WO2021025550A1 - Nanoemulsion de ácido 18p-glicirretínico - Google Patents
Nanoemulsion de ácido 18p-glicirretínico Download PDFInfo
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- WO2021025550A1 WO2021025550A1 PCT/MX2020/050025 MX2020050025W WO2021025550A1 WO 2021025550 A1 WO2021025550 A1 WO 2021025550A1 MX 2020050025 W MX2020050025 W MX 2020050025W WO 2021025550 A1 WO2021025550 A1 WO 2021025550A1
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Definitions
- the present invention relates to formulations and pharmaceutical forms derived from a nanoemulsion that contain 18b-glycyrrhetinic acid as a drug.
- the invention provides a pharmaceutical formulation of a gelled nanoemulsion, with a concentration of glycyrrhetinic acid comprising from 0.001% to 30% P / P (weight percent).
- the different formulations are designed for the treatment of the different conditions on which the drug is known to have a therapeutic effect.
- the therapeutic effects associated with the drug, and therefore with the formulations include anti-inflammatory, antiviral, antibacterial, hepatoprotective, skin disease and anticancer activity.
- HPV human papillomavirus
- HPV Human papillomaviruses
- HPV Human papillomaviruses
- HPV genotypes that infect and replicate in the skin or mucosal epithelium, inducing benign lesions, including warts that are self-limiting and usually return over time.
- HPV replication cycle and its production of virions are closely related to the differentiation of epithelial cells.
- HPVs initially infect poorly differentiated, proliferative cells and those of the stratified epithelium. Initially the viral genome takes up residence as a nuclear plasmid with a low copy number, a subset of viral genes (the early genes) are expressed at low levels and no virions are generated. However, the life cycle of the virus begins when the basal cells are infected and divide and the daughter cells migrate to the suprabasal compartment to complete differentiation.
- Glycyrrhizinic acid is a drug that has been used in some formulations for the treatment of HPV infections. This is extracted from the roots of the Glycyrrhiza uralensis plant or commonly known as licorice. This plant has been attributed antiviral, cytotoxic, antimicrobial, enzyme inhibitory, anti-inflammatory, antioxidant and analgesic properties. There are reports that describe that extracts of this plant have been used in ancient medicine for the treatment of diseases such as cough, asthma, lung diseases, chest diseases, liver diseases, bowel disorders, stomach, indigestion, arterial diseases, diseases of the urinary system, diseases of the urinary bladder, kidney pain, expulsion of kidney stones, wounds, ulcers, granulomas, eye diseases and fever. There are also documented cases where extracts of the plant have been used for the healing of ulcers and for the treatment of spasmodic pain caused by chronic gastritis.
- the EPIGEN® formulation is a solution that contains in its composition AG at a concentration of 0.001 g / mL, labeled as an antiviral agent especially for the treatment of HPV infection, indicated for Herpes Simplex type 1 (labial) infections, Herpes Simple type 2 (genital) and Herpes Zoster.
- Patent MX 351117 B describes a formulation composed of AG in an amount of 0.01 to 0.2 g / mL, thermosetting polymer type POE-POP-POE in a 20 to 30%, trichloroacetic acid 0.5 to 2.0%, methyl paraben and propylene glycol.
- the Mexican application PA / E / 2006/019396 mentions a formulation composed of PF-127 (20 - 30%), AG in concentrations of 0.001 to 0.5 g / mL and propylene glycol.
- 18b-glycyrrhetinic acid is a pentacyclic triterpenoid, its molecular formula is C30H46O4. It is known by the names of (20b) -3b-1i ⁇ Gqc ⁇ -11-oco-olean-12-en-29-oic acid, (3b, 20b) -3-hydroxy-ll-oxo-olean-12 acid -en-29-oic, 3b-1i ⁇ Gqc ⁇ -11-ocoo1qhho-12-qh-30-o ⁇ oo acid, Idb-glycyrrhetic acid, Idb-glycyrrhetinic acid, biosone, enoxolone, glycyrrhetic acid, glycyrrhetin, glycyrrhetinic acid, GM 1658, NSC 35347, olean-12-en-29-oic acid, 3-hydroxy-11-o
- AG acts through the inhibition of enzymes such as thromboxane synthetase, HMGB1 (High-Mob ⁇ l ⁇ ty Group Box 1 protein) and the TNF-a protein.
- thromboxane synthetase thromboxane synthetase
- HMGB1 High-Mob ⁇ l ⁇ ty Group Box 1 protein
- TNF-a protein TNF-a protein
- Idb-AG acts by decreasing the expression of proteins such as NF-k, the vascular endothelial growth factor and the MMP-9 protein. Too The compound is known to induce apoptosis and cell cycle arrest in the G2 phase.
- Idb-AG it is known that this compound interferes with the replication of Rotavirus up to 99% of the infection when it was tested in infected cultures, reducing the amount of the viral proteins VP2, VP6 and NSP2. It also inhibits HIV-1 by reducing the accumulation of the viral antigen. p24 and protecting cells from the cytopathological action of the virus.
- Idb-AG is a compound that is difficult to dissolve in many pharmaceutically accepted solubilizing compounds, since it is insoluble in water.
- the compound has zero permeation in the epithelial layers, which makes it difficult to prepare an effective formulation, as would be the case for use in the treatment of infections with an epithelial tissue tropism.
