WO2022170405A1 - Pharmaceutical composition of aqueous sodium hyaluronate in nasal spray form - Google Patents
Pharmaceutical composition of aqueous sodium hyaluronate in nasal spray form Download PDFInfo
- Publication number
- WO2022170405A1 WO2022170405A1 PCT/BR2021/050068 BR2021050068W WO2022170405A1 WO 2022170405 A1 WO2022170405 A1 WO 2022170405A1 BR 2021050068 W BR2021050068 W BR 2021050068W WO 2022170405 A1 WO2022170405 A1 WO 2022170405A1
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- WIPO (PCT)
- Prior art keywords
- sodium hyaluronate
- pharmaceutical composition
- aqueous sodium
- nasal spray
- spray
- Prior art date
Links
- 229920002385 Sodium hyaluronate Polymers 0.000 title claims abstract description 40
- 229940010747 sodium hyaluronate Drugs 0.000 title claims abstract description 40
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 title claims abstract description 40
- 239000007922 nasal spray Substances 0.000 title claims abstract description 26
- 229940097496 nasal spray Drugs 0.000 title claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 239000007921 spray Substances 0.000 claims abstract description 53
- 239000000203 mixture Substances 0.000 claims abstract description 44
- 238000009826 distribution Methods 0.000 claims abstract description 29
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- 206010028740 Nasal dryness Diseases 0.000 claims abstract description 3
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 claims description 12
- 235000004866 D-panthenol Nutrition 0.000 claims description 8
- 239000011703 D-panthenol Substances 0.000 claims description 8
- 229960003949 dexpanthenol Drugs 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 6
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 4
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 3
- 229940061607 dibasic sodium phosphate Drugs 0.000 claims description 3
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 2
- 206010028735 Nasal congestion Diseases 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 2
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 2
- 230000001954 sterilising effect Effects 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 5
- 238000004519 manufacturing process Methods 0.000 claims 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims 1
- 239000001488 sodium phosphate Substances 0.000 claims 1
- 235000011008 sodium phosphates Nutrition 0.000 claims 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims 1
- 238000009472 formulation Methods 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 7
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 6
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 6
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 6
- 229920002674 hyaluronan Polymers 0.000 description 6
- 229940014041 hyaluronate Drugs 0.000 description 6
- 229960003160 hyaluronic acid Drugs 0.000 description 6
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- 238000006703 hydration reaction Methods 0.000 description 6
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- 210000002345 respiratory system Anatomy 0.000 description 5
- 229940101267 panthenol Drugs 0.000 description 4
- 235000020957 pantothenol Nutrition 0.000 description 4
- 239000011619 pantothenol Substances 0.000 description 4
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 3
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- 230000033001 locomotion Effects 0.000 description 3
- 235000019161 pantothenic acid Nutrition 0.000 description 3
- 239000011713 pantothenic acid Substances 0.000 description 3
- 229940055726 pantothenic acid Drugs 0.000 description 3
- 235000019129 pluma Nutrition 0.000 description 3
- 244000276444 pluma Species 0.000 description 3
- 235000019070 pluma del Caribe Nutrition 0.000 description 3
- 230000000241 respiratory effect Effects 0.000 description 3
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
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- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 229940075564 anhydrous dibasic sodium phosphate Drugs 0.000 description 1
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- 230000000845 anti-microbial effect Effects 0.000 description 1
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- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical compound N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
Definitions
- the present invention relates to an innovative pharmaceutical composition, which consists of a Sodium Hyaluronate nasal spray, which relieves dryness and irritation of the nostrils caused by aging, low humidity, colds, congestion or medication side effects.
- nasal epithelial cells Under certain conditions the ability of nasal epithelial cells to secrete mucus, preserve moisture and filter air may be impaired. Conditions such as low humidity, aging, side effects of medications used to treat allergies, common colds or acne result in dryness of the nose and crust buildup causing discomfort, pain, nosebleeds and coughing.
- Nasal inhalation as a route of drug administration is restricted to the treatment of processes that take place locally, in the upper airways, such as, for example, different cases of rhinitis.
- the respiratory tree can be divided into three well-differentiated zones:
- Nasopharyngeal Region It is the upper respiratory tract, which comprises the nose, mouth, pharynx and larynx.
- Tracheobronchial Region Includes the trachea, bronchi, and terminal bronchioles.
- Pulmonary or respiratory region corresponds to the respiratory bronchioles, the alveolar canal, the alveolar sacs and the alveoli. This region is where gas exchange takes place.
- the factors that condition the transit of nasal medications in spray form are the size of particles or droplets, the breathing mode, the anatomical characteristics of the airways and possible pathological factors, among others. Depending on the size of particles or droplets, these are deposited in the different regions seen above. We can thus make the following differentiation, also shown in Figure 2:
- Patent number 20050164979 Pharmaceutical composition for ophthalmological and rhinological application describes a pharmaceutical composition that contains at least panthenol and/or pantothenic acid and hyaluronic acid and/or hyaluronate and, optionally, additional pharmaceutical auxiliary agents.
- the invention also relates to the use of the pharmaceutical composition for the treatment of ophthalmological and/or rhinological functional defects, failing to mention droplet size and physicochemical properties of the composition so that it has an exclusive action on the nostrils.
- Patent number W02003049747 - Synergistic pharmaceutical composition for treating ophthalmological and/or rhinological dysfunction, containing panthenol or pantothenic acid and hyaluronic acid or hyaluronate) presents a pharmaceutical composition containing panthenol and/or pantothenic acid, hyaluronic acid and/or hyaluronate and optionally additional pharmaceutical aids in the treatment of ophthalmological and/or rhinological dysfunction, specifically rhinological dysfunction associated with dryness of the nasal mucosa, especially chronic rhinitis and/or rhinitis sicca, presenting the advantage of the combination of panthenol and hyaluranate that produces a synergistic effect in the treatment of both ophthalmological disorders and rhinological disorders, for example, healing of lesions in the nasal mucosa and improvement of moisture retention.
- the inventors have developed an innovative composition, which consists of a nasal spray of Sodium Hyaluronate, which relieves dryness and irritation of the nostrils caused by aging, low humidity, colds, congestion or side effects of medicines.
- the Sodium Hyaluronate Nasal Spray of the present invention was developed to act at the level of the Nasopharyngeal region, with the Sodium Hyaluronate adhering to the nasal mucous membrane and moisturizing it, thus preventing its dryness. Dryness of the nasal mucosa is also produced by environmental factors such as heat, air conditioning, wind and sun. Nasal dryness prevents the mucosa from fulfilling its function of wetting and cleaning the air we breathe, leaving the nostrils exposed to the invasion of pathogens. Intensive hydration with Sodium Hyaluronate maintains a protective layer on the nasal mucosa and strengthens the resistance of the nostrils against exogenous invasions.
- the pharmaceutical composition of aqueous Sodium Hyaluronate in nasal spray form of the present invention was developed as a formulation in true aqueous solution, specifically balanced in viscosity and density, so that, when administered through a specific actuator, it produces a particular and constant spray plume pattern and Gaussian droplet size distribution where 100% of the droplets are greater than 10 microns , thus ensuring greater effectiveness in local nasal topical treatment without going beyond the nasopharyngeal region.
- FIG. 1 Figure 1 - scheme showing the regions of the respiratory system, with emphasis on the nasopharyngeal, tracheobronchial and respiratory regions.
- FIG. 1 Figure 2 - diagram showing the relationship between spray particle diameter and maximum level of penetration in each of the regions of the respiratory system.
- Figure 3 Individual results of the mass test of each actuation, or pumping, or pressing.
- Figure 4 Individual results of the droplet size distribution test by laser diffraction measured at a distance of 3 cm from the nozzle to the measurement plane.
- Figure 5 Individual results of the droplet size distribution test by laser diffraction measured at a distance of 6 cm from the nozzle to the measurement plane.
- a system consisting of an aqueous solution was chosen, for spray application, forming a liquid discharge aerosol, without propellant, with mechanical pressurization (actuator) with droplets of size well above 10 microns, which ensures limited action on the nostrils, protecting and strengthening the nasal mucous membrane.
- actuator mechanical pressurization
- this invention sought the optimal relationship between the particular Spray System chosen and the liquid formulation as a true solution in order to comply with ANVISA Normative Instruction No. 2019 that deals specifically with Nasal Sprays, and arriving at the results presented in the “RESULTS OF STUDY” section to a FEATHER Spray Standard.
- the inventors of the present invention determined that the viscosity of the aqueous solution used has a fundamental role in obtaining the characteristics of the Spray Pattern sought and, mainly, in the droplet size. desired, i.e. 100% droplets larger than 10 microns, to avoid inadequate penetration of the product into the aforementioned tracheobronchial and/or respiratory tracts.
- the viscosity of the solution proposed by this invention is strongly influenced by the concentration of Sodium Hyaluronate, and, additionally, by the concentration of Dexpanthenol.
- the inventors of the present invention have obtained intermediate or high molecular weight Hyaluranates, preferably high molecular weight Hyaluranates at low concentration in the final composition, and even more preferably a combination of intermediate molecular weight Hyaluranates and high so that the final concentration of Hyaluronate in the composition is not less than 0.005% weight/volume of Hyaluronate.
- the composition uses hyaluronic acid or its sodium salt, sodium hyaluronate, as the natural active ingredient capable of producing a pronounced hydration and coating effect on the nasal mucosa.
- Hyaluronic acid or its sodium salt is produced according to the microorganism fermentation method and consists of a linear polysaccharide polymer where the repeating unit is a disaccharide of D-Glucuronic acid and D-Glucosamine.
- the purity of sodium hyaluronate is a minimum of 92% W/W, with a maximum moisture content of 10% W/W; it is a hygroscopic substance.
- the molecular weight range of sodium hyaluronate used in the present Nasal Spray composition is from 850,000 Daltons to 1,600,000 Daltons, combination of intermediate and high molecular weights.
