WO2022220669A1 - Oral solid combination for the treatment of virus infection - Google Patents
Oral solid combination for the treatment of virus infection Download PDFInfo
- Publication number
- WO2022220669A1 WO2022220669A1 PCT/MX2021/050019 MX2021050019W WO2022220669A1 WO 2022220669 A1 WO2022220669 A1 WO 2022220669A1 MX 2021050019 W MX2021050019 W MX 2021050019W WO 2022220669 A1 WO2022220669 A1 WO 2022220669A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- agent
- hydroxychloroquine
- azithromycin
- macrolide antibiotic
- Prior art date
Links
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- 238000011282 treatment Methods 0.000 title claims description 17
- 230000009385 viral infection Effects 0.000 title description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to a solid pharmaceutical composition with improved stability and bioavailability, for use in the treatment and/or prevention of infections caused by viruses and associated diseases, disorders or symptoms; comprising: a macrolide antibiotic agent, an antimalarial agent and at least one pharmaceutically acceptable excipient.
- Hydroxychloroquine with CAS name 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol, is an antimalarial agent, useful for the suppressive treatment and attacks of malaria or malaria, due to Plasmodium vivax, P. malarie, P. ovale and P. falciparium, as well as for the treatment of rheumatoid arthritis and systemic and discoid lupus erythematosus.
- Both drugs when formulated for administration in different pharmaceutical forms such as injectable solution, tablet or suspension, present the formation of different impurities, whose origin or appearance during the stability period, lead to a decrease in the potency of the drugs.
- azithromycin it has the following impurities: N, M, G, E, O, B, I, H, J, F, C, D, erythromycin A 9, 11 -amino ether, azithromycin N-oxide, erythromycin A oxime, descladenosyl azithromycin A and N-demetryl azithromycin, among others.
- hydroxychloroquine In the case of hydroxychloroquine, it has the following impurities: R isomer, S isomer, N-desethyl hydroxychloroquine, impurity 1, hydroxychloroquine O-sulfate, hydroxychloroquine D4 sulfate, hydroxychloroquine O-acetate, among others.
- the first object of the present invention refers to a solid pharmaceutical composition for oral administration, which contains the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient. acceptable.
- the present invention relates to a solid pharmaceutical composition for oral administration, which contains the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, where both active ingredients are administered simultaneously, separately or staggered over time.
- the present invention relates to a solid pharmaceutical composition with improved stability that contains the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts, additionally containing: at least one or more basifying agents or at least one or more basifying agents or the combination thereof; and, at least one pharmaceutically acceptable excipient.
- the present invention relates to a solid pharmaceutical composition with improved bioavailability containing the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient. acceptable, where at least one of the active ingredients has a particle size distribution D90 less than 250 microns.
- the present invention refers to a solid pharmaceutical composition
- a solid pharmaceutical composition comprising the combination of 15.0 to 1500.0 mg of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, 10.0 to 500.0 mg of the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts to be used to treat and/or prevent infections caused by the Coronaviridae virus, selected from SARS-CoV (Severe Acute Respiratory Syndrome-CoV), SARS-CoV2 (Severe Acute Respiratory Syndrome-CoV2), MERS (Middle East Respiratory Syndrome), 229E, NL63, OC43 and HKU1; and, diseases, disorders or symptoms associated with infections caused by the Coronaviridae virus, selected from: COVID-19, pneumonia, bronchitis, cough, fever, headache, difficulty breathing, sore or burning throat, runny nose, red eyes , pain in muscles or joints, in patients suffering from said infection.
- SARS-CoV severe Acute Respiratory Syndrome-CoV
- the solid pharmaceutical composition comprises reduced doses of the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts and the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts, containing less than 500.0 mg of Azithromycin or a pharmaceutically acceptable salt.
- SARS-CoV severe Acute Respiratory Syndrome-CoV
- SARS-CoV2 severe Acute Respiratory Syndrome-CoV2
- MERS Middle East respiratory syndrome
- 229E NL63, OC43, and HKU1
- Plasmodium vivax P. malarie, P. ovale, and P. falciparium, also known as malaria or malaria.
- Macrolide antibiotic agent refers to the active ingredient (2R,3S,4R,5R,8R, 10R, 11R, 12S, 13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3 -0-methyl-a-L-ribo- hexopyranosyl)oxy]-2-ethyl-3,4, 10-trihydroxy-3,5,6,8, 10, 12, 14-heptamethyl-11-[[3, 4, 6-trideoxy-3-(dimethylamino)-b- D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one, with the generic name azithromycin; in base form or any of its salts and forms pharmaceutically acceptable crystals, in a pharmaceutically acceptable amount and with therapeutic effectiveness.
- Antimalarial agent refers to the active ingredient 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol, with the generic name hydroxychloroquine; in base form or any of its salts and forms. pharmaceutically acceptable crystals, in a pharmaceutically acceptable amount and with therapeutic effectiveness.
- Baseifying agent refers to the substance or substances that can provide the medium with the properties of an alkali, which, when kept in solution, has a pH greater than 7.
- the alkalinizing agent can be selected from: dibasic calcium phosphate, calcium carbonate, calcium silicate, sodium carbonate, magnesium aluminum silicate, potassium citrate, sodium citrate, calcium hydroxide, diethanolamine, monoethanolamine, potassium bicarbonate, potassium hydroxide and meglumine, among others known in the state of the art.
- Moisture protective agent refers to the substance or substances that can provide the composition with a protection or regulation system for environmental humidity both during the manufacturing process and during the shelf life of the finished product.
- the moisture-protecting agent can be selected from: starch and its derivatives, corn starch, pregelatinized corn starch, hydroxypropylcellulose, polyvinyl alcohol, stearyl acid and vinylpyrrolidone-vinyl acetate copolymers, among others known in the state of the art .
- “Pharmaceutical composition” refers to a product for pharmaceutical use that comprises the ingredients (active ingredients and pharmaceutically acceptable excipients) in the amounts specified, as well as any product resulting directly and indirectly from combinations of the ingredients in the amounts specified.
- “Pharmaceutically acceptable excipient, vehicle or carrier” refers to diluents, adjuvants, excipients or vehicles, all of which are well known in the state of the art.
- Tro-layer tablet refers to a tablet made up of two tablets obtained by compression one on top of the other, in which each of the tablets retains physical and chemical characteristics that are independent of each other.
- first layer and second layer are used to differentiate the content regarding the active ingredients and excipients, however, their presence is not limited to the internal or external part of the final tablet.
- Treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms or disorders associated with such disorder or condition.
- “Therapeutically effective amount” refers to an amount of a compound/drug according to the present invention, safe and effective to produce the desired therapeutic effect.
- Patient or “patient in need” means a human or non-human mammal affected or likely to be affected with the disorders or conditions to which the term applies, or one or more symptoms or disorders associated with such disorders or conditions.
- the patient is preferably a human.
- Stability refers to the ability of a drug, a medicine contained in a container-closure system of a certain material, to maintain, during storage and use, the established quality specifications.
- Bioavailability refers to the proportion of drug that is absorbed into the general circulation after administration of a drug and the time it takes to do so.
- the present invention provides a solid pharmaceutical composition
- a solid pharmaceutical composition comprising the combination of a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; where the antimalarial agent is Hydroxychloroquine in a pharmaceutically acceptable amount, in addition to one or more pharmaceutically acceptable excipients, which is formulated to be administered orally.
- the present invention corresponds to a solid pharmaceutical composition with improved stability, characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is
- Hydroxychloroquine in a pharmaceutically acceptable amount one or more basifying agents and at least one pharmaceutically acceptable excipient, which is formulated to be administered orally.
- the present invention corresponds to a solid pharmaceutical composition with improved stability, characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is
- Hydroxychloroquine in a pharmaceutically acceptable amount one or more moisture barrier agents and at least one pharmaceutically acceptable excipient, which is formulated to be administered orally.
- the present invention corresponds to a solid pharmaceutical composition with improved stability, characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is
- Hydroxychloroquine in a pharmaceutically acceptable amount one or more pharmaceutically acceptable excipients, which is formulated to be administered orally, where the macrolide antibiotic agent has a particle size distribution D90 of less than 250 microns.
- the present invention corresponds to a solid pharmaceutical composition with improved stability, characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is
- Hydroxychloroquine in a pharmaceutically acceptable amount one or more pharmaceutically acceptable excipients, which is formulated to be administered orally, where the antimalarial agent has a particle size distribution D90 of less than 250 microns.
- the preferred dose of the active ingredients in the drug to be administered depends on variables such as the type and degree of progression of infection, disease or disorders and symptoms associated with said infection or disease, the general state of health of the patient in particular, the weight, age, sex or other factors of the particular patient, the formulation of the excipients of the compound and the pharmaceutical form in which it will be administered, among other factors that the health professional must evaluate at the time of diagnosis and treatment planning.
- the amount of the macrolide antibiotic agent in the medicament may generally be between 15.0 mg and 1500.00 mg.
- preferred amounts of the macrolide antibiotic agent are: 15.0 mg, 20.0 mg, 25.0 mg, 50.0 mg, 75.0 mg, 100.0 mg, 125.0 mg, 150.0 mg,
- the amount of the antimalarial agent in the drug may generally be between 4.65 mg and 465.00 mg.
- preferred amounts of macrolide antibiotic agent are: 4.65 mg, 6.2 mg, 7.75 mg, 15.5 mg, 23.25 mg, 31.0 mg, 38.75 mg, 46.5 mg, 54.25 mg, 62.0 mg, 69.75 mg, 77.5 mg.
- the solid pharmaceutical composition for oral administration comprises the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, where both active ingredients are administered simultaneously, separately or staggered over time.
- the solid pharmaceutical composition in addition to the solid pharmaceutical composition, it comprises the administration of one or more additional active ingredients that help control, prevent or treat the infection or disease or for the mitigation, prevention or control of diseases, disorders or symptoms associated with infection, selected from: chloroquine, remdesivir, ivermectin, ritonavir, lopinavir, tocilizumab, ribavirin, camostat, umifenovir, baricitinib, darunavir, favipiravir, galidesivir, nitazoxanide; said active ingredients can be integrated into the same composition or administered simultaneously, separately or staggered over time.
- the pharmaceutical composition object of the present invention can be administered together with vaccines, biotechnological products or prophylactic treatments that are administered simultaneously, separately or staggered over time.
- the solid pharmaceutical composition comprises the administration of one or more additional active ingredients that help control, prevent or treat infections or diseases present in the patient before infection by the virus object of the invention or acquired during or after applying the treatment or for the mitigation, prevention or control of diseases, disorders or symptoms associated with said comorbidities, selected from: antidiabetic agents, agents for weight loss or control, agents for pressure control agents for the control of cardiovascular events, antipyretic agents, antitussive agents, antihistaminic agents, anti-inflammatory agents, antiasthmatic agents, agents for the treatment of renal insufficiency, agents for the treatment of smoking, agents for the treatment of COPD, immunosuppressive agents or for the treatment of anticancer drugs, e others that a patient may require; said active ingredients can be integrated into the same composition or administered simultaneously, separately or staggered over time.
- compositions in an appropriate formulation are preferred.
- Formulations that are suitable for oral administration to a patient who requires it include units such as tablets, bilayer tablets, soft gelatin capsules, hard gelatin capsules, capsule containing one or more tablets or capsules, powder, granules, among other pharmaceutical forms known in the state of the art.
- Gastrointestinal resistant formulations with modified, delayed, pulsatile and prolonged release are also contemplated.
- pharmaceutically acceptable excipients are, for example: diluents, binders, agents to increase solubility, disintegrants, anti-adherents, lubricants, moisture-protecting agents, basifying agents, surfactants, coating materials, sweeteners, flavoring agents, coloring agents.
- Diluting agents include, but are not limited to: kaolin, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, such as anhydrous lactose or lactose monohydrate, sugars, such as dextrose, maltose, sucrose, glucose, fructose or maltodextrin, sugar alcohols, such as mannitol, maltitol, sorbitol, xylitol, cellulose or starch. Diluting agents may preferably be present from 1 to 80% by weight, based on the total weight of the formulation and can be used to increase or decrease the weight of the bulk volume, as well as to form a suitable pharmaceutical dosage form according to the amounts of the active ingredients.
- lactose such as anhydrous lactose or lactose monohydrate
- sugars such as dextrose, maltose, sucrose, glucose, fructose or maltodextrin
- sugar alcohols such as mannitol, maltitol,
- Binding agents include, but are not limited to: acacia, alginic acid, polyvinyl alcohol, pregelatinized starch, compressible sugar, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, ethylhydroxyethylcellulose, gelatin, glucose liquid, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, methacrylic acid compounds, polyacrylates and polyvinylpyrrolidone. Binding agents may preferably be present at 0 to 15% by weight, relative to the total weight of the formulation, and may be used to ensure the required mechanical strength.
- Disintegrating agents include, but are not limited to: alginic acid, sodium alginate, starch, sodium carboxymethyl starch, partially hydrolyzed starch, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, croscarmellose sodium , crospovidone, sodium starch glycolate, hydroxypropylcellulose, potassium polyacrylin, and cross-linked polyvinylpyrrolidone.
- Disintegrating agents can preferably be present from 0.1 to 30% by weight, relative to the total weight of the formulation and can be used to improve the ability of the formulation to break into smaller fragments when in contact with a liquid, preferably water. .
- Lubricating agents according to the present invention include, but are not limited to: calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate, and polyethylene glycol. Lubricating agents can preferably be present from 0.1 to 10% by weight, with respect to the total weight of the formulation and can be used to reduce static friction, sliding friction and rolling friction.
