• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 优先权
    • 专利摘要:
    The present invention describes the preparation of an extract of the crustacean artemia salina, and its use to treat diseases of the ocular surface. The invention describes the application of the extract through, mainly of soaps, eye drops, ocular washed eye solutions, aerosols, in the presence of ointments, creams gels or contact lenses among others. The application of the extract of artemia salina is effective for the treatment of pathologies that comply with ocular dryness (dry eye), and its manifestations such as the appearance of wounds or ulcers of the ocular surface or infections by microorganisms associated with dry eye, also on the ocular surface. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2650981A1
    申请号:ES201600607
    申请日:2016-07-20
    公开日:2018-01-23
    发明作者:Jesús Jerónimo PINTOR JUST；María Jesús PÉREZ DE LARA；Fernando HUETE TORAL；Basilio COLLIGRIS；Juan Gonzalo CARRACEDO RODRÍGUEZ
    申请人:Ocupharm Diagnostics Sl；
    IPC主号:
    专利说明:

    Preparation and use of an extract of Arlem; saline to treat the surface
    ocular
    Technical sector
    S The present invention relates to obtaining and applying extracts obtained from
    the cysts, nauplias or adults of the organism Artemia salina, isolated and mixed in
    different proportions, alone or in combination with other products, extracts
    natural or synthetic for the preparation of pharmaceutical compositions with use
    especially eye. These compositions will be carried out mainly in
    10 Soaps, eye drops, eye solutions, eye washes, sprays, in
    presence of ointments, creams, gels or contact lenses, for the treatment of
    pathologies that have to do with the ocular surface.
    State of the art
    fifteen The problems that patients may have on their ocular surface are diverse.
    The most prevalent are dry eye, which can lead in many cases as
    consequently the appearance of superficial corneal wounds and infections of the
    ocular surface (Thoft RA (1985). Relalionship 01 Ihe dry eye lo primary ocular
    surface disease. Trans Ophlhalmol Soc U K. 104 (PI 4): 452-7).
    twenty
    Dry eye is defined as a multifactorial disease of the tear and the
    ocular surface that causes symptoms of discomfort, visual problems and
    tear film instability, with potential damage to the ocular surface and
    increased risk of infections (AI-Saedi Z, Zimmerman A, Bachu RO, oey S,
    25 Shah Z, Baugh R, Boddu SH (2016). Dry Eye Disease: Present Chattenges in the
    Management and Future Trends. Curr Pharm Des. Jun 13. [Epub ahead 01 print]).
    It is accompanied by an increase in the osmolarity of the tear film and a
    inflammation of the ocular surface.
    In the case of Caucasian populations (white race), normal osmolarity oscillates
    between 319 and 314 mOs (Potvin R, Makari S, Rapuano eJ. (2015). Tear film osmolarity
    and dry eye disease: a review of the IiteratlUra. Clin Ophthalmol. 9: 2039-2047). Though
    S there is no strict border, it is considered that 314 mOs is the lower limit of the
    normality and any measure that is below that value is labeled as "bad
    quality of the tear film and also as dry eye uses ".
    The amount of nominal tear volume ranges between 10 and 15 mm in the strip of
    10 Schirmer Although there is no strict border, 5.5 mm is considered to be the limit
    below normal and any measure that is ~ below that value is labeled
    as ~ poor quality of the tear film and also as ~ suspicion of dry eye. "
    Dry eye is a very prevalent disease, lens affecting between 14 and 33% of
    fifteen the world population, depending on the E! studio and the definition used. Some
    eye surface diseases manifest with dry eyes, such as
    Sjógren's syndrome or aniridia. However, dry eyes and their
    consequences also manifest in systemic diseases such as
    rheumatoid arthritis, lupus or sarcoidosis. Also the dry eye and its
    twenty consequences can occur as a result of environmental situations such as
    for example, very low humidity conditions, high temperatures, devices
    of heating or air conditioners or the use of electronic devices such as
    computers, mobile phones or tablets. On the other hand, it is important to remember that
    some pharmacological and / or surgical treatments can lead to dryness
    25 ocular, such as the use of decongestants: stitive and antihistamines, tranquilizers
    antidepressants and sleeping pills, diuretics, birth control pills, some
    anesthetics, medications for the treatment of high blood pressure (beta
    blockers) and for digestive disorders (anticholinergics) or surgery operations
    refractive (Seot E Moss, Ronald Klein, Barbara E K Klein. (2000). Prevalence of and Risk Factors for Dry Eye Syndrome. Areh Ophthalmol. 118: 1264-1268)
    S The classification of the dry eye is based on two blocks: from an etiological perspective and from the influence of the environment, which predisposes to the development of dry eye.
