WO2022220669A1 - Combinaison solide orale pour le traitement d'une infection virale - Google Patents

Combinaison solide orale pour le traitement d'une infection virale Download PDF

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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
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
agent
hydroxychloroquine
azithromycin
macrolide antibiotic
Prior art date
Application number
PCT/MX2021/050019
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English (en)
Spanish (es)
Inventor
Miguel Ángel GARCÍA PÉREZ
Jeni VÁZQUEZ MENDOZA
Octavio CARO RODRÍGUEZ
Ricardo Zamora Ramírez
Original Assignee
Garcia Perez Miguel Angel
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Application filed by Garcia Perez Miguel Angel filed Critical Garcia Perez Miguel Angel
Priority to PCT/MX2021/050019 priority Critical patent/WO2022220669A1/fr
Publication of WO2022220669A1 publication Critical patent/WO2022220669A1/fr

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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

La présente invention concerne une composition solide à stabilité et biodisponibilité améliorées, qui comprend : une quantité pharmaceutiquement acceptable d'un agent antibiotique macrolide; une quantité pharmaceutiquement acceptable d'un agent antimalarique; et, au moins un excipient pharmaceutiquement acceptable, dans un système d'administration oral qui comprend une forme pharmaceutique solide, granulaire et/ou en poudre en une ou plusieurs phases.
PCT/MX2021/050019 2021-04-16 2021-04-16 Combinaison solide orale pour le traitement d'une infection virale WO2022220669A1 (fr)

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US20050123627A1 (en) * 2003-12-04 2005-06-09 Pfizer Inc Azithromycin dosage forms with reduced side effects
CN102525969A (zh) * 2010-12-28 2012-07-04 上海中西制药有限公司 一种硫酸羟氯喹固体制剂及其制备方法
CN112641738A (zh) * 2020-12-22 2021-04-13 迪沙药业集团有限公司 一种阿奇霉素片组合物

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