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EP4392069A2 - Composition, son procédé de fabrication et ses utilisations - Google Patents

Composition, son procédé de fabrication et ses utilisations

Info

Publication number
EP4392069A2
EP4392069A2 EP22879031.7A EP22879031A EP4392069A2 EP 4392069 A2 EP4392069 A2 EP 4392069A2 EP 22879031 A EP22879031 A EP 22879031A EP 4392069 A2 EP4392069 A2 EP 4392069A2
Authority
EP
European Patent Office
Prior art keywords
weight
surfactant
composition
gel
proniosome
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22879031.7A
Other languages
German (de)
English (en)
Other versions
EP4392069A4 (fr
Inventor
Choon Keong LEE
Giorgia Pastorin
Wei Jiang GOH
Wei Seong TOH
Shipin ZHANG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
National University of Singapore
Original Assignee
National University of Singapore
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by National University of Singapore filed Critical National University of Singapore
Publication of EP4392069A2 publication Critical patent/EP4392069A2/fr
Publication of EP4392069A4 publication Critical patent/EP4392069A4/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the combination of surfactants with different physical properties may aid to facilitate spreading of the composition (in a gel form) onto a subject’s skin, enhancing the release of the active agent from the composition and thereby increasing increase the amount of active agent delivered through the skin.
  • niosome refers to a vesicle comprising a shell of non-ionic surfactants and a cavity filled with an aqueous medium.
  • the vesicles may further comprise cholesterol in the shell.
  • the vesicles may further comprise an active agent that may be in the shell or in the cavity.
  • the composition may consist essentially of: a) a first surfactant having a transition temperature of at least 50 °C; b) a second surfactant having a transition temperature of less than 20 °C; c) a third surfactant having a hydrophilic-lipophilic balance (HLB) value of at least 15; d) cholesterol; e) an active agent; f) a first solvent; and e) a second solvent.
  • HLB hydrophilic-lipophilic balance
  • at least one of the first surfactant, the second surfactant or the third surfactant may be a non-ionic surfactant. At least two of the first surfactant, the second surfactant or the third surfactant may be a non-ionic surfactant.
  • the transition temperature of the first surfactant is at least about 50 °C, at least about 55 °C, at least about 60 °C, at least about 65 °C, at least about 70 °C, about 50 °C to about 70 °C, about 50 °C to about 65 °C, about 50 °C to about 60 °C, about 50 °C to about 55 °C, about 55 °C to about 70 °C, about 60 °C to about 70 °C, or about 65 °C to about 70 °C.
  • the second surfactant may be sorbitan monooleate, sorbitan monolaurate or combinations thereof.
  • the transition temperature of the second surfactant is less than about 20 °C, less than about 15 °C, less than about 10 °C, less than about 5 °C, less than about 0 °C, less than about -5 °C, less than about -10 °C, less than about -15 °C, less than about -20 °C, about -20 °C to about 20 °C, about -20 °C to about 15 °C, about -20 °C to about 10 °C, about -20 °C to about 5 °C, about - 20 °C to about 0 °C, about -20 °C to about -5 °C, about -20 °C to about -10 °C, about -20 °C to about -15 °C, about -15 °C to about 20 °C, about -15 °C to about 15 °C, about -15 °C to about 10 °C, about -15 °C to about 5 °C, about -15 °C
  • the second surfactant may comprise or contain a cis-alkene functional group on the alkyl chain in the surfactant.
  • a cis-alkene functional group on the alkyl chain in the surfactant.
  • this may aid in enhancing permeation of the bilayer and thus improves gel spreadibility and reduction of mechanical strength of the proniosome gel.
  • the presence of the cis-alkene functional group on the alkyl chain corresponds to an increased critical strain value which results in reduced rigidity of the composition (when in the form of a proniosome gel) and allowed it to be more malleable under high shear strain.
  • the third surfactant may be polyoxyethylene (20) sorbitan monolaurate.
  • the combination of the first surfactant, the second surfactant, the third surfactant and cholesterol may have a combined hydrophilic-lipophilic balance value in the range of about 5 to 6, about 5 to 5.5 or about 5.5 to 6.
