Pharmaceutical formulations comprising cineole and amoxicillin

Abstract

The present invention relates to a pharmaceutical formulation comprising amoxicillin, eucalyptol and a pharmaceutically acceptable oil in the form of a powder. The formulation of the present invention can further comprise clavulanic acid. The formulation is intended for oral administration, preferably after suspension in an aqueous solvent. The present invention also relates to a combination of eucalyptol and amoxicillin for use in the treatment of an infectious disease, preferably a bacterial infection, in an individual. The combination of the present invention can further comprise a beta-lactamase inhibitor, preferably clavulanic acid. The combination of the present invention can be particularly useful against infections caused by bacteria that are resistant to antibiotics, preferably to beta-lactam antibiotics.

Description

Technical Field

[0001] This invention relates to the medical field, and more specifically to the field of bacterial infections. The invention relates to novel treatments and pharmaceutical formulations, particularly suitable for medical or veterinary use, for combating bacterial infections, especially antibiotic-resistant infections. Background Technology

[0002] Antibiotics are natural or synthetic substances with bactericidal or bacteriostatic activity. Their widespread introduction after World War II was one of the most important therapeutic advances of the twentieth century. Antibiotic treatment has increased life expectancy by more than ten years, more than any other medical treatment. However, the widespread use, or even abuse, of certain antibiotics—including in preventative or curative treatments, as food supplements in animal feed, in fish farming, in veterinary and human medicine, or as pesticides for treating plants—has created selective pressures, leading to the emergence of antibiotic-resistant microbial populations and an overall reduction in therapeutic efficacy. In hospitals, this results in an increased risk of nosocomial infections, particularly due to the lack of suitable treatments for certain multidrug-resistant bacteria.

[0003] In its recent report (April 2014) on bacterial resistance to antibiotics, the WHO stated that "unless a large number of actors act urgently and in a coordinated manner, the world will move towards a post-antibiotic era, where common infections and minor injuries that we have been able to treat for decades may again become fatal." Resistance to certain "last resort" treatments has become a reality. Therefore, resistance to common intestinal bacteria—Klebsiella pneumoniae (…) Klebsiella pneumoniae Drug resistance to treatment of potentially fatal infections caused by *Escherichia coli* has spread to all parts of the world. E. coli The same applies to resistance to fluoroquinolones, one of the most widely used antibacterial drugs for treating urinary tract infections caused by gonorrhea. Recently, the failure of third-generation cephalosporins—the last resort treatment for gonorrhea—has been confirmed in South Africa, Australia, Austria, Canada, France, Japan, Norway, the United Kingdom, Serbia, and Sweden.

[0004] In response to this threat, the WHO is calling for the development of new diagnostic products, new antibiotics, and other necessary tools to enable healthcare professionals to stay ahead of the development of drug resistance.

[0005] Amoxicillin is an aminopenicillin-type bactericidal β-lactam antibiotic indicated for the treatment of bacterial infections caused by susceptible bacteria. Amoxicillin is one of the most commonly used antibiotics, especially in children, due to its good oral absorption, broad-spectrum antimicrobial activity, and low cost. Amoxicillin is used to treat a wide variety of infectious diseases, particularly those affecting the lungs, bronchi, nose, throat or ears, blood, digestive or urinary organs, reproductive tract, gums, and teeth.

[0006] Amoxicillin is often used in combination with another molecule—clavulanic acid, a β-lactamase inhibitor. β-lactamases are enzymes produced by bacteria resistant to β-lactam antibiotics. By inhibiting β-lactamases, clavulanic acid prevents amoxicillin from being inactivated by β-lactamases, thus allowing it to retain its activity against β-lactamase-producing resistant bacteria.

[0007] However, in recent years, we have witnessed the emergence of particularly resistant bacteria, especially broad-spectrum β-lactamase (BSBL) bacteria, that are no longer or only partially sensitive to conventional β-lactamase inhibitors such as clavulanic acid.

[0008] Therefore, it is necessary to find a solution to restore the efficacy of amoxicillin against drug-resistant bacteria, especially those that produce broad-spectrum β-lactamases (BSBLs). Summary of the Invention

[0009] The inventors discovered that eucalyptol can enhance the efficacy of amoxicillin, particularly against drug-resistant bacteria. Specifically, they demonstrated a synergistic effect between amoxicillin and eucalyptol, which significantly enhances the antibacterial activity of amoxicillin. Therefore, they developed a novel molecular combination comprising amoxicillin, eucalyptol, and optionally clavulanic acid for highly effective combat against drug-resistant bacteria, particularly those resistant to the combination of amoxicillin and clavulanic acid.

[0010] The inventors have also developed a pharmaceutical formulation that significantly enhances the antibacterial activity of amoxicillin, alone or in combination with clavulanic acid, particularly against bacteria resistant to the combination of amoxicillin and clavulanic acid.

[0011] Therefore, in a first aspect, the present invention relates to a pharmaceutical preparation in powder form comprising eucalyptol, amoxicillin and pharmaceutically acceptable oil or consisting essentially of eucalyptol, amoxicillin and pharmaceutically acceptable oil.

[0012] Preferably, the formulation conforming to the present invention further comprises a β-lactamase inhibitor, preferably clavulanic acid.

[0013] Preferably, the pharmaceutically acceptable oil in the formulation conforming to the present invention is a vegetable oil, mineral oil, synthetic oil or animal oil, preferably a vegetable oil, and more preferably peanut oil.

[0014] The formulations conforming to the present invention may contain eucalyptol at a concentration of about 5 mg to about 100 mg per gram of powder, preferably about 10 mg to about 50 mg per gram of powder, more preferably about 20 mg to about 40 mg per gram of powder, and most particularly preferably about 33 mg per gram of powder.

[0015] The formulations conforming to the present invention may also contain amoxicillin at a concentration of about 20 mg to about 500 mg per gram of powder, preferably about 50 mg to about 300 mg per gram of powder, more preferably about 150 mg to about 200 mg per gram of powder, and most particularly preferably about 167 mg per gram of powder.

[0016] The formulations conforming to the present invention may also contain oil between about 2 mg and about 50 mg per gram of powder, preferably between about 10 mg and about 25 mg per gram of powder, more preferably between about 15 mg and about 20 mg per gram of powder, and most particularly preferably between about 17 mg per gram of powder.

[0017] The formulation conforming to the present invention may ultimately contain a β-lactamase inhibitor, preferably clavulanic acid, at a concentration of about 1 mg to about 100 mg per gram of powder, preferably clavulanic acid, more preferably a β-lactamase inhibitor, preferably clavulanic acid, at a concentration of about 5 mg to about 50 mg per gram of powder, more preferably a β-lactamase inhibitor, preferably clavulanic acid, at a concentration of about 15 mg to about 25 mg per gram of powder, and most particularly preferably a β-lactamase inhibitor, preferably clavulanic acid, at a concentration of about 21 mg per gram of powder.

[0018] Specifically, formulations conforming to the present invention may contain eucalyptol, preferably about 10 mg to about 50 mg per gram of powder; and / or amoxicillin, preferably about 50 mg to about 300 mg per gram of powder; and / or oil, preferably about 10 mg to about 25 mg per gram of powder; and / or optionally a β-lactamase inhibitor, preferably clavulanic acid, preferably about 1 mg to about 100 mg per gram of powder, preferably about 5 mg to about 50 mg per gram of powder.

[0019] Preferably, the formulation conforming to the present invention comprises eucalyptol at a concentration of about 20 mg to about 40 mg per gram of powder, preferably about 33 mg; amoxicillin at a concentration of about 150 mg to about 200 mg per gram of powder, preferably about 167 mg; oil at a concentration of about 15 mg to about 20 mg per gram of powder, preferably about 17 mg; and / or optionally a β-lactamase inhibitor, preferably clavulanic acid, at a concentration of about 15 mg to about 25 mg per gram of powder, preferably about 21 mg.

[0020] The formulation conforming to the present invention may have an amoxicillin / eucalyptol mass ratio between 2 and 8, preferably between 3 and 7, more particularly preferably between 4 and 6, and most particularly preferably between about 5.

[0021] The formulations conforming to the present invention may have an amoxicillin / oil mass ratio between 5 and 15, preferably between 7 and 13, more particularly preferably between 8 and 12, and most particularly preferably between about 10.

[0022] The formulation conforming to the present invention may have a eucalyptol / oil mass ratio between 0.1 and 5, preferably between 0.5 and 4, more particularly preferably between 1 and 3, and most particularly preferably between about 2.

[0023] The formulations conforming to the present invention may have an amoxicillin / β-lactamase inhibitor mass ratio of 5 to 11, preferably 6 to 10, more particularly preferably 7 to 9, and most particularly preferably about 8.

[0024] Formulations conforming to the present invention may be intended for oral administration, preferably after suspension in an aqueous solvent.

[0025] The formulations conforming to the present invention can be packaged in single-dose containers, preferably containing between about 1 g and about 150 g of powder, more preferably between about 1 g and about 50 g of powder, even more preferably between about 1 g and about 10 g of powder, and most particularly preferably between about 3 g of powder.

[0026] The formulations conforming to the present invention may further comprise at least one pharmaceutically acceptable excipient or carrier, wherein the pharmaceutically acceptable excipient or carrier is preferably selected from sweeteners, flavoring agents, anti-caking agents, lubricants, disintegrants and mixtures thereof.

[0027] In a second aspect, the present invention relates to preparations as described above, which are used to treat infectious diseases in individuals, preferably animals or humans.

[0028] Preferably, the infectious disease is a bacterial infectious disease, more preferably an infectious disease caused by bacteria resistant to β-lactam antibiotics.

[0029] Preferably, the formulation is administered to the individual in one or more doses at a rate of 3 to 30 grams per day over a period of 1 day to 4 weeks, or is intended to be administered in this manner.

[0030] Thirdly, the present invention also relates to a method for manufacturing a pharmaceutical preparation conforming to the present invention, the method comprising: - By mixing eucalyptol with medicinal oil to produce a wetting solution; and - Wet the powder containing amoxicillin with the wetting solution to obtain a powdered formulation containing amoxicillin, eucalyptol and the oil.

[0031] Optionally, the method may further include mixing the powdered preparation comprising amoxicillin, eucalyptol, and the oil with a powder comprising a β-lactamase inhibitor, preferably clavulanic acid; and / or

[0032] - Add sweeteners, flavorings, and / or lubricants and mix them to obtain a uniform powder; and / or

[0033] - Sieving the powder obtained thereby; and / or

[0034] - The sieved powder is packaged in single-dose containers.

[0035] Preferably, the powder containing amoxicillin and / or the powder containing a β-lactamase inhibitor, preferably clavulanic acid, further contains a disintegrant and / or an anti-caking agent.

[0036] Fourthly, the present invention also relates to a molecular complex comprising more than two amoxicillin molecules arranged in a chain or ring and interacting with each other by non-covalent bonds.

[0037] Preferably, the molecular complex conforming to the present invention is formed of at least 3 amoxicillin molecules, more preferably 3 to 6 amoxicillin molecules, and most particularly preferably 4 amoxicillin molecules.

[0038] The molecular complex conforming to the present invention can be obtained by dissolving amoxicillin in an aqueous solvent in the presence of eucalyptol and in the absence of detergent.

[0039] Fifthly, the present invention also relates to a therapeutic combination comprising eucalyptol and amoxicillin, or substantially consisting of eucalyptol and amoxicillin, for the treatment of bacterial infections in an individual.

[0040] Preferably, the combination further comprises a β-lactamase inhibitor, preferably clavulanic acid.

[0041] Specifically, combinations conforming to the present invention can be combined formulations for simultaneous, separate, or sequential use of eucalyptol, amoxicillin, and optionally a β-lactamase inhibitor, preferably clavulanic acid.

[0042] Preferably, the bacterial infection is caused by bacteria that are resistant to antibiotics, preferably β-lactam antibiotics.

[0043] The individual being treated is an animal, preferably a mammal, and most particularly preferably a human.

[0044] In combinations conforming to the present invention - Eucalyptol can be administered to the individual at a dose between about 0.1 mg / kg body weight / day and about 50 mg / kg body weight / day, preferably between about 0.5 mg / kg body weight / day and about 20 mg / kg body weight / day, most particularly preferably between about 1 mg / kg body weight / day and about 10 mg / kg body weight / day, or is intended to be administered to the individual at said doses, and / or - Amoxicillin can be administered to the individual at a dose between about 5 mg / kg body weight / day and about 200 mg / kg body weight / day, preferably between about 10 mg / kg body weight / day and about 100 mg / kg body weight / day, most particularly preferably between about 15 mg / kg body weight / day and about 50 mg / kg body weight / day, or is intended to be administered to the individual at said doses, and / or - The β-lactamase inhibitor, preferably clavulanic acid, can be administered to the individual at a dose between about 0.1 mg / kg body weight / day and about 50 mg / kg body weight / day, preferably between about 0.5 mg / kg body weight / day and about 20 mg / kg body weight / day, most particularly preferably between about 1 mg / kg body weight / day and about 10 mg / kg body weight / day, or is intended to be administered to the individual at the doses mentioned above.

[0045] Preferably, the combination is administered to the individual at a frequency of only one or a few doses per day over a period of 1 day to 4 weeks, more preferably over a period of about 7 days, or is intended to be administered to the individual in this manner.

[0046] Preferably, the combination of eucalyptol, amoxicillin, and optionally the β-lactamase inhibitor, preferably clavulanic acid, is administered orally to the individual.

[0047] The combination of amoxicillin and a β-lactamase inhibitor can be administered simultaneously or is intended to be administered simultaneously to the individual, preferably from a pharmaceutical composition comprising amoxicillin and a β-lactamase inhibitor.

[0048] The combination of eucalyptol, amoxicillin, and optionally a β-lactamase inhibitor can be administered simultaneously or is intended to be administered simultaneously, preferably from a pharmaceutical composition comprising eucalyptol, amoxicillin, and optionally a β-lactamase inhibitor, or from a pharmaceutical composition comprising eucalyptol and a pharmaceutical composition comprising amoxicillin and optionally a β-lactamase inhibitor.

[0049] Preferably, eucalyptol is administered sequentially or separately from the amoxicillin and / or optionally from the β-lactamase inhibitor, preferably sequentially, or intended to be administered in this manner.

[0050] In a sixth aspect, the present invention also relates to a pharmaceutical composition comprising eucalyptol, amoxicillin, and a pharmaceutically acceptable excipient or carrier, and optionally a β-lactamase inhibitor, preferably clavulanic acid, or substantially composed of eucalyptol, amoxicillin, and a pharmaceutically acceptable excipient or carrier, and optionally a β-lactamase inhibitor, preferably clavulanic acid.

[0051] In a seventh aspect, the present invention also relates to a kit for treating bacterial infections in an individual, comprising: (a) A pharmaceutical composition comprising or substantially composed of eucalyptol, and a pharmaceutical composition comprising or substantially composed of amoxicillin; (b) A pharmaceutical composition comprising eucalyptol or consisting essentially of eucalyptol, and a pharmaceutical composition comprising amoxicillin and a β-lactamase inhibitor, preferably clavulanic acid, or consisting essentially of amoxicillin and a β-lactamase inhibitor, preferably clavulanic acid; (c) A pharmaceutical composition comprising amoxicillin or consisting essentially of amoxicillin, and a pharmaceutical composition comprising eucalyptol and a β-lactamase inhibitor, preferably clavulanic acid or consisting essentially of eucalyptol and a β-lactamase inhibitor, preferably clavulanic acid. (d) A pharmaceutical composition comprising a β-lactamase inhibitor, preferably clavulanic acid, or substantially composed of a β-lactamase inhibitor, preferably clavulanic acid, and a pharmaceutical composition comprising eucalyptol and amoxicillin, or substantially composed of eucalyptol and amoxicillin; or (e) A pharmaceutical composition comprising or substantially composed of eucalyptol, a pharmaceutical composition comprising or substantially composed of amoxicillin, and a pharmaceutical composition comprising a β-lactamase inhibitor, preferably clavulanic acid, or substantially composed of a β-lactamase inhibitor, preferably clavulanic acid; and (f) Optionally, it includes a guide on how to use the kit.

[0052] The present invention also relates to a kit or composition conforming to the present invention for treating bacterial infections in an individual, preferably bacterial infections caused by antibiotic-resistant bacteria.

[0053] Preferably, the bacterial infection is selected from cystitis, especially recurrent acute cystitis, bacterial sinusitis, especially acute maxillary sinusitis, otitis, especially acute otitis media, bronchitis, especially chronic and / or acute bronchitis, bronchopulmonary disease, especially chronic and / or acute bronchopulmonary disease, pyelonephritis, upper genital tract infection, periodontitis, severe oral infection, especially abscess, cellulitis and cellulitis, animal bites, bone and joint infection, especially osteomyelitis; preferably, the bacterial infection is cystitis, especially cystitis caused by bacteria resistant to β-lactam antibiotics. Attached Figure Description

[0054] Figure 1 Antibacterial activity of rabbit serum treated with a combination of amoxicillin, clavulanic acid, and eucalyptol was studied. A (AMC without eucalyptol): After oral administration of a single dose of the combination containing amoxicillin (1.5 g) and clavulanic acid (186.5 mg) to 3 rabbits, the antibacterial activity at times T0 and T1 was calculated. 1h T 2h T 3h and T 6h Serum against Escherichia coli ( Escherichia coli The inhibition percentage of BSBL multidrug-resistant strains was calculated. B (AMC containing eucalyptol): After oral administration of a single dose of a combination containing amoxicillin (1.5 g), clavulanic acid (186.5 mg), and eucalyptol (300 mg) to three rabbits, the inhibition percentages at times T0 and T1 were calculated. 1h T 2h T 3h and T 6h Serum against Escherichia coli ( Escherichia coli The inhibition percentage of BSBL multidrug resistant strains.

[0055] Figure 2 24-hour monitoring of mean serum concentrations of amoxicillin. A (without eucalyptol): Serum concentrations of amoxicillin were monitored for 24 hours in 12 healthy volunteers after oral administration of a single dose (12 g) of a combination containing amoxicillin (2 g) and clavulanic acid (250 mg). B (containing eucalyptol): Serum concentrations of amoxicillin were monitored for 24 hours in 12 healthy volunteers after oral administration of a single dose (12 g) of a combination containing amoxicillin (2 g), clavulanic acid (250 mg), and eucalyptol (400 mg).

