WO1995000124A1

WO1995000124A1 - Enteric alkalising agent

Info

Publication number: WO1995000124A1
Application number: PCT/IB1994/000164
Authority: WO
Inventors: Jean-Denis Rouillon; Joëlle MILLET
Original assignee: Universite De Franche-Comte
Priority date: 1993-06-18
Filing date: 1994-06-17
Publication date: 1995-01-05
Also published as: AU6855494A; FR2706302A1; FR2706302B1

Abstract

An enteric alkalising agent for oral administration including a core made up of a powdered or gelled alkaline substance surrounded by a first, inner coating of a material which is resistant to and inert for said alkaline substance. The inner coating is surrounded by a second, outer coating which is resistant to gastric acidity. Both coatings disintegrate on contact with the alkaline intestinal environment.

Description

ALKALINIZING PRODUCT IN GASTRO-RESISTANT FORM

The present invention relates to a physiologically acceptable basifying product in enteric form, intended for oral absorption. It is a delayed and prolonged release form.

The intense physical exercises (of power higher than approximately 60% of the maximum aerobic power of the subject) and prolonged (of a duration higher than approximately 30 seconds), continuous or intermittent, lead to a progressive appearance of protons in the muscles participating in the work and, more generally, throughout the body.

At first, the protons are neutralized by the acid-base system, in particular by the plasma and tissue bicarbonates also called

"alkaline reserve". The pH of muscles and other compartments of the body is thus maintained in values allowing the continuation of physical activity at the initial power level. In a second step, the decrease in the alkaline reserve decreases the possibilities of neutralization of the protons and their accumulation leads to a state of acidosis which progressively prevents muscle contraction and induces a state of fatigue which obliges the subject to lower his power level or to stop its activity.

Maintaining a sufficient tissue and humoral concentration of sodium bicarbonate attenuates decompensation (sudden drop) in pH and delays the onset of fatigue. We know that the remarkably stable physiological pH is around 7.40 and that the "alkaline reserve", among others, prevents this value from fluctuate too strongly. Alkalosis appears when the pH exceeds about 7.50, which results in the subject by a lack of coordination first, then by dizziness and loss of balance afterwards. Below a pH of around 7.30 acidosis appears which can lead, if it is too accentuated, to the loss of mental faculties.

It is known that the absorption of alkaline substances, in particular sodium bicarbonate, makes it possible to increase the alkaline reserve or to maintain it at an acceptable level when it is too strongly stressed. Some high-level athletes thus absorb varying amounts of sodium bicarbonate before exercise, in order to bring their alkaline reserves around 32 to 33 millimoles of bicarbonate per liter, compared to a normal value at rest of 25 to 27 millimoles per liter. . After the effort in competition, from 10 to 15 millimoles approximately per milliliter of bicarbonate are lost and are reconstituted by a rest of 5 to 7 hours, while without "preventive absorption" of bicarbonate, the level in alkaline reserve would have dropped too much, resulting in acidosis.

One question is knowing when to absorb sodium bicarbonate before exercise and, in any event, ingestion of bicarbonate usually causes unpleasant effects linked to the release of carbon dioxide on contact with gastric acidity. gas, belching, aerophagia, bloating, even gastric intolerance, diarrhea, colitis). These effects will undoubtedly hinder the effort and dissuade the potential user.

The invention aims to eliminate these related drawbacks and greatly facilitates the choice of the appropriate time for ingestion. It relates to an alkalizing product to be absorbed orally to anticipate the needs of an organism drawing on the alkaline reserve. The alkalizing product, intended for oral absorption, is present in a gastro-resistant form. It comprises as nucleus an alkaline substance in powder or gel, surrounded by a first envelope or inner envelope made up of a material resistant to contact with the alkaline substance and inert towards the latter, then a second envelope or external envelope which resists gastric acidity, the two envelopes disintegrating in contact with the intestinal alkaline medium. The disintegration of the envelopes and, consequently, the release of the alkaline substance, occurs essentially at the level of the duodenum.

The action of the basifying product according to the invention aims to increase the plasma and tissue sodium bicarbonate stocks in the rest phase preceding intense and prolonged exercise, to recharge the tissue and plasma sodium bicarbonate stocks as and when of using them as a proton neutralizing agent during exercise and increasing the rate of restoration of sodium bicarbonate stocks after stopping exercise, thereby decreasing the harmful effects of prolonged acidosis on the body.

The alkaline substance is advantageously chosen from the group comprising sodium bicarbonate, potassium bicarbonate and their mixtures, according to the intended uses. For example, we will use pure sodium bicarbonate or in predominant amounts if it is an absorption before exercise.

