• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Nanostructured lipid gel, preparation and use procedure. The object of the invention is a nanostructured lipid gel formed by interleaving of sheets and vesicles and composed of phospholipids, fatty acids and a high water content. Its structure and fluidity respond reversibly to temperature and pH and are capable of transporting at least one active ingredient inside the skin and also to the follicle. Its exclusively lipid composition guarantees high biocompatibility and its rheological behavior makes them easily applicable topically and ocularly. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2754476A1
    申请号:ES201830989
    申请日:2018-10-15
    公开日:2020-04-17
    发明作者:Dominguez Kirian Tallo；Serrano Olga Lopez；Del Moral Veronica Moner
    申请人:Consejo Superior de Investigaciones Cientificas CSIC；
    IPC主号:
    专利说明:

    [0001] Nanostructured lipid gel, PREPARATION AND USE PROCEDURE
    [0002]
    [0003] TECHNICAL SECTOR AND OBJECT OF THE INVENTION
    [0004]
    [0005] The present invention is framed in the field of topical and ocular formulations with potential biomedical applications.
    [0006]
    [0007] The object of the invention is a nanostructured lipid gel formed by intercalating sheets and vesicles and composed of phospholipids, fatty acids and a high water content. Its structure and fluidity respond reversibly to temperature and pH and are capable of transporting at least one hydrophilic substance within the skin and also to the follicle. Their particular organization, with part of the water trapped in vesicles and these vesicles trapped or sandwiched between extended sheets, makes them very suitable as systems to incorporate molecules of different polar nature in different compartments. Its exclusively lipid composition guarantees high biocompatibility and its rheological behavior makes it easily applicable topically and ocularly.
    [0008]
    [0009] Another object of the present invention is the procedure for preparing said gels and their use in topical and ocular applications.
    [0010]
    [0011] STATE OF THE ART
    [0012]
    [0013] Dense lipid emulsion / gel type systems usually form only at high lipid concentrations (> 50%) generating high packaging phases such as cubic or lamellar [L. Rydhag, I. Wilton, The function of phospholipids of soybean lecithin in emulsions, J. Am. Oil Chem. Soc. 58 (1981) 830-837].
    [0014]
    [0015] The more dilute systems require other compounds such as surfactants, gelling agents or polymers to achieve gelation [HE Warriner, SHJ Idziak, NL Slack, P. Davidson, CR Safinya, Lamellar Biogels: Fluid-Membrane-Based Hydmgels Containing Polymer Lipids , Science 271 (1996) p. 969-973] [US6207186].
    [0016]
    [0017] These compounds detract from the biocompatibility of the systems and can cause adverse sensitizations and responses in biomedical applications.
    [0018] Other documents of interest and reflecting the state of the art are:
    [0019] WO2006 / 122638, which refers to hyaluronic acid or derivatives thereof structured in liposomes for the repair of skin and soft tissue defects.
    [0020]
    [0021] The use of fatty acids in the composition of the lipid phase and the proportion of water are not mentioned in this document.
    [0022]
    [0023] ES2423760 describes a process for the manufacture of a base cosmetic composition that includes liposomes with a particle size of 250-600 nm in an aqueous gel with a viscosity in the range of 4,000 to 20,000 mPas, including in its aqueous volume three or four liposomes containing respectively at least one active substance in their aqueous volume, where the active substances contained in the included liposomes are different from each other and the included liposomes have a particle size in the range of 50-200 nm . The three or four liposomes are introduced by stirring in water and then a liposome-forming agent, a gelling agent and a neutralizing product are introduced into the mixture of water and liposomes. As liposome-forming agents there are mentioned, among others, lecithin and phosphatidylcholine, but the presence of fatty acids is not mentioned.
    [0024]
    [0025] Document W02006 / 002050 presents an injectable non-liposomal composition for use as a tissue filler in the form of a gel or paste comprising a phospholipid component in a range between 10% and 90% with respect to the total weight of the composition. No reference is made to the presence of a fatty acid in the lipid composition that is present in a range of 10% to 90%.