    10 The etiological classification in turn is subdivided into two main groups: Dry eye due to deficiency in the aqueous phase of the tear, and evaporative dry eye. However, these groups are not independent, since the disease initiated in one of the main groups may coexist with circumstances that cause dry eye within the other group.
    15 20 Current treatment options for dry eye are tear supplements, also called lubricants, known as artificial rhymes (Marshall LL, Roaeh JM (2016). Treatment of Dry Eye Disease. Consult Pharm. 31 (2): 96106). The effectiveness of this option is difficult to verify, because its effects cannot be observed or because the currently available agents do not have a discernible activity of the lubrication effect. An improvement in the symptoms can be observed, but it is not enough to resolve the pathology on the ocular surface or the inflammation that they present on the ocular surface.
    2S Other treatment options are anti-inflammatory medications such as cyclosporine, corticosteroids, tetracyclines and the like; tear retention devices, such as permanent occlusion plugs of the tear duct; moisture glasses; contact lenses; and tear gland autotransplantation. However, none of these treatments are free of unwanted side effects.
    Corneal and conjunctive lesions beproducehowaconsequencevery
    usual dry eye, since there is no tear or is of poor quality,
    Friction of the eyelids causes the wound or ulcer (Liu ey, Kao NVII (20 15).
    Corneal Epithelial Wound Healing. Prog Mol Biol Transl ScL 134: 61-71).
    S Therapeutic approaches are virtually non-existent and generally focus on
    the application of antibiotic ointments in order to avoid opportunistic infections
    that could occur, leaving the healing process to resolve itself
    (Ljubimov AV, Saghizadeh M. (2015). Progress in corneal wound healing. Prog Retin
    Eye Res. 49: 17-45).
    10
    Infections of the ocular surface as a result of dry eye are the
    result of a defective tear film which favors the settlement of
    pathogenic microorganisms (Narayanan S, Redfern RL, Miller WL, Nichols KK,
    McOermott AM (20 13) Ory eye disease and microbial keratitis: is there a connection
    fifteen Hide Surf 11 (2): 75-92). In most cases these are bacteria, fungi and
    virus. In some cases infections only affect a part of the eye, be it the
    conjunctiva or cornea, but usually the involvement is joint, since the
    Dry eye affects the entire ocular surface exposed to air. Even sometimes
    when the infection is severe, it can pass into the eye, then being very
    twenty difficult to treat.
    The eye, in a healthy state, to defend against opportunistic infections, has two
    defense mechanisms, tear film and corneai epithelium. The tear is a
    structured and specialized wet film that covers the conjunctiva and cornea. its
    25 composition, from the quantitative and qualitative point of view, must be maintained
    stable to achieve adequate eye health and good visual function. Is by
    that a deficiency of the same as occurs in the dry eye is one of the
    most important factors as a cause of infections (O V Seal, J 1 McGiII, I A
    Mackie, G M Liakos, P Jacobs and N J Goulding (1986). Bacteriology and tear protein
    profiles of the dry eye. Br J Ophthalmol; 70: 122-125).
    From the point of view of infections, the tear film is the first
    S ocular defensive line since it contains dissolved substances with
    bactericidal and bacteriostatic capacity. Lysozyme and lactoferrin are the main
    tear components, being the first to which the activity is attributed
    bactericidal and the second bacteriostatic.
    10 If the tear is altered by a physical, chemical process or by a pathological state,
    bactericidal activity may be diminished or not enough and therefore the eye
    Will be prone to infections.
    For the treatment of ocular infections, drugs of different types are used
    fifteen families among those found as bactericidal agents: aminoglycosides,
    penicillins, cephalosporins and quinolones and as bacteriostatic agents:
    erythromycin, tetracycline, chloramphenicol and sulfonamides, as well as substances of
    new creation (use as an example patents: W03015752, US6569443,
    W00119366, W002083178); also antiviral and antifungal agents.
    twenty
    Some of these drugs cause side effects at the ocular and systemic level.
    Among the adverse reactions found at the ocular level, the incidence has been described
    of allergies, allergic blepharitis, precipitates in the anterior part of the cornea, myopia
    transient, white corneal plaques in patients with keratoconjunctivitis sicca,
    25 in addition to the unwanted effect they cause on wound healing
    cornea les (Crews, SJ (1977) Ocular adverse reactions to drugs. Practitioner 219: 72 .;
    Fraunfelder, FT (1989) Drug induced OClUlar side effects and drug interactions 3rd
    Edition Lea and Febiger, Philadelphia; Ball, AP, Geddes, AM, Davey, PG, Farrell, ID
    and Brookes, GR (1980) Clavulanic acid and Amoxycillin: a clinical, bacteriological and
    pharmacological study. lancet 1: 620 ~ 623).