[0056] Figure 3 7-day monitoring of mean plasma concentrations of amoxicillin. A (without eucalyptol): Following a single oral dose (12 g) of a combination containing amoxicillin (2 g) and clavulanic acid (250 mg), 12 volunteers received a maintenance dose (3 g) of the same combination containing amoxicillin (500 mg) and clavulanic acid (62.5 mg) three times daily for 7 days. Plasma concentrations of amoxicillin were monitored for 7 days in the 12 healthy volunteers. B (containing eucalyptol): Following a single oral dose (12 g) of a combination containing amoxicillin (2 g), clavulanic acid (250 mg), and eucalyptol (400 mg), 12 volunteers received a maintenance dose (3 g) of the same combination containing amoxicillin (500 mg), clavulanic acid (62.5 mg), and eucalyptol (100 mg) three times daily for 7 days. Plasma concentrations of amoxicillin were monitored for 7 days in the 12 healthy volunteers.

[0057] Figure 4 Spectroscopic studies of the formation of amoxicillin complexes. A (AMX only): Mass spectrometric analysis of amoxicillin alone in aqueous solution. B (AMX and eucalyptol): Mass spectrometric analysis of amoxicillin and eucalyptol in aqueous solution. Detailed Implementation

[0058] The inventors demonstrated that the combination of amoxicillin and eucalyptol achieves a synergistic effect, significantly enhancing the efficacy of amoxicillin, particularly against drug-resistant bacteria. Specifically, they observed that eucalyptol at subtherapeutic concentrations protects amoxicillin from the inhibitory effects of β-lactamases, enzymes produced by amoxicillin-resistant bacteria.

[0059] Therefore, the inventors have developed a new treatment combination containing amoxicillin, eucalyptol, and optionally clavulanic acid, for highly effective combat against drug-resistant bacteria, particularly those resistant to the combination of amoxicillin and clavulanic acid.

[0060] The inventors also developed a pharmaceutical formulation in powder form that combines eucalyptol, amoxicillin, and clavulanic acid. They observed that this combination significantly enhances the antibacterial activity of amoxicillin, thus effectively treating patients suffering from infections caused by drug-resistant bacteria.

[0061] This new formulation also exhibits excellent storage properties. Specifically, the use of oil in the formulation allows for highly efficient immobilization of eucalyptol, a highly volatile agent, onto a powdered carrier. This provides a single-drug formulation for the administration of the active compound, which, after suspension in an aqueous solvent, can be readily administered orally. The use of a single drug, and moreover, oral administration, significantly improves treatment adherence and, consequently, their efficacy.

[0062] The inventors also demonstrated that amoxicillin forms a complex of at least three amoxicillin molecules in the presence of eucalyptol. This complex formation makes amoxicillin molecules less accessible to β-lactamases, thus enhancing their therapeutic efficacy.

[0063] Therefore, according to a first aspect, the present invention relates to a pharmaceutical preparation in powder form comprising, or substantially composed of, eucalyptol, amoxicillin and pharmaceutically acceptable oil.

[0064] According to a second aspect, the present invention relates to a therapeutic combination comprising eucalyptol and amoxicillin for treating bacterial infections in an individual. The combination conforming to the invention may further comprise a β-lactamase inhibitor, preferably clavulanic acid. Specifically, the combination conforming to the invention may be an active ingredient used in the combination, preferably a combination preparation of eucalyptol, amoxicillin, and clavulanic acid used simultaneously, separately, or sequentially.

[0065] definition

[0066] In this document, the term "about" refers to a range of values ​​that is ± 10% of a specified value. For example, "about 50" includes values ​​of 50 ± 10%, i.e., values ​​in the range of 45 to 55. Preferably, the term "about" refers to a range of values ​​that is ± 5% of a specified value. It should be understood that values ​​following the term "about" should be considered as specifically described in this application.

[0067] When used herein, the term “consistently made of” means that a formulation conforming to the present invention does not contain any other active ingredient besides the active ingredient mentioned in the formulation, and in particular, no other antibiotics or β-lactamase inhibitors.

[0068] When used herein, the term "pharmaceutical excipient or carrier" refers to any substance present in a pharmaceutical preparation other than the active ingredient. Its addition is specifically intended to provide a particular consistency or other particular physical or flavor characteristic to the final product, while simultaneously avoiding any interaction with the active ingredient, particularly chemical interactions.

[0069] When used in this article, the term "active ingredient" refers to a molecule that has therapeutic effects. Specifically, eucalyptol, amoxicillin, and β-lactamase inhibitors are active ingredients.

[0070] When used herein, the term "therapeutic effect" refers to the effect caused by the active ingredient, the composition conforming to the invention, or the combination conforming to the invention, which is able to prevent or delay the occurrence of bacterial infection or cure or alleviate bacterial infection.

[0071] When used herein, the term "antibacterial effect" refers to the effect caused by an active ingredient, a composition conforming to the invention, or a combination conforming to the invention, which is able to reduce the amount and / or concentration of bacteria causing said bacterial infection in an individual.

[0072] When used herein, the term "synergistic effect" refers to a therapeutic and / or antibacterial effect of a composition or combination conforming to the present invention that is greater than the sum of the therapeutic and / or antibacterial effects of all active ingredients present in the composition or combination when used alone. The presence of such an effect can be assessed by calculating the fractional inhibition concentration index (fic index), as shown in Example 1.

[0073] When used herein, the term "treatment" refers to any action aimed at improving the medical condition of a person suffering from a bacterial infection. Treatment may be aimed at improving the patient's condition, i.e., the resolution of the infection or some of its symptoms, or at eradicating the infection or some of its symptoms. Treatment may also have the effect of stopping or slowing the development of the bacterial infection. Treatment may also have a preventative or preventative effect, i.e., preventing or delaying the onset of the bacterial infection.

[0074] When used in this document, the terms “amount” and “dosage” are equivalent and can be used interchangeably.

[0075] When used herein, the term "therapeutic effective amount" means an amount of active ingredient in a composition or combination thereof conforming to the invention that is sufficient to cause a therapeutic effect. Alternatively, the term "therapeutic effective amount" may mean an amount of active ingredient in a composition or combination thereof conforming to the invention that is sufficient to cause an antibacterial effect. Clearly, the amount to be administered can be adjusted by those skilled in the art based on the individual to be treated, the nature of the bacterial infection, etc. Specifically, the dosage and administration regimen depend on the nature, stage, and severity of the bacterial infection to be treated, as well as the individual's weight, age, and overall health status, or on the judgment of the prescribing physician.

[0076] When used herein, the term "subtherapeutic dose" refers to an amount of active ingredient that is insufficient to cause a therapeutic effect on its own. Alternatively, the term "subtherapeutic dose" may refer to an amount of active ingredient that is insufficient to cause an antibacterial effect on its own.

[0077] When used herein, the terms “therapeutic combination” and “combination preparation” refer to a combination of active ingredients, preferably eucalyptol, amoxicillin and optionally declavulanic acid, which may be formulated separately or as one or more formulations for simultaneous, separate or sequential administration, or a combination of these administration methods when the combination contains more than two active ingredients.

[0078] When used herein, the term "simultaneously" refers to a combination conforming to the present invention, wherein the active ingredients of the combination are used or administered simultaneously, i.e. at the same time.

[0079] When used herein, the term "sequential" refers to a combination conforming to the invention, wherein the active ingredients of the combination are used or administered sequentially, i.e., one after another. Preferably, when the administration is sequential, all active ingredients are administered within time intervals not exceeding about 1 hour, preferably not exceeding about 10 minutes, and more preferably not exceeding about 1 minute.

[0080] When used herein, the term "separately" refers to a combination conforming to the invention, wherein the active ingredient of the combination is used or administered at separate times throughout the day. Preferably, when the administration is separate, the active ingredient is administered at intervals of about 1 hour to about 15 hours, preferably about 1 hour to about 8 hours, and more preferably about 1 hour to about 5 hours.

[0081] Eucalyptus oil

[0082] When used herein, the terms “eucalyptol,” “eucalyptol,” or “1,8-eucalyptol” refer to a cyclic ether (CAS No.: 470-82-6) belonging to the monoterpenoid class, i.e., terpenoid compounds containing 10 carbon atoms. Eucalyptol is a natural, colorless organic compound, which can be obtained, in particular, from certain eucalyptus trees (e.g., Eucalyptus polybractea). Eucalyptus polybractea Essential oils of rosemary (e.g.) Rosmarinus officinalis Artemisia species (e.g., Artemisia argyi) Artemisia vulgaris Extracted from wormwood, laurel, sage, basil, and camphor leaves ( Cinnamomum camphora Eucalyptol is an essential oil extract. Eucalyptol can be used in any pharmaceutically acceptable form. When used herein, the term "pharmaceutical acceptable" refers to a molecule, compound, or composition suitable for pharmaceutical administration. It is preferably used in purified form. In its purified form, eucalyptol is a liquid.

[0083] Amoxicillin

[0084] Amoxicillin (CAS No.: 26787-78-0) is an aminopenicillin-type β-lactam antibiotic that is now indicated for the treatment of bacterial infections caused by susceptible bacteria. β-lactams are a broad class of antibiotics, including penicillin derivatives, cephalosporins, monocyclic lactams, and carbapenems. β-lactams are characterized by the presence of a β-lactam nucleus in their molecular structure, which provides them with antibacterial activity.

[0085] In formulations or combinations conforming to the present invention, amoxicillin can take any pharmaceutically acceptable form. Therefore, amoxicillin can take the form of a pharmaceutically acceptable salt, particularly a sodium or potassium salt, anhydrous or hydrated form, preferably a trihydrate form, or a mixture of these forms. In a preferred embodiment, the formulation or combination conforming to the present invention comprises amoxicillin trihydrate.

[0086] Medicinal oil

[0087] Pharmaceutical formulations conforming to the present invention also comprise pharmaceutically acceptable oils. When used herein, the term "oil" refers to a phase consisting of a fatty substance that is liquid at room temperature and immiscible with water.

[0088] The oil used in formulations conforming to this invention can be any pharmaceutically acceptable oil, i.e., an oil whose toxicological data are compatible with oral administration to an individual. The oil is preferably selected from animal oils, mineral oils, vegetable oils, and synthetic oils and mixtures thereof.

[0089] Preferably, the oil used in the combination is not an essential oil. When used herein, the term "essential oil" refers to a concentrated, hydrophobic liquid of volatile aromatic (odor-emitting) compounds from a plant. Essential oils can be obtained by mechanical extraction, by cold pressing, using volatile solvents, using supercritical CO2, by steam entrainment, or by dry distillation.

[0090] The oil can be used in formulations conforming to the present invention due to its adsorbent properties. When used herein, the term "adsorbent" refers to an excipient in pharmaceutical formulations capable of immobilizing liquid molecules, such as eucalyptol molecules, onto a solid carrier, such as a powdered carrier.

[0091] In certain embodiments, the formulations conforming to the present invention comprise mineral oil. The mineral oil is obtained by distillation of coal, petroleum, or certain bituminous rocks. Specifically, the mineral oil comprises hydrocarbons, alkanes, and paraffin wax. More specifically, the mineral oil may be selected from refined paraffin wax, microcrystalline wax, ceresin wax, pure white ceresin wax, petrolatum, and mixtures thereof.

[0092] In another specific embodiment, the formulation conforming to the present invention comprises a synthetic oil. Specifically, the synthetic oil may be selected from silicone oils, synthetic waxes, synthetic monoglycerides, diesters, and triglycerides such as caprylic and caprylic triglycerides and mixtures thereof.

[0093] In yet another specific embodiment, the formulation conforming to the present invention comprises animal oil. Such animal oil may be selected from, for example, mink oil, sperm whale oil, whale oil, seal oil, emu oil, cow's foot oil, fish oil, especially anchovy oil, sardine oil, capelin oil, herring oil, salmon oil, shad oil, cod oil, blue cod oil, pilkendron oil, tuna oil, shark oil, and mixtures thereof.

[0094] In a preferred embodiment, the formulation conforming to the present invention comprises vegetable oil. Examples of vegetable oils that may be used include, but are not limited to, wheat germ oil, corn oil, sunflower oil, shea butter, castor oil, sweet almond oil, macadamia nut oil, almond oil, soybean oil, cottonseed oil, alfalfa oil, poppy seed oil, pumpkin seed oil, sesame oil, zucchini seed oil, avocado oil, hazelnut oil, grapeseed oil, blackcurrant seed oil, evening primrose oil, millet oil, barley oil, quinoa oil, olive oil, peanut oil, rye oil, safflower oil, candelilla oil, passion fruit oil, musk rose oil, coconut oil, argan oil, rapeseed oil, coconut kernel oil, flaxseed oil, walnut oil, cashew oil, neem oil, pistachio oil, rice bran oil, shepherd's purse seed oil, sacha inchi oil, borage oil, hemp oil, pea oil, jojoba oil, neem oil, black fennel oil, perilla seed oil, and mixtures thereof.

[0095] In the most particularly preferred embodiment, the pharmaceutically acceptable oil included in the formulation conforming to the present invention is peanut oil.

[0096] β-lactamase inhibitors

[0097] Pharmaceutical formulations conforming to the present invention may also contain one or more β-lactamase inhibitors. These inhibitors can block the activity of β-lactamases in a variety of different ways, such as by irreversibly binding to these enzymes and acting as suicide substrates, as is particularly the case with clavulanic acid and sulbactam.

[0098] The β-lactamase inhibitor can be any pharmaceutically acceptable β-lactamase inhibitor. This inhibitor is preferably selected from clavulanic acid, sulbactam, tazobactam, aztreonam, avibactam, their pharmaceutically acceptable salts, and mixtures thereof.

[0099] In a preferred embodiment, the formulation conforming to the present invention comprises clavulanic acid. Clavulanic acid (CAS No.: 58001-44-8) is typically used in combination with β-lactam antibiotics, particularly amoxicillin.

[0100] In formulations conforming to the present invention, clavulanic acid may be in any pharmaceutically acceptable form, preferably in the form of a pharmaceutically acceptable salt, particularly in the form of a potassium salt of clavulanic acid.

[0101] pharmaceutical preparations

[0102] According to a first aspect, the present invention relates to a pharmaceutical preparation in powder form comprising, or substantially composed of, eucalyptol, amoxicillin and pharmaceutically acceptable oil.

[0103] When used in this document, the term "powder" refers to the separated state of a substance; it is a solid state that takes the form of small particles.

[0104] Preferably, the powder particles have a diameter of less than or equal to about 5 mm, more preferably less than or equal to about 2.5 mm, and most particularly preferably less than or equal to about 1.25 mm.

[0105] The powder of the pharmaceutical preparation conforming to the present invention is preferably a dry powder. When used herein, the term "dry powder" means a powder with a moisture content of less than or equal to 20%, preferably less than or equal to 15%, and more preferably less than or equal to 10%.

[0106] Pharmaceutical formulations conforming to the present invention preferably meet the requirements of the European Pharmacopoeia (8th edition), particularly in terms of impurities and / or microbiological quality.

[0107] Specifically, the bacterial content in the powder of the pharmaceutical formulation conforming to the present invention is preferably less than 10,000 CFU (colony-forming units) per gram of powder, preferably less than 1,000 CFU per gram of powder, and most particularly preferably less than 100 CFU per gram of powder. Preferably, the powder of the pharmaceutical formulation conforming to the present invention does not contain any Escherichia coli (E. coli). Escherichia coli For other pathogens, the content of fungi and yeasts is preferably less than 1000 CFU per gram of powder, preferably less than 100 CFU per gram of powder, and most particularly preferably less than 50 CFU per gram of powder.

[0108] The pharmaceutical preparations conforming to the present invention comprise, or are substantially composed of, as defined above, eucalyptol, amoxicillin and pharmaceutically acceptable oil.

[0109] Preferably, amoxicillin and eucalyptol are present in the formulation conforming to the invention at concentrations sufficient to achieve therapeutic and / or antibacterial effects, preferably with a synergistic effect, as shown in the examples below. To obtain this effect, amoxicillin and eucalyptol may be administered at therapeutically effective or subtherapeutic amounts.

[0110] In a preferred embodiment, both eucalyptol and amoxicillin are administered in therapeutically effective amounts.

[0111] According to another preferred embodiment, amoxicillin is administered in a therapeutically effective amount, and eucalyptol is administered in a subtherapeutic amount.

[0112] In yet another preferred embodiment, amoxicillin is administered at a subtherapeutic dose, and eucalyptol is administered at a therapeutically effective dose.

[0113] In yet another preferred embodiment, both amoxicillin and eucalyptol are administered at subtherapeutic doses.

[0114] Preferably, the oil is present in the formulation conforming to the present invention at a concentration sufficient to allow eucalyptol to be adsorbed onto the powder of the formulation.

[0115] According to one embodiment, a pharmaceutical formulation conforming to the present invention comprises or is substantially composed of the following components: eucalyptol, preferably between about 5 mg and about 100 mg, more preferably between about 10 mg and about 50 mg, more preferably between about 20 mg and about 40 mg per gram of powder; and / or amoxicillin, preferably between about 50 mg and about 300 mg, more preferably between about 150 mg and about 200 mg per gram of powder; and / or oil, preferably between about 2 mg and about 50 mg, preferably between about 10 mg and about 25 mg, more preferably between about 15 mg and about 20 mg per gram of powder.

[0116] Preferably, the pharmaceutical formulation conforming to the present invention comprises or substantially consists of eucalyptol between about 5 mg and about 100 mg per gram of powder, amoxicillin between about 20 mg and about 500 mg per gram, and oil between about 2 mg and about 50 mg per gram.

[0117] In a more preferred embodiment, the pharmaceutical formulation conforming to the present invention comprises or substantially consists of eucalyptol at a concentration of about 10 mg to about 50 mg per gram of powder, amoxicillin at a concentration of about 50 mg to about 300 mg per gram, and oil at a concentration of about 10 mg to about 25 mg per gram.

[0118] Most particularly preferably, the pharmaceutical preparation conforming to the present invention comprises or is substantially composed of the following components: eucalyptol at a concentration of about 20 mg to about 40 mg per gram of powder, preferably about 33 mg; amoxicillin at a concentration of about 150 mg to about 200 mg per gram of powder, preferably about 167 mg; and oil at a concentration of about 15 mg to about 20 mg per gram of powder, preferably about 17 mg.

[0119] In a preferred embodiment, the pharmaceutical preparation conforming to the present invention comprises, or is substantially composed of, eucalyptol, amoxicillin, pharmaceutical oil and β-lactamase inhibitor as defined above.

[0120] Preferably, the β-lactamase inhibitor is selected from clavulanic acid, sulbactam, tazobactam, and aztreonam. More preferably, the β-lactamase inhibitor is clavulanic acid.

[0121] Therefore, pharmaceutical formulations conforming to the present invention may comprise eucalyptol, amoxicillin and pharmaceutically acceptable oil in proportions as described above, and a β-lactamase inhibitor present at a concentration sufficient to allow administration at a therapeutically effective or subtherapeutic level, or substantially composed of the above-described components.