- Anti-stick agents include, but are not limited to: silicon dioxide and talc. Anti-adherent agents can preferably be present from 0.1 to 10% by weight, with respect to the total weight of the formulation and can be used to improve fluidity.
- Basifying agents according to the present invention include, but are not limited to: dibasic calcium phosphate, calcium carbonate, calcium silicate, sodium carbonate, magnesium aluminum silicate, potassium citrate, sodium citrate, calcium, diethanolamine, monoethanolamine, potassium bicarbonate, potassium hydroxide, and meglumine.
- the basifying agents can preferably be present from 0.3 to 80% by weight, with respect to the total weight of the formulation and can be used to provide a medium with the properties of an alkali, which, when kept in solution, has a pH greater than 7.
- Wet-protecting agents according to the present invention include, but are not limited to: starch and its derivatives, corn starch, pregelatinized corn starch, hydroxypropylcellulose, polyvinyl alcohol, stearyl acid, and vinylpyrrolidone-vinyl acetate copolymers.
- the protective agents can preferably be present from 0.25 to 80% by weight, with respect to the total weight of the formulation and can be used to provide the composition with a system for protection or regulation of environmental humidity both during the manufacturing process and during the preparation process. shelf life of the finished product.
- Agents to increase solubility, surfactants, coating materials, sweeteners, flavoring agents, coloring agents or other pharmaceutically acceptable excipients they can be present in the necessary amounts according to their functions and characteristics of the formulation to be developed.
- one embodiment of the present invention corresponds to a pharmaceutical composition characterized in that it comprises: from 400.0 to 1500.0 mg of Azithromycin or a pharmaceutically acceptable salt; and 124.0 to 465.0 mg of Hydroxychloroquine or a pharmaceutically acceptable salt, plus one or more pharmaceutically acceptable excipients, which is formulated to be administered orally.
- This modality is useful for the treatment of infections caused by the Coronaviridae virus, selected from SARS-CoV (Severe Acute Respiratory Syndrome-CoV), SARS-CoV2 (Severe Acute Respiratory Syndrome-CoV2), MERS (Middle East Respiratory Syndrome) , 229E, NL63, OC43, and HKU1 or infections caused by Plasmodiumvivax, P. malarie, P. ovale, and P. falciparium, also known as malaria or malaria.
- SARS-CoV severe Acute Respiratory Syndrome-CoV
- SARS-CoV2 severe Acute Respiratory Syndrome-CoV2
- MERS Middle East Respiratory Syndrome
- 229E NL63, OC43
- HKU1 Middle East Respiratory Syndrome
- one embodiment of the present invention corresponds to a pharmaceutical composition characterized in that it comprises: from 15.0 to 975.0 mg of Azithromycin or a pharmaceutically acceptable salt; and 4.65 to 302.25 mg of Hydroxychloroquine or a pharmaceutically acceptable salt, plus one or more pharmaceutically acceptable excipients, which is formulated to be administered orally.
- ESP synergistic preventive effect
- This modality is useful for the prevention of infections caused by the Coronaviridae virus, selected from SARS-CoV (Severe Acute Respiratory Syndrome-CoV), SARS-CoV2 (Severe Acute Respiratory Syndrome-CoV2), MERS (Middle East Respiratory Syndrome) , 229E, NL63, OC43 and HKU1 or infections caused by Plasmodium v ⁇ vax, P. malarie, P. ovale and P. falciparium, also known as malaria or malaria.
- SARS-CoV severe Acute Respiratory Syndrome-CoV
- SARS-CoV2 severe Acute Respiratory Syndrome-CoV2
- MERS Middle East Respiratory Syndrome
- Example 1 Solid composition with Azithromycin-Hydroxychloroquine according to the invention.
- Example 2 Composition content with Azithromycin-Hydroxychloroquine.
- synergistic therapeutic effect was shown from an amount of 400.00 mg to 1500.00 mg of azithromycin in combination with 124 mg to 465.00 mg of hydroxychloroquine
- synergistic preventive effect was shown from an amount of 15.00 mg to 975.00 mg of azithromycin in combination with 4.65 mg to 302.25 mg of hydroxychloroquine.
- Example 3 Solid composition with Azithromycin-Hydroxychloroquine, a basifying agent and a moisture protecting agent.
- the humidity, the water content and the solvent content are determined, according to the Pharmacopoeia, to determine the effective basifying agents and moisture-protecting agents, as well as the optimal concentrations in the formulation. composition.
- Example 5 Determination of impurities.
- the basifying agents and moisture-protecting agents were determined, as well as the optimal concentrations in the composition.
- the impurities evaluated are:
- compositions with the combination of at least one basifying agent and at least one moisture protecting agent show an amount of total impurities in the formulation at 3 months in conditions of accelerated stability it is less than 2% and remaining in long-term stabilized conditions.
- Example 6 Solid composition in tablet form with Azithromycin-Hydroxychloroquine.
- Dibasic calcium phosphate 0.00 0.00 0.00 0.00 0.00 20.00 1.00 20.00
- Example 7 Solid composition in the form of a bilayer tablet with Azithromycin-Hydroxychloroquine.
- Example 8 Solid composition in the form of granules with Azithromycin-Hydroxychloroquine.
- Lactose/ crospovidone/ povidone 0.00 0.00 0.00 35.00 2.00 0.00 0.00 0.00
- Example 9 Particle size distribution.
- the distribution obtained for azithromycin is:
- azithromycin "batches” were obtained with each D90 particle size distribution of approximately 350, 300, 250, 150, 90, 75, 45, 38 and 25 micrometers, resulting in an improvement in the bioavailability when using the raw material with a particle size distribution D90 less than 250 micrometers.
- composition was evaluated in patients with COVID-19 disease, showing the synergistic effect of the active ingredients.
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Abstract
The present invention relates to a solid composition with improved stability and bioavailability, which comprises: a pharmaceutically acceptable amount of a macrolide antibiotic agent, a pharmaceutically acceptable amount of an antimalaria agent, and at least one pharmaceutically acceptable excipient, in an oral administration system, said composition comprising a pharmaceutically solid, granule and/or powder form in one or more phases.
Description
COMBINACIÓN SÓLIDA ORAL PARA EL TRATAMIENTO DE INFECCIÓN POR VIRUS SOLID ORAL COMBINATION FOR TREATMENT OF VIRUS INFECTION
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
La presente invención se refiere a una composición farmacéutica sólida de estabilidad y biodisponibildad mejorada, para usarse en el tratamiento y/o prevención de infecciones ocasionadas por virus y enfermedades, desórdenes o síntomas asociados; que comprende: un agente antibiótico macrólido, un agente antimalárico y, al menos un excipiente farmacéuticamente aceptable. The present invention relates to a solid pharmaceutical composition with improved stability and bioavailability, for use in the treatment and/or prevention of infections caused by viruses and associated diseases, disorders or symptoms; comprising: a macrolide antibiotic agent, an antimalarial agent and at least one pharmaceutically acceptable excipient.
ANTECEDENTES BACKGROUND
La Azitromicina con nombre CAS (2R,3S,4R,5R,8R, 10R, 11 R, 12S, 13S, 14R)-13-[(2,6-Dideoxi-3-C- metil-3-0-metil-a-L-ribo-hexopiranosil)oxi]-2-etil-3,4, 10-triidroxi-3,5,6,8, 10, 12, 14-heptametil-11 -[[3, 4,6- trideoxi-3-(dimetilamino)-b-D-xilo-hexopiranosil]oxi]-1-oxa-6-azaciclopentadecan-15-ona es un agente antibiótico macrólido de amplio espectro, utilizado principalmente en el tratamiento de infecciones del tracto respiratorio como bronquitis, neumonía, sinusitis, faringitis y amigdalitis; infecciones odontoestomatológicas u óticas, infecciones de la piel y tejidos blancos; enfermedades de transmisión sexual como Chlamydía, Neíssería y Treponema. Azithromycin with CAS name (2R,3S,4R,5R,8R, 10R, 11 R, 12S, 13S, 14R)-13-[(2,6-Dideoxy-3-C-methyl-3-0-methyl- a-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11 -[[3,4,6-trideoxy-3 -(dimethylamino)-b-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one is a broad-spectrum macrolide antibiotic agent, mainly used in the treatment of respiratory tract infections such as bronchitis, pneumonia, sinusitis , pharyngitis and tonsillitis; odontostomatological or ear infections, skin and white tissue infections; sexually transmitted diseases such as Chlamydia, Neisseria and Treponema.
La hidroxicloroquina con nombre CAS 2-[[4-[(7-cloro-4-quinolinil)amino]pentil]etilamino]etanol, es un agente antimalárico, útil para el tratamiento supresivo y de ataques de paludismos o malaria, debido a Plasmodíum vívax, P. malaríe, P. ovale y P. falcíparíum, así como para el tratamiento de artritis reumatoide y lupus eritematoso sistémico y discoide. Hydroxychloroquine with CAS name 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol, is an antimalarial agent, useful for the suppressive treatment and attacks of malaria or malaria, due to Plasmodium vivax, P. malarie, P. ovale and P. falciparium, as well as for the treatment of rheumatoid arthritis and systemic and discoid lupus erythematosus.
Ambos fármacos, al formularse para su administración en diferentes formas farmacéuticas como solución inyectable, tableta o suspensión, presentan la formación de diferentes impurezas, cuyo origen o aparición durante el período de estabilidad, conducen a la disminución de la potencia de los fármacos. En el caso de azitromicina, presenta las siguientes impurezas: N, M, G, E, O, B, I, H, J, F, C, D, eritromicina A 9, 11 -¡mino éter, azitromicina N-óxido, eritromicina A oxima, descladenosil azitromicina A y N-demetril azitromicina, entre otras. En el caso de hidroxicloroquina, presenta las siguientes impurezas: isómero R, isómero S, hidroxicloroquina N-desetil, impureza 1, hidroxicloroquina O-sulfato, hidroxicloroquina D4 sulfato, hidroxicloroquina O-acetato, entre otras. Both drugs, when formulated for administration in different pharmaceutical forms such as injectable solution, tablet or suspension, present the formation of different impurities, whose origin or appearance during the stability period, lead to a decrease in the potency of the drugs. In the case of azithromycin, it has the following impurities: N, M, G, E, O, B, I, H, J, F, C, D, erythromycin A 9, 11 -amino ether, azithromycin N-oxide, erythromycin A oxime, descladenosyl azithromycin A and N-demetryl azithromycin, among others. In the case of hydroxychloroquine, it has the following impurities: R isomer, S isomer, N-desethyl hydroxychloroquine, impurity 1, hydroxychloroquine O-sulfate, hydroxychloroquine D4 sulfate, hydroxychloroquine O-acetate, among others.
Adicionalmente, en el caso de la hidroxicloroquina, esta presenta una baja y variable biodisponibilidad al ser administrada por vía oral, razón por la que en algunos tratamientos de pacientes que requieren su administración, no se logra obtener el efecto terapéutico deseado.
OBJETO DE LA INVENCIÓN Additionally, in the case of hydroxychloroquine, it has a low and variable bioavailability when administered orally, which is why in some treatments of patients that require its administration, it is not possible to obtain the desired therapeutic effect. OBJECT OF THE INVENTION
El objeto primero de la presente invención se refiere a una composición farmacéutica sólida para administración por vía oral, que contiene la combinación del agente antibiótico macrólido azitromicina o sus sales farmacéuticamente aceptables, el agente antimalárico hidroxicloroquina o sus sales farmacéuticamente aceptables y al menos un excipiente farmacéuticamente aceptable. The first object of the present invention refers to a solid pharmaceutical composition for oral administration, which contains the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient. acceptable.
De acuerdo con otro objeto, la presente invención se refiere a una composición farmacéutica sólida para administración por vía oral, que contiene la combinación del agente antibiótico macrólido azitromicina o sus sales farmacéuticamente aceptables, el agente antimalárico hidroxicloroquina o sus sales farmacéuticamente aceptables y al menos un excipiente farmacéuticamente aceptable, en donde ambos ingredientes activos se administran simultáneamente, por separado o escalonados a lo largo del tiempo. According to another object, the present invention relates to a solid pharmaceutical composition for oral administration, which contains the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, where both active ingredients are administered simultaneously, separately or staggered over time.
De acuerdo a una modalidad, la presente invención se refiere a una composición farmacéutica sólida de estabilidad mejorada que contiene la combinación del agente antibiótico macrólido azitromicina o sus sales farmacéuticamente aceptables, el agente antimalárico hidroxicloroquina o sus sales farmacéuticamente aceptables, contiene adicionalmente: al menos uno o más agentes basificantes o al menos uno o más agentes basificantes o la combinación de los mismos; y, al menos un excipiente farmacéuticamente aceptable. According to one embodiment, the present invention relates to a solid pharmaceutical composition with improved stability that contains the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts, additionally containing: at least one or more basifying agents or at least one or more basifying agents or the combination thereof; and, at least one pharmaceutically acceptable excipient.
De acuerdo con otro objeto, la presente invención se refiere a una composición farmacéutica sólida de biodisponibilidad mejorada que contiene la combinación del agente antibiótico macrólido azitromicina o sus sales farmacéuticamente aceptables, el agente antimalárico hidroxicloroquina o sus sales farmacéuticamente aceptables, y al menos un excipiente farmacéuticamente aceptable, en donde al menos uno de los ingredientes activos presenta una distribución de tamaño de partícula D90 menor de 250 mieras. According to another object, the present invention relates to a solid pharmaceutical composition with improved bioavailability containing the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient. acceptable, where at least one of the active ingredients has a particle size distribution D90 less than 250 microns.