    Artemia salina is a branchiopod crustacean of the Anostraca order typical of continental brackish waters. of very wide distribution throughout the world. Its composition mainly presents fatty acids (Hachem Ben Naceur, Gabila ghazali, Amel Ben Rejeb Jenhani and Mohamed Salah Romdhane. Study 01 the latty acid compasition of Artemia salina cysts from Tunisia. Journal af the Marine Biological Association 01 the United Kingdom, 201: 1 , 93 (7), 1795-1803.), Proteins (Claus C, Benijts F, and Vandeputte. The biochemical compasillon af the larvae of twe straisn of Artemia salina (L.) reared on two different algal toad. J. Exp. Mar. Biol. Eco! .. 1979; 36, 171-183), amino acids (Landa u M, Miyalmoto G, Bolis C. Growth and aminoacid compasition of Artemia salina (L., 17!> 8) fed algae grown in different media (Anostraca), Crustaceana, 1984, 49 (1), 318-321), components of a nucleotide nature with guanine (Warner AH, Mcdean OK. Studies on the Biosynthesis and Role of Oiguanosine Tetraphosphate during Growth and Development of Artemia salina. Oevel Biol. 1968, 18, 278-293), O-myoinositol-1, 4, S-triphosphate and glycans (Gallagher M, Br own WD. Composition o'f San Francisco bay brine shrimp (Artemia salina). J Agric Food Chem. 1975; 23 (4): 6110-842).
    The study of a possible cosmetic use of a crustacean preparation Artemia salina is reflected in several patents (WO / 1 999 / 038483A 1, WO / 1999 / 038483A8, EP1 049455A 1, WO / 2015 / 107286A2, WO / 2015 / 107286A3, EP1049455B1) in which an enzyme extract produced by a method is claimed and with use claims totally different from those described in the
    present invention
    On the composition there are interesting elements that provide the extract of
    Saline artemia of interesting properties such as the absorption of ultraviolet light by nucleotides (painter J. Commentary: Why are such high concentrations of nucleotides in the lens Purinergic signalling. 2011; 7 (2): 169-170), the role of inositol as a second intracellular messenger in some cells and tissues, fatty acids as lubricants and finally glycans, which represent a source of energy for cells because of their carbohydrate composition but are also important for the maintenance of bacterial flora correct in the mucous membranes and have a high hydration capacity due to their high number of hydroxyl groups (Varki A, Cummings RO, Esko JO, Stanley P, Hart G, Aebi M, Oarvill A, Kinoshita T, Packer NH, Prestegard JJ, Sclhnaar RL, Seeberger PH, editors Essentials 01 Glycobiology [Internet). 3rd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press: 2015: Van den Steen P, Rudd PM, Dwek RA, Opdenakker G. Concepts and principies 01 O-linked glycc, sylation. Crit Rev Biochem Mol Biol. 1998; 33 (3): 151-208. Han9 HC, Bertozzi CR. TI, e chemistry and biology 01 mucin-type 0linked glycosylation. Bioorg Med Chem. 2005; 13 (17): 5021-5034).
    Explanation of the invention.
    The present invention relates to the obtaining and application of extracts obtained from the cysts, nauplias or adults of the Artemia saline organism, isolated and mixed in different proportions alone or in combination with other products, natural or synthetic extracts for the preparation of pharmaceutical compositions with especially eye use.
    An "extract of Artemia salina" means a combination of compounds that are extracted from the crustacean Artemia salina through chemical extraction,
    biochemistry, or biological (for example, through water or chemical solvents). He
    Extract may include any of several proteins, carbohydrates, nutrients, secretion products and the like derived from saline Artemia.
    The present invention describes how to obtain Artemia salina extracts, and their applications in aspects such as tear volume, speed of wound healing in the eye's supertice and maintenance of a compensated biota of the ocular superticia .
    The compositions can be made in a wide variety of product types that include, but are not limited to: eye drops, drops, lotions, creams, gels, bars, sprays, ointments, washes, cleaning fluids, shampoos, foams, wipes, Patches, hydrogels and films. These types of products may contain several types of acceptable topical vehicles including, but not limited to: solutions, suspensions, emulsions such as microemulsions and nanoemulsions, gels, solids and liposomes. The following are non-limiting examples of such vehicles.
