CH710622B1 - Topical pharmaceutical formulation containing a hyaluronic acid butyric ester for the treatment of symptoms associated with deciduous dentition. - Google Patents
Topical pharmaceutical formulation containing a hyaluronic acid butyric ester for the treatment of symptoms associated with deciduous dentition. Download PDFInfo
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- CH710622B1 CH710622B1 CH00035/16A CH352016A CH710622B1 CH 710622 B1 CH710622 B1 CH 710622B1 CH 00035/16 A CH00035/16 A CH 00035/16A CH 352016 A CH352016 A CH 352016A CH 710622 B1 CH710622 B1 CH 710622B1
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- hyaluronic acid
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 21
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 21
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 21
- 208000024891 symptom Diseases 0.000 title claims abstract description 6
- 230000000699 topical effect Effects 0.000 title claims abstract description 6
- 230000036343 milk tooth eruption Effects 0.000 title claims abstract description 5
- 210000003133 primary dentition Anatomy 0.000 title claims abstract description 5
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 title description 3
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 34
- 238000009472 formulation Methods 0.000 claims abstract description 29
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims abstract description 14
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 239000000284 extract Substances 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 claims description 12
- 229940101267 panthenol Drugs 0.000 claims description 12
- 235000020957 pantothenol Nutrition 0.000 claims description 12
- 239000011619 pantothenol Substances 0.000 claims description 12
- 244000042664 Matricaria chamomilla Species 0.000 claims description 9
- 235000007232 Matricaria chamomilla Nutrition 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 7
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 claims description 7
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 claims description 7
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 7
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 7
- 240000002129 Malva sylvestris Species 0.000 claims description 6
- 235000006770 Malva sylvestris Nutrition 0.000 claims description 6
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 5
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 5
- 239000000796 flavoring agent Substances 0.000 claims description 5
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 5
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 5
- 235000010234 sodium benzoate Nutrition 0.000 claims description 5
- 239000004299 sodium benzoate Substances 0.000 claims description 5
- 239000001509 sodium citrate Substances 0.000 claims description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
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- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 4
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- 239000003765 sweetening agent Substances 0.000 claims description 2
- 239000000419 plant extract Substances 0.000 claims 2
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- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 5
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
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- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
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- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
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- PYHRZPFZZDCOPH-QXGOIDDHSA-N (S)-amphetamine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C[C@H](N)CC1=CC=CC=C1.C[C@H](N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-QXGOIDDHSA-N 0.000 description 1
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 description 1
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- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
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- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- RLGQACBPNDBWTB-UHFFFAOYSA-N cetyltrimethylammonium ion Chemical compound CCCCCCCCCCCCCCCC[N+](C)(C)C RLGQACBPNDBWTB-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000004489 deciduous teeth Anatomy 0.000 description 1
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- 235000020243 first infant milk formula Nutrition 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
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- 210000000265 leukocyte Anatomy 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
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- 210000002050 maxilla Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
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- 239000008267 milk Substances 0.000 description 1
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- 210000004225 permanent dentition Anatomy 0.000 description 1
- 230000036342 permanent tooth eruption Effects 0.000 description 1
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- 230000035790 physiological processes and functions Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Dermatology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Engineering & Computer Science (AREA)
- Alternative & Traditional Medicine (AREA)
- Molecular Biology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La presente, invenzione si riferisce a una formulazione contenente acido ialuronico butirrato o un suo sale farmaceuticamente accettabile per l'uso nel trattamento topico dei sintomi associati alla dentizione decidua.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.
Description
[0001] La presente invenzione si riferisce a formulazioni contenenti un estere butirrico dell'acido ialuronico per uso topico nel trattamento dei sintomi associati alla dentizione decidua. [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.
