[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2016066864A1 - Nanoparticules pour la libération contrôlée de principes actifs - Google Patents

Nanoparticules pour la libération contrôlée de principes actifs Download PDF

Info

Publication number
WO2016066864A1
WO2016066864A1 PCT/ES2014/070814 ES2014070814W WO2016066864A1 WO 2016066864 A1 WO2016066864 A1 WO 2016066864A1 ES 2014070814 W ES2014070814 W ES 2014070814W WO 2016066864 A1 WO2016066864 A1 WO 2016066864A1
Authority
WO
WIPO (PCT)
Prior art keywords
nanoparticles
chitosan
collagen
hyaluronic acid
active ingredient
Prior art date
Application number
PCT/ES2014/070814
Other languages
English (en)
Spanish (es)
Inventor
Laura CALDERÓN MUÑOZ
Ruth EXPÓSITO HARRIS
Niuris Acosta Contreras
Ángeles María HERAS CABALLERO
Original Assignee
Innovaciones Fisicas Y Quimicas Sostenibles, S.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Innovaciones Fisicas Y Quimicas Sostenibles, S.L. filed Critical Innovaciones Fisicas Y Quimicas Sostenibles, S.L.
Priority to PCT/ES2014/070814 priority Critical patent/WO2016066864A1/fr
Publication of WO2016066864A1 publication Critical patent/WO2016066864A1/fr

