• 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:
    The present invention relates to a formulation containing hyaluronic acid butyrate or a pharmaceutically acceptable salt thereof for use in the topical treatment of symptoms associated with deciduous dentition.
    公开号:CH710622B1
    申请号:CH00035/16
    申请日:2016-01-11
    公开日:2020-05-15
    发明作者:Raso C/O Loacker Remedia S R L Florian；Stucki C/O Loacker Remedia S R L Luca
    申请人:Schwabe Pharma Italia Srl；
    IPC主号:
    专利说明:

    [0001] The present invention relates to formulations containing a hyaluronic acid butyric ester for topical use in the treatment of symptoms associated with deciduous dentition.
    State of art
    [0002] The term "dentition" defines the process of birth and development of the teeth inside the mouth. The milk teeth, or deciduous, are 20, they erupt around 6-7 months of life to reach completion around 3 years.
    [0003] That of the newborn is also called "first dentition" to distinguish it from the permanent dentition of the adult. Although they are already included and partially calcified in the maxillary bones, originating around the seventh week of gestation from the ectodermal germinal leaflet, the deciduous teeth tend to sprout only a few months after birth.
    [0004] After birth, the teeth gradually erupt through the gums and begin to spring towards the sixth month of life. Normally, the first milk teeth to erupt are the two lower central incisors; the other teeth follow gradually according to a fairly defined chronology, even if the dentition of each newborn is a unique case. Just think, for example, that some babies are already born with a tooth (generally, a lower incisor), while others have to wait even 7-8 months before this appears.
    [0005] The second dentition comprises 32 teeth: permanent teeth erupt in a period of time ranging from 6 years to 18 on average.
    [0006] The first dentition is often announced by various symptoms such as abundant salivation, which is due to the annoying sensations and itching caused by the stretching of the gum mucous membranes, and the finding of swollen gums due to the inflammation caused by the push of the tooth. erupting (ML Macknin et al. PEDIATRICS Vol. 105 No. 4 pp. 747 -752, Aprii 1, 2000).
    [0007] Irritation can be very annoying for the child and can sometimes cause pain, irritability, restless sleep, reduced appetite; in some cases, teething can also lead to an increase in body temperature and skin rush.
    [0008] Some creams or gels that are used to soothe the painful sensation due to teething contain anesthetics such as lidocaine and benzocaine, however these products can have important side effects and should be avoided where possible.
    [0009] It has now been found that a cream or gel or solution containing a hyaluronic acid butyric ester restores the physiological state of the gingival tissue, accelerates the healing process, reduces the pathological state due to inflammation and relieves pain.
    [0010] The hyaluronic acid butyrate (HABut) in which the hydroxyl groups of the hyaluronic acid are esterified with butyric acid residues with different degree of substitution is known to have anti-proliferative and dermoprotective properties as elasticizing and moisturizing the skin.
    [0011] EP 0941253 and WO 2005/092929 describe the preparation of the butyric esters of hyaluronic acid with different degrees of substitution. These esters have a high anti-proliferative activity, which makes them useful in the treatment of diseases characterized by abnormal cell proliferation.
    Description of the invention
    Therefore, the object of the present invention is a formulation containing hyaluronic acid butyrate or a pharmaceutically acceptable salt thereof, preferably sodium salt for the topical treatment of the symptoms associated with deciduous dentition.
    [0013] Preferably the hyaluronic acid butyrate sodium salt used in the formulations of the invention has a molecular weight between 10 <3> and 10 <7>, Dalton more preferably between 10 <4> and 10 <6> Dalton, and a degree of substitution (SD) from 0.01 mol / mol to 3, preferably from 0.1 to 2, where the degree of substitution is defined as the ratio between the number of residues of butyric acid and the number of disaccharide units GlcNAc- GlcUA of hyaluronic acid.
    [0014] The hyaluronic acid butyrate sodium salt is preferably present in the formulation from 0.01% to 5% by weight with respect to the total weight of the formulation, more preferably from 0.05% to 1%.
    In a preferred embodiment of the invention the formulation contains panthenol, preferably from 0.1% to 5% by weight with respect to the total weight of the formulation, more preferably from 0.5% to 3%.
    The pharmaceutical formulation preferably contains extracts of plants with soothing properties such as extract of Malva sylvestris and Chamomilla recutita or Matricaria chamomilla (Commiphora myrrha, Calendula officinalis, Aloe barbadensis, Glycyrrhiza glabra).
