed at providing a food supplement composition for the regulation of the gastrointestinal motility, suitable to prevent and/ or treat constipation, without causing undesired side effects.

The research project started from what was already known in the scientific literature about the effects of tamarind (Tamarindus indica). Tamarind is mentioned as delicate laxative in several pharmacopoeias and it is used in various traditional medicines, particular in the African one. The part of tamarind which is used is the fruit pulp, which contains high concentrations of malic acid and tartaric acid, as well as potassium bitartrate, reducing sugars, vitamin B and minerals (Havinga et al., 2010). Organic acids, in particular, have a laxative effect by virtue of osmotic action. Tartaric acid has both a direct and an indirect osmotic effect: following its fermentation by the colon microbiota, in fact, short-chain fatty acids (SCFA) are produced, which in turn draw water and increase feces hydration (Spiller et al., 2003).

Tamarind is considered harmless and no noteworthy side effects are reported in literature except the possibility to cause, like the other osmotic laxatives, some abdominal discomfort.

The patent application IN 2209/CHE/201 1 describes a laxative comprising various vegetable ingredients, among which there are senna, haritiki (Terminalia chebula), and bahera as active ingredients with laxative action, tamarind to improve aroma and palatability and ginger to facilitate digestion.

US 2012/ 156143 discloses a composition comprising one or more plant-derived cathartics and an effervescent coupling system. Among such plant-derived cathartics, buckthorn, alder buckthorn and ginger are mentioned.

Eric Yarnell, "Compendium of Pharmacological Actions of Medicinal Plants and Their Constituents", Actions of Medicinal Plants, 1 October 201 1 , pages 1-65, discloses laxatives with cathartic action, among which Frangula purshiana and Rhamnus frangula, laxatives with osmotic effect such as Tamarindus and spasmolytics with carminative effect, such as Carum carvi and Zingiber officinale. However, this document does not disclose any compositions comprising two or more of these active ingredients.

An aim of the present invention is to provide a composition for the treatment of constipation, suitable in particular for the treatment of chronic and occasional constipation, for which bulk-forming laxatives do not show good results, based on active ingredients of natural origin and with the mildest possible action and without side effects.

Summary of the invention

Such aim was achieved by providing a composition that comprises an active ingredient with a laxative effect of osmotic type, consisting of tamarind extract, a ginger extract (Zingiber officinale Rose.) and a buckthorn (Frangula dodonei) extract, wherein the buckthorn extract is in a weight ratio less than or equal to 0.03 with respect to the tamarind extract.

The ginger extract contained in the composition according to the invention prevents the above-mentioned possible, albeit limited, side effects of tamarind extract, thanks to its antiemetic, prokinetic and antispasmodic effects, which prevent abdominal discomfort that could be caused by tamarind, essentially consisting in abdominal swelling and flatulence.

The buckthorn extract is a contact laxative, whose effect is due to the anthraquinone active ingredient glucofranguline A, and it is considered the mildest anthraquinone laxative. In clinical practice, buckthorn preparations standardized so as to contain 20-30 mg of glucofranguline A are used.

An optional component of the composition according to the present invention is caraway (Carum carvi) extract which, besides having antispasmodic effects similar to those of ginger extract, useful to prevent the possible abdominal discomfort caused by the tamarind extract, also shows a marked carminative effect and a choleretic and anti-fermentation action, thus selectively inhibiting intestinal pathogenic bacteria and helping rebalance the intestinal microbiota.

The present invention also relates to a pharmaceutical or food supplement formulation suitable for oral administration, for the treatment of constipation, comprising the above-described composition and pharmaceutically or nutritionally acceptable excipients.

Such formulation comprises one or more dosage units, each of which comprises from 4.0 to 6.0 g of a 1 : 4 dry extract of Tamarindus indica L. fruit, from 0.10 to 0.30 g of a dry extract of Zingiber officinale Roscoe rhizome, from 0.10 to 0.15 g of a dry extract of buckthorn (Frangula dodonei) bark, and pharmaceutically or nutritionally acceptable excipients.

The above-mentioned dosage unit can further comprise from 0.10 to 0.20 g of dry extract of Carum carvi fruit.

Preferably a dry extract of Zingiber officinale Roscoe rhizome containing 1% total gingerols, a dry extract of buckthorn (Frangula dodonei Ard.) bark containing 7.7%-9.0% glucofranguline A and a dry extract of Carum carvi L. fruit containing 2.5% polyphenols and 0.8% essential oil are used.

Using the above-mentioned dry extract of buckthorn (Frangula dodonei) bark, the formulation according to the invention is such that each dosage unit comprises from 7.7 mg to 13.5 mg of glucofranguline A.

