WO2001034182A2 - Composition for treating respiratory tract infections containing menthol, eucalyptol and an alpha-amylase - Google Patents

Composition for treating respiratory tract infections containing menthol, eucalyptol and an alpha-amylase Download PDF

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Publication number
WO2001034182A2
WO2001034182A2 PCT/FR2000/003114 FR0003114W WO0134182A2 WO 2001034182 A2 WO2001034182 A2 WO 2001034182A2 FR 0003114 W FR0003114 W FR 0003114W WO 0134182 A2 WO0134182 A2 WO 0134182A2
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composition
amylase
eucalyptol
alpha
menthol
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PCT/FR2000/003114
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French (fr)
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WO2001034182A3 (en
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Jean Chatillon
Paul Ghislain Coupan
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Laboratoire Top-Pharm
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Priority to AU16467/01A priority Critical patent/AU1646701A/en
Publication of WO2001034182A2 publication Critical patent/WO2001034182A2/en
Publication of WO2001034182A3 publication Critical patent/WO2001034182A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the subject of the present invention is a composition useful in the treatment of respiratory tract infections and which combines menthol and eucalyptol with an amylolytic enzyme.
  • menthol and eucalyptol have long been known. Two substances that are used mainly in the treatment of bronchopulmonary inflammation.
  • the analgesic properties of menthol and the antiseptic and expectorant properties of eucalyptol have been successfully combined in the treatment of bronchitis, in compositions presented most often in the form of pectoral pastes or lozenges to be sucked.
  • amylases have anti-inflammatory properties. They also have antibacterial and antiviral properties that have been detected more recently. Studies have indeed shown that thanks to their amylolytic properties, the enzymes of this family cause the degradation of the cell wall and the membrane of many bacteria which are rich in carbohydrates. Likewise, amylase degrades the carbohydrate constituents present in the cell envelope of viral particles.
  • the composition according to the invention contains menthol and eucalyptol. These components are in the form of a crystallized powder.
  • Menthol is a natural racemic for 2-isopropyl-5-methylcyclohexane, with a molar mass of 156.3 and a melting point of 34 ° C.
  • Menthol and eucalyptol are present in the composition according to the invention at a concentration which potentiates the activity of amylase and which provides the desired beneficial effect without inducing an unpleasant impression during the appetizer.
  • concentrations meeting these criteria are from 1.25 mg to 3.125 mg of menthol per
  • composition gram of composition and from 0.375 mg to 1 mg of eucalyptol per gram of composition, so that the overall menthol + eucalyptol intake is always between 1.625 mg and 4.125 mg per gram of composition.
  • 2 mg of menthol and 0.6 mg of eucalyptol are incorporated into one gram of said composition.
  • a premix is prepared containing proportions of menthol ranging from 10% to 25% by weight and of eucalyptol ranging from 3% to 8% by weight, on a neutral support such as gum arabic.
  • composition according to the invention also contains an enzyme with amylolytic activity.
  • This enzyme is preferably a (1,4) - ⁇ -D-glucan-glucanohydrolase, commonly called “alpha-amylase”, or “alfa-amylase” according to the International Nonproprietary Name
  • alpha-amylase degrades polysaccharide compounds
  • hydrolysis reaction in which the enzyme acts as a catalyst. This randomly attacks the - (1,4) bonds of the starch releasing glucose and maltose (maltose is a disaccharide composed of two glucose monomers). The cell walls are damaged by this
  • the alpha-amylase secreted naturally by a bacterial microorganism preferably by Bacillus amyloliquefaciens, is used.
  • Bacillus amyloliquefaciens This bacterium, recognized as a full-fledged species in 1987, was previously considered as an atypical representative of the species Bacillus subtilis (Priest et al., Int. J. Syst. Bacteriol. 37:69 1987).
  • the alpha-amylase produced naturally by B. amyloliquefaciens is a 58 kDa protein, of which the first ten amino acids, determined by sequencing are:
  • the alpha-amylase used in the composition according to the invention can be produced by any microbiological culture process using a microorganism competent for the production and excretion of said alpha-amylase, whether it is engineered genetic or not.
  • the bacterial alpha-amylase is obtained by fermentation in a ⁇ - reactor of B. amyloliquefaciens.
  • the processes for producing enzymes by microbiological fermentation and for purification are well known to those skilled in the art and are implemented by companies specialized in the corresponding field.
  • the alpha-amylase used in the claimed composition is produced by a process Q which protects it from contamination by E.S.B. (Spongiform encephalopathy
  • Bovine Bovine
  • the alpha-amylase thus produced is presented as a fine cream to beige powder having no foreign matter, soluble in water and in accordance with the quality and safety standards required for products for pharmaceutical use (absence of metals, sterility). It is marketed in France and in many countries by the company Top 0 Pharm (Revel, France).
  • a composition is prepared containing the alpha-amylase chosen, menthol and eucalyptol, as well as an excipient and various adjuvants intended to facilitate the shaping and to confer on the finished product particular properties by making consumption particularly pleasant.