  • the active agent may be a hydrophobic molecule.
  • the active agent may have a weight percentage in the range of about 0.9 weight% to about 70 weight%, about 20 weight% to about 70 weight%, about 40 weight% to about 70 weight%, about 60 weight% to about 70 weight%, about 0.9 weight% to about 60 weight%, about 0.9 weight% to about 40 weight%, about 0.9 weight% to about 20 weight% or about 0.5 weight% to about 1 weight% based on the total weight of the composition.
  • the first solvent may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 1 ,2-propanediol, 1,3-propanediol or combinations thereof.
  • the first solvent may have a weight ratio in the range of about 10 weight% to about 79.1 weight%, about 20 weight% to about 79.1 weight%, about 40 weight% to about 79.1 weight%, about 60 weight% to about 79.1 weight%, about 10 weight% to about 60 weight%, about 10 weight% to about 40 weight%, about 10 weight% to about 20 weight% or about 15 weight% to about 20 weight% based on the total weight of the composition.
  • the second solvent may be selected from the group consisting of water, a phosphate buffered saline or combinations thereof.
  • the second solvent may have a weight ratio in the range of about 10 weight% to about 79.1 weight%, about 20 weight% to about 79.1 weight%, about 40 weight% to about 79.1 weight%, about 60 weight% to about 79.1 weight%, about 10 weight% to about 60 weight%, about 10 weight% to about 40 weight%, about 10 weight% to about 20 weight% or about 20 weight% to about 30 weight% based on the total weight of the composition.
  • the first solvent and the second solvent may be isopropanol and phosphate buffered saline respectively at a weight ratio in the range of about 1:1 to about 7:5.
  • the first surfactant may have a weight percentage in the range of 5.7wt% to 74.8 wt%; the second surfactant may have a weight percentage in the range of 2.8 wt% to 72 wt%; the third surfactant may have a weight percentage in the range of 0.71 wt% to 69.8 wt%; the cholesterol may have a weight percentage in the range of 0.74 wt% to 69.8 wt%; the active agent may have a weight percentage in the range of 0.9 wt% to about 70 wt%; the first solvent may have a weight ratio in the range of 10 wt% to 79.1 wt%; or the second solvent may have a weight ratio in the range of 10 wt% to 79.1 wt%, based on the total weight of the composition.
  • the first surfactant, the second surfactant, the third surfactant, cholesterol, the first solvent, the second solvent and the active agent may have a weight ratio of about 24.8 : 12.4 : 3.4 : 3.2 : 30.5 : 24.8 : 0.9.
  • the first surfactant is sorbitan monostearate;
  • the second surfactant is sorbitan monooleate, sorbitan mololaurate or combinations thereof;
  • the third surfactant is polyoxyethylene (20) sorbitan monolaurate;
  • the active agent is a hydrophobic molecule;
  • the first solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 1 ,2-propanediol, 1,3-propanediol or combinations thereof; and/or
  • the second solvent is selected from the group consisting of water, a phosphate buffered saline or combinations thereof.
  • composition may be formed by the method as described herein.
  • step (b) heating the mixture of step (a) with a second solvent and cooling the mixture to form the composition, wherein the first surfactant has a transition temperature of at least 50 °C, wherein the second surfactant has a transition temperature of less than 20 °C, and wherein the third surfactant has a hydrophilic-lipophilic balance (HLB) value of at least 15.
  • HLB hydrophilic-lipophilic balance
  • the first surfactant may be sorbitan monostearate.
  • the first surfactant may have a weight percentage in the range of about 5.7 weight% to about 74.8 weight%, about 20 weight% to about 74.8 weight%, about 40 weight% to about 74.8 weight%, about 60 weight% to about 74.8 weight%, about 5.7 weight% to about 60 weight%, about 5.7 weight% to about 40 weight%, about 5.7 weight% to about 20 weight% or about 20 weight% to about 30 weight% based on the total weight of the mixture.
  • the transition temperature of the first surfactant is at least about 50 °C, at least about 55 °C, at least about 60 °C, at least about 65 °C, at least about 70 °C, about 50 °C to about 70 °C, about 50 °C to about 65 °C, about 50 °C to about 60 °C, about 50 °C to about 55 °C, about 55 °C to about 70 °C, about 60 °C to about 70 °C, about 65 °C to about 70 °C.