    [0026]
    [0027] In EP2210589 the object of the invention is a pharmaceutical composition for the controlled release of an active compound, which comprises a vesicular phospholipid gel with packaged liposomes. The percentage of phospholipid in the composition is at least 30% and the presence of any fatty acid is not related.
    [0028]
    [0029] Liposomes containing cosmetic or dermopharmaceutical active ingredients and adjuvants linked to cationic polymers are claimed in W02011 / 101153. Whatever phospholipid is in the liposome composition, there is always the presence of a polymer.
    [0030] The article by Talló, K; López, O. et al. Vesicular nanostructures composed of oleica cid and phosphatidylcholine: Effect of pH and molar ratio ; Chemistry and Physics of Lipids 213 (2018) 96-101 refers to nanostructured systems consisting of hydrogenated soybean phosphatidylcholine and oleic acid. The alkaline media and the high proportions of oleic acid were observed to increase the fluidity of the membranes. The product obtained is a liquid dispersion. In this article, the term "gel" refers to the gel phase, also known as the crystalline or solid phase of lipid membranes. This does not mean that the system behaves macroscopically as a gel, but that at the molecular level the hydrocarbon chains are they are packaged giving greater rigidity to the membranes that form the systems.
    [0031]
    [0032] BRIEF EXPLANATION OF THE INVENTION
    [0033]
    [0034] The object of the present invention is a nanostructured lipid gel formed by intercalating sheets and vesicles.
    [0035]
    [0036] In the context of the present invention, the term "nanostructured gel" should be understood as referring to materials with gel-like rheological behavior that are organized with at least one dimension below 100 nm. It has been observed that they are also organized on the scale In other words, they are organized both on the nano and on the microscale.
    [0037]
    [0038] Unlike most of the known methods reflected in the discussion of the state of the art, in the present invention the nanostructured gel can be formed with a low lipid content, the intervention of polymers or surfactants not being necessary to promote dispersion.
    [0039]
    [0040] The first aspect of the present invention is a nanostructured lipid gel formed by intercalating sheets and vesicles, characterized in that it comprises:
    [0041]
    [0042] - Between 3% and 30% lipid concentration formed by a mixture of phospholipids and fatty acids in a molar ratio between 5: 1 and 1: 1 without the presence of polymers or surfactants
    [0043] - between 70% and 97% of water.
    [0044] In a preferred embodiment, the lipid gel has:
    [0045] - a lipid concentration between 3% and 10%
    [0046] - a molar ratio between phospholipids and fatty acids between 3: 1 and 1: 1
    [0047] - a water content of between 90% and 97%.
    [0048]
    [0049] The phospholipid is selected, among others, from phosphatidylcholines, phosphatidylserines, phosphatidylglycerol, phosphatidylinositol and phosphatidylethanolamines, preferably being hydrogenated soybean phosphatidylcholine.
    [0050]
    [0051] Fatty acid is a chain length fatty acid between 10 and 24 C atoms, saturated or unsaturated with one or more double bonds; Fatty acid is preferably selected from palmitic, stearic, oleic, linoleic, lignoceric, icosapentaenoic (EPA) or docosahexaenoic (DHA). Oleic acid is that used in preferred embodiments.
    [0052]
    [0053] For use in cutaneous or ocular application systems, the lipid gel incorporates an active ingredient that is selected from a hydrophilic compound or a lipophilic compound.
    [0054]
    [0055] Some active ingredient options are:
    [0056] - sphingolipids
    [0057] - cholesterol
    [0058] - antioxidants
    [0059] antibiotics
    [0060] - anti-inflammatory
    [0061] - proteins
    [0062]
    [0063] To check that molecules of different nature are well incorporated into the system and to be able to monitor them inside the skin, compounds such as fluorescein sodium or a lipophilic conjugate of rhodamine are used.