Stato dell'arteState of art
[0002] Con il termine „dentizione“ si definisce il processo di nascita e di sviluppo dei denti all'interno della bocca. I denti da latte, o decidui, sono 20, essi erompono verso i 6-7 mesi di vita per arrivare al completamento attorno ai 3 anni. [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] Quella del neonato, viene chiamata anche „prima dentizione“ per distinguerla dalla dentizione permanente dell'adulto. Nonostante siano già inclusi e parzialmente calcificati nelle ossa mascellari, originandosi già intorno alla settima settimana di gestazione dal foglietto germinale ectodermico, i denti decidui tendono a spuntare solo qualche mese dopo la nascita. [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] Dopo la nascita, i denti erompono gradualmente attraverso le gengive ed iniziano a spuntare tendenzialmente verso il sesto mese di vita. Normalmente, i primi denti da latte ad erompere sono i due incisivi centrali inferiori; gli altri denti seguono via via secondo una cronologia abbastanza definita, anche se la dentizione di ogni neonato è un caso unico. Basti pensare, ad esempio, che alcuni bambini nascono già con un dente (in genere, un incisivo inferiore), mentre altri devono attendere anche 7-8 mesi prima che questo faccia la sua comparsa. [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] La seconda dentizione comprende 32 denti: i denti permanenti erompono in un lasso di tempo che mediamente va dai 6 anni fino ad arrivare a 18. [0005] The second dentition comprises 32 teeth: permanent teeth erupt in a period of time ranging from 6 years to 18 on average.
[0006] La prima dentizione è spesso annunciata da vari sintomi come la salivazione abbondante, che è dovuta alle sensazioni fastidiose e al senso di prurito causati dallo stiramento delle mucose gengivali, e il riscontro di gengive gonfie dovute all'infiammazione provocata dalla spinta del dente in fase di eruzione (M L Macknin et al. PEDIATRICS Vol. 105 No. 4 pp. 747 -752, Aprii 1, 2000). [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] L'irritazione, può risultare molto fastidiosa per il bambino e talvolta può causare dolore, irritabilità, sonno agitato, riduzione dell'appetito; in alcuni casi la dentizione può comportare anche un innalzamento della temperatura corporea e rush cutanei. [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] Alcune creme o gel che vengono utilizzati, per lenire la sensazione dolorosa dovuta alla dentizione, contengono anestetici quali lidocaina e benzocaina, tuttavia questi prodotti possono avere effetti collaterali anche importanti e andrebbero evitati ove possibile. [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] Si è ora trovato che una crema o gel o soluzione contenente un estere butirrico dell'acido ialuronico ripristina lo stato fisiologico del tessuto gengivale, accelera il processo di guarigione, riduce lo stato patologico dovuto ad infiammazione e dà sollievo al dolore. [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] L'acido ialuronico butirrato (HABut) in cui i gruppi idrossilici dell'acido ialuronico sono esterificati con residui dell'acido butirrico con diverso grado di sostituzione è noto avere proprietà anti-proliferative e dermoprotettive come elasticizzante e idratante della pelle. [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 e WO 2005/092929 descrivono la preparazione degli esteri butirrici dell'acido ialuronico con diverso grado di sostituzione. Tali esteri hanno una elevata attività antiproliferativa, che li rende utili nel trattamento di malattie caratterizzate da una abnorme proliferazione cellulare. [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.
Descrizione dell'invenzioneDescription of the invention
[0012] Oggetto della presente invenzione è quindi una formulazione contenente acido ialuronico butirrato o un suo sale farmaceuticamente accettabile, preferibilmente sale sodico per il trattamento topico dei sintomi associati alla dentizione decidua. 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] Preferibilmente l'acido ialuronico butirrato sale sodico utilizzato nelle formulazioni dell'invenzione ha un peso molecolare compreso tra 10<3>e 10<7>, Dalton più preferibilmente tra 10<4>e 10<6>Dalton, e un grado di sostituzione (D.S.) da 0,01 mol/mol a 3, preferibilmente da 0,1 a 2, dove il grado di sostituzione è definito come il rapporto tra il numero di residui di acido butirrico e il numero di unità disaccaridiche GlcNAc-GlcUA dell'acido ialuronico. [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] L'acido ialuronico butirrato sale sodico è preferibilmente presente nella formulazione dal 0,01% al 5% in peso rispetto al peso totale della formulazione, più preferibilmente dal 0,05% al 1%. [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%.