  • the second surfactant may be sorbitan monooleate, sorbitan mololaurate or combinations thereof.
  • the second surfactant may have a weight percentage in the range of about 2.8 weight% to about 72 weight%, about 20 weight% to about 72 weight%, about 40 weight% to about 72 weight%, about 60 weight% to about 72 weight%, about 2.8 weight% to about 60 weight%, about 2.8 weight% to about 40 weight%, about 2.8 weight% to about 20 weight% or about 10 weight% to about 15 weight% based on the total weight of the mixture.
  • the transition temperature of the second surfactant is less than about 20 °C, less than about 15 °C, less than about 10 °C, less than about 5 °C, less than about 0 °C, less than about -5 °C, less than about -10 °C, less than about -15 °C, less than about -20 °C, about -20 °C to about 20 °C, about -20 °C to about 15 °C, about -20 °C to about 10 °C, about -20 °C to about 5 °C, about - 20 °C to about 0 °C, about -20 °C to about -5 °C, about -20 °C to about -10 °C, about -20 °C to about -15 °C, about -15 °C to about 20 °C, about -15 °C to about 15 °C, about -15 °C to about 10 °C, about -15 °C to about 5 °C, about -15 °C
  • the third surfactant may be polyoxyethylene (20) sorbitan monolaurate.
  • the third surfactant may have a weight percentage in the range of about 0.71 weight% to about 69.8 weight%, about 20 weight% to about 69.8 weight%, about 40 weight% to about 69.8 weight%, about 60 weight% to about 69.8 weight%, about 0.71 weight% to about 60 weight%, about 0.71 weight% to about 40 weight%, about 0.71 weight% to about 20 weight% or about 3 weight% to about 4 weight% based on the total weight of the mixture.
  • the hydrophilic-lipophilic balance (HLB) value of the third surfactant may be at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 15 to about 20, at least about 16 to about 20, at least about 17 to about 20, at least about 18 to about 20, at least about 19 to about 20, at least about 15 to about 19, at least about 16 to about 19, at least about 17 to about 19, at least about 18 to about 19, at least about 15 to about 18, at least about 16 to about 18, at least about 17 to about 18, at least about 15 to about 17, at least about 16 to about 17, at least about 15 to about 16.
  • cholesterol may have a weight percentage in the range of about 0.74 weight% to about 69.8 weight%, about 20 weight% to about 69.8 weight%, about 40 weight% to about 69.8 weight%, about 60 weight% to about 69.8 weight%, about 0.74 weight% to about 60 weight%, about 0.74 weight% to about 40 weight%, about 0.74 weight% to about 20 weight% or about 3 weight% to about 4 weight% based on the total weight of the mixture.
  • the active agent may additionally or alternatively be a drug molecule.
  • the active agent may be an anti-inflammatory agent, an anticancer agent or an anti-infection agent.
  • the active agent may be berberine, capsaicin or a salt or a combination thereof.
  • the first solvent may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 1 ,2-propanediol, 1,3-propanediol or combinations thereof.
  • the first solvent may be isopropanol.
  • the first solvent may be 1 ,2-propanediol.
  • the first solvent may have a weight percentage in the range of about 10 weight% to about 79.1 weight%, about 20 weight% to about 79.1 weight%, about 40 weight% to about 79.1 weight%, about 60 weight% to about 79.1 weight%, about 10 weight% to about 60 weight%, about 10 weight% to about 40 weight%, about 10 weight% to about 20 weight% or about 15 weight% to about 20 weight% based on the total weight of the mixture.
  • step (a) the heating may be undertaken at a temperature in the range of about 50 °C to about 80 °C, about 60 °C to about 80 °C, about 70 °C to about 80 °C, about 50 °C to about 70 °C, about 50 °C to about 60 °C or about 60 °C to about 70 °C.
  • the heating may be undertaken for a duration in the range of about 2 minutes to about 8 minutes, about 4 minutes to about 8 minutes, about 6 minutes to about 8 minutes, about 2 minutes to about 6 minutes, about 2 minutes to about 4 minutes or about 4 minutes to about 6 minutes.