Links

Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes

Definitions

  • the invention relates to nanoparticles with active ingredients for the controlled release of these and their use in pharmacy and cosmetics.
  • the nanoparticles object of the present invention are manufactured from colloidal systems that allow the incorporation of active ingredients and that result in nanoparticles with the characteristics suitable for the administration of the active ingredient.
  • Vehicular systems are currently under development. In this sense, it is a priority objective to develop a transport system that allows the active ingredients to be selectively released and reduce their dose, avoiding adverse effects that occur in conventional therapies.
  • Release is defined as the process in which the active ingredient reaches the appropriate site of action at the appropriate concentration (minimum effective concentration but low enough to avoid toxicity) for the correct period of time (sufficient time to allow the ingredient active do your job).
  • the size can vary from nanometer to millimeter allowing to differentiate two groups whose vehicle possibilities are completely different. For sizes smaller than the micrometer, the insertion of the vehicle systems between the corneal cells can occur.
  • the encapsulation of active principles in nanoparticulate systems have many advantages, such as: they protect the active principle from biodegradation, control the release of the latter through the matrix in which it is encapsulated and allow it to be selectively released at the appropriate site for exercise your function
  • Document ES2226567 discloses a process for obtaining nanoparticles for the administration of an active ingredient comprising an acid salt hyaluronic and a cationic polymer of the chitosan, collagen or gelatin type.
  • the process consists of a preparation of an aqueous solution of the hyaluronic acid salt, adding it to another aqueous solution of the cationic polymer and mixing it by stirring, obtaining the nanoparticles spontaneously.
  • the active ingredient is dissolved in one of the initial solutions or in the suspension of the nanoparticles subsequently obtained, becoming absorbed by them.
  • nanoparticles are of a pharmaceutical composition for administration on mucous, topical or parenteral.
  • a system for the treatment of migraine which consists of a needle and a carrier of the drug that also controls its release over a period of more than four hours.
  • the system can come in the form of nanoparticle, colloid, suspension, emulsion, or gel among others and is composed of hyaluronic acid, collagen and / or chitosan.
  • Some of the active substances disclosed and transported in the nanoparticles are triptan, sumatriptan, almotriptan, eletriptan, rizatriptan, and zomitriptan.
  • WO2007135164 a system for the release of biologically active substances composed of nanoparticles of hyaluronic acid and chitosan is described.
  • the active molecule disclosed is of the oligonucleotide, siRNA, or polynucleotide type.
  • the estimated release time is one hour, after adding specific enzymes for the degradation of the polymers that constitute the polymer matrix.
  • EP1891943 describes nanoparticles for the release of biologically active molecules composed of at least 40% chitosan and less than 60% cyclodextrin or one of its derivatives.
  • the administration of the medication can be topically.
  • the estimated release time is approximately 5h and is released between 30-55% active ingredient.
  • a composition is described which includes each and every one of the following ingredients: at least 2 or more polyanions, among which is collagen; 1 or more polycations, among which is the low molecular weight chitosan; 1 or more cations (sodium, potassium or calcium); 1 or more proteins, among which is hyaluronic acid; and that can be made in the form of a film, microcapsules or nanoparticles.
  • certain compounds used in the vehiculization systems are capable of altering the barrier properties of the skin, thereby promoting the penetration of the encapsulated agent through the stratum corneum.
  • the particle size of these systems determines the degree of contact with the skin and, therefore, the amount of active ingredient that will reach the site of action.
  • the size can vary from nanometer to millimeter allowing to differentiate two groups whose vehicle possibilities are completely different. For sizes smaller than the micrometer, the insertion of the vehicular systems between the corneal cells can occur, characteristic of great applicability in the field of cosmetics.
  • a small particle size ensures a closer contact with the stratum corneum, so nanoparticulate systems are the most suitable for this application.
  • nanoparticulate systems encounters the viscosity of the formulation is very high thus preventing the passage of said systems through the skin.
  • the nanoparticulate system must pass through the first layer of the epidermis: The stratum corneum (lipophilic layer that constitutes the first barrier to the passage of most of the active ingredients). Once the nanoparticulate system is in that layer, it is carried by diffusion at the end of it and then diffused through the following layers that make up the epidermis and are polar.
  • the present invention relates to nanoparticles comprising a matrix of natural composition to which active ingredients can be added in a controlled manner, for application both for the manufacture of pharmaceutical formulations as cosmetics
  • the present invention relates to nanoparticles comprising chitosan, hyaluronic acid and collagen (from now on, we will refer to them as nanoparticles of the invention) and also comprise an active ingredient, which is selected from a drug, vitamins, peptides, proteins, an oxidizing agent or any combination thereof.
  • nanoparticles in the present invention those particles with a size less than 1000 nm, preferably with a size between 150 and 700 nm.
  • the antioxidant agent is selected from the list comprising antioxidants from olive leaf extract, alperujo, yerba mate, thistle oil, tea, vitamin C, vitamin E, retinoids, idebenone, coenzyme Q10, lipoic acid, Picnogenol or any of its combinations.
  • the antioxidant agent is selected from olive leaf extract, mate, cake and thistle oil or alperujo.
  • the nanoparticles of the invention due to collagen and chitosan, have high biocompatibility, biodegradation control and excellent mechanical properties.
  • a second aspect of the present invention relates to the use of the nanoparticles of the invention for the manufacture of a pharmaceutical composition or cosmetic composition.
  • nanoparticulate systems Being nanoparticulate systems, it is easy to penetrate through epithelial barriers and protects them from being degraded. The ability of nanoparticulate systems to cross these barriers depends on their size and composition.