  • the amount of alpha-amylase incorporated into the composition is defined by its level of enzymatic activity expressed in CEIP international unit, noted "U. CEIP", the value of a U. CEIP unit being equal to 0.714 unit of the pharmacopoeia European. It is between 1800 and 2600 U. CEIP, and is preferably 2400 U. CEIP, per gram of composition.
  • the enzymatic activity of the powdered alpha-amylase is assayed before the preparation of the composition and the quantity by weight qu is calculated. 'must be incorporated into the composition to obtain a defined activity.
  • composition of the invention is intended to be presented in a galenical form suitable for administration by the oral route, preferably in the form of sucking tablets, in general of 0.5 gram each.
  • the enzymatic activity of alpha-amylase in each tablet will ideally be 1200 U.
  • the amount of menthol will be 1 mg per tablet and the amount of eucalyptol 0.3 mg per tablet.
  • the active ingredients thus defined are incorporated into an excipient.
  • This can be chosen from any compound available to those skilled in the art, compatible with an oral intake of the product according to the invention.
  • a sweet excipient is used, such as glucose in the form of icing sugar, or a sweetening product.
  • a colorant can be added to the preparation. Chlorophyll is advantageously used because of its green color spontaneously associated with mint by the public. Any coloring authorized in food products can also be used.
  • Additives to facilitate the manufacturing process may be used within the limits of the regulations in force.
  • a wetting agent can be used, such as Polyvidone K30 (BASF, Levalloy Perret - France).
  • Lubricants improving the compression step of the composition in tablet form can be added, such as talc or magnesium stearate.
  • the manufacture of the composition according to the invention is carried out in several stages, in accordance with the methods customarily used for shaping cachets containing fragile active substances. For example, it can be carried out in the following way: In a first stage called “wet granulation", the excipient is mixed with a wetting agent to allow the formation of granules, which are then dried and calibrated. A second step is to mix the granules with the active ingredients in powder form. Then the various adjuvants are added. Finally, the granules are compressed into tablets and packaged.
  • wet granulation the excipient is mixed with a wetting agent to allow the formation of granules, which are then dried and calibrated.
  • a second step is to mix the granules with the active ingredients in powder form. Then the various adjuvants are added. Finally, the granules are compressed into tablets and packaged.
  • composition according to the invention is indicated in the treatment of pathologies of the respiratory system, such as acute and chronic bronchopulmonary infections, as well as pathologies affecting the ENT sphere and in particular the oropharyngeal sphere, such as oropharyngeal inflammatory syndrome, angina, nasopharyngitis or pharyngitis, among others.
  • pathologies of the respiratory system such as acute and chronic bronchopulmonary infections
  • pathologies affecting the ENT sphere and in particular the oropharyngeal sphere such as oropharyngeal inflammatory syndrome, angina, nasopharyngitis or pharyngitis, among others.
  • the enzymatic activity of the alpha-amylase to be incorporated has been determined beforehand. It is 227,786 CEIP Units / g.
  • the total mass of the composition C1 thus prepared is 649.168 kg.
  • Tests have been carried out in order to determine the acceptability and the tolerance of the patients when using the composition in the form of sucking tablets.
  • test subjects then answered two sets of questions.
  • the patients have a general impression of the treatment very good or good in 78.73% of the cases.

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Abstract

The invention concerns a composition for treating respiratory tract infections, characterised in that it combines menthol, eucalyptol and an amylolytic enzyme, said enzyme being preferably Bacillus Amyolicfaciens bacteria alpha-amylase. The inventive composition is particular suited for treating broncho-pulmonary and ORL sphere infections, particularly the oropharyngeal sphere.

Description

COMPOSITION POUR LE TRAITEMENT DES INFECTIONS DES VOIES RESPIRATOIRES COMPOSITION FOR THE TREATMENT OF RESPIRATORY INFECTIONS
La présente invention a pour objet une composition utile dans le traitement des infections des voies respiratoires et qui associe le menthol et l' eucalyptol à une enzyme amylolytique.The subject of the present invention is a composition useful in the treatment of respiratory tract infections and which combines menthol and eucalyptol with an amylolytic enzyme.
On connaît depuis longtemps les propriétés pharmacologiques du menthol et de l' eucalyptol. deux substances qui sont utilisées principalement dans le traitement des inflammations broncho-pulmonaires. Les propriétés analgésiques du menthol et les propriétés antiseptiques et expectorantes de l' eucalyptol ont été associées avec succès dans le traitement de la bronchite, dans des compositions présentées le plus souvent sous forme de pâtes pectorales ou de pastilles à sucer.The pharmacological properties of menthol and eucalyptol have long been known. two substances that are used mainly in the treatment of bronchopulmonary inflammation. The analgesic properties of menthol and the antiseptic and expectorant properties of eucalyptol have been successfully combined in the treatment of bronchitis, in compositions presented most often in the form of pectoral pastes or lozenges to be sucked.
