NZ744196B2 - Viscosity and stability modified ultrasound gel - Google Patents
Viscosity and stability modified ultrasound gel Download PDFInfo
- Publication number
- NZ744196B2 NZ744196B2 NZ744196A NZ74419616A NZ744196B2 NZ 744196 B2 NZ744196 B2 NZ 744196B2 NZ 744196 A NZ744196 A NZ 744196A NZ 74419616 A NZ74419616 A NZ 74419616A NZ 744196 B2 NZ744196 B2 NZ 744196B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- gel
- viscosity
- cnc
- agent
- ultrasound
- Prior art date
Links
- 238000002604 ultrasonography Methods 0.000 title claims abstract description 79
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 68
- 238000000034 method Methods 0.000 claims abstract description 37
- 235000011187 glycerol Nutrition 0.000 claims abstract description 32
- 239000001913 cellulose Substances 0.000 claims abstract description 11
- 229920002678 cellulose Polymers 0.000 claims abstract description 11
- 239000002159 nanocrystal Substances 0.000 claims abstract description 8
- 229940075508 carbomer homopolymer type b Drugs 0.000 claims abstract description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 47
- 230000005855 radiation Effects 0.000 claims description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 31
- 239000003755 preservative agent Substances 0.000 claims description 24
- 230000002335 preservative effect Effects 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 18
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 18
- 239000000811 xylitol Substances 0.000 claims description 18
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 18
- 235000010447 xylitol Nutrition 0.000 claims description 18
- 229960002675 xylitol Drugs 0.000 claims description 18
- 239000002562 thickening agent Substances 0.000 claims description 16
- 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 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 229940124378 dental agent Drugs 0.000 claims description 15
- 239000004302 potassium sorbate Substances 0.000 claims description 15
- 229940069338 potassium sorbate Drugs 0.000 claims description 15
- 235000010241 potassium sorbate Nutrition 0.000 claims description 15
- 229920000642 polymer Polymers 0.000 claims description 10
- 150000005846 sugar alcohols Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 244000005700 microbiome Species 0.000 claims description 6
- 239000002243 precursor Substances 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- 230000004075 alteration Effects 0.000 claims description 4
- 206010013781 dry mouth Diseases 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- 230000008719 thickening Effects 0.000 claims description 3
- 239000000499 gel Substances 0.000 description 299
- 229920002125 Sokalan® Polymers 0.000 description 37
- 238000009472 formulation Methods 0.000 description 17
- 210000001519 tissue Anatomy 0.000 description 16
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 15
- 235000013305 food Nutrition 0.000 description 15
- 238000002156 mixing Methods 0.000 description 15
- 230000001954 sterilising effect Effects 0.000 description 14
- 238000004659 sterilization and disinfection Methods 0.000 description 13
- 229960001631 carbomer Drugs 0.000 description 12
- 230000015556 catabolic process Effects 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 230000037406 food intake Effects 0.000 description 9
- 239000000017 hydrogel Substances 0.000 description 9
- 238000003384 imaging method Methods 0.000 description 9
- 150000002500 ions Chemical class 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 210000004872 soft tissue Anatomy 0.000 description 9
- 210000000214 mouth Anatomy 0.000 description 8
- 206010073306 Exposure to radiation Diseases 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000003349 gelling agent Substances 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- 238000004806 packaging method and process Methods 0.000 description 6
- 210000003296 saliva Anatomy 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 238000012285 ultrasound imaging Methods 0.000 description 6
- 210000001124 body fluid Anatomy 0.000 description 5
- 230000036512 infertility Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 210000004400 mucous membrane Anatomy 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- -1 but not limited to Chemical class 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 208000002925 dental caries Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000002105 nanoparticle Substances 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
- RFIMISVNSAUMBU-UHFFFAOYSA-N 2-(hydroxymethyl)-2-(prop-2-enoxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)COCC=C RFIMISVNSAUMBU-UHFFFAOYSA-N 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 235000021472 generally recognized as safe Nutrition 0.000 description 3
- 238000011194 good manufacturing practice Methods 0.000 description 3
- 229920001519 homopolymer Polymers 0.000 description 3
- 239000011814 protection agent Substances 0.000 description 3
- 238000009210 therapy by ultrasound Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 229920001046 Nanocellulose Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 2
- 206010039424 Salivary hypersecretion Diseases 0.000 description 2
- OKKRPWIIYQTPQF-UHFFFAOYSA-N Trimethylolpropane trimethacrylate Chemical compound CC(=C)C(=O)OCC(CC)(COC(=O)C(C)=C)COC(=O)C(C)=C OKKRPWIIYQTPQF-UHFFFAOYSA-N 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 229940031663 carbomer-974p Drugs 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000001879 gelation Methods 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 231100000344 non-irritating Toxicity 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000012744 reinforcing agent Substances 0.000 description 2
- 208000026451 salivation Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- 241000193171 Clostridium butyricum Species 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 206010058667 Oral toxicity Diseases 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000194019 Streptococcus mutans Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005250 alkyl acrylate group Chemical group 0.000 description 1
- 229940086737 allyl sucrose Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000001680 brushing effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000037123 dental health Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000806 elastomer Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000002864 food coloring agent Nutrition 0.000 description 1
- 238000009920 food preservation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 231100000003 human carcinogen Toxicity 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- NJTGANWAUPEOAX-UHFFFAOYSA-N molport-023-220-454 Chemical compound OCC(O)CO.OCC(O)CO NJTGANWAUPEOAX-UHFFFAOYSA-N 0.000 description 1
- 230000003232 mucoadhesive effect Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 231100000804 nongenotoxic Toxicity 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 231100000418 oral toxicity Toxicity 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical class O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
- A61B17/225—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for for extracorporeal shock wave lithotripsy [ESWL], e.g. by using ultrasonic waves
- A61B17/2251—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for for extracorporeal shock wave lithotripsy [ESWL], e.g. by using ultrasonic waves characterised by coupling elements between the apparatus, e.g. shock wave apparatus or locating means, and the patient, e.g. details of bags, pressure control of bag on patient
- A61B2017/2253—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for for extracorporeal shock wave lithotripsy [ESWL], e.g. by using ultrasonic waves characterised by coupling elements between the apparatus, e.g. shock wave apparatus or locating means, and the patient, e.g. details of bags, pressure control of bag on patient using a coupling gel or liquid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
- A61B8/12—Diagnosis using ultrasonic, sonic or infrasonic waves in body cavities or body tracts, e.g. by using catheters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
- A61B8/42—Details of probe positioning or probe attachment to the patient
- A61B8/4272—Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue
- A61B8/4281—Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue characterised by sound-transmitting media or devices for coupling the transducer to the tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N7/00—Ultrasound therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
Abstract
ultrasound gel comprising carbomer homopolymer Type B, cellulose nanocrystals and glycerine. The gel has an acoustic impedance of 1.45 to 1.60 MRayls and can be safely used internally or orally. The gel can be sterilized by exposure to gamma-radiation and substantially retains its viscosity. The invention also relates to a method of altering the viscosity of a gel after exposure to gamma-radiation by use of cellulose nanocrystals at a concentration of between 4% and 15% of the gel by weight. invention also relates to a method of altering the viscosity of a gel after exposure to gamma-radiation by use of cellulose nanocrystals at a concentration of between 4% and 15% of the gel by weight.
Description
(12) Granted patent specificaon (19) NZ (11) 744196 (13) B2
(47) Publicaon date: 2021.12.24
(54) VISCOSITY AND STABILITY MODIFIED ULTRASOUND GEL
(51) Internaonal Patent Classificaon(s):
A61K 49/22 A61B 8/13 A61K 47/04 A61K 47/38 A61N 7/00
(22) Filing date: (73) Owner(s):
2016.12.09 SMILESONICA INC.
(23) Complete specificaon filing date: (74) Contact:
2016.12.09 PIPERS
(30) Internaonal ty Data: (72) Inventor(s):
US 62/276,927 1.10 SCURTESCU, Cristian
GILL, Gleam
(86) Internaonal Applicaon No.:
2016/051452
(87) Internaonal Publicaon number:
WO/2017/117650
(57) Abstract:
An ultrasound gel comprising carbomer homopolymer Type B, cellulose nanocrystals and glycerine.