- the infections of greatest interest in public health are viral infections that affect the genitourinary tract. Some of these are caused by members of the families Papillomaviridae, Herpesviridae, Flaviviridae, Rotaviridae, etc.
- Vaginal drug delivery systems include solutions, semisolids (creams, ointments, and gels), and solid formulations (tampons, capsules, tablets, suppositories, films, sponges, powders, and controlled drug-release devices such as vaginal rings).
- the efficacy of these delivery systems will depend on their ability to achieve the appropriate local concentration of the drug at the site of action, their mucoadhesive properties, and their compatibility with the vaginal microbiota.
- vaginal secretions can reduce the bioavailability of the drug.
- Idb-AG In the case of Idb-AG, it is important to obtain a formulation whose permeation is increased, since the Idb-AG compound by itself has undesirable physicochemical properties such as poor lipophilic capacity, poor bioavailability and low solubility in water, which drastically decrease its absorption profile.
- percutaneous Hao J., et al. Int J. Pharmaceut. 399, 102-108 (2010)
- Li, S., et al. Drug Dev. Ind. Pharm. 38, 855-865 (2012) It is widely known that the penetration of a compound into the skin depends on the logarithm of the partition coefficient (log P), which is an indicator of the lipophilicity of a compound and its molecular weight.
- micro- and nanoemulsions are emulsions with a high content of surfactant and cosurfactant, capable of forming dispersed, translucent liquid systems and whose main characteristic is their reduced particle size that ranges from 1 nanometer (nm) to 1 micrometer ( my h).
- nanoemulsions are formulations that can penetrate through different membranes or tissues and enhance the bioavailability of the drug or drugs that have a reduced permeability, either topically or orally.
- Idb-AG there are some formulations and pharmaceutical forms for the treatment of HPV infections, precancerous lesions and cervical cancer that contain Idb-AG as an active ingredient.
- the application MX / a / 2017/010806 mentions a gel dosage form with a formulation that is composed of a thermoreversible gel type POE-POP-POE, Idb-AG, a phytoalexin (resveratrol), a biguadine (metformin) and extract of Lactobacillus sp.
- Idb-AG at a concentration of 0.1 to 0.75 g / mL.
- resveratrol is physically unstable at room temperature (which reduces its half-life and compromises the shelf-life formulation).
- this formulation does not comprise a nanoemulsion, as it is only a gelled Idb-AG solution.
- Puglia C. et al. Mention a nanoemulsion of Idb-AG with particle sizes of 180 to 240 nm, a concentration of 0.5%, a reduced stability and a permeability of 0.6010.08pg / h / cm2, designed for use as an anti-inflammatory.
- the present invention refers to a nanoemulsion that potentiates the bioavailability of Idb-AG when absorbed in the site or area of application, due to the composition of excipients (formula) that in combinations they form nanoeulsions with polarity, structure and particle size of 1 to 500 nm, preferably 1 to 50 nm, and 500 to 1000 nm, preferably 600 to 700 nm, capable of potentiating the permeability, and consequently the bioavailability of the drug on the application tissue.
- Said nanoemulsion can be gelled to improve retention in the area of application for the treatment of certain conditions, for example, cutaneous HPV infections, cervical intraepithelial lesions and cervical cancer.
- the dosage forms of the present invention exhibit specific permeability, diffusion coefficient, polydispersity values that help the invention provide its technical advantages.
- the formulations and pharmaceutical forms according to the present invention are solutions, micro- and nanoemulsions that have a high concentration of Idb-AG, and a reduced particle size, compared to other formulations previously reported.
- formulations with equal or higher concentrations of the active ingredient or micro and nanoemulsions with Idb-AG have been reported, the formulation of the present invention combines a high concentration of the active compound, a micro- or nano emulsion and excipients that allow greater permeation. The combination of these properties gives the present formulation superior properties of performance and stability, not previously reported in the literature.
- the present invention refers to nanoemulsions with high permeation due to the combined effect of the reduced particle size, the high concentration of the active compound, the structural composition of their polar micelles and the emollient effect of their excipients, mainly adapted for their optimal application in the vaginal-cervical tract, for the treatment of various conditions related to infections, preneoplastic lesions and cervical cancer.
- the present invention corresponds to formulations, preferably solutions, micro and nanoemulsions that contain Idb-AG as active principle, solubilizing elements such as derivatives of diethylene glycol, derivatives of propylene glycol or polyethylene glycol, surfactant elements such as polyoxyglycerides of capric, lauric, linoleic, oleic acid, or of stearic acid triglycerides, one or more ethoxylated fatty alcohols as cosurfactants, and an emollient oil carrier such as isopropyl myristate.
- solubilizing elements such as derivatives of diethylene glycol, derivatives of propylene glycol or polyethylene glycol
- surfactant elements such as polyoxyglycerides of capric, lauric, linoleic, oleic acid, or of stearic acid triglycerides, one or more ethoxylated fatty alcohols as cosurfactants, and an emollient oil carrier
- formulations have the property of having high permeation due to their reduced particle size, the structural composition and the polarity of the micelles formed in the nanoemulsion, by modifying the structure of the skin tissue in its area of application.
- Said formulations they contain the drug in concentrations ranging from 0.001% to 30% by weight (0.0001 to 0.3 g / mL).
- various compositions and pharmaceutical forms derived from said formulations include aerosols, nebulizers, solutions, sterile solutions, foams, lyophilisates, solids, soft gelatin capsules, implants, transdermal patches and gels.