  • the second solvent may be selected from the group consisting of water, a phosphate buffered saline or combinations thereof.
  • the second solvent may have a weight percentage in the range of about 10 weight% to about 79.1 weight%, about 20 weight% to about 79.1 weight%, about 40 weight% to about 79.1 weight%, about 60 weight% to about 79.1 weight%, about 10 weight% to about 60 weight%, about 10 weight% to about 40 weight%, about 10 weight% to about 20 weight% or about 20 weight% to about 30 weight% based on the total weight of the mixture.
  • step (b) the heating may be undertaken at a temperature in the range of about 50 °C to about 80 °C, about 60 °C to about 80 °C, about 70 °C to about 80 °C, about 50 °C to about 70 °C, about 50 °C to about 60 °C or about 60 °C to about 70 °C.
  • step (b) the heating may be undertaken for a duration in the range of about 2 minutes to about 8 minutes, about 4 minutes to about 8 minutes, about 6 minutes to about 8 minutes, about 2 minutes to about 6 minutes, about 2 minutes to about 4 minutes or about 4 minutes to about 6 minutes.
  • kits may comprise the composition as described herein and instructions for using the composition.
  • the kit may be for use in therapy or in treating a disease in a patient.
  • the disease may be selected from the group consisting of inflammation, cancer, infection or combinations thereof.
  • the disease may be inflammation.
  • the inflammation disease may be osteoarthritis.
  • composition may be administered by dermal or topical administration.
  • composition may comprise about 200 mg to about 400 mg of the active agent.
  • composition may be administered for about 2 to 3 times daily.
  • kits for the treatment of a disease selected from the group consisting of inflammation, cancer, infection or combinations thereof.
  • the kit may include instructions for using the composition.
  • the method of treating a disease in a patient comprises administering to the patient an effective amount of the composition as described herein, wherein the disease is selected from the group consisting of inflammation, cancer, infection or combinations thereof.
  • the disease may be inflammation.
  • the inflammation disease may be osteoarthritis.
  • the administering step may be undertaken by dermal or topical administration.
  • composition may comprise about 200 mg to about 400 mg of the active agent.
  • composition may be administered for about 2 to 3 times daily.
  • the method of delivering an active agent to a target site comprises the steps of:
  • composition (b) administering the composition at a first site to allow the active agent to move to or be transported to the target site.
  • composition may be administered for about 2 to 3 times daily.
  • Fig. 5 shows atomic density maps determined for bilayers composed of only S60 (Formulation (A)). S60 mixed with S80 (Formulation (B)) and S60, S80 and polyethlene glycol sorbitan monolaurate (T20) (Formulation (C)). In all cases some number (2048) of water molecules was added into the simulation model.
  • 9C(I)-9C(III) shows images of niosomes in Fig. 9C(I) bright field, Fig. 9C(II) fluorescent and Fig. 9C(III) overlay.
  • Fig. 9D(I)-9D(III) shows images of niosomes in Fig. 9D(I)-bright field, Fig. 9D(II) -fluorescent and Fig. 9D(III) overlay when loaded with berberine.
  • Scale bar of images is at 100 pm.
  • Microscope images of niosome were taken at 20x magnification while the enlarged image of niosomes in Fig. 9C(I)was taken at 50x.
  • Fig. 11A-11C shows charts and graph plotting the application of proniosome gels in an in vivo mouse model of OA.
  • Fig. 11B shows a chart plotting the Mankin scores for histopathological assessment of the articular cartilage from mice in various experimental groups at day 6.
  • Fig. 11C shows a chart plotting the relative gene expression of pro-inflammatory cytokines detected in the mice joint capsule after mice treated with formulation (C) at day 10 and in comparison, to day 6.
  • the simulation box consisted of 576 +19 surfactant molecules and either 2048 or 4608 water molecules.
  • the 576 surfactant molecules were divided between S60 and S80 molecules, thus the system contains either pure S60 (SP60 system, Formulation (A)) or mixture of S60 and S80 in a ratio of 2:1 (SP60/SP80 system, Formulation (B)).