The solid or pasty core comprising the alkaline substance is in powder, paste or gel form, that is to say in non-liquid form, so as not to attack the envelope in which it is enclosed, even though this will later disintegrate on contact with the alkaline medium encountered once the stomach has been crossed. The alkaline substance may be in the form of a loose or packed powder, more or less compacted, depending on the "delay effects" desired, so as to allow it to dissolve more or less quickly and thus have effects lasting more or less long. It can also be in an already developed form, in tablets for example, which allows a reduction in the total volume and, possibly, in the number of unit doses to be absorbed.

The envelope surrounding the alkaline substance may be a gelatin envelope, a substance which does not react on contact with powder or alkaline gel, of the capsule type. This envelope may for example be an envelope, such as those which are known in the pharmaceutical field, based on gelatin, glycerin and water.

The second envelope or outer envelope is intended to cover the first envelope and to protect it from the acidogastric attack of the stomach. Here too, a capsule known in pharmacies can be used as an envelope. Such envelopes generally consist of a gelatin reinforced and made acid-resistant by cellulose derivatives, such as methyl cellulose, cellulose acetophthalate and hydroxypropyl methyl cellulose phthalates, acetophthalate. polyvinyl or acrylic and methacrylic resins.

Preferably, the outer envelope at least is sealed so as to prevent any acid-gastric attack.

Advantageously, the basifying product is therefore in the form of a double capsule, that is to say two capsules nested one inside the other, and containing the alkalizing substance in powder or gel. If the outer capsule is not waterproof, it can be made waterproof using an enteric adhesive, for example an adhesive containing cellulose derivatives such as those indicated above.

It goes without saying that the system of double nested capsules as described above can be replaced by any another means of isolating the alkaline core from the gastro-resistant envelope by coating the alkaline substance.

When a subject swallows the basifying product according to the invention, this product resists passage through the stomach by means of its outer envelope which is gastro-resistant. Note that the alkalizing substance is protected from any contact with the outer envelope from which it is isolated by the inner capsule. Once the stomach is crossed, we enter the intestinal tract where the pH gradually becomes alkaline. The double capsule disintegrates under the action of the alkaline aqueous medium encountered from the duodenum and the alkalizing substance is thus released to be absorbed into the bloodstream without release of carbon dioxide.

In other words, the capsules according to the invention do not cause undesirable effects during their stay in the digestive tract.

In fact, they are not attacked in an acid medium. Being gastro-resistant, they do not open on contact with gastric juice, which, because of the proportion of hydrochloric acid it contains, would cause an immediate chemical reaction accompanied by the release of carbon dioxide.

They are not attacked from the inside by sodium bicarbonate, which would harm the conservation of the capsule which, in a few hours or a few days, would be self-destructive by its own content, especially in the presence of moisture.

On the other hand, they are attackable from the outside when they are placed in an alkaline medium. This property is the basis of the expected activity. After crossing the pylorus, that is to say after the stomach in the direction of normal transit, the digestive medium gradually becomes alkaline and the capsules release their contents, which are absorbed by the intestinal mucosa and from there, gain the blood to be distributed to the various tissues of the organism.

Double capsules can be prepared, that is to say placed one inside the other according to the principle of Russian dolls, for example as follows.

A first ordinary capsule, generally made from gelatin and of relatively small size (size No. 1 commercially available for information) is filled with alkaline powder, for example pure sodium bicarbonate. It is possible to use other forms of sodium bicarbonate, in particular sodium bicarbonate previously compressed so as to put in the capsule a larger amount of product. In powder form, 380 to 400 mg is placed in each capsule. The capsule is closed by its cover and then dusted. The objective of this first packaging is to avoid direct contact between the sodium bicarbonate and the second capsule in which the first capsule thus produced will be placed.

This second capsule of size immediately larger than the first is gastro-resistant, either by the nature of the material which composes it, or as a result of a surface treatment which it has undergone, which makes it unassailable by acids during a some time, usually more than 90 or 120 minutes.

After closing, the two parts of this second capsule are bonded to each other by an adhesive which is itself gastro-resistant.

The absorption of the basifying product according to the invention should preferably be done while respecting the physiological rules of isotonicity so as to avoid undesirable effects. This means respect for a determined quantity of water in order to obtain a tone equal to that of the interior medium of the organism, that is to say the equivalent of 9 g of NaCl / 1.