De acuerdo con otro objeto, la presente invención se refiere a una composición farmacéutica sólida comprende la combinación de 15.0 a 1500.0 mg del agente antibiótico macrólido azitromicina o sus sales farmacéuticamente aceptables, 10.0 a 500.0 mg el agente antimalárico hidroxicloroquina o sus sales farmacéuticamente aceptable para usarse para tratar y/o prevenir infecciones ocasionadas por el virus Coronavírídae, seleccionadas de SARS-CoV (Síndrome respiratorio agudo grave-CoV), SARS-CoV2 (Síndrome respiratorio agudo grave-CoV2), MERS (Síndrome respiratorio del Medio Oriente), 229E, NL63, OC43 y HKU1; y, enfermedades, desórdenes o síntomas asociados a infecciones ocasionadas por el virus Coronavírídae, seleccionados de: COVID-19, neumonía, bronquitis, tos, fiebre, dolor de cabeza, dificultad para respirar, dolor o ardor de garganta, escurrimiento nasal, ojos rojos, dolores en músculos o articulaciones, en pacientes que padecen dicha infección. According to another object, the present invention refers to a solid pharmaceutical composition comprising the combination of 15.0 to 1500.0 mg of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, 10.0 to 500.0 mg of the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts to be used to treat and/or prevent infections caused by the Coronaviridae virus, selected from SARS-CoV (Severe Acute Respiratory Syndrome-CoV), SARS-CoV2 (Severe Acute Respiratory Syndrome-CoV2), MERS (Middle East Respiratory Syndrome), 229E, NL63, OC43 and HKU1; and, diseases, disorders or symptoms associated with infections caused by the Coronaviridae virus, selected from: COVID-19, pneumonia, bronchitis, cough, fever, headache, difficulty breathing, sore or burning throat, runny nose, red eyes , pain in muscles or joints, in patients suffering from said infection.
En una modalidad de la presente invención, la composición farmacéutica sólida comprende dosis reducidas de la combinación del agente antibiótico macrólido azitromicina o sus sales farmacéuticamente aceptables y del agente antimalárico hidroxicloroquina o sus sales farmacéuticamente aceptable, conteniendo menos de 500.0 mg de Azitromicina o una sal farmacéuticamente aceptable; y menos de
155.0 mg de Hidroxicloroquina o una sal farmacéuticamente aceptable, para tratar y/o prevenir infecciones ocasionadas por el virus Coronavírídae, seleccionadas de SARS-CoV (Síndrome respiratorio agudo grave- CoV), SARS-CoV2 (Síndrome respiratorio agudo grave-CoV2), MERS (Síndrome respiratorio del Medio Oriente), 229E, NL63, OC43y HKU1 o infecciones ocasionadas por Plasmodíum vívax, P. malaríe, P. ovale y P. falcíparíum, también conocidos como malaria o paludismo. In one embodiment of the present invention, the solid pharmaceutical composition comprises reduced doses of the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts and the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts, containing less than 500.0 mg of Azithromycin or a pharmaceutically acceptable salt. acceptable; and less than 155.0 mg of Hydroxychloroquine or a pharmaceutically acceptable salt, to treat and/or prevent infections caused by the Coronaviridae virus, selected from SARS-CoV (Severe Acute Respiratory Syndrome-CoV), SARS-CoV2 (Severe Acute Respiratory Syndrome-CoV2), MERS (Middle East respiratory syndrome), 229E, NL63, OC43, and HKU1 or infections caused by Plasmodium vivax, P. malarie, P. ovale, and P. falciparium, also known as malaria or malaria.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
Algunos términos se definen a continuación, mismos que serán utilizados a lo largo del presente documento: Some terms are defined below, which will be used throughout this document:
"Agente antibiótico macrólido” se refiere al ingrediente activo (2R,3S,4R,5R,8R, 10R, 11 R, 12S, 13S,14R)-13-[(2,6-Dideoxi-3-C-metil-3-0-metil-a-L-ribo- hexopiranosil)oxi]-2-etil-3,4, 10-triidroxi-3,5,6,8, 10, 12, 14-heptametil-11-[[3, 4,6-trideoxi-3-(dimetilamino)-b- D-xilo-hexopiranosil]oxi]-1-oxa-6-azaciclopentadecan-15-ona, con el nombre genérico azitromicina; en forma de base o cualquiera de sus sales y formas cristalinas farmacéuticamente aceptables, en una cantidad farmacéuticamente aceptable y con efectividad terapéutica. "Macrolide antibiotic agent" refers to the active ingredient (2R,3S,4R,5R,8R, 10R, 11R, 12S, 13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3 -0-methyl-a-L-ribo- hexopyranosyl)oxy]-2-ethyl-3,4, 10-trihydroxy-3,5,6,8, 10, 12, 14-heptamethyl-11-[[3, 4, 6-trideoxy-3-(dimethylamino)-b- D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one, with the generic name azithromycin; in base form or any of its salts and forms pharmaceutically acceptable crystals, in a pharmaceutically acceptable amount and with therapeutic effectiveness.
"Agente antimalárico” se refiere al ingrediente activo 2-[[4-[(7-cloro-4- quinolinil)amino]pentil]etilamino]etanol, con el nombre genérico hidroxicloroquina; en forma de base o cualquiera de sus sales y formas cristalinas farmacéuticamente aceptables, en una cantidad farmacéuticamente aceptable y con efectividad terapéutica. "Antimalarial agent" refers to the active ingredient 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol, with the generic name hydroxychloroquine; in base form or any of its salts and forms. pharmaceutically acceptable crystals, in a pharmaceutically acceptable amount and with therapeutic effectiveness.
"Agente basificante” se refiere a la o las sustancias que pueden aportar a un medio las propiedades de un álcali, el cual al mantenerse en forma de solución presenta un pH superior a 7. Para el objeto de la presente invención, el agente alcalinizante puede seleccionarse de: fosfato de calcio dibásico, carbonato de calcio, silicato de calcio, carbonato de sodio, silicato de aluminio y magnesio, citrato de potasio, citrato de sodio, hidróxido de calcio, dietanolamina, monoetanolamina, bicarbonato de potasio, hidróxido de potasio y meglumina, entre otros conocidos en el estado de la técnica. "Basifying agent" refers to the substance or substances that can provide the medium with the properties of an alkali, which, when kept in solution, has a pH greater than 7. For the purpose of the present invention, the alkalinizing agent can be selected from: dibasic calcium phosphate, calcium carbonate, calcium silicate, sodium carbonate, magnesium aluminum silicate, potassium citrate, sodium citrate, calcium hydroxide, diethanolamine, monoethanolamine, potassium bicarbonate, potassium hydroxide and meglumine, among others known in the state of the art.
"Agente protector de humedad” se refiere a la o las sustancias que pueden aportar a la composición un sistema de protección o regulación de la humedad ambiental tanto durante el proceso de fabricación como durante la vida de anaquel del producto terminado. Para el objeto de la presente invención, el agente protector de humedad puede seleccionarse de: almidón y sus derivados, almidón de maíz, almidón de maíz pregelatinizado, hidroxipropilcelulosa, alcohol polivinílico, ácido estearílico y copolímeros de vinilpirrolidona-vinil acetato, entre otros conocidos en el estado de la técnica. "Moisture protective agent" refers to the substance or substances that can provide the composition with a protection or regulation system for environmental humidity both during the manufacturing process and during the shelf life of the finished product. For the purpose of the present invention, the moisture-protecting agent can be selected from: starch and its derivatives, corn starch, pregelatinized corn starch, hydroxypropylcellulose, polyvinyl alcohol, stearyl acid and vinylpyrrolidone-vinyl acetate copolymers, among others known in the state of the art .
"Composición farmacéutica” se refiere a un producto para uso farmacéutico que comprende los ingredientes (principios activos y excipientes farmacéuticamente aceptables) en
las cantidades especificadas, así como cualquier producto que resulte de manera directa e indirecta de las combinaciones de los ingredientes en las cantidades especificadas. "Pharmaceutical composition" refers to a product for pharmaceutical use that comprises the ingredients (active ingredients and pharmaceutically acceptable excipients) in the amounts specified, as well as any product resulting directly and indirectly from combinations of the ingredients in the amounts specified.
"Excipiente, vehículo o portador farmacéuticamente aceptable” se refiere a diluyentes, adyuvantes, excipientes o vehículos, todos ellos bien conocidos en el estado de la técnica. "Pharmaceutically acceptable excipient, vehicle or carrier" refers to diluents, adjuvants, excipients or vehicles, all of which are well known in the state of the art.
"Tableta bicapa” se refiere a una tableta conformada por dos tabletas obtenidas por compresión una sobre otra, en la que cada una de las tabletas conserva características fisicoquímicas independientes una de la otra. Para efecto de la presente invención los términos "primer capa” y "segundo capa” se utilizan para diferenciar el contenido respecto a los principios activos y excipientes, sin embargo, no se limita su presencia en la parte interna o externa del comprimido final. "Two-layer tablet" refers to a tablet made up of two tablets obtained by compression one on top of the other, in which each of the tablets retains physical and chemical characteristics that are independent of each other. For the purposes of the present invention, the terms "first layer" and "second layer" are used to differentiate the content regarding the active ingredients and excipients, however, their presence is not limited to the internal or external part of the final tablet.
"Tratar” o “tratamiento” se refiere a revertir, aliviar, inhibir el progreso de, o prevenir el trastorno o afección a la que se aplica el término, o uno o más síntomas o desordenes asociados a tal trastorno o condición. "Treating" or "treatment" means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms or disorders associated with such disorder or condition.
"Cantidad terapéuticamente efectiva” se refiere a una cantidad de un compuesto/medicamento de acuerdo con la presente invención, seguro y eficaz para producir el efecto terapéutico deseado. "Therapeutically effective amount" refers to an amount of a compound/drug according to the present invention, safe and effective to produce the desired therapeutic effect.
"Paciente” o "paciente que lo necesita” se refiere a un mamífero humano o no humano afectado o que pueda verse afectado con los trastornos o afecciones a la que se aplica el término, o uno o más síntomas o desórdenes asociados a tales trastornos o condiciones. El paciente es preferentemente un humano. "Patient" or "patient in need" means a human or non-human mammal affected or likely to be affected with the disorders or conditions to which the term applies, or one or more symptoms or disorders associated with such disorders or conditions. The patient is preferably a human.
"Estabilidad” se refiere a la capacidad de un fármaco, un medicamento contenido en un sistema contenedor-cierre de determinado material, para mantener, durante el tiempo de almacenamiento y uso, las especificaciones de calidad establecidas. "Stability" refers to the ability of a drug, a medicine contained in a container-closure system of a certain material, to maintain, during storage and use, the established quality specifications.
"Biodisponibilidad” se refiere a la proporción de fármaco que se absorbe a la circulación general después de la administración de un medicamento y el tiempo que requiere para hacerlo . "Bioavailability" refers to the proportion of drug that is absorbed into the general circulation after administration of a drug and the time it takes to do so.
La información que ahora se presenta en detalle, a ciertas modalidades de la invención, integrando ejemplos para que un experto en la materia pueda reproducirla. En tanto que la invención será descrita en conjunto con las modalidades mencionadas, será entendido que su propósito no es limitar la invención, siendo que la invención se propone para cubrir todas las alternativas, modificaciones, y equivalentes, que se pueden incluir dentro del alcance de la presente invención. The information that is now presented in detail, to certain modalities of the invention, integrating examples so that a person skilled in the art can reproduce it. While the invention will be described in conjunction with the aforementioned embodiments, it will be understood that its purpose is not to limit the invention, and the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of this the present invention.
La presente invención, proporciona una composición farmacéutica sólida que comprende la combinación de un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico
es Hidroxicloroquina en una cantidad farmacéuticamente aceptable, además de uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral. The present invention provides a solid pharmaceutical composition comprising the combination of a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; where the antimalarial agent is Hydroxychloroquine in a pharmaceutically acceptable amount, in addition to one or more pharmaceutically acceptable excipients, which is formulated to be administered orally.
En una modalidad alternativa adicional, la presente invención corresponde a una composición farmacéutica sólida de estabilidad mejorada, caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico esIn an additional alternative embodiment, the present invention corresponds to a solid pharmaceutical composition with improved stability, characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is
Hidroxicloroquina en una cantidad farmacéuticamente aceptable, uno o más agentes basificantes y al menos un excipiente farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral. Hydroxychloroquine in a pharmaceutically acceptable amount, one or more basifying agents and at least one pharmaceutically acceptable excipient, which is formulated to be administered orally.
En una modalidad alternativa adicional, la presente invención corresponde a una composición farmacéutica sólida de estabilidad mejorada, caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico esIn an additional alternative embodiment, the present invention corresponds to a solid pharmaceutical composition with improved stability, characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is
Hidroxicloroquina en una cantidad farmacéuticamente aceptable, uno o más agentes protectores de humedad y al menos un excipiente farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral. Hydroxychloroquine in a pharmaceutically acceptable amount, one or more moisture barrier agents and at least one pharmaceutically acceptable excipient, which is formulated to be administered orally.
En una modalidad alternativa adicional, la presente invención corresponde a una composición farmacéutica sólida de estabilidad mejorada, caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico esIn an additional alternative embodiment, the present invention corresponds to a solid pharmaceutical composition with improved stability, characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is
Hidroxicloroquina en una cantidad farmacéuticamente aceptable, uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral, en donde el agente antibiótico macrólido presenta una distribución de tamaño de partícula D90 menor de 250 mieras. Hydroxychloroquine in a pharmaceutically acceptable amount, one or more pharmaceutically acceptable excipients, which is formulated to be administered orally, where the macrolide antibiotic agent has a particle size distribution D90 of less than 250 microns.