The gel has an acousc impedance of 1.45 to 1.60 MRayls and can be safely used internally or
. The gel can be ized by exposure to radiaon and substanally retains its
viscosity. The invenon also relates to a method of altering the viscosity of a gel aer exposure to
gamma-radiaon by use of cellulose nanocrystals at a concentraon of between 4% and 15% of
the gel by weight.
744196 B2
TITLE: VISCOSITY AND STABILITY MODIFIED ULTRASOUND GEL
CROSS REFERENCE T0 RELATED APPLICATIONS:
This application claims priority of United States Provisional Patent
Application Serial No. 62/276,927, entitled “Viscosity and Stability Modified
ound Gel", filed January 10, 2016, and hereby incorporated by reference
herein in its entirety.
TECHNICAL FIELD:
The present application relates to ultrasound gels, and more particularly,
ultrasound gels that can be safely used internally and/or orally.
BACKGROUND:
By way of background, it is standard ce to use aqueous gels as
coupling agents for ultrasound producing/sensing devices in ultrasound imaging
and y. A key element of an ultrasound gel is to have acoustic impedance
similar to that of soft tissue.
Some ultrasound therapies and imaging are done by inserting an
ultrasound probe into a body cavity (intracavitary ultrasound procedures) or
othenlvise internally into a patient. For example, ultrasonic dental y or
g devices require the patient to apply the gel intra-orally, however there is
presently no known ultrasonic gel product specifically approved and ed for
intra-oral applications. While there are existing non-ultrasonic intra-oral gels, the
gels are still labelled as “not to be ingested”. The use of a gel with ultrasonic
dental therapy or oralfintracavitary g devices requires the patient to apply
the gel intra—orally, which can lead to ingestion of small quantities of gel.
Some gels face difficulty in maintaining the gel viscosity high after gamma
radiation ization. For example, a gel may have a target viscosity in the
order of 80,000 cPs (centipoises) -100,000 cPs after sterilization with gamma
radiation, however where the initial gel is very viscous (>100,000 cPs) before
gamma radiation sterilization, after the gel iss exposed to gamma radiation (for
example, a 25-40kGy standard dose for ization used in the ry) it
becomes a near liquid of very low ity (for example, less than 10,000 cPs).
Accordingly, a solution is desired to obtain a gel compatible with gamma
irradiation (for sterilization) and has a high post-irradiation ity 0-
100,000 cPs) usable for intracavitary ultrasound where high viscosity and sterility
is required. As such, there remains a need to provide products and methods,
such as internally and orally compatible ultrasound gels, that can overcome the
shortcomings of the prior art.
SUMMARY:
The present disclosure relates to an ultrasound gel for use with internal
and oral ultrasound g and/or therapy. The gel can have ound
acoustic properties that can closely match a soft tissue to be /treated and
can be of a high viscosity that is maintained at body temperature or when
d to bodily fluids (for instance, ). In some embodiments, the gel can
act as a lubricant. gh water—based, the gel can be hydrophobic and not
readily dissolvable in bodily fluids. In some embodiments, the gel can be sterile,
safe for ingestion, and include a preservative. The gel can be used for oral or
non-oral applications and when used orally, can comprise a dental agent for
inhibiting growth of dental rganisms. In order to achieve sterility while
maintaining a desired viscosity range, the gel can include a viscosity stabilising
agent such as a viscosity protection agent for protection from radiation induced
breakdown. In some ments, methods of altering or maintaining the
viscosity of a gel is ed.
In some embodiments, the gels can provide an ultrasound couplant and
device lubricant suitable for medical use of ultrasound acoustic energy for intra—
oral and dental therapy, intracavitary ultrasound imaging or other measurements,
while contacting the intra-oral, dental tissue or food pipe tissue, mucous
membranes, fluids and neighbouring/adjacent organs. The gel can have acoustic
properties similarto soft tissue or gums, or other internal bio—structures.
The term “CNC”, as used herein, can refer to Qellulose flanogrystals,
erstalline _N_anoge||ulose, and is also known as flanogrystalline Qellulose
(NCC). CNC can be a polymer and can comprise nanoparticles in some
embodiments.
CNC can have cross-linkage ties and can disperse in water.
Polymeric systems based on cellulose with sive behaviors can show
unique properties such as biocompatibility, biodegradability, and biological
functions.
Use of CNC according to the present disclosure, can provide for at least
two new and cted behaviours:
a) addition of small amounts of CNC can maintain high viscosity of a
carbomer based ultrasound gel after undergoing gamma radiation sterilization.
Adding CNC can reduce or prevent a gel ity drop observed during shelf life
testing post irradiation. In addition, to achieving a high viscosity pre and post
ion, the use of small concentrations of CNC can allow the use of less highly
cross-linked CarbopolsTM. For example, there are various grades of CarbopolsTM
available, some with higher linking than others.
b) gels made of only CNC (no carbomer) and water increased gel
viscosity after exposure to gamma radiation.
The state of the art does not teach:
a) the use of CNC as an additional gelling agent in carbomer based
ultrasound gels. The use of CNC as an additional component (a few % by mass
being added) in ultrasound gel based on a carbomer gelling agent (such as
CarbopolTM), can increase the viscosity of the resulting gel, while maintaining
appropriate acoustic ties of the gel;
b) the use of CNC as a protection agent in carbomer based ultrasound
gels against the loss in viscosity caused by gamma radiation sterilization. Where
CNC is added to a ultrasound gel based on a carbomer gelling agent (such as
olTM), and the gel is ized using gamma radiation, the resulting post
radiated gel can remain much more viscous (for example, twice as viscous) as
compared with a post radiated gel that did not have any CNC added; and
c) the thickening behavior of CNC gels (just CNC, without carbomer)
when irradiated during gamma radiation sterilization. CNC gels (without
er) can increase their viscosity when irradiated with gamma rays, and this
can provide a method to obtain high viscosity ultrasound gels post radiation, and
control the viscosity post ion by controlling the radiation dose and the initial
CNC concentration in pre-radiation gel.
ing the term “CarbopolTM”, as used herein, can refer to high
molecular weight, crosslinked polyacrylic acid polymers. CarbopolsTM can differ
by ink density and can be grouped as homopolymers or copolymers.
CarbopolTM lyers can be polymers of acrylic acid crosslinked with allyl
sucrose or allyl pentaerythritol. CarbopolTM 974P NF is a homopolymer (acrylic
acid crosslinked with allyl pentaerythritol). CarbopoITM copolymers can be
rs of acrylic acid and 010-030 alkyl acrylate crosslinked with allyl
pentaerythritol.
The term “carbomer", as used herein, is a generic (i.e. nonproprietary)
name d by USP-NF, United States Adopted Names Council (USAN) and
CTFA for various CarbopolTM polymers. As such CarbopolTM 974P NF can be
referred to as a carbomer homopolymer Type B. Carbomers 71G and 971P NF
are categorized as Homopolymer Type A, while 974P NF is Type B based on
their viscosity characteristics.
Broadly stated, in some embodiments, an internal ultrasound gel is
provided, comprising: water; a thickening agent for thickening the water into a
gel; a neutralizer for setting the gel viscosity and adjusting a pH level of the gel;
a viscosity agent for reducing s of gel viscosity due to radiation exposure;
and a preservative for preserving the gel; wherein the gel has an acoustic
impedance similar to soft tissue and can be safely used internally or .
In some ments, the viscosity agent comprises nanoparticles, CNC,
and/or glycerin. In some embodiments, the thickening agent comprises a
carbomer, a CarbopolTM, and/or carbomer homopolymer Type B (CarbopolTM
974P NF). In some embodiments, the neutralizer comprises a base selected
from the group consisting of potassium hydroxide, sodium hydroxide, and
triethanolamine and the pH level of the gel is between 5.8 and 6.4. In some
embodiments, the preservative comprises a food grade preservative and/or
potassium e. In some ments, the gel further comprises a dental
agent for ting growth of dental microorganisms, such as, but not limited to a
sugar alcohol, such as, but not limited to, xylitol. In some embodiments, the gel
further comprises a colourant for colouring the gel.
