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WO2010010394A2 - Compositions pharmaceutiques locales - Google Patents

Compositions pharmaceutiques locales Download PDF

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Publication number
WO2010010394A2
WO2010010394A2 PCT/GB2009/050905 GB2009050905W WO2010010394A2 WO 2010010394 A2 WO2010010394 A2 WO 2010010394A2 GB 2009050905 W GB2009050905 W GB 2009050905W WO 2010010394 A2 WO2010010394 A2 WO 2010010394A2
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WO
WIPO (PCT)
Prior art keywords
composition according
composition
extract
spilanthes
treatment
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Ceased
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PCT/GB2009/050905
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English (en)
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WO2010010394A3 (fr
Inventor
Iain Chessell
Mark Treherne
Fei-Yue Zhao
Francoise Barbira Freedman
David Spanswick
Kevin Lee
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NEUROSOLUTIONS Ltd
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NEUROSOLUTIONS Ltd
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Publication date
Priority claimed from GB0813395A external-priority patent/GB0813395D0/en
Priority claimed from GB0908970A external-priority patent/GB0908970D0/en
Application filed by NEUROSOLUTIONS Ltd filed Critical NEUROSOLUTIONS Ltd
Publication of WO2010010394A2 publication Critical patent/WO2010010394A2/fr
Publication of WO2010010394A3 publication Critical patent/WO2010010394A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the invention relates to a composition adapted to supply locally to a patient in need thereof a compound having a pharmaceutical activity, wherein the active agent of said composition comprises an extract of Spilanthes oleracea.
  • aspects of the invention relate to buccal and topical formulations of the said extract including immediate and sustained release formulations.
  • Spilanthes oleracea is a native South American herbaceous plant, which has been used for human consumption since pre-Hispanic times, both as food and for its medicinal effects without any known adverse effect. Its medicinal use is featured by its effect as a local anaesthetic (known colloquially as the toothache plant), an antibacterial and an anti-fungal agent.
  • Spilanthes oleracea is a flowering herb in the plant family Asteraceae. It is also known as “toothache plant” or “paracress” as the leaves and flower heads contain an analgesic agent spilanthol as well as other chemical identities including alkaloids.
  • the active agent has been used in documented empirical form for more than five centuries as a dental analgesic in Peru, with anti-inflammatory and disinfectant effects, in chewed form, with or without other meals.
  • Spilanthes oleracea is used to treat headaches, infections of the throat and gums, and for toothache. Typically it is mixed in equal proportions with conventional additives to form a topical or intradermal injection form. The compositions have been used as topical, ointment or spray forms.
  • US Patent 6264926 discloses that extracts of Spilanthes calva can be used in a natural herbal tooth powder as a synergistic composition with zanthoxylum. Spilanthes calva flowers are made into paste in formulation useful as a natural herbal tooth powder and for toothache.
  • Formulations comprising Spilanthes oleracea have also been used against toothache and gum disease and are moderately effective as a local anaesthetic for a duration of 5 to 20 minutes.
  • NSAIDs non-steroidal antiinflammatory drugs
  • composition adapted to supply locally to the site of need in a patient in need thereof a compound having a pharmaceutical activity, wherein the active agent of said composition comprises an extract of a plant of the genus Spilanthes .
  • composition according to (1) and (2), wherein the said extract is of Spilanthes oleracea.
  • composition according to (3) wherein the said extract is characterised by the UV chromatographic profile shown in Figure 3a or Figure 3b.
  • the active agent has an analgesic activity.