[0122] According to one embodiment, the pharmaceutical preparation conforming to the present invention comprises or is substantially composed of the following components: eucalyptol, amoxicillin and pharmaceutically acceptable oil in proportions as described above, and a β-lactamase inhibitor, preferably clavulanic acid, at a concentration of about 1 mg to about 100 mg per gram of powder, preferably about 5 mg to about 50 mg, more preferably about 15 mg to about 25 mg, and most particularly preferably about 20.8 mg per gram of powder.

[0123] In another specific embodiment, the pharmaceutical preparation conforming to the present invention comprises or is substantially composed of the following components: eucalyptol, amoxicillin, and pharmaceutically acceptable oil, wherein the proportion of eucalyptol is between about 0.02 mg and about 0.5 mg per gram of amoxicillin, preferably between about 0.1 mg and about 0.3 mg per gram of amoxicillin, and more preferably equal to about 0.2 mg of eucalyptol per gram of amoxicillin; and / or the proportion of oil is between about 0.01 mg and about 0.5 mg per gram of amoxicillin, preferably between about 0.05 mg and about 0.2 mg per gram of amoxicillin, and more preferably equal to about 0.1 mg of oil per gram of amoxicillin. Preferably, the pharmaceutical formulation conforming to the present invention further comprises a β-lactamase inhibitor, preferably clavulanic acid, wherein the proportion of the β-lactamase inhibitor is between about 0.01 mg and about 0.5 mg per gram of amoxicillin, preferably between 0.1 mg and about 0.2 mg per gram of amoxicillin, and more preferably the proportion of the β-lactamase inhibitor is equal to about 0.125 mg per gram of amoxicillin.

[0124] In a particular embodiment, the amoxicillin / eucalyptol mass ratio is between 2 and 8, preferably between 3 and 7, and more particularly preferably between 4 and 6. In a preferred embodiment, the amoxicillin / eucalyptol mass ratio is approximately 5.

[0125] In a particular embodiment, the mass ratio of amoxicillin to the β-lactamase inhibitor, preferably clavulanic acid, is between 5 and 11, more preferably between 6 and 10, and even more particularly preferably between 7 and 9. In a preferred embodiment, the mass ratio of amoxicillin to the β-lactamase inhibitor, preferably clavulanic acid, is about 8.

[0126] In a particular embodiment, the amoxicillin / oil mass ratio is between 5 and 15, preferably between 7 and 13, and more particularly preferably between 8 and 12. In a preferred embodiment, the amoxicillin / eucalyptol mass ratio is approximately 10.

[0127] In a particular embodiment, the mass ratio of eucalyptol to oil is between 0.1 and 5, preferably between 0.5 and 4, and more particularly preferably between 1 and 3. In a preferred embodiment, the mass ratio of eucalyptol to oil is approximately 2.

[0128] Pharmaceutical formulations conforming to the present invention may also contain at least one other active ingredient.

[0129] Therefore, in certain embodiments, the pharmaceutical formulations conforming to the present invention comprise or are substantially composed of the following components: eucalyptol as defined above, amoxicillin, pharmaceutically acceptable oil, optionally a β-lactamase inhibitor, preferably clavulanic acid, and another active ingredient. Preferably, the additional active ingredient of the formulations conforming to the present invention is another antibiotic, particularly a β-lactam antibiotic, and / or another β-lactamase inhibitor, and / or an antifungal agent and / or an antiparasitic agent and / or an analgesic.

[0130] Pharmaceutical formulations conforming to the present invention may contain the aforementioned components or consist substantially of the following components: eucalyptol, amoxicillin, pharmaceutically acceptable oil and optionally a β-lactamase inhibitor, preferably clavulanic acid, in amounts as described above, and another active ingredient present at a concentration sufficient to allow administration at a therapeutically effective or subtherapeutic level.

[0131] excipient

[0132] In addition to the pharmaceutically usable oil, pharmaceutical preparations conforming to the present invention may also contain at least one pharmaceutically usable excipient or carrier.

[0133] The pharmaceutically acceptable excipient or carrier of the formulation conforming to the present invention is preferably selected from sweeteners, flavoring agents, anti-caking agents, lubricants, disintegrants and mixtures thereof.

[0134] Therefore, in certain embodiments, the pharmaceutical formulation conforming to the present invention further comprises at least one disintegrant.

[0135] When used herein, the term "disintegrant" refers to an excipient that improves the disintegration of molecules present in the pharmaceutical preparation, i.e., their separation in a liquid medium, preferably an aqueous medium, and their uniform suspension.

[0136] Preferably, the disintegrant is selected from microcrystalline cellulose, cross-linked carboxymethyl starch, cross-linked polyvinylpyrrolidone, and cross-linked carboxymethyl cellulose.

[0137] When used in this document, the terms “crosslinked carboxymethyl cellulose” and “crosslinked carboxymethyl cellulose” are equivalent and can be used interchangeably.

[0138] In another preferred embodiment, the pharmaceutical formulation conforming to the present invention comprises a disintegrant of about 10 mg to about 1000 mg per gram of powder, preferably about 100 mg to about 600 mg, more preferably about 450 mg to about 550 mg, for example about 513.7 mg.

[0139] Specifically, the formulation may comprise microcrystalline cellulose, preferably in the form of a powder consisting of particles with a diameter of about 20 to about 200 µm, more preferably about 50 to about 100 µm. Specifically, the microcrystalline cellulose is selected from microcrystalline cellulose of the Avicel®, Emcocel®, and Vitacel® types, or mixtures thereof; preferably, the microcrystalline cellulose is selected from microcrystalline celluloses Avicel PH 101, 102, 103, 104, 112, 113, 301, and 302, and most particularly preferably, the microcrystalline cellulose is of the Avicel PH 112 type.

[0140] Therefore, in a particular embodiment, the pharmaceutical formulation conforming to the present invention comprises microcrystalline cellulose at a concentration of about 100 mg to about 800 mg per gram of powder, preferably about 300 mg to about 500 mg, more preferably about 400 mg to about 420 mg, for example about 413.7 mg.

[0141] Optionally, the formulation may comprise cross-linked carboxymethyl cellulose. Specifically, the cross-linked carboxymethyl cellulose may be in the form of a powder composed of particles with an average diameter of less than 36 μm. Preferably, the cross-linked carboxymethyl cellulose is sodium cross-linked carboxymethyl cellulose.

[0142] In another specific embodiment, the pharmaceutical formulation conforming to the present invention comprises about 10 mg to about 250 mg per gram of powder, preferably about 50 mg to about 150 mg, more preferably about 80 mg to 120 mg, for example about 100 mg.

[0143] According to a particularly preferred embodiment, the pharmaceutical formulation conforming to the present invention comprises microcrystalline cellulose and cross-linked carboxymethyl cellulose as defined above. Therefore, the pharmaceutical formulation conforming to the present invention may comprise microcrystalline cellulose at a concentration of about 100 mg to about 800 mg per gram of powder, preferably about 300 mg to about 500 mg, more preferably about 400 mg to about 420 mg, for example about 413.7 mg; and / or cross-linked carboxymethyl cellulose at a concentration of about 10 mg to about 250 mg per gram of powder, preferably about 50 mg to about 150 mg, more preferably about 80 mg to 120 mg, for example about 100 mg.

[0144] Pharmaceutical formulations conforming to the present invention may also contain at least one excipient of the anti-caking type.

[0145] When used herein, the term "anti-caking agent" refers to an excipient that restricts the adhesion of particles in a powder product and thus ensures its flowability.

[0146] Preferably, the anti-caking agent is selected from talc, silicon dioxide and its derivatives, sodium carbonate, ammonium carbonate, ammonium bicarbonate, magnesium carbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide or mixtures thereof.

[0147] More preferably, the anti-caking agent is selected from silicon dioxide and its derivatives, particularly silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate, sodium aluminosilicate, potassium aluminosilicate, calcium aluminosilicate, zinc silicate, aluminum silicate, or mixtures thereof.

[0148] Most particularly preferably, the anti-caking agent is silica, preferably amorphous synthetic silica, especially Syloid® Al-1 FP.

[0149] In a preferred embodiment, the pharmaceutical preparation conforming to the present invention comprises an anti-caking agent, preferably silica, at a concentration of about 20 mg to about 500 mg per gram of powder, preferably about 50 mg to about 300 mg, more preferably about 150 mg to about 200 mg, for example about 180 mg.

[0150] Pharmaceutical formulations conforming to the present invention may also contain at least one excipient of the lubricant type.

[0151] When used herein, the term "lubricant" refers to an excipient intended to facilitate the process of manufacturing the powder, particularly by utilizing its flow-aiding, non-sticky, and anti-friction effects.

[0152] Preferably, the lubricant is selected from magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, zinc stearate, sodium stearyl fumarate, propylene glycol, glyceryl monostearate, or mixtures thereof. More preferably, the lubricant is magnesium stearate.

[0153] According to a preferred embodiment, the pharmaceutical preparation conforming to the present invention comprises a lubricant, preferably magnesium stearate, per gram of powder, between about 1 mg and about 40 mg, preferably between about 2 mg and about 15 mg, more preferably between about 4 mg and about 10 mg, for example about 6 mg.

[0154] Pharmaceutical formulations conforming to the present invention may also contain at least one excipient of the sweetener type.

[0155] When used in this document, the term "sweetener" refers to an excipient designed to alter the flavor of a pharmaceutical preparation by providing sweetness.

[0156] Preferably, the sweetener is selected from acesulfame potassium (E950), alitane (E956), aspartame (E951), cyclohexylsulfamic acid salt (E952), neotame, saccharin (E954), aspartame-acesulfame potassium salt (E962), sucralose, kiwifruit protein, polyols, brazzein, curculigo protein, glycyrrhizin, hydrogenated starch hydrolysate, areca nut protein, miracle fruit protein, indigo nut protein, pentadine, steviol glycosides, tagatose, trehalose, isomaltulose, erythritol, and mixtures thereof. Particularly preferably, the sweetener is aspartame.

[0157] According to a preferred embodiment, the pharmaceutical preparation of the present invention comprises a sweetener comprising between about 1 mg and about 60 mg per gram of powder, preferably between about 3 mg and about 20 mg, and more preferably, the pharmaceutical preparation of the present invention comprises a sweetener comprising between about 8 mg and about 15 mg per gram of powder, for example about 12 mg, preferably aspartame.

[0158] Pharmaceutical formulations conforming to the present invention may also contain at least one type of excipient of the flavoring agent type.

[0159] When used herein, the term "flavoring agent" refers to an excipient intended to alter the taste of a pharmaceutical preparation by providing flavor.

[0160] Preferably, the flavoring agent is selected from strawberry, raspberry, cherry, banana, lemon, orange, peach, apple, caramel flavoring agent, or a mixture thereof. More preferably, the flavoring agent is a mixture of lemon, strawberry, and peach flavoring agents.

[0161] According to a preferred embodiment, the pharmaceutical preparation conforming to the present invention comprises a flavoring agent of about 1 mg to about 100 mg per gram of powder, preferably about 10 mg to about 50 mg, more preferably about 20 mg to about 40 mg, for example about 30 mg.

[0162] To prevent the risk of microbial contamination, pharmaceutical formulations conforming to the present invention may also contain preservatives.

[0163] Preservatives that can be used in formulations conforming to the present invention include, but are not limited to, benzoic acid and its sodium or potassium salts, such as sodium benzoate; parabens, such as methylparaben, propylparaben, or butylparaben; sorbic acid and its sodium or potassium salts, such as potassium sorbate; quaternary ammonium salts, such as benzalkonium chloride; mercury derivatives, such as phenylmercuric salts (acetate, borate, or nitrate) or thimerosal, and combinations thereof.

[0164] Pharmaceutical formulations conforming to the present invention may also contain excipients of the pH buffer type, such as various acids and their salts, such as citric acid, sodium citrate and succinic acid.

[0165] The formulation may also contain coloring agents to enhance its acceptability, particularly among children. Preferably, the coloring agents are used to enhance the credibility of the flavor (e.g., pink coloring agents for strawberry flavor).

[0166] In a particularly preferred embodiment, the pharmaceutical formulation conforming to the present invention does not contain any detergents. When used herein, the term "detergent" (or "surfactant") refers to an amphiphilic molecule having surfactant properties. Detergents commonly used in pharmaceutical formulations are, for example, ionic detergents such as sodium dodecyl sulfate (SDS), deoxycholates and cholates, nonionic detergents such as Triton X-100, n-dodecyl β-D-maltopyranoside (DDM), digitalis saponins, Tween 20 and Tween 80, and amphoteric detergents such as 3-[(3-cholamidopropyl)dimethylammonium]-1-propanesulfonic acid (CHAPS) or 3-[dimethylammonium]-1-propanesulfonic acid.

[0167] In another preferred embodiment, the pharmaceutical formulation conforming to the invention is in powder form, comprising or consisting of or substantially consisting of the following components as defined above: eucalyptol, amoxicillin, pharmaceutically acceptable oil, and at least one sweetener, flavoring agent, anti-caking agent, lubricant and / or disintegrant, and optionally a β-lactamase inhibitor as defined above, preferably clavulanic acid.

[0168] Preferably, the pharmaceutical formulation conforming to the present invention is in powder form and comprises or consists of or substantially consists of the following components: eucalyptol, amoxicillin and oil in the proportions described above, and a sweetener, preferably aspartame, between about 1 mg and about 60 mg per gram of powder, and / or a flavoring agent, between about 1 mg and about 60 mg, and / or an anti-caking agent, preferably silica, between about 20 mg and about 500 mg, and / or a lubricant, preferably magnesium stearate, between about 1 mg and about 40 mg, and / or a disintegrant, preferably a mixture of microcrystalline cellulose and cross-linked carboxymethyl cellulose, and optionally a β-lactamase inhibitor, preferably clavulanic acid, in the proportions described above.

[0169] More preferably, the pharmaceutical formulation conforming to the present invention is in powder form and comprises or consists of or substantially consists of the following components: eucalyptol, amoxicillin and oil in the proportions described above, and a sweetener, preferably aspartame, between about 3 mg and about 20 mg per gram of powder, and / or a flavoring agent, between about 10 mg and about 50 mg, and / or an anti-caking agent, preferably silica, between about 50 mg and about 300 mg, and / or a lubricant, preferably magnesium stearate, between about 2 mg and about 15 mg, and / or a disintegrant, preferably a mixture of microcrystalline cellulose and cross-linked carboxymethyl cellulose, and optionally a β-lactamase inhibitor, preferably clavulanic acid, in the proportions described above.

[0170] Most particularly preferably, the pharmaceutical formulation conforming to the present invention is in powder form, comprising or consisting of or substantially consisting of the following components: eucalyptol, amoxicillin and oil in the proportions described above, and a sweetener, preferably aspartame, between about 8 mg and about 15 mg per gram of powder, for example about 12 mg, and / or a flavoring agent, between about 20 mg and about 40 mg per gram of powder, for example about 30 mg, and / or an anti-caking agent, preferably silica, between about 150 mg and about 200 mg per gram of powder, for example about 180 mg, and / or a lubricant, preferably magnesium stearate, between about 4 mg and about 8 mg per gram of powder, for example about 6 mg, and / or a disintegrant, such as about 513.7 mg between about 450 mg and about 550 mg per gram of powder, for example about 100 mg of cross-linked carboxymethyl cellulose and about 413.7 mg of microcrystalline cellulose, and optionally a β-lactamase inhibitor, preferably clavulanic acid, in the proportions described above.

[0171] Packaging, stability and route of administration of formulations conforming to the present invention

[0172] The inventors have demonstrated that the pharmaceutical formulations conforming to this invention are particularly stable. The stability of the product is characterized by the fact that, under various environmental factors, particularly temperature and humidity, the amount of the product remains constant over a given time interval (ICH standard). No change can be observed in the final percentages of amoxicillin, eucalyptol, and optionally declavulanic acid, with the change in percentage relative to the initial value preferably not exceeding 5%.

[0173] Therefore, in a particular embodiment, the pharmaceutical preparation conforming to the present invention is stable for at least 18 months, preferably at least 24 months, and more preferably at least 36 months at a temperature of about 25°C and a relative humidity of at least about 60%.

[0174] In another specific embodiment, the pharmaceutical formulation conforming to the present invention is stable for at least 6 months, preferably at least 12 months, and more preferably at least 24 months at a temperature of about 30°C and a relative humidity of at least about 65%.

[0175] In yet another specific embodiment, the pharmaceutical preparation conforming to the invention is stable for at least 3 months, preferably at least 6 months, and more preferably at least 12 months at a temperature of about 40°C and a relative humidity of at least about 75%.

[0176] Artificial climate chambers, as is known to those skilled in the art, can subject pharmaceutical formulations conforming to the present invention to the temperature and relative humidity conditions mentioned above.

[0177] When used herein, the term “relative humidity” refers to the ratio of the partial pressure of water vapor in the air to the saturated vapor pressure (or vapor tension) at the same temperature.

[0178] The pharmaceutical formulations conforming to this invention are intended for oral administration.

[0179] Preferably, the pharmaceutical preparation is administered after being suspended in an aqueous solvent and subsequently mixed; preferably, the aqueous solvent is water. Particularly preferably, the pharmaceutical preparation is temporarily dissolved. Pharmaceutical preparations conforming to the present invention, after being suspended in an aqueous medium, are stable for at least 48 hours, preferably at least 72 hours, and more preferably at least 96 hours at a temperature of about 20°C and a relative humidity of about 15%.

[0180] After being suspended in an aqueous solvent, preferably water, the pharmaceutical formulation of the present invention can form a solution with a slightly acidic pH. Preferably, the pH of the solution formed by suspending the pharmaceutical formulation of the present invention in an aqueous solvent is between about 5 and about 7.

[0181] Pharmaceutical formulations conforming to the present invention can be packaged in single-dose or multi-dose containers, preferably in single-dose containers.

[0182] In a preferred embodiment, the pharmaceutical preparation conforming to the present invention is packaged in a single-dose container containing between about 1 g and about 150 g of powder, more preferably between about 1 g and about 50 g of powder, even more preferably between about 1 g and about 10 g of powder, and even more particularly preferably about 3 g of powder.

[0183] When the pharmaceutical preparation is packaged in a single-dose container, the single-dose container can be further packaged in a box. The box may contain, for example, between 3 and 31 single-dose containers, preferably between 5 and 21 single-dose containers, and more preferably between 7 and 14 single-dose containers.

[0184] In another embodiment, the pharmaceutical solution conforming to the invention is packaged in a multi-dose container. The container may contain, for example, between about 10 grams and about 500 grams of powder, preferably between about 20 grams and about 200 grams of powder, more preferably between about 30 grams and about 100 grams of powder, and most particularly preferably about 50 grams of powder.