- the gels in particular are designed for use and application for the treatment of diseases related to viral infections such as those of the human papillomavirus and therefore cancer. Additionally, the gels are designed to increase their absorption in the application area due to a mucoadhesive effect in viscosities that comprise 1500 to 2500 cP (centipoise) and have a pH of 3.8 to 6.5, preferably 4.5 to 5.5, since their properties as high permeation and viscosity enhance the bioavailability of the drug, thereby helping the drug to have a better effect and in less time.
- cP centipoise
- the comet test is an experiment that allows us to see if the drug has an effect cytotoxic related to DNA fragmentation of cells. This difference is visualized by the size of the "tails" of the "comets", which is the fragmented DNA from the cells under study.
- Idb-AG generates considerable DNA fragmentation in cancer cells (HeLa) treated with the drug.
- healthy cells HaCaT
- cells, both cancer (HeLa) and healthy (HaCaT), treated with GA do not show such fragmentation.
- Figure 2B shows the graphs and statistical analyzes performed on the results of said test.
- Figure 1 shows the percentage of survival of cancer cells and HPV infection in the face of exposure to AG drugs and Idb-AG. In it, it is observed that Idb-AG has a more extensive and powerful cytotoxic effect compared to AG.
- Figure 2 describes representative data of the percentage of tail-DNA.
- A Photomicrographs of the alkaline comet assay showing representative images of CC cell lines and their negative control with their 18B and AG treatments of HeLa (HPV 18 cervical cancer) and HaCaT (HPV negative immortalized keratinocyte)
- B Graph of Comet Assay Data for Percentage of Tail-DNA ** P ⁇ 0.43 for HaCaT and P ⁇ 2 16 . Larger comments are observed with 18B treatment.
- Figure 3 shows the in vitro permeability test
- the system consists of a culture well, with lxlO 6 monolayer cells. Inside the well are placed 8-10 mL of culture medium and a device that has the ability to float on the medium; the internal part of the device has a Millipore Strat-M® membrane with a pore size designed to simulate skin conditions and is hermetically sealed. Inside the flotation device and once the membrane is in place, the pharmaceutical form to be tested is placed. If the dosage form permeates the membrane, a greater effect on cell survival will be observed.
- Figure 4 depicts the flow cytometry of in vitro permeability assays.
- (AC) Results show the survival and cell death data of the experiments performed with the assembly of figure 3.
- the quantification of viable and non-viable cells was determined by flow cytometry by means of live and dead cell analysis Live / Dead Cell Double Staining Kit (Sigma).
- the results show that HeLa cervical cancer cell cultures exposed to emulsion and nanoemulsion have a higher proportion of non-viable cells (41-94% non-viable cells, respectively), compared to a solution (13%).
- the control cells HaCaT
- the higher the permeability of the active compound the better the cytotoxic effect on cancer cells.
- Figure 5 shows the graph of the mean particle size of the different formulations. The averages of the different formulations with their different different particle sizes are observed in a wide range of sizes. Emulsion: 2500 nm; Nanoemulsion 1: 789.45 nm;
- Nanoemulsion 2 678.13 nm
- Nanoemulsion 3 7.08 nm
- Nanoemulsion 4 nm The sizes depend on the proportion of the excipients used in the formulation, the size being non-linearly dependent on a specific component.
- Figure 6 shows the graph of the means of the hydrodynamic radii of the particles of the different formulations of the invention.
- Emulsion 2850 nm; Nanoemulsion 1: 820 nm; Nanoemulsion 2: 750 nm; Nanoemulsion 3: 21.16 nm;
- Figure 7 describes the graph of the permeability obtained from the different formulations of the invention.
- Figure 8 shows a linear regression between the particle size and the Idb-AG permeation of the formulation.
- the value close to 0 of R 2 (r squared) and the value of P> 0.05 (p-value) indicate that there is no correlation between the particle size and the permeation of the Idb-AG. It indicates that, for a given formulation, all its components (particle size, type and proportion of excipients, concentration of the active principle and emollient effect of the excipients) intervene in achieving greater permeability.
- the present invention refers to a nanoemulsion that enhances the bioavailability of Idb-AG, by being absorbed in the site or area of application to be treated due to its reduced particle size of 1 to 100 nm and 500 to 1000 nm, preferably at a concentration of 0.01% to 30% and a particle or micelles size of 1 to 500 nanometers, preferably 1 to 50 nm, preferably 1 to 20 nm in one mode, and 500 to 1000 nanometers, preferably 600 to 700 nm in another mode.
- the formulation is composed of the active principle glycyrrhetinic acid (Idb-AG), a solubilizing element such as derivatives of diethylene glycol, derivatives of propylene glycol or derivatives of polyethylene glycol, a surfactant element such as a polyoxyglyceride, for example, polyoxyglyceride of capric acid, lauric, linoleic, oleic, or stearic acid triglycerides, a cosurfactant such as one or more ethoxylated fatty alcohols, for example alcohols with the structure R- (OCH2CH2) n -OH where R is an alkyl chain with size 12 at 18 carbons and n represents the moles of ethylene oxide, which can have a value of 2 to 25 and an emollient oil carrier, for example isopropyl myristate.
- a solubilizing element such as derivatives of diethylene glycol, derivatives of propylene glycol or derivatives of poly
- the combination of the different excipients with the drug generates micelles with a polar structural composition that improve the bioavailability of the active principle by contributing to the permeation of the formula.