  • composition in the present invention a compound that contains at least one high purity chemical used in the prevention of a disease, or to prevent the occurrence of an unwanted physiological process.
  • cosmetic composition in the present invention a product used for body hygiene or for the purpose of improving beauty, especially of the face, body and lips.
  • the usefulness of the nanoparticles of the invention in the field of pharmacy and cosmetics is due to the fact that active ingredients can be introduced into the pores thereof, which can be released in a controlled manner, thus acting the nanoparticles of the invention as a controlled release system of active ingredients.
  • controlled release system of active ingredients in the present invention, it is understood a way of administering the active ingredient, as may be by way of example but not limited to the invention pharmaceutical and / or cosmetic compositions, which They are administered locally.
  • the active ingredient is specifically released for a period of time in the place where it has been incorporated, acting effectively and precisely to promote bioactivity and without the need to be applied systemically.
  • the active ingredient is incorporated in a necessary quantity to the nanoparticles, depending on the use that is desired to give them, the matrix nanoparticles acting.
  • the pharmaceutical or cosmetic composition is topically or dermatologically administered; optionally, in the form of cream, mousse, serum, emulsion, spray, patch or film.
  • Topical administration is of superficial application form on the dermis, and can be formulated, by way of example and without limitation, such as lotions, oils, ointments, creams, gels, powders, ointments, aerosols, microemulsions, pastes, poultices or solutions .
  • the cosmetic composition in addition to the nanoparticles of the invention, to promote topical or dermatological administration may comprise at least one cosmetically acceptable excipient that is selected from the group consisting of emulsifiers, solubilizers, dispersants, humectants, co-emulsifiers, emollients, surfactants, thickeners, agents to increase viscosity, lipid components to increase the consistency of the emulsion, preservatives, pH adjusting agents, flavoring agents and perfumes, or any of their mixtures; said cosmetically acceptable excipients, liquid or solid, being both aqueous, lipidic or organic in nature.
  • the present invention relates to a process for obtaining the nanoparticles of the invention, which comprises the steps:
  • solution A comprises hyaluronic acid
  • solution B comprises a crosslinking agent
  • step (b) mixing the product obtained in step (a) with a solution C and D, where solution C comprises chitosan and solution D comprises collagen.
  • step (a) of the process of the invention further comprises the addition of the active ingredient.
  • the active ingredient is added in a weight percentage of between 5 and 80%.
  • the crosslinking agent is selected from sodium tripolyphosphate, genipin, polyethylene glycol or any combination thereof.
  • the mass ratio between chitosan / hyaluronic acid / collagen is between 1: 1: 2 and 9: 3: 9. In a more preferred embodiment, the mass ratio between chitosan / hyaluronic acid / collagen is between 2: 1: 9 and 9: 1: 2.
  • Figure 1 Transmission electron microscopy images of nanoparticles comprising chitosan, hyaluronic acid and collagen, corresponding to formulations a) and b) prepared respectively according to mass ratios of 2: 1: 9 and 9: 1: 2.
  • Figure 2 Transmission electron microscopy images of nanoparticles comprising chitosan, hyaluronic acid and collagen, with 20% encapsulated bovine serum albumin, corresponding to formulations a) and b) prepared respectively according to 2: 1 mass ratios: 9 and 9: 1: 2.
  • Figure 3 Transmission electron microscopy images of nanoparticles comprising chitosan, hyaluronic acid and collagen, with 20% encapsulated olive leaf extract, corresponding to formulations a) and b) prepared respectively according to mass ratios of 2: 1 : 9 and 9: 1: 2.
  • Figure 4 Size distribution of nanoparticles (nm) comprising chitosan, hyaluronic acid and collagen, according to a mass ratio of 9: 1: 2, corresponding to formulations a) empty or free of active ingredient, and b) with a % of encapsulated olive leaf extract, prepared at a pH of 4.5.
  • Figure 5 Chart of% antioxidant release vs.
  • BSA Bovine serum albumin
  • Chitosan hydrochloride, hyaluronic acid and collagen nanoparticles were prepared, using sodium tripolyphosphate as a crosslinking agent.
  • the solution of hyaluronic acid (3 mg / ml) and sodium tripolyphosphate (0.1%) was added to the solution containing chitosan hydrochloride (0.15%), under constant stirring and for 10 minutes, allowing the stabilization of the generated nanoparticles.
  • the centrifugation of these was carried out in order to eliminate the possible unreacted chitosan and hyaluronic acid residues and the resulting pellet is resuspended in a collagen solution (5 mg / ml) for 2 hours, under constant stirring.
  • Nanoparticles of chitosan hydrochloride, hyaluronic acid, collagen and sodium tripolyphosphate were prepared as crosslinking agent.
  • Bovine serum albumin (BSA) was incorporated. It was incorporated into the chitosan solution due to its easy solubility in it. A theoretical load of 20% was established with respect to the weight of the polymers. Its average diameter was measured, as well as its surface electric charge and its morphology was studied by transmission electron microscopy.
  • Table 3 and Figure 2 show the values that take the parameters mentioned according to the proportion of HCS, HA and Col used and the morphology of the nanoparticles obtained.
  • Nanoparticles of chitosan hydrochloride, hyaluronic acid, collagen and tripol phosphate sodium were prepared as crosslinking agent.
  • a set of antioxidants was incorporated, selecting for this purpose an olive leaf extract (OLE). It was incorporated into the solution of sodium tripolyphosphate, due to its hydrophilic character and easy solubility in it.
  • a theoretical load of 20% was established with respect to the weight of the polymers. Its average diameter was measured, as well as its surface electric charge and its morphology was studied by transmission electron microscopy.
  • Table 4 and Figures 3 and 4 show the values that take the parameters mentioned, depending on the proportion of HCS, HA and Col used.
  • the encapsulation efficiency was determined by evaluating the amount of free polyphenols, using the Folin-Ciocalteu method. In-vitro release studies were carried out, at 37 ° C in aqueous medium, at pH: 5.5 for a period of 24h. The amount of active ingredient released was determined by visible ultraviolet spectrophotometry. In the graph of Figure 5,% release of polyphenols vs. time (hours), different lines are represented: one with squares, for the formulation d); one with triangles, for the formulation b); one with circles, for formulation c) and one without geometric elements, for formulation a).