[0185] When the pharmaceutical preparation is packaged in a multi-dose container, the container may be repackaged in a box and optionally accompanied by a measuring device, such as a medicine spoon, for dispensing a predetermined amount of powder, preferably about 1 mg to about 30 mg of powder, more preferably about 2 mg to about 20 mg of powder, and even more preferably about 3 mg to about 12 mg of powder. Specifically, the measuring device may dispense about 3 g, about 6 g, about 9 g, about 12 g, about 15 g, and / or about 18 g of powder.

[0186] The combination of eucalyptol and amoxicillin

[0187] In a second aspect, the present invention also relates to a composition comprising eucalyptol and amoxicillin, or substantially composed of eucalyptol and amoxicillin, for the treatment of bacterial infections in an individual.

[0188] Preferably, in combinations conforming to the present invention, amoxicillin and eucalyptol are administered at doses capable of achieving therapeutic and / or antibacterial effects, preferably synergistically, as shown in the examples below. To obtain this effect, amoxicillin and / or eucalyptol may be administered at therapeutically effective or subtherapeutic doses.

[0189] In a preferred embodiment, both eucalyptol and amoxicillin are administered in therapeutically effective amounts.

[0190] In another preferred embodiment, amoxicillin is administered in a therapeutically effective amount, and eucalyptol is administered in a subtherapeutic amount.

[0191] In yet another preferred embodiment, amoxicillin is administered at a subtherapeutic dose, and eucalyptol is administered at a therapeutically effective dose.

[0192] In yet another preferred embodiment, both amoxicillin and eucalyptol are administered at subtherapeutic doses.

[0193] According to one embodiment, eucalyptol can be administered to the individual at a dose between about 0.1 mg / kg body weight / day and about 50 mg / kg body weight / day, preferably between about 0.5 mg / kg body weight / day and about 20 mg / kg body weight / day, most particularly preferably between about 1 mg / kg body weight / day and about 10 mg / kg body weight / day; and / or amoxicillin can be administered to the individual at a dose between about 5 mg / kg body weight / day and about 200 mg / kg body weight / day, preferably between about 10 mg / kg body weight / day and about 100 mg / kg body weight / day, most particularly preferably between about 15 mg / kg body weight / day and about 50 mg / kg body weight / day.

[0194] Preferably, the combination of eucalyptol conforming to the invention is administered to the individual at a dose between about 0.1 mg / kg body weight / day and about 50 mg / kg body weight / day, and the combination of amoxicillin conforming to the invention is administered to the individual at a dose between about 5 mg / kg body weight / day and about 200 mg / kg body weight / day.

[0195] More preferably, the combination of eucalyptol conforming to the present invention is administered to the individual at a dose between about 0.5 mg / kg body weight / day and about 20 mg / kg body weight / day, and the combination of amoxicillin conforming to the present invention is administered to the individual at a dose between about 10 mg / kg body weight / day and about 100 mg / kg body weight / day.

[0196] Most particularly preferably, the combination of eucalyptol conforming to the invention is administered to the individual at a dose between about 1 mg / kg body weight / day and about 10 mg / kg body weight / day, and the combination of amoxicillin conforming to the invention is administered to the individual at a dose between about 15 mg / kg body weight / day and about 50 mg / kg body weight / day.

[0197] In a preferred embodiment, the combination conforming to the present invention comprises, or is substantially composed of, eucalyptol, amoxicillin, and a β-lactamase inhibitor, wherein the β-lactamase inhibitor is preferably selected from clavulanic acid, sulbactam, tazobactam, and aztreonam, and mixtures thereof, and the combination is used to treat bacterial infections in an individual. Preferably, the β-lactamase inhibitor is clavulanic acid.

[0198] Therefore, the combination of eucalyptol and amoxicillin conforming to the present invention can be administered to the individual in the amounts described above, and the β-lactamase inhibitor can be administered to the individual in a therapeutically effective amount or a subtherapeutic amount.

[0199] According to a specific embodiment, the combination of eucalyptol and amoxicillin conforming to the present invention is administered to the individual at the doses described above, and a β-lactamase inhibitor, preferably clavulanic acid, is administered to the individual at a dose between about 0.1 mg / kg body weight / day and about 50 mg / kg body weight / day, preferably between about 0.5 mg / kg body weight / day and about 20 mg / kg body weight / day, and most particularly preferably between about 1 mg / kg body weight / day and about 10 mg / kg body weight / day.

[0200] In another specific embodiment, the combination conforming to the invention comprises eucalyptol and amoxicillin, or is substantially composed of eucalyptol and amoxicillin, wherein the proportion of eucalyptol is between about 0.02 mg and about 0.5 mg per gram of amoxicillin, preferably between about 0.1 mg and about 0.3 mg, and more preferably, the proportion of eucalyptol is equal to about 0.2 mg of eucalyptol per gram of amoxicillin. Preferably, the combination conforming to the invention further comprises a β-lactamase inhibitor, preferably clavulanic acid, wherein the proportion of the β-lactamase inhibitor is between about 0.01 mg and about 0.5 mg per gram of amoxicillin, preferably between 0.1 mg and about 0.2 mg, and more preferably, the proportion of the β-lactamase inhibitor is equal to about 0.125 mg of β-lactamase inhibitor per gram of amoxicillin.

[0201] Combinations conforming to the present invention may also contain at least one other active ingredient. Preferably, the other active ingredient in combinations conforming to the present invention is another antibiotic, particularly a β-lactam antibiotic, and / or another β-lactamase inhibitor, and / or an antifungal agent and / or an antiparasitic agent and / or an analgesic.

[0202] Therefore, the combination of eucalyptol, amoxicillin, and optionally a β-lactamase inhibitor, preferably clavulanic acid, conforming to the present invention, can be administered in the amounts described above, and the other active ingredients can be administered to the individual in therapeutically effective or subtherapeutic amounts.

[0203] Packaging and administration routes conforming to the present invention

[0204] The active ingredients in combinations conforming to the present invention can be administered to the individual simultaneously, sequentially, separately, or in combination via these routes of administration.

[0205] When the active ingredients conforming to the present invention are administered sequentially or separately, the time interval is preferably selected to allow the desired therapeutic effect to be achieved, preferably with a synergistic effect between eucalyptol and amoxicillin.

[0206] Preferably, the active ingredients conforming to the combination of the present invention are administered simultaneously. When the administration of the active ingredients conforming to the combination of the present invention is simultaneous, it is preferably carried out by administration of a single formulation comprising all the active ingredients of the combination.

[0207] When a combination conforming to the present invention contains more than two active ingredients, some active ingredients may be administered simultaneously, some active ingredients may be administered sequentially, and / or some active ingredients may be administered separately. For example, when a combination conforming to the present invention contains three active ingredients, two active ingredients may be administered simultaneously, and the third active ingredient may be administered sequentially or separately, preferably sequentially.

[0208] In a particular embodiment, the combination conforming to the invention comprises eucalyptol and amoxicillin, which are administered simultaneously to the individual, preferably from a pharmaceutical composition comprising eucalyptol and amoxicillin or from a two-pharmaceutical composition, one comprising eucalyptol and the other comprising amoxicillin.

[0209] In another specific embodiment, the combination conforming to the invention comprises eucalyptol and amoxicillin, which are administered to the individual sequentially or separately, preferably sequentially, from two pharmaceutical compositions, one comprising eucalyptol and the other comprising amoxicillin.

[0210] In yet another specific embodiment, the combination conforming to the invention comprises eucalyptol, amoxicillin, and a β-lactamase inhibitor, preferably clavulanic acid, which are simultaneously administered to the individual. The eucalyptol, amoxicillin, and β-lactamase inhibitor can be simultaneously administered to the individual from a pharmaceutical composition comprising: (a) A pharmaceutical composition comprising eucalyptol, amoxicillin and a β-lactamase inhibitor; (b) A pharmaceutical composition containing eucalyptol and a pharmaceutical composition containing amoxicillin and a β-lactamase inhibitor; (c) A pharmaceutical composition containing amoxicillin and a pharmaceutical composition containing eucalyptol and a β-lactamase inhibitor; (d) A pharmaceutical composition containing a β-lactamase inhibitor and a pharmaceutical composition containing eucalyptol and amoxicillin; or (e) Pharmaceutical compositions containing eucalyptol, pharmaceutical compositions containing amoxicillin, and pharmaceutical compositions containing β-lactamase inhibitors.

[0211] In yet another specific embodiment, the combination conforming to the invention comprises eucalyptol, amoxicillin, and a β-lactamase inhibitor, preferably clavulanic acid, which are administered to the individual sequentially or separately, preferably sequentially, from the pharmaceutical composition comprising eucalyptol, the pharmaceutical composition comprising amoxicillin, and the pharmaceutical composition comprising a β-lactamase inhibitor.

[0212] In yet another specific embodiment, the combination conforming to the invention comprises eucalyptol, amoxicillin, and a β-lactamase inhibitor, preferably clavulanic acid, wherein the amoxicillin and the β-lactamase inhibitor are simultaneously administered to the individual from a pharmaceutical composition thereof, and the eucalyptol is administered to the individual sequentially or separately, preferably sequentially: (a) A pharmaceutical composition containing eucalyptol, a pharmaceutical composition containing amoxicillin, and a pharmaceutical composition containing a β-lactamase inhibitor; or (b) A pharmaceutical composition containing eucalyptol and a pharmaceutical composition containing amoxicillin and a β-lactamase inhibitor.

[0213] In yet another specific embodiment, the combination conforming to the invention comprises eucalyptol, amoxicillin, and a β-lactamase inhibitor, preferably clavulanic acid, wherein the eucalyptol and the β-lactamase inhibitor are administered simultaneously to the individual from a pharmaceutical composition thereof, and the amoxicillin is administered to the individual sequentially or separately, preferably sequentially: (a) A pharmaceutical composition containing eucalyptol, a pharmaceutical composition containing amoxicillin, and a pharmaceutical composition containing a β-lactamase inhibitor; or (b) A pharmaceutical composition containing amoxicillin and a pharmaceutical composition containing eucalyptol and a β-lactamase inhibitor.

[0214] In yet another specific embodiment, the combination conforming to the invention comprises eucalyptol, amoxicillin, and a β-lactamase inhibitor, preferably clavulanic acid, wherein the amoxicillin and eucalyptol are simultaneously administered to the individual from a pharmaceutical composition thereof, and the β-lactamase inhibitor is administered to the individual sequentially or separately, preferably sequentially: (a) A pharmaceutical composition containing eucalyptol, a pharmaceutical composition containing amoxicillin, and a pharmaceutical composition containing a β-lactamase inhibitor; or (b) A pharmaceutical composition containing a β-lactamase inhibitor and a pharmaceutical composition containing eucalyptol and amoxicillin.

[0215] In a preferred embodiment, amoxicillin and a β-lactamase inhibitor, preferably clavulanic acid, are preferably administered simultaneously to the individual from a pharmaceutical composition comprising amoxicillin and a β-lactamase inhibitor.

[0216] In another preferred embodiment, eucalyptol, amoxicillin, and optionally a β-lactamase inhibitor, preferably clavulanic acid, are preferably administered to the individual simultaneously from a pharmaceutical composition comprising eucalyptol, amoxicillin, and optionally a β-lactamase inhibitor, or from a pharmaceutical composition comprising eucalyptol and a pharmaceutical composition comprising amoxicillin and optionally a β-lactamase inhibitor.

[0217] In yet another preferred embodiment, eucalyptol is administered to the individual sequentially or separately, preferably sequentially, relative to amoxicillin and / or optionally relative to a β-lactamase inhibitor, preferably clavulanic acid.

[0218] The active ingredients of the combination conforming to the present invention can be administered to the individual via the same or different routes. The route of administration generally depends on the pharmaceutical formulation used. The active ingredients of the combination conforming to the present invention are preferably administered parenterally or enterally, preferably enterally, more preferably orally or rectally to the individual. Particularly preferably, the active ingredients of the combination conforming to the present invention are administered to the individual orally.

[0219] In a particular embodiment, amoxicillin and optionally a β-lactamase inhibitor, preferably clavulanic acid, are administered orally to the individual, and the eucalyptol is administered rectally to the individual.

[0220] In a preferred embodiment, amoxicillin, eucalyptol, and optionally a β-lactamase inhibitor, preferably clavulanic acid, are orally administered to the individual.

[0221] The active ingredients of the combination conforming to the present invention, particularly amoxicillin, eucalyptol, and optionally a β-lactamase inhibitor, preferably clavulanic acid, can be administered to the individual in any pharmaceutical formulation, preferably compatible with parenteral or enteral administration, more preferably with oral or rectal administration, and most particularly preferably with oral administration.

[0222] Therefore, the active ingredients conforming to the combination of the present invention, particularly amoxicillin, eucalyptol, and optionally a β-lactamase inhibitor, preferably clavulanic acid, can be formulated into tablets, capsules, gel capsules, granules, powders, suspensions, emulsions, solutions, polymers, nanoparticles, microspheres, suppositories, rectal capsules, enemas, gels, pastes, ointments, creams, plasters, decoctions, injections, implants, sprays, or aerosols.

[0223] In a preferred embodiment, the active ingredients conforming to the combination of the present invention are formulated into powder form, preferably a powder for use in drinking water suspensions.

[0224] In certain embodiments, the active ingredient is formulated as a suppository or rectal capsule.

[0225] In another specific embodiment, eucalyptol is formulated in the form of an oil, suppository, or rectal capsule, preferably in the form of an encapsulated oil, and other active ingredients are formulated in the form of a powder, preferably a powder for use in a drinkable suspension.

[0226] Treatment of infectious diseases in individuals

[0227] On the other hand, the present invention also relates to pharmaceutical formulations conforming to the present invention for treating infectious diseases in an individual. The present invention further relates to pharmaceutical formulations conforming to the present invention for preparing a medicament intended for treating infectious diseases. The present invention also relates to a treatment method comprising administering a therapeutically effective amount of the formulation conforming to the present invention to an individual in need, particularly an individual suffering from an infectious disease.

[0228] The present invention also relates to combinations conforming to the invention for treating infectious diseases, preferably bacterial infections, in an individual. The present invention also relates to a treatment method comprising administering a therapeutically effective amount of a combination conforming to the invention, preferably a combination of eucalyptol, amoxicillin, and clavulanic acid, to an individual in need, particularly an individual suffering from an infectious disease, preferably a bacterial infection.

[0229] Preferably, the infectious disease is of bacterial origin; more preferably, the infectious disease is caused by one or more bacteria resistant to antibiotics, particularly β-lactam antibiotics. Preferably, the term "antibiotic-resistant bacteria" refers to bacteria that are, depending on the circumstances, insensitive or not very sensitive to antibiotics. Similarly, bacteria resistant to β-lactam antibiotics are those that are insensitive or not very sensitive to these antibiotics. Therefore, bacterial infections caused by bacteria resistant to β-lactam antibiotics cannot be effectively treated with these antibiotics.

[0230] In a preferred embodiment, the infectious disease is caused by amoxicillin-resistant bacteria. Preferably, the bacteria causing the infectious disease are at least partially resistant to the combination of amoxicillin and clavulanic acid.

[0231] In another preferred embodiment, the bacteria causing the infectious disease are β-lactamase-producing bacteria. β-lactamases are either "active serine" inactivating enzymes (classes A, C, and D) or metalloenzymes (class B) whose substrates are β-lactam antibiotics. Narrow-spectrum β-lactamases differ from broad-spectrum β-lactamases (BSBLs) in that the latter can inhibit a wide variety of different β-lactam antibiotics, particularly penicillins including amoxicillin, first, second, and third generation (e.g., cefotaxime, ceftazidime) and fourth generation (e.g., cefepime) cephalosporins, and monocyclic lactams (e.g., aztreonam).

[0232] In a particularly preferred embodiment, the bacteria causing the infectious disease are broad-spectrum β-lactamase (BSBL)-producing bacteria, especially BSBL-producing bacteria insensitive to clavulanic acid. Alternatively, the bacteria produce BSBL that is only partially inhibited by clavulanic acid. BSBL-producing bacteria can be detected by tests known to those skilled in the art, such as the two-disc method, the combined disc method, and the BSBL E-test.

[0233] The bacterial infections treated with the pharmaceutical preparations or combinations of the present invention can be selected from cystitis, particularly recurrent acute cystitis; bacterial sinusitis, particularly acute maxillary sinusitis; otitis, particularly acute otitis media; bronchitis, particularly chronic and / or acute bronchitis; bronchopulmonary disease, particularly chronic and / or acute bronchopulmonary disease; pyelonephritis; upper genital tract infections; periodontitis; severe oral infections, particularly abscesses; cellulitis and cellulitis; animal bites; bone and joint infections, particularly osteomyelitis; endocarditis; pericarditis; sepsis; and skin infections. Preferably, the bacterial infection is cystitis, more preferably cystitis resistant to β-lactam antibiotics, even more preferably amoxicillin-resistant cystitis, and most particularly preferably cystitis resistant to a combination of amoxicillin and clavulanic acid.

[0234] In the context of this invention, the terms "individual" and "patient" are equivalent and can be used interchangeably. When used herein, the term "individual" refers to an animal, preferably a mammal, and more preferably, a human being.

[0235] Therefore, in certain embodiments, the individual to whom the formulation or combination conforming to the present invention is administered is a human being. This person can be a newborn, a child, an adolescent, an adult, or an elderly person. When used herein, the term "newborn" refers to a person less than 12 months of age, preferably less than 6 months, and more preferably less than 3 months of age. When used in the present invention, the term "child" refers to a person aged 1 to 12 years, preferably 1 to 8 years, and more preferably 1 to 5 years. When used herein, the term "adult" refers to a person aged 12 to 60 years, preferably 15 to 60 years, and more preferably 18 to 60 years. When used in the present invention, the term "elderly person" refers to a person aged 60 years or older, preferably 65 years or older, and more preferably 70 years or older.

[0236] In a preferred embodiment, the formulation conforming to the present invention is administered to an adult.

[0237] In the field of veterinary applications, the individuals of the present invention can be non-human animals, preferably pets or breeding livestock, more preferably animals selected from dogs, cats, cattle, sheep, rabbits, pigs, goats, horses, rodents, especially hamsters and guinea pigs, non-human primates and poultry, preferably broilers, laying hens, roosters and breeding chickens, guinea fowl, turkeys, quails, ducks, geese and pigeons.

[0238] In a most particularly preferred embodiment, the present invention relates to a formulation or combination thereof conforming to the invention for the treatment in humans of cystitis resistant to β-lactam antibiotics.