- the concentration of hyaluronic acid or its sodium salt used in the Nasal Spray is in the range of 0.020% W/V to 0.050% W/V, even more preferably between 0.040% W/V and 0.045% W/V and preferably 0.040% W/V. v.
- Higher concentrations of Sodium Hyaluronate could increase the viscosity of the system whose main result would be the total deformation of the Spray Pattern sought with Dmax/Dmin values » 1 ,12. It should be noted that the Spray-PLUMA Standard is very important for all Sprays as it shows the efficiency of product entry into the nasal cavities, without the need to introduce the applicator pump tip into them.
- Dexpanthenol at 1.0% P/V helps to obtain the correct Viscosity needed to obtain both the Spray Pattern and the desired droplet size distribution.
- a concentration of dexpanthenol greater or less than the concentration of 1.0% W/V would result in the same effect mentioned above for Sodium Hyaluronate.
- concentrations greater than 1% P/V can also cause an increase in the final density of the Spray, and the latter, as we will see below, also strongly influences the Spray Pattern and Droplet Size Distribution of the product.
- the inventors of the present invention determined that the density (in g/ml at 25°C) of the aqueous solution strongly influences the characteristics of the Spray Pattern sought and, mainly , the desired droplet size, i.e. 100% droplets larger than 10 microns, to avoid inadequate penetration of the product into the aforementioned tracheobronchial and/or respiratory tract.
- the density of the product of the present invention is mainly influenced by the concentrations of Dexpanthenol and the pH Regulating System Dibasic Sodium Phosphate Anhydrous and Monobasic Sodium Phosphate Anhydrous.
- concentrations chosen for each of these components of the formulation were balanced in order to stay within the allowable range of densities of the final product compatible with the PLUMA Spray Standard and the Gaussian-type droplet size distribution with 100% of the droplets containing a size greater than 10 microns.
- Sodium Hyaluronate is the active hydration agent of the nasal mucosa and an agent for obtaining an optimal viscosity
- Dexpanthenol assists in said hydration, in the relief of any epithelial wound, also acting in the control of the viscosity and density of the formulation in order to obtain an optimal spray effect with the chosen Spray Pump applicator.
- the Viscosity and Density required to obtain a constant and Elliptical Plume Spray Pattern with Dmax/Dmin from 1.00 to 1.12 to 3 and 6 cm of distance, with 100% of the Droplets larger than 10 microns and in Spray distribution must meet the following specifications:
- the pH (7.0 - 7.5) and physiological isotonicity are provided by the pH Regulator Monobasic Sodium Phosphate/Dibasic Sodium Phosphate. This system also strongly controls the density of the final product. To preserve the sterility of the product throughout its use, the classic Benzalkonium Chloride/EDTA antimicrobial system is used in nasal preparations. This formulation allows for continuous wetting of the nostrils, relief from nasal congestion, and lacks irritating effects.
- the content should range from 0.038% to 0.042% W/V of Sodium Hyaluronate.
- the density should range from 1.015 to 1.025 g/ml at 25°C by the pycnometry method. Brookfield viscosity at 25°C, Spindle 1 , 100 rpm should range from 4.0 to 5.0 cps.
- the liquid content should vary between 32 to 34 ml/vial.
- the pH should be between 7.0 and 7.5.
- the flow for each actuation must vary between 0.054 to 0.058 ml/pump.
- the product must pass the sterility test.
- Droplet size distribution assay by laser diffraction measured at a distance of 3 cm from the nozzle to the measurement plane
- REPLACEMENT SHEETS (RULE 26) [047] This test was performed on 10 vials of the composition manufactured according to example 1; each one of them was initially activated 1 time and the measurement called START was performed on the spray launched; then the bottle was activated without interruption until reaching the final content, where the final pump was carried out, whose spray released was measured again, called FIM.
- the laser beam diffractor performed the reading of the droplet size distribution results at a distance of 3 cm, which have a direct relationship with the formulation of example 1 and the peculiar spray system used. The result is expressed as a percentage of droplets that have a certain size expressed in microns. So, for example, choose:
- DV (10) indicates that 10% by volume of the droplets has a size equal to or smaller than that reported in the result, in microns.
- Dv (10) and Dv (90) together delimit the lower and upper limits of droplet size comprising 80% of the distribution centered on the mean Dv (50) with 40% for each side; the remaining 20% of the distribution is, 10% below the Dv value (10), and 10% above the value Dv (90).
- 10% that are below Dv (10) as mentioned before, looking at the individual distribution of each vial, it is easy to understand that, in all cases, there is no droplet size equal to or less than 10 microns.
- Droplet size distribution assay by laser diffraction measured at a distance of 6 cm from the nozzle to the measurement plane
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Abstract
Pharmaceutical composition of aqueous sodium hyaluronate in nasal spray form for relief and remedy of nasal dryness and irritation caused by ageing, low humidity, colds, congestion, or side effects from medication by moisturizing and wetting the entire nostril, developed as a formulation in a real aqueous solution with specially balanced viscosity and density to ensure, when administered using a specific actuator, a specific and constant plume spray pattern and a Gaussian droplet size distribution in which 100% of the droplets are larger than 10 microns, thereby guaranteeing enhanced efficiency of local nasal topical treatment without surpassing the nasopharyngeal region.
Description
COMPOSIÇÃO FARMACÊUTICA DE HIALURONATO DE SÓDIO AQUOSA EM FORMA DE SPRAY NASAL
PHARMACEUTICAL COMPOSITION OF AQUEOUS SODIUM HYALURONATE IN THE FORM OF NASAL SPRAY
[001] A presente invenção refere-se a uma composição farmacêutica inovadora, que consiste em um spray nasal de Hialuronato de sódio, que alivia a secura e irritação das narinas causadas pelo envelhecimento, baixa umidade, resfriados, congestão ou efeitos colaterais de medicamentos. [001] The present invention relates to an innovative pharmaceutical composition, which consists of a Sodium Hyaluronate nasal spray, which relieves dryness and irritation of the nostrils caused by aging, low humidity, colds, congestion or medication side effects.
ESTADO DA TÉCNICA STATUS OF THE TECHNIQUE
[002] Sob certas condições a habilidade das células epiteliais nasais para secretar muco, preservar a umidade e filtrar o ar podem ser prejudicadas. Condições como baixa umidade, envelhecimento, efeitos colaterais de medicamentos usados para tratar alergias, resfriados comuns ou acne resultam em secura do nariz e acumulação de crosta causando desconforto, dor, sangramento nasal e tosse. [002] Under certain conditions the ability of nasal epithelial cells to secrete mucus, preserve moisture and filter air may be impaired. Conditions such as low humidity, aging, side effects of medications used to treat allergies, common colds or acne result in dryness of the nose and crust buildup causing discomfort, pain, nosebleeds and coughing.
[003] A inalação nasal como via de administração de medicamentos fica restringida ao tratamento de processos que tem lugar a nível local, nas vias aéreas superiores, como, por exemplo, os diferentes casos de rinites. [003] Nasal inhalation as a route of drug administration is restricted to the treatment of processes that take place locally, in the upper airways, such as, for example, different cases of rhinitis.
[004] Como podemos visualizar na Figura 1 , a árvore respiratória pode se dividir em três zonas bem diferenciadas: [004] As we can see in Figure 1, the respiratory tree can be divided into three well-differentiated zones:
Região Nasofaríngea: é o trato respiratório superior, que compreende o nariz, a boca, a faringe e a laringe. Nasopharyngeal Region: It is the upper respiratory tract, which comprises the nose, mouth, pharynx and larynx.
Região Traqueobronquial: inclui a traqueia, os brônquios e os bronquíolos terminais. Tracheobronchial Region: Includes the trachea, bronchi, and terminal bronchioles.
Região pulmonar ou respiratória: corresponde aos bronquíolos respiratórios, o canal alveolar, os sacos alveolares e os alvéolos. Essa região é onde ocorrem as trocas gasosas. Pulmonary or respiratory region: corresponds to the respiratory bronchioles, the alveolar canal, the alveolar sacs and the alveoli. This region is where gas exchange takes place.
[005] Os fatores que condicionam o trânsito de medicamentos nasais em forma de spray são o tamanho de partículas ou gotículas, o modo respiratório, as características anatômicas das vias respiratórias e possíveis fatores patológicos, entre outros. Dependendo do tamanho de partículas ou gotículas, estas depositam- se nas diferentes regiões vistas acima. Podemos assim fazer a seguinte diferenciação, também apresentada na Figura 2: [005] The factors that condition the transit of nasal medications in spray form are the size of particles or droplets, the breathing mode, the anatomical characteristics of the airways and possible pathological factors, among others. Depending on the size of particles or droplets, these are deposited in the different regions seen above. We can thus make the following differentiation, also shown in Figure 2:
Diâmetro de partículas/gotículas Nível Máximo de penetração
Particle/droplet diameter Maximum penetration level
[006] Existem na literatura atual, numerosas patentes, trabalhos de desenvolvimento, e ainda produtos no mercado, relativos a composições de produtos para a saúde e medicamentos, todos destinados a aliviar a secura e irritação das narinas. Algumas dessas anterioridades também mencionam a forma física dos preparados como Suspensões, Soluções, Gel, Comprimidos e Pós; referente a forma de administração do produto, mencionam-se Spray Nasal, Gel, Gotas, inalantes diversos, Orais, Injetáveis e outras. Tratamentos também estão relacionados em tais anterioridades. [006] In the current literature, there are numerous patents, development works, and even products on the market, relating to compositions of health products and medicines, all aimed at relieving dryness and irritation of the nostrils. Some of these priorities also mention the physical form of preparations such as Suspensions, Solutions, Gels, Pills and Powders; regarding the form of administration of the product, mention should be made of Nasal Spray, Gel, Drops, various inhalants, Oral, Injectable and others. Treatments are also listed in such prior art.