Broadly stated, in some embodiments, a method of imaging a tissue with
ultrasound is provided, the method comprising: providing an ultrasound imaging
apparatus, the apparatus comprising a transducer for emitting ultrasound;
applying an ultrasound gel, as described herein, n the transducer and the
tissue to be imaged; positioning the transducer proximate the tissue to be
imaged; and emitting ound through the gel to image the tissue.
Broadly stated, in some embodiments, a method of treating a tissue with
ultrasound is provided, the method sing: providing an ultrasound
treatment apparatus, the tus comprising a transducer for emitting
ultrasound; applying an ultrasound gel, as described herein, between the
transducer and the tissue to be d; positioning the ucer proximate the
tissue to be d; and emitting ultrasound through the gel to treat the tissue.
Broadly stated, in some embodiments, a kit for applying ultrasound to a
tissue is provided, the kit comprising, an ultrasound gel, as described herein, and
ctions for use of the gel.
Broadly stated, in some ments, a method of protecting a viscosity
of a polymer based ultrasound gel is provided, the method comprising: providing
an ultrasound gel comprising water; a thickening agent for ning the water
into a gel; a neutralizer for setting the gel viscosity and adjusting a pH level of
the gel; and a preservative for preserving the gel; wherein the gel has an
acoustic impedance similar to soft tissue and can be safely used internally or
orally; adding a viscosity agent to the ultrasound gel for reducing changes of
ultrasound gel viscosity due to radiation exposure; and exposing the ultrasound
gel to radiation; wherein a decrease in ound gel viscosity, due to exposure
to radiation, is reduced by the viscosity agent.
in some embodiments, the viscosity agent comprises nanoparticles, CNC,
and/or in.
Broadly stated, in some embodiments, a method of altering the viscosity
of a gel is provided, the method comprising: providing a gel precursor comprising
water; ng a mixture by adding a ity agent to the gel precursor, the
viscosity agent for altering viscosity of the gel precursor due to radiation
exposure; and exposing the mixture to radiation; wherein an alteration in mixture
viscosity changes, due to exposure to radiation, is caused by the viscosity agent.
In some embodiments, the viscosity agent comprises nanoparticles, CNC,
and/or glycerin.
y stated, in some embodiments, an internal ultrasound gel is
provided, said ultrasound gel as produced by any of methods disclosed herein.
Broadly stated, in some embodiments, a use of CNC as a viscosity agent
is provided to cause a decrease a change to ultrasound gel viscosity due to
exposure to radiation.
Broadly stated, in some embodiments, a use of CNC as a viscosity agent
is provided to cause an alteration in el viscosity changes due to exposure
to radiation.
BRIEF PTION OF THE DRAWINGS:
Figure 1 is a schematic block diagram depicting an embodiment of an
ultrasound gel.
DETAILED DESCRIPTION OF EMBODIMENTS:
An ultrasound gel is provided for use with internal and oral ultrasound
imaging and/or therapy. The gel can have ultrasound acoustic ties that
can closely match a soft tissue to be imaged/treated and can be of a high
ity that is maintained at body temperature or when exposed to bodily fluids
(for instance, saliva). In some embodiments, the gel can act as a lubricant.
Although water-based, the gel can be hydrophobic and not readily dissolvable in
bodily fluids. In some embodiments, the gel can be sterile, safe for ingestion, and
include a preservative. The gel can be used for oral or non-oral applications and
when used orally, can comprise a dental agent for inhibiting growth of dental
microorganisms. In order to achieve sterility while maintaining a desired
ity range, the gel can e a viscosity stabilising agent such as a
viscosity protection agent for protection from radiation induced breakdown. In
some embodiments, s of altering or maintaining the viscosity of a gel is
provided.
ing now to Figure 1, a schematic block diagram is shown depicting
possible components and ial functional characteristics of an embodiment
of an ultrasound gel. In some embodiments, the ultrasound gel can comprise a
thickening agent, water, a neutralizer, a preservative, a viscosity affecting agent/
a radiation breakdown protective agent, and a dental agent. In some
embodiments, the ultrasound gel can be biocompatible, safe for ingestion and
application over mucous nes, insipid, hydrophobic, of high viscosity that
can be maintained when heated, food grade and/or sterile, reduce and prevent
oral bacteria and dental decay, le for ultrasound propagation/acoustic
properties match soft tissue, have reduced ity breakdown following
exposure to gamma irradiation, and also be a good lubricant.
In some embodiments, the gel can be used as a medical ultrasound
coupling media and lubricant. The gel can possess certain properties as
outlined herein.
In some embodiments, the gel can be biocompatible, orally compatible,
mucous membrane compatible, and ingestible by humans or animals. The
components of the gel can be based on the US. Food and Drug Administration
(FDA) Generally Recognized as Safe (GRAS) list and/or Food Additive Status
list for acceptable ingredients and additives. In some ic embodiments, the
gel components can be olTM 974P NF, water, potassium sorbate,
ium hydroxide, glycerine, CNC, and/or xylitol, with an acidity at a nonirritating
level (for example, between pH 5.5 and 7.5, and in some embodiments,
pH 6.0). As all gel components can be safe for ingestion and mucous
membrane application, the gel will be safe if a patient ingests the gel accidentally
or intentionally. In some ments, the gel can be food grade, following good
manufacturing practice (GMP) or natural health products (NHP) standards, or
sterile. The gel can be sterilized by heat (for example, by autoclaving) or other
sterilization methods as known in the art (for example, by e-beam or gamma
ation). In sterile embodiments, the gel can also be used on open wounds. In
some ments, the gel can be safe for long term repeated ingestion. For
example, users can ingest small quantities (a few mL) daily without adverse
effects as per FDA's GRAS database. The gels can be excretable by natural
pathways or ses. In some embodiments, the gels also do not ely
affect tooth health, gum tissue, or corrode teeth.
In some embodiments, the gel formulation may require additional
compounds in order to maintain its integrity through sterilization, for example
gamma radiation sterilization. These stability compounds can include, for
example, glycerine (glycerol) or propylene . ol has very low toxicity
when ingested and it is used widely in foods, beverages, and personal care
preparations. The oral toxicity of propylene glycol is also very low, and it does
not cause ization. Glycerol and propylene glycol can also be compatible
(and not ) ultrasound transducer encapsulation such as commonly used
silicone.
Different strategies can be used to achieve a gel of a certain viscosity.
Glycerine, for example, can be added to an initial gel formulation in order to
protect the gel during gamma radiation sterilization. In addition, a sterilizing
radiation dosage can be kept as low as possible (for example, a 25—40kGy
standard dose for sterilization used in the industry). Further, increasing the
concentration of the polymer (for example CarbopolTM) in the gel so that the
resulting radiated gel will be thicker. These modifications, however, do still do
not result in a on to the problem of creating a gel has a target viscosity in
the order of 80,000 cPs -100,000 cPs after ization with gamma radiation.
Further increases in the concentration of olTM in the gel to increase
its viscosity cannot create a safe internal and ingestible ound gel as the
higher amount of CarbopolTM will be potentially ed by a patient during each
use, leading to safety concerns.
Adjusted gel viscosities also push the manufacturing of the gel into a less
predictable outcome and the manufacturability of such a product is constrained.
For example, there is a limit to reducing the ion dose exposure to the gel
while ensuring a minimum exposure of 25 KGy dose. When irradiating the gel,
with the minimum exposure set at 25 KGy a feasible dose range is required
(while following the VDmax method for sterilization validation). Hence, the gel
still will be exposed to a radiation dose much higher than 25 KGy. As such, the
industry practice for sterile ts is to develop a formulation that remains
stable for the maximum gamma radiation dose of 40kGy or higher, which will
ensure that the normal dose of 25—40kGy used in the industry will always result
in post-irradiation products with the desired parameters.
An example is provided using the following terminology and formulations:
a) al Gel" formulation (per 1009 of gel): 1.3g CarbopolTM, 4.299 of
18% KOH, 0.59 xylitol, 0.1g Potassium Sorbate (optional), and the rest
demineralized water, all mixed under vacuum; and
b) "Adjusted gel” formulation (per 100g of gel): 1.89 CarbopolTM, 9.5g
glycerine, 4.299 KOH, 0.5g xylitol, 0.1g Potassium Sorbate (optional), and the
rest demineralized water, all mixed under vacuum.