[0239] dose

[0240] Pharmaceutical formulations or combinations conforming to the invention for treating infectious diseases, preferably bacterial infections, in an individual may be administered in a single dose (single administration) or in several doses (several administrations), depending on the individual, their age, their health status, and the infection to be treated. When several doses (several administrations) of the pharmaceutical formulation or combination conforming to the invention are administered, they may be spread over one or more days. Therefore, the pharmaceutical formulation or combination conforming to the invention may be administered at a frequency of a single dose (single administration) per treatment administration day. Preferably, the individual receives several doses (several administrations) of the pharmaceutical formulation or combination conforming to the invention per treatment administration day. More preferably, the individual receives three doses (three administrations) of the pharmaceutical formulation or combination conforming to the invention per treatment administration day, preferably in the morning, afternoon, and evening.

[0241] The number of doses (or administrations) received by the individual on each treatment day can also vary over time. Therefore, the time interval during which the individual receives a single dose (single administration) on each treatment day can alternate with the time interval during which the individual receives several doses (several administrations) on each treatment day, preferably three doses (three administrations) distributed in the morning, afternoon, and evening. Specifically, the individual may receive a single dose (single administration) on the first day of treatment, which is typically referred to as the "loading dose," and then receive several doses (several administrations) on each subsequent treatment day, referred to as "maintenance doses," preferably three maintenance doses (three administrations) on each treatment day, preferably in the morning, afternoon, and evening.

[0242] Typically, on the first day of treatment, the loading dose administered to the individual, preferably in a single dose intake, is a dose greater than or equal to the maintenance dose of the formulation conforming to the invention; more preferably, when the individual receives at least two maintenance doses per treatment day, the loading dose is greater than or equal to two maintenance doses. Preferably, the loading dose is between about 5 g and about 20 g, more preferably between about 10 g and about 15 g, and most particularly preferably the loading dose is about 12 g. Preferably, the maintenance dose is between about 1 g and about 15 g, more preferably between about 3 g and about 6 g, and most particularly preferably the maintenance dose is about 3 g or about 6 g.

[0243] The pharmaceutical formulations or combinations conforming to the present invention can be administered daily, every two days, or weekly, preferably daily. The periodicity of intake of said formulations or combinations depends on various parameters and can be readily determined by those skilled in the art based on, for example, the planned total duration of intake of said pharmaceutical formulations or combinations, the individual's age, and / or the infection to be prevented or treated, preferably the severity of a bacterial infection. In a given individual, the periodicity of intake (administration) of said pharmaceutical formulations or combinations can also vary over time, particularly with the evolution of the individual's infection and / or their overall health status.

[0244] Specifically, the pharmaceutical formulation or combination conforming to the present invention can be administered to the individual for a period of 1 day to approximately 3 months, 2 months, 1 month, 3 weeks, 2 weeks, 1 week, 5 days, 3 days, or 2 days, preferably for a period of approximately 2 to approximately 21 days, and more preferably for a period of approximately 7 to approximately 14 days. In a particularly preferred embodiment, the pharmaceutical formulation or combination conforming to the present invention is administered to the individual for approximately 7 days. Alternatively, the pharmaceutical formulation or combination conforming to the present invention can be administered throughout the entire duration of the infection. In the case of a urinary tract infection, the formulation or combination conforming to the present invention can be administered until sterile urine is obtained in the individual.

[0245] In certain embodiments, pharmaceutical formulations or combinations conforming to the present invention can be administered for several months, optionally several years, for example in the case of chronic bacterial infection.

[0246] The pharmaceutical formulation conforming to the present invention can be administered to the individual at a rate of about 1 to about 150 grams, preferably about 1 to about 50 grams, more preferably about 2 to about 30 grams, and most particularly preferably about 3 to about 20 grams per treatment day. For example, about 9 grams of the pharmaceutical formulation conforming to the present invention can be administered to the individual per treatment day. In another example, about 18 grams of the formulation conforming to the present invention can be administered to the individual per treatment day.

[0247] A pharmaceutical combination of eucalyptol and amoxicillin

[0248] On the other hand, the present invention also relates to a pharmaceutical composition comprising eucalyptol, amoxicillin, and a pharmaceutically acceptable excipient or carrier, and optionally a β-lactamase inhibitor, or substantially consisting of eucalyptol, amoxicillin, and a pharmaceutically acceptable excipient or carrier, and optionally a β-lactamase inhibitor.

[0249] In a preferred embodiment, the β-lactamase inhibitor is selected from clavulanic acid, sulbactam, tazobactam, and aztreonam; preferably, the β-lactamase inhibitor is clavulanic acid.

[0250] In certain embodiments, the compositions conforming to the present invention comprise eucalyptol, amoxicillin, optionally a β-lactamase inhibitor, preferably clavulanic acid, and another active ingredient, or are substantially composed of eucalyptol, amoxicillin, optionally a β-lactamase inhibitor, preferably clavulanic acid, and another active ingredient. Preferably, the other active ingredient in the compositions conforming to the present invention is another antibiotic, particularly a β-lactam antibiotic, and / or another β-lactamase inhibitor and / or an antifungal agent and / or an antiparasitic agent and / or an analgesic.

[0251] Preferably, the compositions conforming to the present invention comprise, preferably, amoxicillin and eucalyptol, or consist essentially of, active ingredients, preferably amoxicillin and eucalyptol, said active ingredients being present at concentrations sufficient to achieve therapeutic and / or antibacterial effects, preferably synergistic effects, as illustrated in the examples below. To obtain such effects, amoxicillin and eucalyptol may be administered at therapeutically effective or subtherapeutic amounts.

[0252] In a preferred embodiment, both eucalyptol and amoxicillin are administered in therapeutically effective amounts.

[0253] In another preferred embodiment, amoxicillin is administered in a therapeutically effective amount, and eucalyptol is administered in a subtherapeutic amount.

[0254] In yet another preferred embodiment, amoxicillin is administered at a subtherapeutic dose, and eucalyptol is administered at a therapeutically effective dose.

[0255] In yet another preferred embodiment, both amoxicillin and eucalyptol are administered at subtherapeutic doses.

[0256] When present in a composition conforming to the present invention, the β-lactamase inhibitor and / or other active ingredients may be administered at a therapeutically effective amount or at a subtherapeutic amount.

[0257] The compositions conforming to the present invention may comprise or consist essentially of the following components: eucalyptol, about 5 mg to about 100 mg per gram of composition, preferably about 10 mg to about 50 mg, more preferably about 20 mg to about 40 mg, and most particularly preferably about 33 mg per gram of composition; and / or amoxicillin, about 20 mg to about 500 mg per gram of composition, preferably about 50 mg to about 300 mg, more preferably about 150 mg to about 200 mg, and most particularly preferably about 167 mg per gram of composition; and / or optionally a β-lactamase inhibitor, preferably clavulanic acid, about 1 mg to about 100 mg per gram of composition, preferably about 5 mg to about 50 mg, more preferably about 15 mg to about 25 mg, and most particularly preferably about 21 mg per gram of composition.

[0258] Preferably, the composition conforming to the present invention comprises or is substantially composed of the following components: eucalyptol at a concentration of about 5 mg to about 100 mg per gram of composition, amoxicillin at a concentration of about 20 mg to about 500 mg, and optionally a β-lactamase inhibitor, preferably clavulanic acid, at a concentration of about 1 mg to about 100 mg per gram of composition.

[0259] More preferably, the composition conforming to the present invention comprises or is substantially composed of the following components: eucalyptol at a concentration of about 10 mg to about 50 mg per gram of the composition, amoxicillin at a concentration of about 50 mg to about 300 mg, optionally a β-lactamase inhibitor at a concentration of about 50 mg to about 50 mg, preferably clavulanic acid.

[0260] Most particularly preferably, the composition conforming to the present invention comprises or is substantially composed of the following components: eucalyptol at about 20 mg to about 40 mg per gram of composition, preferably about 33 mg; amoxicillin at about 150 mg to about 200 mg per gram of composition, preferably about 167 mg; and optionally about 15 mg to about 25 mg, most particularly preferably about 21 mg, a β-lactamase inhibitor, preferably clavulanic acid.

[0261] The compositions conforming to the present invention may be in the form of tablets, capsules, gel capsules, granules, powders, suspensions, emulsions, solutions, polymers, nanoparticles, microspheres, suppositories, rectal capsules, enemas, gels, pastes, ointments, creams, plasters, decoctions, injections, implants, sprays, or aerosols. Preferably, the pharmaceutical compositions conforming to the present invention are in the form of powders, more specifically powders for use in drinkable suspensions.

[0262] Preferably, the technical characteristics of the powder are as defined above for pharmaceutical formulations conforming to the present invention.

[0263] The compositions conforming to the present invention further comprise at least one pharmaceutically acceptable excipient or carrier. Those skilled in the art can readily determine the required excipients for the composition based on the chosen pharmaceutical form.

[0264] In practice, when the composition conforming to the present invention is in powder form, the pharmaceutically acceptable excipient or carrier of the composition conforming to the present invention is preferably selected from sweeteners, flavoring agents, anti-caking agents, lubricants, disintegrants, adsorbents and mixtures thereof.

[0265] Preferably, when the composition conforming to the present invention is in powder form, the composition comprises at least one sweetener, preferably aspartame, a flavoring agent, an anti-caking agent, preferably silica, a lubricant, preferably magnesium stearate, a disintegrant, preferably a mixture of croscarmellose and microcrystalline cellulose, and an adsorbent, preferably an oil. This composition may also contain preservatives, colorants, and / or pH buffers.

[0266] Therefore, in a preferred embodiment, the composition conforming to the present invention is in powder form, comprising or consisting of or substantially consisting of the following components: eucalyptol, amoxicillin, and at least one sweetener, flavoring agent, anti-caking agent, lubricant, disintegrant, and / or adsorbent as defined above, and optionally a β-lactamase inhibitor as defined above, preferably clavulanic acid.

[0267] Preferably, the composition conforming to the present invention is a powder comprising or consisting of or substantially consisting of the following components: eucalyptol and amoxicillin in the above proportions, a sweetener of about 1 mg to about 60 mg per gram of powder, preferably aspartame, and / or a flavoring agent of about 1 mg to about 60 mg, and / or an anti-caking agent of about 20 mg to about 500 mg, preferably silica, and / or a lubricant of about 1 mg to about 40 mg, preferably magnesium stearate, and / or a disintegrant of about 10 mg to about 1000 mg, preferably a mixture of microcrystalline cellulose and cross-linked carboxymethyl cellulose, and / or an adsorbent of about 2 mg to about 50 mg, preferably an oil, and optionally a β-lactamase inhibitor in the above proportions, preferably clavulanic acid.

[0268] In particular, compositions conforming to the present invention may contain at least one excipient of the adsorbent type. When used herein, the term "adsorbent" refers to an excipient capable of immobilizing liquid molecules, such as eucalyptol molecules, onto a solid carrier, such as a powdered carrier, in a pharmaceutical composition. Preferably, the adsorbent is a pharmaceutically acceptable oil. The pharmaceutically acceptable oil is as described above.

[0269] In another particularly preferred embodiment, the composition conforming to the invention does not contain any detergent. The detergent is as described above in the section on excipients.

[0270] The present invention also relates to pharmaceutical compositions conforming to the present invention for the treatment of infectious diseases, preferably bacterial infections, in an individual.

[0271] The present invention also relates to a treatment method comprising administering a therapeutically effective amount of a pharmaceutical composition conforming to the present invention to an individual in need, particularly an individual suffering from an infectious disease, preferably a bacterial infection.

[0272] In this regard, the embodiments and definitions described for the use of combinations or pharmaceutical preparations conforming to the invention in treating infectious diseases, preferably bacterial infections, in an individual, as well as the embodiments and definitions related to the dosage of such combinations or preparations, are also taken into consideration.

[0273] Preferably, the infectious disease is caused by one or more bacteria that are resistant to antibiotics, preferably β-lactam antibiotics, more preferably amoxicillin, and most particularly preferably a combination of amoxicillin and clavulanic acid.

[0274] In the most particularly preferred embodiment, the present invention relates to a pharmaceutical composition conforming to the invention for treating cystitis, particularly cystitis resistant to antibiotics, preferably β-lactam antibiotics, more preferably amoxicillin, and most particularly preferably a combination of amoxicillin and clavulanic acid.

[0275] medicine box

[0276] On the other hand, the present invention also relates to a kit for treating infectious diseases, preferably bacterial infections, in an individual, comprising: (a) A pharmaceutical composition comprising or substantially composed of eucalyptol, and a pharmaceutically acceptable composition comprising or substantially composed of amoxicillin. (b) A pharmaceutical composition comprising eucalyptol or consisting essentially of eucalyptol, and a pharmaceutical composition comprising amoxicillin and a β-lactamase inhibitor, preferably clavulanic acid or consisting essentially of amoxicillin and a β-lactamase inhibitor, preferably clavulanic acid; (c) A pharmaceutical composition comprising amoxicillin or consisting essentially of amoxicillin, and a pharmaceutical composition comprising eucalyptol and a β-lactamase inhibitor, preferably clavulanic acid or consisting essentially of eucalyptol and a β-lactamase inhibitor, preferably clavulanic acid. (d) A pharmaceutical composition comprising a β-lactamase inhibitor, preferably clavulanic acid, or substantially composed of a β-lactamase inhibitor, preferably clavulanic acid, and a pharmaceutical composition comprising eucalyptol and amoxicillin, or substantially composed of eucalyptol and amoxicillin; or (e) A pharmaceutical composition comprising or substantially composed of eucalyptol, a pharmaceutical composition comprising or substantially composed of amoxicillin, and a pharmaceutical composition comprising a β-lactamase inhibitor, preferably clavulanic acid, or substantially composed of a β-lactamase inhibitor, preferably clavulanic acid; and (f) Optionally, it includes a guide on how to use the kit.

[0277] Preferably, each composition contained in the kit is in a separate receiver, container, and / or package.

[0278] In certain embodiments, at least one pharmaceutical composition of the kit conforming to the present invention further comprises at least one other active ingredient. Preferably, the other active ingredient conforming to the present invention is another antibiotic, particularly a β-lactam antibiotic, and / or another β-lactamase inhibitor and / or an antifungal agent and / or an antiparasitic agent and / or an analgesic.

[0279] Preferably, the active ingredients of the composition conforming to the kit of the present invention, particularly amoxicillin and eucalyptol, are present at a concentration sufficient to achieve therapeutic and / or antibacterial effects, preferably synergistically, when said active ingredients are present in the same composition or in different compositions and are used simultaneously, sequentially, or separately. To obtain this effect, eucalyptol and amoxicillin can be administered at therapeutically effective or subtherapeutic amounts.

[0280] In a preferred embodiment, both eucalyptol and amoxicillin are administered in therapeutically effective amounts.

[0281] In another preferred embodiment, amoxicillin is administered in a therapeutically effective amount, and eucalyptol is administered in a subtherapeutic amount.

[0282] In yet another preferred embodiment, amoxicillin is administered at a subtherapeutic dose, and eucalyptol is administered at a therapeutically effective dose.

[0283] In yet another preferred embodiment, both amoxicillin and eucalyptol are administered at subtherapeutic doses.

[0284] When present in a composition conforming to the kit of the present invention, the β-lactamase inhibitor and / or additional active ingredients may be administered at a therapeutically effective amount or a subtherapeutic amount.

[0285] The pharmaceutical composition containing eucalyptol in the kit of the present invention may contain eucalyptol in the form of about 5 mg to about 100 mg per gram of composition, preferably about 10 mg to about 50 mg, more preferably about 20 mg to about 40 mg, and most particularly preferably about 33 mg per gram of composition.

[0286] The pharmaceutical composition containing amoxicillin in the kit of the present invention may contain amoxicillin at a concentration of about 20 mg to about 500 mg per gram of composition, preferably about 50 mg to about 300 mg, more preferably about 150 mg to about 200 mg, and most particularly preferably about 167 mg per gram of composition.

[0287] When the pharmaceutical composition of the kit conforming to the present invention contains a β-lactamase inhibitor, preferably clavulanic acid, the composition may contain between about 1 mg and about 100 mg per gram of the composition, preferably between about 5 mg and about 50 mg, even more preferably between about 15 mg and about 25 mg, and most particularly preferably about 21 mg of the β-lactamase inhibitor.

[0288] The composition of the medicine box conforming to the present invention is in the form of tablets, capsules, gel capsules, granules, powders, suspensions, emulsions, solutions, polymers, nanoparticles, microspheres, suppositories, rectal capsules, enemas, gels, pastes, ointments, creams, oral liquids, injections, implants, sprays, or aerosols.

[0289] Preferably, the pharmaceutical composition conforming to the present invention is in the form of powder, suppository or rectal capsule, preferably in the form of powder, more preferably in the form of dry powder, and more specifically in the form of dry powder for use in drinking suspensions.

[0290] When eucalyptol is the sole active ingredient in a composition, it can be taken in the form of an oil, particularly an encapsulated oil.

[0291] The pharmaceutical composition of the kit conforming to the present invention preferably contains at least one pharmaceutically acceptable excipient or carrier. A person skilled in the art can easily determine the required excipient for the composition based on the selected pharmaceutical form. The pharmaceutically acceptable excipient or carrier is as defined above for pharmaceutical compositions.

[0292] On the other hand, the present invention relates to a medicine kit conforming to the present invention, which is used to treat infectious diseases in an individual, preferably bacterial infections.

[0293] In this regard, the embodiments and definitions described for the use of formulations or combinations conforming to the present invention in treating infectious diseases in an individual, as well as those relating to the administration and dosing of such combinations or formulations, are also taken into consideration.

[0294] Preferably, the infectious disease is caused by one or more bacteria that are resistant to antibiotics, preferably β-lactam antibiotics, more preferably amoxicillin, and most particularly preferably by one or more bacteria that are at least partially resistant to the combination of amoxicillin and clavulanic acid.

[0295] In the most particularly preferred embodiment, the present invention relates to a pharmaceutical composition conforming to the invention for treating cystitis, particularly cystitis resistant to antibiotics, preferably β-lactam antibiotics, more preferably amoxicillin, and most particularly preferably a combination of amoxicillin and clavulanic acid.

[0296] Methods for manufacturing pharmaceutical preparations

[0297] Thirdly, the present invention also relates to a method for manufacturing a pharmaceutical composition or formulation conforming to the present invention, the method comprising: - A wetting solution is produced by mixing eucalyptol with medicinal oil; - Wet the powder containing amoxicillin with the wetting solution to obtain a powdered formulation containing amoxicillin, eucalyptol and oil.

[0298] The present invention also relates to pharmaceutical compositions or formulations obtained by methods conforming to the present invention.

[0299] When used herein, the term "wetting solution" refers to a solution used to wet or humidify dry powder. Specifically, the wetting operation can be performed by spraying the wetting solution onto the powder to be wetted.