En una modalidad alternativa adicional, la presente invención corresponde a una composición farmacéutica sólida de estabilidad mejorada, caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico esIn an additional alternative embodiment, the present invention corresponds to a solid pharmaceutical composition with improved stability, characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is
Hidroxicloroquina en una cantidad farmacéuticamente aceptable, uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral, en donde el agente antimalárico presenta una distribución de tamaño de partícula D90 menor de 250 mieras. Hydroxychloroquine in a pharmaceutically acceptable amount, one or more pharmaceutically acceptable excipients, which is formulated to be administered orally, where the antimalarial agent has a particle size distribution D90 of less than 250 microns.
En términos generales, la dosis preferida de los ingredientes activos en el medicamento a administrar, depende de variables como el tipo y grado de progresión de infección, enfermedad o los desórdenes y síntomas asociados a dicha infección o enfermedad, el estado general de salud del paciente en específico, el peso, edad, sexo u otros factores del paciente en particular, la formulación de
los excipientes del compuesto y la forma farmacéutica en la que se administrará, entre otros factores que el profesional de la salud deberá evaluar al momento de su diagnóstico y planteamiento del tratamiento. In general terms, the preferred dose of the active ingredients in the drug to be administered depends on variables such as the type and degree of progression of infection, disease or disorders and symptoms associated with said infection or disease, the general state of health of the patient in particular, the weight, age, sex or other factors of the particular patient, the formulation of the excipients of the compound and the pharmaceutical form in which it will be administered, among other factors that the health professional must evaluate at the time of diagnosis and treatment planning.
La cantidad del agente antibiótico macrólido en el medicamento en general puede estar comprendida entre 15.0 mg y 1500.00 mg. A manera de ejemplo, las cantidades del agente antibiótico macrólido preferidas son: 15.0 mg, 20.0 mg, 25.0 mg, 50.0 mg, 75.0 mg, 100.0 mg, 125.0 mg, 150.0 mg,The amount of the macrolide antibiotic agent in the medicament may generally be between 15.0 mg and 1500.00 mg. By way of example, preferred amounts of the macrolide antibiotic agent are: 15.0 mg, 20.0 mg, 25.0 mg, 50.0 mg, 75.0 mg, 100.0 mg, 125.0 mg, 150.0 mg,
175.0 mg, 200.0 mg, 225.0 mg, 250.0 mg, 275.0 mg, 300.0 mg, 325.0 mg, 350.0 mg, 375.0 mg, 400.0 mg,175.0mg, 200.0mg, 225.0mg, 250.0mg, 275.0mg, 300.0mg, 325.0mg, 350.0mg, 375.0mg, 400.0mg,
425.0 mg, 450.0 mg, 475.0 mg, 500.0 mg, 525.0 mg, 550.0 mg, 575.0 mg, 600.0 mg, 625.0 mg, 650.0 mg,425.0mg, 450.0mg, 475.0mg, 500.0mg, 525.0mg, 550.0mg, 575.0mg, 600.0mg, 625.0mg, 650.0mg,
675.0 mg, 700.0 mg, 725.0 mg, 750.0 mg, 775.0 mg, 800.0 mg, 825.0 mg, 850.0 mg, 875.0 mg, 900.0 mg,675.0mg, 700.0mg, 725.0mg, 750.0mg, 775.0mg, 800.0mg, 825.0mg, 850.0mg, 875.0mg, 900.0mg,
925.0 mg, 950.0 mg, 975.0 mg, 1000.0 mg, 1025.0 mg, 1050.0 mg, 1075.0 mg, 1100.0 mg, 1125.0 mg, 1150.0 mg, 1175.0 mg, 1200.0 mg, 1225.0 mg, 1250.0 mg, 1275.0 mg, 1300.0 mg, 1325.0 mg, 1350.0 mg, 1375.0 mg, 1400.0 mg, 1425.0 mg, 1450.0 mg, 1475.0 mg y 1500.0 mg. 925.0 mg, 950.0 mg, 975.0 mg, 1000.0 mg, 1025.0 mg, 1050.0 mg, 1075.0 mg, 1100.0 mg, 1125.0 mg, 1150.0 mg, 1175.0 mg, 1200.0 mg, 1225.0 mg, 1250.0 mg, 1275.0 mg, 1300.0 mg. , 1350.0 mg, 1375.0 mg, 1400.0 mg, 1425.0 mg, 1450.0 mg, 1475.0 mg and 1500.0 mg.
La cantidad del agente antimalárico en el medicamento en general puede estar comprendida entre 4.65 mg y 465.00 mg. A manera de ejemplo, las cantidades del agente antibiótico macrólido preferidas son: 4.65 mg, 6.2 mg, 7.75 mg, 15.5 mg, 23.25 mg, 31 .0 mg, 38.75 mg, 46.5 mg, 54.25 mg, 62.0 mg, 69.75 mg, 77.5 mg, 85.25 mg, 93.0 mg, 100.75 mg, 108.5 mg, 116.25 mg, 125.0 mg, 131.75 mg, 139.5 mg, 147.25 mg, 155.0 mg, 162.75 mg, 170.5 mg, 178.25 mg, 186.0 mg, 193.75 mg, 201.5 mg, 209.25 mg, 217.0 mg, 224.75 mg, 232.50 mg, 240.25 mg, 248.0 mg, 255.75 mg, 263.5 mg, 271.25 mg, 279.0 mg, 286.75 mg, 294.5 mg, 302.25 mg, 310.0 mg, 317.75 mg, 325.50 mg, 333.25 mg, 341.0 mg, 348.75 mg, 356.50 mg, 364.25 mg, 372.0 mg, 379.75 mg, 387.50 mg, 395.25 mg, 403.0 mg, 410.75 mg, 418.50 mg, 426.25 mg, 434.0 mg, 441.75 mg, 449.50 mg, 457.25 mg y 465.0 mg. The amount of the antimalarial agent in the drug may generally be between 4.65 mg and 465.00 mg. By way of example, preferred amounts of macrolide antibiotic agent are: 4.65 mg, 6.2 mg, 7.75 mg, 15.5 mg, 23.25 mg, 31.0 mg, 38.75 mg, 46.5 mg, 54.25 mg, 62.0 mg, 69.75 mg, 77.5 mg. mg, 85.25mg, 93.0mg, 100.75mg, 108.5mg, 116.25mg, 125.0mg, 131.75mg, 139.5mg, 147.25mg, 155.0mg, 162.75mg, 170.5mg, 178.25mg, 186.0mg, 193.75.5mg 209.25mg, 217.0mg, 224.75mg, 232.50mg, 240.25mg, 248.0mg, 255.75mg, 263.5mg, 271.25mg, 279.0mg, 286.75mg, 294.5mg, 302.25mg, 310.0mg, 3.5mg 3.2533.253 , 341.0 mg, 348.75 mg, 356.50 mg, 364.25 mg, 372.0 mg, 379.75 mg, 387.50 mg, 395.25 mg, 403.0 mg, 410.75 mg, 418.50 mg, 426.25 mg, 434.0 mg, 5 mg, 441.50 mg, 4.04 7 mg, 249.5 mg, 4.04 mg.
De acuerdo con una modalidad adicional, la composición farmacéutica sólida para administración por vía oral, comprende la combinación del agente antibiótico macrólido azitromicina o sus sales farmacéuticamente aceptables, el agente antimalárico hidroxicloroquina o sus sales farmacéuticamente aceptables y al menos un excipiente farmacéuticamente aceptable, en donde ambos ingredientes activos se administran simultáneamente, por separado o escalonados a lo largo del tiempo. According to an additional embodiment, the solid pharmaceutical composition for oral administration comprises the combination of the macrolide antibiotic agent azithromycin or its pharmaceutically acceptable salts, the antimalarial agent hydroxychloroquine or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, where both active ingredients are administered simultaneously, separately or staggered over time.
De acuerdo con una modalidad adicional, adicional a la composición farmacéutica sólida, comprende la administración de uno o más ingrediente activos adicionales que ayuden al control, prevención o tratamiento de la infección o enfermedad o para la mitigación, prevención o control de enfermedades, desórdenes o síntomas asociados a la infección, seleccionados de: cloroquina, remdesivir, ivermectina, ritonavir, lopinavir, tocilizumab, ribavirina, camostat, umifenovir, baricitinib, darunavir, favipiravir, galidesivir, nitazoxanida; dichos ingredientes activos, se pueden integran en la misma composición o administrarse simultáneamente, por separado o escalonados a lo largo del tiempo. Adicionalmente, la composición farmacéutica objeto de la presente invención, puede ser administrada en conjunto con vacunas, productos biotecnológicos o tratamientos profilácticos que se administren simultáneamente, por separado o escalonados a lo largo del tiempo.
De acuerdo con una modalidad adicional, a la composición farmacéutica sólida, comprende la administración de uno o más ingrediente activos adicionales que ayuden al control, prevención o tratamiento de infecciones o enfermedades presentes en el paciente antes de la infección por el virus objeto de la invención o adquiridos durante o después de aplicar el tratamiento o para la mitigación, prevención o control de enfermedades, desórdenes o síntomas asociados a dichas comorbilidades, seleccionados de: agentes antidiabéticos, agentes para el control o disminución de peso, agentes para el control de la presión arterial, agentes para el control de eventos cardiovasculares, agentes antipiréticos, agentes antitusivos, agentes antihistamínicos, agentes antiinflamatorios, agentes antiasmáticos, agentes para el tratamiento de insuficiencia renal, agentes para el tratamiento de tabaquismo, agentes para el tratamiento de EPOC, agentes inmunosupresores o para el tratamiento de anticancerígenos, entre otros que un paciente pueda requerir; dichos ingredientes activos, se pueden integran en la misma composición o administrarse simultáneamente, por separado o escalonados a lo largo del tiempo. According to an additional modality, in addition to the solid pharmaceutical composition, it comprises the administration of one or more additional active ingredients that help control, prevent or treat the infection or disease or for the mitigation, prevention or control of diseases, disorders or symptoms associated with infection, selected from: chloroquine, remdesivir, ivermectin, ritonavir, lopinavir, tocilizumab, ribavirin, camostat, umifenovir, baricitinib, darunavir, favipiravir, galidesivir, nitazoxanide; said active ingredients can be integrated into the same composition or administered simultaneously, separately or staggered over time. Additionally, the pharmaceutical composition object of the present invention can be administered together with vaccines, biotechnological products or prophylactic treatments that are administered simultaneously, separately or staggered over time. According to an additional modality, to the solid pharmaceutical composition, it comprises the administration of one or more additional active ingredients that help control, prevent or treat infections or diseases present in the patient before infection by the virus object of the invention or acquired during or after applying the treatment or for the mitigation, prevention or control of diseases, disorders or symptoms associated with said comorbidities, selected from: antidiabetic agents, agents for weight loss or control, agents for pressure control agents for the control of cardiovascular events, antipyretic agents, antitussive agents, antihistaminic agents, anti-inflammatory agents, antiasthmatic agents, agents for the treatment of renal insufficiency, agents for the treatment of smoking, agents for the treatment of COPD, immunosuppressive agents or for the treatment of anticancer drugs, e others that a patient may require; said active ingredients can be integrated into the same composition or administered simultaneously, separately or staggered over time.
De acuerdo con la presente invención, se prefiere la administración oral de la composición en una formulación apropiada. Las formulaciones que son adecuadas para su administración por vía oral a un paciente que así lo requiere, incluye unidades tales como tableta, tableta bicapa, cápsulas de gelatina blanda, cápsulas de gelatina dura, cápsula con un contenido de una o más tabletas o cápsulas, polvo, gránulos, entre otras formas farmacéuticas conocidas en el estado de la técnica. También se contemplan formulaciones resistentes gastrointestinales con liberación modificada, retardada, pulsátil y prolongada. In accordance with the present invention, oral administration of the composition in an appropriate formulation is preferred. Formulations that are suitable for oral administration to a patient who requires it, include units such as tablets, bilayer tablets, soft gelatin capsules, hard gelatin capsules, capsule containing one or more tablets or capsules, powder, granules, among other pharmaceutical forms known in the state of the art. Gastrointestinal resistant formulations with modified, delayed, pulsatile and prolonged release are also contemplated.
En este sentido, de acuerdo con la presente invención, los excipientes farmacéuticamente aceptables son, por ejemplo: diluentes, aglutinantes, agentes para incrementar la solubilidad, desintegrantes, antiadherentes, lubricantes, agentes protectores de humedad, agentes basificantes, tensoactivos, materiales de recubrimiento, edulcorantes, agentes saborizantes, agentes colorantes. In this sense, according to the present invention, pharmaceutically acceptable excipients are, for example: diluents, binders, agents to increase solubility, disintegrants, anti-adherents, lubricants, moisture-protecting agents, basifying agents, surfactants, coating materials, sweeteners, flavoring agents, coloring agents.