The ity of the adjusted gel before irradiation was approximately
94,500 cPs (formulation of 1.3% CarbopolTM with 5% glycerin), however,
viscosity can be >100,000cPs with an increase in CarbopolTM from 1.39 to 1.89.
The viscosity of the adjusted gel after irradiation (range 27.6-32.8kGy) was
85,000 cPs, being on the lower side of a desired range (80,000-100,000). When
viscosity was re-measured after a few , viscosity had decreased
significantly. Using nt viscosity measurements, ity continued to
decrease and stabilized at around 65,000 cPs after 11 months of storage at
room temperature. While this is still considered a thick gel in industry terms, the
viscosity is lower than initially desired for medical/dental applications and it has
to be thick so that it stays firm on ound devices and limits the amount of gel
that is washed away by bodily fluids, such as saliva and then ingested.
While the adjusted gel can be used for dental applications, because it
viscosity is lower than desired, its applicability for other ultrasound applications
(such as intracavitary ultrasound) is less and less of an option or fit. For
example, the adjusted gel viscosity of 65000 cPs after radiation compares to
existing sterile and non-sterile ultrasounds gels on the market (30,000-45,000
cPs).
In some embodiments, a small amount of glycerol (from a few percent to
a few tens of percent) can be used to enhance gel resistance to breaking down
under larger doses of gamma radiation. For oral use of a gel, a low glycerol
concentration (for example, 5%-10%) can be used without significantly
ning the gel, while allowing the gel to withstand larger dose of gamma
radiation (for example 40kGy) and ining the high viscosity of the gel post—
irradiation.
A low glycerol concentration (5%~10%) can also cause a negligible
increase in the ic impedance of the gel therefore ining an acoustic
impedance y similar to that of soft tissue ximately 1.5MRayl), which
can be important for ultrasound wave propagation to minimize transducer-gel-
tissue interface ultrasound reflections.
In addition, some embodiments of the gels can also be safe for use with
ultrasound transducer ent, such as ultrasound transducers and
transducer heads known to those d in the art (including materials such as
ne elastomers, epoxy, or plastic, for instance). Accordingly, the gels can be
used with ultrasound ent without causing damage to the equipment. In
some embodiments, the gel can be complementary to, and easily orated
within, intra-oral ultrasonic devices and emerging ultrasonic dental imaging
systems.
In some embodiments, the gels can have antimicrobial properties. For
example, the gels can resist microbial growth after the gel package/bottle is
opened, and after possible ination by the environment or end user. In
some embodiments, a preservative can be used to inhibit molds, yeasts and
bacteria in the gel. In some embodiments, the gels can have a long shelf life at
room temperature. When under proper conditions, some embodiments of the gel
can be shelf-stable and will not physically degrade/decompose at room
temperature for a period of approximately at least two years and can also be
resistant to microbial spoilage for approximately at least two years.
In some embodiments, the gel can both comprise a preservative and also
be sterilized as discussed herein. In these embodiments, the combination of
preservative and sterilization can provide for additional safety for usage in
internal or oral applications.
In some embodiments, the gels can have a high viscosity as would be
understood by one skilled in the art. Viscosity can be difficult to quantify and
measure and the measurement can be dependent on the measuring apparatus
used and the conditions under what the viscosity is measured. Having said that,
one skilled in the art would have a g knowledge of the relative viscosity of
a gel with high ity. The viscosity and pH can be of an appropriate level to
be comfortable and non—irritating to a user. In addition, in some embodiments,
the viscosity of the gel is not significantly affected/reduced when the gel heats up
in contact with tissue/gums/saliva. The gel can also be able to withstand
nments it is exposed to during ound g/treatment without a
change in viscosity characteristics. Gel viscosity and acoustic impedance can
continue to be within acceptable imaging/treatment ranges even after use as
intended.
The gel can act as an ound couplant and the high viscosity can
provide good ic coupling to tissues such as gums and allow for the gel to
stay in place when positioned. As such, the gel can enhance the desired
acoustic properties of the applied ultrasound devices and/or treatments. The
ultrasound gel can have similar acoustic properties to the tissue it couples to, as
ound (sounds of a frequency higher than 20kHz) propagates poorly through
air.
In some embodiments, the gels can be ess (insipid) and do not
stimulate salivary glands. The absence of taste in the mouth can reduce
salivation which assists in reducing the amount of gel being washed by saliva
and potentially ingested. Slight fragrance or flavors in the mouth can provide an
increase in salivation which can be undesirable. In addition, the e of taste
can allow users to tolerate the gel in their mouths. In some embodiments, the gel
can be mildly sant in the mouth. As such, patients/users would be less
likely to intentionally consume the gel.
In some embodiments, the gel manufacturing process can be done under
vacuum to reduce/eliminate air trapped in the gel. The gel can be produced free
of, or with a reduced amount of, air bubbles. In some embodiments, this
characteristic can be achieved by vacuum mixing and manipulation during.
manufacturing.
Undissolved polymer or other insoluble particulate material can be
d by thorough mixing, general adherence to GMP practices, and by using
high grade compounds such as use of National Formulary (NF) standard
compounds.
To achieve some or all of these properties, in some embodiments, the gel
can comprise water, a neutralizer, a gelling/thickening agent, a preservative, a
viscosity ing agent, a radiation tive agent, a dental agent, and/or a
colourant. In some embodiments, the colorant can be, for example, FD&C (Food,
Drug, and Cosmetic) Green 3 colour , although any other safe coulorant
known in the art could be used.
In some embodiments, the gel can be water-based, but not water soluble
(hydrophobic) and therefore not readily dissolved by . In addition, some
embodiments of the gel do not dry out easily. In some embodiments, the water
used in the gel can be demineralized, degassed, distilled and/or reverse
sln addition, the water can be free of salts or alkali, as the presence of
electrolyte can significantly reduce the viscosity of the gel. The water used in the
gel can have low or acceptable levels of minerals, bacteria, etc. as would be
known in the art.
In some embodiments, a neutralizer can be used to neutralize the pH of
the gel to a biologically acceptable level. In some embodiments, a base can be
used as a neutralizer, for instance potassium hydroxide (KOH), sodium
hydroxide (NaOH), or anolamine. An appropriate amount of base can be
used to obtain a final gel pH similar to saliva, in the range of 6.5+/—1, or in the
range of 6+/—0.5. In some embodiments, KOH can be used (instead of NaOH) in
order to minimize the ity loss/reduction due to the neutralizer, thereby
maintaining high viscosity of the gel.
In some embodiments, the gel formulation can n a gelling/thickening
agent to increase the viscosity of the gel. In some embodiments, the
gelling/thickening agent can be a carbomer. In some cases, the carbomer can be
a CarbopoITM. As known in the art, there are a variety of CarbopolTM r
grades which differ in the performance characteristics (US pat no 221 by
Buchalter, incorporated by reference herein in its entirety). In some cases, the
CarbopolTM can be a highly cross-linked polymer such as a CarbopoITM974P NF.
CarbopolTM 974P NF can e low irritancy and non—sensitizing properties. In
addition, CarbopolTM 974P NF is generally not bio-absorbed or metabolized in
the body due to the high molecular weight and can be cross-linked exhibiting
high viscosities. CarbopolTM 974P NF concentrations of 0.1% to 5% by weight in
the gel can be used in some ments to provide suitable viscosity for oral,
or mucous membrane, use. As known in the art, these percentages can be
measured as being relative to the weight of the water. That is, adding 1 gram of
polymer to 100 grams of water would likely be known to those versed in the art
as "1%”. It can also be possible however, that one could have an alternate
n, that a 1% solution is 1 gram dissolved in 99 grams of water, as this
would have a total mass of 100 grams, giving what may be interpreted as a 1%
solution. In this case, either interpretation can be allowed. In some
embodiments, the CarbopolTM 974P NF tration can be 1.3-1.8% by
weight in the gel.
Carbopol 974P s from other carbomers in the following ways:
a) Solvent used/safety: A significant area of ence among
carbomers is the solvent system used to synthesize them.
"Traditional" polymers are synthesized in benzene (carcinogenic), such as
934 NF, 934P NF, 940 NF, 941 NF, 1342 NF. There are regulatory restrictions
on the use of benzene in pharmaceutical formulations. In addition, according to
Guidance for industry QBC guidelines, Benzene is grouped into Class 1 (Human
Carcinogens).