    The topical compositions useful in the present invention can be formulated as solutions. While preferring that the solution be aqueous, in certain cases, the composition may, in addition to, or instead of water, include acceptable organic solvents. Examples of suitable organic solvents include: propylene glycol, polyethylene glycol (200-600), polypropylene glycol (425-2025), glycerol, 1,2,4-butanothriol, sorbitol esters, 1,2,6 · hexanotriol, ethanol, and mixtures of The same as well as others. One or more solvents may be present from proportions of about 50% to 99.99% or about 90% to 99% of an acceptable aqueous or organic solvent.
    While it is preferred that the topical composition of the present invention include water,
    topical compositions may alternatively be compositions or ointments
    that include organic and / or silicone solvents, oils, lipids and anhydrous waxes. A
    ointment can containabasesirnplefromoilsanimalsor vegetablesor
    S semi-solid hydrocarbons. An ointment can contain about one
    2% to 10% of an emollient or emollients more than 0.1% to 2% of an agent or
    thickening agents Examples of thickening agents include, but are not limited to
    those exposed in the Handbook 2979-84.
    10 Useful topical compositionsinThe present invention can be formulated
    As emulsions The emulsifiers can be nonionic, anionic or cationic.
    Examples of emulsifiers include, but are not limited to those set forth in the Manual.
    ICI, pp. 2962-71.
    1S Other useful materials may also be present in the compositions inthe
    present invention These include humectants, viscosifiers, pH adjusters,
    minerals, and preservatives. Examples of such agents are listed on pp. 2922-23,
    2926-28, and 2892 of the ICI Manual.
    Eg emplos
    Obtaining Artemia salina extracts
    The extracts were obtained from the cysts of Artemia salina, or from their
    S nauplias or mature individuals, weighing amounts ranging from 1 mg to
    grams
    Extraction A): As an example of extraction A, 20 mg of cysts, nauplias or
    mature individuals of Artemia salina and mixed with 1 mL of ultrapure water
    10 (final concentration 20 mg / mL). This preparation is mechanically homogenized
    for 30 seconds twice in a row. The result of homogenization and
    In order to remove the proteins it is placed in an eppendorff tube in a dry bath
    98 ° C for two minutes. It is then incubated in an ice bath for 5
    To proceed to separate the denatured proteins the samples are
    fifteen centrifuge at 22,000xg for 4 minutes at 4 ° C. The supernatant result of the
    Centrifugation is taken and filtered in sterile hood through a filter of 0.22) .1. This
    "Extract g is tested in the examples that follow.
    Extraction 8) As an example of extraction 8, 20 mg of Artemia cysts are taken
    twenty saline and mix with 1 mL of a 0.9% sodium chloride solution (20 mg / mL).
    This preparation is mechanically homogenized for 30 seconds twice
    consecutive. The result of homogenization and in order to eliminate proteins
    It is placed in an eppendorff tube in a 98 ° C dry bath for two minutes. TO
    then incubate in an ice bath for 5 min. To proceed to separate the
    25 denatured proteins samples are centrifuged at 22,000xg for 4 minutes
    at 4 ° C. The supernatant resulting from centrifugation is taken and filtered in a hood
    Sterile through a 0.22 ~ filter. This "Extract B" is tested in the examples.
    that come later.
    Effect of Artemia salina extracts on tear levels To carry out studies on tear production, a 10 JlL aliquot of ~ Extract A "was taken and applied topically on the ocular surface of albino rabbits of the New Zealand breed. Tear volume was measured after instillation of "Extract N for a maximum time of 170 minutes. For this, the Schirmer test was performed, which consists of placing a strip of filter paper graduated in the lower eyelid of the experimental animal (Cho P, Yap M. Schirmer test. 1. A review. Optom Vis Sci. 1993; 70 ( 2): 152-156). During this period it was found that the tear volume remained high for about 90 min to subsequently return to its initial levels (Figure 1). When the same protocol was performed with "Extract B", a similar profile was obtained except that in the case of the latter, the tear level was higher than in the case of "Extract A" (Figure 1).
    The control experiment was performed by administering 10JlL of 0.9% saline solution, where there are no changes in the tear volume.
    Effect of Saline Arlemia extracts on corneal healing To mimic corneal wounds caused by dry eyes, extracts A and B were tested on superficial lesions performed according to the protocol described (Cintron, e, Hassinger L, Kublin e L, Friend JA simple method for the removal of rabbit corneal epithelium utilizing n-heptanol. Ophthalmic Res. 1979; 11,90-96.), in which, after anesthetizing the rabbits of the New Zealand breed, a wound is made by placing a Circular filter paper soaked in n-heptanol on the animal's cornea. The healing rate is measured by quantifying the decrease in disc diameter versus time either with the control (0.9% saline solution), the 10 j.JL of the "S ~ Extract" is applied on the ocular surface of New Zealand rabbits. Next, 5 j.JL of tear was taken at intervals of one hour during the 5 hours following the application of the "S- Extract.