    [0064]
    [0065] A second aspect of the present invention constitutes a method of preparing a nanostructured lipid gel as defined above, comprising the steps of:
    [0066]
    [0067] - dispersion of the mixture of lipid components in water without the intervention of polymers or surfactants
    [0068] - gel formation from the lipid dispersion obtained in the previous step
    [0069]
    [0070] The procedure is carried out without the intervention of polymers or surfactants, the formation of the gel comprising the following sub-stages:
    [0071]
    [0072] - adjusting the pH of the lipid dispersion between 5 and 8 with a basic compound.
    [0073] - freezing of the dispersion with pH adjusted to a temperature equal to or below -20 ° C for a period of time of at least 1 minute.
    [0074] thawing and heating the dispersion to a temperature between 5 and 90 ° C.
    [0075] - cooling to room temperature of the gelled dispersion from the previous stage.
    [0076]
    [0077] In a preferred embodiment, the dispersion of the mixture is carried out by mixing the lipid components at the specified concentrations and molar ratios in an organic solvent, particularly chloroform. Depending on the lipids used, other solvents such as ethanol, methanol or mixtures thereof may be required. Subsequently, the solvent is evaporated on a rotary evaporator followed by drying and subsequent hydration by adding the water in the specified concentration range under stirring conditions and at room temperature. As for adjusting the pH of the lipid dispersion, it can be done with a sodium hydroxide solution.
    [0078]
    [0079] Finally, a third aspect of the invention is the use of a nanostructured lipid gel as defined above in cutaneous, mucous or ocular application systems.
    [0080]
    [0081] BRIEF DESCRIPTION OF THE FIGURES
    [0082]
    [0083] Figure 1: oscillatory test as a function of frequency to confirm the rheological behavior of the material as a gel and comparison with the lipid dispersion of the article by Talló K. et al. (2018).
    [0084]
    [0085] Figure 2: images of transmission electron cryomicroscopy (cryo-TEM) showing the lamellar and vesicular structure of the gels.
    [0086] Figure 3: A) Small angle X-ray scattering profile (SAXS)
    [0087] B) lamellar structure
    [0088]
    [0089] Figure 4: A) Large angle X-ray scattering profile (WAXS)
    [0090] B) hexagonal packing
    [0091]
    [0092] Figure 5: section of skin showing retention of the lipid system (red) and marking of the epidermis (blue).
    [0093]
    [0094] Figure 6: section of skin with a follicle (white arrow) where the permeation of fluorescence (green) and the marking of the epidermis (blue) can be seen.
    [0095]
    [0096] DETAILED DESCRIPTION AND MODE OF CARRYING OUT THE INVENTION
    [0097]
    [0098] The main novel feature of the lipid gels object of the present invention is that a mixture formed solely of lipids, without the intervention of polymers or surfactants, and that contains a very high water content, up to 97%, is capable of being structured as a gel. As indicated in the discussion of the state of the art, dense emulsion / gel type systems consisting solely of lipids usually form at high lipid concentrations (> 50%) generating high packaging phases such as cubic or lamellar, while the More dilute systems require other compounds such as surfactants, gelling agents or polymers to achieve a gel-like rheological behavior.
    [0099]
    [0100] Once formed, the gel maintains a semi-rigid structure and shows a translucent white color at room temperature, while it becomes fluid and transparent from a certain temperature that varies depending on the lipid composition of the system and can be from 5 ° C. It should be noted that this process is reversible and the gel structure recovers once cooled below that variable temperature depending on the lipid composition of the system.
    [0101]
    [0102] Composition
    [0103]
    [0104] The phospholipids most used to prepare the systems are part of the group of phosphatidylcholines and are a commercial product obtained from soy lecithin known in English as "hydrogenated soy phosphatidylcholine (HSPC)".
    [0105] To form the gel, the HSPC is mixed with the oleic acid (AO) in a molar ratio of 3: 1 and the pH is adjusted between 5 - 8 by means of sodium hydroxide. This pH range is a determining factor for the correct formation of the gel. The total lipid concentration by weight (HSPC AO) has been established as optimal at 5% since highly diluted systems (<3%) do not form, while more concentrated systems (> 10%) are difficult to disperse with conventional methods. .
    [0106]
    [0107] For the formation of the gels, a freezing process of the lipid dispersion is necessary, followed by a heating process.