[007] A patente número 20050164979 - Pharmaceutical composition for ophthalmological and rhinological application descreve uma composição farmacêutica que contém pelo menos pantenol e/ou ácido pantotênico e ácido hialurônico e/ou hialuronato e, opcionalmente, agentes auxiliares farmacêuticos adicionais. A invenção refere-se ainda ao uso da composição farmacêutica para o tratamento de defeitos funcionais oftalmológicos e/ou rinológicos, falhando em mencionar tamanho de gotículas e propriedades físico- químicas da composição para que esta tenha ação exclusiva nas narinas. [007] Patent number 20050164979 - Pharmaceutical composition for ophthalmological and rhinological application describes a pharmaceutical composition that contains at least panthenol and/or pantothenic acid and hyaluronic acid and/or hyaluronate and, optionally, additional pharmaceutical auxiliary agents. The invention also relates to the use of the pharmaceutical composition for the treatment of ophthalmological and/or rhinological functional defects, failing to mention droplet size and physicochemical properties of the composition so that it has an exclusive action on the nostrils.
[008] Já a patente número W02003049747 - Synergistic pharmaceutical composition for treating ophthalmological and/or rhinological dysfunction, containing panthenol or pantothenic acid and hyaluronic acid or hyaluronate) apresenta uma composição farmacêutica contendo pantenol e / ou ácido pantotênico, ácido hialurônico e / ou hialuronato e opcionalmente auxiliares farmacêuticos adicionais no tratamento de disfunção oftalmológica e / ou rinológica, especificamente disfunção rinológica associada à secura da mucosa nasal, especialmente rinite crónica e / ou rinite seca, apresentando como vantagem a combinação de pantenol e hialuranato que produz um efeito sinérgico no tratamento de ambos os distúrbios oftalmológicos e distúrbios rinológicos, por exemplo, cicatrização de lesões na mucosa nasal e melhoria da retenção de umidade. Apresenta ainda faixas de concentração para estes dois ativos e faixa de peso molecular para o hialuronato. Como propriedades físico-químicas, apresenta
apenas o pH como sendo importante, não mencionando tamanho de gotículas ou partículas, nem tampouco outras propriedades físico-químicas da formulação, como viscosidade de densidade, que podem garantir um padrão spray específico. [008] Patent number W02003049747 - Synergistic pharmaceutical composition for treating ophthalmological and/or rhinological dysfunction, containing panthenol or pantothenic acid and hyaluronic acid or hyaluronate) presents a pharmaceutical composition containing panthenol and/or pantothenic acid, hyaluronic acid and/or hyaluronate and optionally additional pharmaceutical aids in the treatment of ophthalmological and/or rhinological dysfunction, specifically rhinological dysfunction associated with dryness of the nasal mucosa, especially chronic rhinitis and/or rhinitis sicca, presenting the advantage of the combination of panthenol and hyaluranate that produces a synergistic effect in the treatment of both ophthalmological disorders and rhinological disorders, for example, healing of lesions in the nasal mucosa and improvement of moisture retention. It also presents concentration ranges for these two actives and molecular weight range for hyaluronate. As physicochemical properties, it presents only pH is important, not mentioning droplet or particle size, nor other physicochemical properties of the formulation, such as density viscosity, which can guarantee a specific spray pattern.
[009] O que podemos perceber é que nenhuma das formulações existentes no mercado ou descritas em outras patentes mencionam ou salientam o Tamanho de Gotículas no caso de Soluções, ou Tamanho de Partículas nos outros casos como sendo um fator importante no tratamento de secura e irritação das narinas, tampouco encontra-se descrita a relação existente entre esse tamanho de gotícula e as propriedades físico-químicas da formulação, especificamente quanto a viscosidade, a densidade e ao Sistema de aplicação usado para a administração do produto. [009] What we can see is that none of the existing formulations on the market or described in other patents mention or emphasize Droplet Size in the case of Solutions, or Particle Size in other cases as being an important factor in the treatment of dryness and irritation. of the nostrils, the relationship between this droplet size and the physicochemical properties of the formulation is not described, specifically in terms of viscosity, density and the application system used to administer the product.
[010] O que se pode perceber nos documentos acima apresentados é que existem formulações muito boas, mas que estas, quando aplicadas, por não haver a preocupação com o tamanho de gotículas, acabam penetrando além das fossas nasais, podendo chegar até aos alvéolos pulmonares, o que pode acarretar em absorção a nível plasmático, alvo fora do objetivo perseguido. [010] What can be seen in the documents presented above is that there are very good formulations, but that, when applied, because there is no concern with the size of droplets, they end up penetrating beyond the nasal cavities, reaching the pulmonary alveoli. , which can lead to absorption at the plasma level, target outside the objective pursued.
[011] Para resolver este problema da técnica, os inventores desenvolveram uma composição inovadora, que consiste em um spray nasal de Hialuronato de sódio, que alivia a secura e irritação das narinas causadas pelo envelhecimento, baixa umidade, resfriados, congestão ou efeitos colaterais de medicamentos. [011] To solve this problem of the technique, the inventors have developed an innovative composition, which consists of a nasal spray of Sodium Hyaluronate, which relieves dryness and irritation of the nostrils caused by aging, low humidity, colds, congestion or side effects of medicines.
[012] O spray nasal de Hialuronato de sódio da presente invenção foi desenvolvido para agir a nível da região Nasofaríngea, com o Hialuronato de sódio se aderindo a membrana mucosa nasal e hidratando-a, prevenindo assim sua secura. A secura da mucosa nasal é produzida também por fatores ambientais como calor, ar condicionado, vento e sol. A secura nasal evita que a mucosa possa cumprir a sua função de umectação e limpeza do ar que se respira, deixando as narinas expostas a invasão de patógenos. Uma intensiva hidratação com Hialuronato de sódio mantém uma capa protetora na mucosa nasal e fortalece a resistência das narinas contra invasões exógenas.
[012] The Sodium Hyaluronate Nasal Spray of the present invention was developed to act at the level of the Nasopharyngeal region, with the Sodium Hyaluronate adhering to the nasal mucous membrane and moisturizing it, thus preventing its dryness. Dryness of the nasal mucosa is also produced by environmental factors such as heat, air conditioning, wind and sun. Nasal dryness prevents the mucosa from fulfilling its function of wetting and cleaning the air we breathe, leaving the nostrils exposed to the invasion of pathogens. Intensive hydration with Sodium Hyaluronate maintains a protective layer on the nasal mucosa and strengthens the resistance of the nostrils against exogenous invasions.
[013] A composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal da presente invenção foi desenvolvida como uma
formulação em solução aquosa verdadeira, especificamente balanceada em viscosidade e densidade, para que, ao ser administrada através de atuador específico, produzir um padrão spray pluma particular e constante e distribuição de tamanho de gotículas gaussiana onde o 100% das gotículas são maiores que 10 micras, garantindo assim uma maior eficácia no tratamento tópico local nasal sem ultrapassar a região nasofaríngea. [013] The pharmaceutical composition of aqueous Sodium Hyaluronate in nasal spray form of the present invention was developed as a formulation in true aqueous solution, specifically balanced in viscosity and density, so that, when administered through a specific actuator, it produces a particular and constant spray plume pattern and Gaussian droplet size distribution where 100% of the droplets are greater than 10 microns , thus ensuring greater effectiveness in local nasal topical treatment without going beyond the nasopharyngeal region.
[014] Demonstramos nesta invenção como a formulação fornece as propriedades físicas necessárias para a obtenção de uma distribuição de gotículas de Solução especialmente adaptada para não ultrapassar a região Nasofaríngea, quando aplicada em forma de Spray usando um atuador específico. Desta forma, a invenção aqui apresentada relaciona-se às Propriedades Físicas da Formulação e uma peculiar Bomba aplicadora de Spray necessária para assegurar que o produto tenha um Padrão Spray-Pluma constante, e que não ultrapasse a Laringe ou Faringe. Isso assegura um efeito tópico localizado ao nível das narinas, alvo único do produto aqui desenvolvido, se evitando regiões onde o produto pode ser absorvido a nível plasmático, alvo fora do objetivo perseguido. [014] We demonstrate in this invention how the formulation provides the physical properties necessary to obtain a solution droplet distribution specially adapted to not exceed the Nasopharyngeal region, when applied in the form of a Spray using a specific actuator. Thus, the invention presented here relates to the Physical Properties of the Formulation and a peculiar Spray Applicator Pump necessary to ensure that the product has a constant Spray-Feather Pattern, and does not go beyond the Larynx or Pharynx. This ensures a localized topical effect at the level of the nostrils, the unique target of the product developed here, avoiding regions where the product can be absorbed at the plasma level, a target outside the objective pursued.
[015] Lista de desenhos e sua explicação [015] List of drawings and their explanation
[016] Figura 1 - esquema mostrando as regiões do sistema respiratório, com destaque para as regiões nasofaríngea, tranqueobronquial e respiratória. [016] Figure 1 - scheme showing the regions of the respiratory system, with emphasis on the nasopharyngeal, tracheobronchial and respiratory regions.
[017] Figura 2 - esquema mostrando a relação entre diâmetro de partícula do spray e nível máximo de penetração em cada uma das regiões do sistema respiratório. [017] Figure 2 - diagram showing the relationship between spray particle diameter and maximum level of penetration in each of the regions of the respiratory system.
[018] Figura 3 - Resultados individuais do ensaio de massa de cada atuação, ou bombeio, ou pressionamento. [018] Figure 3 - Individual results of the mass test of each actuation, or pumping, or pressing.
[019] Figura 4 - Resultados individuais do ensaio de distribuição de tamanhos de gotículas por difração a laser medido a uma distância de 3 cm desde o bico ao plano de medição. [019] Figure 4 - Individual results of the droplet size distribution test by laser diffraction measured at a distance of 3 cm from the nozzle to the measurement plane.
[020] Figura 5 - Resultados individuais do ensaio de distribuição de tamanhos de gotículas por difração a laser medido a uma distância de 6 cm desde o bico ao plano de medição. [020] Figure 5 - Individual results of the droplet size distribution test by laser diffraction measured at a distance of 6 cm from the nozzle to the measurement plane.