Par ailleurs, il est connu depuis longtemps que les amylases sont dotées de propriétés antiinflammatoires. Elles possèdent également des propriétés antibactériennes et antivirales qui ont été décelées plus récemment. Des travaux ont en effet démontré que grâce à leurs propriétés amylolytiques, les enzymes de cette famille provoquaient la dégradation de la paroi cellulaire et de la membrane de nombreuses bactéries qui sont riches en hydrates de carbone. De la même manière, l'amylase dégrade les constituants glucidiques présents dans l'enveloppe cellulaire des particules virales.Furthermore, it has long been known that amylases have anti-inflammatory properties. They also have antibacterial and antiviral properties that have been detected more recently. Studies have indeed shown that thanks to their amylolytic properties, the enzymes of this family cause the degradation of the cell wall and the membrane of many bacteria which are rich in carbohydrates. Likewise, amylase degrades the carbohydrate constituents present in the cell envelope of viral particles.
II est donc apparu intéressant d'associer aux effets apaisants du menthol et de l' eucalyptol les effets anti-inflammatoires, antibactériens et antiviraux de l'amylase. Des doses d'emploi optimales ont été déterminées. Il a été observé que cette association réalisée dans certaines proportions, renforce l'action de chaque composant pris séparément, produisant un effet synergique inattendu.It therefore appeared interesting to combine the soothing effects of menthol and eucalyptol with the anti-inflammatory, antibacterial and antiviral effects of amylase. Optimal use doses have been determined. It has been observed that this association, carried out in certain proportions, strengthens the action of each component taken separately, producing an unexpected synergistic effect.
La composition selon l'invention contient du menthol et de l'eucalyptol. Ces composants se présentent sous la forme d'une poudre cristallisée. Le menthol est un racemique naturel du 2-isopropyl-5-méthylcyclohexane, dont la masse molaire est de 156,3 et le point de fusion 34°C. L'eucalyptol est le composant majeur de l'huile essentielle d'eucalyptus, de formule chimique 1,3,3 triméthyl-2-oxabicyclo [2.2.2] octane et de masse molaire 154,24. Son point de fusion est pF= 1 ,5°C.The composition according to the invention contains menthol and eucalyptol. These components are in the form of a crystallized powder. Menthol is a natural racemic for 2-isopropyl-5-methylcyclohexane, with a molar mass of 156.3 and a melting point of 34 ° C. Eucalyptol is the major component of eucalyptus essential oil, with the chemical formula 1,3,3 trimethyl-2-oxabicyclo [2.2.2] octane and a molecular weight of 154.24. Its melting point is pF = 1.5 ° C.
Le menthol et l'eucalyptol sont présents dans la composition selon l'invention à une concentration qui potentialise l'activité de l'amylase et qui apporte l'effet bénéfique recherché sans induire d'impression désagréable lors de la mise en bouche. Les concentrations répondant à ces critères se situent de 1 ,25 mg à 3,125 mg de menthol parMenthol and eucalyptol are present in the composition according to the invention at a concentration which potentiates the activity of amylase and which provides the desired beneficial effect without inducing an unpleasant impression during the appetizer. The concentrations meeting these criteria are from 1.25 mg to 3.125 mg of menthol per
] gramme de composition et de 0,375 mg à 1 mg d'eucalyptol par gramme de composition, de sorte que l'apport global menthol+eucalyptol est toujours compris entre 1 ,625 mg et 4,125 mg par gramme de composition. De manière commode, on incorpore 2 mg de menthol et 0,6 mg d'eucalyptol dans un gramme de ladite composition.] gram of composition and from 0.375 mg to 1 mg of eucalyptol per gram of composition, so that the overall menthol + eucalyptol intake is always between 1.625 mg and 4.125 mg per gram of composition. Conveniently, 2 mg of menthol and 0.6 mg of eucalyptol are incorporated into one gram of said composition.
15 De manière avantageuse, un prémélange est préparé contenant des proportions de menthol allant de 10% à 25% en poids et d'eucalyptol allant de 3% à 8% en poids, sur un support neutre tel que la gomme arabique.Advantageously, a premix is prepared containing proportions of menthol ranging from 10% to 25% by weight and of eucalyptol ranging from 3% to 8% by weight, on a neutral support such as gum arabic.
Les produits décrits ci-dessus sont communément commercialisés par des sociétés 20 spécialisées dans les ingrédients pharmaceutiques.The products described above are commonly marketed by companies specializing in pharmaceutical ingredients.
