FR2799372A1 - Application of weak acid-based water-soluble coating to solid medicaments, dietetic products or foodstuffs, to stimulate secretion of saliva and facilitate swallowing - Google Patents

Abstract

In a method for coating solid medicaments, dietetic products or foodstuffs using a water-soluble composition (I) based on one or more weak acids and optionally their salts, (I) contains sufficient acid to reduce the pH of an aqueous sodium hydroxide solution containing 0.01-3 milliequivalents of (I) and 0.4-120 mg of sodium hydroxide to 2.2.

Description

The present invention relates to coating compositions of active drug products or dietary products or solid food products to be absorbed orally.

The said coating compositions are soluble in water and comprise one or more acid substances, mineral or organic, used either separately, or mixed with several, or further mixed with one or more of their salts compounds with mineral or organic substances . The said compositions may also contain other additive substances the purpose of which is to improve the adhesion of the composition, its texture, its physical or chemical qualities, its taste, its aroma, its consistency and various other qualities independent of its acidity. .

These acidic compositions are intended to cause an intense salivary secretion having the effect of facilitating very importantly the deglutition of medicamentous active principles or dietary products or food products thus coated.

This acidic coating process of solid products intended to be ingested is applicable to active drug principles, dietary products or food products.

Certain food or dietetic products have an unpleasant taste (for example, fish oils or vitamin B1) and can be easily ingested only if they have been either coated with a composition concealing their taste or introduced into the inside a sealed container (such as, for example, a capsule).

Many active drug principles have a very bad taste and must also be coated or carried in a sealed container. In addition, certain drugs must be protected by a coating or film isolating them either air or certain digestive secretions that could alter their active ingredients. All these products can not be crunched or chewed in the mouth but must be swallowed as is, without being crushed or crushed; and they must be swallowed as quickly as possible in order to remain intact.

Many people have great difficulty swallowing and swallowing medicated, dietary or solid food products. Their inability is even greater if they are not allowed to chew or chew them or crush and grind them with their teeth. These people must then drink a quantity of liquid more or less large to slide the solid products in their pharynx and their esophagus.

Today, medicine has made tremendous progress. Many patients can be cured or patients suffering from very serious illnesses can be kept alive for a very long time, thanks to treatments that must be followed often for a very long time and in a very regular way. It is often the case that patients are forced to take a large number of tablets and capsules orally 3 or 4 times a day and that the number of tablets or capsules may be 20 or 30 per day.

The fact that some patients have great difficulties in swallowing medications even when drinking various liquids causes many of them to feel disgust, often leading them to not follow their treatment properly, to follow it irregular and discontinuous.

This poor compliance is very dangerous because it is a cause of poor therapeutic efficacy and is often the cause of the emergence of "drug-resistant" forms of microorganisms that cause disease.

A method for coating drug or dietetic or food products invented by the applicant, is with compositions containing weak mineral or organic acids, either pure or mixed together, or mixed with some of their salts; these robotic compositions having the effect of stimulating salivary secretions, thereby facilitating the deglutition of coated solid products.

This coating process is of great importance because it has the effect of improving the comfort of people to ingest products without chewing or chewing, and consequently, it leads them to better observe the pres criptions that they were made; as a result it will prevent the occurrence of resistance of microorganisms to the drugs. The treatments will be more effective.

The present invention is based on the physiology of swallowing in humans.

Humans, unlike many animals, have extremely fragile esophagus that can easily be dilated or torn by traumatic foods. On the other hand, for example, a dog that is a carnivore accustomed to eating bone that has been crushed with its jaws, has a very solid esophageal mucosa that can not be injured by bone splinters.

This esophageal fragility in man forces him, before swallowing a solid body, to carry out his extremely minute intrabuccal examination himself subjected to a very active neuro-psychic control.

During this examination, the physical, chemical, organoleptic (ie taste and olfactory) qualities of the body will be appreciated. Thus will be appreciated the heat of the body so that it can not cause burns or frostbite, its consistency, its hardness, its volume (it must not (be too big), its mechanical aggression (fishbone, bone splotch) , its chemical aggressiveness (acidity or alkalinity too strong), etc., etc. On the olfactory and taste plans, an odor or a taste of rot will lead to the rejection of the solid body.