- the excipients used in the formulation help synergistically to increase permeation, due to the emollient effect of some of these.
- the pharmaceutical forms according to the present invention have a permeation value of 0.6 to 47.8 pg / h / cm 2 , where the composition has a diffusion coefficient of 0.003 to 1.5 pm 2 / s and a polydispersity of 2 to 50.
- Said formulation can be used in liquid form and packaged in various presentations for the treatment of different conditions for which Idb-AG is known to have a therapeutic effect.
- the nano-emulsion can be gelled, with the help of certain excipients for its convenient application in the treatment of certain conditions such as injuries, viral infections and the treatment of certain cancers.
- the present invention provides a series of formulations containing Idb-AG, in combination with other suitable excipients for each pharmaceutical formulation.
- the formulation is composed of derivatives of diethylene glycol, polyoxyglycerides, an oleaginous vehicle, fatty alcohols and their derivatives, castor oil and silicon dioxide, as well as preservatives and stabilizers.
- the formulations meet the need for formulations whose active ingredient is Idb-AG in concentrations of 0.001 to 30% by weight with a high permeation of the active ingredient.
- the different formulations are intended for administration by various routes, such as oral, inhaled, injectable, and topical.
- the formulation is a solution of Idb-AG, which is composed of a solubilizing element, for example, derivatives of diethylene glycol, propylene glycol or polyethylene glycols, preferably 2- (2-ethoxyethoxy) -ethanol, a stabilizing element, for example polyoxyglycerides of capric, lauric, linoleic, oleic or stearic acid triglycerides, and an emollient oleaginous vehicle, for example isopropyl myristate.
- the mixture may contain one or more ethoxylated fatty alcohols or their derivatives, as well as castor oil or a derivative thereof, such as castor oil polyoxyethylenes as stabilizing elements.
- the method of preparation of the solution consists of mixing the components of the formula and heating the previous mixture until the active principle is solubilized, after the dissolution of the active principle, cool to room temperature with constant stirring.
- the components of the mixture are in a percentage w / w (percentage by weight) of 0.001 to 30%, preferably 0.001 to 5% for the Idb-AG, 40 to 60% for the derivative of diethylene glycol, 1 to 15 % for the polyoxyglyceride, 10 to 20% for the oleaginous or emollient vehicle, from 0 to 15% for the ethoxylated fatty alcohol and from 0 to 20% for the castor oil or its derivatives.
- the formulation is an emulsion, where the emulsion is composed of a derivative of diethylene glycol, preferably 2- (2-ethoxyethoxy) -ethanol, an emollient oleaginous vehicle, for example isopropyl myristate, castor oil or a derivative of this and distilled water.
- the method of preparation is a reversed phase inversion emulsion.
- the components are mixed in percentages w / w of 40% to 60% for the derivative of diethylene glycol, 10% to 20% for the oleaginous vehicle, 0% to 20% for castor oil or its derivatives, and 0% to 15% for ethoxylated fatty alcohol.
- the active principle 18B is added to these components in a concentration p / p of 0.001 to 30%, preferably 0.001. at 5%.
- the mixture is kept under stirring and heated until the active principle dissolves.
- distilled water is added in the necessary quantity, ranging from 5 to 50% by weight of the total mixture.
- the formulation is a nano-emulsion, which is composed of a derivative of diethylene glycol, preferably 2- (2-ethoxyethoxy) -ethanol, a polyoxyglyceride of capric, lauric, linoleic, oleic, or triglycerides.
- the method of preparation is a reversed phase inversion emulsion.
- the components are mixed in percentages w / w of 40% to 60% for the derivative of diethylene glycol, 10% to 20% for the oleaginous vehicle and 0 to 15% for the ethoxylated fatty alcohol.
- the active ingredient Idb-AG is added to these components in a concentration w / w of 0.001 to 30%, preferably 0.001 to 5%.
- the mixture is kept under stirring and heated until the active principle dissolves. Once the active principle has been dissolved, distilled water is added in the necessary quantity, ranging from 5 to 50% by weight of the total mixture.
- the increased permeability of Different formulations is achieved thanks to the combined action of the different components of the formulation. Specifically, there are three elements that give the increased permeability: ⁇
- the solubilizing element in this case the derivative of diethylene glycol, referred to as 2- (2-ethoxyethoxy) - ethanol helps to achieve a high solubility of the active compound Idb-AG and therefore it increases the concentration of this in the formulation and consequently a greater permeation of this.
- fatty alcohols and their derivatives for example alcohols with the general structure R- (OCH2CH2) n -OH where R is an alkyl chain with a size of 12 to 18 carbons and n represents the moles of Ethylene oxide, which can have a value of 2 to 25, which help to give the particles their micellar structure with polarity.
- R- (OCH2CH2) n -OH where R is an alkyl chain with a size of 12 to 18 carbons and n represents the moles of Ethylene oxide, which can have a value of 2 to 25, which help to give the particles their micellar structure with polarity.
- the lipophilic part of fatty alcohols encapsulate the diluent, in this case the derivative of diethylene glycol, for example 2- (2-ethoxyethoxy) -ethanol, with the compound active in the micelles
- the polar hydrophilic part of the alcohols helps the dispersion of the particles or micelles in the aqueous and oily phases of the medium, preventing their agglomeration due to the electrostatic repulsion between particles, thereby granting stability to the formula.