“Toxicologically preferred" polymers are sized in either ethyl
acetate or a cosolvent (ethyl e/cyclohexane mixture). As exane is
classified as Class 2 solvents (non-genotoxic animal ogens or possible
causative agents of irreversible toxicity, such as neurotoxicity or teratogenicity),
Carbomers such as 980 NF, 981 NF, 5984 EP, ETD 2020 NF, Ultrez 10 NF were
not desirable in the present gel applications.
Three carbomers (namely 71G NF, 971P NF, and 974P NF) use only
Ethyl Acetate as a polymerization solvent.
b) Viscosity: Among the three carbomers mentioned above (71G NF,
971P NF, and 974P NF), the viscosity of Carbopol 974P NF is 3-4 times higher
than that of Carbopol 71G NF or 971 P NF.
c) Mucoadhesion: Carbopol 974P NF has the highest mucoahesive
strength.
As such CarbopolTM 974P can be used in the present gels for the these
reasons:
1. it is safe for use in oral cavity or for intracavity ultrasound
procedures, where the gel can be potentially ingested over a period of time (for
oral use, a patient will continue ingesting this gel daily over many years).
2. Among the carbomers that are safe for oral or intracavitary use,
carbomer 974P has the highest viscosity for any given amount added to water.
Further meaning that to achieve the same level of viscosity, the least amount of
carbomer is used when using carbomer 974P, which further contributes to
safety.
3. Among the carbomers that are safe for oral or intracavitary use
er 974P has the highest mucoadhesive strength for any given amount
added to water.
In addition, Glycerin can be used for increasing l ic
impedance of the gel, as well as to protect the gel from decreasing in viscosity
after exposure to gamma irradiation.
In some embodiments, a preservative can also be added to the gel to
preserve the gel and increase its safety for internal ultrasound applications. In
some embodiments, the preservative can be a food grade preservative, for
example, potassium sorbate, parabens, or monolaurin. Potassium sorbate can
be used in the range of 0.01% to 1% of the gel to provide suitable preservation
against common pathogens for a pH in the range of 3 to 6.5, or in the range of
6+/—O.5, which is also a common acidity range for saliva. In addition, other
preservatives such as parabens can be used if a higher pH range is desired (for
example, from pH 3 to 9). In some embodiments, the ium sorbate
concentration can be n acceptable daily ingestion intake of potassium
sorbate can be 875mg daily for an average adult of or some oral
applications, only few grams of the gel can be used per day (for example, an
estimated 3-5 grams per day). Assuming full ingestion and a potassium sorbate
tration of 0.1% of the gel, the daily dose would be on the order of few
milligrams, which is well below the acceptable daily ingestion of 875mg.
In some embodiments, a dental agent can be used in the gel to e
added dental benefits to a atient when the gel is used orally. In some
embodiments, the dental agent can be a sugar alcohol. In some embodiments,
the sugar alcohol can be xyIItoI. The dental agent can provide an additional
treatment/therapeutic effect to a user/patient by preventing/reducing dental/oral
bacteria and/or atory infections. For preventing dental decay, sugar
alcohol, for instance xyIitoI in the range of 0.1 % to 5% has been shown to reduce
oral bacterial flora (for example Streptococcus mutans) and can lead to reduced
risk of dental cavities and improved oral and dental health. A preferred
concentration to reduce and prevent dental decay is 0.5% (this concentration
was used in Kontiokari, T. et al. 1995. "Effect of l on Growth of
Nasopharyngeal ia In Vitro”, Antimicrobial Agents and Chemotherapy.
39:1820, orated by reference herein in its entirety). Xylitol was also shown
(same reference) to reduce bacteria in nasopharyngeai flora and ng
atory infections (for example inhibiting the growth of Streptococcus
pneumoniae). In addition, xylitol is known to also have food preservation
properties inhibiting the growth of microorganisms such as clostridium butyricum,
Iactobacillus bulgaricus, saccharomyces cerevisiae, Escherichia coli, salmonella
typhi en, K. K. and Soderling, E. 1981. "Effect of Xylitol on Some Food-
Spoilage rganisms", Journal of Food Science. , incorporated by
reference herein in its entirety).
In some embodiments, a colorant (food, drug and/or cosmetic grade)
could also be added to the gel if a colored gel is desired.
In some embodiments, CNC can be added to an ted Gel”
formulation to increase overall viscosity of the gel, as well as to prevent
breakdown of gel during irradiation, leading to a much lower decrease in overall
viscosity post-irradiation. In some embodiments, both glycerin and CNC can be
added together to an initial formulation for better protection from breakdown due
to irradiation.
A CNC gel sample, as shown in Table 1 below, can be formulated by
mixing Carbopol in water, allowing the mixture to stay overnight, then
neutralizing with 18% KOH solution, followed by addition of CNC. Glycerin can
also be added as a final additive. In CNC gels samples without CarbopolTM, CNC
can be simply mixed in water, followed by pH adjustment by adding a small
amount of KOH solution. Glycerin can also be added as a final ve. The
above gel samples can also have xylitol added as a dental agent, and potassium
sorbate as a preservative.
An effect on post-radiation ity can also seen in a CNC hydrogel (i.e.
no Carbopol in the formulation). CNC can accelerate the formation of hydrogels
and can increase the effective crosslink density of hydrogels. CNC can be not
only a reinforcing agent for hydrogel, but can also act as a multifunctional cross~
linker for gelation.
Other concentrations of the gel ents can also be used to obtain
similar desired properties and results.
With regard to packaging and uses, the gels can be packed in sachet
bags (for single or multiple uses), tubes (for single or multiple uses), or in s
(squeeze bottles or bottle with pump), although any other appropriate packaging
and/or sing means, as apparent to one skilled in the art, could be used.
Prior art gel formulations, that risk spoilage and/or contamination with undesired
microbes when the package is opened and exposed to air, are generally
available in small, sterile pouches for single use. These are commonly used as
lubricants or in ions where sterility is d. As such, these prior art gel
formulations are limited to -use packaging. By contrast, some
ments of the present gels do not have the same risk of spoilage,
degradation, or contamination and can be ed for multiple uses, adding
increased convenience for the manufacturer and the user. In some
embodiments, the intended uses of the presently disclosed gels do not
necessarily require sterility.
In some embodiments, the gel can be used with ultrasound devices for
ultrasound imaging and/or ultrasound treatment (therapy). Some examples of
uses include methods of intra-oral and dental ultrasound treatment (therapy in
the oral cavity or the teeth/dental), methods of ound imaging in the oral
cavity (tongue, cheek, etc.) or dental ultrasound g,methods of internal
imaging such as endorectal (transrectal) ultrasonography, transvaginal
ultrasonography, or trans-esophageal rdiography (ultrasound imaging of
the heart through the food pipe).ln addition, the gels can be used in general
ltrasound) dental applications, such as gels to improve denture comfort, to
alleviate symptoms of dry mouth, and as a vehicle for chemical/pharmaceutical
agents aimed at improving tooth and gum sensitivity or help the treatment of oral
organs or food pipe organs where a gel is required. In some embodiments,
imaging/therapy can be performed from outside of a mouth, where the
imager/therapist adds gel (an external ultrasound gel as known in the art, or a
gel as disclosed herein) in between the transducer and the cheek, and also an
oral compatible gel (as disclosed herein) between the cheek and the dental
organ for ultrasound coupling for imaging or therapy.
The specific ties of the gels provided herein can provide benefits in
these types of applications. For e, the high viscosity of the gel can permit
the gel to stay on an ultrasound transducer head and reach the target site,
(particularly during intracavitary ultrasound procedures), whereas prior art gels
are washed away or eroded by the body cavity prior to ng the target site.
The gels can be biocompatible with oral, food pipe, and vaginal and rectal
mucous membrane tissue and fluids.
While the gels and uses thereof described herein are generally applicable
to human imaging and therapy, the gels and uses thereof can also be applicable
to nary ultrasound applications.
Without any tion to the foregoing, the present gels and methods are
further described by way of the following es.