Thus, the fact, in humans, of swallowing and swallowing a solid body medicated or dietary or food with great circumspection, is normal.

If, because the solid body can not be chewed or kneaded and kneaded in the mouth, the examination of its various qualities of this body can not be done properly, this can lead to a psychic and nervous blocking totally opposing the swallowing.

In this case, even the absorption of a liquid will not be really effective because the subject, inhibited by his apprehension, will oppose the progression of the solid body in the mouth towards the pharynx antagonistic muscle contractions.

The applicant has discovered that if in a subject having to swallow a solid body (for example a capsule), a solution of a weak acid in sufficient quantity (for example 30 milligrams of citric acid in aqueous solution) is first instilled in its mouth, the acidification of the oral cavity will trigger a strong salivary secretion, which will force the subject to swallow his saliva by making the deglutition of the solid body very easy, overcoming the neuropsychic blockages of which it could be the object.

Through experiments on many subjects, the applicant has been able to establish that this facilitation of swallowing by the excitation of salivary secretion by an acid is constant.

Salivary secretion is stimulated, physiologically, by various factors (Reference: The book Physiology of the digestive system, author Horace Davenport, Masson SA publisher, 120 Bd St. Germain, Paris 75006, 1975 edition, pages 87 to 97) . One of them is the sight of a desired food or its smell. Another factor is chewing. Another factor is the excitation by an acidic substance of the oral and lingual mucous membranes. The Applicant has found that salivation triggered by an acid is much larger and faster than that triggered by chewing. This is understandable because the human esophagus is very fragile towards the 5 acids (for example in the disease of "gastro-oesophageal reflux" of gastric juice which contains hydrochloric acid in large quantities, often ulcers of the esophagus).

The flow of salivary secretion, at rest, when there is no stimulation of the salivary glands, is, in normal man, about 0.5 milliliters per minute. But under the effect of stimulating the salivary glands by the introduction in the mouth of a solution of citric acid (or ascorbic acid or other weak acid), the secretion of saliva can be up to 7 ml per minute (Davenport 1975).

Salivary stimulation by acidic substance occurs mainly at the edge of the tongue as well as at the level of the mucous membranes of the palate and the pharynx (reference book "Review of physiology - author William F Gannong, publisher Lange medical publication, Draner L, Los Altos, California, 1985 edition, pages 144 to 149).

The saliva obtained by acid stimulation are very alkaline. According to the article by Mr Pellat, published in the Encyclopédie médico-chirurgicale (address 18 rue Séguier, 75006 Paris) in the volume Stomatology and odontology, article 22008 A05, page 4, published in 1991, titled "oral time of swallowing salivary ", it is said that acid stimulation results in the emission of saliva containing per liter, approximately 90 milliequivalents of sodium ions, 20 mEq of potassium, 50 mEq of chlorine and 60 mEq of CO 3 H- ions.

Thus saliva contains a large amount of bicarbonates of alkaline ions, such as sodium and potassium. These bicarbonates give the saliva a strong acid neutralizing power, to which it is given the name of buffer power. The applicant has been able to establish that the amount of saliva secreted by the introduction of a certain quantity of acid into the mouth is proportional to this quantity: in fact, the secretion of the alkaline ions of saliva takes place up to acidic ions have been neutralized and the pH of the oral cavity has returned to normal.

There is thus a real physiological law that the stimulation of salivary secretion by an acid introduced into the mouth continues until the return of the oral pH to its normal level. One can also consider that there is a real feedback controlling the salivary secretion in order to keep the oral pH constant.

The acids used by the applicant are weak acids which in the diluted state can not cause burns of the oral mucosa or the digestive tract.

The applicant has been able to establish, by experimentation, that the introduction in the mouth of 60 milligrams of ascorbic acid causes the secretion of about 4 milliliters of saliva in less than one minute.