    Other pharmaceutically acceptable agents can be added to the formulation such as for example carrier agents, emulsifying agents, gelling agents, preservatives, antioxidant agents, buffering agents, sweeteners, flavorings and / or their mixtures.
    The formulations of the invention are preferably in the form of a cream, gel or solution for topical use for use in the oral cavity.
    [0019] The formulations of the invention can be applied on the gum from 1 to 20 times, preferably from 1 to 10 times a day according to the need.
    [0020] A preferred embodiment of the invention is the formulation containing:<tb> Purified Water / Demineralized Water <SEP> q.b. 100 g<tb> Panthenol / Panthenol <SEP> from 0.1 to 5 g<tb> Malva sylvestris Extract (Hydroglyceric Extract <1%) <SEP> from 0.01 to 5 g<tb> Chamomilla recutita Extract (Hydroglyceric Extract <1%) <SEP> from 0.5 to 5 g<tb> Xantana / Xanthan Gum <SEP> gum from 0.01 to 1 g<tb> Stevia <SEP> from 0 to 0.7 g<tb> Apple flavor (1: 150) natural <SEP> from 0 to 2 g<tb> Hydroxyethylcellulose <SEP> from 0.5 to 5 g<tb> Sodium Hyaluronate Butyrate <SEP> from 0.05 to 1 g<tb> Potassium Sorbate <SEP> from 0 to 0.5 g<tb> Sodium Benzoate <SEP> from 0 to 0.5 g<tb> Citric Acid <SEP> from 0 to 5 g<tb> Sodium Citrate <SEP> From 0 to 5 g
    Example 1
    CHAMODENT BABY GEL
    [0021]<tb> Purified Water / Demineralized Water <SEP> q.b. 100 g<tb> Panthenol / Panthenol <SEP> 1.00 g<tb> Malva sylvestris Extract (Hydroglyceric Extract <1%) <SEP> 1.00 g<tb> Chamomilla recutita Extract (Hydroglyceric Extract <1%) <SEP> 2.00 g<tb> Xantana Gum / Xanthan Gum <SEP> 0.20 g<Tb> Stevia <SEP> 0.10 g<tb> Apple flavor (1: 150) natural <SEP> 0.50 g<Tb> Hydroxyethylcellulose <SEP> 2.00 g<tb> Sodium Hyaluronate Butyrate (SHB of Sigea S.r.l.) <SEP> 0.10 g<tb> Potassium Sorbate <SEP> 0.10 g<tb> Sodium Benzoate <SEP> 0.10 g<tb> Citric Acid <SEP> 3.60 g<tb> Sodium Citrate <SEP> 1.20 g
    Example 2
    [0022]<tb> Purified Water / Demineralized Water <SEP> q.b. 100 g<tb> Panthenol / Panthenol <SEP> 1.5 g<tb> Malva sylvestris Extract (Hydroglyceric Extract <1%) <SEP> 1.50 g<tb> Chamomilla recutita Extract (Hydroglyceric Extract <1%) <SEP> 3.00 g<tb> Xantana Gum / Xanthan Gum <SEP> 0.20 g<Tb> Stevia <SEP> 0.30 g<tb> Aroma Apple (1: 150) natural <SEP> 0.40 g<Tb> Hydroxyethylcellulose <SEP> 3.00 g<tb> Sodium Hyaluronate Butyrate (SHB of Sigea S.r.l.) <SEP> 0.10 g<tb> Potassium Sorbate <SEP> 0.10 g<tb> Sodium Benzoate <SEP> 0.10 g<tb> Citric Acid <SEP> 3.00 g<tb> Sodium Citrate <SEP> 1.00 g
    The formulation was obtained with the following process:<tb> <SEP> PHASE 1: The demineralized water was loaded in a suitable mixer with blades and turbine and panthenol, glycerine extract of mallow, glycerine extract of chamomile, potassium were added in the order sorbate, sodium benzoate, apple juice flavor, stevia, citric acid and sodium citrate. The mixture was stirred under vacuum.<tb> <SEP> PHASE 2: The solution obtained in the previous phase was filtered in series at 0.5 and 0.2 microns.<tb> <SEP> PHASE 3: Sodium hyaluronate butyrate, xanthan gum and hydroxyethylcellulose were added and the obtained mixture was kept under stirring under vacuum.<tb> <SEP> PHASE 4: The product obtained was discharged into the loading hopper of the tube filling machine, suitably calibrated for distribution in the primary packaging.