EXAMPLE 1
MATERIALS
Materials: Purified Water 1100 g, Carbopol 974P NF 13g, Potassium
Hydroxide 18g, Club HouseTM green food colour 1 mL, Xylitol Sg, Potassium
sorbate 1g, glycerine 50g.
Equipment: Clockfl‘imer — ated, Vacuum pump, 5/16” lD vacuum
tubing, Vacuum chamber, Top-loading balance (0.1g precision), Time-of—flight
acoustic measurement system, pH meter + electrode, ieldTM viscometer.
General Supplies: ator, Spatula, Scoopula, Mixing vessel (eg. large
jar or vat), Weighing paper, 50 mL plastic syringe — Luer—lock, Dropper bottle with
dropper, Kim VlfipesTM, Paper towels, Label sheets, Pen, Felt marker, Anti-static
brush, 50 mL beaker, Broad spatula.
EXAMPLE 2
PRODUCTION
Note that in some embodiments, mixing steps can be performed under
vacuum so as to minimize gas/bubbles in the gel. If water or solutions are not
previously degassed, the water or solution can be degassed prior to use so as to
minimize gas/bubbles in the gel.
Prepare 18% KOH(aq) neutralizer: Weigh out 100 grams pure water into a
small . Weigh out 18 grams solid KOH into a beaker or onto a weighing
paper. Slowly add solid KOH to water, allow to dissolve with occasional stirring
(glass rod or plastic spatula).When fully dissolved, pour mixture into dropper
bottle ed as “18% )”.
Prepare gel dispersion: Weigh out 900 grams water into mixing vessel
(eg. 1000 mL beaker).Weigh out 5 grams xylitol. Dissolve xylitol in water with
stirring. Weigh out 1 gram potassium e. Dissolve potassium sorbate in
xylitol solution above. Weigh out 13 grams CarbopolTM 974P NF. N: This
material is a fluffy, lightweight powder. Ensure that any air currents are
minimized and that all weighing surfaces are static free. Static can be zed
by light brushing of contacting surfaces with anti-static brush. Add CarbopolTM
powder to potassium sorbate/xylitol solution above, with gentle manual mixing
using a spatula. Allow the gel to hydrate, for example by ng it to sit d
overnight in order to hydrate. *NOTE: the gel hydration can also be sped up by
adding the CarbopolTM powder to a spinning volume of water, as with a magnetic
stirrer.
Prepare gel: Add 42.9 grams of KOH solution above to a small beaker or
other transfer . The neutralizer solution should be added in a weight ratio
of 3.3 grams neutralizer per gram of CarbopolTM powder. Add 42.9 grams KOH
neutralizer solution to gel dispersion with manual stirring using broad spatula.
Finally, add 509 of glycerine to the gel dispersion. Mix until homogeneous gel is
ed. *NOTE: the gel will be highly viscous, making convection very difficult.
Because of this, the mixing requires a lot of physical mixing. Unless the entire
volume of the gel is thoroughly mixed, there will be regions of differing pH.
Confirm pH is approximately 6.0 using a standard pH meter. With a pH meter,
after calibrating the meter, dip the electrode into the gel and stir it around briefly
to coat the electrode in gel, then take a reading. Take a few readings, mixing in
between. If the readings are inconsistent, mix the gel thoroughly and check
again. If the readings were inconsistent on a sample volume, then it is likely that
the entire batch is not properly mixed. Target pH = 6.010.2.lf the pH is low, add
neutralizer in appropriate increments until pH is in correct range. Note that the
readings will not be consistent without extremely thorough mixing. If desired, add
an acceptable ant to the gel, for example add FD&C (Food, Drug, and
ic) Green 3 colour powder to gel. Mix until colour is evenly dispersed.
This will take thorough mixing with a broad a, or mixing by pallets in an
industrial mixing chamber, under a vacuum.
Degas gel: The degassing step is intended to remove bubbles introduced
in the formulation s. Place the gel in an open container. Place this
container into the vacuum chamber, seal the chamber, and pump down- to 600
mm Hg for 10 minutes (stopwatch). Allow the gel to warm up to room
temperature before making any further measurements.
A CNC gel sample, as shown in Table 1 below, can be formulated by
mixing Carbopol in water, allowing the mixture to stay overnight, then
neutralizing with 18% KOH solution, followed by on of CNC. Glycerin can
also be added as a final additive. In CNC gels samples without CarbopolTM, CNC
can be simply mixed in water, followed by pH adjustment by adding a small
amount of KOH solution. Glycerin can also be added as a final additive. The
above gel s can also have xylitol added as a dental agent, and potassium
sorbate as a preservative.
Characterize gel density: Multiple methods to characterize gel density are
known in the art and can be used. In one example, draw some degassed gel
into a 50 mL syringe, avoiding drawing in air bubbles as much as possible. Use
some easily readable part of the piston to make an initial reading of
volume.*Note that the total volume is not ant, only the difference between
the initial and final volume readings. Wipe all excess gel from the outside of the
syringe using a paper towel or KimWipeTM, then weigh the syringe. Draw some
more degassed gel into the syringe, studiously avoiding drawing in air bubbles.
The more gel used here, the lower the relative error, so get at least 10 mL of gel
on top of the initial amount. Record the final volume measurement using the
same part of the piston as was used for the initial measurement. Vlflpe all excess
gel from the outside of the syringe using a paper towel or Kim VlfipeTM, and then
weigh the syringe. Typical values are in the range 1.0-1.1 g/mL, with most
readings around 1.045g/ml.
Characterize gel ic velocity: le methods to characterize gel
ic velocity are known in the art and can be used. in one example, using a
spatula or something similar, fill the time-of—flight device with gel. One example
of an in-house time-of—flight device can be a plastic cylinder with a length of
approximately 100mm, with an ultrasound transducer attached to one end, and a
thin sheet of metal attached at the other end. The tube can be filled with gel, the
transducer can generate short ound pulses when driven by a function
generator, the transducer can sense a returning ound pulse when
connected to an oscilloscope, and the thin metal sheet can work as an
ound reflector. Place the device in the vacuum chamber and degas as
. There should be no bubbles or air gaps in the gel during the
measurement. Use the function generator and digital oscilloscope to record the
time of flight. Using the in-house apparatus, typical values for the acoustic
velocity can be in the range of 550m/s.
Calculate acoustic impedance: Calculations were done based on in—house
device gh multiple s to calculate acoustic impedance are known in
the art and can be used. In one example, impedance = (density)(acoustic
velocity). Typical values calculated in-house have ranged from 1.45-1.60
MRayls, although other values are possible.
Packaging and Quality Control: Dispense gel into final packaging, which
can be a multiple use packaging like bottles, jars, etc, or single use sterile or
erile pouches.
Viscosity testing: The viscosity ined for the gel at pH 6 was 50,000
to 100,000+ mPa.s (or cPs), and 85,000 mPa.s (or GP) in one sample [at 37°C
using ieldTM Viscometer LVF, SIN: 03390 spindle #4, 6 rpm]. This can be
a target spec, although deviations may occur in different circumstances and
when scaling up production. Viscosity can be difficult to quantify and measure
and the measurement can be dependent on the measuring apparatus used and
the conditions under what the viscosity is measured. Having said that, one
skilled in the art would have a working knowledge of the relative viscosity of a gel
with high viscosity.
EXAMPLE 3
RESULTS: VISCOSITY TESTING AND STABILITY
TABLE 1: s of Radiation on Viscosity
Gamma Acoustic Pre-radiation Post— afion used
ion Impedance viscosity radiation
dose post (cPs) viscosity
(kGy) ion (cPs)
(MRa yl)
Initial ~1 5 >100,000 fluid 1.39 Carbopol, NO giycerine,
9e| 40-43 KGy <10,000 NO CNC
Gamma
Radiation
Level test)
Adjusted 36.6-41.7 1 .49 94500 57,750 1.39 Carbopol, 59 giycerine,
Gel KGy NO CNC
Adjusted 27.6—32 8 1 590 94500 85,000 1.89 Carbopol, 9.59 giycerine,
9e| KGy 65,000 NO CNC
(after 11
months
aging)
CNC gel 6 40-495 1 540 >100,000 41,000 1.39 Carbopol, 59 giycerine,
CNC gel 1 40-495 1.517 >100,000 86,000 1.39 Carbopol, 59 giycerine,
CNC gel 8 4049.5 1.519 >100,000 8000 1.39 Carbopol, NO giycerine,
CNC gel 2 40-495 1.498 >100,000 >100,000 1.39 ol, 59 giycerine,
CNC gel 9 40—495 1.539 >100,000 52,000 1.39 Carbopol, NO giycerine,
CNC gel 3 40 49.5 1.587 >100,000 >100,000 1.3g Carbopol, 59 giycerine,
CNC gel 10 40—49 5 1.521 >100,000 91,000 1.39 Carbopol, NO giycerine,
69 CNC
CNC gel 7 40 49 5 appears 73,000 NO Carbopol, 59 glycerin,
similar but 159 CNC
lower than
CNC 9ei11
CNC gel 11 40-495 1,575 39,000 >100,000 NO Carbopol, NO giycerine,
159 CNC
*All gel samples from Table 1 were adjusted to have a pH of 6 using 18%
Potassium Hydroxide solution. The above samples are water—based, and also
contain 0.5% xylitol as a dental agent, and 0.1% potassium sorbate as a
preservative.