Solid dosage forms for oral administration include for example capsules, tablets, powders, granules and gels. In such solid dosage forms the active ingredient can be mixed with at least one inert diluent such as for example sucrose, lactose, starch or maltodextrin. Generally, these dosage forms also include additional substances different from inert diluents, such as for example sweeteners, such as sorbitol, sucralose and steviol glycosides, flavours and anti-caking agents such as silicon dioxide.

The pharmaceutical preparations according to the present invention can be produced using conventional pharmaceutical techniques, as they are described in the various pharmacopoeias or in handbooks of the art such as for example "Remington's Pharmaceutical Sciences 15 Handbook", Mack Publishing, New York, 18th Ed., 1990.

The daily mean dosage of the compounds according to the present invention depends on many factors, such as for example the severity of the constipation and the condition of the patient (age, weight, sex): the dose can usually vary from 2.0 g to 15.0 g, preferably from 2.7 to 1 1.0 g, of composition according to the invention per day, possibly divided in several administrations.

In a further aspect, the present invention relates to a functional food containing the above-described composition. Preferably this functional food is such that a predetermined portion thereof contains from 4.0 to 6.0 g of a 1 :4 dry extract of Tamarindus indica L. fruit, from 0.10 to 0.30 g of a dry extract of Zingiber officinale Roscoe rhizome and from 0.10 to 0.15 g of a dry extract of buckthorn (Frangula dodonei) bark.

Conveniently, such portion also contains from 0.10 to 0.20 g of a dry extract of Carum caraway fruit.

The functional food of interest can be for example a cereal bar, a yogurt or a similar dairy product, a bakery product or a fruit juice.

Detailed description

The characteristics and benefits of the present invention will better result from the description of some embodiments reported below by way of non-limiting examples:

Example 1

Dosage unit of a formulation according to the invention:

1 : 4 dry extract of Tamarindus indica L. fruit 5.2 g Dry extract of Zingiber officinale Roscoe rhizome 0.25 g

Dry extract of buckthorn (Frangula dodonei) bark 0.15 g

Maltodextrin 1.0 g Sorbitol 0.6 g

Sucralose 0.7 g

Flavours 0.2 g

Silicon dioxide 0.1 g Example 2

Dosage unit of a formulation according to the invention:

1 : 4 dry extract of Tamarindus indica L. fruit 5.0 g

Dry extract of Zingiber officinale Roscoe rhizome 0.20 g

Dry extract of buckthorn (Frangula dodonei) bark 0.13 g Dry extract of Carum carvi fruit 0.15 g

Maltodextrin 0.5 g

Sorbitol 0.7 g

Stevia (powder extract) 0.05 g

Flavours 0.3 g Coloring agent 0.3 g

Silicon dioxide 0.1 g

The dry extracts mentioned in the examples above are more precisely the following: dry extract of Zingiber officinale Roscoe rhizome containing 1% total gingerols, dry extract of buckthorn (Frangula dodonei Ard.) bark containing 7.7%-9.0% glucofranguline A and dry extract of Carum carvi L. fruit containing 2.5% polyphenols and 0.8% essential oil.

The dosage units of examples 1 and 2 were realized in form of powder sachets, possibly bipartite, intended to be dissolved in water for oral administration.

Example 3

The composition according to example 2 was tested in patients affected by chronic constipation, selected on the basis of the diagnostic criteria set in the Consensus Conference on the Diagnostic Criteria of Functional Disorders of the Intestine (called Rome III), namely on the basis of the presence of at least two of the following characteristics: straining during defecation, hard stools or fecalomas, sensation of incomplete evacuation, sensation of anorectal obstruction/blockage, need to perform manual maneuvers for evacuation, fewer than three defecations per week. This in the absence of a diagnosis of irritable bowel syndrome.

1 1 patients were selected on the basis of the above-mentioned criteria and such patients were divided into two groups A and B, composed of 8 and 3 patients respectively, on the basis of how severe was the constipation, which was more severe in group A.

Patients from group A were asked to take twice a day one dosage unit according to example 2, in the form of a powder sachet, dissolved in 200 ml water and stirred until a clear solution without clumps was obtained, until the first evacuation. Successively the patient took only one dosage unit a day for a total period (starting from the first dosage unit taken) of two weeks.

Patients from group B were asked to take twice a day half the dosage unit according to example 2, in the form of half a powder sachet, dissolved in 200 ml water and stirred until a clear solution without clumps was obtained, until the first evacuation. Successively the patient took only half a dosage unit a day for a total period (starting from the first dosage unit taken) of two weeks.

