FR2947454A1 - Composition, useful e.g. in cosmetic product, comprises mixture of lyophilizate of natural human protease inhibitor from egg white of quail Coturnix coturnix japonica and lyophilizate of medicinal plants, and combination consisting mixture - Google Patents

Abstract

Medicamentous composition (I) comprises a mixture of a lyophilizate of one or more natural inhibitors of human proteases extracted from the egg white of quail Coturnix coturnix japonica(strain B.mina), and a lyophilizate of one or several entire medicinal plants, or one or more of their fractions and the combination consisting an active mixture. ACTIVITY : Immunostimulant; Antiallergic; Antiinflammatory; Antimicrobial; Antiasthmatic; Anabolic. MECHANISM OF ACTION : Human protease inhibitor.

Description

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The present invention relates to novel medicinal compositions for human and animal use comprising the combination of lyophilizates of natural inhibitors of human and animal protease enzymes (extracts of the white of the quail egg of Coturnix coturnix Japonica strain B. mina), lyophilisates of medicinal plants prescribed in herbal medicine and listed in the pharmacopoeia, using one or more whole plants or one or more of their most pharmacologically active fractions, an association of lyophilisates intimately mixed and incorporated, for example, in fast disintegrating capsules for the oral route, for example, it being understood that all the manufacturing techniques which guarantee the homogeneity, the duration of action and the stability of the active ingredients, can be used without restrictions.

This combination potentiates the effectiveness of each of the active ingredients and maximizes their therapeutic actions, for example, innovation that benefits from the surprising technical effect obtained by lyophilization and by the intimate mixing of the active principles, which induces an excellent synergy of actions and potentiates each of its components.

The formulations that will be proposed for a capsule, for example, may also be used for the manufacture of food supplements for human and animal use, for example, cosmetological products and for all other products, these formulations being proposed only for purely indicative without any restrictions. 2947454 - 2 -

The present invention more particularly describes, for example, novel drug compositions indicated in allergic diseases, infectious diseases, general pathology, and immunostimulant and immune system corrector.

It is obvious that the various formulations proposed may be obtained in liquid, solid, powder, freeze-dried, cream and ointment form, for example, or in all the pharmaceutically acceptable dosage forms, such as tablets, capsules, globules, granules, fluids, powders, sachets and ampoules, for example, for oral, sublingual, nasal, ocular and cutaneous use, for example. By human serine proteases is meant pro-inflammatory and proteolytic enzymes such as trypsin secreted by exocrine cells of the pancreas, for example, and its cell homologs, included in intracytoplasmic granulations of immune cells such as mast cells, basophils. , neutrophils and eosinophils.

In the physiological state, each individual possesses endogenous anti-proteases, which inhibit the deleterious effect of these protease enzymes and maintain the equilibrium of the enzyme-anti-enzyme system.

In some individuals, these anti-enzymes have deficient activity, which imbalances the anti-enzyme enzyme system and promotes pro-inflammatory and proteolytic activity: this imbalance induces the appearance of 2947454 - 3

allergic manifestations, for example, infectious, immune imbalance and clinical symptoms observed in general pathology.

By natural inhibitors of human protease enzymes, we mean glycoproteins (of which there are more than a hundred in the vegetable, animal, bacterial, viral and parasitic kingdom), contained in the white of the Japanese quail egg. species Coturnix coturnix Japonica 10 (the egg being considered a natural product), for example, endowed with a potent anti-protease human activity, and a very strong specific anti-inflammatory (allergy) and non-specific activity (infection and general pathology); two fractions were isolated from the white of the quail egg: ovomucoid, with a molecular weight of 28 kDa, inhibits pancreatic human trypsin and its homologues such as neutrophil elastase, tryptase and carboxypeptidase of mastocyte, for example, and, - the ovoinhibitor, of a molecular weight of 57 kDa, which does not inhibit human trypsin, but the proteinase, serine protease of a mold called aspergillus orizae and subtilisin, serine protease bacillus subtilis, and lastly, al-chymotrypsin. The combination of these two natural inhibitors of human proteases, in a proportion, for example, of three ovomucoid fractions for an ovoinhibitor fraction, confers on the innovation a broader and more potent anti-protease activity by compared to each of these inhibitors taken separately. 2947454 - 4

The innovation consists, for example, of an intimate mixture of a lyophilizate of one or more natural inhibitors of human proteases (ovomucoid and ovoinhibitor) and a lyophilizate of one or more whole plants, or of One or more fractions of these plants, the most pharmacologically active, incorporated in a fast disintegrating capsule, or in tablets proposed for the oral and sublingual routes, creams and ointments for the dermal route, for example. According to the previous state, our patent No. 02,047,002 is known in which a medicinal composition comprising a neutral excipient solution in which is incorporated, for example, a quail egg homogenate (a mixture of yolks and whole whites) and or one or more solutions of medicinal plant extracts used in herbal medicine.