[0300] The step of obtaining a wetting solution according to the method of the present invention can be carried out by mixing eucalyptol as described above with a pharmaceutically acceptable oil in a mass ratio of about 0.1 to about 1, preferably about 0.2 to about 0.8, and more preferably about 0.4 to about 0.6. Most particularly preferably, the mass ratio of oil to eucalyptol is about 0.5. For example, about 50 mg of oil is mixed with about 100 mg of eucalyptol, or about 16.7 mg of oil is mixed with about 33.3 mg of eucalyptol.

[0301] Preferably, the mixture of eucalyptol and oil used to obtain the wetting solution is prepared in a closed chamber, preferably at a temperature not exceeding about 20°C, to avoid evaporation of eucalyptol, but sufficient to keep the mixture in liquid form.

[0302] In a particular embodiment, the powder containing amoxicillin and intended to be wetted with the wetting solution also contains a β-lactamase inhibitor, preferably selected from clavulanic acid, sulbactam, tazobactam, aztreonam and pharmaceutically acceptable salts thereof, more preferably, the β-lactamase inhibitor is clavulanic acid.

[0303] Preferably, the powder containing amoxicillin and intended to be wetted with the wetting solution further comprises at least one pharmaceutically acceptable excipient or carrier, preferably selected from sweeteners, flavoring agents, anti-caking agents, lubricants, disintegrants, and mixtures thereof. More preferably, the powder containing amoxicillin comprises at least one sweetener, flavoring agent, anti-caking agent, lubricant, and disintegrant as defined above.

[0304] In another particular embodiment, the powder containing amoxicillin and intended to be wetted with the wetting solution also contains clavulanic acid, silica, colloidal silica, aspartame, cross-linked carboxymethyl cellulose, microcrystalline cellulose, magnesium stearate, and flavoring agents as defined above.

[0305] Preferably, the method according to the invention further includes the step of compacting the amoxicillin-containing powder before wetting it with the wetting solution. Preferably, the granules obtained by compaction are calibrated and then graded before wetting with the wetting solution.

[0306] In another embodiment, the method for manufacturing a pharmaceutical composition or formulation conforming to the present invention includes: - A wetting solution is produced by mixing eucalyptol with medicinal oil; - Wet the powder containing amoxicillin with a wetting solution to obtain a powder preparation containing amoxicillin, eucalyptol and oil; - The preparation obtained in the previous step is mixed with a powder containing a β-lactamase inhibitor, preferably selected from clavulanic acid, sulbactam, tazobactam, aztreonam and pharmaceutically acceptable salts thereof; more preferably, the β-lactamase inhibitor is clavulanic acid; - The powder obtained thereby is sieved.

[0307] In this method, the powder containing amoxicillin and / or the powder containing a β-lactamase inhibitor, preferably clavulanic acid, may also contain disintegrants as defined above, preferably two disintegrants, particularly microcrystalline cellulose and cross-linked carboxymethyl cellulose. In a preferred embodiment, the powder containing amoxicillin and the powder containing a β-lactamase inhibitor, preferably clavulanic acid, contain two disintegrants, namely microcrystalline cellulose and cross-linked carboxymethyl cellulose.

[0308] The powder containing amoxicillin and / or the powder containing a β-lactamase inhibitor, preferably clavulanic acid, may also contain an anti-caking agent as defined above. In a preferred embodiment, both the powder containing amoxicillin and the powder containing a β-lactamase inhibitor, preferably clavulanic acid, contain an anti-caking agent, preferably silica.

[0309] In the most particularly preferred embodiment, both the powder containing amoxicillin and the powder containing a β-lactamase inhibitor, preferably clavulanic acid, contain microcrystalline cellulose, cross-linked carboxymethyl cellulose, and silica.

[0310] Therefore, the method according to the present invention may include the steps of sieving and subsequently mixing the disintegrant and the anti-caking agent. Alternatively, the disintegrant may be mixed with the anti-caking agent, and then the mixture may be sieved. Specifically, microcrystalline cellulose, croscarmellose cellulose, and silica may be mixed in a ratio of about 200 mg to about 400 mg, preferably about 300 mg of croscarmellose cellulose, and about 400 mg to about 600 mg, preferably about 540 mg of silica, and about 1000 mg to about 1500 mg, preferably about 1241 mg of microcrystalline cellulose.

[0311] The method according to the present invention may further include the step of mixing the excipients with a powder containing amoxicillin and / or with a powder containing clavulanic acid; preferably, a portion of the excipients is mixed with a powder containing amoxicillin, and the remainder of the excipients is mixed with a powder containing clavulanic acid.

[0312] In another preferred embodiment, the powder containing a β-lactamase inhibitor, preferably clavulanic acid, further contains colloidal silica, preferably in a mass ratio of about 0.7 to about 1.3, more preferably about 0.9 to about 1.1, and even more preferably about 1, relative to clavulanic acid. Preferably, a mixture of clavulanic acid and colloidal silica is prepared before adding any other excipients or mixing with a powder containing amoxicillin.

[0313] Preferably, the method according to the invention further includes a step of compacting the powder containing amoxicillin before wetting with the wetting solution. Preferably, the granules obtained by compaction are calibrated and then graded before wetting with the wetting solution.

[0314] Similarly, the method according to the present invention preferably includes a step of compacting a powder containing a β-lactamase inhibitor, preferably clavulanic acid, before mixing it with a mixture of amoxicillin powder moistened with a wetting solution. Preferably, the granules obtained by compaction are calibrated and then graded before wetting with the wetting solution.

[0315] During the step of wetting the powder containing amoxicillin with a wetting solution, the wetting solution may be used in a ratio of about 100 to about 200 mg of the powder containing about 400 to about 600 mg, preferably about 500 mg of amoxicillin, preferably about 150 mg of the wetting solution.

[0316] During the step of mixing the preparation of amoxicillin, eucalyptol and oil with the powder containing a β-lactamase inhibitor, preferably clavulanic acid, the preparation of amoxicillin, eucalyptol and oil is mixed with the powder containing about 550 mg to about 750 mg, preferably about 650 mg, of a β-lactamase inhibitor.

[0317] Optionally, after the step of mixing the preparation of amoxicillin, eucalyptol, and oil with the powder containing clavulanic acid, the method of the present invention may include further steps of adding sweeteners, flavoring agents, and / or lubricants as described above. Preferably, sweeteners, flavoring agents, and lubricants are added. Preferably, the sweetener is aspartame, and the lubricant is magnesium stearate.

[0318] During this step, these other excipients may be added in proportions of about 30 mg to about 50 mg, preferably about 36 mg, of sweetener, preferably aspartame, about 15 mg to about 25 mg, preferably about 18 mg, of lubricant, preferably magnesium stearate, and / or about 70 mg to about 110 mg, preferably 90 mg, of flavoring agent per 3 grams of pharmaceutical preparation.

[0319] After the steps of adding sweeteners, flavorings and / or lubricants, the resulting preparations are mixed until a uniform powder is obtained.

[0320] In a preferred embodiment, the final sieving step is performed using a sieve with a pore diameter of no more than 5 mm, preferably no more than 2.5 mm, and more preferably no more than 1.25 mm.

[0321] Optionally, the method of the present invention may include additional steps such as packaging the sieved powder obtained by the method of the present invention into a single-dose or multi-dose container, preferably in a single-dose container.

[0322] In a preferred embodiment, the sieved powder obtained by the method of the present invention is packaged in a single-dose container containing between about 1 g and about 150 g of powder, more preferably between about 1 g and about 50 g of powder, more preferably between about 1 g and about 10 g of powder, and more particularly preferably about 3 g of powder.

[0323] In another embodiment, the sieved powder obtained by the method of the present invention is packaged in a multi-dose container containing, for example, between about 10 grams and about 500 grams of powder, preferably between about 20 grams and about 200 grams of powder, more preferably between about 30 grams and about 100 grams of powder, and most particularly preferably between about 50 grams of powder.

[0324] Optionally, the method of the present invention may include an additional step of secondary packaging the sieved powder obtained by the method of the present invention from a primary packaging.

[0325] In a preferred embodiment, the single-dose containers containing the sieved powder are then packaged in a box. Specifically, the box may contain, for example, between 3 and 31 single-dose containers, preferably between 5 and 21 single-dose containers, and more preferably between 7 and 14 single-dose containers.

[0326] In another embodiment, the multi-dose container containing the sieved powder is repackaged in a box, optionally accompanied by a measuring device, such as a medicine spoon, for dispensing a predetermined amount of powder, preferably about 1 mg to about 30 mg of powder, more preferably about 2 mg to about 20 mg of powder, and most particularly preferably about 3 mg to about 12 mg of powder. Specifically, the measuring device can dispense about 3 g, about 6 g, about 9 g, about 12 g, about 15 g, and / or about 18 g of powder.

[0327] molecular complex

[0328] Amoxicillin is an antibiotic sensitive to β-lactamases. β-lactamases produced by amoxicillin-resistant bacteria recognize and inactivate the β-lactam core of amoxicillin. When placed in solution, preferably an aqueous solution, amoxicillin can transiently form complexes of two amoxicillin molecules. The formation of these complexes is too transient to provide any protection against β-lactamases. However, when the pharmaceutical formulation of the present invention is placed in solution, stable amoxicillin complexes containing at least three amoxicillin molecules are formed and protect the antibiotic from the action of β-lactamases. The formation of these complexes can also be achieved by placing amoxicillin in solution in the presence of eucalyptol.

[0329] Therefore, in this final aspect, the invention also relates to a molecular complex comprising more than two amoxicillin molecules grouped in a chain or ring form and interacting with each other by non-covalent bonds.

[0330] Preferably, the molecular complex of the present invention is formed only of amoxicillin molecules.

[0331] The molecular complex of the present invention is formed from at least 3 amoxicillin molecules, preferably 3 to 6 amoxicillin molecules, more preferably 3 or 4 amoxicillin molecules, and most particularly preferably 4 amoxicillin molecules.

[0332] The amoxicillin molecules in the molecular complex of the present invention can be arranged in a chain or cyclic form. Preferably, they are arranged in a cyclic form such that each amoxicillin molecule interacts with two other amoxicillin molecules.

[0333] In certain embodiments, amoxicillin molecules can freely transition from being a chain complex to being a cyclic complex by breaking or forming non-covalent bonds.

[0334] The molecular complex of the present invention can be obtained by placing amoxicillin in solution in an aqueous solvent in the presence of eucalyptol. Preferably, the molecular complex of the present invention is obtained by placing amoxicillin in solution in an aqueous solvent in the presence of eucalyptol and in the absence of detergent.

[0335] In a particular embodiment, the molecular complex of the present invention is obtained by placing the pharmaceutical preparation of the present invention in an aqueous solvent in a solution.

[0336] Preferably, the amoxicillin molecule in the molecular complex of the present invention is not recognized by β-lactamases. Therefore, the molecular complex of the present invention can be used to treat bacteria considered to be resistant to amoxicillin.

[0337] In a particular embodiment, the molecular complex of the present invention can be obtained in an aqueous medium, wherein the mass ratio of amoxicillin to eucalyptol is between about 0.01 and about 1000, preferably between about 0.1 and about 100, more preferably between about 1 and about 10, and most particularly preferably wherein the mass ratio of amoxicillin to eucalyptol is about 5.

[0338] This invention also relates to the use of molecular complexes conforming to the invention as pharmaceuticals. This invention also relates to molecular complexes conforming to the invention for the treatment of infectious diseases in an individual. This invention also relates to molecular complexes conforming to the invention for the preparation of pharmaceuticals intended to treat infectious diseases. This invention also relates to a treatment method comprising administering a therapeutically effective amount of the molecular complex conforming to the invention to an individual in need, particularly an individual suffering from an infectious disease.

[0339] In this respect, embodiments described for formulations or combinations conforming to the present invention are also taken into consideration.

[0340] All references cited in this patent application, including journal articles or summaries, published patent applications, granted patents or any other references, are incorporated herein by reference, including all results, tables, figures and text presented in said references.

[0341] Although they have different meanings, the terms “comprising,” “having,” “containing,” and “composed of” can be used interchangeably in the description of this invention.

[0342] Other features and advantages of the invention will become clearer after reading the embodiments given below as non-limiting descriptions.

[0343] Example

[0344] Example 1 - In vitro study of the antibacterial activity of the combination of amoxicillin and eucalyptol

[0345] Materials and methods

[0346] Biological materials, culture media and antimicrobial agents

[0347] The six bacterial strains tested in this study were purified clinical isolates identified in the bacteriology laboratory of Hassan II University Teaching Hospital Center (CHU, Fès, Morocco). Three of the six bacterial strains tested were BSBL-bacterium coli (…). Escherichia coli ) strains (P956, P933 and P7847), the other 3 bacterial strains tested were BSBL Klebsiella pneumoniae ( Klebsiella pneumoniæ ) strains (H1878, H2001 and H1893).

[0348] For each experiment, a preculture of the bacterial strain (pre-frozen at -20°C) was prepared and incubated at 37°C for 24 h. From these precultures, a sample containing 2 x 10⁻⁶ bacteria was prepared. 7 The bacterial inoculum was prepared at CFU (colony forming units) / ml, and the optical density was adjusted to 540 nm.

[0349] Liquid and agar Mueller-Hinton (MH) media were supplied by BIOKAR (France). The former was used for the growth of the strain, while the latter, supplemented with 20% (v / v) glycerol, was used for storage. Both media were prepared according to the supplier's instructions.

[0350] Amoxicillin (AMX) and eucalyptol were supplied by Sigma Aldrich (France). A stock solution of AMX (400 µg / ml) was prepared by dissolving 40 mg of the antibiotic in 100 ml of sterile distilled water. Serial dilutions were performed from this stock solution. The eucalyptol concentrate used was prepared by emulsifying pure eucalyptol in 0.2% (v / v) agar, as described by Remmal A et al. (J. Essent. Oil. Res [books], 1993, 5: pp. 1179-1184).

[0351] Assessment of the inhibitory percentage of the combination of AMX and eucalyptol

[0352] Partial inhibitory concentration (PIC) is the concentration of antibacterial agent that inhibits the growth of a given percentage (90%, 75%, 50%, 40%, ...) of the studied bacterial population. Based on monitoring bacterial growth by measuring optical density, the PICs of AMX and eucalyptol against the six bacterial strains used were determined using microplate microdilution techniques (Casey JT et al., J. Microbiol. Meth [book], 2004, 58: 327–334; Patton T et al., J. Microbiol. Meth [book], 2006, 64: 84–95).

[0353] Use 96-well U-shaped sterile microplates with a capacity of 200 µl. For each microplate, prepare two control rows: One row contains 200 µl of MH liquid culture medium (sterile control and negative control).

[0354] One row contains 150 µl of MH liquid medium and 50 µl of 2x10 7 CFU / ml bacterial inoculum (positive control).

[0355] For AMX and eucalyptol, prepare a solution containing 100 µl MH liquid medium and 50 µl 2x10 7 Two rows of bacterial inoculum at CFU / ml and antimicrobial agents at gradually decreasing concentrations of 50 µl each were used. The AMX concentrations used were: 50-25-12.5-6.25-3.1-1.6-0.8-0.4-0.20-0.10-0.05-0.025 µg / ml. The eucalyptol concentrations used were: 100-50-25-12.5-6.25-3.1-1.6-0.8-0.4-0.20-0.10-0.05 µl / ml. Optical density (OD) was determined at 540 nm using a microplate spectrophotometer (Versamax, Molecular Devices, USA). OD was measured at time t = 0 and after incubation at 30°C for 22 hours. According to Casey JT et al. (J. Microbiol. Meth. [Book], 2004, 58: 327–334), the percentage inhibition of the antimicrobial agent against each of the six strains was calculated using the following formula:

[0356] OD T0 = OD of the test well at t = 0, OD T22= OD of the test well after 22 h of incubation, OD C0 = OD of the positive control well at t = 0, OD C22 = OD of the positive control well after 22 h of incubation.

[0357] After determining the PIC of AMX and cineole individually, the antibacterial activity of the combination of AMX and cineole was evaluated. The same microplate microdilution technique was used. The following AMX-cineole combinations were prepared in sterile test tubes: AMX 50% PIC + cineole 40% PIC AMX 50% PIC + cineole 30% PIC AMX 50% PIC + cineole 20% PIC AMX 25% PIC + cineole 40% PIC AMX 25% PIC + cineole 30% PIC AMX 25% PIC + cineole 20% PIC The fractional inhibitory concentration index (FIC index), which represents the degree of synergism of the AMX-cineole combination, was calculated according to the following formula (Odds F.C. et al., J. Antimicrob. Chemoth. [book], 2003, 52: page 1).

[0358]

[0359] The AMX-cineole combination is considered as: Synergistic, when the FIC index ≤ 0.5; Additive, when 0.5 < FIC index < 1; Indifferent, when 1 < FIC index < 2; Antagonistic, when the FIC index > 2.

[0360] Results

[0361] Determination of PIC for amoxicillin and eucalyptol

[0362] AMX against 3 strains of E. coli and K. pneumoniaeThe three strains of eucalyptol showed comparable antibacterial activity (see Table 1). The minimum inhibitory concentration (MIC, the lowest concentration at which 100% inhibition is achieved) was in the order of 50 µg / ml (p > 0.05). Eucalyptol showed antibacterial activity against *Escherichia coli* (…). E. coli 3 strains of Klebsiella pneumoniae and Klebsiella pneumoniae K. pneumoniae Three strains also showed considerable antibacterial activity (see Table 2). The MICs were in the range of 100 µl / ml (p > 0.05).

[0363]

[0364] Table 1: Partial Inhibitory Concentrations of Amoxicillin

[0365] Table 2: Partial Inhibitory Concentrations of Eucalyptol

[0366] Assessment of the inhibitory percentage of the combination of amoxicillin and eucalyptol

[0367] The combination of AMX and eucalyptol yielded a higher percentage of inhibition than the sum of the two (see Tables 3 and 4). Specifically, the combination of 50% PIC AMX (1.1–1.7 µg / ml) and 40% PIC eucalyptol (6.2–7.1 µl / ml) produced 100% growth inhibition in all tested strains.

[0368]

[0369] Table 3: Inhibition percentage of combinations of AMX (50% PIC) with eucalyptol (40% PIC, 30% PIC, and 20% PIC)

[0370] Table 4: Inhibition percentage of combinations of AMX (25% PIC) with eucalyptol (40% PIC, 30% PIC, and 20% PIC)

[0371] This strong synergistic effect was confirmed by calculating the fractional index (FIC index, see Table 5) of the MICs of amoxicillin and eucalyptol. For the six bacterial strains tested, these values ​​varied between 0.08 and 0.10. These results, less than 0.5, are evidence of a strong synergistic effect between AMX and eucalyptol.