- the polar nature of the particles helps the particles pass through the different cell layers that make up the tissue at the site of application.
- the emollient element of the oil phase in this case the oil vehicle, for example, isopropyl myristate. Its activity as an emollient helps to improve the permeability of substances through the skin, as it has the effect of softening the outer layers of the skin, due to their moisturizing effect.
- the particle sizes of the micro-emulsion and nano-emulsion are in the range of 1 nm to 500 nm (nanometer nm), preferably 1 to 50 nm, preferably 1 to 20 nm. In another preferred embodiment, the particle sizes are in the range of 500 to 1000 nm, preferably 500 to 700 nm, preferably 500 to 600 nm.
- the present invention also provides a method for the preparation of gelled solution, emulsion and nanoemulsion formulations, wherein the method comprises the steps of:
- the pH is adjusted according to the pharmacological application, this adjustment being preferably 4 to 5 for its application in the vagina.
- the excipients and gelling elements are: cellulose derivatives, for example, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HC) or hydroxypropyl methyl cellulose (HPmC), acrylic acid polymers or a member of the family of poloxamers.
- HPC hydroxypropyl cellulose
- HC hydroxyethyl cellulose
- HPmC hydroxypropyl methyl cellulose
- the preservatives and stabilizers can be: Butylhydroxytoluene (BHT)
- antioxidants butylhydroxyanisole, L-cysteine, propylparaben, methylparaben, benzalkonium chloride, sodium benzoate, and benzoic acid.
- Polyoxyglycerides polyoxyglyceride of capric, lauric, linoleic, oleic, triglycerides of stearic acid.
- Oily or emollient vehicle Isopropyl myristate.
- R- (OCH2CH2) n -OH where R is an alkyl chain with a size of 12 to 18 carbons and n represents the moles of ethylene oxide, which can have a value of 2 to 25
- Anti crystalline agent Polyvinylpyrrolidone in its different degrees of polymerization and cyclodextrins.
- the invention refers to a solution with the composition:
- the invention refers to an emulsion, with a composition of:
- the preparation method consists of mixing 2- (2-ethoxyethoxy) -ethanol and isopropyl myristate, the mixture is heated in a range of 50 to 80 degrees Celsius, preferably 60 to 70 degrees Celsius. Once the desired temperature is reached, the mixture is stirred and the Idb-AG is added. Once the active principle has dissolved, distilled water is added to the mixture, stirring is stopped and it is allowed to cool to room temperature.
- the resulting emulsion has a permeation of 1.8 pg / h / cm2, a particle size of 2500 nm, a hydrodynamic radius of 2850 nm, a diffusion coefficient of 1.26 pm 2 / s, and a polydispersity of 39.8.
- the invention refers to a nano-emulsion, with a composition of:
- the preparation method consists of mixing the 2- (2-ethoxyethoxy) -ethanol, the 12-carbon ethoxylated fatty alcohol, the hydrogenated Castor Oil and the isopropyl myristate.
- the mixture is heated to a temperature of 50 to 80 degrees Celsius, preferably 60 to 70 degrees Celsius. Once the desired temperature is reached, the mixture is stirred and the Idb-AG is added. Once the active principle has dissolved, distilled water is added to the mixture, stirring is stopped and it is allowed to cool to room temperature.
- the resulting nano-emulsion has a permeability of 2.8 pg / h / cm 2 , a particle size of 789 nm, a hydrodynamic radius of 820 nm, a diffusion coefficient of 0.0038 pm 2 / s and a polydispersity of 26.
- the invention refers to a nano-emulsion, with a composition of:
- the mixture is heated to a temperature of 50 to 80 degrees Celsius, preferably 60 to 70 degrees Celsius. Once the desired temperature is reached, the mixture is stirred and the Idb-AG is added. Once the active principle has dissolved, distilled water is added to the mixture, stirring is stopped and it is allowed to cool to room temperature.
- the resulting nano-emulsion has a permeability of 8 pg / h / cm2, a particle size of 678.13 nm, a hydrodynamic radius of 750 nm, a diffusion coefficient of 0.0029 pm 2 / s and a polydispersity of 2.3.
- Example 5 In another preferred embodiment, the invention refers to a nano-emulsion, with a composition of:
- the preparation method consists in mixing the 2- (2-ethoxyethoxy) -ethanol, the 12-carbon ethoxylated fatty alcohol, the 18-carbon ethoxylated fatty alcohol, the Caprylocaproyl Polyoxyl-8 glyceride and the isopropyl myristate.
- the mixture is heated to a temperature of 50 to 80 degrees Celsius, preferably 60 to 70 degrees Celsius. Once the desired temperature is reached, the mixture is stirred and the Idb-AG is added. Once the active principle has dissolved, distilled water is added to the mixture, stirring is stopped and it is allowed to cool to room temperature.
- the resulting nano-emulsion has a permeability of 47.85 pg / h / cm2, a particle size of 7.08 nm, a hydrodynamic radius of 21.16 nm, a diffusion coefficient of 0.067 pm 2 / s and a polydispersity of 47.9, the same sampled example only the time 24 hours, without using stirring in the Franz cell and quantifying through HPLC coupled to UV (C18 / 5pm / 25cm, l: 250nm, Sodium acetate-Tetrahydrofuran pH 4.8) obtained a recovery of 276.07 ⁇ 9.08 pg / mL (2.62 ⁇ 0.09 mg / cm2) equivalent to 5.75 ⁇ 0.19 pg / h / cm2, which denotes that the use of dynamic systems (agitation) in the receptor medium of the Franz cell favor the diffusion of the drug through the membranes under evaluation, same systems used by several authors such as S.