The method used to measure saliva volumes is that described in the French Review of Stomatology and Maxillofacial Surgery by P. Laudenbach under the title "For practical salivary flow measurement" on pages 130 to 133 of N 2 of volume 95 of 1994 - publisher Masson BP 22-F 41354 Vineuil Cedex-France. It consists in placing in the mouth of the subject a small compress of gauze (40X40 compressed cut in 4) weighing 0.9 grams and then to introduce into the mouth the substance or an acid solution. The compress is kept in the mouth 2 minutes, the subject refraining from chewing and swallowing, and is weighed wet.

The oral introduction of 60 mg of ascorbic acid, without compresses, causes the intraoral pH to drop in seconds to about 3.5. This pH then increases gradually under the influence of alkaline saliva and is again between 7 and 7.6 after 2 to 4 minutes.

It is remarkable that each introduction of acid in the mouth causes a new stimulation of the salivary secretion without there being any exhaustion of this effect.

The introduction in the mouth of 40 mg of citric acid in aqueous solution also causes an intense salivary secretion.

Thus, in general, such a small amount of a weak acid as that corresponding to 0.2-0.3 mEq of acidic ions, will cause an important salivary secretion: the weak acid expels the CO 3 H- ions from the salivary buffer system which thus loses its CO2 which allows a lowering of the oral pH, but in a moderate, non-aggressive way. The amount of saliva secreted in about one minute which ranges from 4 to 7 milliliters, facilitates swallowing by the subject of the solid body coated with an acidic composition which he must swallow without chewing or grinding it with his teeth.

 Optionally, the acidic coating composition may consist of a mixture of one or more weak acids and one or more of their salts (for example ascorbic acid and sodium ascorbate) this mixture being buffered and better tolerated by some subjects. The key is that the amount of free acid ions introduced into the mouth by the coating is sufficient to stimulate salivary secretion.

The Henderson-Hasselbach law applies to such a mixture. It is written: pH-pKa = log (ionized C / non-ionized C) where C are the concentrations of the ions of the acid and pKa the dissociation constant of this acid (reference Encyclopedia of pharmaceutical technology, volume 5, page 190 Author James Swarbrick, 1992 Marcel Dekker Edition, 270 Madison Avenue, New York, New York 10016). Explanations on how to use this law, are given in the book Chemistry Oeonological Luciano Usseglio-Tomasset, French edition translated by Alain Bertrand, Technical Edition and Documentation 1995, 11 rue Lavoisier 75384 Paris, pages 201 to 211. In pages 209 and 210 explain the percentages of free citric acid in solutions of citric acid and sodium citrate when these solutions have a pH of 3 or 3.5. On page 212 it is said that a classic wine has a pH close to 3.2: it should be noted that this wine pH is perfectly tolerated by the oral mucosa and the digestive tract and therefore a coating causing in the mouth a lowering of the pH up to 3 can not be harmful. It will be noted that in this book, pages 211 to 247, are described acidification techniques for wines that are not sufficiently acidic: the table on page 245 explains the results of such acidifications.

The applicant was thus able to verify, for example, that the solution mixture of 4.2 grams of citric acid hydrate and 0.7 grs of sodium hydrogencarbonate has a pH of 3 after the total departure of CO 2. Similarly, 4.2 g of citric acid in solution with 0.84 g of sodium tricitrate dihydrate has a pH of 3; the use of compositions comprising a mixture of one or more weak acids with one or more of their salts thus makes it possible to develop coatings of different pHs, thereby increasing the tolerability of the products thus coated.

In the current state of the art, there is no coating composition containing free weak acids whose purpose is to stimulate salivary secretions and to make the swallowing of solid medicinal or dietary or food bodies easier.

The process described in the present application is therefore entirely new.

It is useful to note that wine, with excellent tolerability, is in fact a solution of various weak acids and their salts (reference: Oenological chemistry mentioned above).

Various substances will be used to make the coating compositions. First weak acids, not aggressive to the mucous membranes: thus mineral acids or weak organic acids, pure or mixed together and / or associated with some of their salts; among these acids it is possible to use orthophosporic acid, citric acid, tartaric acid, malic acid, amino acids, such as glutamic acid, other acids, for example ascorbic acid, this enumeration given by way of example n not being limiting.