  • compositions according to the invention include:
  • composition according to any one of (1) to (6), wherein said composition is adapted to be delivered bucally;
  • composition according to (7) wherein said buccal composition is selected from the group consisting of lozenges, tablets, solutions, suppositories, gels and gelfoams;
  • compositions according to (8) wherein said buccal composition is in the form of a lozenge;
  • HPMC hydroxypropylmethylcellulose
  • polycarbophil sodium alginate
  • polyvinyl alcohol polyvinyl alcohol
  • acacia chitosan
  • carrageenan acacia
  • chitosan carrageenan
  • tragacanth polyoxyethylene
  • composition according to (11) wherein said buccal composition is a tablet wherein an alcoholic extract of Spilanthes oleracea is formulated with a mucoadhesive polymer, lactose and a filling agent;
  • composition according to (11) wherein said buccal composition is a tablet, wherein an alcoholic extract of Spilanthes oleracea is formulated with an emulsifier, a mucoadhesive polymer, and a filling agent;
  • composition according to (11) wherein said buccal composition is a tablet, wherein an alcoholic extract of Spilanthes oleracea is formulated with a mucoadhesive polymer, a binder, water and a filling agent;
  • composition according to (18) wherein the gel is a mucoadhesive gel
  • composition according to (18), wherein said buccal composition is a gel wherein an alcoholic extract of Spilanthes oleracea is formulated with xanthan gum, buffering agent, a preservative and water;
  • composition according to (18) wherein said buccal composition is a gel wherein an alcoholic extract of Spilanthes oleracea is formulated with a mucoadhesive polymer, buffering agent, a preservative and water;
  • composition according to (22), wherein the gelfoam comprises a piece of gelfoam saturated with a concentrated solution of Spilanthes oleracea;
  • composition according to (2) adapted to supply locally to the site of need in a patient in need thereof a compound having a wound treating activity, wherein the active agent of said composition comprises an extract of Spilanthes oleracea.
  • compositions according to (1) to (2) and (5) to (23) for the manufacture of a medicament for the treatment of inflammatory pain, neuropathic pain and nociceptive pain;
  • composition as defined in (1) to (2) and (5) to (23) for use as an analgesic or anaesthetic;
  • (32) a composition as defined in (1) to (2) and (5) to (23) for use in the treatment of vulvodynia;
  • composition as defined in (1) to (2) and (5) to (23) for use in the treatment of irritable bowel syndrome (IBS); and
  • (42) a method for the prophylaxis or treatment of a disease or condition selected from the group consisting of wounds, inflammatory pain, neuropathic pain, nociceptive pain, inflammation, vulvodynia, periodontitis, alloydnia, mouth ulcers and irritable bowel syndrome, which comprises administering to a mammal in need thereof an effective amount of a composition according to (1) to (2) and (5) to (24).
  • a disease or condition selected from the group consisting of wounds, inflammatory pain, neuropathic pain, nociceptive pain, inflammation, vulvodynia, periodontitis, alloydnia, mouth ulcers and irritable bowel syndrome
  • a method for the prophylaxis or treatment of analgesia or anaesthesia which comprises administering to a mammal in need thereof an effective amount of a composition according to (1) to (2) and (5) to (24).
  • Extracts of Spilanthes oleracea used in the example of preparation of NSL-101 in the present application originate from the same plot and are obtained using the same process. Extracts were collected at different times of the year and, as such, the yields are subject to seasonal variation. Lot 1 corresponds to extracts collected in February and Lot 2 corresponds to extracts collected in May. Figures 3 a and 3 b show the chromato graphic profile of Lots 1 and 2 recorded at 230 ran and the UV spectra of the peaks corresponding to spilanthol.
  • Figure 3a shows the chromatographic profile at 230 ran of the Spilanthes extract corresponding to Lot 1.
  • the peak with a retention time of 30.646 minutes corresponds to alkylamides, as shown by the UV spectrum with an absorption peak at approximately 228 nm.
  • Figure 3b shows the chromatographic profile at 230 nm of the Spilanthes extract corresponding to Lot 2.
  • the peaks with retention times of 30.675 and 33.046 minutes correspond to alkylamides, as shown by the UV spectra with an absorption peak at approximately 228 nm.
  • One problem to be addressed by the present invention was to produce formulations that had a rapid local analgesic effect. Also, another problem was to produce formulations having a reasonably long lasting local anaesthetic effect.
  • compositions are adapted so that the extract of Spilanthes oleracea is delivered locally to the site of need in the patient in need thereof.
  • compositions are adapted so that they are suitably conformed to be in direct or close contact with the site of treatment or prophylaxis (e.g. topical application).
  • prophylaxis e.g. topical application.
  • the present inventors have found that using these compositions the active agents in the extract of Spilanthes oleracea axe rapidly delivered to the site of need. In patients suffering from neuropathic pain, these local compositions give a rapid analgesic effect not previously achieved and this can last for several hours. They can also be adapted to provide a rapid anaesthetic affect that can last for several hours.
  • the active agent is obtainable from the plant of the genus Spilanthes.
  • the active agent is an extract from Spilanthes oleracea and contains spilanthol. Suitable extraction techniques to obtain the active agent are detailed in the examples, but the active extract can be obtained using aqueous, alcoholic and dry extraction techniques, for example.