[021] Figura 6 - Resultados individuais da análise de padrão de spray pluma. [021] Figure 6 - Individual results of the plume spray pattern analysis.
FOLHAS DE SUBSTITUIÇÃO (REGRA 26)
DESCRIÇÃO DETALHADA DA INVENÇÃO REPLACEMENT SHEETS (RULE 26) DETAILED DESCRIPTION OF THE INVENTION
[022] Devido ao alvo do produto ser a região nasofaríngea, foi escolhido um sistema consistente numa solução aquosa, de aplicação tipo spray, formando um aerossol de descarga líquida, sem propelente, com pressurização mecânica (atuador) com gotículas de tamanho bem superior a 10 micras, com o qual assegura-se ação limitada as narinas, protegendo e fortalecendo a membrana da mucosa nasal. [022] Due to the product's target being the nasopharyngeal region, a system consisting of an aqueous solution was chosen, for spray application, forming a liquid discharge aerosol, without propellant, with mechanical pressurization (actuator) with droplets of size well above 10 microns, which ensures limited action on the nostrils, protecting and strengthening the nasal mucous membrane.
[023] Vários aspectos foram levados em conta para o desenvolvimento desta invenção, a saber: [023] Several aspects were taken into account for the development of this invention, namely:
[024] Formulação liquida - para evitar a lesão do epitélio nasal, procurou-se (1 ) conservar a integridade da função excretora e ciliar, para o qual é necessário que a solução seja iso osmótica ou ligeiramente hipertônica, pois as soluções hipotônicas danam o epitélio nasal provocando irritação; (2) que esta solução apresente um pH entre 6,5 e 8,3 para conservar o movimento ciliar, pois soluções que apresentem pH fora desse intervalo podem provocar paralises do movimento; (3) concentração adequada de agentes de viscosidade para evitar a paralisação temporal de movimento ciliar, mas o suficientemente alta para incrementar a hidratação das narinas e, principalmente, para obter o Padrão de Spray PLUMA desejado para a particular bomba aplicadora escolhida e com tamanho de gotículas 100% maior que 10 micras em distribuição Gaussiana; (4) esterilidade do preparado evitando entrada de patógenos; (5) incorporação de um aditivo sinérgico de hidratação e alívio de possíveis feridas presentes nas narinas dos pacientes, que também funcione regulando a viscosidade; (6) balanceamento de componentes de formulação de forma a permitir a obtenção de uma densidade final do produto adequada, como requerido na relação entre densidade e bomba aplicadora Spray, por exemplo, através da ausência de óleos ou excessiva quantidade de sais. [024] Liquid formulation - to avoid injury to the nasal epithelium, it was sought (1 ) to preserve the integrity of the excretory and ciliary function, for which it is necessary that the solution is isoosmotic or slightly hypertonic, as hypotonic solutions damage the nasal epithelium causing irritation; (2) that this solution has a pH between 6.5 and 8.3 to preserve ciliary movement, as solutions with a pH outside this range can cause movement paralysis; (3) adequate concentration of viscosity agents to avoid temporal stoppage of ciliary movement, but high enough to increase nostril hydration and, most importantly, to obtain the desired PLUMA Spray Pattern for the particular chosen applicator pump and with droplets 100% larger than 10 microns in Gaussian distribution; (4) sterility of the preparation, preventing the entry of pathogens; (5) incorporation of a synergistic additive for hydration and relief of possible wounds present in the patients' nostrils, which also works by regulating viscosity; (6) balancing of formulation components in order to allow obtaining a suitable final product density, as required in the relationship between density and Spray applicator pump, for example, through the absence of oils or excessive amounts of salts.
[025] Para o Sistema Spray, buscou-se um peculiar sistema aplicador spray com as características de (1) Volume total de líquido de 30,0 ml, que assegura 0,056 ml por cada acionamento. Uma dose para uma narina é composta por 3 acionamentos, que equivalem a 0,168 ml da formulação; (2) Bico spray com abertura otimizada para gerar gotículas muito maiores que 10 micras em
distribuição Gaussiana com um Padrão Spray PLUMA Elíptico constante e assegurando uma descarga de 0,056 ml por cada acionamento. [025] For the Spray System, a peculiar spray applicator system was sought with the characteristics of (1) Total volume of liquid of 30.0 ml, which ensures 0.056 ml for each activation. A dose for one nostril consists of 3 activations, which are equivalent to 0.168 ml of the formulation; (2) Spray nozzle with optimized aperture to generate droplets much larger than 10 microns in Gaussian distribution with a constant Elliptical PLUMA Spray Pattern and ensuring a discharge of 0.056 ml per actuation.
[026] Sobre a Relação entre a Formulação e o Sistema Spray, esta invenção buscou a relação ótima entre o particular Sistema Spray escolhido e a formulação líquida como solução verdadeira de forma tal a cumprir com a Instrução Normativa ANVISA NQ 33 de 16 de abril de 2019 que trata especificamente de Spray Nasais, e chegando aos resultados apresentados na seção “RESULTADOS DE ESTUDOS” a um Padrão de Spray PLUMA. [026] Regarding the Relationship between the Formulation and the Spray System, this invention sought the optimal relationship between the particular Spray System chosen and the liquid formulation as a true solution in order to comply with ANVISA Normative Instruction No. 2019 that deals specifically with Nasal Sprays, and arriving at the results presented in the “RESULTS OF STUDY” section to a FEATHER Spray Standard.
[027] Para resolver o problema apresentado no estado da técnica quanto a viscosidade, os inventores da presente invenção determinaram que a viscosidade da solução aquosa usada possui um papel fundamental na obtenção das características do Padrão de Spray buscado e, principalmente, no tamanho de gotícula desejado, isto é, 100% gotículas maiores que 10 micras, para evitar penetração inadequada do produto em vias traqueobronquial e/ou respiratória acima mencionadas. A viscosidade da solução proposta por esta invenção é influenciada fortemente pela concentração de Hialuronato de sódio, e, adicionalmente, pela concentração de Dexpantenol. [027] To solve the problem presented in the state of the art regarding viscosity, the inventors of the present invention determined that the viscosity of the aqueous solution used has a fundamental role in obtaining the characteristics of the Spray Pattern sought and, mainly, in the droplet size. desired, i.e. 100% droplets larger than 10 microns, to avoid inadequate penetration of the product into the aforementioned tracheobronchial and/or respiratory tracts. The viscosity of the solution proposed by this invention is strongly influenced by the concentration of Sodium Hyaluronate, and, additionally, by the concentration of Dexpanthenol.
[028] Para alcançar as características físico-químicas desejadas e assim a um tamanho de gotícula que caracterizam a presente invenção, os inventores descobriram que quanto maior é o Peso Molecular usado de Hialuronato de sódio, maior é a viscosidade da solução obtida e menor a sua penetração através de epitélios. Hialuranatos de baixo peso molecular, até aproximadamente 50.000 Dalton, por exemplo, 50.000 Dalton, apresentam baixa viscosidade e alta penetração através de epitélios. Os Hialuranatos de peso molecular intermediários, isto é, entre 50.000 Dalton até aproximadamente 700.000 - 800.000 Dalton apresentam viscosidade moderada e mínima penetração em epitélios. Já os Hialuranatos de alto peso molecular, acima de 1.000.000 - 2.000.000 Dalton apresentam viscosidade alta e não penetram através de epitélios, sendo considerados excelentes hidratantes. [028] To achieve the desired physicochemical characteristics and thus a droplet size that characterize the present invention, the inventors found that the greater the Molecular Weight of Sodium Hyaluronate used, the greater the viscosity of the solution obtained and the lower the penetration through epithelia. Low molecular weight hyaluranates, up to approximately 50,000 Dalton, eg 50,000 Dalton, have low viscosity and high penetration through epithelia. Intermediate molecular weight Hyaluranates, ie, between 50,000 Daltons to approximately 700,000 - 800,000 Daltons have moderate viscosity and minimal penetration into epithelia. On the other hand, high molecular weight Hyaluranates, above 1,000,000 - 2,000,000 Dalton have high viscosity and do not penetrate through epithelium, being considered excellent moisturizers.
[029] Desta forma, os inventores da presente invenção obtaram por Hialuranatos de peso molecular intermediário ou alto, preferivelmente Hialuranato de alto peso molecular em concentração baixa na composição final, e ainda mais preferivelmente uma combinação de Hialuranatos de peso molecular intermediário
e alto para que a concentração final de Hialuranato na composição não seja menor que 0,005% peso/volume de Hialuronato. [029] In this way, the inventors of the present invention have obtained intermediate or high molecular weight Hyaluranates, preferably high molecular weight Hyaluranates at low concentration in the final composition, and even more preferably a combination of intermediate molecular weight Hyaluranates and high so that the final concentration of Hyaluronate in the composition is not less than 0.005% weight/volume of Hyaluronate.