EXAMPLE 4
ATIONS: CNC AND GEL VISCOSITY
n observations were made regarding the creation, ation, and
viscosity testing of the gel samples, as outlined in Table 1.
1) Glycerin can help maintain crosslinking of CarbopolTM gels, but not
of pure CNC gels during gamma radiation;
2) CNC can provide crosslinking protection against breakdown due to
gamma radiation in the case of CarbopoITM gels with or without glycerin;
3) CNC and glycerin both added to the ted Gel” ation can
result in gels with the least drop in ity after irradiation;
4) Glycerin can increase the acoustic impedance of a gel, but adding
glycerin is often needed to maintain gel viscosity after radiation. However,
adding CNC does not appear to change the acoustic impedance, and only
protects the gel viscosity;
5) Pure CNC gels can present an acoustic impedance too high for
coupling to soft tissue, but adding less than 15% CNC can result in both a
viscous gel and desired acoustic impedance;
6) Certain concentrations of CNC gels can show an se in
viscosity after irradiation (for example, see results of CNC Sample 11 in Table
1); and
7) Adding glycerin adds a sweet taste to the gel, while adding CNC
adds no taste.
EXAMPLE5
'30 CONCLUSIONS: CRYSTALLINE NANOCELLULOSE (CNC) AND GEL
In some embodiments, CNC can be added to an “Adjusted Gel"
formulation to increase overall viscosity of the gel, as well as to prevent
breakdown of gel during irradiation, leading to a much lower decrease in overall
viscosity rradiation. In some embodiments, both glycerin and CNC can be
added together to an initial formulation for better protection from breakdown due
to irradiation.
An effect on adiation viscosity can also seen in a CNC hydrogel (i.e.
no Carbopol in the formulation). CNC can accelerate the formation of hydrogels
and can increase the effective crosslink density of hydrogels. CNC can be not
only a reinforcing agent for el, but can also act as a unctional cross-
linker for gelation.
The scope of the claims should not be limited by the ments as set
forth in the examples herein, but should be given the broadest interpretation
consistent with the description as a whole.
Although a few embodiments have been shown and described, it will be
appreciated by those skilled in the art that various changes and modifications
can be made to the ments described herein. The terms and expressions
used in the above description have been used herein as terms of description and
not of limitation, and there is no ion in the use of such terms and
expressions of excluding equivalents of the features shown and described or
portions thereof, it being recognized that the invention is defined and limited only
by the claims that follow.
The teachings provided herein can be applied to other methods, not
necessarily the method described herein. The elements and acts of the various
embodiments described above can be ed to provide further
embodiments.
These and other changes can be made to the invention in light of the
above description. While the above description details certain embodiments of
the invention and describes certain ments, no matter how detailed the
above appears in text, the ion can be practiced in many ways. Details of
the method may vary erably in their implementation details, while still
being encompassed by the invention disclosed herein.
Particular terminology used when describing certain features or aspects of
the invention should not be taken to imply that the terminology is being redefined
herein to be restricted to any specific characteristics, features, or aspects of the
invention with which that terminology is associated. In general, the terms used in
the following claims should not be construed to limit the invention to the specific
embodiments sed in the specification. Accordingly, the actual scope of the
invention encompasses not only the disclosed embodiments, but also all
equivalent ways of practicing or implementing the invention.
The above description of the embodiments of the ion is not intended
to be exhaustive or to limit the invention to the precise form disclosed above or
to the particular field of usage mentioned in this disclosure. While specific
embodiments of, and es for, the invention are described above for
rative purposes, various equivalent modifications are possible within the
scope of the invention, as those skilled in the relevant art will recognize. The
elements and acts of the various embodiments described above can be
combined to provide further embodiments.
While certain s of the invention are presented below in certain
claim forms, the inventors contemplate the s aspects of the invention in
any number of claim forms. Accordingly, the inventors reserve the right to add
onal claims after filing the application to pursue such additional claim forms
for other aspects of the invention.
REFERENCES
The following references are hereby incorporated by reference into this
application in their entirety.
1. US. Provisional Application No. 61/740,408, entitled "lntemal Ultrasound
Gel", filed on December 20, 2012.
PCT tional Application No.: 2013/001058, Pub. No.:
WO/2014/094127, entitled "internal Ultrasound Gel", filed on December
18, 2013.
Modification and Characterization of Biodegradable Methylcellulose Films
with TrimethylolpropaneTrimethacrylate (TMPTMA) by v Radiation: Effect
of Nanocrystalline Cellulose. J. Agric. Food Chem., 2): 623-629;
Mechanical and Barrier Properties of Nanocrystalline ose
Reinforced Po|y(caprolactone) Composites: Effect of Gamma Radiation.
J. Applied Polym. Sci., 129(2013): 3038-2046;
Radiation grafting on natural films. Rad Phys. And Chem., 94(2014): 88-
U.S. Patent No. 8,618,1752, ound medical gel composition
etherified hydroxyethylcellulose;
US. Patent No. 3,108,890, Aqueous Cellulosic Compositions and
Methods of Making Same;
Comparison of Gamma Radiation Crosslinking and Chemical Crosslinking
on Properties of Methylcellulose Hydrogel. Engineering Journal, Col
16(4): pp. 15 —28 (“Rimdusit et al.).
Sultana, Islam, Dafader and Haque. Preparation of carboxymethyl
cellulose/acrylamide Copolymer hydrogel using gamma radiation and
Investigation of its swelling or. Journal of Bangladesh Chemical
Society, Vol. 25(2), 132-138, 2012.
. Xiaoyun Qiu and Shuwen Hu. “Smart” Materials Based on Cellulose: A
Review of the
‘11. ations, Properties, and Applications. als 2013, 6, 738-781;
doi:10.3390/ma6030738
12. Chengjun Zhou, Qinglin Wua, Yiying Yue, o Zhang. Application of
rod-shaped cellulose nanocrystals in rylamide hydrogels. Journal of
Colloid and Interface Science 353 (2011) 116—123
13. B. L. Peng, N. Dhar, H. L. Liu, and K. C. Tam. Chemistry and Applications
of Nanocrystalline Cellulose and its Derivatives: a [Nanotechnology
Perspective. The Canadian Journal of Chemical Engineering Volume
9999, 2011 .
14. Chengjun Zhou and Qinglin Wu. Recent Development in Applications of
Cellulose Nanocrystals for Advanced Polymer-Based Nanocomposites by
Novel Fabrication Strategies.
. Alessandro Sannino, ian Demitri and Marta Madaghiele.
Biodegradable ose-based Hydrogels: Design and Applications.
Materials 2009, 2, 353—373; doi:10.3390/ma2020353
16. Canadian Patent Application Number 2,770,837
17. Canadian Patent Number 614
18. US Patent ation Number 281045
19. US Patent Application Number 2008/0311545
. US Patent Application Number 2010/0124732
21. US Patent Application Number 2012/0040312
22. US Patent Number 4,002,221
23. US Patent Number 7,004,933
24. US Patent Number 7,070,565
. US Patent Number 7,078,015
26. US Patent Number 7,269,873
27. US Patent Number 7,285,093
28. US Patent Number 8,273,024
29. Makinen, K. K. and Soderling, E. 1981. "Effect of l on Some Food-
Spoilage Microorganisms", Journal of Food Science. 46:950.