    [0108]
    [0109] With other phospholipids with different characteristics to HSPC, particularly different polar heads and different alkyl chains, and with other fatty acids other than oleic acid, the results obtained are equivalent, although the formation and reversibility conditions vary depending on physical-chemical parameters of lipids. The molar ratio between the lipids present in the mixture can vary with similar results. Although the lipid concentration with which most of our results have been obtained has been 5%, higher concentrations also give rise to the formation of these gels.
    [0110]
    [0111] Characterization
    [0112]
    [0113] Rheology
    [0114] The main objective of this technique is to determine if the obtained samples behaved rheologically like a gel.
    [0115]
    [0116] Initially, an amplitude oscillatory test ("Strain Sweep") was carried out, where the linear viscoelasticity zone (LVR) was determined in order to work with reliable parameters. Subsequently, an oscillatory test was performed as a function of frequency ("Frequency Sweep" ) to evaluate the viscous and elastic properties of the material.
    [0117]
    [0118] As mentioned in the discussion of the state of the art, in the article by Talló, K; López, O. et al. Vesicular nanostructures composed of oleica cid and phosphatidylcholine: Effect of pH and molar ratio ; Chemistry and Physics of Lipids 213 (2018) 96-101 presents an aqueous dispersion of vesicles that at the macroscopic level behaves like a viscous liquid. This system clearly differs rheologically and structurally from the nanostructured lipid gel of the present invention. Although they both have the same chemical components, the method of preparation allows the system described in the present application to be structured as a gel and not as a simple dispersion. At first glance it can be seen how the gel maintains a rigid structure while the aqueous dispersion of vesicles flows into its container. In order to show that these are different products, with a different rheological behavior, an oscillatory test was carried out on both systems with the same conditions of pH, concentration and temperature (Figure 1).
    [0119]
    [0120] As can be seen in Figure 1, the gel (invention) and the lipid dispersion (prepared with the protocol described in Talló et al. 2018) show very different rheological behavior. The values of the elastic modulus (G ’) and the viscous modulus (G’ ’) of the gel exceed by two orders of magnitude the values of G’ and G ’’ of the vesicle dispersion described in the article. This means that the lipid gel object of the present invention is much more structured at the microscopic level, giving greater consistency and rigidity to the product. It is also seen how the G ’value of the gel is clearly higher than the G’ ’which indicates that the elastic (solid) behavior prevails over the viscous. On the other hand, for vesicle dispersion the values of G ’and G’ ’are almost identical, crossing at some point, indicating the viscous behavior of the dispersion is comparable to elastic.
    [0121]
    [0122] Electron microscopy
    [0123] In order to appreciate the nanoscopic structure of the gels, the samples were cryofixed following different procedures. In some cases, a fracture was forced through the sample to reveal possible lamellar or vesicular aggregates. Samples were observed by transmission electron cryomicroscopy (cryo-TEM). Figure 2 shows different images of the sample where stacks of extended flat membranes combined with unilamillary vesicles can be seen. The extension of the sheets reached microns although the thickness conforms to a lipid membrane. The vesicles are sandwiched between the sheets and exhibit sizes around 100-150 nm in diameter.
    [0124]
    [0125] Small Angle X-ray Scattering ( SAXS)
    [0126] With this technique it was determined that the gel is composed of a lamellar structure. This fact can be seen from the narrow angle X-ray scattering profile (SAXS) shown in Figure 3A. This figure shows a wide band corresponding to a repetition spacing of approximately 7 nm, calculated at from the dispersion vector q and the equation qn = 2n ^ / d, where d is the repetition distance, n the order of dispersion and q the dispersion vector. The location of the following Bragg bands at positions 3q and 4q indicate a multilayered structure that would have a spacing of 7 nm and an organization as shown in Figure 3B.
    [0127]
    [0128] Wide Angle X-ray Scattering ( WAXS)
    [0129] Using this technique, it was possible to determine the lateral packaging of the phospholipids. As shown in Figure 4A, there is only a single peak corresponding to a polar head spacing value of 4.2A, which would indicate that it is a hexagonal packing as shown in Figure 4B.