[030] A composição utiliza ácido hialurônico ou seu sal sódico, hialuronato de sódio, como o ingrediente ativo natural capaz de produzir um pronunciado efeito de hidratação e revestimento da mucosa nasal. O ácido hialurônico ou seu sal sódico é produzido de acordo com o método de fermentação de microrganismos e consiste de um polímero linear polissacarídeo onde a unidade repetitiva é um dissacarídeo de ácido D-Glucurônico e D-Glucosamina. A pureza de hialuronato de sódio é de no mínimo 92% P/P, com um máximo de umidade de 10% P/P; é uma substância higroscópica. A faixa de peso molecular de hialuronato de sódio usado na presente composição de Spray Nasal é de 850.000 Dalton a 1.600.000 Dalton, combinação de pesos moleculares intermediário e alto. A concentração usada de ácido hialurônico ou seu sal sódico no Spray Nasal está na faixa de 0,020% P/V a 0,050% P/V, ainda mais preferivelmente entre 0,040% P/V e 0,045% P/V e preferivelmente 0,040% P/V. Menores concentrações de Hialuronato de Sódio na composição poderiam diminuir a viscosidade do sistema e trazer como resultado uma deformação no Padrão Spray Pluma buscado (especificado em Dmax/Dmin = 1 ,00 a 1 ,12 para 3 e 6 cm de distância) e uma distribuição de tamanho de gotículas não Gaussiana com, ao menos, 2 tamanhos principais de gotículas incluindo de 5 a 15 % de gotículas menores que 10 micras. Maiores concentrações de Hialuronato de sódio poderiam aumentar a viscosidade do sistema cujo resultado principal seria a total deformação do Padrão Spray buscado com valores de Dmax/Dmin » 1 ,12. Salienta-se que o Padrão de Spray- PLUMA é muito importante para todos os Spray pois mostra a eficiência de entrada do produto nas cavidades nasais, sem necessidade de introdução da ponta da bomba aplicadora nas mesmas. [030] The composition uses hyaluronic acid or its sodium salt, sodium hyaluronate, as the natural active ingredient capable of producing a pronounced hydration and coating effect on the nasal mucosa. Hyaluronic acid or its sodium salt is produced according to the microorganism fermentation method and consists of a linear polysaccharide polymer where the repeating unit is a disaccharide of D-Glucuronic acid and D-Glucosamine. The purity of sodium hyaluronate is a minimum of 92% W/W, with a maximum moisture content of 10% W/W; it is a hygroscopic substance. The molecular weight range of sodium hyaluronate used in the present Nasal Spray composition is from 850,000 Daltons to 1,600,000 Daltons, combination of intermediate and high molecular weights. The concentration of hyaluronic acid or its sodium salt used in the Nasal Spray is in the range of 0.020% W/V to 0.050% W/V, even more preferably between 0.040% W/V and 0.045% W/V and preferably 0.040% W/V. v. Lower concentrations of Sodium Hyaluronate in the composition could decrease the viscosity of the system and result in a deformation in the desired Spray Plume Pattern (specified in Dmax/Dmin = 1.00 to 1.12 for 3 and 6 cm of distance) and a distribution non-Gaussian droplet size with at least 2 major droplet sizes including 5 to 15% droplets smaller than 10 microns. Higher concentrations of Sodium Hyaluronate could increase the viscosity of the system whose main result would be the total deformation of the Spray Pattern sought with Dmax/Dmin values » 1 ,12. It should be noted that the Spray-PLUMA Standard is very important for all Sprays as it shows the efficiency of product entry into the nasal cavities, without the need to introduce the applicator pump tip into them.
[031] O Dexpantenol a 1 ,0% P/V auxilia na obtenção da Viscosidade correta necessária para obter tanto o Padrão de Spray quanto a Distribuição de tamanhos de gotículas desejados. Uma concentração de dexpantenol maior ou menor que a concentração de 1 ,0% P/V teria como resultado o mesmo efeito antes mencionado para o Hialuronato de sódio. Além do mais, o uso de concentrações maiores que 1 % P/V pode ocasionar também um aumento na densidade final do Spray, e esta última, como veremos mais abaixo, também
influi fortemente o Padrão Spray e a Distribuição do tamanho de gotículas do produto. [031] Dexpanthenol at 1.0% P/V helps to obtain the correct Viscosity needed to obtain both the Spray Pattern and the desired droplet size distribution. A concentration of dexpanthenol greater or less than the concentration of 1.0% W/V would result in the same effect mentioned above for Sodium Hyaluronate. Furthermore, the use of concentrations greater than 1% P/V can also cause an increase in the final density of the Spray, and the latter, as we will see below, also strongly influences the Spray Pattern and Droplet Size Distribution of the product.
[032] Para resolver o problema apresentado no estado da técnica quanto a densidade, os inventores da presente invenção determinaram que a densidade (em g/ml a 25°C) da solução aquosa influencia fortemente as características do Padrão de Spray buscado e, principalmente, o tamanho de gotícula desejado, ou seja, 100% de gotículas maiores que 10 micras, para evitar penetração inadequada do produto em via traqueobronquial e/ou respiratória acima mencionadas. Os inventores descobriram que a faixa ótima de densidade para esse fim é de 1 ,015 a 1 ,025 g/ml a 25°C; valores maiores que 1,025 g/ml a 25°C determinam uma deformação do Padrão Spray especificado com valores Dmax/Dmin » 1 ,12; valores menores que 1 ,015 g/ml a 25°C trazem como resultado uma deformação no Padrão Spray Pluma buscado (especificado Dmax/Dmin = 1 ,00 a 1 ,12 para 3 e 6 cm de distância) e uma distribuição de tamanho de gotículas não Gaussiana que incluem de 5 a 10 % de gotículas menores que 10 micras. A densidade do produto da presente invenção é influenciada principalmente pelas concentrações de Dexpantenol e pelo Sistema regulador de pH Fosfato dibásico de sódio anidro e Fosfato monobásico de sódio anidro. As concentrações escolhidas para cada um desses componentes da formulação foram balanceadas com o objetivo de ficar dentro da faixa permitida de densidades do produto final compatível com o Padrão de Spray PLUMA e a Distribuição de tamanhos de gotículas de tipo Gaussiana com 100% das gotículas contendo um tamanho superior a 10 micras. [032] To solve the problem presented in the state of the art regarding density, the inventors of the present invention determined that the density (in g/ml at 25°C) of the aqueous solution strongly influences the characteristics of the Spray Pattern sought and, mainly , the desired droplet size, i.e. 100% droplets larger than 10 microns, to avoid inadequate penetration of the product into the aforementioned tracheobronchial and/or respiratory tract. The inventors have found that the optimum density range for this purpose is 1.015 to 1.025 g/ml at 25°C; values greater than 1.025 g/ml at 25°C determine a deformation of the specified Spray Standard with values Dmax/Dmin » 1 .12; values less than 1.015 g/ml at 25°C result in a deformation in the desired Spray Plume Pattern (specified Dmax/Dmin = 1.00 to 1.12 for 3 and 6 cm distance) and a size distribution of non-Gaussian droplets that include 5 to 10% droplets smaller than 10 microns. The density of the product of the present invention is mainly influenced by the concentrations of Dexpanthenol and the pH Regulating System Dibasic Sodium Phosphate Anhydrous and Monobasic Sodium Phosphate Anhydrous. The concentrations chosen for each of these components of the formulation were balanced in order to stay within the allowable range of densities of the final product compatible with the PLUMA Spray Standard and the Gaussian-type droplet size distribution with 100% of the droplets containing a size greater than 10 microns.
[033] Formulação preferencial:
[034] Nessa fórmula otimizada, o Hialuronato de sódio é o agente de hidratação ativo da mucosa nasal e um agente para a obtenção de uma viscosidade ótima, sendo que o Dexpantenol auxilia na dita hidratação, no alívio de qualquer ferida epitelial, atuando também no controle da viscosidade e densidade da formulação a fim de se obter um ótimo efeito spray com a Bomba Spray aplicadora escolhida. A Viscosidade e Densidade necessárias para a obtenção de um Padrão Spray Pluma constante e Elíptico com Dmax/Dmin de 1 ,00 a 1 ,12 a 3 e 6 cm de distância, com 100% das Gotículas maiores que 10 micras e em distribuição Spray devem cumprir as seguintes especificações: [033] Preferred formulation: [034] In this optimized formula, Sodium Hyaluronate is the active hydration agent of the nasal mucosa and an agent for obtaining an optimal viscosity, and Dexpanthenol assists in said hydration, in the relief of any epithelial wound, also acting in the control of the viscosity and density of the formulation in order to obtain an optimal spray effect with the chosen Spray Pump applicator. The Viscosity and Density required to obtain a constant and Elliptical Plume Spray Pattern with Dmax/Dmin from 1.00 to 1.12 to 3 and 6 cm of distance, with 100% of the Droplets larger than 10 microns and in Spray distribution must meet the following specifications:
[035] Viscosidade Brookfield a 25°C, Spindle 1 , 100 rpm = 4,0 - 5,0 cps [035] Brookfield Viscosity at 25°C, Spindle 1 , 100 rpm = 4.0 - 5.0 cps
[036] Densidade a 25°C por Picnometria: 1 ,015 a 1 ,025 g/ml. [036] Density at 25°C by Pycnometrics: 1.015 to 1.025 g/ml.
[037] O pH (7,0 - 7,5) e a isotonicidade fisiológica são proporcionados pelo Regulador de pH Fosfato monobásico de sódio/ Fosfato dibásico de sódio. Esse sistema também controla fortemente a densidade do produto final. Para conservar a esterilidade do produto durante todo o tempo de uso, usa-se o sistema antimicrobiano Cloreto de Benzalcônio/ EDTA, clássico, em preparados nasais. Essa formulação permite uma umectação continua das narinas, alívio de congestão nasal, e carece de efeitos irritantes. [037] The pH (7.0 - 7.5) and physiological isotonicity are provided by the pH Regulator Monobasic Sodium Phosphate/Dibasic Sodium Phosphate. This system also strongly controls the density of the final product. To preserve the sterility of the product throughout its use, the classic Benzalkonium Chloride/EDTA antimicrobial system is used in nasal preparations. This formulation allows for continuous wetting of the nostrils, relief from nasal congestion, and lacks irritating effects.
[038] A seguir estão listados exemplos de dita composição inovadora, sendo estes exemplos ilustrativos e não esgotam todas as combinações e possibilidades. [038] Examples of such innovative composition are listed below, these examples being illustrative and do not exhaust all combinations and possibilities.
EXEMPLO 1
EXAMPLE 1
[039] Para um tamanho de lote de 500 litros, em reator em aço inoxidável de capacidade mínima 800 litros, e provido de agitador que entregue, ao menos, 300 rpm, acrescentar 450,0 Kg de Água purificada, 5,0 Kg de Dexpantenol. Agitar a 300 rpm até total dissolução a temperatura ambiente. [039] For a batch size of 500 liters, in a stainless steel reactor with a minimum capacity of 800 liters, and equipped with an agitator that delivers at least 300 rpm, add 450.0 kg of purified water, 5.0 kg of dexpanthenol. Stir at 300 rpm until completely dissolved at room temperature.