. Kontiokari, T. et al. 1995. "Effect of Xylitol on Growth of Nasopharyngeal
Bacteria In Vitro", Antimicrobial Agents and Chemotherapy. 3921820.
Claims (27)
1. An internal gel comprising: - water; - a thickening agent for ning the water into a gel, the thickening agent comprising carbomer homopolymer Type B; - a neutralizer for g the gel viscosity and adjusting a pH level of the gel; - a viscosity agent for protecting the gel viscosity following gamma radiation exposure, the viscosity agent sing cellulose ystals (CNC) and glycerin, wherein the CNC is at a concentration of at least 2% of the gel by weight; and wherein the gel has an acoustic impedance of 1.45 to 1.60 MRayls and can be safely used internally or orally.
2. The gel of claim 1 wherein the neutralizer comprises a base selected from the group consisting of potassium hydroxide, sodium hydroxide, and anolamine.
3. The gel of claim 1 or 2 wherein the pH level of the gel is between 5.8 and 6.4.
4. The gel of any one of claims 1 to 3, further comprising a preservative.
5. The gel of claim 4 wherein the preservative comprises potassium sorbate.
6. The gel of any one of claims 1 to 5 further comprising a dental agent for inhibiting growth of dental microorganisms.
7. The gel of claim 6 wherein the dental agent is a sugar alcohol.
8. The gel of claim 7 wherein the sugar alcohol is xylitol.
9. The gel of any one of claims 1 to 8 further comprising a colourant for ing the gel.
10. A kit for applying ultrasound to a tissue, the kit comprising, the gel of any one of claims 1 to 9, and instructions for use of the gel.
11. A method of protecting viscosity of a polymer based gel, the method comprising: - providing a gel comprising water; a thickening agent for ning the water into a gel, the thickening agent comprising carbomer homopolymer Type B; and a neutralizer for setting the gel viscosity and adjusting a pH level of the gel; wherein the gel has an acoustic impedance of 1.45 to 1.60 MRayls and can be safely used internally or orally; - adding a viscosity agent to the gel for protecting the gel viscosity following gamma radiation exposure, the ity agent comprising ose nanocrystals (CNC) and glycerin, wherein the CNC is at a concentration of at least 2% of the gel by weight; - exposing the gel to gamma radiation; wherein a decrease in gel viscosity, due to exposure to gamma radiation, is reduced by the viscosity agent.
12. The method of claim 11, further comprising adding a preservative to the gel prior to ng the gel to the radiation.
13. A method of altering viscosity of a gel, the method comprising: - providing a gel precursor comprising water; - creating a mixture by adding a thickening agent to the gel sor, the thickening agent comprising cellulose ystals (CNC) at a concentration of between 4% and 15% of the gel by weight; and - ng the e to gamma radiation; wherein an alteration in mixture viscosity, following exposure to gamma radiation, is caused by the CNC.
14. The method of claim 13 further comprising adding glycerin to the gel precursor.
15. The method of claim 13 or 14, further comprising adding a preservative to the gel precursor.
16. A use of cellulose nanocrystals (CNC) as a viscosity agent in a carbomer homopolymer Type B-based ultrasound gel to protect the ultrasound gel ity following exposure to gamma radiation; wherein the CNC is at a concentration of at least 2% of the gel by weight; and n the gel further comprises in.
17. A use of cellulose ystals (CNC) as a thickening agent to thicken the water into a gel and to cause an alteration in the gel viscosity following exposure to gamma radiation; wherein the CNC is at a concentration of between 4% and 15% of the gel by .
18. Use of the gel of any one of claims 1 to 9 in the manufacture of a medicament to alleviate symptoms of dry mouth.
19. An internal gel comprising: - water; - a thickening agent for thickening the water into a gel, the thickening agent comprising cellulose nanocrystals (CNC) at a concentration of between 4% and 15% of the gel by weight; wherein the gel has been exposed to gamma radiation; wherein the gel has a post-radiation viscosity between 50,000 and 100,000 cPs when measured using a viscometer at 37oC; and wherein the gel has an acoustic nce of 1.45 to 1.60 MRayls and can be safely used internally or orally.
20. The gel of claim 19, further sing a preservative.
21. The gel of claim 20, wherein the preservative comprises potassium sorbate.
22. The gel of any one of claims 19 to 21, further comprising a dental agent for inhibiting growth of dental microorganisms.
23. The gel of claim 22, wherein the dental agent is a sugar alcohol.
24. The gel of claim 23, wherein the sugar alcohol is xylitol.
25. The gel of any one of claims 19 to 24, further comprising glycerin.
26. Use of the gel of any one of claims 19 to 25 in the manufacture of a medicament for ating the symptoms of dry mouth.
27. A kit for applying ultrasound to a tissue, the kit comprising the gel of any one of claims 19 to 25. 33:00 203:? E 3:0 >820 90006
03300905. .mi 020006 m>=mm 3:990 33:00 :030209: Emmw 33.0003 :38sz UZU 00030505091»: 30: w ucm :303090 0:0 .mdv :0\_0:m mmosvmm m:_=00 0303000 05.9% 30: _m:.__::>_ Emmm 023050090 330900 0303330 :03m>:mm :05 0:930 0.09% .00 00032205 E23300 009m :0 0000 f9. .mdv 93:03sz 000: @330 0.3 0:38.035 3: 0333:5005 00:33 HmmDOE £833 .m.mv 93 €000.0me E: 00302, 5503005 .mdv 020 E 0.:me :0\_0:m ”00307530920 03003:: 3:0 . certs 03003 ”35:00:60 350 00:09:82.: >300 33 0303000 0:0 00:30:: .mi :030_3mm €308.90 £5020 _m:030:3 ‘co3mmm5 00:_m3:_mE 9.33 :09, Em w:_:00_0_:._. 3:0wm 2000900 _mm :03 3300 03mm 330005 338; mEmtsm \:03mmmn_90 0036090 33:00.00 33:30; :80
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662276927P | 2016-01-10 | 2016-01-10 | |
US62/276,927 | 2016-01-10 | ||
PCT/CA2016/051452 WO2017117650A1 (en) | 2016-01-10 | 2016-12-09 | Viscosity and stability modified ultrasound gel |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ744196A NZ744196A (en) | 2021-08-27 |
NZ744196B2 true NZ744196B2 (en) | 2021-11-30 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11890355B2 (en) | Viscosity and stability modified ultrasound gel | |
CA2895225C (en) | Internal ultrasound gel | |
Sipavičiūtė et al. | Pain and flare-up after endodontic treatment procedures | |
US20050074407A1 (en) | PVP and PVA as in vivo biocompatible acoustic coupling medium | |
US6566418B2 (en) | Calcium hydroxide-based root canal filling material | |
WO1997025968A1 (en) | Film coating composition for whitening teeth | |
CN106178111B (en) | A kind of gel filled preparation of rhinology Thermo-sensitive and preparation method thereof and the application in nasal surgery | |
Funk et al. | Efficacy and potential use of novel sustained release fillers as intracanal medicaments against Enterococcus faecalis biofilm in vitro | |
CN102580121A (en) | Medical disinfection coupling agent | |
US20060127316A1 (en) | Polyols and PVP as in vivo biocompatible acoustic coupling media | |
US11478435B2 (en) | Artificial saliva, related methods, and uses | |
CA2993012C (en) | Topical formulations and treatments | |
CN110585450B (en) | Medical disinfection sterilization type ultrasonic coupling agent | |
NZ744196B2 (en) | Viscosity and stability modified ultrasound gel | |
CN108096272B (en) | Antifungal infection product for children skin and preparation method thereof | |
US20140308361A1 (en) | Composition for management of periodontal diseases | |
CN114028239B (en) | Root canal disinfection paste and preparation method thereof | |
Bayakewar et al. | FORMULATION AND EVALUATION OF THE PERIODONTAL GEL FOR PEDIATRIC USE WITH AN OBJECTIVE OF INCREASING RESIDENCE TIME OF DRUG | |
Shwetha et al. | Design of Chlorhexidine Loaded Periochip | |
JP2001288028A (en) | Calcium hydroxide-based root canal filling material |