Los agentes diluentes de acuerdo con la presente invención incluyen, pero no se limitan a: caolín, celulosa microcristalina, celulosa microcristalina silicificada, lactosa, tales como lactosa anhidra o monohidrato de lactosa, azúcares, tales como dextrosa, maltosa, sacarosa, glucosa, fructosa o maltodextrina, alcoholes de azúcar, tales como manitol, maltitol, sorbitol, xilitol, celulosa o almidón. Los agentes diluentes de preferencia pueden estar presentes del 1 al 80 % en peso, respecto del peso total de la formulación y puede utilizarse para aumentar o reducir el peso del volumen a granel, así como para formar una forma de dosificación farmacéutica adecuada conforme a las cantidades de los ingredientes activos. Diluting agents according to the present invention include, but are not limited to: kaolin, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, such as anhydrous lactose or lactose monohydrate, sugars, such as dextrose, maltose, sucrose, glucose, fructose or maltodextrin, sugar alcohols, such as mannitol, maltitol, sorbitol, xylitol, cellulose or starch. Diluting agents may preferably be present from 1 to 80% by weight, based on the total weight of the formulation and can be used to increase or decrease the weight of the bulk volume, as well as to form a suitable pharmaceutical dosage form according to the amounts of the active ingredients.
Los agentes aglutinantes de acuerdo con la presente invención incluyen, pero no se limitan a: acacia, ácido algínico, alcohol polivínilico, almidón pregelatinizado, azúcar comprimible, carboximetilcelulosa, carboximetilce-lulosa de calcio, carboximetilcelulosa de sodio, etilcelulosa, etilhidroxietilcelulosa, gelatina, glucosa líquida, hidroxietilcelulosa, hidroxipropilcelulosa, hidroxipropilmetilcelulosa, metilcelulosa, compuestos de ácido metacrilico, polia-crilatos y
polivinilpirrolidona. Los agentes aglutinantes de preferencia pueden estar presentes del 0 al 15 % en peso, respecto del peso total de la formulación y puede utilizarse para asegurar la resistencia mecánica requerida. Binding agents according to the present invention include, but are not limited to: acacia, alginic acid, polyvinyl alcohol, pregelatinized starch, compressible sugar, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, ethylhydroxyethylcellulose, gelatin, glucose liquid, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, methacrylic acid compounds, polyacrylates and polyvinylpyrrolidone. Binding agents may preferably be present at 0 to 15% by weight, relative to the total weight of the formulation, and may be used to ensure the required mechanical strength.
Los agentes desintegrantes de acuerdo con la presente invención incluyen, pero no se limitan a: ácido algínico, alginato de sodio, almidón, almidón de carboximetil de sodio, almidón parcialmente hidrolizado, carboximetilcelulosa de calcio, carboximetilcelulosa de sodio, celulosa microcristalina, croscarmelosa de sodio, crospovidona, glicolato de almidón de sodio, hidroxipropilcelulosa, poliacrilina de potasio y polivinilpirrolidona reticulada. Los agentes desintegrantes de preferencia pueden estar presentes del 0.1 al 30 % en peso, respecto del peso total de la formulación y puede utilizarse para mejorar la capacidad de la formulación para romperse en fragmentos más pequeños al estar en contacto con un líquido, de preferencia agua. Disintegrating agents according to the present invention include, but are not limited to: alginic acid, sodium alginate, starch, sodium carboxymethyl starch, partially hydrolyzed starch, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, croscarmellose sodium , crospovidone, sodium starch glycolate, hydroxypropylcellulose, potassium polyacrylin, and cross-linked polyvinylpyrrolidone. Disintegrating agents can preferably be present from 0.1 to 30% by weight, relative to the total weight of the formulation and can be used to improve the ability of the formulation to break into smaller fragments when in contact with a liquid, preferably water. .
Los agentes lubricantes de acuerdo con la presente invención incluyen, pero no se limitan a: estearato de calcio, estearato de magnesio, aceite mineral, ácido esteárico, ácido fumárico, estearil fumarato de sodio, estearato de zinc y polietilenglicol. Los agentes lubricantes de preferencia pueden estar presentes del 0.1 al 10 % en peso, respecto del peso total de la formulación y puede utilizarse para reducir la fricción estática, la fricción por deslizamiento y la fricción de rodadura. Lubricating agents according to the present invention include, but are not limited to: calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate, and polyethylene glycol. Lubricating agents can preferably be present from 0.1 to 10% by weight, with respect to the total weight of the formulation and can be used to reduce static friction, sliding friction and rolling friction.
Los agentes antiadherentes de acuerdo con la presente invención incluyen, pero no se limitan a: dióxido de silicio y talco. Los agentes antiadherentes de preferencia pueden estar presentes del 0.1 al 10 % en peso, respecto del peso total de la formulación y puede utilizarse para mejorar la fluidez. Anti-stick agents according to the present invention include, but are not limited to: silicon dioxide and talc. Anti-adherent agents can preferably be present from 0.1 to 10% by weight, with respect to the total weight of the formulation and can be used to improve fluidity.
Los agentes basificantes de acuerdo con la presente invención incluyen, pero no se limitan a: fosfato de calcio dibásico, carbonato de calcio, silicato de calcio, carbonato de sodio, silicato de aluminio y magnesio, citrato de potasio, citrato de sodio, hidróxido de calcio, dietanolamina, monoetanolamina, bicarbonato de potasio, hidróxido de potasio y meglumina. Los agentes basificantes de preferencia pueden estar presentes del 0.3 al 80 % en peso, respecto del peso total de la formulación y puede utilizarse para aportar a un medio las propiedades de un álcali, el cual al mantenerse en forma de solución presenta un pH superior a 7. Basifying agents according to the present invention include, but are not limited to: dibasic calcium phosphate, calcium carbonate, calcium silicate, sodium carbonate, magnesium aluminum silicate, potassium citrate, sodium citrate, calcium, diethanolamine, monoethanolamine, potassium bicarbonate, potassium hydroxide, and meglumine. The basifying agents can preferably be present from 0.3 to 80% by weight, with respect to the total weight of the formulation and can be used to provide a medium with the properties of an alkali, which, when kept in solution, has a pH greater than 7.
Los agentes protectores de humedad de acuerdo con la presente invención incluyen, pero no se limitan a: almidón y sus derivados, almidón de maíz, almidón de maíz pregelatinizado, hidroxipropilcelulosa, alcohol polivinílico, ácido estearílico y copolímeros de vinilpirrolidona-vinil acetato. Los agentes protectores de preferencia pueden estar presentes del 0.25 al 80 % en peso, respecto del peso total de la formulación y puede utilizarse para aportar a la composición un sistema de protección o regulación de la humedad ambiental tanto durante el proceso de fabricación como durante la vida de anaquel del producto terminado. Wet-protecting agents according to the present invention include, but are not limited to: starch and its derivatives, corn starch, pregelatinized corn starch, hydroxypropylcellulose, polyvinyl alcohol, stearyl acid, and vinylpyrrolidone-vinyl acetate copolymers. The protective agents can preferably be present from 0.25 to 80% by weight, with respect to the total weight of the formulation and can be used to provide the composition with a system for protection or regulation of environmental humidity both during the manufacturing process and during the preparation process. shelf life of the finished product.
Los agentes para incrementar la solubilidad, tensoactivos, materiales de recubrimiento, edulcorantes, agentes saborizantes, agentes colorantes u otro excipiente farmacéuticamente aceptable
pueden estar presentes en las cantidades necesarias de acuerdo con sus funciones y características de la formulación a desarrollar. Agents to increase solubility, surfactants, coating materials, sweeteners, flavoring agents, coloring agents or other pharmaceutically acceptable excipients they can be present in the necessary amounts according to their functions and characteristics of the formulation to be developed.
Derivado de la exhaustiva evaluación del efecto sinérgico terapéutico (EST) de la combinación Azitromicina e Hidroxicloroquina, una modalidad de la presente invención corresponde a una composición farmacéutica caracterizada por que comprende: de 400.0 a 1500.0 mg de Azitromicina o una sal farmacéuticamente aceptable; y 124.0 a 465.0 mg de Hidroxicloroquina o una sal farmacéuticamente aceptable, además de uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral. La presente modalidad resulta útil para el tratamiento de infecciones ocasionadas por el virus Coronavírídae, seleccionadas de SARS-CoV (Síndrome respiratorio agudo grave- CoV), SARS-CoV2 (Síndrome respiratorio agudo grave-CoV2), MERS (Síndrome respiratorio del Medio Oriente), 229E, NL63, OC43y HKU1 o infecciones ocasionadas por Plasmodiumvivax, P. malarie, P. ovale y P. falciparium, también conocidos como malaria o paludismo. Prefiriendo una composición con 500.00 mg de azitromicina y 155.00 mg de hidroxicloroquina. Derived from the exhaustive evaluation of the synergistic therapeutic effect (EST) of the combination of Azithromycin and Hydroxychloroquine, one embodiment of the present invention corresponds to a pharmaceutical composition characterized in that it comprises: from 400.0 to 1500.0 mg of Azithromycin or a pharmaceutically acceptable salt; and 124.0 to 465.0 mg of Hydroxychloroquine or a pharmaceutically acceptable salt, plus one or more pharmaceutically acceptable excipients, which is formulated to be administered orally. This modality is useful for the treatment of infections caused by the Coronaviridae virus, selected from SARS-CoV (Severe Acute Respiratory Syndrome-CoV), SARS-CoV2 (Severe Acute Respiratory Syndrome-CoV2), MERS (Middle East Respiratory Syndrome) , 229E, NL63, OC43, and HKU1 or infections caused by Plasmodiumvivax, P. malarie, P. ovale, and P. falciparium, also known as malaria or malaria. Preferring a composition with 500.00 mg of azithromycin and 155.00 mg of hydroxychloroquine.
Derivado de la exhaustiva evaluación del efecto sinérgico preventivo (ESP) de la combinación Azitromicina e Hidroxicloroquina, una modalidad de la presente invención corresponde a una composición farmacéutica caracterizada por que comprende: de 15.0 a 975.0 mg de Azitromicina o una sal farmacéuticamente aceptable; y 4.65 a 302.25 mg de Hidroxicloroquina o una sal farmacéuticamente aceptable, además de uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrad por vía oral. La presente modalidad resulta útil para la prevención de infecciones ocasionadas por el virus Coronavírídae, seleccionadas de SARS-CoV (Síndrome respiratorio agudo grave- CoV), SARS-CoV2 (Síndrome respiratorio agudo grave-CoV2), MERS (Síndrome respiratorio del Medio Oriente), 229E, NL63, OC43y HKU1 o infecciones ocasionadas por Plasmodíum vívax, P. malarie, P. ovale y P. falciparium, también conocidos como malaria o paludismo. Prefiriendo una composición con menos de 500.00 mg de azitromicina y menos de 155.00 mg de hidroxicloroquina, esto tomando en cuenta la presencia de efectos secundarios y efectos adversos atribuibles a los ingredientes activos. Derived from the exhaustive evaluation of the synergistic preventive effect (ESP) of the combination of Azithromycin and Hydroxychloroquine, one embodiment of the present invention corresponds to a pharmaceutical composition characterized in that it comprises: from 15.0 to 975.0 mg of Azithromycin or a pharmaceutically acceptable salt; and 4.65 to 302.25 mg of Hydroxychloroquine or a pharmaceutically acceptable salt, plus one or more pharmaceutically acceptable excipients, which is formulated to be administered orally. This modality is useful for the prevention of infections caused by the Coronaviridae virus, selected from SARS-CoV (Severe Acute Respiratory Syndrome-CoV), SARS-CoV2 (Severe Acute Respiratory Syndrome-CoV2), MERS (Middle East Respiratory Syndrome) , 229E, NL63, OC43 and HKU1 or infections caused by Plasmodium vívax, P. malarie, P. ovale and P. falciparium, also known as malaria or malaria. Preferring a composition with less than 500.00 mg of azithromycin and less than 155.00 mg of hydroxychloroquine, taking into account the presence of side effects and adverse effects attributable to the active ingredients.
EJEMPLOS EXAMPLES
A continuación se presentan de manera descriptiva no limitativa, diferentes composiciones, así como el proceso de preparación de las mismas:
Ejemplo 1 : Composición sólida con Azitromicina-Hidroxicloroquina de acuerdo con la invención.Different compositions, as well as their preparation process, are presented below in a non-limiting descriptive manner: Example 1: Solid composition with Azithromycin-Hydroxychloroquine according to the invention.
Componente Cantidad Component Quantity
Azitromicina 15.0 mg - 1500.00 mgAzithromycin 15.0mg - 1500.00mg
Hidroxicloroquina 10.0 mg - 1000.00 mg Hydroxychloroquine 10.0mg - 1000.00mg
Agente para incrementar la solubilidad 0.1 - 30 % Agente aglutinante 0 - 15 % Agente antiadherente 0.1 - 10 % Agente desintegrante 0.1 - 30 % Agente diluente 1 - 80 % Agente lubricante 0.1 - 10 % Agent to increase solubility 0.1 - 30% Binding agent 0 - 15% Anti-stick agent 0.1 - 10% Disintegrating agent 0.1 - 30% Diluting agent 1 - 80% Lubricating agent 0.1 - 10%
Otros excipientes farmacéuticamente aceptables 0.1 - 80 % Other pharmaceutically acceptable excipients 0.1 - 80%
Ejemplo 2: Contenido de composición con Azitromicina-Hidroxicloroquina. Example 2: Composition content with Azithromycin-Hydroxychloroquine.