[0372]

[0373] Table 5: FIC Index of Amoxicillin and Eucalyptol Combinations

[0374] discuss

[0375] The results clearly showed that the tested strains, which were highly resistant to AMX, became sensitive at the lowest possible AMX concentrations when AMX was combined with eucalyptol. Therefore, 100% growth inhibition was achieved for all tested bacterial strains using the AMX-eucalyptol combination (50% IC + 40% IC). This combination makes it possible to obtain antibacterial efficacy similar to that of AMX or eucalyptol alone when used at concentrations significantly lower than their MICs. Specifically, by comparing the concentrations used for 100% inhibition, it was noted that the concentration of AMX used in the combination with eucalyptol was 25 times lower than that of AMX alone, and the concentration of eucalyptol used in the combination with AMX was 15 times lower than that of eucalyptol alone.

[0376] The bactericidal activity of this combination of AMX and eucalyptol is produced by a strong synergistic effect, as confirmed by calculations of the fractional index (index less than or equal to 0.1).

[0377] These trials, in general, confirmed the efficacy of the combination of AMX and eucalyptol against BSBL-resistant bacteria and its value in the fight against further bacterial resistance.

[0378] Example 2 - In vitro study of the effect of eucalyptol on the inhibition of amoxicillin by β-lactamase

[0379] This study was based on the following enzymatic experiments: first, AMX combined with eucalyptol was contacted with β-lactamase, and then Escherichia coli (E. coli) Escherichia coli The antibacterial activity of this antibiotic was examined on AMX-sensitive strains.

[0380] Materials and methods

[0381] Biological materials, culture media and antimicrobial agents

[0382] Escherichia coli ( Escherichia coli The amoxicillin-sensitive bacterial strain (ATCC 8739) was supplied by the National Institutes of Health (INH-Rabat).

[0383] For each experiment conducted, this *Escherichia coli* strain (previously frozen at -20°C) was prepared from this bacterial strain. E. coli Pre-cultures of the strain were prepared at 37°C for 24 h. 3.3 x 10⁻⁶ cells / mL were then prepared from these pre-cultures. 6 The bacterial inoculum was prepared at CFU / ml, and the optical density was adjusted to 540 nm.

[0384] Liquid and agar Mueller-Hinton medium were supplied by BIOKAR (France). The composition of this medium has been described previously. Both media were prepared according to the supplier's instructions.

[0385] Round paper discs (diameter Ø = 6 mm) loaded with antibiotics were used for enzymatic tests in agar medium (AMX: amoxicillin and AMC: amoxicillin + clavulanic acid). They were supplied by the National Institutes of Health (INH-Rabat). AMX used for enzymatic tests in liquid medium was supplied by Sigma Aldrich (France).

[0386] Eucalyptol was supplied by Sigma Aldrich (France). It was prepared according to the method described by Remmal et al. (J. Essent. Oil. Res. [Book], 1993, 5: pp. 1179-1184), by emulsification in 0.2% (v / v) agar.

[0387] β-lactamase powder was supplied by Sigma Aldrich (France). It was dissolved at a concentration of 10 mg / ml in 0.1 M Tris HCl at pH 7 containing 0.1% gelatin, according to the supplier's instructions. The resulting β-lactamase (0.03 U / ml) was stored between 2 and 8°C.

[0388] Experimental procedures in agar medium

[0389] In agar medium, the infra-inhibitory concentration (the highest concentration at which eucalyptol does not cause any inhibition) was determined by the microdilution method described above. It was on the order of 0.002 µl / ml.

[0390] From Escherichia coli ( E. coli Starting with a 24-hour sensitivity pre-culture, 18 Piper dishes were inoculated with agar MH medium on the surface. Six control dishes and two experimental dishes were prepared as follows: Petri dishes 1 and 2 correspond to controls for the strain's sensitivity to antibiotics: - Control 1: Three round paper discs containing only 20 µg / ml AMX were aseptically placed on the surface of culture dish 1.

[0391] - Control 2: Three round paper discs containing only 30 µg / ml AMC were aseptically placed on the surface of culture dish No. 2.

[0392] Petri dishes 3 and 4 correspond to controls for the activity of β-lactamase against antibiotics: - Control 3: Three discs loaded with 20 µg / ml AMX were aseptically placed on the surface of Petri dish #3. 10 µl of 0.03 U / ml β-lactamase was added to the surface of each of the three discs.

[0393] - Control 4: Aseptically place three discs loaded with 30 µg / ml AMC on the surface of culture dish 4. Add 10 µl of 0.03 U / ml β-lactamase to the surface of each of the three discs.

[0394] Petri dishes 5 and 6 correspond to controls for the antibacterial activity of the combination of antibiotics and eucalyptol (subinhibitory concentration): - Control 5: Three discs loaded with 20 µg / ml AMX were aseptically placed on the surface of Petri dish #5. 10 µl of 0.002 µl / ml eucalyptol was added to the surface of each of the three discs.

[0395] - Control 6: Three discs loaded with 30 µg / ml AMC were aseptically placed on the surface of Petri dish 6. 10 µl of 0.002 µl / ml eucalyptol was added to the surface of each of the three discs.

[0396] Petri dishes 7 and 8 correspond to the experiment on the effect of eucalyptol on the inhibition of amoxicillin by β-lactamase: - Experiment 1: Three discs loaded with 20 µg / ml AMX were aseptically placed on the surface of Petri dish 7. 10 µl of 0.03 U / ml β-lactamase and 10 µl of 0.002 µl / ml eucalyptol were added to the surface of each of the three discs.

[0397] - Experiment 2: Three discs loaded with 30 µg / ml AMC were aseptically placed on the surface of Petri dish No. 8. 10 µl of 0.03 U / ml β-lactamase and 10 µl of 0.002 µl / ml eucalyptol were added to the surface of each of the three discs.

[0398] After incubating the eight Petri dishes at 37°C for 18 hours, the diameter of the inhibition zone was measured.

[0399] Experimental procedures in liquid culture media

[0400] The AMX concentration against Escherichia coli was determined using the microdilution method described above. Escherichia coli The 100% MIC of the susceptible strain is in the range of 6 µg / ml.

[0401] From Escherichia coli ( E. coli Starting with a 24-hour pre-culture of the susceptible strain, prepare 3.3 x 10⁻⁶ cultures. 6 The bacterial inoculum was prepared at CFU / ml, and the optical density was adjusted to 540 nm.

[0402] Prepare 5 control tubes and 1 test tube as described in Table 6 (see below).

[0403] Tube 1 corresponds to the sterility control of the culture medium. Tube 2 corresponds to the positive control of bacterial strain viability. Tube 3 corresponds to the control of the strain's sensitivity to AMX. Tube 4 corresponds to the control showing no inhibition of bacterial growth when using sub-inhibitory concentrations of eucalyptol. Tube 5 corresponds to the control of AMX degradation in the presence of β-lactamase. Tube 6 corresponds to the test of the effect of eucalyptol on the inhibition of amoxicillin by β-lactamase.

[0404]

[0405] Table 6: Contents of control and test tubes used in studies in liquid culture media

[0406] OD was measured at t = 0 and after a 22-hour incubation at 30°C. The inhibition percentage was then calculated using the formula described earlier.

[0407] OD T0 = The OD of the test tube at t = 0, OD T22 = After incubating in a warm water bath for 22 hours, the OD of the test tube was measured. C0 = OD of the positive control tube at t = 0, OD C22 = OD of the positive control tube after 22 h of incubation.

[0408] result

[0409] In agar medium (See Table 7 below)

[0410] Table 7: Diameter of inhibition zones of susceptible Escherichia coli (in mm) The average of the three inhibition zone values Measurements of the diameter of the inhibition zone showed: - The Escherichia coli used ( E. coli The strain was indeed sensitive to AMX (20 µg) and the combination of AMX and clavulanic acid (AMC 30 µg), with inhibition zone diameters of 15 and 16 mm, respectively.

[0411] - Adding a sub-inhibitory concentration (0.002 µl / ml) of eucalyptol slightly increased the size of the inhibition zone, to 17 mm for AMX (20 µg) and to 18 mm for AMC (30 µg).

[0412] - The addition of β-lactamase (0.03 U / ml) eliminated the AMX inhibition zone (20 µg) (6 mm is the diameter of the circular paper) and reduced the AMC inhibition zone (30 µg) to about 13 mm.

[0413] - The addition of β-lactamase (0.03 U / ml) and eucalyptol (0.002 µl / ml) significantly reduced the inhibition caused by β-lactamase, with inhibition zones on the order of 12 mm for AMX (20 µg) and on the order of 15 mm for AMC (30 µg).

[0414] In liquid culture medium (See Table 8 below)

[0415] Table 8: Percentage inhibition of growth of susceptible Escherichia coli strains

[0416] Table 8 shows: - The concentration of eucalyptol used (0.002 µl / ml) was indeed a sub-inhibitory concentration, with no growth inhibition (Control 4).

[0417] - In the presence of β-lactamase (0.03 U / ml), the growth of sensitive strains treated with AMX (6 µg / ml) was inhibited by a percentage of zero (Control 5).

[0418] - In the presence of β-lactamase (0.03 U / ml) and eucalyptol (0.002 µl / ml), the growth of susceptible strains treated with AMX (6 µg / ml) was inhibited by an order of magnitude of 83.4% (Experiment 1).

[0419] discuss

[0420] The studies conducted on agar medium can show that: - In the presence of subinhibitory concentrations of eucalyptol, the antibacterial activity of AMX and AMC is enhanced (the diameter of the inhibition zone is larger than that obtained using the antibiotics alone). Therefore, the activity of AMX and AMC is enhanced in the presence of eucalyptol (subinhibitory concentration).

[0421] - In the presence of β-lactamase, inhibition induced by AMX (20 µg) was zero, and inhibition induced by AMC (30 µg) was significantly reduced. This is due to the hydrolysis of the β-lactam ring of amoxicillin. β-lactamase is only partially inhibited by clavulanic acid.

[0422] - In the presence of β-lactamase and eucalyptol, the antibacterial activity of AMX and AMC is enhanced (the diameter of the inhibition zone obtained is comparable to that obtained using the antibiotic alone). The enhanced antibacterial activity at sub-inhibitory concentrations of eucalyptol can be explained by the reduced efficacy of β-lactamase against amoxicillin in the presence of eucalyptol.

[0423] The studies conducted in liquid culture media can show that: - In the presence of β-lactamase, AMX completely loses its antibacterial activity, which proves that this antibiotic is completely degraded through the hydrolysis of the β-lactam ring.

[0424] - In the presence of β-lactamase and eucalyptol, AMX exhibited an inhibition percentage on the order of 83.4%. These results demonstrate that, in the presence of sub-inhibitory concentrations of eucalyptol, AMX acquires protective activity against β-lactamase, which no longer maintains its activity. Therefore, the antibacterial activity of AMX is preserved.

[0425] These results, in general, suggest that amoxicillin in combination with eucalyptol is only slightly sensitive to β-lactamases. Not limited to this theory, this could be due to the complexation of the amoxicillin molecule in the presence of eucalyptol, which prevents β-lactamases from attacking the β-lactam ring of AMX.

[0426] Example 3 – Study on the antibacterial activity of rabbit serum treated with a combination of amoxicillin, clavulanic acid and eucalyptol

[0427] Materials and methods

[0428] Biological materials, culture media and antimicrobial agents

[0429] Escherichia coli ( Escherichia coli The multidrug-resistant BSBL bacterial strain was supplied by the National Institutes of Health (INH-Rabat). A 24-hour preculture at 37°C was prepared using the bacterial strain (previously frozen at -20°C). 2 x 10⁻⁶ cultures were prepared using these precultures. 7 The bacterial inoculum was prepared at CFU / ml, and the optical density was adjusted to 540 nm.

[0430] Liquid and agar Mueller-Hinton (MH) media were supplied by BIOKAR (France). The composition of this medium has been described above. Both media were prepared according to the supplier's instructions.

[0431] The six rabbits used in this study were New Zealand female rabbits supplied by a professional breeder. They were 70 to 75 days old and weighed approximately 2 kg. They were randomly divided into two groups of three rabbits each and were free-range fed a fattening type of industrial feed.

[0432] Experimental Procedure

[0433] The first batch of rabbits received a single dose of AMC, which contained 1.5 g amoxicillin and 186.5 mg clavulanic acid. The second batch of rabbits received a single dose of AMC in combination with eucalyptol, which contained 1.5 g amoxicillin, 186.5 g clavulanic acid, and 300 mg eucalyptol.

[0434] The solutions of the two treatments, reconstituted with pure water, were administered to rabbits via enteral tube feeding.

[0435] After the treatment was administered, the rabbits were restrained using a suitable device. Their ears were exposed to an infrared lamp to cause the peripheral and central ear veins to swell. Blood samples of 0.5 ml were then collected from the central ear vein at T = 0 (T0) (before administration), T1 (1 hour later), T2 (2 hours later), T3 (3 hours later), and T6 (6 hours later).

[0436] The inhibition percentage of serum samples was determined using the microdilution method described above.

[0437] 96-well U-shaped sterile microplates with a capacity of 200 µl were used. The negative control consisted of 200 µl of liquid MH medium, and the positive control consisted of 150 µl of liquid MH medium and 50 µl of 2x10⁻⁶ microplates. 7 CFU / ml bacterial inoculum composition. Two wells were prepared for each serum sample collected at a given time, each containing 100 µl of liquid MH medium and 50 µl of 2x10... 7 CFU / ml bacterial inoculum and 50 µl serum.

[0438] For each sample, OD readings were acquired at t = 0 and after the microplate was incubated at 30°C for 22 hours. The inhibition percentage for each serum sample was calculated using the formula described earlier.

[0439] Among them OD T0 = OD of the test hole at t = 0, ODT22 = OD of the test well after 22 h in a warm bath, OD C0 = OD of the positive control well at t = 0, OD C22 = OD of the negative control well after 22 h of incubation.

[0440] result

[0441] Figure 1 The percentage of bacterial growth inhibition is shown in serum samples from rabbits treated with AMC alone (amoxicillin / clavulanic acid combination) and AMC enhanced with eucalyptus oil, monitored over time.

[0442] Prior to the treatment (time T0), the antibacterial activity of serum samples from both batches of rabbits was virtually zero. One hour after the treatment (T1), the inhibition induced by serum from rabbits treated with AMC alone was on the order of 40 ± 1.2%, while the inhibition induced by serum from rabbits treated with both AMC and eucalyptol was on the order of 47 ± 2.1%. Two hours after treatment, the inhibition percentage was 50 ± 2.5% for serum from rabbits treated with AMC alone and 54 ± 2.9% for serum from rabbits treated with AMC enhanced with eucalyptol. Three hours after treatment, the inhibition percentage decreased to 41 ± 3.2% for rabbits treated with AMC alone and 48 ± 1.6% for rabbits treated with AMC enhanced with eucalyptol. Finally, after 6 hours of treatment, the inhibition percentage decreased to 16 ± 1.3% for serum from rabbits treated with AMC alone, while for rabbits treated with AMC enhanced with eucalyptus oil, they remained in the order of 44 ± 1.5%.

[0443] Therefore, the inhibition percentage obtained using serum samples from the first batch of rabbits treated with a combination of amoxicillin, clavulanic acid, and eucalyptol was significantly higher than that obtained using serum samples from the reference batch of rabbits treated with a combination of amoxicillin and clavulanic acid (p < 0.05).

[0444] Example 4 – Development of a Galen Formulation Containing Amoxicillin, Clavulanic Acid, and Eucalyptol

[0445] Materials and methods

[0446] All starting materials, active ingredients, and excipients used are pharmaceutical grade.

[0447] This formulation is characterized by the presence of eucalyptol, a volatile active ingredient. To stabilize this volatile compound, several excipients or combinations of excipients with adsorbent properties were tested (see Table 9 below).

[0448] The method for testing dosage form 8 (peanut oil) includes the step of introducing granules obtained by wetting a mixture of other active ingredients, amoxicillin, and clavulanic acid with excipients with an oil phase containing eucalyptol. Lubrication, mixing, and sieving steps may follow the wetting step.

[0449]

[0450] Table 9: Composition of the adsorbent in the test formulation

[0451] All starting materials are sieved on various grids of a Frewitt screen before mixing.

[0452] The mixing of the starting materials is carried out in a HOBART mixer.

[0453] Bagging was performed using a MARCHESINI bagging machine.

[0454] The temperature and relative humidity in the manufacturing room are on the order of < 20℃ and < 15%, respectively.

[0455] The wetting solution for the eucalyptus stabilization process is prepared in a closed chamber to avoid any evaporation.

[0456] For each test dosage form, complete quality control was performed, including the dosage of the three active ingredients (amoxicillin, clavulanic acid, and eucalyptol): On the final mixture, at the end of manufacturing (10 sampling points), at T0, and after exposure to < 20°C and < 15% ambient humidity for 24 h, 48 h, and 72 h; At the end of filling, on the bag (10 sampling points).

[0457] An active ingredient content (%) between 95% and 105% is considered acceptable. The homogeneity of the mixture is checked by calculating the coefficient of variation (CV %) for each content obtained from 10 sampling points. A CV % less than or equal to 2% is considered acceptable.

[0458] result

[0459] For all tested formulations (formulas 1 to 8), the average content of amoxicillin and clavulanic acid was acceptable. For eucalyptol (see Table 10 below), formulations 1 to 7 showed eucalyptol content below 95% in the final mixture, which further decreased significantly after exposure to <20°C and <15% ambient humidity for 24 h, 48 h, and 72 h.

[0460] However, formulation 8 (peanut oil) can stabilize eucalyptol. Specifically, the eucalyptol content present in this formulation is between 95% and 105% in the final mixture and remains within this range after exposure to <20°C and <15% ambient humidity for 24 h, 48 h, and 72 h.

[0461] For dosage form 8, the uniformity of the final mixture and packaging is also acceptable, and the coefficient of variation (CV %) of the content does not exceed 2%.

[0462]

[0463] Table 10: Variation of eucalyptol content (%) with different adsorbents in the experiment

[0464] Furthermore, quantitative tests for impurities in the three active ingredients (amoxicillin, clavulanic acid, and eucalyptol) in the final mixtures exposed to <20°C and <15% ambient humidity for 24 h, 48 h, and 72 h all met the acceptance criteria (results not shown). Other tests for the mass of the final mixture and its distribution in the bags also met the acceptance criteria (results not shown).

[0465] Example 5 – Examples of pharmaceutical formulations conforming to the present invention Adjust the amount of microcrystalline cellulose to make the total weight 3 g.

[0466] This formulation is obtained through the following process: Step 1: Sieving and Premixing Avicel PH 112, croscarmellose sodium, and Syloid Al were mixed after sieving.

[0467] Step 2: Compacting

[0468] 2-1 Amoxicillin

[0469] Amoxicillin trihydrate was mixed with a portion of the powder premix obtained in step 1, and then compacted. The resulting particles were then calibrated and graded.