The amount of sodium bicarbonate that can be administered orally and without any special device to a healthy adult subject is between 0.05 g and 0.4 g of pure sodium bicarbonate per kg of body mass, and this without causing him to run particular risks.

As the product cannot be neutralized and attacked in the stomach, almost all of the product from the capsules will reach the intestine intact, as shown by controlled trials which have been carried out on healthy, voluntary and informed subjects. with low dosages (0.1 g sodium bicarbonate per kg body weight), then several days apart with higher dosages. Bicarbonate blood tests and electrochemical pH measurements were carried out at regular time intervals (every 30 minutes) and until the parameters returned to values close to the initial values (4 to 6 hours on average).

Thus it was possible to determine that the alkalizing effect is observable from a dosage of 0.1 g / kg and that, compared to the alkalizing effect sought in athletes, it can reach 0.4 g / kg for certain subjects. The standard dosage of 0.2 g / kg leads to an average increase of 0.1 pH unit and 7 moles / 1 of alkaline reserve.

The time for the appearance of blood alkalinization is very little dependent on the dosage used and varies according to the individual, in particular according to their gastric emptying time, the degree of prior filling of the stomach and the length of time since the last meal, the subject's state of stress, as well as the quantity and temperature of liquid absorbed for taking capsules or capsules and possible simultaneous taking of other compounds or foods. In good standing general, alkalinization begins after about 60 minutes, finds its maximum between 120 and 240 minutes. If the subject practices physical activities such as those described above, consumption of sodium bicarbonate will occur in proportion to the intensity and duration of the exercise and the kinetics will be shortened.

The intensity and duration of alkalinity depend on the individual and the amount of product absorbed. In some individuals, maximum effectiveness is obtained with relatively low doses. Others must take larger doses or repeat the product.

They also depend on the desired result. Protective muscular effects, for example the reduction of body aches, the improvement of comfort during sporting activities, can manifest themselves with minimal amounts. If it is a question of improving performance or tolerance to very intense efforts, we will rather be at the top of the dosage ranges.

An effect on the recovery which follows the performance of exercises requiring the acid-base balance has been observed in the sense of a faster return of the pH and of the alkaline reserve of the subject towards the normal normal values.

Of course, it is possible to add to the alkalizing substance substances intended to cover other physiological needs of the individual, for example energetic nutrients such as slow, semi-slow or fast sugars, amino acids, lipids or non-energetic nutrients such as vitamins, minerals or trace elements. If desired, pharmacologically active principles can also be added to it.

If necessary, sodium or potassium bicarbonate can be combined or accompanied by other energetic, non-energetic or pharmacologically active substances, as such or in the form of precursors.

The basifying product according to the invention is aimed above all at two types of individuals.

First athletes, both recreational and competitive athletes, for products based on sodium bicarbonate, because it causes a protective effect of muscle against lactic acidosis with reduction of muscle pain on exertion , decrease in aches and contractures, better recovery after exhausting efforts and a faster return to the feeling of being able to repeat the competition test or the intense training session, an improvement in performance for continuous and intense exercises of duration greater than a few minutes or for intermittent exercises alternating work phases at maximum power and recovery phases.

Then the patients, for products based on sodium or potassium bicarbonate as the case may be, in particular for infants, patients with respiratory insufficiency, comatose patients and any patient with acute or chronic deficits in the alkaline reserve, especially since, as already indicated above, pharmaceutical products can be incorporated into the alkaline heart.

The invention will be better understood with reference to the examples which follow, given without implied limitation. The results given relate to tests carried out with the gastro-resistant capsule form of sodium bicarbonate. Example 1 relates to subjects at rest, while the following examples relate to sportsmen.

Example 1: Study of the alkalizing effect of the product proposed on the subject at rest (healthy healthy volunteers). Amount of product administered: 0.3 grams of sodium bicarbonate per kilogram of total body mass. 5 Administration conditions: Subjects on an empty stomach since the previous evening. Taking the product around 8am with

0.75 liter of water. No physical activity for the duration of the test. Only walking is allowed.

Fasting subjects throughout the duration of the study (8h). 10 Method for evaluating the alkalizing effect:

Positioning a few minutes before the administration of the product of a microcatheter in a vein of the forearm.

Collection every 30 minutes of a blood sample of approximately 5 ml anticoagulated with heparin intended for the analysis of blood gasometry according to the usual methods used in clinical biology. Device used:

Blood Gas Analyzer Corning 178.

Parameters measured: pH, partial pressure of oxygen and carbon dioxide. 20 Calculated parameters: plasma bicarbonate level, excess plasma bases.