Los diversos comportamientos de la combinación a diferentes concentraciones, fueron evaluados con la finalidad de determinar los efecto sinérgico terapéutico para el tratamiento de la infección en pacientes con COVID-19 (EST) y diferenciarlos del efecto sinérgico preventivo de la infección por COVID-19 (ESP). A continuación se presentan los resultados de dicha evaluación: The various behaviors of the combination at different concentrations were evaluated in order to determine the synergistic therapeutic effect for the treatment of infection in patients with COVID-19 (EST) and differentiate them from the synergistic preventive effect of COVID-19 infection ( ESP). The results of said evaluation are presented below:
Ejemplo Azitromicina (mg) Hidroxicloroquina (mg) EST ESP Example Azithromycin (mg) Hydroxychloroquine (mg) EST ESP
2.1 15.00 4.65 NO SI 2.1 15.00 4.65 NO YES
2.2 20.00 6.20 NO SI 2.2 20.00 6.20 NO YES
2.3 25.00 7.75 NO SI 2.3 25.00 7.75 NO YES
2.4 50.00 15.50 NO SI 2.4 50.00 15.50 NO YES
2.5 75.00 23.25 NO SI 2.5 75.00 23.25 NO YES
2.6 100.00 31.00 NO SI 2.6 100.00 31.00 NO YES
2.7 125.00 38.75 NO SI 2.7 125.00 38.75 NO YES
2.8 150.00 46.50 NO SI 2.8 150.00 46.50 NO YES
2.9 175.00 54.25 NO SI 2.9 175.00 54.25 NO YES
2.10 200.00 62.00 NO SI 2.11 225.00 69.75 NO SI 2.12 250.00 77.50 NO SI 2.10 200.00 62.00 NO YES 2.11 225.00 69.75 NO YES 2.12 250.00 77.50 NO YES
2.13 275.00 85.25 NO SI 2.13 275.00 85.25 NO YES
2.14 300.00 93.00 NO SI 2.14 300.00 93.00 NO YES
2.15 325.00 100.75 NO SI 2.15 325.00 100.75 NO YES
2.16 350.00 108.50 NO SI 2.16 350.00 108.50 NO YES
2.17 375.00 116.25 NO SI 2.17 375.00 116.25 NO YES
2.18 400.00 124.00 SI SI 2.18 400.00 124.00 YES YES
2.19 425.00 131.75 SI SI 2.19 425.00 131.75 YES YES
2.20 450.00 139.50 SI SI 2.21 475.00 147.25 SI SI 2.22 500.00 155.00 SI SI 2.20 450.00 139.50 YES YES 2.21 475.00 147.25 YES YES 2.22 500.00 155.00 YES YES
2.23 525.00 162.75 SI SI 2.23 525.00 162.75 YES YES
2.24 550.00 170.50 SI SI 2.24 550.00 170.50 YES YES
2.25 575.00 178.25 SI SI 2.25 575.00 178.25 YES YES
2.26 600.00 186.00 SI SI 2.26 600.00 186.00 YES YES
2.27 625.00 193.75 SI SI 2.27 625.00 193.75 YES YES
2.28 650.00 201.50 SI SI 2.28 650.00 201.50 YES YES
2.29 675.00 209.25 SI SI 2.29 675.00 209.25 YES YES
2.30 700.00 217.00 SI SI 2.30 700.00 217.00 YES YES
2.31 725.00 224.75 SI SI
2.32 750.00 232.50 SI SI 2.31 725.00 224.75 YES YES 2.32 750.00 232.50 YES YES
2.33 775.00 240.25 SI SI 2.33 775.00 240.25 YES YES
2.34 800.00 248.00 SI SI 2.34 800.00 248.00 YES YES
2.35 825.00 255.75 SI SI 2.35 825.00 255.75 YES YES
2.36 850.00 263.50 SI SI 2.36 850.00 263.50 YES YES
2.37 875.00 271.25 SI SI 2.37 875.00 271.25 YES YES
2.38 900.00 279.00 SI SI 2.38 900.00 279.00 YES YES
2.39 925.00 286.75 SI SI 2.39 925.00 286.75 YES YES
2.40 950.00 294.50 SI SI 2.40 950.00 294.50 YES YES
2.41 975.00 302.25 SI SI 2.41 975.00 302.25 YES YES
2.42 1000.00 310.00 SI NO 2.42 1000.00 310.00 YES NO
2.43 1025.00 317.75 SI NO 2.43 1025.00 317.75 YES NO
2.44 1050.00 325.50 SI NO 2.44 1050.00 325.50 YES NO
2.45 1075.00 333.25 SI NO 2.45 1075.00 333.25 YES NO
2.46 1100.00 341.00 SI NO 2.46 1100.00 341.00 YES NO
2.47 1125.00 348.75 SI NO 2.47 1125.00 348.75 YES NO
2.48 1150.00 356.50 SI NO 2.48 1150.00 356.50 YES NO
2.49 1175.00 364.25 SI NO 2.49 1175.00 364.25 YES NO
2.50 1200.00 372.00 SI NO 2.50 1200.00 372.00 YES NO
2.51 1225.00 379.75 SI NO 2.51 1225.00 379.75 YES NO
2.52 1250.00 387.50 SI NO 2.52 1250.00 387.50 YES NO
2.53 1275.00 395.25 SI NO 2.53 1275.00 395.25 YES NO
2.54 1300.00 403.00 SI NO 2.54 1300.00 403.00 YES NO
2.55 1325.00 410.75 SI NO 2.55 1325.00 410.75 YES NO
2.56 1350.00 418.50 SI NO 2.56 1350.00 418.50 YES NO
2.57 1375.00 426.25 SI NO 2.57 1375.00 426.25 YES NO
2.58 1400.00 434.00 SI NO 2.58 1400.00 434.00 YES NO
2.59 1425.00 441.75 SI NO 2.59 1425.00 441.75 YES NO
2.60 1450.00 449.50 SI NO 2.61 1475.00 457.25 SI NO 2.62 1500.00 465.00 SI NO 2.60 1450.00 449.50 YES NO 2.61 1475.00 457.25 YES NO 2.62 1500.00 465.00 YES NO
El efecto sinérgico terapéutico (EST) se mostró a partir de una cantidad de 400.00 mg hasta 1500.00 mg de azitromicina en combinación con 124 mg a 465.00 mg de hidroxicloroquina, mientras que el efecto sinérgico preventivo (ESP) se mostró a partir de una cantidad de 15.00 mg hasta 975.00 mg de azitromicina en combinación con 4.65 mg a 302.25 mg de hidroxicloroquina. Cabe destacar que si bien, las cantidades mayores de 1000 mg hasta 1500.00 de azitromicina con 310.00 mg a 465.00 mg de hidroxicloroquina, siguen manteniendo el efecto preventivo, la presencia de los efectos secundarios y adversos son más significativos a partir de una concentración de 500 mg de azitromicina y 155 mg de hidroxicloroquina, sin embargo, a partir de la dosis de 1000 mg de azitromicina con 341 mg de hidroxicloroquina, dichos efectos secundarios empiezan a afectar significativamente al paciente. The synergistic therapeutic effect (EST) was shown from an amount of 400.00 mg to 1500.00 mg of azithromycin in combination with 124 mg to 465.00 mg of hydroxychloroquine, while the synergistic preventive effect (ESP) was shown from an amount of 15.00 mg to 975.00 mg of azithromycin in combination with 4.65 mg to 302.25 mg of hydroxychloroquine. It should be noted that although amounts greater than 1000 mg to 1500.00 mg of azithromycin with 310.00 mg to 465.00 mg of hydroxychloroquine continue to maintain the preventive effect, the presence of secondary and adverse effects are more significant from a concentration of 500 mg of azithromycin and 155 mg of hydroxychloroquine, however, from the dose of 1000 mg of azithromycin with 341 mg of hydroxychloroquine, these side effects begin to affect the patient significantly.
Ejemplo 3: Composición sólida con Azitromicina-Hidroxicloroquina, un agente basificante y un agente protector de humedad. Example 3: Solid composition with Azithromycin-Hydroxychloroquine, a basifying agent and a moisture protecting agent.
Ejemplo / Contenido (%) Example / Content (%)
Componente 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8Component 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8
Azitromicina 45.45 5.45 45.45 5.45 45.45 5.45 45.45 45.45Azithromycin 45.45 5.45 45.45 5.45 45.45 5.45 45.45 45.45
Hidroxicloroquina 22.73 2.73 22.73 2.73 22.73 2.73 22.73 22.73
Fosfato de calcio Hydroxychloroquine 22.73 2.73 22.73 2.73 22.73 2.73 22.73 22.73 Calcium phosphate
1 80 0 0 0 0 0 0 dibásico 1 80 0 0 0 0 0 0 dibasic
Carbonato de calcio 0 0 1 80 0 0 0 0 Silicato de calcio 0 0 1 80 0 0 Carbonato de sodio 0 0 0 0 0 0 2 5 Otros excipientes farmacéuticamente 30.82 11.82 30.82 11.82 30.82 11.82 29.82 26.82 aceptables Calcium carbonate 0 0 1 80 0 0 0 0 Calcium silicate 0 0 1 80 0 0 Sodium carbonate 0 0 0 0 0 0 2 5 Other pharmaceutically acceptable excipients 30.82 11.82 30.82 11.82 30.82 11.82 29.82 26.82
Ejemplo / Contenido (%) Example / Content (%)
Componente 3.9 3.10 3.11 3.12 3.13 3.14 3.15 3.16Component 3.9 3.10 3.11 3.12 3.13 3.14 3.15 3.16
Azitromicina 45.45 10.5 45.45 45.45 45.45 45.45 45.45 5.45 Hidroxicloroquina 22.73 5.25 22.73 22.73 22.73 22.73 22.73 2.73 Silicato de aluminio y Azithromycin 45.45 10.5 45.45 45.45 45.45 45.45 45.45 5.45 Hydroxychloroquine 22.73 5.25 22.73 22.73 22.73 22.73 22.73 2.73 Aluminum silicate and
1 80 0 0 0 0 0 0 magnesio 1 80 0 0 0 0 0 0 magnesium
Citrato de potasio 0 0 2 3 0 0 0 0 Citrato de sodio 0 0 0 0 0.3 2 0 0 Almidón de maíz pre-Potassium citrate 0 0 2 3 0 0 0 0 Sodium citrate 0 0 0 0 0.3 2 0 0 Corn starch pre-
0 0 0 0 0 0 1 80 gelatinizado Otros excipientes farmacéuticamente 30.82 4.25 29.82 28.82 31.52 29.82 30.82 11.82 aceptables 0 0 0 0 0 0 1 80 gelatinized Other pharmaceutically acceptable excipients 30.82 4.25 29.82 28.82 31.52 29.82 30.82 11.82
Ejemplo / Contenido (%) Example / Content (%)
Componente 3.17 3.18 3.19 3.20 3.21 3.22 3.23 3.24Component 3.17 3.18 3.19 3.20 3.21 3.22 3.23 3.24
Azitromicina 45.45 10.5 45.45 45.45 45.45 45.45 45.45 45.45 Hidroxicloroquina 22.73 5.25 22.73 22.73 22.73 22.73 22.73 22.73 Hidroxipropilcelulosa 2 35 0 0 0 0 0 0 Alcohol polivinílico 0 0 0.25 3 0 0 Ácido estearílico 0 0 0 0 1 20 0 0 Copolímero de vinilpirrolidona-vinil 0 0 0 0 0 0 2 5 acetato Azytromycin 45.45 10.5 45.45 45.45 45.45 45.45 45.45 45.45 HYDROXICLORLING 22.73 5.25 22.73 22.73 22.73 22.73 22.73 22.73 0 0 0 0 0 0 2 5 acetate
Otros excipientes farmacéuticamente 29.82 49.25 31.57 28.82 30.82 11.82 29.82 26.82 aceptables Other pharmaceutically acceptable excipients 29.82 49.25 31.57 28.82 30.82 11.82 29.82 26.82
Ejemplo / Contenido (%) Example / Content (%)
Componente 3.25 3.26 3.27 3.28 3.29 3.30 3.31 3.32Component 3.25 3.26 3.27 3.28 3.29 3.30 3.31 3.32
Azitromicina 45.45 45.45 45.45 45.45 45.45 45.45 45.45 45.45 Hidroxicloroquina 22.73 22.73 22.73 22.73 22.73 22.73 22.73 22.73 Fosfato de calcio Azithromycin 45.45 45.45 45.45 45.45 45.45 45.45 45.45 45.45 Hydroxychloroquine 22.73 22.73 22.73 22.73 22.73 22.73 22.73 22.73 Calcium phosphate
10 9 0 0 0 5 0 5 dibásico 10 9 0 0 0 5 0 5 dibasic
Carbonato de calcio 0 0 15 12 0 0 0 Silicato de calcio 0 0 0 0 5 0 0 0 Carbonato de sodio 0 0 0 0 0 0 8 0 Silicato de aluminio y Calcium carbonate 0 0 15 12 0 0 0 Calcium silicate 0 0 0 0 5 0 0 0 Sodium carbonate 0 0 0 0 0 0 8 0 Aluminum silicate and
0 0 0 0 0 0 0 0 magnesio 0 0 0 0 0 0 0 0 magnesium
Citrato de potasio 0 0 0 0 0 0 0 0 Citrato de sodio 0 0 0 0 0 0 0 0
Almidón de maíz pre-Potassium citrate 0 0 0 0 0 0 0 0 Sodium citrate 0 0 0 0 0 0 0 0 Corn starch pre-
12 12 2 0 0 5 5 0 gelatinizado Hidroxipropilcelulosa 0 0 0 0 5 0 0 0 Alcohol polivinílico 0 0 0 2 0 0 0 0 Ácido estearílico 0 0 0 0 0 0 0 5 Copolímero de vinilpirrolídona-vinil 0 0 0 0 0 0 0 0 acetato 12 12 2 0 0 5 5 0 gelatinized Hydroxypropylcellulose 0 0 0 0 5 0 0 0 Polyvinyl alcohol 0 0 0 2 0 0 0 0 Stearyl acid 0 0 0 0 0 0 0 5 Vinylpyrrolidone-vinyl copolymer 0 0 0 0 0 0 0 0 acetate
Otros excipientes farmacéuticamente 9.82 10.82 14.82 17.82 21.82 21.82 18.82 21.82 aceptables Other pharmaceutically acceptable excipients 9.82 10.82 14.82 17.82 21.82 21.82 18.82 21.82
Ejemplo / Contenido (%) Example / Content (%)
Componente 3.33 3.34 3.35 3.36 3.37 3.38 3.39 3.40Component 3.33 3.34 3.35 3.36 3.37 3.38 3.39 3.40
Azitromicina 45.45 45.45 45.45 45.45 45.45 45.45 45.45 45.45 Hidroxicloroquina 22.73 22.73 22.73 22.73 22.73 22.73 22.73 22.73 Fosfato de calcio Azithromycin 45.45 45.45 45.45 45.45 45.45 45.45 45.45 45.45 Hydroxychloroquine 22.73 22.73 22.73 22.73 22.73 22.73 22.73 22.73 Calcium phosphate
0 0 2.5 5 2.5 0 20 10 dibásico 0 0 2.5 5 2.5 0 20 10 dibasic
Carbonato de calcio 0 0 0 0 0 0 0 0 Silicato de calcio 0 0 0 0 2.5 0 0 0 Carbonato de sodio 0 0 0 0 0 7.5 0 0 Silicato de aluminio y Calcium carbonate 0 0 0 0 0 0 0 0 Calcium silicate 0 0 0 0 2.5 0 0 0 Sodium carbonate 0 0 0 0 0 7.5 0 0 Aluminum silicate and
5 2.5 2.5 5 0 0 0 5 magnesio 5 2.5 2.5 5 0 0 0 5 magnesium
Citrato de potasio 0 2.5 0 0 0 0 0 0 Citrato de sodio 0 0 0 0 0 0 0 0 Almidón de maíz pre-Potassium citrate 0 2.5 0 0 0 0 0 0 Sodium citrate 0 0 0 0 0 0 0 0 Corn starch pre-
0 5 2.5 2.5 0 5 5 2.5 gelatinizado Hidroxipropilcelulosa 0 0 0 0 2.5 0 0 0 Alcohol polivinílico 0 0 0 0 0 0 0 2.5 Ácido estearílico 0 0 2.5 0 0 0 0 0 Copolímero de vinilpirrolidona-vinil 7 0 0 0 5 0 0 0 acetato 0 5 2.5 2.5 0 5 5 2.5 gelatinized Hydroxypropylcellulose 0 0 0 0 2.5 0 0 0 Polyvinyl alcohol 0 0 0 0 0 0 0 2.5 Stearyl acid 0 0 2.5 0 0 0 0 0 Vinylpyrrolidone-vinyl copolymer 7 0 0 0 5 0 0 0 acetate
Otros excipientes farmacéuticamente 19.82 21.82 21.82 19.32 19.32 19.32 6.82 11.82 aceptables
Other pharmaceutically acceptable excipients 19.82 21.82 21.82 19.32 19.32 19.32 6.82 11.82
Ejemplo 4: Determinación de solventes. Example 4: Determination of solvents.