    [0130]
    [0131] Application on skin
    [0132]
    [0133] The structural consistency of a gel is a clear advantage over a liquid lipid dispersion such as that of Talló K. et al. (2018) since it facilitates the application at the topical level. This factor is evident considering that the majority of commercial products for cutaneous application are creams or gels. At the structural level, the laminar organization of lipid membranes confers greater stability to the product, while a vesicular system such as that described in Talló et al. (2018) tends to aggregate and flocculate if stabilizers are not added. Likewise, small structural differences at the microscopic level can make a big difference in the field of pharmacokinetics and drug administration.
    [0134]
    [0135] To evaluate the potential of these gels as cutaneous application systems, an "in vitro" permeation test was performed on pig skin and observations were made using fluorescence microscopy.
    [0136]
    [0137] Two gels were formed which were applied to the skin surface. In one of them the gel was formed incorporating a red fluorescent probe (rhodamine B) in order to observe in which areas of the skin the phospholipids that form the gel are retained. In the other gel, a green fluorescent probe (fluorescein) was added in the aqueous phase in order to simulate a possible water soluble active principle incorporated in the gel. The gel was gently applied to the skin and allowed to permeate overnight at 37 ° C in a humid environment. The skin was then cut into sections and the cells were marked in blue in order to distinguish the different skin layers.
    [0138] In Figure 5 it can be seen how the lipid matrix of the gel (red) is retained in the upper part of the stratum corneum (outermost layer of the skin) without reaching the epidermis (blue). Figure 6 shows how fluorescein dissolved in the aqueous phase of the gel (green) is able to permeate through the skin, covering the entire stratum corneum and the epidermis. In the same way it can be seen how it is also able to go down through the follicle, even dyeing the hair (blue arrow). It is important to mention that a control was performed with an aqueous solution with fluorescein (without incorporating the gel) and it only got to incorporate slightly in the stratum corneum. Therefore, the gel promoted the passage of this molecule (fluorescein) through the skin.
    [0139]
    [0140] These results demonstrate that the formation of gels formed by combination of phospholipids and oleic acid in water is possible, with the water content being very high (up to 97%). These gels lack the usual gelling molecules such as polymers or surfactants and their structure and fluidity respond reversibly to temperature and pH. Furthermore, they are capable of transporting at least one hydrophilic substance inside the skin and also to the follicle.
    [0141]
    [0142] Their particular organization, with part of the water trapped in vesicles and these vesicles trapped or sandwiched between extended sheets, makes them very suitable as systems to incorporate molecules of different polar nature in different compartments. Its exclusively lipid composition guarantees high biocompatibility. Their rheological behavior makes them easily applicable at the topical and ocular level and their ability to respond to biological parameters points to potential biomedical applications.
    权利要求:
    Claims (15)
    [1]
    1. - Nanostructured lipid gel formed by intercalating sheets and vesicles, characterized in that it comprises:
    - Between 3% and 30% lipid concentration formed by a mixture of phospholipids and fatty acids in a molar ratio between 5: 1 and 1: 1 without the presence of polymers or surfactants
    - between 70% and 97% of water.
    [2]
    2. - Lipid gel according to claim 1, characterized in that:
    - the lipid concentration is between 3% and 10%
    - the molar ratio between phospholipids and fatty acids is between 3: 1 and 1: 1
    - the water content is between 90% and 97%.
    [3]
    3. - Lipid gel according to claims 1 or 2, characterized in that the phospholipid is selected from phosphatidylcholines, phosphatidylserines, phosphatidylglycerol, phosphatidylinositol and phosphatidylethanolamines.
    [4]
    4. - Lipid gel according to claim 3, characterized in that the phospholipid is hydrogenated soybean phosphatidylcholine.
    [5]
    5. - Lipid gel according to any one of claims 1 to 4, characterized in that the fatty acid is a fatty acid of chain length between 10 and 24 C atoms, saturated or unsaturated with one or more double bonds.
    [6]
    6. - Lipid gel according to claim 5 characterized in that the fatty acid is selected from palmitic, stearic, oleic, linoleic, lignoceric, EPA or DHA.