  • it will have an activity selected from analgesic activity, wound treatment activity, neuropathic pain treatment activity, antiinflammatory activity, anaesthetic activity, activity in the treatment of vulvodynia, activity in the treatment of irritable bowel syndrome, activity in the treatment of periodontitis, activity in the treatment of allodynia and activity in the treatment of mouth ulcers.
  • analgesic activity selected from analgesic activity, wound treatment activity, neuropathic pain treatment activity, antiinflammatory activity, anaesthetic activity, activity in the treatment of vulvodynia, activity in the treatment of irritable bowel syndrome, activity in the treatment of periodontitis, activity in the treatment of allodynia and activity in the treatment of mouth ulcers.
  • the composition is that the local composition of the invention can be adapted to be delivered bucally.
  • delivery systems were found to be suitable for the proposed indications and mechanisms of action of the product.
  • Preferred formulations of the present invention include lozenges, mucoadhesive tablets, mucoadhesive gels and gelfoams as the means for buccal/local delivery. Delivery systems such as suppositories or pessaries are preferred formulations for the localised and systemic treatment of IBS and vulvodynia.
  • Lozenges according to the invention typically comprise a Spilanthes oleracea extract, an excipient, a binder, a sweetening agent and a filling agent.
  • excipient suitable for use examples include organic excipients such as sugar derivatives, e.g. lactose, sucrose, glucose, mannitol or sorbitol, starch derivatives, e.g. corn starch, potato starch, ⁇ -starch, dextrin or carboxymethyl starch, cellulose derivatives, e.g. crystalline cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally crosslinked sodium carboxymethyl cellulose, and gum Arabic, dextran or pullulan; and, inorganic excipients such as silicate derivatives, e.g.
  • binders examples include polyvinylpyrrolidone, Macrogol and compounds similar to the aforementioned excipients, of which polyvinylpyrrolidone resins are preferred.
  • the filling agents include stearic acid, metal stearates such as calcium stearate and magnesium stearate; talc; colloidal silica; wax such as beeswax and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; fatty acid sodium salts; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and said starch derivatives.
  • metal stearates such as magnesium stearate are preferred.
  • Tablets containing an extract of Spilanthes oleracea are also suitable formulations for buccal delivery.
  • the preferred form is a non-dissolving matrix tablet, wherein the said non-dissolving matrix is prepared using a mucoadhesive polymer.
  • Mucoadhesive polymers have been utilised in many different dosage forms in efforts to achieve systemic delivery of drugs through the different mucosae. These dosage forms include tablets, patches, tapes, films, and powders.
  • Mucoadhesive tablets according to the invention typically comprise a Spilanthes oleracea extract, an exipient, a filling agent and a mucoadhesive polymer.
  • Non-disintegrating tablets were prepared from a range of mucoadhesive polymers.
  • a mucoadhesive polymer suitable for use include hydroxypropylmethlycellulose (HPMC), polycarbophil, sodium alginate, polyvinyl alcohol, acacia, chitosan, carrageenan, tragacanth and polyoxyethylene.
  • HPMC hydroxypropylmethlycellulose
  • Polycarbophil, polyvinyl alcohol, chitosan, polyox and carrageenan are preferred.
  • an excipient examples include those listed above for use in the preparation of lozenges. Polyvinylpyrrolidone resins or lactose arc preferred.
  • filling agents examples include those listed above for use in the preparation of lozenges. Again metal stearates such as magnesium stearate are preferred.
  • suitable candidates for buccal delivery include gels, wherein the gel is a mucoadhesive gel.
  • Mucoadhesive gels/pastes typically comprise a Spilanthes oleracea extract, a mucoadhesive polymer, a buffering agent, a preservative and water.
  • buffering agents include acetic acid, potassium hydroxide, sodium hydroxide, citric acid, hydrochloric acid, lime, magnesium oxide, and sodium carbonate.
  • Common preservatives suitable for use include metal sorbates, such as sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, ethyl p-hydroxybenzoate, sodium ethyl p- hydroxybenzoate, propyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, methyl p-hydroxybenzoate, sodium methyl p-hydroxybenzoate, sodium methyl p-hydroxybenzoate, sulphites such as sodium sulphite, sodium hydrogen sulphite, sodium metabi sulphite, potassium metabisulphite, potassium sulphite, calcium sulphite, calcium hydrogen sulphite, potassium hydrogen sulphite, formates including formic acid, sodium formate, calcium formate, metal nitrites and metal nitrates e.