[040] Acrescentar no mesmo reator 5,325 Kg de Fosfato dibásico de sódio anidro, 4,500 Kg de Fosfato monobásico de sódio anidro, 0,500 Kg de EDTA dissódico e 0,100 Kg de Cloreto de Benzalcônio. Agitar a 300 rpm até total dissolução a temperatura ambiente.
[041 ] Agregar, aos poucos e agitando a temperatura ambiente com agitação de 300 rpm, 0,200 Kg de Hialuronato de sódio. Continuar a agitação até total dissolução e verificar o pH acertando para 7,2 com solução saturada de NaOH. [040] Add 5.325 kg of anhydrous dibasic sodium phosphate, 4,500 kg of anhydrous monobasic sodium phosphate, 0.500 kg of disodium EDTA and 0.100 kg of Benzalkonium Chloride in the same reactor. Stir at 300 rpm until completely dissolved at room temperature. [041] Gradually add 0.200 kg of sodium hyaluronate, stirring at room temperature at 300 rpm. Continue stirring until complete dissolution and check the pH adjusting to 7.2 with saturated NaOH solution.
[042] Acertar a volume total de 500,0 litros com água purificada e filtrar em forma estéril em área limpa usando filtro esterilizante de 0,22 micras. [042] Adjust the total volume of 500.0 liters with purified water and filter in sterile form in a clean area using a 0.22 micron sterilizing filter.
[043] Fracionar o produto estéril sob fluxo laminar vertical usando frascos spray plásticos estéreis com as seguintes especificações: Volume de líquido por frasco = 32,0 ml (para assegurar 30 ml mínimos de uso no paciente), vazão do bico spray no frasco = mínimo 0, 140 ml/ bombeio (1 dose completa / bombeio). [043] Fractionate the sterile product under vertical laminar flow using sterile plastic spray bottles with the following specifications: Volume of liquid per bottle = 32.0 ml (to ensure a minimum of 30 ml of use on the patient), flow of the spray nozzle in the bottle = minimum 0.140 ml / pump (1 full dose / pump).
[044] Verificar as características do lote em questão através de análises de Controle de qualidade. O teor deve variar de 0,038% a 0,042% P/V de Hialuronato de sódio. A densidade deve variar de 1 ,015 a 1 ,025 g/ml a 25°C pelo método de picnometria. A viscosidade Brookfield a 25°C, Spindle 1 , 100 rpm deve variar de 4,0 a 5,0 cps. O conteúdo líquido deve variar entre 32 a 34 ml/ frasco. O pH deve estar entre 7,0 e 7,5. A vazão por cada acionamento deve variar entre 0,054 a 0,058 ml/ bombeio. O produto deve passar no teste de esterilidade. [044] Check the characteristics of the batch in question through Quality Control analyses. The content should range from 0.038% to 0.042% W/V of Sodium Hyaluronate. The density should range from 1.015 to 1.025 g/ml at 25°C by the pycnometry method. Brookfield viscosity at 25°C, Spindle 1 , 100 rpm should range from 4.0 to 5.0 cps. The liquid content should vary between 32 to 34 ml/vial. The pH should be between 7.0 and 7.5. The flow for each actuation must vary between 0.054 to 0.058 ml/pump. The product must pass the sterility test.
RESULTADOS DE ESTUDOS STUDY RESULTS
[045] Para demonstrar as vantagens da formulação, realizaram-se os seguintes estudos: [045] To demonstrate the advantages of the formulation, the following studies were carried out:
Ensaio de massa de cada atuação, ou bombeio, ou presionamento Mass test of each actuation, or pumping, or pressing
[046] Foram analisados 2 frascos da composição fabricados de acordo com o exemplo 1 ; em cada um deles se realizou 3 replicatas de bombeio de spray; em cada replicata se pesou o frasco antes do bombeio e depois do bombeio e, por diferença, calculou-se o conteúdo expelido de spray em uma atuação ou bombeio. Com os 2 frascos obteve-se 6 dados de conteúdo expelido e logo calculou-se a média como sendo 0,0568 g; usando a densidade de 1 ,020 g/ml, resultando em um volume expelido em cada atuação de 0,056 ml. Usando 3 atuações por Narina chegamos ao valor desejado de 0,168 ml/dose. Os resultados individuais encontram-se na Fig. 3. [046] 2 vials of the composition manufactured according to example 1 were analyzed; in each of them, 3 spray pump replicates were performed; in each replicate, the vial was weighed before pumping and after pumping and, by difference, the content expelled from the spray in one actuation or pumping was calculated. With the 2 vials, 6 data of expelled content were obtained and then the average was calculated as 0.0568 g; using the density of 1.020 g/ml, resulting in a volume expelled in each actuation of 0.056 ml. Using 3 actuations per nostril we arrived at the target value of 0.168 ml/dose. The individual results are shown in Fig. 3.
Ensaio de distribuição de tamanhos de gotículas por difração a laser medido a uma distância de 3 cm desde o bico ao plano de medição Droplet size distribution assay by laser diffraction measured at a distance of 3 cm from the nozzle to the measurement plane
FOLHAS DE SUBSTITUIÇÃO (REGRA 26)
[047] Esse ensaio foi realizado em 10 frascos da composição fabricados de acordo com o exemplo 1 ; cada um deles foi acionado inicialmente 1 vez e sobre o Spray lançado se fez a medição chamada INÍCIO; logo o frasco foi acionado ininterrompidamente até chegar ao conteúdo final onde se realizou o bombeio final, cujo spray lançado foi medido novamente se chamando FIM. O difrator de raios Laser realizou a leitura dos resultados de distribuição de tamanho de gotículas a uma distância de 3 cm, que possuem uma relação direta com a formulação do exemplo 1 e o peculiar sistema de spray usado. O resultado é expresso em porcentagem de gotículas que tem um certo tamanho expresso em micras. Assim, escolhem-se, por exemplo: REPLACEMENT SHEETS (RULE 26) [047] This test was performed on 10 vials of the composition manufactured according to example 1; each one of them was initially activated 1 time and the measurement called START was performed on the spray launched; then the bottle was activated without interruption until reaching the final content, where the final pump was carried out, whose spray released was measured again, called FIM. The laser beam diffractor performed the reading of the droplet size distribution results at a distance of 3 cm, which have a direct relationship with the formulation of example 1 and the peculiar spray system used. The result is expressed as a percentage of droplets that have a certain size expressed in microns. So, for example, choose:
[048] DV (10): indica que 10 % em volume das gotículas tem um tamanho igual ou inferior ao informado no resultado, em micras. [048] DV (10): indicates that 10% by volume of the droplets has a size equal to or smaller than that reported in the result, in microns.
[049] DV (50): indica que 50 % em volume das gotículas tem um tamanho igual ou inferior ao informado no resultado, em micras. Esse número é normalmente denominado como o Tamanho Médio das Gotículas no Spray todo. [049] DV (50): indicates that 50% by volume of the droplets has a size equal to or smaller than that reported in the result, in microns. This number is commonly referred to as the Average Droplet Size in the entire Spray.
[050] DV (90): indica que 90 % em volume das gotículas tem um tamanho menor ou igual ao informado no resultado, em micras. [050] DV (90): indicates that 90% by volume of the droplets have a size smaller than or equal to that reported in the result, in microns.
[051] Observou-se nos dados individuais das atuações, tanto para Início, quanto para Fim, que sempre, invariavelmente, 100 % das gotículas apresentaram tamanho maior que 10 micras, devido a relação entre formulação (Viscosidade, Densidade) e o peculiar Sistema de aplicação escolhido. [051] It was observed in the individual data of the actions, both for Start and for End, that always, invariably, 100% of the droplets had a size greater than 10 microns, due to the relationship between formulation (Viscosity, Density) and the peculiar System of chosen application.
[052] Span é uma medida de relação ou de tendência entre grupos das maiores e menores gotículas pela média central, ou seja, SPAN = (Dv 90 - Dv 10)/Dv 50, uma medida adimensional que indica tendência para Dv 90 ou Dv 10 em relação a Dv 50. Assim, caso Span = 1 indica que a diferença entre Dv 90 e Dv 10 é igual a Dv 50, o que significa que a curva de Gauss é simétrica e não existe tendência de resultados maiores que Dv 90 ou menores que Dv 10; caso Span > 1 indica tendência de resultados serem maiores que Dv 90, e caso Span < 1 indica tendência de resultados serem menores que Dv 10. [052] Span is a measure of the relationship or trend between groups of the largest and smallest droplets by the central mean, that is, SPAN = (Dv 90 - Dv 10)/Dv 50, a dimensionless measure that indicates a trend towards Dv 90 or Dv 10 in relation to Dv 50. Thus, if Span = 1, it indicates that the difference between Dv 90 and Dv 10 is equal to Dv 50, which means that the Gauss curve is symmetrical and there is no tendency for results greater than Dv 90 or less than Dv 10; if Span > 1 indicates a tendency for results to be greater than Dv 90, and if Span < 1 indicates a tendency for results to be less than Dv 10.
[053] É muito importante notar que Dv (10) e Dv (90) em conjunto, delimitam os limites inferior e superior de tamanho de gotículas compreendido por 80% da distribuição centrado na média Dv (50) com 40% para cada lado; os 20% restantes da distribuição estão, 10% abaixo do valor Dv (10), e 10 % acima do valor
Dv (90). Com relação aos 10% que estão abaixo de Dv (10), como mencionado anteriormente, olhando a distribuição individual de cada frasco facilmente compreende-se que, em todos os casos, não existe tamanho de gotícula igual ou inferior a 10 micras. [053] It is very important to note that Dv (10) and Dv (90) together delimit the lower and upper limits of droplet size comprising 80% of the distribution centered on the mean Dv (50) with 40% for each side; the remaining 20% of the distribution is, 10% below the Dv value (10), and 10% above the value Dv (90). Regarding the 10% that are below Dv (10), as mentioned before, looking at the individual distribution of each vial, it is easy to understand that, in all cases, there is no droplet size equal to or less than 10 microns.