The present invention more particularly discloses, for example, and without limitation, novel drug compositions particularly indicated in inflammatory immunoallergic diseases, infectious diseases, immune imbalances, but also in general pathology. It was therefore not obvious, even for those skilled in the art, to associate a lyophilizate of one or more medicinal plants or one or more of their most pharmacologically active fractions with a freeze-dried product. one or more natural inhibitors of human serine proteases. 2947454 - 5 -

By medicinal plants we mean all the plants whose effectiveness has been demonstrated in human and animal medicine and which appear in the pharmacopoeia; after pharmaceutical preparation they can be used whole or in part according to the most pharmacologically active fraction of the plant, for example, and according to the industrial process which has been chosen to prepare, for example, a lyophilizate of the whole plant or of the plant. one of his fractions; it is thus possible to prepare different galenic forms from the whole plant or from one of its fractions. Medicinal plants have a therapeutic efficacy in all pathologies and have a high immunostimulatory and immune system corrective activity, this is the case of plants such as chicory, echinacea, propolis, for example. By medicinal plant extracts is meant a part of the plant such as, for example, the root, stem, leaf, flower or fruit or any other active constituent of said plant used in herbal medicine. In accordance with the present invention, the intimate mixture of a lyophilizate composed of one or more natural protease inhibitors and a lyophilizate of an extract or whole plant is proposed. According to the invention, and particularly in allergic inflammatory diseases, plantain is indicated in hay fever, for example, perennial rhinitis, sinusitis, laryngitis, tracheitis and asthma; these indications are obviously not limiting. 20 2947454 - 6 -

The plantain leaf, for example and according to the present invention, contains pharmacologically active substances such as iridoids including the dominant active ingredient and aucuboside; Plantain is also indicated for the treatment of bronchopulmonary conditions because it contains mucilage with a softening and emollient action which facilitates expectoration.

In addition, and because of its composition, the plantain is also anti-inflammatory.

Any other fraction or component of a medicinal plant or all of said plant may be intimately mixed with one or more natural inhibitors of human proteases.

According to the invention, the white horehound, for example, is a perennial medicinal plant with downy serrated leaves with white flowers; these flowers contain diterpene lactones, including marrubine, giving the white horehound amazing properties on the respiratory system: it liquefies bronchial secretions and facilitates expectoration, it is antitussive and calms the rebel cough of tracheitis; the presence of soothing and anti-inflammatory mucilages justifies its use in inflammations of the throat; dilator of the bronchi, it is indicated in asthma and its association with plantain induces a surprising synergy of action which maximizes and potentiates the effects. Red clover is used whole in menopause; it is traditionally known for its phytoestrogens. - 7

It contains four isoflavones: biochanin, formononetin, genistene and daidzein, which alleviate menopausal discomfort associated with estrogen deficiency; red clover is also involved in osteoporosis present during menopause.

1 / Obtaining lyophilisates of natural inhibitors of human proteases and medicinal plants. A lyophilizer is used; freeze-drying or cold drying is a process of removing water from a food or other solid or liquid product to make it stable at room temperature and to facilitate its preservation; lyophilization comprises three stages: freezing, primary drying and secondary drying or final drying:

- The freezing consists of reducing the temperature of the product to be freeze-dried at a temperature between -20 ° and -80 ° C so as to block the water in the form of ice, it avoids the alteration of the active ingredients, - the primary desiccation or sublimation, is the passage of a substance from the solid or liquid state to the gaseous state; the product or the food is dried by putting it under vacuum, the ice then becomes steam; the dehydration of the product causes a loss of water of 80 to 90%, - the secondary drying begins when all the ice is sublimed or suppressed, the food or the products are dried, the temperature of the lyophilizer rises spontaneously and briefly once that all the water is sublimated which makes it possible to obtain a dry product to 95% or more, without the slightest alteration of its composition 2947454 -8-