De acuerdo con las composiciones formuladas en el ejemplo 3, se determina la humedad, el contenido de agua y el contenido de solventes, conforme a la Farmacopea, para determinar los agentes basificantes y agentes protectores de humedad efectivos, así como las concentraciones óptimas en la composición. According to the compositions formulated in example 3, the humidity, the water content and the solvent content are determined, according to the Pharmacopoeia, to determine the effective basifying agents and moisture-protecting agents, as well as the optimal concentrations in the formulation. composition.
Ejemplo 5: Determinación de impurezas. Example 5: Determination of impurities.
Mediante los métodos conocidos en el estado de la técnica, se determinaron los agentes basificantes y agentes protectores de humedad, así como las concentraciones óptimas en la composición. Using the methods known in the state of the art, the basifying agents and moisture-protecting agents were determined, as well as the optimal concentrations in the composition.
Las impurezas evaluadas son: The impurities evaluated are:
Componente Impurezas Component Impurities
N, M, G, E, O, B, I, H, J, F, C, D, eritromicina A 9, 11 -imino éter, azitromicina N-óxido,N, M, G, E, O, B, I, H, J, F, C, D, erythromycin A 9, 11 -imino ether, azithromycin N-oxide,
Azitromicina eritromicina A OXIMA, descladenosil azitromicina A y N- demetril azitromicina isómero R, isómero S, hidroxicloroquina N-desetil,Azithromycin erythromycin A OXIME, descladenosyl azithromycin A and N-demetryl azithromycin R isomer, S isomer, N-desethyl hydroxychloroquine,
Hidroxicloroquina impureza 1, hidroxicloroquina O-sulfato, hidroxicloroquina d4 sulfato, hidroxicloroquina O-acetato Las composiciones con la combinación de al menos un agente basificante y al menos un agente protector de humedad, muestran una cantidad de impurezas totales en la formulación a los 3 meses en condiciones de estabilidad acelerada es de menos de 2% y manteniéndose en condiciones de estabilizada a largo plazo. Hydroxychloroquine impurity 1, hydroxychloroquine O-sulfate, hydroxychloroquine d4 sulfate, hydroxychloroquine O-acetate The compositions with the combination of at least one basifying agent and at least one moisture protecting agent, show an amount of total impurities in the formulation at 3 months in conditions of accelerated stability it is less than 2% and remaining in long-term stabilized conditions.
Ejemplo 6: Composición sólida en forma de tableta con Azitromicina-Hidroxicloroquina. Example 6: Solid composition in tablet form with Azithromycin-Hydroxychloroquine.
Ejemplo / Contenido (%) Example / Content (%)
Componente 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8Component 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8
Hidroxicloroquina 22.73 10.5 10.5 10.5 22.73 22.73 10.5 22.73Hydroxychloroquine 22.73 10.5 10.5 10.5 22.73 22.73 10.5 22.73
Azitromicina 45.45 5.25 5.25 5.25 45.45 45.45 5.25 45.45Azithromycin 45.45 5.25 5.25 5.25 45.45 45.45 5.25 45.45
Hidroxipropilcelulosa 2.00 20.00 35.00 19.00 10.00 0.00 0.00 0.00Hydroxypropylcellulose 2.00 20.00 35.00 19.00 10.00 0.00 0.00 0.00
Lactosa anhidra 24.82 18.65 1.00 40.00 10.00 5.00 2.15 0.00Anhydrous lactose 24.82 18.65 1.00 40.00 10.00 5.00 2.15 0.00
Copovidona 2.00 5.00 5.00 2.35 1.00 0.00 0.00 0.00Copovidone 2.00 5.00 5.00 2.35 1.00 0.00 0.00 0.00
Celulosa microcristalina 1.00 40.00 43.15 21.90 10.52 0.00 0.00 0.00Microcrystalline cellulose 1.00 40.00 43.15 21.90 10.52 0.00 0.00 0.00
Estearato de magnesio 2.00 0.60 0.10 1.00 0.30 0.82 1.00 0.82Magnesium stearate 2.00 0.60 0.10 1.00 0.30 0.82 1.00 0.82
Almidón pregelatinizado 0.00 0.00 0.00 0.00 0.00 1.00 80.00 5.75Pregelatinized starch 0.00 0.00 0.00 0.00 0.00 1.00 80.00 5.75
Croscarmelosa sódica 0.00 0.00 0.00 0.00 0.00 5.00 0.10 5.00Croscarmellose sodium 0.00 0.00 0.00 0.00 0.00 5.00 0.10 5.00
Fosfato de calcio di básico 0.00 0.00 0.00 0.00 0.00 20.00 1.00 20.00Dibasic calcium phosphate 0.00 0.00 0.00 0.00 0.00 20.00 1.00 20.00
Alcohol polivinílico 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 Polyvinyl alcohol 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25
Ejemplo 7: Composición sólida en forma de tableta bicapa con Azitromicina-Hidroxicloroquina. Example 7: Solid composition in the form of a bilayer tablet with Azithromycin-Hydroxychloroquine.
Ejemplo / Contenido (%) Example / Content (%)
Componente 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Component 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8
CAPA 1 LAYER 1
Hidroxicloroquina 71.43 16.50 16.50 71.43 42.00 16.50 92.00 16.50Hydroxychloroquine 71.43 16.50 16.50 71.43 42.00 16.50 92.00 16.50
Almidón pregelatinizado 27.12 60.00 23.00 1.00 0.00 0.00 1.00 80.00Pregelatinized starch 27.12 60.00 23.00 1.00 0.00 0.00 1.00 80.00
Ácido esteárico 0.25 0.25 0.25 2.00 0.00 0.00 0.00 0.00Stearic acid 0.25 0.25 0.25 2.00 0.00 0.00 0.00 0.00
Croscarmelosa sódica 0.10 0.10 0.10 5.00 5.00 1.00 5.00 2.50Croscarmellose sodium 0.10 0.10 0.10 5.00 5.00 1.00 5.00 2.50
Carbonato de calcio 1.00 23.00 60.00 18.57 0.00 0.00 0.00 0.00
Estearato de magnesio 0.10 0.15 0.15 2.00 2.00 0.50 2.00 1.00Calcium carbonate 1.00 23.00 60.00 18.57 0.00 0.00 0.00 0.00 Magnesium stearate 0.10 0.15 0.15 2.00 2.00 0.50 2.00 1.00
Celulosa microcrlstalina 0.00 0.00 0.00 0.00 40.00 1.00 0.00 0.00Microcrystalline cellulose 0.00 0.00 0.00 0.00 40.00 1.00 0.00 0.00
Silicato de calcio 0.00 0.00 0.00 0.00 1.00 80.00 0.00 0.00Calcium silicate 0.00 0.00 0.00 0.00 1.00 80.00 0.00 0.00
Povidona 0.00 0.00 0.00 0.00 10.00 1.00 0.00 0.00 Povidone 0.00 0.00 0.00 0.00 10.00 1.00 0.00 0.00
CAPA 2 LAYER 2
Azitromicina 84.00 17.55 5.25 9.00 17.55 66.67 66.67 66.67Azithromycin 84.00 17.55 5.25 9.00 17.55 66.67 66.67 66.67
Almidón pregelatinizado 1.00 80.00 1.00 80.00 5.00 10.00 28.00 25.63Pregelatinized starch 1.00 80.00 1.00 80.00 5.00 10.00 28.00 25.63
Alcohol polivinílico 3.00 0.25 0.25 3.00 11.45 0.00 1.00 2.00Polyvinyl alcohol 3.00 0.25 0.25 3.00 11.45 0.00 1.00 2.00
Croscarmelosa sódica 5.00 0.10 0.10 5.00 4.00 2.50 2.00 3.00Croscarmellose sodium 5.00 0.10 0.10 5.00 4.00 2.50 2.00 3.00
Copolímero de vinilpirrolidona-vinil 5.00 2.00 0.00 0.00 0.00 0.00 1.33 2.00 acetato Vinylpyrrolidone-vinyl acetate copolymer 5.00 2.00 0.00 0.00 0.00 0.00 1.33 2.00
Estearato de magnesio 2.00 0.10 0.10 2.00 2.00 1.00 1.00 0.70Magnesium stearate 2.00 0.10 0.10 2.00 2.00 1.00 1.00 0.70
Fosfato de calcio n nn Calcium phosphate n nn
0.00 93.30 1.00 60.00 19.83 0.00 0.00 dibasico 0.00 93.30 1.00 60.00 19.83 0.00 0.00 dibasic
Ejemplo 8: Composición sólida en forma de gránulos con Azitromicina-Hidroxicloroquina. Example 8: Solid composition in the form of granules with Azithromycin-Hydroxychloroquine.
Ejemplo / Contenido (%) Example / Content (%)
Componente 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8Component 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8
Hidroxicloroquina 5.25 5.25 5.25 5.25 23.00 20.30 22.73 22.73 Azitromicina 10.50 10.50 10.50 10.50 49.00 43.40 45.45 45.45 Almidón pregelatinizado 1.00 80.00 1.25 1.00 20.00 1.00 23.82 14.00 Hidroxipropilcelulosa 35.00 2.00 2.00 0.00 0.00 0.00 0.00 5.32 Croscarmelosa sódica 0.10 0.40 5.00 0.00 0.00 0.00 0.00 3.70 Fosfato de calcio di básico 47.85 1.00 70.00 47.95 0.00 0.00 0.00 7.90 Saborizante 0.10 0.15 2.00 0.10 2.00 0.10 2.00 0.50 Edulcorante 0.10 0.30 2.00 0.10 2.00 0.10 2.00 0.20 Estearil fumarato de sodio 0.10 0.40 2.00 0.10 2.00 0.10 2.00 0.20Hidroxicloroquina 5.25 5.25 5.25 5.25 23.00 20.30 22.73 22.73 Azitromicina 10.50 10.50 10.50 10.50 49.00 43.40 45.45 45.45 Almidón pregelatinizado 1.00 80.00 1.25 1.00 20.00 1.00 23.82 14.00 Hidroxipropilcelulosa 35.00 2.00 2.00 0.00 0.00 0.00 0.00 5.32 Croscarmelosa sódica 0.10 0.40 5.00 0.00 0.00 0.00 0.00 3.70 Fosfato de calcio BASIC DI 47.85 1.00 70.00 47.95 0.00 0.00 0.00 7.90 Flavoring 0.10 0.15 2.00 0.10 2.00 0.10 2.00 0.50 Sweetener 0.10 0.30 2.00 0.10 2.00 0.10 2.00 0.20 Sodium Sodium Sod
Lactosa/crospovidona/ povidona 0.00 0.00 0.00 35.00 2.00 0.00 0.00 0.00Lactose/ crospovidone/ povidone 0.00 0.00 0.00 35.00 2.00 0.00 0.00 0.00
Manitol 0.00 0.00 0.00 0.00 0.00 35.00 2.00 0.00 Mannitol 0.00 0.00 0.00 0.00 0.00 35.00 2.00 0.00
Ejemplo 9: Distribución de tamaño de partícula. Example 9: Particle size distribution.