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nanoparticules pour la libération contrôlée de principes actifs, lesquels comprennent du chitosane, de l'acide hyaluronique et du collagène et contiennent en outre un principe actif; un procédé d'obtention desdites nanoparticules, lequel implique la transformation d'une phase liquide, qui contient les polymères en phase solide, qui à son tour contient le principe actif qui satisfait la forme requise pour être administrée avec un profil de libération contrôlée et qui, en outre, permet l'incorporation directe du principe actif tout en préservant son intégrité ou son action thérapeutique, et l'utilisation des nanoparticules dans la fabrication de compositions pharmaceutiques ou cosmétiques.
PCT/ES2014/070814 2014-10-30 2014-10-30 Nanoparticules pour la libération contrôlée de principes actifs WO2016066864A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/ES2014/070814 WO2016066864A1 (fr) 2014-10-30 2014-10-30 Nanoparticules pour la libération contrôlée de principes actifs

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/ES2014/070814 WO2016066864A1 (fr) 2014-10-30 2014-10-30 Nanoparticules pour la libération contrôlée de principes actifs

Publications (1)

Publication Number Publication Date
WO2016066864A1 true WO2016066864A1 (fr) 2016-05-06

Family

ID=52117904

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/ES2014/070814 WO2016066864A1 (fr) 2014-10-30 2014-10-30 Nanoparticules pour la libération contrôlée de principes actifs

Country Status (1)

Country Link
WO (1) WO2016066864A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107550750A (zh) * 2016-06-30 2018-01-09 株式会社爱茉莉太平洋 含有不同分子量透明质酸的化妆品组合物
CN108484923A (zh) * 2018-03-20 2018-09-04 华东理工大学 基于硫辛酸类化合物的超分子聚合物及其制备方法
CN110101681A (zh) * 2019-05-16 2019-08-09 中国计量大学 提高火龙果γ-生育酚生物利用度的微粒制备方法
EP3932201A1 (fr) * 2020-07-03 2022-01-05 Uniwersytet Ekonomiczny W Poznaniu Préparation antimicrobienne a base de fer et d'extrait de plante, son procédé de préparation et d'application

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000064954A1 (fr) 1999-04-22 2000-11-02 Vanderbilt University Systeme d'encapsulation de polymeres facilitant l'angiogenese
ES2226567A1 (es) 2003-06-20 2005-03-16 Universidad De Santiago De Compostela Nanoparticulas de acido hialuronico.
WO2007135164A1 (fr) 2006-05-24 2007-11-29 Advanced In Vitro Cell Technologies, S.A. Nanoparticules de chitosane et de hyaluronane pour l'administration de molécules actives
EP1891943A2 (fr) 2005-06-02 2008-02-27 Universidade De Santiago De Compostela Nanoparticules qui contiennent du chitosane et de la cyclodextrine
EP1977739A1 (fr) 2007-04-03 2008-10-08 Bioiberica, S.A. Composition à nanoparticules d'un sulfure de chitosan et de chondroïtine
WO2009134336A1 (fr) 2008-04-28 2009-11-05 Zogenix, Inc. Compositions inédites destinées au traitement de la migraine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000064954A1 (fr) 1999-04-22 2000-11-02 Vanderbilt University Systeme d'encapsulation de polymeres facilitant l'angiogenese
ES2226567A1 (es) 2003-06-20 2005-03-16 Universidad De Santiago De Compostela Nanoparticulas de acido hialuronico.
EP1652517A1 (fr) * 2003-06-20 2006-05-03 Advanced in Vitro Cell Technologies, S.L. Nanoparticules d'acide hyaluronique
EP1891943A2 (fr) 2005-06-02 2008-02-27 Universidade De Santiago De Compostela Nanoparticules qui contiennent du chitosane et de la cyclodextrine
WO2007135164A1 (fr) 2006-05-24 2007-11-29 Advanced In Vitro Cell Technologies, S.A. Nanoparticules de chitosane et de hyaluronane pour l'administration de molécules actives
EP1977739A1 (fr) 2007-04-03 2008-10-08 Bioiberica, S.A. Composition à nanoparticules d'un sulfure de chitosan et de chondroïtine
WO2009134336A1 (fr) 2008-04-28 2009-11-05 Zogenix, Inc. Compositions inédites destinées au traitement de la migraine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107550750A (zh) * 2016-06-30 2018-01-09 株式会社爱茉莉太平洋 含有不同分子量透明质酸的化妆品组合物
CN107550750B (zh) * 2016-06-30 2021-12-17 株式会社爱茉莉太平洋 含有不同分子量透明质酸的化妆品组合物
CN108484923A (zh) * 2018-03-20 2018-09-04 华东理工大学 基于硫辛酸类化合物的超分子聚合物及其制备方法
CN108484923B (zh) * 2018-03-20 2020-07-31 华东理工大学 基于硫辛酸类化合物的超分子聚合物及其制备方法
CN110101681A (zh) * 2019-05-16 2019-08-09 中国计量大学 提高火龙果γ-生育酚生物利用度的微粒制备方法
CN110101681B (zh) * 2019-05-16 2021-11-05 中国计量大学 提高火龙果γ-生育酚生物利用度的微粒制备方法
EP3932201A1 (fr) * 2020-07-03 2022-01-05 Uniwersytet Ekonomiczny W Poznaniu Préparation antimicrobienne a base de fer et d'extrait de plante, son procédé de préparation et d'application