In addition to these acids and their salts, the coating compositions may contain sugars such as monosaccharides, di or polysaccharides, alcohol-type substances such as sorbitol, maltitol, substances with a sweet taste (type aspartame), aromatic or coloring substances, substances having the effect of increasing the adhesion of the compositions to the products to be coated (for example gum arabic or gelatin), various cellulose derivatives. Generally speaking, it will be possible to use any substances, additives or excipients making it possible to produce the acidic compositions.

All these substances will have to be water-soluble so that the acid composition coating the drug or dietetic or food products can be dissolved very quickly in the mouth.

In the book Pharmaceutical Dosages Forms, Volume III, published in 1990 by Marcel Dekker Inc., 270 Madison Avenue, New York, 10016, author Herbert A Lieberman, pages 77-93, there are given <U> coating formulas without acid </ U> that the Applicant used by adding acids. Acidic coatings may be made with such formulas but also with any other formulation compatible with the acidic nature of said composition, this acid character of the coating constituting the novelty of the present invention.

The salts of the weak acids used may be non-toxic metal salts (for example sodium or potassium salts) or amino acid salts or salts of any substance which does not have any toxicity for humans.

The medicinal or dietetic or food products to be coated with the acidic compositions according to the method described hereinabove may optionally have been coated beforehand with a coating which insulates them from the moisture of the syrup or the solution constituting the acid composition before it was dried in a turbine. This isolation technique, which is quite conventional, is described in the book Pharmaceutical Dosage Forms Volume III on page 80 under the title Sealing.

In the Encyclopedia of pharmaceutical technology (references above on page 7) are stated: 1 / volume 6 - published in 1992 - on page 1, the goals sought by the coating of the medicinal principles, either by coating or by coating with an insulating film; in this enumeration there is absolutely no mention of acid coatings intended to promote salivary secretions and swallowing; 2 / volume 14-published in 1996- on pages 355 to 384 the conventional techniques of coating tablets and the substances used to make these coatings. It is absolutely not spoken in these texts of acid coating.

The applicant, to make and implement his acidic coating compositions, has used the conventional techniques described in these works of art, adding to the conventional coating compositions various acidic substances, non-buffered or buffered. The quantities of free acids provided by the coating of the solid body intended to be swallowed whole, without chewing or fragmentation must be at least 0.01 milliequivalent and at most 3 mEq of free acid (ie no salified) being ionizable at a pH below 6.

The various types of coating may be made with conventional techniques as described in French Patent 2,705,208 pages 2 to 4 (as well as, if possible, by the technique described in this patent), the point The essence of the present invention is the incorporation of acidic substances into the coating composition.

Thus can be used: scrub, soft or hard coating, smoothing more or less thick, icing, "sugaring" using a sugar powder with acidic substances, candying, and finally all varieties of coating as they are currently described or as they may be in the future.

Finally, it should be noted that the coating composition being water-soluble, the products coated with it must necessarily be stored in the absence of moisture, in a sealed container containing a desiccant.

On the basis of all that has been said, the plaintiff has established the following.

The realization of coatings of solid active drug principles or solid dietary principles or solid food principles can thus be obtained with a water-soluble composition based on one or more weak acids and / or, optionally, one or more of their salts. , allowing the creation on the surface of said principles or products of a coating characterized in that it contains an amount of acids sufficient to lower to 2.2 the pH of an aqueous solution of sodium hydroxide containing not less than 0.01 milliequivalent and not more than 3 milliequivalents of that substance, that is at least 0.4 milligrams and not more than 120 milligrams of that sodium hydroxide.

The production of coatings may be obtained by using additional coating agents that may be of any kind, and in particular in order to facilitate the adhesion of the solution or the powder to each unit of medicinal principles or dietary products. or food to be coated and improve its visual appearance or taste or smell or texture and in general its various qualities.

Coatings of medicinal principles or dietary or solid dietary principles can thus be obtained by using solutions of additional coating agents which may be syrups comprising sugars, gums, derivatives of cellulose and in general, solutions comprising various natural or synthetic agents that are favorable to its adhesiveness and viscosity.