The results of the clinical trial are summarized in the following Table

1

Table 1

Group A Group A Group B Group B First week Second week First week Second week (Arithmetic (Arithmetic (Arithmetic (Arithmetic mean)) mean) mean) mean)

3.6 4.1 2.0 3.6

Number of spontaneous

evacuations

3.5 3.5 2,0 3,6

Number of spontaneous

evacuations not induced by other

laxatives

0 0 0 0

Number of evacuations which

required manual maneuvers

1.1 2.6 2.3 1.3

Number of evacuations with

optimal consistency

0 0 0 0

Days in which diarrhea appeared

0.2 0 0 0

Mean score of abdominal pain

4 5 2 2

Number of patients with more

than 3 spontaneous evacuations

1 3 0 0

Number of patients who needed

another laxative The score of the abdominal pain was valued asking the patients to draw a sign on a scale from 0 to 4, where 0 indicates no abdominal pain and 4 the maximal abdominal pain.

As it can be seen from the data of Table 1 , the composition according to the present invention proves to be effective in opposing constipation already at a dose corresponding to half the dosage unit of the example 2. Moreover, the composition proves to be very well tolerated, since it did not provoke abdominal pain except in a very mild form in only two patients from group A and did not provoke diarrhea episodes. In addition, it was not observed any abdominal swelling. Finally, patients evaluated pleasant the taste of the composition according to the present invention.

It is significant to note that the buckthorn extract is comprised in the tested composition in such an amount to have around 10- 12 mg glucofranguline A in each dosage unit, a dose which corresponds to around half the minimum dose of glucofranguline A used to achieve a laxative effect (monographs about buckthorn suggest typical glucofranguline A intake equal to 20 mg or 30 mg). This suggests a synergic effect of the buckthorn extract with the tamarind extract in causing a significant laxative effect of the present composition even if the amount of buckthorn extract would not by itself be sufficient to perform any therapeutically useful activity.

Claims

1. A composition with laxative effect which comprises a tamarind (Tamarindus indica L.) extract, a ginger (Zingiber officinale Rose.) extract and a buckthorn (Frangula dodonei) extract, wherein the buckthorn extract is in a weight ratio less than or equal to 0.03 with respect to the tamarind extract.

2. The composition according to claim 1 , further comprising a caraway (Carum carvi) extract, endowed with carminative effect.

3. A pharmaceutical or food supplement formulation suitable for oral administration, for the treatment of constipation, comprising the composition according to claim 1 and at least one pharmaceutically or nutritionally acceptable excipient.

4. The formulation according to claim 3, comprising one or more dosage units, each of which comprises from 4.0 to 6.0 g of a 1 : 4 dry extract of Tamarindus indica L. fruit, from 0.10 to 0.30 g of a dry extract of Zingiber officinale Roscoe rhizome, and from 0.10 to 0.15 g of a dry extract of buckthorn (Frangula dodonei) bark.

5. A pharmaceutical or food supplement formulation suitable for oral administration, for the treatment of constipation, comprising the composition according to 2 and at least one pharmaceutically or nutritionally acceptable excipient.

6. The formulation according to claim 5, wherein each dosage unit comprises from 4.0 to 6.0 g of a 1 : 4 dry extract of Tamarindus indica L. fruit, from 0.10 to 0. 30 g of a dry extract of Zingiber officinale Roscoe rhizome, from 0.10 to 0.15 g of a dry extract of buckthorn (Frangula dodonei) bark and from 0.10 to 0.20 g of dry extract of Carum carvi fruit. 7. The formulation according to claim 4 or 6, wherein each dosage unit comprises from 7.

7 mg to 13.5 mg of glucofranguline A.

8. The formulation according to any one of claims 3 to 7, wherein said at least one pharmaceutically or nutritionally acceptable excipient is selected from the group comprising diluents, such as sucrose, lactose, starch and maltodextrin, sweetener, such as sorbitol, sucralose and steviol glycosides, anti-caking agents such as silicon dioxide, and aromas.

9. The formulation according to claim 8, characterized in that it is in the form of water-soluble powder, packaged in sachets.

10. A functional food containing the composition according to claim 1 or 2.

1 1. The functional food of claim 1 1 , containing, in each of its portions, from 4.0 to 6.0 g of a 1 :4 dry extract of Tamarindus indica fruit L., from 0.10 to 0.30 g of a dry extract of Zingiber officinale Roscoe rhizome and from 0.10 to 0.15 g of a dry extract of Frangula dodonei bark.

12. The functional food of claim 1 1 , containing, in each of its portions, also from 0.10 to 0.20 g of a dry extract of Carum caraway fruit.

13. The functional food according to any one of claims 10 to 12, selected from the group consisting of cereal bars, yogurt and the like dairy products, bakery products and fruit juices.