- the invention refers to a nano-emulsion, with a composition of:
- Distilled water 10%
- the preparation method consists of mixing 2- (2-ethoxyethoxy) -ethanol, hydrogenated castor oil, 18-carbon ethoxylated fatty alcohol, caprylocaproyl Polyoxyl-8 glyceride and isopropyl myristate.
- the mixture is heated to a temperature of 50 to 80 degrees Celsius, preferably 60 to 70 degrees Celsius. Once the desired temperature is reached, the mixture is stirred and the Idb-AG is added. Once the active principle has dissolved, distilled water is added to the mixture, stirring is stopped and it is allowed to cool to room temperature.
- the resulting nano-emulsion has a permeability of 8 pg / h / cm2, a particle size of 7.54 nm, a hydrodynamic radius of 26.94 nm, a diffusion coefficient of 0.176 pm 2 / s and a polydispersity of 37.14.
- the invention refers to a nano-emulsion, with a composition of:
- the preparation method consists of mixing the 2- (2-ethoxyethoxy) -ethanol, the 12-carbon ethoxylated fatty alcohol, the 18-carbon ethoxylated fatty alcohol and the isopropyl myristate.
- the mixture is heated to a temperature of 50 to 80 degrees Celsius, preferably 60 to 70 degrees Celsius. Once the desired temperature is reached, the mixture is stirred and the Idb-AG is added. Once the active principle has dissolved, distilled water is added to the mixture, stirring is stopped and it is allowed to cool to room temperature.
- the resulting nano-emulsion has a permeability of 2.36 ⁇ 0.75 pg / h / cm2, a particle size of 10.35 nm, a hydrodynamic radius of 37.7 nm, a diffusion coefficient of 12.98 pm 2 / s, and a polydispersity of 26.8, the above Example denotes that the exclusion of Caprylocaproyl Polyoxyl-8 glyceride with respect to example 5 reduces the permeation of the drug significantly (2.36 vs 47.85 pg / h / cm2), due to the effect of change in polarity in the Nano-emulsion formed since the particles presented a similar size between both systems (10.5 vs 7.08 nm).
- the invention refers to a nano-emulsion, with a composition of:
- R- (OCH2CH2) n -OH where R is an alkyl of 18 carbons and n is equal to 5: 10.1%
- the preparation method consists of mixing 2- (2-ethoxyethoxy) -ethanol, 18-carbon ethoxylated fatty alcohol, Caprylocaproyl Polyoxyl-8 glyceride, and isopropyl myristate.
- the mixture is heated to a temperature of 50 to 80 degrees Celsius, preferably 60 to 70 degrees Celsius. Once the desired temperature is reached, the mixture is stirred and the Idb-AG is added. Once the active principle has dissolved, distilled water is added to the mixture, stirring is stopped and it is allowed to cool to room temperature.
- the resulting nano-emulsion has a permeability of 4.06 pg / h / cm2.
- the invention refers to a nano-emulsion, with a composition of:
- the preparation method consists in mixing the 2- (2-ethoxyethoxy) -ethanol, the 12-carbon ethoxylated fatty alcohol, the 18-carbon ethoxylated fatty alcohol, the Caprylocaproyl Polyoxyl-8 glyceride and the isopropyl myristate.
- the mixture is heated to a temperature of 50 to 80 degrees Celsius, preferably 60 to 70 degrees Celsius. Once the desired temperature is reached, the mixture is stirred and the Idb-AG is added. Once the active principle has dissolved, distilled water is added to the mixture, stirring is stopped and it is allowed to cool to room temperature.
- the resulting nano-emulsion has a permeability of 1.98 pg / h / cm2, this indicates that isopropyl myristate in proportions lower than those stated in example 5 decreases the permeation of the drug in the system formed, therefore, it is concluded that there is a dependence and synergism between the inputs used and their proportions within the nano-emulsion of acid Idb-AG.
- Figure 5 shows the different particle sizes of the different formulations exemplified above. The size was determined by means of the dynamic light scattering technique, with a litesizer equipment, previously verified with a suspension of 220 nm polystyrene latex nanoparticles.
- Figure 7 shows the results of the permeability analysis of the different formulations.
- the test was carried out by means of a study of permeability of synthetic membranes in a Franz cell, where the amount of active principle that passed through a membrane composed of two layers of polyethersulfone and a polyolefin marketed under the brand Millipore with polarity and size of pore similar to that of human skin and as a receiving medium isotonic phosphate solution pH 7.4 (PBS: 7.4).
- PBS isotonic phosphate solution pH 7.4
- the particle size and the specific composition of the micelle or particles affect the permeability (the polarity of the micellar structures can favor or reduce the permeability of the formed system independently of the particle size of the structures produced).
- excipients that act as surfactants and cosurfactants give the structure of the micelles of the nano-emulsion a polarity, which is another factor that increases the permeation of the formula and helps its stabilization, preventing agglomeration of the particles. by the electrostatic repulsion between them.
- Table 1 shows the comparison between different properties of the formulations described above and the nano-emulsion of the present invention.
- the table describes the properties of the best formulation reported in each case.