  • SP60/SP80/T20 system Formulation (C)
  • the molecules were arranged in the simulation box using self-designed scripts.
  • Porcine ear skin was used as a model for the skin permeation studies.
  • the skin was harvested, and the subcutaneous fat was removed using a scalpel.
  • the thickness of the skin specimens ranged between 1.38 mm and 1.98 mm.
  • the skin tissues were cut into small portions with an area of 2.5 cm x 2.5 cm and were hydrated with 5 mL of PBS for 30 minutes before the start of experiment.
  • 30 mg of various proniosome gel formulations were loaded onto the donor chamber of the Franz cell and the permeation study was carried out for 24 hours. Thereafter, the porcine skin specimens were removed from the diffusion cell.
  • the stratum corneum of the skin samples were wiped with gauze to remove excess test samples.
  • the skin samples were minced and immersed in 4:1 acetonitrile/methanol to extract berberine from the skin specimen and 50 nM of buspirone HC1 was added as an internal standard (IS) for LC-MS/MS analysis.
  • IS internal standard
  • the source parameters for ESI were as followed: Ion spray voltage: +4000V, source temperature: 650 °C, curtain gas: 20 psi, GS1 (sheath gas): 45 psi, GS2 (drying gas): 55 psi, collision gas (nitrogen) medium.
  • the compound dependent MS parameters were presented in Table 2 below:
  • HaCaT keratinocytes could be purchased from Cell line service (Eppelheim, Germany). Keratinocytes were maintained in DMEM supplemented with 10% FBS under a humidified atmosphere of 5% CO2 at 37 °C. The medium was changed every alternate day. Upon confluency, keratinocytes were dissociated using trypsin and the cells were harvested for cell viability assay. In the cell viability assay, 2 x 10 4 HaCaT keratinocytes were seeded with 100 pL of growth medium in each well and the cells were incubated for 24 hours at 37 °C.
  • chondrocytes were harvested from femoral head articular cartilage of 7-week old BALB/c female mice, following the procedure as follows. Briefly, the cartilage tissues were washed 3 times with PBS and digested with 0.2% (w/v) collagenase II overnight at 37 °C. The cells were then passed through a 40-pm cell strainer (Corning®, Corning, NY, USA) to disperse the cells into single cells before seeding at a density of 2 x 10 4 cells/cm 2 .
  • Nitric oxide (NO) was measured in the cell culture supernatants using the Griess reaction assay and nitrite standards from the Griess reagent kit (Thermofisher Scientific) according to the manufacturer's protocol. The absorbance readings were obtained at 548 nm using a microplate reader (Infinite® 200 PRO). The concentration of sGAG and NO was expressed as fold change by normalizing against the control group that was not stimulated with IL- 1 [3 and TNF-a.
  • mice All procedures were performed according to the Institutional Animal Care and Use Committee at National University of Singapore under the protocol number: R18-1188. A total of forty-eight 6-7 weeks old female BALB/c mice with a mean weight of 18.0 ⁇ 0.5 g were used in this study. The mice were randomly allocated into 6 groups: OA + Formulation (A), OA + Formulation (B), OA + Formulation (C), OA + no treatment, OA + Formulation (C) placebo and healthy mice. OA was induced in the right knee by intra-articular injection of 0.5 mg of MIA dissolved in 10 pL of PBS, as previously described. Three days after inducing OA, the mice received their treatment according to their assigned groups for 7 days.
  • mice were housed under controlled temperature with a 12-hour light and 12-hour dark cycle. They were allowed free movement and access to food and water.
  • a value of 50% represents an equal weight distribution across both limbs and a value of less than 50% indicates that there is a reduction in weight borne on right hindlimb. Baseline measurements were recorded prior to the injection of MIA and the mice were assessed daily from day 3 to day 10 after injection.
  • the quality of joint repair was assessed for parameters including cartilage structure, cellularity, matrix staining and tidemark integrity using the Mankin’s histological scoring system.
  • the score for healthy mouse cartilage is 0 and the maximum score for degenerative articular cartilage is 14.
  • the solvent accessible surface area (SAS A) describes the area at the interface of the bilayers that are available to interact with water molecules.