[0015] In una realizzazione preferita dell'invenzione la formulazione contiene pantenolo, preferibilmente dal 0,1% al 5% in peso rispetto al peso totale della formulazione, più preferibilmente dal 0,5% al 3%. 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%.
[0016] La formulazione farmaceutica preferibilmente contiene estratti di piante con proprietà lenitive quali estratto di Malva sylvestris e Chamomilla recutita o Matricaria chamomilla (Commiphora myrrha, Calendula officinalis, Aloe barbadensis, Glycyrrhiza glabra). 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).
[0017] Altri agenti farmaceuticamente accettabili possono essere aggiunti alla formulazione come per esempio agenti veicolanti, agenti emulsionanti, agenti gelificanti, conservanti, agenti antiossidanti, agenti tamponanti, dolcificanti, aromi e/o loro miscele. 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.
[0018] Le formulazioni dell'invenzione sono preferibilmente in forma di crema, gel o soluzione per uso topico per utilizzo nel cavo orale. 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] Le formulazioni dell'invenzione possono essere applicate sulla gengiva da 1 a 20 volte, preferibilmente da 1 a 10 volte al giorno a seconda della necessità. [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] Una realizzazione preferita dell'invenzione è la formulazione contenente: <tb>Acqua Depurata / Demineralised Water<SEP>q.b. 100 g <tb>Pantenolo / Panthenol<SEP>da 0,1 a 5 g <tb>Malva sylvestris Extract (Estratto Idroglicerico < 1%)<SEP>da 0,01 a 5 g <tb>Chamomilla recutita Extract (Estratto Idroglicerico < 1%)<SEP>da 0,5 a 5 g <tb>Gomma Xantana / Xanthan Gum<SEP>da 0,01 a 1 g <tb>Stevia<SEP>da 0 a 0,7 g <tb>Aroma Mela (1:150) naturale<SEP>da 0 a 2 g <tb>Idrossietilcellulosa<SEP>da 0,5 a 5 g <tb>Sodium Hyaluronate Butyrate<SEP>da 0,05 a 1 g <tb>Potassio Sorbato<SEP>da 0 a 0,5 g <tb>Sodio Benzoato<SEP>da 0 a 0,5 g <tb>Acido Citrico<SEP>da 0 a 5 g <tb>Sodio Citrato<SEP>Da 0 a 5 g[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
Esempio1Example 1
CHAMODENT BABY GELCHAMODENT BABY GEL
[0021] <tb>Acqua Depurata / Demineralised Water<SEP>q.b. 100 g <tb>Pantenolo / Panthenol<SEP>1,00 g <tb>Malva sylvestris Extract (Estratto Idroglicerico < 1%)<SEP>1,00 g <tb>Chamomilla recutita Extract (Estratto Idroglicerico < 1%)<SEP>2,00 g <tb>Gomma Xantana / Xanthan Gum<SEP>0,20 g <tb>Stevia<SEP>0,10 g <tb>Aroma Mela (1:150) naturale<SEP>0,50 g <tb>Idrossietilcellulosa<SEP>2,00 g <tb>Sodium Hyaluronate Butyrate (SHB di Sigea S.r.l.)<SEP>0,10 g <tb>Potassio Sorbato<SEP>0,10 g <tb>Sodio Benzoato<SEP>0,10 g <tb>Acido Citrico<SEP>3,60 g <tb>Sodio Citrato<SEP>1,20 g[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
Esempio 2Example 2
[0022] <tb>Acqua Depurata / Demineralised Water<SEP>q.b. 100 g <tb>Pantenolo / Panthenol<SEP>1,5 g <tb>Malva sylvestris Extract (Estratto Idroglicerico < 1%)<SEP>1,50 g <tb>Chamomilla recutita Extract (Estratto Idroglicerico < 1%)<SEP>3,00 g <tb>Gomma Xantana / Xanthan Gum<SEP>0,20 g <tb>Stevia<SEP>0,30 g <tb>Aroma Mela (1:150) naturale<SEP>0,40 g <tb>Idrossietilcellulosa<SEP>3,00 g <tb>Sodium Hyaluronate Butyrate (SHB di Sigea S.r.l.)<SEP>0,10 g <tb>Potassio Sorbato<SEP>0,10 g <tb>Sodio Benzoato<SEP>0,10 g <tb>Acido Citrico<SEP>3,00 g <tb>Sodio Citrato<SEP>1,00 g[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