La composition selon l'invention contient également une enzyme à activité amylolytique. Cette enzyme est de préférence une (l ,4)-α-D-glucan-glucanohydrolase, communément appelée "alpha-amylase", ou "alfa-amylase" selon la Dénomination Commune InternationaleThe composition according to the invention also contains an enzyme with amylolytic activity. This enzyme is preferably a (1,4) -α-D-glucan-glucanohydrolase, commonly called "alpha-amylase", or "alfa-amylase" according to the International Nonproprietary Name
25 préconisée par l'Organisation Mondiale de la Santé pour les substances pharmaceutiques. Le mécanisme par lequel l' alpha-amylase dégrade les composés polysaccharidiques est une réaction d'hydrolyse où l'enzyme joue le rôle de catalyseur. Celle-ci attaque au hasard les liaisons -(l,4) de l'amidon libérant du glucose et du maltose (le maltose est un disaccharide composé de deux monomères glucoses). Les parois cellulaires sont endommagées par cette25 recommended by the World Health Organization for pharmaceutical substances. The mechanism by which alpha-amylase degrades polysaccharide compounds is a hydrolysis reaction in which the enzyme acts as a catalyst. This randomly attacks the - (1,4) bonds of the starch releasing glucose and maltose (maltose is a disaccharide composed of two glucose monomers). The cell walls are damaged by this
30 hydrolyse, ce qui conduit à une perte de virulence et à l'arrêt de la prolifération des agents infectieux dans l'organisme. Dans un mode de réalisation particulier, on utilise l' alpha-amylase sécrétée naturellement par un micro-organisme bactérien, de préférence par Bacillus amyloliquefaciens. Cette bactérie, reconnue comme espèce à part entière en 1987, était considérée antérieurement comme un représentant atypique de l'espèce Bacillus subtilis (Priest et al. , Int. J. Syst. Bacteriol. 37:69 1987).30 hydrolysis, which leads to a loss of virulence and a halt to the proliferation of infectious agents in the body. In a particular embodiment, the alpha-amylase secreted naturally by a bacterial microorganism, preferably by Bacillus amyloliquefaciens, is used. This bacterium, recognized as a full-fledged species in 1987, was previously considered as an atypical representative of the species Bacillus subtilis (Priest et al., Int. J. Syst. Bacteriol. 37:69 1987).
L' alpha-amylase produite naturellement par B. amyloliquefaciens est une protéine de 58 kDa, dont les dix premiers acides aminés, déterminés par séquençage sont:The alpha-amylase produced naturally by B. amyloliquefaciens is a 58 kDa protein, of which the first ten amino acids, determined by sequencing are:
Val - Asn - Gly - Thr - Leu - Met - Gin - Tyr - Phe - GluVal - Asn - Gly - Thr - Leu - Met - Gin - Tyr - Phe - Glu
L' alpha-amylase utilisée dans la composition selon l'invention peut être produite par tout procédé de culture microbiologique mettant en œuvre un micro-organisme compétent pour la production et l'excrétion de ladite alpha-amylase, qu'il soit transformé par génie génétique ou non. De manière préférée, l' alpha-amylase bactérienne est obtenue par fermentation en <- réacteur de B. amyloliquefaciens. Les procédés de production d'enzymes par fermentation microbiologique et de purification sont bien connus de l'homme du métier et sont mis en œuvre par des entreprises spécialisées dans le domaine correspondant.The alpha-amylase used in the composition according to the invention can be produced by any microbiological culture process using a microorganism competent for the production and excretion of said alpha-amylase, whether it is engineered genetic or not. Preferably, the bacterial alpha-amylase is obtained by fermentation in a < - reactor of B. amyloliquefaciens. The processes for producing enzymes by microbiological fermentation and for purification are well known to those skilled in the art and are implemented by companies specialized in the corresponding field.
En particulier, l' alpha-amylase entrant dans la composition revendiquée est produite par un Q procédé la mettant à l'abri d'une contamination par l'E.S.B. (Encéphalopathie SpongiformeIn particular, the alpha-amylase used in the claimed composition is produced by a process Q which protects it from contamination by E.S.B. (Spongiform encephalopathy
Bovine). En effet, aucune matière première utilisée dans l'ensemble du cycle de production (fermentation, extraction, finition) n'est d'origine bovine ou ovine. D'autre part, toutes les matières premières utilisées en fermentation (source de carbone et de protéines, azote, sel minéraux) sont stérilisés à 125°C pendant 30 minutes. 5Bovine). Indeed, no raw material used throughout the production cycle (fermentation, extraction, finishing) is of bovine or ovine origin. On the other hand, all the raw materials used in fermentation (source of carbon and proteins, nitrogen, mineral salts) are sterilized at 125 ° C for 30 minutes. 5
L'alpha-amylase ainsi produite se présente comme une poudre fine de couleur crème à beige ne présentant aucune matière étrangère, soluble dans l'eau et conforme eux normes de qualité et de sécurité exigées pour les produits à usage pharmaceutique (absence de métaux, stérilité). Elle est commercialisée en France et dans de nombreux pays, par la Société Top 0 Pharm (Revel, France).The alpha-amylase thus produced is presented as a fine cream to beige powder having no foreign matter, soluble in water and in accordance with the quality and safety standards required for products for pharmaceutical use (absence of metals, sterility). It is marketed in France and in many countries by the company Top 0 Pharm (Revel, France).