  • mucoadhesive polymer suitable for use examples include hydroxypropylmethly cellulose (HPMC), polycarbophil, sodium alginate, xanthan gum, polyvinyl alcohol, acacia, chitosan, carrageenan, tragacanth and polyoxyethylene.
  • Preferred mucoahdehesive polymers for use in the preparation of gels of the invention include sodium alginate, Xanthan gum, chitosan and hydroxypropylmethylcellulose.
  • Gelfoams according to the invention typically comprise a piece of precut gelfoam saturated with a concentrated solution of Spilanthes oleracea. The precut gelfoam is saturated with a solution obtained by the procedure as described earlier.
  • Suppositories and pessaries are also suitable formulations for buccal delivery of Spilanthes oleracea.
  • Suppositories can take the form of capsules or molds which contain the active product either solely or with suitable exipients dissolved in a greasy base such as cocoa butter, other vegetable fats or oils, biocompatible polymers, gels or aqueous solutions.
  • a greasy base such as cocoa butter, other vegetable fats or oils, biocompatible polymers, gels or aqueous solutions.
  • Pessaries and urethal suppositories combine the active ingredient with exicpients in a water-soluble base, such as polyethylene glycol, geletine, or glycerinated geletin.
  • Such formulations can be designed to release the active product within 30 minutes of administration or can be designed to maximise the duration of exposure. These formulations are preferred for the treatment of IBS and vulvodynia, providing immediate or slow (or intermediaries thereof) release of the active ingredient.
  • Figure 1 is a plot of the paw withdrawal threshold (PWT) against time for CCI rats before and after oral dosing with either aqueous extract of Spilanthes oleracea or saline; and Figure 2 shows discharges for CCI rats with exposed sciatic nerve on application of control, vehicle, aqueous extract of Spilanthes oleracea, removal of aqueous extract of Spilanthes oleracea and application of lidocaine.
  • PWT paw withdrawal threshold
  • Figure 3 a shows the chromato graphic profile at 230 nm of the Spilanthes extract corresponding to Lot 1.
  • Figure 3 b shows the chromatographic profile at 230 nm of the Spilanthes extract corresponding to Lot 2.
  • Figure 4 shows the number of patients needing medication during the post-SRP observation period was 6% in the NSL-101 group and 14% of patients in the 5% lidocaine group.
  • Figure 5 shows the least square mean pain intensity difference and 95% CI at each evaluation time.
  • Figure 6 demonstrates the differences between the NSL-101 and 5% lidocaine groups, showing that the weighted summed pain intensity difference is larger in the 5% lidocaine group.
  • Figure 7a shows the comparison of the gingival inflammation at baseline and post- SRP.
  • Figure 7b shows that 98% of patients presented moderate inflammation whilst only 2% presented severe inflammation.
  • the Spilanthes oleracea plant material was washed in distilled water.
  • the washed plant material was macerated with a solution of 3:7 ethanol: distilled water solution for 48 hours in a sterile environment.
  • the solution was filtered to give extract 1.
  • Extracts 1 and 2 were separated, and each solvated in distilled water (1/5 parts) to obtain two separate solutions of Spilanthes olaracea. Both solutions were filtered.
  • the ethanol was removed from both solutions by steam extraction under reduced pressure.
  • the resulting aqueous solutions 1 and 2 were filtered, bottled and refrigerated.
  • Solution 1 obtained from steam extraction was freeze-dried.
  • the resulting freeze- dried extract was used for the formulation of the gelfoam and 5% gel dose.
  • the freeze-dried extract was combined with solution 2 and re-filtered to obtain a final concentrated solution for use in the formulation of the gelfoam.
  • the precut gelfoam is saturated with a solution obtained by the procedure as described above. Typically 2.5 ml of the Spilanthes oleracea solution is placed in a sterile 5ml corning containing typically 1.5 cm gelfoam. This mixture is left for approximately fifteen minutes or until complete saturation has occurred.
  • Example 3 Preparation of a Lozenge
  • the povidone K30 was dissolved in the alcoholic extract of Spilanthes oleracea.
  • the sucrose and lactose were granulated in a suitable mixer using the povidone solution containing the extract of Spilanthes oleracea together with an appropriate amount of ethanol, and dried in an air oven.
