IT201600109433A1 - GASTRORESISTIC COMPOSITIONS INCLUDING BROMELINE ASSOCIATED WITH A DRIED EXTRACT OF ANANAS COMOSUS (L.) - Google Patents

Description

"GASTRORESISTANT COMPOSITIONS INCLUDING BROMELAIN ASSOCIATED WITH A DRY EXTRACT OF PINEAPPLE COMOSUS (L.)"

The invention relates to a composition for oral use in the form of granules or micro-granules comprising bromelain associated with a dry extract of Ananas comosus (L.) and maltodextrin, said granulate or micro-granule being coated with a gastro-resistant film

State of the art

The term bromelain indicates a group of enzymes with a prevalent proteolytic activity, which is naturally present in different parts of the Pineapple comosus (L.) Merr plant. (syn. Ananas sativus Schult. & Schult.f.), plant of the Bromeliaceae family. Several bromelain-based raw materials are available on the market, commonly used in food supplements.

Bromelain is mainly composed of cysteine proteases but also contains small amounts of other enzymes (acid phosphatase, amylase, peroxidase, etc.). It boasts various effects on the body, including digestive, anti-inflammatory, immuno-modulatory, anti-diarrheal, anti-carcinogenic and healing activities. Many of these activities are related to enzymatic activity.

The enzymatic activity of bromelain can be expressed in different ways, the most common of which are the GDU (Gelatin Dissolving Units) and FIP U (Federation International Pharmaceutical Units). Another measure that is found is the MCU (Milk Clotting Units); 1 GDU is equivalent to approximately 1.5 MCU.

In double-blind placebo-controlled studies, bromelain has been shown to be effective in decreasing pain and accelerating healing time after surgery of various kinds, including oral surgery and episiotomy. These positive effects were related to an anti-inflammatory action of bromelain but the exact mechanism of action has not been fully clarified. In addition, it has been successfully used in the treatment of various sports bruises, leading to a reduction in edema and pain in the musculoskeletal system of 59 patients.

Bromelain also demonstrated a certain inhibition of platelet aggregation with positive effects in patients suffering from angina or thrombosis, as demonstrated by a double-blind study involving patients with acute thrombophlebitis. The use of bromelain, even in combination with other nutrients, can bring significant benefits against cardiovascular diseases, which are nowadays one of the main causes of death.

Bromelain, in combination with other nutrients, showed an effect comparable to that of diclofenac, one of the main non-steroidal anti-inflammatory drugs (NSAIDs) in the reduction of pain and inflammation in 103 subjects with osteoarthritis of the knee. Other clinical studies have shown that bromelain can be useful in case of osteoarthritis.

The usefulness of using bromelain in chronic bronchitis and sinusitis has been confirmed by some studies. In particular, a study conducted on children with acute sinusitis showed improvements in symptoms after oral intake of bromelain.

At the level of the immune system in a randomized controlled trial, it was found that bromelain was able to modulate the release of some cytokines after oral administration, hypothesizing that the observed effects are partly related to the proteolytic activity of the enzyme at the level cell membrane, due to alterations in ligand-receptor interactions. Furthermore, there is evidence that bromelain may produce benefit in patients suffering from rheumatoid arthritis.

The pharmacokinetics of bromelain in humans is not fully known. Despite its enzymatic activity taking place over a wide pH range (3-10), once ingested bromelain undergoes the attack of gastric juices. To carry out its activities, in particular the anti-inflammatory and immunomodulating action, bromelain must be absorbed in the intestine, involving the passage through the stomach, which is a critical element.

Given the multiple activities attributed to bromelain, this is widely used in food supplements alone or in combination with other active substances. Bromelain is preferably used in a gastroprotected form, to prevent partial or total gastric degradation thereof.

Various technologies are known that modify the release profile, advantageously used if you want to avoid contact of compounds sensitive to the acidic environment with gastric juices. These technologies are generally applied to solid pharmaceutical forms, mainly tablets but also hard gelatin capsules.