The results obtained are collated in Table 1 below. They demonstrate that from the 120th minute after taking a quantity of sodium bicarbonate capsules corresponding to a dosage of 0.3 g of bicarbonate per kg of body weight, there is an increase in blood parameters showing an alkalizing effect (pH, plasma bicarbonates, excess of bases) which continues until the 8th hour.

30

Example 2: Tests during sports activities (1) * Cross-country skiing for competition.

Numerous tests have been carried out on 3.5 subjects entered on the list of high performance athletes national (annual list issued by the French Ministry of Youth and Sports).

These tests were carried out either during training during sessions with repetitive phases of intense work, or during competitions. The experimental protocol is similar to that described in a).

The dosage fluctuated between 0.15 and 0.30 g of pure sodium bicarbonate per kg of body weight. In the vast majority of cases (approximately 2 out of 3), it was observed by the subject:

- an improvement in performance with a feeling of ease in the muscles,

- greater ease in carrying out difficult phases such as very inclined and very long climbs,

- a delay in the appearance of the feeling of tiredness during the session or the competition,

- an improvement in partial recovery which occurs between the intense exercise phases, - an improvement in recovery after the end of the exercises,

- less tired feeling in the hours and days that follow,

- rarer muscle aches, contractures, cramps and aches.

Example 3: Tests during sports activities (2) * Football (Soccer).

Three attempts were made during the match.

The goal was to avoid the feeling of fatigue that often occurs in the last third of each half. A third of the subjects noted the desired effect, that is to say finished each half-time in better physical condition or retained a high percentage of their physical fitness until the end of the match. Post-match recovery has been shown to be of better quality with fewer muscle problems and a shorter duration of these problems.

Example 4: Tests during sports activities (3) * Road cycling.

An experimental protocol was carried out on a group of 4 cyclists of international level (hereinafter coded PE, DP, HD, JM) preparing a higher level test.

The conditions of administration of the product were the same as those described in a). The dosage was 0.25 g of pure sodium bicarbonate per kilogram of body weight.

Two days apart, each subject performed a test comprising three phases of approximately 20 minutes carried out at maximum speed on a calibrated loop, separated from relative recovery phases of 30 minutes. Blood tests were performed at each phase transition, that is to say:

- at rest at time 0,

- at rest, 60 minutes after taking the bicarbonates, - at rest, 120 minutes after taking the bicarbonates,

- at the end of the heating up,

- at the end of the second 20-minute effort window,

- at the end of the 2nd partial recovery, - at the end of the 3rd 20-minute effort,

- at the 15th minute of final recovery.

The first test was performed without taking sodium bicarbonate. The second test was carried out with sodium bicarbonate. The results obtained, which are summarized in Table 2 below, provide convincing evidence for all 4 riders:

- an improvement in visible performance over the total time of the test,

- lower blood acidity despite more highly energetic exercise,

- a very significant increase in the level of blood lactates (La).

In terms of their sensations, the runners reported after the test involving the use of sodium bicarbonate:

- less muscular pain on exertion but feeling of muscular edema, - feeling of ease in carrying out the exercise but with a relative feeling of difficulty in reaching their maximum,

- improvement of recovery in the hours following the test.

Table 1

Table 2

Claims

1. Gastro-resistant alkalizing product intended for oral absorption, characterized in that it comprises as nucleus an alkaline substance in powder or gel, surrounded by a first envelope or inner envelope made of a material resistant to contact of the alkaline substance and inert towards it, then of a second envelope or external envelope which resists gastric acidity, the two envelopes disintegrating in contact with the intestinal alkaline medium.

2. Basifying product according to claim 1, characterized in that the alkaline substance is chosen from the group comprising sodium bicarbonate, potassium bicarbonate and their mixtures.

3. Basifying product according to claim 1, characterized in that the alkaline substance is in the form of loose or packed powder.

4. Basifying product according to claim 1, characterized in that the alkaline substance is in the form of tablets.

5. Basifying product according to claim 1, characterized in that it is in the form of a double capsule, an inner capsule containing the alkalizing substance fitted into an outer gastro¬ resistant capsule or made gastro-resistant.

6. Basifying product according to claim 5, characterized in that the outer capsule is made waterproof using an enteric adhesive.

7. Use of the basifying product according to one of the preceding claims in the field of sport.

8. Use according to claim 7 in an amount of 0.1 to 0.4 g of bicarbonate per kg of body mass of the subject.

9. Use of the basifying product according to one of claims 1 to 6 in the field of care.