  • SASA solvent accessible surface area
  • the SASA increased from 246 ⁇ 4 nm 2 to 268 ⁇ 4 nm 2 (Formulation (B)) and 312 + 8 nm 2 (Formulation (C)), respectively.
  • the corrugated surface increased the SASA at the interface of the bilayers and allowed the bilayers to adsorb more water.
  • Formulations (B) and (C) can be attributed to the presence of the cA-alkene functional group on the alkyl chain of S80, which reduced the rigidity of the proniosome gel and allowed it to be more malleable under higher shear strain. Indeed, the reduction of the mechanical strength can favor the release of niosomes from the formulation. It was observed that Formulation (A) had a G value of 168 ⁇ 50.4 kPa while Formulation (B) had a G value 8.90 ⁇ 0.74 kPa (P ⁇ 0.0001 ) and (C) had a G value of 9.21 ⁇ 3.27 kPa (P ⁇ 0.0001 ) as shown in Fig 6A.
  • proniosome gel with shear thinning properties was advantageous as it allowed the ease of spreading the formulation onto the skin.
  • Fig. 6B there was a reduction of viscosity for all three proniosome gels with an increasing shear rate.
  • Formulation (A) had the highest viscosity while Formulation (C) had the lowest viscosity, and this shows that it is easier to spread Formulation (C) onto the skin.
  • Formulation (C) would retain on the skin and provide continuous release of the encapsulated compound on the application area.
  • Formulation (C) was compared to Formulations (A) and (B) in terms of gel-like consistency, spreadability and ability to hydrate, and it was used for loading of berberine in the subsequent experiments.
  • the proniosome gel was expected to be applied onto the skin to achieve a localized delivery of berberine at the OA knee joint. It was also expected that the amount of water on the skin would be much lower and the release profile of berberine from the proniosome gel might differ substantially in actual applications. Hence, the release of berberine from various proniosome gels was measured by setting up a more realistic ex vivo skin permeation study using porcine ear skin. Fig. 8A showed the accumulation of berberine on the skin from the various proniosome gel formulations.
  • Sulphated glycosaminoglycan is a composition of proteoglycan that exists naturally in the extracellular matrix of cartilage tissue.
  • sGAG was used as a chondrocyte marker to evaluate the effect of gel/noisome system for the treatment of osteoarthritis (OA).
  • OA osteoarthritis
  • Col II is a major extracellular matrix component of cartilage, which can be degraded by metalloproteinases- 13 (MMP13) during OA.
  • a proniosome gel was prepared by the following procedures. Briefly, non-ionic surfactants (see Table 5) and cholesterol were added to a glass vial. 125 pL of IPA was added and the mixture was heated at 65 °C for 5 minutes. 80 pL of PBS was added into the mixture and it was heated at 65 °C for 5 minutes. The samples were taken out and the proniosome gel was left to cool at room temperature and this allowed the formation of the proniosome gel.
  • the first essential step was to form the proniosome gel by optimizing the main ingredient which was Span® 60, IPA and PBS.
  • the main ingredient which was Span® 60, IPA and PBS.
  • Span® 80 and Tween® 20 were added to optimize the mechanical strength and the HLB value of the gel.
  • the overall composition as indicated above was normalized against the entire mass of the composition in the proniosome gel (i.e. Surfactants + cholesterol + IPA + PBS and berberine).
  • sGAG sulphated glycosaminoglycans
  • IC50 33 pg mL 1

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition comprenant :a) un premier tensioactif ayant une température de transition 5 d'au moins 50 °C ;b) un second tensioactif ayant une température de transition inférieure à 20 °C ;c) un troisième tensioactif ayant une valeur d'équilibre hydrophile-lipophile (HLB) d'au moins 15 ; d) du cholestérol ; e) un agent actif ; f) un premier solvant ; et e) un second solvant. L'invention concerne également un procédé de fabrication de la composition, un kit comprenant la composition et un procédé d'administration de la composition.
EP22879031.7A 2021-10-08 2022-10-07 Composition, son procédé de fabrication et ses utilisations Pending EP4392069A4 (fr)

Applications Claiming Priority (2)

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SG10202111225V 2021-10-08
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