The production of coatings may be carried out with a coating composition consisting of a syrup comprising, for one liter: 450 grams of sucrose, 80 grams of gum arabic, 160 grams of ascorbic acid added with water up to a volume of 1 liter. This syrup is heated to a temperature of 45 centigrade and is sprayed into a ventilated turbine on the solid bodies to be coated; the rotation of the turbine is carried out until drying; "spray-drying" cycles are repeated until a coating is formed such that it contains, by unitary solid body, of the tablet type, from 5 to 200 milligrams of ascorbic acid. Coatings of solid medicamentous principles or solid dietary principles or solid food principles can thus be obtained with a coating composition consisting of a syrup comprising, for one liter: 450 grams of sucrose, 80 grams of gum arabic, 120 grams of citric acid, 24 grams of trisodium citrate di hydrate plus the amount of water needed to obtain a volume of 1 liter. This syrup is brought to 45 centigrade then is applied by spray-drying cycles in turbine on the unitary solid bodies, to be coated, the rotation of the turbine is carried out until drying; "spray-drying" cycles are repeated until a coating is obtained containing, for each solid body to be individually deglued, a quantity of citric acid of 5 to 200 milligrams and a quantity of sodium tricitrate of 2 to 40 milligrams. The realization of coatings can be carried out in five steps. In a first step an adhesive syrup is prepared comprising, for one liter: 450 grams of saccha rose, 80 grams of gum arabic added with water to a volume of 1 liter; in a second step, a finely powdered mixture of 100 grams of sucrose and 100 grams of ascorbic acid is prepared; in a third step, the solid bodies to be coated with an acid composition, are moistened with the adhesive syrup; in a fourth step, the solid bodies are coated by dusting with the sugar-ascorbic acid mixture; in a fifth step, these bodies are dried. The moistening, dusting drying cycle will be repeated the desired number of times, until a coating having 5 to 200 milligrams of ascorbic acid is obtained. On the basis of what has just been said in the present application, the applicant has made tablet coatings with various compositions which are given below examples which should not be considered as limiting.

<U> Example 1 </ U> <U> Coating with ascorbic acid. </ U>

A syrup comprising 45 grams of sucrose, 10 grams of gum arabic, 14 grams of ascorbic acid and the amount of water sufficient to obtain 100 milliliters is prepared. Ascorbic acid is dissolved in water and the gum arabic is dissolved and finally the sugar is added. The mixture is heated to 60 degrees and is then cooled to 45 and is sprayed into a conventional swirling turbine (in slow rotation) on the tablets to be coated. The tablets are then dried by ventilation. Several syrup spraying and then drying cycles are repeated until the tablets are compressed. In the example, tablets having a weight of 400 milligrams, having a diameter of 13 mm and a thickness of 6 mm, are isolated by a moisture-protecting film and then coated with the syrup to a thickness of magnification such that their average weight is about 750 milligrams. The amount of ascorbic acid coating each tablet is about 60 milligrams, a quantity that is largely sufficient to trigger an intense salivary secretion that promotes the swallowing of the tablet.

<U> Example 2 </ U> <U> Coating with citric acid and </ U> tricitrate <U> of sodium di </ U> <U> hydrated </ U> In this formulation, a syrup is composed, according to the previous arrangements, with 45 grams of sucrose, 10 grams of gum arabic, 10 grams of citric acid and 1.6 grams of tri-sodium citrate dihydrate and sufficient water to obtain 100 ml of syrup.

The tablets are coated by spraying the syrup and then drying, all in a ventilated turbine until enlargement of the tablets as above. Each coating of 360 milligrams brings about the equivalent of 60 milligrams of free citric acid, this amount largely inducing salivation. The syrup is prepared by dissolving citric acid in water first, then trisodium citrate dihydrate, then gum arabic and sugar. In this example the pH of the syrup or the dissolved coating is about 3 to 3.5. In this example, the coating, while being clearly acidic, is much less aggressive for the oral and esophageal mucosa, and even gastric, than if it were composed of pure citric acid, not buffered. Such a coating, while exciting the salivary secretion, provides a great comfort to the subject to swallow products thus coated.