[0023] La formulazione è stata ottenuta con il seguente procedimento: <tb><SEP>FASE 1 : In un opportuno miscelatore con pale e turbina è stata caricata l'acqua demineralizzata e sono stati aggiunti nell'ordine il pantenolo, l'estratto glicerico di malva, l'estratto glicerico di camomilla, il potassio sorbato, il sodio benzoato, l'aroma di succo di mela, la stevia, l'acido citrico e il sodio citrato. La miscela è stata tenuta in agitazione sotto vuoto. <tb><SEP>FASE 2: La soluzione ottenuta nella fase precedente è stata filtrata in serie a 0,5 e 0,2 micron. <tb><SEP>FASE 3: Il sodio ialuronato butirrato, la gomma xantana e l'idrossietilcellulosa sono stati aggiunti e la miscela ottenuta è stata tenuta in agitazione sotto vuoto. <tb><SEP>FASE 4: Il prodotto ottenuto è stato scaricato nella tramoggia di carico dell'intubettatrice opportunamente tarata per la ripartizione nel confezionamento primario.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.
Comparazione tra Chamodent Baby Gel e prodotti commercialiComparison between Chamodent Baby Gel and commercial products
[0024] Per valutare l'influenza della formulazione Chamodent Baby Gel sul processo infiammatorio acuto, comparandola con quella di prodotti commerciali, è stato utilizzato un modello sperimentale in vitro che fa uso dei leucociti che per primi raggiungono il sito di flogosi: i polimorfonucleati neutrofili (PMN). L'idea è quella di simulare un ambiente infiammatorio e valutare come queste cellule, stimolate da una citochina pro-infiammatoria (TNF-α, fattore di necrosi tumorale), rispondono in presenza delle sostanze in esame. [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.
[0025] L'effetto anti-infiammatorio è stato analizzato valutando due risposte funzionali fondamentali dei PMN: la produzione di specie reattive dell'ossigeno (ROS) in seguito ad attivazione metabolica e la capacità di aderire a superfici biologiche. 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.
[0026] La risposta infiammatoria acuta promossa dal trattamento con la citochina pro-infiammatoria si considera proporzionale al numero di cellule adese a alla quantità di ROS prodotti. 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.
Valutazione della produzione di anione superossidoEvaluation of superoxide anion production
[0027] La produzione di ROS, indice dell'attivazione metabolica dei PMN, è stata valutata in termini di anione superossido (O2<->) rilasciato nel medium in seguito ad incubazione per 60 minuti delle cellule con TNF-α in pozzetti di piastre da microtitolazione rivestiti con Acido Ialuronico (HA), Acido Ialuronico Butirrato (HABut), Dentinale, Dentinale n. e Alovex. Ci si è avvalsi di un metodo spettrofotometrico che permette di misurare la quantità di citocromo c ridotto dall'anione superossido prodotto dalle cellule durante l'incubazione in piastra. I pozzetti rivestiti con i vari substrati sono riempiti con una soluzione di citocromo c 0.18 mM e TNF 0.15 ng/ml in tampone Hepes. I moduli così allestiti vengono riscaldati per 10' a 37 gradi in un incubatore umidificato; ad ogni pozzetto è aggiunta una sospensione cellulare di 1.5X10<6>PMN/ml in tampone Hepes. Ad intervalli di 15 minuti la piastra viene prelevata dall'incubatore e sottoposta ad analisi spettrofotometrica in un lettore per micropiastre alla lunghezza d'onda di 550 nm e 540 nm, che corrispondono rispettivamente al picco d'assorbimento del citocromo c ridotto e al punto isosbestico degli spettri di assorbimento del citocromo c ridotto ed ossidato. La differenza tra i valori di assorbanza registrati alle due lunghezze d'onda risulta proporzionale alla quantità di citocromo c ridotto. La quantità di O2<->prodotta da 10<6>cellule viene calcolata come segue: nmoli O2<->/ 10<6>PMN = D.O. × 10<6>/ 0.0037 × n dove n è il numero di cellule aggiunte ad ogni pozzetto. 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 × n where n is the number of cells added to each well.