- the present formulation has significantly smaller particle sizes compared to the previously reported results. Also, the permeation of the drug is significantly higher.
- the dosage form is an aerosol.
- a nano-emulsion of Idb-AG with a particle size of 1-50 pm is dispersed in a pharmaceutically acceptable gas such as hydrorofluorocarbon hydrocarbons such as chlorofluorocarbons, hrofluorocarbons specifically tetrafluoroethane, liquefied gases or inert gases such as nitrogen dioxide. carbon, nitrous oxide or compressed air, in doses ranging from 4 pg to 20 mg per applied dose.
- the pharmaceutical form is a nebulizing agent, for its elaboration to a solution of Idb-AG dissolved in 25 - 80% of the final mixture, a Surfactant 5 - 30%, cosurfactant 2 - 20%, surfactant is added. 5 -
- antioxidant 0.1 - 1.0% such as co or diethylene glycol monoethyl ether, polysorbate derivatives, Polyoxyglycerides or Iristic acid derivatives, ethanol to be used in nebulization therapies, when dispersing the product in isotonic solutions or in water prior to the start of the treatment and obtaining sizes of particle ranging from 8 nm to 1 mih.
- the dosage form is a sterile solution.
- glycyrrhetinic acid (18b) dissolved in a solvent (25 - 90%), surfactant 5 - 50% and a diluent, such as diethylene glycol monoethyl ether, ethoxylated derivatives of polyethylene glycol with alkylated chains from CIO to C 20, Polyoxyglycerides, oil of castor bean and its derivatives, water, ethanol, in doses of glycyrrhetinic acid (18b) that can comprise from 0.5 - 15%, the solution obtained is filtered through a 0.22 pm membrane under aseptic conditions to be sterilized terminal by moist heat.
- a diluent such as diethylene glycol monoethyl ether, ethoxylated derivatives of polyethylene glycol with alkylated chains from CIO to C 20, Polyoxyglycerides, oil of castor bean and its derivatives, water, ethanol
- the dosage form is a foam.
- the formulation is composed of dissolved enoxolone a solvent (25 - 90%), Surfactant 5 - 50%, surfactant 5 - 30%, preservative 0.5 - 2%, antioxidant 0.1 - 1.0% and a diluent, such as diethylene glycol monoethyl ether, ethoxylated derivatives polyethylene glycol with alkylated chains from CIO to C 20, Polyoxyglycerides, Derivatives of myristic acid, castor oil and its derivatives, water, ethanol, in doses that can comprise from 0.5 - 15%, the previous description will be packaged with an inert gas as propellant, such gases comprise but not they are limited to compressed air, nitrogen and carbon dioxide.
- the formulation is a Lyophilisate.
- Enoxolone dissolved a solvent (25 - 90%), Surfactant 5 - 50%, surfactant 5 - 30%, preservative 0.5 - 2%, antioxidant 0.1 - 1.0%, cryoprotectants 10 - 40% a liquid and solid diluent, such as diethylene glycol monoethyl ether , ethoxylated derivatives of polyethylene glycol with alkylated chains from CIO to C 20, Polyoxyglycerides, Derivatives of myristic acid, castor oil and its derivatives, water, ethanol, sorbitol, mannitol or lactose, in Enoxolone doses that can comprise from 0.5 - 15%, to be subjected to lyophilization and obtain a low-water product.
- a liquid and solid diluent such as diethylene glycol monoethyl ether , ethoxylated derivatives of polyethylene glycol with alkylated chains from CIO
- the formulation is a solid.
- enoxolone mixed in pharmaceutically acceptable excipients that comprise and are not limited to Diluent 30 - 90%, lubricant 0.5 - 5.0%, disintegrant 0.5 - 5.0%, non-stick 0.5 - 5.0%, surfactants 0.5 - 10% and binders 1.0 - 20.0 %; as diluents we can mention but not limit to cellulose microcrystalline, carbohydrates and their derivatives (lactose, mannitol, sorbitol, etc.) / ⁇ co-processed derivatives of cellulose and their combinations, Lubricants: Sodium benzoate Stearic acid and its derivatives, disintegrant: croscar elose sodium, corn starch, crospovidone, etc., Non-stick: talc, silicon dioxide, leucine, etc.
- Surfactant sodium lauryl sulfate, polysorbate and its derivatives, docusate sodium, binder: polyvinylpyrrolidone, corn starch, cellulose derivatives.
- binder polyvinylpyrrolidone, corn starch, cellulose derivatives. The above mixture may be encapsulated in hard gelatin capsules or tabletted by compression.
- the formulation is a soft gelatin capsule.
- enoxolone a solvent (25 - 90%)
- Surfactant 5 - 30% a solvent (25 - 90%)
- Surfactant 5 - 30% a solvent (25 - 90%)
- Surfactant 5 - 30% a solvent (25 - 90%)
- cosurfactant 2 - 20% a surfactant 5 - 30%
- an oily vehicle 5 - 30%
- antioxidant 0.1 - 1.0% such as diethylene glycol monoethyl ether, ethoxylated derivatives of polyethylene glycol with alkylated chains from CIO to C 20,
- Polyoxyglycerides, castor oil and its derivatives in doses that can comprise from 0.5 - 15%, the previous description may be dosed in soft gelatin capsules.
- the formulation is an implant.