In conclusion, this coating process with a composition comprising between 0.01 and 3 mEq of free acid ions (for an unmanageable unit), after dissolution, of solid bodies to be ingested intact, will make it possible to manufacture oral drugs. easier to swallow, improving the comfort of patients and their compliance with medical prescriptions; as regards the coating of dietary or food products of the same nature, this process will increase consumer satisfaction.

The main and fundamental feature of the present invention is to incorporate into the coating composition acidic ions in order to excite salivary secretion and thereby improve the swallowing of solid bodies to be ingested.

Claims (1)

<U> Claims </ U> 1 - A process for coating active solid drug principles or solid dietary principles or solid food principles with a water-soluble composition based on one or more weak acids and / or, optionally, a or more of their salts, allowing the creation on the surface of said principles or products of a coating characterized in that it contains an amount of acids sufficient to lower to 2.2 the pH of an aqueous solution of sodium hydroxide containing not less than 0.01 milliequivalent and not more than 3 milliequivalents of this substance, being a minimum of 0.4 milligrams and not more than 120 milligrams of that sodium hydroxide. 2 - coating method according to the preceding claim, medicinal principles or dietetic or food products of a solid nature, intended to be absorbed orally in separate units, without being crunched or chewed, characterized in that in a first step is prepared an aqueous solution of one or more weak acids and optionally one or more of their salts, that in a second step, is deposited with or without intermediate insulation, the drug principles or dietary products or food, the acidic aqueous solution, after addition of any additional coating agents, in a third step the solution covering the surface of said principles or products is dehydrated by ventilation or other drying mode, the second and third stages being repeated until at desired magnification of the coating. characterized in that the acid coating deposit is by prior moistening of the medicinal principles or dietetic or food products with an adhesive solution, that in a second step, it is sprayed on the principles or the products thus moistened and made adhesive, a powder containing one or more weak acids and / or optionally one or more of their salts, combined with any additional coating agents, until the desired thickness of the coating and the deposition of the coating are obtained; amount of acidic ions sought. 4 - coating process according to any one of the preceding claims, characterized in that the solutions of additional coating agents can be syrups containing sugars, gums, derivatives of cellulose and in a manner general solutions comprising various natural or synthetic agents favorable to its adhesiveness and its viscosity. 5 - Coating process according to any one of the preceding claims, characterized in that the coating composition consists of a syrup comprising per liter: 450 grams of sucrose, 80 grams of gum arabic, 160 grams of ascorbic acid with water up to 1 liter. This syrup is brought to a temperature of 45 centigrade and is sprayed into a ventilated turbine on the solid bodies to be coated; the rotation of the turbine is carried out until drying; "spray-drying" cycles are repeated until a coating is formed such that it contains 5 to 200 milligrams of ascorbic acid per unit solid, of the tablet type. 6 - coating process according to any one of the preceding claims, characterized in that the coating composition consists of a syrup comprising per liter: 450 grams of sucrose, 80 grams of gum arabic, 120 grams of citric acid, 24 grams of trisodium citrate di hydrate plus the amount of water needed to obtain a volume of 1 liter. This syrup is brought to 45 centigrade and is then applied by spray-drying cycles to the solid individual units, to be coated, as in claim 5, until a coating containing for each solid body to be deglued unitarily a quantity of citric acid of 5 to 200 milligrams and a quantity of sodium tricitrate of 2 to 40 milligrams. 7 - Coating process according to any one of the preceding claims, characterized in that the coating is carried out in 5 steps, in a first step an adhesive syrup is prepared comprising, for one liter: 450 grams of sucrose, 80 grams of gum arabic added with water to a volume of 1 liter; in a second step, a finely powdered mixture of 100 grams of sucrose and 100 grams of ascorbic acid is prepared; in a third step, the solid bodies to be coated with an acid composition, are moistened with the adhesive syrup; in a fourth step, the solid bodies are coated by dusting with the sugar-ascorbic acid mixture; in a fifth step, these bodies are dried. The moistening, dusting drying cycle will be repeated the desired number of times, until a coating having 5 to 200 milligrams of ascorbic acid is obtained.