    Comparison between Chamodent Baby Gel and commercial products
    [0024] To evaluate the influence of the Chamodent Baby Gel formulation on the acute inflammatory process, comparing it with that of commercial products, an in vitro experimental model was used which makes use of the leukocytes that first reach the site of inflammation: the neutrophil polymorphonucleate (PMN). The idea is to simulate an inflammatory environment and evaluate how these cells, stimulated by a pro-inflammatory cytokine (TNF-α, tumor necrosis factor), respond in the presence of the test substances.
    The anti-inflammatory effect was analyzed by evaluating two fundamental functional responses of PMNs: the production of reactive oxygen species (ROS) following metabolic activation and the ability to adhere to biological surfaces.
    The acute inflammatory response promoted by treatment with the pro-inflammatory cytokine is considered proportional to the number of cells adhered to and to the quantity of ROS produced.
    Evaluation of superoxide anion production
    The production of ROS, index of the metabolic activation of PMN, was evaluated in terms of superoxide anion (O2 <->) released in the medium following incubation for 60 minutes of the cells with TNF-α in wells of plates by microtitration coated with Hyaluronic Acid (HA), Hyaluronic Acid Butyrate (HABut), Dentin, Dentin n. and Alovex. A spectrophotometric method was used which allows to measure the quantity of cytochrome c reduced by the superoxide anion produced by the cells during plate incubation. The wells coated with the various substrates are filled with a cytochrome c solution 0.18 mM and TNF 0.15 ng / ml in Hepes buffer. The modules thus prepared are heated for 10 'at 37 degrees in a humidified incubator; a cell suspension of 1.5X10 <6> PMN / ml in Hepes buffer is added to each well. At 15 minute intervals the plate is taken from the incubator and subjected to spectrophotometric analysis in a microplate reader at the wavelength of 550 nm and 540 nm, which correspond respectively to the absorption peak of the reduced cytochrome c and to the isosbestic point absorption spectra of reduced and oxidized cytochrome c. The difference between the absorbance values recorded at the two wavelengths is proportional to the amount of cytochrome c reduced. The amount of O2 <-> produced by 10 <6> cells is calculated as follows:nmoli O2 <-> / 10 <6> PMN = D.O. × 10 <6> / 0.0037 × nwhere n is the number of cells added to each well.
    Assessment of adhesion to biological surfaces
    The amount of cells that had adhered to the substrate during the metabolic assay was assessed by measuring the activity of the myeloperoxidase enzyme, taken as a marker of neutrophils. After taking the spectrophotometric readings for the measurement of the production of O2 <->, the wells of the microplate are filled with PBS and centrifuged at 200 g for 5 minutes to remove the cells not attached to the surface. The myeloperoxidase activity is measured by measuring the oxidation of the substrate 3 ', 5,5'-tetramethylbenzidine (TMB) by the MPO enzyme in the presence of H2O2. Acetate buffer wells containing TMB, cetyltrimethylammonium (CTAB) and 3-amino-1,2-4-triazole (AMT) are added to each well and the plate is stirred for 5 'to facilitate cell lysis and promote the release of MPO from the granules. . The activity of eosinophiloperoxidase deriving from eosinophils which can contaminate the preparation of PMNs is inhibited with ATM. After 2 minutes from the addition of H2O2 the reaction stops with H2SO4 and the absorbance of each well is measured at the wavelength of 405 nm. The percentage of adhered cells is calculated by referring to a standard curve constructed, in each experiment, on the basis of the peroxidase activity values calculated for known quantities of cells.
    [0029] The results of the experimentation are reported in Fig. 1 and Fig. 2.
    [0030] Fig. 1: Production of superoxide anion released by neutrophils in contact with surfaces coated with Ha, HABut Chamodent Dentinale, Dentinale Natura and Alovex.
    [0031] Resting: PMNs not activated with TNF. TNF: PMN activated with TNF-α.
    [0032] Fig. 2: Adhesion of PMNs to a surface coated with Ha, HABut, Chamodent Dentinale, Dentinale Natura and Alovex.
    [0033] Resting: PMNs not activated with TNF. TNF: PMN activated with TNF-α.
    Conclusions
    The experiments show a clear anti-inflammatory activity of Chamodent Baby Gel, better also than only sodium hyaluronate butyrate (HABut produced by Sigea), but above all compared to commercial formulated products (Dentinale produced by Montefarmaco, Dentinale Natura produced by Montefarmaco and Alovex produced by Recordati). Compared to the other tested substances, in the presence of Chamodent Baby Gel the activated neutrophils show a lower release of superoxide and a lower level of adhesion to the surface behavior indicative of the action of a compound with anti-inflammatory activity. As a reference we wanted to use sodium hyaluronate (HA) which has worse performance than Chamodent Baby Gel.