Similar Documents

Publication Publication Date Title
Nasr et al. Formulation and evaluation of cubosomes containing colchicine for transdermal delivery
Firooz et al. Novel drug delivery strategies for improving econazole antifungal action
KR100394770B1 (ko) 토코페롤 유도체를 이용하여 나노유화입자를 안정화시키는방법 및 나노유화입자를 함유하는 피부 외용제 조성물
ES2385995B2 (es) Nanocápsulas con cubierta polimérica
Zakaria et al. Recent advances in encapsulation of drug delivery (active substance) in cubosomes for skin diseases
JP2011509947A (ja) 薬物送達システムおよびその調整方法と使用
EP3900709A1 (fr) Nanocapsules enrobées de chitosane et leur utilisation
WO2012169518A1 (fr) Composition liquide, et produit cosmétique et agent de croissance des cheveux comprenant chacun la composition liquide
KR102611992B1 (ko) 키토산으로 코팅된 나노 캡슐 및 이의 용도
Rizwanullah et al. Exemestane encapsulated polymer-lipid hybrid nanoparticles for improved efficacy against breast cancer: Optimization, in vitro characterization and cell culture studies
JP2010150151A (ja) ヒアルロン酸担持ナノ粒子及びヒアルロン酸含有複合粒子並びにそれらを用いた化粧料
Chaudhary et al. Cubosomes: a potential drug delivery system
US20230017661A1 (en) Compositions and modular nano- and microparticles for the delivery of various agents and use thereof
WO2016066864A1 (fr) Nanoparticules pour la libération contrôlée de principes actifs
US20220151944A1 (en) Fluorouracil-containing formulations
US20170367978A1 (en) Aqueous topical drug formulation with controlled release and increased stability
KR101830180B1 (ko) 생체 유래 콜레스테릭 액정, 이를 함유하는 자외선 차단제용 캡슐, 자외선 차단제용 조성물 및 이의 제조방법
KR102384243B1 (ko) 레티놀 또는 레티놀 유도체를 포함하는 키토산이 코팅된 나노캡슐 및 이의 용도
KR20120114730A (ko) 마이크로에멀젼에 의한 감마오리자놀을 함유한 경피약물전달 조성물
AU2012275091B2 (en) Topical formulations including lipid microcapsule delivery vehicles and their uses
Chakraborty et al. Antifungal gel: for different routes of administration and different drug delivery system
Almoshari Novel Hydrogels for Topical Applications: An Updated Comprehensive Review Based on Source. Gels 2022, 8, 174
Dubey et al. CUBOSOME-A Novel Drug Delivery for Anticancer Drugs
WO2018163215A2 (fr) Composition pour administration transdermique de micronutriments et sa méthode de préparation
HAMZA et al. LOXOPROFEN NANOSPONGES: FORMULATION, CHARACTERIZATION AND EX-VIVO STUDY

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14814903

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC , EPO FORM 1205A DATED 03.08.2017.

122 Ep: pct application non-entry in european phase

Ref document number: 14814903

Country of ref document: EP

Kind code of ref document: A1