Conformément aux enseignements de l'invention, on prépare une composition contenant l' alpha-amylase choisie, du menthol et de l'eucalyptol, ainsi qu'un excipient et différents adjuvants destinés à faciliter le façonnage et à conférer au produit fini des propriétés particulières en rendant la consommation particulièrement agréable.In accordance with the teachings of the invention, a composition is prepared containing the alpha-amylase chosen, menthol and eucalyptol, as well as an excipient and various adjuvants intended to facilitate the shaping and to confer on the finished product particular properties by making consumption particularly pleasant.
La quantité d'alpha-amylase incorporée à la composition est définie par son niveau d'activité enzymatique exprimée en unité internationale CEIP, notée "U. CEIP", la valeur d'une unité U. CEIP étant égale à 0,714 unité de la pharmacopée européenne. Elle est comprise entre 1800 et 2600 U. CEIP, et est de préférence de 2400 U. CEIP, par gramme de composition.The amount of alpha-amylase incorporated into the composition is defined by its level of enzymatic activity expressed in CEIP international unit, noted "U. CEIP", the value of a U. CEIP unit being equal to 0.714 unit of the pharmacopoeia European. It is between 1800 and 2600 U. CEIP, and is preferably 2400 U. CEIP, per gram of composition.
Dans la pratique du fait que les procédés microbiologiques de fermentation ne sont pas à l'abri de légères variations, on dose l'activité enzymatique de l' alpha-amylase en poudre avant la préparation de la composition et on calcule la quantité en poids qu'il faut incorporer à la composition, pour obtenir une activité définie.In practice, since the microbiological fermentation processes are not immune to slight variations, the enzymatic activity of the powdered alpha-amylase is assayed before the preparation of the composition and the quantity by weight qu is calculated. 'must be incorporated into the composition to obtain a defined activity.
Ces valeurs sont contrôlées au moment de la préparation de la composition et de sa formulation éventuelle en comprimés, et vont décroître dans le temps par un phénomène naturel de dégradation de l'enzyme. Cependant cette décroissance. est légère, de sorte que l'activité enzymatique au bout de trois ans sera encore au moins de 2000 U.CEIP par gramme de composition, avec une marge d'incertitude maximum de ±5 %.These values are controlled during the preparation of the composition and its possible formulation in tablets, and will decrease over time by a natural phenomenon of degradation of the enzyme. However this decrease . is light, so that the enzymatic activity after three years will still be at least 2000 U.CEIP per gram of composition, with a maximum margin of uncertainty of ± 5%.
La composition de l'invention est destinée à être présentée sous une forme galénique adéquate pour être administrée par voie orale, de préférence sous forme de comprimés à sucer, en général de 0,5 gramme chacun. L'activité enzymatique de l' alpha-amylase dans chaque comprimé sera idéalement de 1200 U. CEIP au moment de la fabrication, et de 1000 ± 50 U. CEIP au bout de trois années. La quantité de menthol sera de 1 mg par comprimé et la quantité d'eucalyptol de 0,3 mg par comprimé.The composition of the invention is intended to be presented in a galenical form suitable for administration by the oral route, preferably in the form of sucking tablets, in general of 0.5 gram each. The enzymatic activity of alpha-amylase in each tablet will ideally be 1200 U. CEIP at the time of manufacture, and 1000 ± 50 U. CEIP after three years. The amount of menthol will be 1 mg per tablet and the amount of eucalyptol 0.3 mg per tablet.
Les principes actifs ainsi définis sont incorporés dans un excipient. Celui-ci peut être choisi parmi tout composé à la disposition de l'homme du métier, compatible avec une prise orale du produit selon l'invention. Dans un mode de réalisation avantageux, un excipient sucré est utilisé, tel que le glucose sous forme de sucre glace, ou un produit édulcorant. Un colorant peut être ajouté à la préparation. La chlorophylle est avantageusement utilisée du fait de sa teinte verte associée spontanément à la menthe par le public. Tout colorant autorisé dans les produits à usage alimentaire peut également être employé.The active ingredients thus defined are incorporated into an excipient. This can be chosen from any compound available to those skilled in the art, compatible with an oral intake of the product according to the invention. In an advantageous embodiment, a sweet excipient is used, such as glucose in the form of icing sugar, or a sweetening product. A colorant can be added to the preparation. Chlorophyll is advantageously used because of its green color spontaneously associated with mint by the public. Any coloring authorized in food products can also be used.
Des adjuvants facilitant le processus de fabrication peuvent être employés dans les limites de la réglementation en vigueur. Par exemple un agent mouillant peut être utilisé, comme la Polyvidone K30 (BASF, Levalloy Perret - France). Des lubrifiants améliorant l'étape de compression de la composition sous forme de comprimés peuvent être ajoutés, comme le talc ou le stéarate de magnésium.Additives to facilitate the manufacturing process may be used within the limits of the regulations in force. For example, a wetting agent can be used, such as Polyvidone K30 (BASF, Levalloy Perret - France). Lubricants improving the compression step of the composition in tablet form can be added, such as talc or magnesium stearate.