It is known, for example, that in order to obtain gastro-resistant tablets, it is possible to cover them with films capable of conferring gastro-resistant characteristics. Also by using hard gelatin capsules it is possible to obtain a control of the release of substances; for example by using gastro-resistant gelatin wrappers, which dissolve specifically in the intestinal lumen. The main limitation of this technology consists in preventing the prior disaggregation of the tablet at the gastric level, thus limiting the absorption of any other active ingredients combined with the gastro-labile active. On the other hand, in the case of tablets made with previously gastroprotected granules, the disaggregation begins at the gastric level, where the tablet is fragmented into smaller parts and the active ingredients are partially absorbed. However, this phenomenon does not concern the active ingredients contained in the gastro-resistant granules, which arrive intact in the intestinal lumen where they can be absorbed, after a dissolution process. Dissolution is an essential step for a certain active to be released from the pharmaceutical form and then absorbed; this process is governed by several parameters and described by the Noyes-Withney law:

dc / dt = KS (CS - CT)

The parameter that most influences the dissolution with the same other factors, considered constant by type of substance, is the specific surface of the solid particles "S" exposed to the dissolution medium; in other words, this can be defined as the area per unit volume of the solid particle, which increases as the particle size decreases. It follows, therefore, that the size of the solids greatly influence their degree of dissolution and that the presence of granules in the intestinal lumen, rather than an entire tablet or capsule, can lead to a significant advantage in absorption.

Although tablets and capsules are oral pharmaceutical forms of very common use among food supplements, other forms are also used, for example pre-dosed powders, collected in sachets to be reconstituted in water or to be taken as is. Their use is required when it is necessary to administer large quantities of active ingredients (in the order of grams), which cannot be included in tablets or capsules. Furthermore, the need to use products in bags may arise when the intake of components is required which, before being ingested, require hydration, in order to carry out their beneficial action. In addition to these reasons, the use of products in bags is particularly useful for those people who, for pathological reasons but not only, have difficulty swallowing. The products in bags represent a useful solution to the difficulty of swallowing: in fact, in the case of powders to be reconstituted in water, the addition of thickening agents in suitable quantities is an easy way to improve the consistency of the reconstituted solution. Particularly sensitive to swallowing difficulties is the pediatric target.

Technologies are known which apply the granulation process, mainly using excipients of a hydrophobic nature. In particular, EP 1861075 describes the realization of formulations in the form of granules for oral use coated with hydrogenated vegetable fats and surfactants for various purposes, including protection from gastric juices. The granules obtained using these technologies are by their nature incompatible with water, an indispensable means for administration, generating precipitates that cannot be taken, thus compromising the effectiveness of the products. Usually, in cases of difficult homogeneity of the reconstituted solution, an attempt is made to intervene with the addition of suitable excipients that favor the dispersion of hydrophobic granules. This strategy, however, does not always lead to satisfactory solutions because it requires the use of large quantities of excipients.

Description of the invention

It has now been found that bromelain associated with an enzymatic active dry extract of Ananas comosus (L.) can be advantageously formulated in gastro-resistant granules or micro-granules using maltodextrins as granulation excipients and suitable gastro-resistant coatings.

The invention therefore relates to a composition for oral use in the form of granules or micro-granules comprising bromelain associated with a dry extract of Ananas comosus (L.) and maltodextrin, said granulate or micro-granule being coated with a gastro-resistant film.

According to a further aspect, the invention relates to a kit comprising: - a liquid phase in a vial, and

- a powder phase in a measuring cap of said vial, said cap containing the gastro-resistant granules or micro-granules of bromelain associated with a dry extract of Ananas comosus (L.) and maltodextrin.

According to yet another aspect, the invention relates to food supplements or medical foods or medical devices comprising granules or gastro-resistant micro-granules of bromelain associated with a dry extract of Ananas comosus (L.) and maltodextrins.

Detailed description of the invention

The compositions of the invention contain bromelain associated with a further source of bromelain, in particular an extract of Ananas comosus (L.) Merr. (syn. Ananas sativus Schult. & Schult.f.), in particular an extract obtained from the stems and / or the fruit of the plant.

The overall enzymatic activity of the granulate is preferably between 200 and 2,500 GDU / g, more preferably between 500 and 1,250 GDU / g and even more preferably between 600 and 900 GDU / g. The enzymatic activity of bromelain is typically 2,500 GDU / g, while that of the pineapple extract is approximately 250 GDU / g.

In terms of weight, the compositions of the invention contain for example from 200 to 400 parts by weight of bromelain and from 100 to 200 parts by weight of pineapple extract.

A particularly preferred composition comprises from 250 to 300 parts by weight of bromelain and from 125 to 150 parts by weight of Ananas comosus (L.) extract.

The ratio of maltodextrin to bromelain with pineapple extract is typically between 1: 2 and 2: 1.

The gastro-resistant coating of the granules is preferably made from shellac rubber.

Preferably, the compositions of the invention do not contain other excipients in addition to maltodextrin and the gastro-resistant coating, in particular shellac.