[054] Para esse ensaio, os valores individuais de Dv foram agrupados em Médias correspondentes obtidas a seguir: Distribuição de Gotículas por difração Laser a 3 cm de distância: [054] For this test, the individual Dv values were grouped into corresponding Averages obtained below: Droplet Distribution by Laser Diffraction at 3 cm distance:
[055] Média Dv (10) INÍCIO = 91 ,20 MICRAS; CV (%) = 10,80 [055] Average Dv (10) START = 91.20 MICRAS; CV (%) = 10.80
[056] Média Dv (10) FIM = 97,50 MICRAS; CV (%) = 9,91[056] Average Dv (10) END = 97.50 MICRAS; CV (%) = 9.91
[057] Como a diferença entre Início e Fim é menor que o CV, então não há diferença significativa entre o valor de Dv (10) no Início com relação ao Fim. [057] As the difference between Start and End is smaller than the CV, then there is no significant difference between the value of Dv(10) at Start with respect to End.
[058] A média entre INÍCIO e FIM Dv (10) = (91 ,20 + 97,50) 12 94,35 micras, significando que 10% das gotículas são iguais ou menores que 94,35 micras, porém todas as medidas desses 10% tem um tamanho superior a 10 micras. [058] The average between START and END Dv (10) = (91.20 + 97.50) 12 94.35 microns, meaning that 10% of the droplets are equal to or smaller than 94.35 microns, but all measurements of these 10% are larger than 10 microns.
[059] Média Dv (50) INÍCIO = 213,75 MICRAS; CV (%) = 8,22 [059] Average Dv (50) START = 213.75 MICRAS; CV (%) = 8.22
[060] Média Dv (50) FIM = 222,35 MICRAS; CV (%) = 8,32[060] Average Dv (50) END = 222.35 MICRAS; CV (%) = 8.32
[061 ] Como a diferença entre Início e Fim é menor que o CV, então não há diferença significativa entre o valor de Dv (50) no Início com relação ao Fim. [061 ] As the difference between Start and End is less than the CV, then there is no significant difference between the value of Dv(50) at Start versus End.
[062] A média entre INÍCIO e FIM Dv (50) = (213,75 +222,35) /2 = 218,05 micras, significando que 50% das gotículas são iguais ou menores que 218,05 micras. [062] The average between START and END Dv (50) = (213.75 +222.35) /2 = 218.05 microns, meaning that 50% of the droplets are equal to or smaller than 218.05 microns.
[063] Média Dv (90) INÍCIO = 499,01 MICRAS; CV (%) = 8,43 [063] Average Dv (90) START = 499.01 MICRAS; CV (%) = 8.43
[064] Média Dv (90) FIM = 504,82 MICRAS; CV (%) = 8,63[064] Mean Dv (90) END = 504.82 MICRAS; CV (%) = 8.63
[065] Como a diferença entre Início e Fim é menor que o CV, então não há diferença significativa entre o valor de Dv (90) no Início com relação ao Fim. [065] As the difference between Start and End is smaller than the CV, then there is no significant difference between the value of Dv(90) at Start with respect to End.
[066] A média entre INÍCIO e FIM Dv (90) = (499,01 +504,82) 12 501 ,92 micras, significando que 90% das gotículas são iguais ou menores que 501 ,92 micras. [066] The average between START and END Dv (90) = (499.01 +504.82) 12 501 .92 microns, meaning that 90% of the droplets are equal to or smaller than 501 .92 microns.
[067] O Span da distribuição de tamanhos de gotículas foi Span Inicial = 1 ,910 e Span do Fim = 1 ,832. [067] The Span of the droplet size distribution was Start Span = 1.910 and End Span = 1.832.
[068] Conclui-se assim que a distribuição a 3 cm está mais voltada para gotículas maiores que 218,05 micras, com 80 % das gotículas na faixa 94,35
- 501 ,92 micras e 100% das gotículas maiores que 10 micras. A distribuição é de tipo Gaussiana. Os resultados individuais encontram-se na Fig. 4. [068] It is concluded that the distribution at 3 cm is more focused on droplets larger than 218.05 microns, with 80% of the droplets in the range 94.35 - 501 .92 microns and 100% of droplets larger than 10 microns. The distribution is Gaussian type. The individual results are shown in Fig. 4.
Ensaio de distribuição de tamanhos de gotículas por difração a laser medido a uma distância de 6 cm desde o bico ao plano de medição Droplet size distribution assay by laser diffraction measured at a distance of 6 cm from the nozzle to the measurement plane
[069] Esse ensaio foi realizado em 10 frascos da composição fabricados de acordo com o exemplo 1 , da mesma forma que explicado no Ensaio acima, mas a uma distância maior, a 6 cm desde o bico aplicador até o plano de medição por difração a Laser. Nesse caso, os resultados foram os seguintes - Distribuição de Gotículas por difração Laser a 6 cm de distância: [069] This test was performed on 10 vials of the composition manufactured according to example 1, in the same way as explained in the above Test, but at a greater distance, 6 cm from the applicator nozzle to the measurement plane by diffraction at Laser. In this case, the results were as follows - Droplet Distribution by Laser Diffraction at 6 cm distance:
[070] Média Dv (10) INÍCIO = 50,65 MICRAS; CV (%) = 13,87 [070] Average Dv (10) START = 50.65 MICRAS; CV (%) = 13.87
[071] Média Dv (10) FIM = 41 ,52 MICRAS; CV (%) = 6,37[071] Mean Dv (10) END = 41.52 MICRAS; CV (%) = 6.37
[072] Como a diferença entre Início e Fim é maior que o CV, então há diferença significativa entre o valor de Dv (10) no Início em relação ao Fim. [072] As the difference between Start and End is greater than the CV, then there is a significant difference between the value of Dv (10) at Start compared to End.
[073] A média entre INÍCIO e FIM Dv (10) = (50,65 + 41 ,52) 12 = 46,08 micras, significando que 10% das gotículas são iguais ou menores que 46,08 micras, porém todo esse 10% tem um tamanho superior a 10 micras. [073] The average between START and END Dv (10) = (50.65 + 41.52) 12 = 46.08 microns, meaning that 10% of the droplets are equal to or smaller than 46.08 microns, but all this 10 % is larger than 10 microns.
[074] Média Dv (50) INÍCIO = 139,87 MICRAS; CV (%) = 9,74 [074] Average Dv (50) START = 139.87 MICRAS; CV (%) = 9.74
[075] Média Dv (50) FIM = 122,25 MICRAS; CV (%) = 3,55[075] Average Dv (50) END = 122.25 MICRAS; CV (%) = 3.55
[076] Como a diferença entre Início e Fim é maior que o CV, então há diferença significativa entre o valor de Dv (50) no Início com relação ao Fim. [076] As the difference between Start and End is greater than the CV, then there is a significant difference between the value of Dv (50) at Start compared to End.
[077] A média entre INÍCIO e FIM Dv (50) = (139,87 + 122,25) 12 = 131 ,06 micras, o que significa que 50% das gotículas são iguais ou menores que 131 ,06 micras. [077] The average between START and END Dv (50) = (139.87 + 122.25) 12 = 131.06 microns, which means that 50% of the droplets are equal to or smaller than 131.06 microns.
[078] Média Dv (90) INÍCIO = 291 ,46 MICRAS; CV (%) = 11 ,08[078] Mean Dv (90) START = 291.46 MICRAS; CV (%) = 11.08
[079] Média Dv (90) FIM: 266,58 MICRAS; CV (%) = 8,43[079] Average Dv (90) END: 266.58 MICRAS; CV (%) = 8.43
[080] Como a diferença entre Início e Fim é maior que o CV, então há diferença significativa entre o valor de Dv (90) no Início com relação ao Fim. [080] As the difference between Start and End is greater than the CV, then there is a significant difference between the value of Dv (90) at Start with respect to End.
[081] A média entre INÍCIO e FIM Dv (90) = (291 ,45 +266,58) 12 = 279,05 micras, o que significa que 90% das gotículas são iguais ou menores que 279,05 micras. [081] The average between START and END Dv (90) = (291.45 +266.58) 12 = 279.05 microns, which means that 90% of the droplets are equal to or smaller than 279.05 microns.
[082] O Span da distribuição de tamanhos de gotículas foi Span Inicial = 1 ,721 e Span do Fim = 1 ,840 [082] The Span of the droplet size distribution was Start Span = 1,721 and End Span = 1,840
FOLHAS DE SUBSTITUIÇÃO (REGRA 26)
[083] Conclui-se assim que a distribuição a 6 cm está mais voltada para gotículas maiores que 131 ,06 micras, com 80 % das gotículas na faixa 46,08 - 279,05 micras e 100 % das gotículas maiores que 10 micras. A distribuição é de tipo Gaussiana. [084] Como esperado, devido ao dobro de distância comparada com o caso de 3 cm, as médias de DV na distribuição de 6 cm diminuem quase que proporcionalmente pela metade, causando assim filtração de gotículas maiores e mais densas que não conseguem atingir o plano a 6 cm. Os resultados individuais encontram-se na Fig. 5. Análise de padrão de spray pluma REPLACEMENT SHEETS (RULE 26) [083] It is concluded that the distribution at 6 cm is more focused on droplets larger than 131.06 microns, with 80% of the droplets in the range 46.08 - 279.05 microns and 100% of the droplets larger than 10 microns. The distribution is Gaussian type. [084] As expected, due to the double distance compared to the 3 cm case, the DV averages in the 6 cm distribution decrease almost proportionately by half, thus causing filtration of larger and denser droplets that fail to reach the plane. to 6 cm. The individual results are shown in Fig. 5. Feather spray pattern analysis
[085] Esse ensaio foi realizado a uma distância de 3 e 6 cm utilizando em cada caso 2 frascos com 2 repetições cada um. Em ambas distâncias o Padrão Spray Pluma obtido seguiu o mesmo formato elíptico com Diâmetro Máximo (Dmax) e Diâmetro Mínimo (Dmin) similares formando assim o mesmo cone de spray em ambas distâncias. Logicamente isso foi só possível pela correta relação entre a Formulação e o peculiar Sistema Spray utilizado para a aplicação. [085] This test was carried out at a distance of 3 and 6 cm using in each case 2 flasks with 2 repetitions each. At both distances, the Spray Plume Pattern obtained followed the same elliptical shape with similar Maximum Diameter (Dmax) and Minimum Diameter (Dmin) forming the same spray cone at both distances. Of course, this was only possible due to the correct relationship between the Formulation and the peculiar Spray System used for the application.