La fabrication de la composition selon l'invention est réalisée en plusieurs étapes, conformément aux méthodes pratiquées usuellement pour le façonnage des cachets contenant des substances actives fragiles. Par exemple, il peut être procédé de la manière suivante: Dans une première étape dite "granulation humide", l'excipient est mélangé à un agent de mouillage pour permettre la formation de granules, qui sont ensuite séchées et calibrées. Une deuxième étape consiste à mélanger les granules avec les principes actifs sous forme de poudre. Puis les différents adjuvants sont ajoutés. Enfin, les granules sont compressées sous forme de comprimés et conditionnées.The manufacture of the composition according to the invention is carried out in several stages, in accordance with the methods customarily used for shaping cachets containing fragile active substances. For example, it can be carried out in the following way: In a first stage called "wet granulation", the excipient is mixed with a wetting agent to allow the formation of granules, which are then dried and calibrated. A second step is to mix the granules with the active ingredients in powder form. Then the various adjuvants are added. Finally, the granules are compressed into tablets and packaged.
La composition selon l'invention est indiquée dans le traitement des pathologies du système respiratoire, comme les infections broncho-pulmonaires aiguës et chroniques, ainsi que les pathologies affectant la sphère ORL et en particulier la sphère oropharyngée, telles que le syndrome inflammatoire oropharyngé, l'angine, la rhinopharyngite ou la pharyngite, entre autres.The composition according to the invention is indicated in the treatment of pathologies of the respiratory system, such as acute and chronic bronchopulmonary infections, as well as pathologies affecting the ENT sphere and in particular the oropharyngeal sphere, such as oropharyngeal inflammatory syndrome, angina, nasopharyngitis or pharyngitis, among others.
Les exemples ci-après sont donnés à titre purement illustratif et non limitatif.The examples below are given purely by way of non-limiting illustration.
EXEMPLE 1 Préparation d'un lot industriel: formule de la composition Cl.EXAMPLE 1 Preparation of an industrial batch: formula of composition Cl.
L'activité enzymatique de l' alpha-amylase à incorporer a été préalablement dosée. Elle est de 227 786 Unités CEIP/ g.The enzymatic activity of the alpha-amylase to be incorporated has been determined beforehand. It is 227,786 CEIP Units / g.
Alpha-amylase 6,838 kgAlpha-amylase 6.838 kg
Menthol 1,298 kgMenthol 1,298 kg
Eucalyptol 0,389 kgEucalyptol 0.389 kg
Talc 6,492 kgTalc 6.492 kg
Stéarate de Magnésium 6,492 kgMagnesium stearate 6.492 kg
Polyvidone K30 10,583 kgPolyvidone K30 10.583 kg
Colorant chlorophylle 0,066 kgChlorophyll dye 0.066 kg
Sucre glace quantité suffisante pour 649,168 kgIcing sugar sufficient quantity for 649.168 kg
La masse totale de la composition Cl ainsi préparée est de 649,168 kg.The total mass of the composition C1 thus prepared is 649.168 kg.
EXEMPLE 2EXAMPLE 2
Composition chimique d'un comprimé préparé à partir de la composition Cl:Chemical composition of a tablet prepared from composition Cl:
A partir de la composition Cl obtenue à l'exemple 1, 1 298 000 comprimés de 0,5 g chacun ont été produits. Leur formule unitaire est la suivante:From composition C1 obtained in Example 1, 1,298,000 tablets of 0.5 g each were produced. Their unit formula is as follows:
Alpha-amylase 5,268 mg, soit 1200 U. CEIP5.268 mg alpha-amylase, i.e. 1200 U. CEIP
Menthol 1,000 mgMenthol 1,000 mg
Eucalyptol 0,300 mgEucalyptol 0.300 mg
Talc 5,000 mgTalc 5,000 mg
Stéarate de Magnésium 5,000 mgMagnesium stearate 5,000 mg
Polyvidone K30 16,300 mgPolyvidone K30 16.300 mg
Colorant chlorophylle 0,050 mgChlorophyll dye 0.050 mg
Sucre glace quantité suffisante pour 500 mg EXEMPLE 3 Essais cliniquesIcing sugar sufficient for 500 mg EXAMPLE 3 Clinical trials
Des essais ont été réalisés afin de déterminer l'acceptabilité et la tolérance des patients lors de l'utilisation de la composition sous forme de comprimés à sucer.Tests have been carried out in order to determine the acceptability and the tolerance of the patients when using the composition in the form of sucking tablets.