The granules of the invention can be prepared in a fluid bed granulator by granulating the mixture of maltodextrin, bromelain and pineapple extract with water. After drying, the film-forming solution of shellac or similar polymer is applied.

The gastro-resistant characteristics of the granulate are such as to guarantee at least 70%, preferably at least 80%, of the enzymatic activity declared on the theoretical after 2 hours in an acidic environment.

The compositions of the invention can be used in sachets or stick packs to be reconstituted or taken directly, swallowable tablets, hard capsules, soft capsules, sachets or stick packs to be reconstituted or taken directly, effervescent tablets or granules, chewable tablets, oral suspensions in bottles , vials, stick packs or pouches.

The compositions of the invention, in addition to the gastro-resistance characteristic, have an excellent degree of dispersion in water and allow to obtain a perfectly homogeneous suspension, without the use of additional excipients. Furthermore, the administration of the granules is pleasant, leaving no residue in the mouth or on the tongue.

Conventional gastro-resistant granulates are inhomogeneous and with organoleptic characteristics unsuitable for oral use, thus discouraging the use by the user and compromising the effectiveness of the treatment.

The following examples illustrate the invention in greater detail.

Example 1. Preparation of the granulate

A mixture of powders containing bromelain 2500 GDU / g, pineapple extract 250 GDU / g, in addition to maltodextrin with carrier function was prepared.

The mixture is prepared in the special pre-heated basket of a fluidized bed granulator and heated until the optimum temperature for processing is reached (about 40-45 ° C); then the granulation process with water takes place. At the end of this operation the obtained granules must be completely dry to proceed to the coating phase. For this purpose, a filming solution was used obtained by diluting a solution of shellac ammonium salt, commonly available on the market. At the end of the drying and cooling process, a granulate is obtained with the qualitative-quantitative composition shown in Table I:

Table I.

Bromelain 2500 GDU / g 28.4%

Pineapple Extract 250 GDU / g 14.3%

Maltodextrin 54.8%

Shellac Acquagold 2.5% dry (equal to 10.0% of a solution at 25 ° Bx)

Example 2. Gastro-resistance test

The gastro-resistance characteristics attributed to the granules were analyzed and quantified by means of a test determining the enzymatic activity of the bromelain contained in the granulate, suitably dissolved in solution as required by the gastro-resistance test Ref. Official Pharmacopoeia.

First, the enzymatic activity of bromelain on the solution was analyzed, obtained following the maintenance of the sample in an acid solution of 0.1 M HCl for two hours. Subsequently, the undissolved residue was filtered and kept in a neutral phosphate buffer solution at pH 7 for one hour; finally, the enzymatic activity of bromelain was also determined from this. The activities determined in both solutions were expressed in GDU / g.

The results, shown in Table II, confirmed the passing of the gastro-resistance test, as on an overall theoretical value of 745 GDU / g of the granulate, the acid solution after two hours resulted in an enzymatic activity not exceeding 20% of the theorist; while the activity in the neutral buffer solution was at least 80% of the theoretical value.

Table II

Enzymatic activity

(GDU / g)

Acid solution (pH = 1) 140

Neutral solution (pH = 7) 630

Claims (11)

CLAIMS 1. Composition for oral use in the form of granules or micro-granules comprising bromelain associated with a dry extract of Ananas comosus (L.) and maltodextrin, said granules or micro-granules being coated with a gastro-resistant film. 2. Composition according to claim 1, in which the enzymatic activity of the granulate is between 200 and 2,500 GDU / g. 3. Composition according to claim 2, in which the enzymatic activity of the granulate is preferably between 500 and 1,250 GDU / g. 4. Composition according to one or more of the preceding claims comprising from 200 to 400 parts by weight of bromelain and from 100 to 200 parts by weight of Ananas comosus extract (L.). 5. Composition according to one or more of the preceding claims, in which said granulate is used in envelopes or stick packs to be reconstituted or taken directly, swallowable tablets, hard capsules, soft capsules, effervescent tablets or granules, chewable tablets. 6. Composition according to one or more of the preceding claims in which the gastro-resistant coating consists of shellac. 7. Composition according to one or more of the preceding claims characterized in that it does not include other excipients. 8. A kit including: to. a dietary acceptable liquid phase in a vial, and b. a powder phase in a metering cap of said vial, said cap containing a composition of claims 1-7. Food supplement comprising a composition of claims 1-7 or the kit of claim 8. Medical food comprising a composition of claims 1-7 or the kit of claim 8. Medical device comprising a composition of claims 1-7 or the kit of claim 8.