    [7]
    7. - Lipid gel according to claim 6, characterized in that the fatty acid is oleic acid.
    [8]
    8. - Lipid gel according to any one of claims 1 to 7, characterized in that it incorporates an active principle that is selected from a hydrophilic compound or a lipophilic compound.
    [9]
    9. - Lipid gel according to claim 8, characterized in that the active ingredient is a sphingolipid, cholesterol, an antioxidant, an antibiotic, an anti-inflammatory, a protein or combinations thereof.
    [10]
    10. - Lipid gel according to any one of claims 1 to 9, characterized in that it incorporates sodium fluorescein.
    [11]
    11. - Lipid gel according to any one of claims 1 to 9, characterized in that it incorporates a lipophilic rhodamine conjugate.
    [12]
    12. - Procedure for preparing a nanostructured lipid gel as defined in claims 1 to 11, comprising the steps of:
    - dispersion of the mixture of lipid components in water without the intervention of polymers or surfactants
    - gel formation from the lipid dispersion obtained in the previous step, characterized in that the process is carried out without the intervention of polymers or surfactants, the gel formation comprising the following sub-stages:
    - adjustment of the pH of the lipid dispersion between 5 and 8 with a basic compound
    - freezing the dispersion with pH adjusted to a temperature equal to or less than - 20 ° C for a period of time equal to or greater than 1 minute.
    - thawing and heating the dispersion to a temperature
    between 5 ° C and 90 ° C.
    - cooling to room temperature of the gelled dispersion from the previous stage.
    [13]
    13. - Procedure for the preparation of a lipid gel according to claim 12, characterized in that the dispersion of the mixture is carried out by mixing the lipid components at the concentrations and molar ratios specified in an organic solvent and evaporation of the same in rotavapor followed by drying and subsequent hydration by adding water in the specified concentration range under stirring conditions and at room temperature.
    [14]
    14. - Procedure for the preparation of a lipid gel according to claims 12 or 13, characterized in that the organic solvent is chloroform and in that the adjustment of the pH of the lipid dispersion is carried out with a sodium hydroxide solution.
    [15]
    15. Use of a nanostructured lipid gel as defined in claims 1 to 11 in cutaneous, mucous or ocular application systems.
    类似技术:
    公开号 | 公开日 | 专利标题
    Milak et al.2015|Glycerol monooleate liquid crystalline phases used in drug delivery systems
    Chen et al.2014|Cubic and hexagonal liquid crystals as drug delivery systems
    Manca et al.2014|Development of novel diolein–niosomes for cutaneous delivery of tretinoin: Influence of formulation and in vitro assessment
    Bramer et al.2007|Pharmaceutical applications for catanionic mixtures
    US6610322B1|2003-08-26|Self forming, thermodynamically stable liposomes and their applications
    Eccleston1997|Functions of mixed emulsifiers and emulsifying waxes in dermatological lotions and creams
    Schulz et al.2011|Hybrid lipid/polymer giant unilamellar vesicles: effects of incorporated biocompatible PIB–PEO block copolymers on vesicle properties
    Johnsson et al.1999|Effect of PEO− PPO− PEO triblock copolymers on structure and stability of phosphatidylcholine liposomes
    ES2606903T3|2017-03-28|Cosmetic base comprising collagen modified liposome
    ES2211984T3|2004-07-16|PREPARED FOR THE TRANSPORTATION OF AN ACTIVE SUBSTANCE THROUGH BARRIERS.