[0470] 2-2 Clavulanic acid

[0471] Clavulanic acid was mixed with a portion of the powder premix obtained in step 1, and then compacted. The resulting particles were then calibrated and graded.

[0472] Step 3: Granulation

[0473] 3-1 Preparation of wetting solution (S1)

[0474] The wetting solution is obtained by mixing eucalyptol and peanut oil in a closed container and then grading.

[0475] 3-2 Moistening

[0476] The fraction of the compacted mixture containing amoxicillin obtained in step 2 is wetted with the fraction of solution S1 and then mixed. The fraction of the compacted mixture containing clavulanic acid obtained in step 2 is added.

[0477] 3-3 Mix

[0478] Combine and mix the different grades.

[0479] Step 4: Lubrication

[0480] The aspartame and flavoring composition are mixed after sieving. Then magnesium stearate is added.

[0481] Step 5: Sieving and final mixing

[0482] Sift the final powder and then mix it for a few minutes.

[0483] Step 6: Allocation

[0484] Dispense the final mixture into bags.

[0485] Step 7: Repackage in a box

[0486] Example 6 – Stability study of a pharmaceutical formulation containing amoxicillin, clavulanic acid, eucalyptol, and peanut oil in powder form.

[0487] Materials and methods

[0488] The stability of the pharmaceutical formulation of Example 5 was tested under three different conditions (see Table 11).

[0489]

[0490] Table 11: Experimental conditions for formulation stability studies

[0491] An artificial climate chamber with controlled temperature and relative humidity is used to maintain the formulation under the selected conditions.

[0492] For condition 1, quality control is conducted every three months in the first year and every six months in the second year (0, 3, 6, 9, 12, 18, and 24 months).

[0493] For conditions 2 and 3, quality control shall be carried out every three months (0, 3, 6, 9 and 12 months for condition 2, and 0, 3 and 6 months for condition 3).

[0494] This quality control involves: Control sensory quality, water content, and pH of the suspension.

[0495] Dosage of the three active ingredients (amoxicillin, clavulanic acid, and eucalyptol).

[0496] Quantitative analysis of impurities in the three active ingredients.

[0497] Microbiological control.

[0498] result

[0499] Under all three conditions, the contents of the three active ingredients were measured to be between 95% and 105% throughout the study (see Tables 12 to 14 below), confirming the stability of the composition.

[0500]

[0501] Table 12: Results of the stability study under condition 1

[0502] Table 13: Results of the stability study under condition 2

[0503] Table 14: Results of the stability study under condition 3

[0504] For the three conditions mentioned above, the quantitative analysis of impurities in the three active ingredients also meets the acceptance criteria (results not shown).

[0505] Other controlled parameters (water content, appearance of powder and reconstituted suspension, pH of reconstituted suspension and microbiological control) met the acceptance criteria (results not shown).

[0506] Therefore, the formulations of the present invention retain their chemical, physical, sensory and microbiological properties under the three experimental conditions.

[0507] Example 7 – Pharmacokinetic Study in Humans

[0508] Experimental procedure: Forty-eight healthy volunteers were recruited for these experiments.

[0509] In the first experiment, volunteers were divided into two groups of 12 each and orally received either 12 g of the composition of Example 5 (i.e., a total of 2 g amoxicillin, 250 mg clavulanic acid, and 400 mg eucalyptol) or 12 g of a composition identical in all respects except for the absence of eucalyptol. Blood samples were collected every 30 minutes for the first 3 hours, then every hour up to 6 hours, and then at 8, 10, and 24 hours. The plasma concentration of amoxicillin in the collected samples was determined by chromatography, and serum amoxicillin kinetics were analyzed.

[0510] In the second experiment, volunteers were divided into two groups of 12. Both groups initially received the same dose as in the previous experiment, followed by a maintenance dose of 3 g of the same composition three times daily for one week. This included either 3 g of the composition from Example 5 three times daily (i.e., 500 mg amoxicillin, 62.5 mg clavulanic acid, and 100 mg eucalyptol per dose) or 3 g of the same composition three times daily except for the absence of eucalyptol. Blood samples were collected every 24 hours (at the lowest concentration) and at peak concentrations (t = 26 h, 50 h, 72 h, etc.) for 7 days. Plasma concentrations of amoxicillin in the collected samples were determined by chromatography, and serum amoxicillin kinetics were analyzed.

[0511] Amoxicillin kinetics 24 h after a single dose: The monitoring curves for mean serum amoxicillin concentrations obtained in volunteers treated with amoxicillin and clavulanic acid or a combination of amoxicillin, clavulanic acid, and eucalyptol almost perfectly overlapped, despite strong inter-individual variability (see [link]). Figure 2 They have the same shape during the absorption phase and reach peak concentration (Cmax) at approximately 2.5 hours for both dosage forms. Concentrations begin to decline at and after 2.5 hours for both dosage forms, and the two elimination curves remain almost parallel between administration and 24 hours later.

[0512] For all pharmacokinetic parameters studied, i.e., the area under the curve (AUC0- t The highest concentration (Cmax), peak time (Tmax), and half-life (t) 1 / 2 For the two conditions, the obtained values ​​did not differ significantly (see Table 15 below).

[0513] The relative bioavailability of amoxicillin formulations containing eucalyptol relative to those without is: F(AUC). 0.888.

[0514] These results lead to the conclusion that the two compositions studied have the same bioavailability.

[0515]

[0516] Table 15: Pharmacokinetic parameters of serum amoxicillin

[0517] Amoxicillin pharmacokinetics during repeated-dose administration (7 days): The monitoring curves for the mean serum concentrations of amoxicillin obtained from volunteers treated with amoxicillin and clavulanic acid or a combination of amoxicillin, clavulanic acid and eucalyptol almost perfectly overlapped (see [link]). Figure 3 ).

[0518] These results show that the two compositions studied exhibited the same pharmacokinetic behavior during repeated dosing.

[0519] Example 8 - Clinical trial conducted in patients with susceptible bacterial infections

[0520] The aim of this clinical trial was to evaluate the efficacy of a formulation containing amoxicillin, clavulanic acid, and eucalyptol relative to a formulation containing only amoxicillin and clavulanic acid in patients with amoxicillin-susceptible bacterial urinary tract infections. This randomized clinical trial was conducted in a cohort of 28 patients, who were randomly assigned to two groups (or branches) of 14 patients each. Patients in each group received treatment in parallel for 7 days. The patients were men and women over 20 years of age.

[0521] Antimicrobial spectrum studies conducted on the patients prior to the start of treatment confirmed that they all had urinary tract infections caused by susceptible bacteria.

[0522] Efficacy evaluation criteria: The efficacy of the treatment was assessed by cytological examination of urine (CBEU) performed at the end of treatment.

[0523] Products and dosages

[0524] The test formulation of Example 5 (amoxicillin, clavulanic acid, and eucalyptol) contains 500 mg amoxicillin, 62.5 mg clavulanic acid, and 100 mg eucalyptol per 3 g powder (corresponding to the contents of one sachet).

[0525] Eligible patients suitable for treatment in this study were randomly assigned to the study according to a randomization table: - On the first day, administer 12 grams of the test formulation (4 sachets in a single dose), followed by 3 sachets of the same formulation daily (one sachet in the morning, one sachet at noon, and one sachet in the evening) for a total of 6 days (branch A).

[0526] - On the first day, administer 12 grams of the test formulation (4 sachets in a single dose), followed by 6 sachets of the same formulation daily (two sachets in the morning, two sachets at noon, and two sachets in the evening) for a total of 6 days (branch B).

[0527] Table 16 below summarizes the distribution of patients in each branch prior to treatment and the nature of bacterial infections detected during CBEU.

[0528] result: Except for one patient in branch A (patient 2) for whom the treatment was ineffective, the treatment was effective in all other cases (eliminating the bacteria initially detected).

[0529] The treatment has also proven effective even in some patients who are considered more complicated due to the difficulty in eradicating the infection, namely those presenting with benign prostatic hyperplasia, diabetes, urethral stricture, urinary diversion, bladder stones, or bladder tumors.

[0530] In summary, the tested treatments (amoxicillin, clavulanic acid, and eucalyptol) are as effective as the reference treatments (amoxicillin and clavulanic acid) in treating urinary tract infections caused by susceptible bacteria, including urinary tract infections in difficult cases.

[0531]

[0532] Table 16: Patient characteristics and their distribution

[0533] Example 9 – Clinical trial in patients with drug-resistant bacterial infections

[0534] The aim of this clinical trial was to evaluate the efficacy of a drug formulation containing amoxicillin, clavulanic acid, and eucalyptol in patients with urinary tract infections caused by bacteria resistant to the combination of amoxicillin and clavulanic acid. This clinical trial was conducted in a cohort of 23 patients treated for 7 days.

[0535] The tested formulation (refer to Example 2) is a powder, and each 3 grams of powder (corresponding to the contents of one sachet) contains 500 mg of amoxicillin, 62.5 mg of clavulanic acid and 100 mg of eucalyptol.

[0536] Each patient first received a 12-gram loading dose (4 sachets in a single dose) of the test formulation on the first day, followed by 6 sachets of the same formulation daily (two sachets in the morning, two sachets at noon, and two sachets in the evening) for a total of 6 days.

[0537] Table 17 below summarizes the characteristics of the patients in this trial, including the nature of bacterial infections detected during CBEU prior to treatment.

[0538] result: Except for one patient (Patient 6), the treatment was effective in all other cases (eliminating the bacteria initially detected).

[0539] The case of patient number 22 is particularly interesting. Specifically, this patient presented with a urinary tract infection that was considered refractory to almost all available antibiotics tested over nearly 20 years, including amoxicillin and clavulanic acid, and was cured using a formulation conforming to the present invention.

[0540] In summary, the formulations comprising amoxicillin, clavulanic acid, and eucalyptol according to the present invention have been shown to be highly effective against urinary tract infections caused by bacteria resistant to the reference treatment, namely formulations comprising amoxicillin and clavulanic acid.

[0541]

[0542] Table 17: Patient Characteristics

[0543] Example 10 – Spectroscopic Study of the Formation of Amoxicillin Complex

[0544] Spectroscopic analysis was performed using a solution containing 500 mg amoxicillin dissolved in 100 ml of water and, where appropriate, 62.5 mg clavulanic acid or 100 mg eucalyptol.

[0545] Mass spectrometry analysis of amoxicillin dissolved in water (see) Figure 4 -A) shows the presence of a main peak corresponding to molecular amoxicillin (peak at 349.06 amu) and another peak corresponding to the dimer form of amoxicillin (peak at 731.17 amu). The amplitude of the amoxicillin dimer peak is much smaller than that of the molecular amoxicillin peak. Therefore, when present alone in solution, amoxicillin is predominantly in its molecular form.

[0546] When amoxicillin dissolved in the presence of eucalyptol, new peaks appeared in the mass spectrum in addition to those already observed for amoxicillin alone (see [link to mass spectrometry]). Figure 4 -B). These peaks correspond to amoxicillin trimer (peak at 1134.24 amu) and amoxicillin tetramer (peak at 1499.34 amu).

[0547] However, when amoxicillin was dissolved in the presence of clavulanic acid and in the absence of eucalyptol, the spectrum of amoxicillin remained unchanged (results not shown).

[0548] Therefore, the addition of eucalyptol allows amoxicillin molecules in solution to rearrange into oligomers of 3 to 4 amoxicillin molecules. This rearrangement was not observed when amoxicillin was present only in the presence of clavulanic acid.

Claims

1. A pharmaceutical preparation in powder form comprising eucalyptol, amoxicillin, and peanut oil, wherein the mass ratio of eucalyptol to peanut oil in the preparation is 2:1, and wherein the preparation is free of detergents.

2. The formulation according to claim 1, wherein the formulation further comprises a β-lactamase inhibitor.

3. The formulation according to claim 1 or 2, wherein the formulation comprises 5 mg to 100 mg of eucalyptol per gram of powder.

4. The formulation according to claim 1 or 2, wherein the formulation comprises 10 mg to 50 mg of eucalyptol per gram of powder.

5. The formulation according to claim 1 or 2, wherein the formulation comprises 20 mg to 40 mg of eucalyptol per gram of powder.

6. The formulation according to claim 1 or 2, wherein the formulation comprises 33 mg of eucalyptol per gram of powder.

7. The formulation according to claim 1 or 2, wherein the formulation comprises 20 mg to 500 mg of amoxicillin per gram of powder.

8. The formulation according to claim 1 or 2, wherein the formulation comprises 50 mg to 300 mg of amoxicillin per gram of powder.

9. The formulation according to claim 1 or 2, wherein the formulation comprises 150 mg to 200 mg of amoxicillin per gram of powder.

10. The formulation according to claim 1 or 2, wherein the formulation comprises 167 mg of amoxicillin per gram of powder.

11. The formulation according to claim 1 or 2, wherein the formulation comprises 2 mg to 50 mg of peanut oil per gram of powder.

12. The formulation according to claim 1 or 2, wherein the formulation comprises 10 mg to 25 mg of peanut oil per gram of powder.

13. The formulation according to claim 1 or 2, wherein the formulation comprises 15 mg to 20 mg of peanut oil per gram of powder.

14. The formulation according to claim 1 or 2, wherein the formulation comprises 17 mg of peanut oil per gram of powder.

15. The formulation according to claim 2, wherein the β-lactamase inhibitor is clavulanic acid and the formulation comprises 1 mg to 100 mg of clavulanic acid per gram of powder.

16. The formulation according to claim 2, wherein the β-lactamase inhibitor is clavulanic acid and the formulation comprises 5 mg to 50 mg of clavulanic acid per gram of powder.

17. The formulation according to claim 2, wherein the β-lactamase inhibitor is clavulanic acid and the formulation comprises 15 mg to 25 mg of clavulanic acid per gram of powder.

18. The formulation according to claim 2, wherein the β-lactamase inhibitor is clavulanic acid and the formulation comprises 21 mg of clavulanic acid per gram of powder.

19. The formulation according to claim 1 or 2, wherein the mass ratio of amoxicillin to eucalyptol is 2 to 8.

20. The formulation according to claim 1 or 2, wherein the mass ratio of amoxicillin to eucalyptol is 4 to 6.

21. The formulation according to claim 1 or 2, wherein the mass ratio of amoxicillin to peanut oil is 5 to 15.

22. The formulation according to claim 1 or 2, wherein the mass ratio of amoxicillin to peanut oil is 10.

23. The formulation according to claim 2, wherein the mass ratio of amoxicillin to β-lactamase inhibitor is 5 to 11.

24. The formulation according to claim 2, wherein the mass ratio of amoxicillin to β-lactamase inhibitor is 8.

25. The formulation according to claim 1 or 2, wherein the formulation is intended for oral administration.

26. The formulation according to claim 1 or 2, wherein the formulation is packaged in a single-dose container.

27. The formulation according to claim 1 or 2, wherein the formulation is packaged in a single-dose container containing 1 g to 150 g of powder.

28. The formulation according to claim 1 or 2, wherein the formulation further comprises at least one pharmaceutically acceptable excipient or carrier.

29. The formulation according to claim 2, wherein the β-lactamase inhibitor is clavulanic acid.

30. Use of the formulation according to any one of claims 1-29 in the preparation of a medicament for treating an infectious disease in an individual.

31. The use according to claim 30, wherein the individual is an animal.

32. The use according to claim 30, wherein the individual is a person.

33. The use according to any one of claims 30 to 32, wherein the disease is an infectious disease of bacterial origin.

34. The use according to any one of claims 30 to 32, wherein the disease is an infectious disease caused by bacteria resistant to β-lactam antibiotics.

35. The use according to any one of claims 30 to 32, wherein the formulation is intended to be administered to the individual in one or more doses at a rate of 3 to 30 grams per day over a period of 1 day to 4 weeks.

36. The use according to any one of claims 30 to 32, wherein the dose of eucalyptol intended to be administered to said individual is from 0.1 mg / kg body weight / day to 50 mg / kg body weight / day.

37. The use according to any one of claims 30 to 32, wherein the dose of amoxicillin intended to be administered to said individual is from 5 mg / kg body weight / day to 200 mg / kg body weight / day.

38. The use according to any one of claims 30 to 32, wherein the formulation comprises a β-lactamase inhibitor and wherein the dose of the β-lactamase inhibitor intended to be administered to the individual is from 0.1 mg / kg body weight / day to 50 mg / kg body weight / day.

39. The use according to any one of claims 30 to 32, wherein the formulation is intended for administration to the individual at a frequency of one or more doses per day over a period of 1 day to 4 weeks.

40. The use according to any one of claims 30 to 32, wherein the formulation comprises a β-lactamase inhibitor and wherein amoxicillin and the β-lactamase inhibitor are intended to be administered simultaneously to the individual.

41. The use according to any one of claims 30 to 32, wherein eucalyptol, amoxicillin, and optionally a β-lactamase inhibitor are intended to be administered simultaneously.

42. The use according to claim 33, wherein the bacterial infectious disease is selected from cystitis, bacterial sinusitis, otitis, bronchitis, bronchopulmonary disease, pyelonephritis, upper genital tract infection, periodontitis, severe oral infection, animal bite, or bone and joint infection.

43. The use according to claim 42, wherein the cystitis is recurrent acute cystitis, the bacterial sinusitis is acute maxillary sinusitis, the otitis is acute otitis media, the bronchitis is chronic and / or acute bronchitis, the bronchopulmonary disease is chronic and / or acute bronchopulmonary disease, the severe oral infection is an abscess or cellulitis, and the bone and joint infection is osteomyelitis.

44. The use according to claim 33, wherein the bacterial infectious disease is cystitis caused by bacteria resistant to β-lactam antibiotics.

45. The use according to claim 38, wherein the β-lactamase inhibitor is clavulanic acid.

46. ​​A method for manufacturing a pharmaceutical preparation according to any one of claims 1 to 29, the method comprising: - A wetting solution is produced by mixing eucalyptol and peanut oil at a mass ratio of eucalyptol / peanut oil of 2:1; - Wet the powder containing amoxicillin with the wetting solution to obtain a powdered preparation containing amoxicillin, eucalyptol and the peanut oil; - Optionally, the method may further include mixing the powdered preparation containing amoxicillin, eucalyptol, and the peanut oil with a powder containing a β-lactamase inhibitor; and / or - Optionally, add flavoring agents and / or lubricants, and mix them to obtain a uniform powder; and / or - Optionally, the powder obtained therefrom is sieved; and / or - Optionally, the sieved powder may be packaged in a single-dose container.

47. The manufacturing method according to claim 46, wherein the powder containing amoxicillin and / or the powder containing a β-lactamase inhibitor further comprises a disintegrant and / or an anti-caking agent.

48. The manufacturing method according to claim 46, wherein the β-lactamase inhibitor is clavulanic acid.

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