Valutazione dell'adesione a superfici biologicheAssessment of adhesion to biological surfaces
[0028] La quantità di cellule che avevano aderito al substrato durante il saggio metabolico è stata valutata dosando l'attività dell'enzima mieloperossidasi, assunto come marker dei neutrofili. Dopo aver effettuato le letture spettrofotometriche per la misura della produzione di O2<->, i pozzetti della micropiastra vengono riempiti con PBS e centrifugato a 200 g per 5 minuti per rimuovere le cellule non adese alla superficie. Il dosaggio dell'attività mieloperossidasica si effettua misurando l'ossidazione del substrato 3',5,5'-tetramethylbenzidine (TMB) ad opera dell'enzima MPO in presenza di H2O2. Si aggiunge a ciascun pozzetto tampone acetato contenete TMB, cetiltrimetilammonio (CTAB) e 3-ammino-1,2-4-triazolo (AMT) e la piastra è agitata per 5' per facilitare la lisi cellulare e favorire il rilascio della MPO dai granuli. L'attività della eosinofiloperossidasi derivante dagli eosinofili che possono contaminare la preparazione dei PMN, viene inibita con l'ATM. Dopo 2 minuti dall'aggiunta di H2O2la reazione si blocca con H2SO4e si misura l'assorbanza di ciascun pozzetto alla lunghezza d'onda di 405 nm. La percentuale di cellule adese si calcola facendo riferimento ad una curva standard costruita, in ciascun esperimento, sulla base dei valori di attività perossidasica calcolati per quantità note di cellule. 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] I risultati della sperimentazione sono riportati nella Fig. 1 e Fig. 2. [0029] The results of the experimentation are reported in Fig. 1 and Fig. 2.
[0030] Fig. 1 : Produzione di anione superossido rilasciato da neutrofili a contatto con superfici rivestite da Ha, HABut Chamodent Dentinale, Dentinale Natura e Alovex. [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: PMN non attivati con TNF. TNF: PMN attivati con TNF-α. [0031] Resting: PMNs not activated with TNF. TNF: PMN activated with TNF-α.
[0032] Fig.2: Adesione dei PMN ad una superficie rivestita con Ha, HABut, Chamodent Dentinale, Dentinale Natura e Alovex. [0032] Fig. 2: Adhesion of PMNs to a surface coated with Ha, HABut, Chamodent Dentinale, Dentinale Natura and Alovex.
[0033] Resting: PMN non attivati con TNF. TNF: PMN attivati con TNF-α. [0033] Resting: PMNs not activated with TNF. TNF: PMN activated with TNF-α.
ConclusioniConclusions
[0034] Gli esperimenti dimostrano una chiara attività anti-infiammatoria di Chamodent Baby Gel, migliore anche rispetto al solo sodio ialuronato butirrato (HABut prodotto da Sigea), ma soprattutto rispetto ai prodotti formulati commerciali (Dentinale prodotto da Montefarmaco, Dentinale Natura prodotto da Montefarmaco e Alovex prodotto da Recordati). Rispetto alle altre sostanze testate, in presenza di Chamodent Baby Gel i neutrofili attivati mostrano un minor rilascio di superossido ed un più basso livello di adesione alla superficie comportamento indicativo dell'azione di un composto ad attività anti infiammatoria. Come riferimento si è voluto impiegare sodio ialuronato (HA) che ha delle prestazioni peggiori di Chamodent Baby Gel. 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] Tutti i risultati sono coerenti con la tesi di una migliore prestazione di Chamodent Baby Gel rispetto le altre sostanze, pure o formulate, testate. Risorse genetiche secondo l'art. 49a LBI <tb>Risorse genetiche:<SEP>Origine delle risorse genetiche: (paese d'origine; distributore locale) <tb>Stevia<SEP>Cina, Aoxing Stevia; Italia, Tillmanns SpA, Via Benigno Crespi, 10/a Milano[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
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