    ~ Extract N or "Extract B ~. Extract control applications were performed
    adding 10) .lL of each of them with repetitions of them with an interval
    of application not exceeding 6 hours (figure 2).
    S The control experiment with 0.9% saline solution showed an estimated time of
    healing (time it takes to close the wound) of about 42 h, compared to 26 h
    which took in the case of the ~ Extract AM and 19 h that took the "Extract B ~.
    Effect of Artemia salina extracts on the biota of the ocular surface
    10 To verify the effect of these extracts, 5 j.JL of tear were collected twice
    before applying the invention (basal levels of antimicrobial activity in the
    surface of the animal). This volume of collected tear was applied on a disk of
    filter paper (Whatman n01) and deposited on a petri dish on which
    previously Micrococcus lisodeikticus bacteria had been seeded. This bacterium is
    fifteen commonly used for the determination of lysozyme / lactoferrin levels in
    the biological systems (van Bijsterveld, O.P., Arch Ophthalmol. 91, 432-434, 1974).
    This method compares the conditions in the absence of any substance or
    extract, measuring the halo of bacterial growth inhibition, and comparing
    the mm of inhibition with those obtained for the extracts.
    twenty
    10 j.JL of ~ Extract A ~ are applied on the ocular surface of New rabbits
    Zeeland Then we proceeded to take 5 j.JL of tear at intervals of one hour
    during the 5 hours following the application of ~ Extract N. In figure 3 you can
    perceive the effect that this extract has on bacteria.
    25
    Brief description of the figures To facilitate the understanding of the descriptive invention, a series of figures are attached: and being part of thismemory
    S Figure 1 shows the increase l: te tear volume measured with the Schirmer test when a 0.9% NaCI solution (control) and extracts A and 8 are applied over 170 min. Extracts A and B retain a tear volume greater than the control.
    10 Figure 2 shows the decrease in the diameter of the wound over time for the control solution (NaCI solution% OB), and for extracts A and B. It can be seen by the slope of the lines that is the extract 8 which favors a healing rate slightly higher than extract A.
    fifteen Figure 3 shows the behavior of the control and extracts A and B on microorganisms, in which it can be seen that the extracts are more effective than the control (0.9% NaCI solution) limiting the development of microorganisms.
    权利要求:
    Claims (2)
    [1]
     Claims

    S 1. · Use of the extract of Arlemia salinGl and the pharmaceutically acceptable formulations thereof for the preparation of a medicament or a medical device intended to increase tear secretion.
    [2]
    2. Use according to claim 1 for the treatment and / or prevention of dry eye where this disease occurs with corneal wounds and / or bacterial infections.
    10 15 20 3. Use according to claims 1-2, wherein the extract is administered in an effective prophylactic and / or therapeutic amount and is adapted for administration by a route selected from the group comprised by the topical routes, contact lenses, intracamerular, intravitrea, subconjunctival, intradermal, subcutaneous, or by means of ocular devices with regulated release. 4. Use according to claims 1 · 3, wherein the extract is administered topically, whether or not the compound is vehiculized by liposomes, and has a pharmaceutical form selected from the group comprised of solutions, suspensions, emulsions, eye drops, drops, of liquid, liquid washes, contact lenses, gels, creams, ointments, ointments and sprays.
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    同族专利:
    公开号 | 公开日
    EP3488855A1|2019-05-29|
    US10933100B2|2021-03-02|
    EP3488855A4|2019-12-25|
    ES2650981B2|2018-05-04|
    WO2018015582A1|2018-01-25|
    US20190275089A1|2019-09-12|
    引用文献:
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    WO2010106571A2|2009-03-19|2010-09-23|Medivis S.R.L.|Ophthalmic compositions based on polyunsaturated omega-3 and omega-6 fatty acids|
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    WO2015169728A1|2014-05-07|2015-11-12|Croma-Pharma Gesellschaft M.B.H.|Aqueous ophthalmic solution and method for treating dry eye syndrome|
    FR2817748B1|2000-12-13|2003-01-17|Seporga|COSMETIC AND / OR DERMATOLOGICAL COMPOSITION CONTAINING ARTEMIA SALINA EXTRACT|
    CN101857623B|2010-05-25|2011-11-02|天津强微特生物科技有限公司|Method for extracting GP4G from organism|
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    US16/318,987| US10933100B2|2016-07-20|2017-07-14|Preparation and use of an extract of Artemia salina to treat the ocular surface|
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