    [0035] All the results are consistent with the thesis of a better performance of Chamodent Baby Gel than the other substances, pure or formulated, tested. Genetic resources according to art. 49th LBI<tb> Genetic resources: <SEP> Origin of genetic resources: (country of origin; local distributor)<tb> Stevia <SEP> China, Aoxing Stevia; Italy, Tillmanns SpA, Via Benigno Crespi, 10 / a Milan
    权利要求:
    Claims (13)
    [1]
    1. Formulation containing hyaluronic acid butyrate or a pharmaceutically acceptable salt thereof for use in the topical treatment of symptoms associated with deciduous dentition.
    [2]
    2. Formulation according to claim 1 containing hyaluronic acid butyrate sodium salt.
    [3]
    Formulation according to claim 2 wherein the hyaluronic acid butyrate sodium salt has a molecular weight of between 10 <3> and 10 <7> Dalton.
    [4]
    Formulation according to claim 3 wherein the hyaluronic acid butyrate sodium salt has a molecular weight of between 10 <4> and 10 <6> Dalton.
    [5]
    Formulation according to one of claims 2 to 4 wherein the hyaluronic acid butyrate sodium salt has a degree of substitution of 0.1 to 2 mol / mol.
    [6]
    Formulation according to one of claims 2 to 5 wherein the hyaluronic acid butyrate sodium salt is present at a concentration of 0.05% to 1% by weight with respect to the total weight of the formulation.
    [7]
    7. Formulation according to one of the preceding claims, further containing panthenol.
    [8]
    8. Formulation according to claim 7 wherein panthenol is present at a concentration of 0.1% to 5% by weight with respect to the total weight of the formulation.
    [9]
    Formulation according to one of the preceding claims, further containing one or more plant extracts with soothing and / or anti-inflammatory properties.
    [10]
    10. Formulation according to claim 9 wherein the plant extract with soothing properties is selected from the extract of Malva sylvestris, Chamomilla recutita, Matricaria chamomilla, Commiphora myrrha, Calendula officinalis, Aloe barbadensis, Glycyrrhiza glabra.
    [11]
    Formulation according to one of the preceding claims, further containing a carrier, emulsifying, gelling, preserving, antioxidant, buffering, sweetening and / or flavoring agent and / or mixtures thereof.
    [12]
    Formulation according to one of the preceding claims having the following composition:<tb> Purified Water / Demineralized Water <SEP> q.b. 100 g<tb> Panthenol / Panthenol <SEP> from 0.1 to 5 g<tb> Malva sylvestris Extract (Hydroglyceric Extract <1%) <SEP> from 0.01 to 5 g<tb> Chamomilla recutita Extract (Hydroglyceric Extract <1%) <SEP> from 0.5 to 5 g<tb> Xantana / Xanthan Gum <SEP> gum from 0.01 to 1 g<tb> Stevia <SEP> from 0 to 0.7 g<tb> Apple flavor (1: 150) natural <SEP> from 0 to 2 g<tb> Hydroxyethylcellulose <SEP> from 0.5 to 5 g<tb> Sodium Hyaluronate Butyrate <SEP> from 0.05 to 1 g<tb> Potassium Sorbate <SEP> from 0 to 0.5 g<tb> Sodium Benzoate <SEP> from 0 to 0.5 g<tb> Citric Acid <SEP> from 0 to 5 g<tb> Sodium Citrate <SEP> from 0 to 5 g
    [13]
    Formulation according to one of the preceding claims in the form of a cream, gel or solution.
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    同族专利:
    公开号 | 公开日
    CH710622A2|2016-07-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    SG11201608225PA|2014-04-03|2016-11-29|Pola Chem Ind Inc|Melanogenesis inhibitor comprising d-pantothenyl alcohol, and skin-whitening cosmetic containing same melanogenesis inhibitor|
    法律状态:
    2017-09-29| PFA| Name/firm changed|Owner name: SCHWABE PHARMA ITALIA SRL, IT Free format text: FORMER OWNER: LOACKER REMEDIA S.R.L., IT |
    2017-11-15| PCOW| Change of address of patent owner(s)|Free format text: NEW ADDRESS: VIA SILVIO MENESTRINA, 1, 39044 EGNA (BZ) (IT) |
    优先权:
    申请号 | 申请日 | 专利标题
    ITMI20150016|2015-01-13|
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