  • the dried product was milled, sieved, and blended with the magnesium using a tumbling blender. Tablets were compressed using a tablet machine to produce tablets with a breaking strength of at least 10 kg.
  • the ingredients (except the magnesium stearate) were mixed together, dried in an air oven, and sieved through a 1 mm sieve.
  • the sieved material was mixed with the magnesium stearate in a tumbling blender, and compressed into tablets with a hardness of 1 Okg.
  • the ingredients were mixed in a tumbling blender, and compressed into tablets with a hardness of 10kg.
  • the freeze-dried extract was combined with solution 2 and a support gel comprising Polyethylene Glycol 4000 and Polyethylene Glycol 400.
  • HPMC HPMC was dispersed in approximately half of the water and allowed to dissolve.
  • the aqueous extract was added, and the pH of the solution adjusted to pH 4-8.
  • the solution was then made up to volume while taking care to avoid the incorporation of air bubbles.
  • gel would be placed in the mouth on the source of the pain using the finger. It is anticipated on the basis of the Test Examples below that pain relief will be rapid and last for several hours.
  • the xanthan gum was dispersed in approximately half of the water and allowed to dissolve.
  • the aqueous extract was added, and the pH of the solution adjusted to pH 4- 8.
  • the solution was then made up to volume while taking care to avoid the incorporation of air bubbles.
  • Example 12 Preparation of a Gel
  • the chitosan was dispersed in approximately half of the water and allowed to dissolve.
  • the aqueous extract was added, and the pH of the solution adjusted to pH A- 8.
  • the solution was then made up to volume while taking care to avoid the incorporation of air bubbles.
  • the freeze-dried extract was combined with solution 2 and a support gel comprising Polyethylene Glycol 4000 and Polyethylene Glycol 400.
  • CCI chronic constriction injury
  • the rats were made neuropathic by placing four ligatures on the left sciatic nerve under pentobarbitone anaesthesia. 14 days after surgery, the animals showed typical phenomenon of neuropathic pain: their paw withdrawal threshold (PWT) in response to mechanical stimulation (von Frey hairs) significantly decreased ( ⁇ 4 gram compared to the normal level of 10-15 gram). Only the animals showing mechanical allodynia were selected for behavioural and electrophysiological experiments.
  • the aim of this study was to evaluate the analgesic efficacy, anti-inflammatory action and safety of the dental NSL-101 gel, in comparison with 5% lidocaine, during dental root scaling and planing procedures (SRP) as a non-surgical treatment for periodontitis.
  • SRP dental root scaling and planing procedures
  • the quadrants for application of one of the two treatments were selected randomly. All the selected patients completed the study, in total performing 100 clinical tests, 50 corresponding to the dental gel NSL-101 and 50 to the 5% lidocaine treatment.
  • the NSL-101 gel was prepared as described in Example 14 previously.
  • the mean probing depth of the treated quadrants was similar for both the NSL-101 treated group (3.8 (3.0 - 5.5) mm and (3.8 (3.2 - 6.0) mm). The percentage of bleeding pockets on probing was also similar for both groups (60.7%).
  • the contents of 9 syringes containing NSL- 101 and 17 syringes containing 5% lidocaine were randomly placed inside the periodontal pockets (total number of syringes deposited 26).
  • the contents of 9 syringes were used containing 5% lidocaine and 17 containing NSL-101.
  • a total of 26 blunt syringes were used in the maxilla.
  • 12 syringes of NSL-101 and 12 of 5% lidocaine were used, with an equal number of syringes in the contra-lateral side (quadrant III). The total number of blunt syringes used in the mandible was 24.
  • NSL-101 (compared to 5% lidocaine) has a longer anaesthetic effect and delayed appearance of pain for approximately 75 minutes post-SRP.
  • the primary efficacy variable was the summed pain intensity difference (weighted in time) between the baseline evaluation time and 90 minutes after the application of the product (WSPI).
  • the secondary variables included the pain intensity difference (PID) at each evaluation time and the summed pain intensity difference (SPID).
  • both treatments provided similar levels of analgesia and they both improved the SPID score at the 90 minutes evaluation time. Pain was first apparent after 60 minutes in the NSL-101 group, and after 30 minutes in the 5% lidocaine group.
  • Figure 5 shows the least square mean pain intensity difference and 95% CI at each evaluation time.
  • the summed PID shows significant difference between the NSL-101 and the 5% lidocane group, between the values obtained at time 0 (baseline) and 90 minutes.