Les observations ont été réalisées sur un échantillon représentatif de 94 patients présentant les symptômes de différentes pathologies: syndrome inflammatoire oropharyngé, angine, pharyngite et pharyngite. L'âge des patients était compris entre 19 et 90 ans, 53 femmes et 41 hommes pesant de 42 kg à 108 kg et mesurant de 1 ,44 m à 1 ,96 m ont participé aux tests. Les malades ont reçu un traitement durant 4 jours, à raison de 9 comprimés à sucer par 24 heures.The observations were carried out on a representative sample of 94 patients presenting the symptoms of different pathologies: oropharyngeal inflammatory syndrome, angina, pharyngitis and pharyngitis. The age of the patients was between 19 and 90 years, 53 women and 41 men weighing from 42 kg to 108 kg and measuring from 1.44 m to 1.96 m participated in the tests. The patients received treatment for 4 days, 9 tablets to be sucked per 24 hours.
RÉSULTATSRESULTS
Les observations cliniques ont montré un taux de guérison de 92,55% à l'issue du traitement, soit 87 patients guéris, et 7 patients présentant encore des symptômes pathologiques.Clinical observations showed a cure rate of 92.55% at the end of the treatment, ie 87 patients cured, and 7 patients still showing pathological symptoms.
Les personnes testées ont ensuite répondu à deux séries de questions.The test subjects then answered two sets of questions.
1) ACCEPTABILITÉ1) ACCEPTABILITY
IMPRESSIONIMPRESSION
GOÛT PARFUM GÉNÉRALEGENERAL PERFUME TASTE
Nb % Nb % Nb %Nb% Nb% Nb%
Très bon 39 41,49 39 41,49 23 24,47Very good 39 41.49 39 41.49 23 24.47
Bon 44 46,81 46 48,94 il 54,26Good 44 46.81 46 48.94 il 54.26
Moyen 11 11,70 9 9,57 20 21,27Medium 11 11.70 9 9.57 20 21.27
Nul - - - - - -No - - - - - -
Total 94 100 94 100 94 100 Conclusions:Total 94 100 94 100 94 100 conclusions:
Le goût a été côté très bon ou bon dans 88,30% des cas. Les patients ont trouvé le parfum très bon ou bon dans 90,43% des cas.The taste was rated very good or good in 88.30% of the cases. The patients found the scent very good or good in 90.43% of the cases.
L'impression générale du traitement, comprenant le soulagement perçu, la diminution de la douleur et la dispaπtion des symptômes a été cotée très bonne dans 24,47%o des cas, bonne dans 54,26% des cas et moyenne dans 21,27% des cas.The general impression of the treatment, including perceived relief, reduction of pain and disappearance of symptoms was rated very good in 24.47% o of the cases, good in 54.26% of the cases and average in 21.27 % of cases.
En conclusion, les patients ont une impression générale du traitement très bonne ou bonne dans 78,73% des cas.In conclusion, the patients have a general impression of the treatment very good or good in 78.73% of the cases.
2) REPRISE ÉVENTUELLE DU TRAITEMENT2) POSSIBLE RESUMPTION OF THE TREATMENT
Les personnes ayant suivi le traitement ont indiqué quel serait leur comportement dans le cas où elles souffrirait à nouveau des mêmes symptômes.People who followed the treatment indicated what their behavior would be if they suffered the same symptoms again.
A la question: "Le traitement vous a-t-il fait du bien?", 87 personnes (soit 92,55%) ont répondu OUI.When asked: "Did the treatment do you any good?", 87 people (92.55%) answered YES.
A la question "Reprendπez-vous ce traitement?". 88 personnes ( soit 93,62%) ont reponduTo the question "Do you resume this treatment?". 88 people (93.62%) answered
OUI. YES.

Claims

REVENDICATIONS
1. Composition pour le traitement des infections des voies respiratoires, associant le menthol, l'eucalyptol et une enzyme amylolytique.1. Composition for the treatment of respiratory tract infections, combining menthol, eucalyptol and an amylolytic enzyme.
2. Composition selon la revendication 1 , caractérisée en ce que ladite enzyme amylolytique est une alpha-amylase, de préférence d'origine bactérienne.2. Composition according to claim 1, characterized in that said amylolytic enzyme is an alpha-amylase, preferably of bacterial origin.
3. Composition selon une des revendications 1 et 2, caractérisée en ce que ladite enzyme amylolytique est une protéine de 58 kDa, produite naturellement par Bacillus amyloliquefaciens (anciennement assimilé à B. subtilis).3. Composition according to one of claims 1 and 2, characterized in that said amylolytic enzyme is a protein of 58 kDa, produced naturally by Bacillus amyloliquefaciens (formerly assimilated to B. subtilis).
4. Composition selon l'une des revendications 1 à 3, caractérisée en ce que ladite enzyme amylolytique est présente à raison de 1800 à 2600 Unités CEIP, et de préférence 2400 Unités CEIP, par gramme de ladite composition.4. Composition according to one of claims 1 to 3, characterized in that said amylolytic enzyme is present in an amount of 1800 to 2600 CEIP units, and preferably 2400 CEIP units, per gram of said composition.