initial ; lyophilization allows the mixing of the products thus obtained, their preservation and stability can last several years; the excellent pharmacological action of the finished product (natural inhibitors of human proteases and medicinal plants) is based on the surprising effect induced by the freeze-drying technique, the combination of the products potentiates and maximizes their efficiency thanks to an excellent synergy of action . 2 / Obtaining one or more natural human protease inhibitors: The natural inhibitors of human proteases extracted from the white of the quail egg include: - the violomucoid, which is contained in the white, is isolated by precipitation at using trichloroacetic acid and acetone; the isolated protein fraction is then purified by sequential chromatography on DEAE-cellulose; once purified, the ovomucoid is lyophilized; the anti-human protease activity (trypsin and homologues) is tested on a casein substrate; 2 μg of ovomucoid are reacted with 1 μg of human trypsin: the ovomucoid of the white of the quail egg is not destroyed by digestion or by an acidic gastric pH, which allows its oral administration, for example, the inhibitor is obtained by precipitation with trichloroacetic acid and acetone; a precipitate is obtained which is dialysed and lyophilized; the inhibitory capacity of the protease inhibitors is measured by reacting the fraction obtained on the proteinase 2947454

aspergillus orizae using a casein substrate, then subtilisin from bacillus subtilis, achymotrypsin and human trypsin: the ovoinhibitor does not inhibit the protease activity of human trypsin, but inhibits proteinase, subtilisin and α-chymotrypsin.

3 / Example of formulation of a freeze-dried capsule of natural inhibitors of human proteases and plantain.

Ovomucoid 3 mg Ovoinhibitor 1 mg Plantain (leaf) 431 mg

4 / Example of formulation of a freeze-dried capsule of natural inhibitors of human proteases and white horehound.

Ovomucoid 3 mg Ovoinhibitor 1 mg White horehound (flower) 431 mg

5 / Example of formulation of a freeze-dried capsule of natural inhibitors of human proteases of plantain and white horehound. Ovomucoid 3 mg Ovoinhibitor 1 mg Plantain (leaf) 216 mg White horehound (flower) 215 mg 10 15 20 30 5 2947454 - 10 -

6 / Example of formulation of a freeze-dried capsule of natural inhibitors of human proteases and red clover.

Ovomucoid 3 mg Ovoinhibitor 1 mg Red clover (whole) 431 mg 10 15 20 25 30

Claims (1)

CLAIMS1 / Drug compositions intended for human and animal medicine, characterized in that they contain an intimate mixture of a lyophilizate of one or more natural inhibitors of human proteases extracted from the white of the quail egg of the species Coturnix coturnix Japonica of the B.mina strain, and a lyophilizate of one or more whole medicinal plants, or one or more of their fractions and in that this combination constitutes a pharmacologically active mixture through its components . 2 / drug compositions according to claim 1, characterized in that the combination of the two lyophilizates comprises one or more natural inhibitors of human protease enzymes such as ovomucoid and ovoinhibitor, in a proportion of three fractions of ovomucoid for a fraction. of ovoinhibitor, for example, intimately mixed with a lyophilizate of one or more whole medicinal plants or one or more of their fractions, maximizes the overall drug activity of the present innovation which benefits, moreover, the effect surprising technique conferred by lyophilization, so that the administration of this new composition can be oral, sublingual or percutaneous depending on the selected dosage form, capsule, tablet, fluid, powder, cream or ointment, for example, or all pharmaceutically acceptable dosage forms. 3 / drug compositions according to claims 1 and 2, characterized in that they comprise, a lyophilisate of one or more natural inhibitors of human protease enzymes, a lyophilisate of one or more medicinal plants whole or one or more of their fractions, such as plantain leaf, white horehound flower, whole red clover, for example, each active ingredient alone can constitute a new product. 4 / Drug compositions according to any one of the preceding claims, characterized in that they are in the form of capsules fast disintegration. 5 / drug compositions according to any one of the preceding claims, characterized in that they have an immunostimulatory and immune system corrective activity and a potent activity in general pathology (allergy, infections, for example), related to the activity of each of its components. 6 / Drug compositions according to any of the preceding claims, characterized in that the formulations used can be applied to the manufacture of food supplements, cosmetics and all other products. Pharmaceutical compositions according to any one of the preceding claims, characterized in that the different formulations can be used for all the pharmacologically acceptable dosage forms by the freeze-drying technique or any other manufacturing method which guarantees homogeneity. the stability of this innovation and its duration of action. 2947454 - 13 - 8 / Drug compositions according to any one of the preceding claims, characterized in that the natural inhibitors of human protease enzymes can be of animal, plant, bacterial, viral and parasitic origin or from any other source and that the medicinal plants or their fractions used all have a proven pharmacological activity. 10