  • Figure 6 demonstrates the differences between the NSL-101 and 5% lidocaine groups, showing that the weighted summed pain intensity difference is larger in the 5% lidocaine group.
  • FIG. 7a shows that the percentage of patients that presented moderate inflammation at baseline was reduced from 98% to 86%.
  • Figure 7b shows that 98% of patients presented moderate inflammation whilst only 2% presented severe inflammation.
  • the NSL-101 anaesthetic gel was as efficacious as the 5% lidocaine gel at reducing pain during SRP.
  • the analgesic efficacy of the NSL-101 gel lasts for approximately 75 minutes after termination of treatment, compared to 45 minutes for the 5% lidocaine gel.
  • the patients reported no feeling of anaesthesia on tissues surrounding the treatment area, such as lips, tongue or cheeks; they behaved in a relaxed manner throughout the periodontal procedure and were pleased to return for the second treatment appointment, if it would include the use of anaesthetic gel.

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Abstract

La présente invention concerne une composition conçue pour fournir localement au site le nécessitant, chez un patient le nécessitant, un composant ayant une activité pharmaceutique, l’agent actif de ladite composition comprenant un extrait de Spilanthes oleracea. La composition est particulièrement utile, par exemple, en tant qu’analgésique pour fournir un traitement rapide de la douleur neuropathique et en tant qu’anesthésique à longue durée d’action. Les compositions de l’invention destinées à une administration orale peuvent de préférence se trouver sous la forme de pastilles, de comprimés ou de gels mucoadhésifs.
PCT/GB2009/050905 2008-07-22 2009-07-22 Compositions pharmaceutiques locales Ceased WO2010010394A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0813395.1 2008-07-22
GB0813395A GB0813395D0 (en) 2008-07-22 2008-07-22 Local pharmaceutical compositions
GB0908970A GB0908970D0 (en) 2009-05-26 2009-05-26 Local pharmaceutical compositions
GB0908970.7 2009-05-26

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WO2010010394A2 true WO2010010394A2 (fr) 2010-01-28
WO2010010394A3 WO2010010394A3 (fr) 2010-03-18

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014059254A1 (fr) 2012-10-12 2014-04-17 Premier Dental Products Company Compositions de complément oral d'ubiquinol topique avec du phosphate de calcium amorphe
WO2014059143A1 (fr) 2012-10-12 2014-04-17 Premier Dental Products Company Compositions topiques de complément oral à base de vitamine d et d'ubiquinol
US9522168B2 (en) 2014-05-29 2016-12-20 Johnson & Johnson Consumer Inc. Topical compositions comprising Acmella oleracea extracts and uses thereof
US9586064B2 (en) 2012-10-12 2017-03-07 Premier Dental Products Company Enamel protectant and repair brushing gels
US9877929B2 (en) 2011-10-13 2018-01-30 Premier Dental Products Company Topical vitamin D and ubiquinol oral supplement compositions
WO2019049142A1 (fr) * 2017-09-08 2019-03-14 Scicann Therapeutics Inc. Compositions comprenant un cannabinoïde et du spilanthol

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Publication number Priority date Publication date Assignee Title
US3720762A (en) * 1970-07-11 1973-03-13 Lion Hamigaki Kk Spilanthol-containing compositions for oral use
US6746697B2 (en) * 2000-12-15 2004-06-08 Phytos, Inc. Composition containing Heliopsis longipes root extract and oral carrier
JP4567940B2 (ja) * 2002-12-10 2010-10-27 株式会社林原生物化学研究所 皮膚外用剤とその用途
US7687081B2 (en) * 2004-12-28 2010-03-30 Council Of Scientific And Industrial Research Herbal formulation useful as local anesthetic

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9877929B2 (en) 2011-10-13 2018-01-30 Premier Dental Products Company Topical vitamin D and ubiquinol oral supplement compositions
CN104968317B (zh) * 2012-10-12 2017-12-01 第一牙科产品公司 含无定形磷酸钙的局部用泛醇口腔补充组合物
US9585818B2 (en) 2012-10-12 2017-03-07 Premier Dental Products Company Enamel protectant and repair toothpaste treatments
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JP2015533172A (ja) * 2012-10-12 2015-11-19 プレミア デンタル プロダクツ カンパニー アモルファスリン酸カルシウムを有する局所用口腔ユビキノールサプリメント組成物
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