A partir de diferentes tamices, se estableció la distribución de tamaño de partícula de los ingredientes activos Azitromicina e Hidroxicloroquina; separando las fracciones para determinar en cada una de ellas el efecto de mejora en la biodisponibilidad de los mismos. From different sieves, the particle size distribution of the active ingredients Azithromycin and Hydroxychloroquine was established; separating the fractions to determine in each of them the effect of improvement in their bioavailability.
La distribución obtenida para azitromicina es: The distribution obtained for azithromycin is:
Tamaño de poro pore size
ASTM # % retenido (micrómetros) ASTM # % Retained (micrometers)
45 355 14.206 45 355 14,206
50 300 6.664 50 300 6,664
60 250 27.39 60 250 27.39
100 150 11.769 100 150 11,769
170 90 6.423 170 90 6,423
200 75 11.62 200 75 11.62
325 45 2.465 325 45 2,465
400 38 5.848
500 25 13.615 400 38 5,848 500 25 13,615
Utilizando las diferentes distribuciones de tamaño de partícula, se obtuvieron "lotes” de azitromicina con cada distribución de tamaño de partícula D90 de aproximadamente 350, 300, 250, 150, 90, 75, 45, 38 y 25 micrometros, resultando en una mejora en la biodisponibilidad al utilizar la materia prima con una distribución de tamaño de partícula D90 menor de 250 micrometros. Dichos ensayos de biodisponibilidad se realizaron en voluntarios sanos. Using the different particle size distributions, azithromycin "batches" were obtained with each D90 particle size distribution of approximately 350, 300, 250, 150, 90, 75, 45, 38 and 25 micrometers, resulting in an improvement in the bioavailability when using the raw material with a particle size distribution D90 less than 250 micrometers.These bioavailability tests were carried out in healthy volunteers.
La distribución obtenida para hidroclorquina es: The distribution obtained for hydrochlorquine is:
Tamaño de poro pore size
ASTM # % retenido (micrometros) ASTM # % Retained (micrometers)
50 300 12.15 50 300 12.15
60 250 20.40 60 250 20.40
100 150 35.41 100 150 35.41
170 90 7.73 170 90 7.73
200 75 4.00 200 75 4.00
325 45 10.30 325 45 10.30
400 38 5.00 400 38 5.00
500 25 5.00 500 25 5.00
Utilizando las diferentes distribuciones de tamaño de partícula, se obtuvieron "lotes” de hidroxicloroquina con cada distribución de tamaño de partícula D90 de aproximadamente 300, 250,Using the different particle size distributions, "batches" of hydroxychloroquine were obtained with each D90 particle size distribution of approximately 300, 250,
150, 90, 75, 45, 38 y 25 micrometros, resultando en una mejora en la biodisponibilidad al utilizar la materia prima con una distribución de tamaño de partícula D90 menor de 100 micrometros.150, 90, 75, 45, 38 and 25 micrometers, resulting in an improvement in bioavailability when using the raw material with a particle size distribution D90 less than 100 micrometers.
Dichos ensayos de biodisponibilidad se realizaron en voluntarios sanos. Said bioavailability tests were carried out in healthy volunteers.
Adicionalmente, la composición se evaluó en pacientes con enfermedad COVID-19, mostrando el efecto sinérgico de los ingredientes activos.
Additionally, the composition was evaluated in patients with COVID-19 disease, showing the synergistic effect of the active ingredients.
Claims
1. Una composición farmacéutica sólida caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico es Hidroxicloroquina en una cantidad farmacéuticamente aceptable, además de uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral. 1. A solid pharmaceutical composition characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is Hydroxychloroquine in a pharmaceutically acceptable amount, in addition to one or more pharmaceutically acceptable excipients, which is formulated to be administered orally.
2. Una composición farmacéutica sólida caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico es Hidroxicloroquina en una cantidad farmacéuticamente aceptable, uno o más agentes basificantes y al menos un excipiente farmacéuticamente aceptable, la cual esta formulada para ser administrada por vía oral. 2. A solid pharmaceutical composition characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is Hydroxychloroquine in a pharmaceutically acceptable amount, one or more basifying agents and at least one pharmaceutically acceptable excipient, which is formulated to be administered orally.
3. Una composición farmacéutica caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico es Hidroxicloroquina en una cantidad farmacéuticamente aceptable, uno o más agentes protectores de humedad y al menos un excipiente farmacéuticamente aceptable, la cual esta formulada para ser administrada por vía oral. 3. A pharmaceutical composition characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is Hydroxychloroquine in a pharmaceutically acceptable amount, one or more moisture protecting agents and at least one pharmaceutically acceptable excipient, which is formulated to be administered orally.
4. Una composición farmacéutica caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico es Hidroxicloroquina en una cantidad farmacéuticamente aceptable, al menos un agente basificante, al menos un agente para el control de la humedad y uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral. 4. A pharmaceutical composition characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; wherein the antimalarial agent is Hydroxychloroquine in a pharmaceutically acceptable amount, at least one basifying agent, at least one moisture control agent and one or more pharmaceutically acceptable excipients, which is formulated to be administered orally.
5. Una composición farmacéutica caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico es Hidroxicloroquina en una cantidad farmacéuticamente aceptable, uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral, en donde el agente antibiótico macrólido presenta una distribución de tamaño de partícula D90 menor de 250 mieras.
5. A pharmaceutical composition characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; where the antimalarial agent is Hydroxychloroquine in a pharmaceutically acceptable amount, one or more pharmaceutically acceptable excipients, which is formulated to be administered orally, where the macrolide antibiotic agent has a particle size distribution D90 less than 250 microns.
6. Una composición farmacéutica caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimalárico; en donde el agente antimalárico es Hidroxicloroquina en una cantidad farmacéuticamente aceptable, uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral, en donde el agente antimalárico presenta un tamaño de partícula D90 menor de 100 mieras. 6. A pharmaceutical composition characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; where the antimalarial agent is Hydroxychloroquine in a pharmaceutically acceptable amount, one or more pharmaceutically acceptable excipients, which is formulated to be administered orally, where the antimalarial agent has a D90 particle size of less than 100 microns.
7. Una composición farmacéutica caracterizada por que comprende: de 15.0 a 975.0 mg de Azitromicina o una sal farmacéuticamente aceptable; y 4.65 a 302.25 mg de Hidroxicloroquina o una sal farmacéuticamente aceptable, además de uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral. 7. A pharmaceutical composition characterized in that it comprises: from 15.0 to 975.0 mg of Azithromycin or a pharmaceutically acceptable salt; and 4.65 to 302.25 mg of Hydroxychloroquine or a pharmaceutically acceptable salt, plus one or more pharmaceutically acceptable excipients, which is formulated to be administered orally.
8. Una composición farmacéutica caracterizada por que comprende: de 400.0 a 124.0 mg de Azitromicina o una sal farmacéuticamente aceptable; y 124.0 a 302.25 mg de Hidroxicloroquina o una sal farmacéuticamente aceptable, además de uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral. 8. A pharmaceutical composition characterized in that it comprises: from 400.0 to 124.0 mg of Azithromycin or a pharmaceutically acceptable salt; and 124.0 to 302.25 mg of Hydroxychloroquine or a pharmaceutically acceptable salt, plus one or more pharmaceutically acceptable excipients, which is formulated to be administered orally.
9. Una composición farmacéutica caracterizada por que comprende: menos de 500.0 mg de Azitromicina o una sal farmacéuticamente aceptable; y menos de 155.0 mg de Hidroxicloroquina o una sal farmacéuticamente aceptable, además de uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral. 9. A pharmaceutical composition characterized in that it comprises: less than 500.0 mg of Azithromycin or a pharmaceutically acceptable salt; and less than 155.0 mg of Hydroxychloroquine or a pharmaceutically acceptable salt, plus one or more pharmaceutically acceptable excipients, which is formulated to be administered orally.
10. Una composición farmacéutica caracterizada por que comprende: un agente antibiótico macrólido; en donde el agente antibiótico macrólido es Azitromicina en una cantidad farmacéuticamente aceptable y un agente antimaláñeo; en donde el agente antimaláñeo es Hidroxicloroquina en una cantidad farmacéuticamente aceptable, además de uno o más excipientes farmacéuticamente aceptables, la cual esta formulada para ser administrada por vía oral, en donde, la cantidad de impurezas totales en la formulación a los 3 meses en condiciones de estabilidad acelerada es de menos de 2%. 10. A pharmaceutical composition characterized in that it comprises: a macrolide antibiotic agent; wherein the macrolide antibiotic agent is Azithromycin in a pharmaceutically acceptable amount and an antimalarial agent; where the anti-maláñeo agent is Hydroxychloroquine in a pharmaceutically acceptable amount, in addition to one or more pharmaceutically acceptable excipients, which is formulated to be administered orally, where, the amount of total impurities in the formulation at 3 months in conditions accelerated stability is less than 2%.
11. Una composición farmacéutica de conformidad con las reivindicaciones 1 a 9, en donde la forma farmacéuticamente aceptable se selecciona de: tableta, tableta bicapa, cápsulas de gelatina blanda, cápsulas de gelatina dura, cápsula con un contenido de una o más tabletas o cápsulas, polvo, gránulos. 11. A pharmaceutical composition according to claims 1 to 9, wherein the pharmaceutically acceptable form is selected from: tablet, bilayer tablet, soft gelatin capsules, hard gelatin capsules, capsule containing one or more tablets or capsules , powder, granules.
12. La composición farmacéutica como la que se reclama en las reivindicaciones 1 a 11, para usarse en el tratamiento y/o prevención de infecciones ocasionadas por el virus Coronavírídae, seleccionadas de SARS-CoV (Síndrome respiratorio agudo grave-CoV), SARS-CoV2 (Síndrome respiratorio agudo
grave-CoV2), MERS (Síndrome respiratorio del Medio Oriente), 229E, NL63, OC43 y HKU1 o infecciones ocasionadas por Plasmodíum vívax, P. malaríe, P. ovale y P. falcíparíum, también conocidos como malaria o paludismo.
12. The pharmaceutical composition as claimed in claims 1 to 11, for use in the treatment and/or prevention of infections caused by the Coronaviridae virus, selected from SARS-CoV (Severe Acute Respiratory Syndrome-CoV), SARS- CoV2 (Acute respiratory syndrome severe-CoV2), MERS (Middle East respiratory syndrome), 229E, NL63, OC43 and HKU1 or infections caused by Plasmodium vívax, P. malaríe, P. ovale and P. falcíparíum, also known as malaria or malaria.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/MX2021/050019 WO2022220669A1 (en) | 2021-04-16 | 2021-04-16 | Oral solid combination for the treatment of virus infection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/MX2021/050019 WO2022220669A1 (en) | 2021-04-16 | 2021-04-16 | Oral solid combination for the treatment of virus infection |
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| Publication Number | Publication Date |
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| WO2022220669A1 true WO2022220669A1 (en) | 2022-10-20 |
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| PCT/MX2021/050019 WO2022220669A1 (en) | 2021-04-16 | 2021-04-16 | Oral solid combination for the treatment of virus infection |
Country Status (1)
| Country | Link |
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| WO (1) | WO2022220669A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050123627A1 (en) * | 2003-12-04 | 2005-06-09 | Pfizer Inc | Azithromycin dosage forms with reduced side effects |
| CN102525969A (en) * | 2010-12-28 | 2012-07-04 | 上海中西制药有限公司 | Hydroxychloroquine sulphate solid preparation and preparation method thereof |
| CN112641738A (en) * | 2020-12-22 | 2021-04-13 | 迪沙药业集团有限公司 | Azithromycin tablet composition |
-
2021
- 2021-04-16 WO PCT/MX2021/050019 patent/WO2022220669A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050123627A1 (en) * | 2003-12-04 | 2005-06-09 | Pfizer Inc | Azithromycin dosage forms with reduced side effects |
| CN102525969A (en) * | 2010-12-28 | 2012-07-04 | 上海中西制药有限公司 | Hydroxychloroquine sulphate solid preparation and preparation method thereof |
| CN112641738A (en) * | 2020-12-22 | 2021-04-13 | 迪沙药业集团有限公司 | Azithromycin tablet composition |
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| Title |
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| FANTINI JACQUES; CHAHINIAN HENRI; YAHI NOUARA: "Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal", INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, ELSEVIER, AMSTERDAM, NL, vol. 56, no. 2, 13 May 2020 (2020-05-13), AMSTERDAM, NL , XP086234679, ISSN: 0924-8579, DOI: 10.1016/j.ijantimicag.2020.106020 * |
| GAUTRET PHILIPPE ET AL.: "Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial", INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, vol. 56, no. 1, 30 June 2020 (2020-06-30), XP086227544, ISSN: 0924-8579, DOI: 10.1016/j.ijantimicag.2020.105949 * |
| LAGIER JEAN-CHRISTOPHE, ET AL.: "Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis", TRAVEL MEDICINE AND INFECTIOUS DISEASE, ELSEVIER, AMSTERDAM, NL, vol. 36, 1 July 2020 (2020-07-01), AMSTERDAM, NL , pages 101791, XP093000055, ISSN: 1477-8939, DOI: 10.1016/j.tmaid.2020.101791 * |
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