[086] Distância de 3 cm - Dmax médio = 34,38 mm; Dmin = 32,68 mm; Razão Dmax/Dmin = 1 ,05 [086] Distance of 3 cm - average Dmax = 34.38 mm; Dmin = 32.68 mm; Dmax/Dmin ratio = 1.05
[087] Distância de 6 cm - Dmax médio = 34,43 mm; Dmin = 31 ,50 mm; Razão Dmax/Dmin = 1 ,09 [087] Distance of 6 cm - average Dmax = 34.43 mm; Dmin = 31.50 mm; Dmax/Dmin ratio = 1.09
[088] Ambas razões estão na faixa pretendida como Padrão de Spray Pluma, que varia de 1 ,00 a 1 ,12. Os resultados individuais encontram-se na Fig. 6. [088] Both ratios are in the range intended as the Plume Spray Standard, which ranges from 1.00 to 1.12. The individual results are shown in Fig. 6.
FOLHAS DE SUBSTITUIÇÃO (REGRA 26)
REPLACEMENT SHEETS (RULE 26)
Claims
1 . Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal CARACTERIZADA POR possuir viscosidade, densidade e adjuvantes que proporcionam padrão spray pluma constante e distribuição de tamanho de gotículas de tipo Gaussiana de tamanho superior a 10 micras. 1 . Pharmaceutical composition of aqueous Sodium Hyaluronate in the form of a nasal spray CHARACTERIZED BY having viscosity, density and adjuvants that provide a constant spray plume pattern and a Gaussian-type droplet size distribution greater than 10 microns.
2. Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo a Reivindicação 1 CARACTERIZADA POR dita composição apresentar, quando administrada com aplicador Spray de vazão de 0,056 mL/ acionamento e volume de líquido por frasco de 32,000 mL, um padrão spray constante tipo pluma de forma Elíptica com Razão Diâmetro máximo/Diâmetro mínimo de 1 ,00 cm a 1 ,12 cm a 3 cm e 6 cm de distância com 100% das Gotículas maiores que 10 micras. 2. Pharmaceutical composition of aqueous Sodium Hyaluronate in the form of a nasal spray according to Claim 1 CHARACTERIZED BY said composition having, when administered with a Spray applicator, a flow rate of 0.056 mL/activation and a volume of liquid per bottle of 32,000 mL, a spray pattern constant plume of Elliptical shape with Maximum Diameter/Minimum Diameter Ratio of 1.00 cm to 1.12 cm to 3 cm and 6 cm distance with 100% of the droplets greater than 10 microns.
3. Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a Reivindicação 1 CARACTERIZADO POR dita composição possuir uma combinação de Hialuronato de Sódio de peso molecular médio e alto. 3. Pharmaceutical composition of aqueous Sodium Hyaluronate in the form of a nasal spray according to Claim 1 CHARACTERIZING IN THAT said composition has a combination of Sodium Hyaluronate of medium and high molecular weight.
4. Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a Reivindicação 2 CARACTERIZADO POR dita composição possuir uma concentração de Hialuronato de Sódio superior a 0,005% peso/volume. 4. Pharmaceutical composition of aqueous Sodium Hyaluronate in the form of a nasal spray according to Claim 2 CHARACTERIZED IN THAT said composition has a concentration of Sodium Hyaluronate greater than 0.005% weight/volume.
5. Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a Reivindicação 2 CARACTERIZADO POR dita composição possuir uma combinação de Hialuronato de Sódio de peso molecular médio, variando de 50.000 Daltons a 800.000 Daltons e Hialuronato de Sódio de peso molecular alto, variando de 1.000.000 Daltons a 2.000.000 Daltons. 5. Pharmaceutical composition of aqueous Sodium Hyaluronate in the form of a nasal spray according to Claim 2 CHARACTERIZED IN THAT said composition has a combination of Sodium Hyaluronate of average molecular weight, ranging from 50,000 Daltons to 800,000 Daltons and Sodium Hyaluronate of molecular weight high, ranging from 1,000,000 Daltons to 2,000,000 Daltons.
6. Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a Reivindicação 1 CARACTERIZADO POR dita composição possuir como adjuvante Dexpantenol na concentração de 1 ,000% peso/volume. 6. Pharmaceutical composition of aqueous Sodium Hyaluronate in the form of a nasal spray according to Claim 1 CHARACTERIZED IN THAT said composition has Dexpanthenol as an adjuvant at a concentration of 1,000% weight/volume.
7. Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a Reivindicação 1 CARACTERIZADO POR dita composição possuir como adjuvante regulador de pH Fosfato monobásico de sódio e Fosfato dibásico de sódio.
7. Pharmaceutical composition of aqueous Sodium Hyaluronate in the form of a nasal spray according to Claim 1 CHARACTERIZED IN THAT said composition has Monobasic Sodium Phosphate and Dibasic Sodium Phosphate as a pH-regulating adjuvant.
8. Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a Reivindicação 6 CARACTERIZADO POR dita composição possuir como adjuvante regulador de pH Fosfato monobásico de sódio na concentração de 0,900% peso/volume. 8. Pharmaceutical composition of aqueous Sodium Hyaluronate in the form of a nasal spray according to Claim 6 CHARACTERIZED IN THAT said composition has as a pH-regulating adjuvant Monobasic sodium phosphate at a concentration of 0.900% weight/volume.
9. Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a Reivindicação 6 CARACTERIZADO POR dita composição possuir como adjuvante regulador de pH Fosfato dibásico de sódio na concentração de 1 ,065% peso/volume. 9. Pharmaceutical composition of aqueous Sodium Hyaluronate in the form of a nasal spray according to Claim 6 CHARACTERIZED IN THAT said composition has dibasic sodium phosphate as a pH-regulating adjuvant at a concentration of 1.065% weight/volume.
10. Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a Reivindicação 1 CARACTERIZADO POR dita composição possuir viscosidade Brookfield a 25°C, Spindle 1 , 100 rpm entre 4,0 - 5,0 cps. 10. Pharmaceutical composition of aqueous Sodium Hyaluronate in nasal spray form according to Claim 1 CHARACTERIZED IN THAT said composition has Brookfield viscosity at 25°C, Spindle 1, 100 rpm between 4.0 - 5.0 cps.
11 . Composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a Reivindicação 1 CARACTERIZADO POR dita composição possuir densidade entre 1 ,015 a 1 ,025 g/ml a 25°C. 11 . Pharmaceutical composition of aqueous Sodium Hyaluronate in the form of a nasal spray according to Claim 1 CHARACTERIZED IN THAT said composition has a density between 1.015 to 1.025 g/ml at 25°C.
12. Método de fabricação de composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal CARACTERIZADO POR compreender as etapas de: a. Misturar a frio, com agitação a 300 rpm, água purificada e Dexpantenol até completa dissolução; b. Misturar a frio, com agitação a 300 rpm, o item anterior com Fosfato dibásico de sódio anidro, Fosfato monobásico de sódio anidro, EDTA dissódico, Cloreto de Benzalcônio até completa dissolução; c. Misturar a frio, com agitação a 300 rpm, o item anterior com Hialuronato de Sódio até total dissolução; d. Acertar o pH para 7,2 com solução saturada de NaOH; e. Acertar a volume total com água purificada; f. Filtrar utilizando filtro esterilizante de 0,22 micras; g. Fracionar o produto estéril em frascos spray. 12. Method of manufacturing aqueous Sodium Hyaluronate pharmaceutical composition in nasal spray form CHARACTERIZED BY comprising the steps of: a. Cold mix, with stirring at 300 rpm, purified water and Dexpanthenol until complete dissolution; B. Cold mix, with stirring at 300 rpm, the previous item with Dibasic Anhydrous Sodium Phosphate, Monobasic Anhydrous Sodium Phosphate, Disodium EDTA, Benzalkonium Chloride until complete dissolution; ç. Cold mix, with stirring at 300 rpm, the previous item with Sodium Hyaluronate until total dissolution; d. Adjust the pH to 7.2 with saturated NaOH solution; and. Make up to full volume with purified water; f. Filter using 0.22 micron sterilizing filter; g. Fraction the sterile product into spray bottles.
13. Método de fabricação de composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a
Reivindicação 11 CARACTERIZADO POR dito frasco spray possuir volume de líquido por frasco de 32,000 mL. 13. Method of manufacturing aqueous Sodium Hyaluronate pharmaceutical composition in nasal spray form according to Claim 11 CHARACTERIZED BY said spray bottle having a volume of liquid per bottle of 32,000 mL.
14. Método de fabricação de composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal de acordo com a Reivindicação 11 CARACTERIZADO POR dito frasco spray possuir vazão do bico spray no frasco de 0,056 mL/ acionamento. 14. Method of manufacturing an aqueous Sodium Hyaluronate pharmaceutical composition in the form of a nasal spray according to Claim 11 CHARACTERIZED IN THAT said spray bottle has a flow rate of the spray nozzle in the bottle of 0.056 ml/activation.
15. Uso de composição farmacêutica de Hialuronato de Sódio aquosa em forma de spray nasal CARACTERIZADO POR ser para o tratamento da secura nasal, umectação continua das narinas e alivio de congestão nasal.
15. Use of pharmaceutical composition of aqueous Sodium Hyaluronate in nasal spray form CHARACTERIZED IN BEING for the treatment of nasal dryness, continuous wetting of the nostrils and relief of nasal congestion.
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