    US20210137829A1|2021-05-13|Topical delivery systems for active compounds
    PT1545757E|2007-03-30|Perfluorocarbon emulsions with non-fluorinated surfactants
    HU198836B|1989-12-28|Composition suitable for forming liposomes
    DE112010001765T5|2012-12-27|Formulations for the treatment of tissue depth pain
    Rajak et al.2019|Liquid crystals: an approach in drug delivery
    Garcia et al.2018|Improvement of cutaneous delivery of methylene blue by liquid crystals
    ES2754476B2|2020-09-14|NANOSTRUCTURED LIPID GEL, PREPARATION AND USE PROCEDURE
    Dixit et al.2015|Microemulsions: platform for improvement of solubility and dissolution of poorly soluble drugs
    KR100654102B1|2006-12-05|Preparation of ph-responsive polymer-liposome complexes with various hydrophobic bioactive materials and the composition of skin external application containing the same
    Pathan et al.2019|Formulation and evaluation of ketoprofen loaded chitosan nanogel for pain management: Ex-vivo and In-vivo study
    Esposito et al.2013|Design and characterization of fenretinide containing organogels
    Nakagawa et al.2014|Requirement of charged lipids for the hexadecanol-induced gelation in the phospholipid bilayer system
    Ghosh et al.2015|Aggregation behavior of poly | chain-containing anionic amphiphiles: Thermodynamic, spectroscopic and microscopic studies
    Chaudhary et al.2017|Liquid Crystal Systems in Drug Delivery
    Rodríguez et al.2013|Characterization of new DOPC/DHPC platform for dermal applications
    同族专利:
    公开号 | 公开日
    WO2020079302A2|2020-04-23|
    ES2754476B2|2020-09-14|
    WO2020079302A3|2020-06-11|
    EP3868362A2|2021-08-25|
    US20210361569A1|2021-11-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2006002050A1|2004-06-15|2006-01-05|Encore Therapeutics, Inc.|Phospholipid compositions and methods for their preparation and use|
    EP2210589A1|2009-01-22|2010-07-28|Ludwig-Maximilians-Universität München|Vesicular phospholipid gels comprising proteinaceous substances|
    US5234767A|1987-03-13|1993-08-10|Micro-Pak, Inc.|Hybrid paucilamellar lipid vesicles|
    US6207186B1|1997-02-14|2001-03-27|The Regents Of The University Of California|Lamellar gels and methods for making and using|
    ITPD20050146A1|2005-05-20|2006-11-21|Fidia Farmaceutici|RE-ABSORBABLE FILLERS CONSISTING OF LIPOSOMAS AND HYALURONIC ACID AND OR ITS DERIVATIVES|
    DE102008035834A1|2008-07-31|2010-02-04|Coty Prestige Lancaster Group Gmbh|Process for the preparation of liposome complexes with different active substances and products produced therewith, in particular cosmetic products|
    IT1398268B1|2009-03-10|2013-02-22|Prigen Srl|GLYCEROSOMES AND THEIR USE IN PHARMACEUTICAL AND COSMETIC PREPARATIONS FOR TOPICAL USE|
    ES2373704B1|2010-02-18|2013-01-24|Lipotec S.A.|LIPOSOMES FOR THE TREATMENT OF TEXTILE MATERIALS.|
    US8871811B2|2011-02-07|2014-10-28|Professional Compounding Centers of America, Ltd|Permeation enhancers for topical formulations|
    法律状态:
    2020-04-17| BA2A| Patent application published|Ref document number: 2754476 Country of ref document: ES Kind code of ref document: A1 Effective date: 20200417 |
    2020-09-14| FG2A| Definitive protection|Ref document number: 2754476 Country of ref document: ES Kind code of ref document: B2 Effective date: 20200914 |
    优先权:
    申请号 | 申请日 | 专利标题
    ES201830989A|ES2754476B2|2018-10-15|2018-10-15|NANOSTRUCTURED LIPID GEL, PREPARATION AND USE PROCEDURE|ES201830989A| ES2754476B2|2018-10-15|2018-10-15|NANOSTRUCTURED LIPID GEL, PREPARATION AND USE PROCEDURE|
    PCT/ES2019/070699| WO2020079302A2|2018-10-15|2019-10-15|Nanostructured lipid gel, method for preparation and use|
    EP19839634.3A| EP3868362A2|2018-10-15|2019-10-15|Nanostructured lipid gel, method for preparation and use|
    US17/285,281| US20210361569A1|2018-10-15|2019-10-15|Nanostructured Lipid Gel, Method for Preparation and Use|
    [返回顶部]