- enoxolone dispersed in thermoplastic polymers including, but not limited to, polyurethane derivatives or polylactic acid derivatives in proportions comprising 30-95%, the above mixture may be mixed and will not be limited to a plasticizer, mucoadherent for fusion molding for its final application, in Enoxolone doses that may comprise and not limit at least 20%.
- the dosage form is a transdermal patch.
- enoxolone a solvent (25 - 90%), Surfactant 5 - 30%, cosurfactant 2 - 20%, surfactant 5 - 30% and an oily vehicle (5 - 30%) conservative 0.5 - 2%, antioxidant 0.1 - 1.0% and a diluent, such as diethylene glycol monoethyl ether, ethoxylated derivatives of polyethylene glycol with alkylated chains from CIO to C 20, Polyoxyglycerides, Myristic acid derivatives, castor oil and its derivatives, water, ethanol, in doses that can comprise from 0, 5-20%, the previous mixture is sprayed or atomized on a surface of thermoplastic polyurethane, polyisobutylene or derivatives of polylactic acid, to form the release modulator film which will be adhered to a layer of polyethylene teraphthalate that will constitute the carrier film.
- a diluent such as diethylene glycol monoethyl ether, ethoxylated derivatives of polyethylene glyco
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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CN202080068420.7A CN114450001A (zh) | 2019-08-08 | 2020-08-07 | 18β-甘草次酸的纳米乳液 |
EP20849613.3A EP4023219A4 (en) | 2019-08-08 | 2020-08-07 | PHARMACEUTICAL FORMS OF 18BETA-GLYCYRRHETINIC ACID |
BR112022002176A BR112022002176A2 (pt) | 2019-08-08 | 2020-08-07 | Nanoemulsão de ácido 18ss-glicirretínico. |
CA3147206A CA3147206A1 (en) | 2019-08-08 | 2020-08-07 | Nanoemulsion of 18.beta.-glycyrrhetinic acid |
US17/633,823 US20220296544A1 (en) | 2019-08-08 | 2020-08-07 | Nanoemulsion of 18beta-glycyrrhetinic acid |
ZA2022/02125A ZA202202125B (en) | 2019-08-08 | 2022-02-18 | Nanoemulsion of 18 beta-glycyrrhetinic acid |
CONC2022/0002493A CO2022002493A2 (es) | 2019-08-08 | 2022-03-01 | Nanoemulsion de ácido 18p-glicirretínico |
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MX2019009482A MX2019009482A (es) | 2019-08-08 | 2019-08-08 | FORMAS FARMACEUTICAS DEL ACIDO 18ß-GLICIRRETINICO. |
MXMX/A/2019/009482 | 2019-08-08 |
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US (1) | US20220296544A1 (es) |
EP (1) | EP4023219A4 (es) |
CN (1) | CN114450001A (es) |
BR (1) | BR112022002176A2 (es) |
CA (1) | CA3147206A1 (es) |
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FR3134005A1 (fr) | 2022-02-25 | 2023-10-06 | L'oreal | Composition de soin des matières kératineuses |
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RU2493852C1 (ru) * | 2012-04-12 | 2013-09-27 | Леонид Леонидович Клопотенко | Композиция, содержащая фермент дезоксирибонуклеазу и/или стеарилглицирретинат или глицирризиновую кислоту или ее соли: глицирризинат аммония, или дикалия, или тринатрия |
WO2019039931A1 (es) * | 2017-08-22 | 2019-02-28 | Atso Corporate Affairs, S.A. De C.V. | Formulación de ácido 18-beta-glicirretínico en combinación con revesterol y metformina, usos y método de fabricación |
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GB2072014B (en) * | 1980-03-08 | 1984-02-15 | Kanebo Ltd | Cosmetics containing 18-glycyrrhizins |
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CN105342987A (zh) * | 2015-12-04 | 2016-02-24 | 亚飞(上海)生物医药科技有限公司 | 一种凝胶及其制备方法和应用 |
ITUB20159218A1 (it) * | 2015-12-21 | 2017-06-21 | Valitudo Pharma Srls | Composizione, per uso topico, utile per favorire la cicatrizzazione di lesioni sulla pelle. |
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2019
- 2019-08-08 MX MX2019009482A patent/MX2019009482A/es unknown
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2020
- 2020-08-07 WO PCT/MX2020/050025 patent/WO2021025550A1/es unknown
- 2020-08-07 CA CA3147206A patent/CA3147206A1/en active Pending
- 2020-08-07 CN CN202080068420.7A patent/CN114450001A/zh active Pending
- 2020-08-07 US US17/633,823 patent/US20220296544A1/en active Pending
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RU2493852C1 (ru) * | 2012-04-12 | 2013-09-27 | Леонид Леонидович Клопотенко | Композиция, содержащая фермент дезоксирибонуклеазу и/или стеарилглицирретинат или глицирризиновую кислоту или ее соли: глицирризинат аммония, или дикалия, или тринатрия |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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FR3134005A1 (fr) | 2022-02-25 | 2023-10-06 | L'oreal | Composition de soin des matières kératineuses |
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CA3147206A1 (en) | 2021-02-11 |
BR112022002176A2 (pt) | 2022-05-03 |
CN114450001A (zh) | 2022-05-06 |
MX2019009482A (es) | 2021-02-09 |
US20220296544A1 (en) | 2022-09-22 |
CO2022002493A2 (es) | 2022-04-29 |
ZA202202125B (en) | 2023-11-29 |
EP4023219A4 (en) | 2023-04-26 |
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