5. Composition selon l'une des revendications 1 à 4, caractérisée en ce que la teneur totale (menthol + eucalyptol) est comprise entre 1.625 mg et 4,125 mg par gramme de ladite composition.5. Composition according to one of claims 1 to 4, characterized in that the total content (menthol + eucalyptol) is between 1.625 mg and 4.125 mg per gram of said composition.
6. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle est présentée sous une forme appropriée à l'administration orale, de préférence sous forme de comprimés à sucer.6. Composition according to any one of the preceding claims, characterized in that it is presented in a form suitable for oral administration, preferably in the form of sucking tablets.
7. Utilisation de la composition selon la revendication 6 dans le traitement des infections broncho-pulmonaires ou des pathologies affectant la sphère ORL et en particulier la sphère oropharyngée. 7. Use of the composition according to claim 6 in the treatment of bronchopulmonary infections or pathologies affecting the ENT sphere and in particular the oropharyngeal sphere.
PCT/FR2000/003114 1999-11-10 2000-11-09 Composition for treating respiratory tract infections containing menthol, eucalyptol and an alpha-amylase WO2001034182A2 (en)

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FR2827776A1 (en) * 2001-07-25 2003-01-31 Top Pharm Lab COMPOSITION CONSISTING OF AN ENZYMATIC ANTI-INFLAMMATORY AND A MUCOLYTIC
DE102006032233A1 (en) * 2006-07-12 2008-01-17 Ewabo Chemikalien Gmbh & Co. Kg Use of a preparation containing eucalyptol/menthol for the production of medicament for combating and preventing virus infection and secondary bacterial infection
FR2927256A1 (en) * 2008-02-13 2009-08-14 Top Pharm Sarl Lab Composition, useful for treating inflammatory disease of respiratory track, comprises alpha-amylase enzyme and local anesthetic
WO2019175777A1 (en) * 2018-03-12 2019-09-19 Better Air International Limited Compositions comprising bacterial strains and use thereof in controlling pathogenic microorganisms
US11384333B2 (en) 2018-03-12 2022-07-12 Better Air International Limited Compositions comprising bacterial strains and use thereof in controlling pathogenic microorganisms
US11396643B2 (en) 2018-03-12 2022-07-26 Better Air International Limited Compositions comprising bacterial strains and use thereof in controlling pathogenic microorganisms
US11602550B2 (en) 2018-03-12 2023-03-14 Better Air International Limited Compositions comprising bacterial strains and use thereof in controlling pathogenic microorganisms
US12016513B2 (en) 2018-05-21 2024-06-25 Ecological Balancing Technologies Corporation Automated device and method for spreading environmental friendly microbes on a surface
US12064778B2 (en) 2018-03-12 2024-08-20 Ecological Balancing Technologies Corporation Electronic safety feature for an automated aerosol dispensing device

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WO2010078392A2 (en) * 2008-12-31 2010-07-08 Novozymes North America, Inc. Processes of producing fermentation products

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2827776A1 (en) * 2001-07-25 2003-01-31 Top Pharm Lab COMPOSITION CONSISTING OF AN ENZYMATIC ANTI-INFLAMMATORY AND A MUCOLYTIC
WO2003009799A1 (en) * 2001-07-25 2003-02-06 Laboratoire Top Pharm Liquid composition comprising an enzymatic anti-inflammatory agent and a mucolytic
DE102006032233A1 (en) * 2006-07-12 2008-01-17 Ewabo Chemikalien Gmbh & Co. Kg Use of a preparation containing eucalyptol/menthol for the production of medicament for combating and preventing virus infection and secondary bacterial infection
FR2927256A1 (en) * 2008-02-13 2009-08-14 Top Pharm Sarl Lab Composition, useful for treating inflammatory disease of respiratory track, comprises alpha-amylase enzyme and local anesthetic
WO2019175777A1 (en) * 2018-03-12 2019-09-19 Better Air International Limited Compositions comprising bacterial strains and use thereof in controlling pathogenic microorganisms
US11384333B2 (en) 2018-03-12 2022-07-12 Better Air International Limited Compositions comprising bacterial strains and use thereof in controlling pathogenic microorganisms
US11396643B2 (en) 2018-03-12 2022-07-26 Better Air International Limited Compositions comprising bacterial strains and use thereof in controlling pathogenic microorganisms
US11602550B2 (en) 2018-03-12 2023-03-14 Better Air International Limited Compositions comprising bacterial strains and use thereof in controlling pathogenic microorganisms
US11618880B2 (en) 2018-03-12 2023-04-04 Better Air International Limited Compositions comprising bacterial strains and use thereof in controlling pathogenic microorganisms
US12064778B2 (en) 2018-03-12 2024-08-20 Ecological Balancing Technologies Corporation Electronic safety feature for an automated aerosol dispensing device
US12016513B2 (en) 2018-05-21 2024-06-25 Ecological Balancing Technologies Corporation Automated device and method for spreading environmental friendly microbes on a surface

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FR2800614A1 (en) 2001-05-11
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FR2800614B1 (en) 2002-01-04

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