JP-2022515294-A5 -

Dates

Publication Date

20221219

Application Date

20191210

Description

Statistics Statistical tests were performed using GraphPad Prism software v8. Data are presented as mean ± SD and subjected to standard one-way ANOVA, using a two-tailed, unpaired Student's t-test for two datasets, or Tukey's multiple comparison test for three or more datasets. Significance was assessed using the following p-value cutoffs: *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. Specific dataset analyses are described in the legend of the figures. The present invention provides, for example, the following items. (Item 1) A composition comprising a muscarinic agonist encapsulated in a hydrogel formulated for topical administration to the salivary glands for use in the treatment of xerostomia (dry mouth). (Item 2) The composition according to item 1, wherein the muscarinic agonist is selective for M1 and/or M3 muscarinic receptor subtypes. (Item 3) The composition according to item 2, wherein the muscarinic agonist is cevimeline. (Item 4) The composition according to item 1, wherein the muscarinic agonist is pilocarpine. (Item 5) The composition according to any one of items 1 to 4, wherein the hydrogel comprises an alginate. (Item 6) The composition according to item 5, wherein the alginate is ionically crosslinked. (Item 7) The composition according to item 6, wherein the alginate is ionically crosslinked by divalent calcium cations. (Item 8) The composition according to any one of items 5 to 7, wherein the concentration of the alginate in the hydrogel is in the range of about 2 to about 10 weight percent (weight%). (Item 9) The composition according to any one of items 5 to 7, wherein the alginate is at least partially oxidized. (Item 10) The composition according to item 8, wherein about 2% to about 10% of the alginate is oxidized. (Item 11) The composition according to item 9, wherein about 2% of the alginate is oxidized, and the concentration of the alginate in the hydrogel is about 5% by weight. (Item 12) The composition according to any one of items 1 to 11, wherein the hydrogel maintains the delivery of the muscarinic agonist for at least one week, at least two weeks, at least three weeks, or at least four weeks after administration to a subject. (Item 13) A composition according to any one of items 1 to 12, further comprising pharmaceutically acceptable excipients. (Item 14) A composition according to any one of items 1 to 13, further comprising a contrast agent. (Item 15) A method for treating xerostomia, comprising administering a therapeutically effective amount of a composition described in any one of items 1 to 14 to the salivary glands of the subject. (Item 16) The method according to item 15, wherein the composition is injected into or adjacent to the salivary gland. (Item 17) The method according to item 15 or 16, further comprising performing medical imaging or palpation to locate the salivary gland before injection. (Item 18) The method according to item 17, wherein the medical imaging includes performing ultrasound. (Item 19) The method according to any one of items 15 to 18, wherein a plurality of therapeutically effective doses of the composition are administered to the subject. (Item 20) The method according to any one of items 15 to 19, wherein the xerostomia is caused by damage to the salivary glands due to radiation or Sjögren's syndrome. (Item 21) The method according to any one of items 15 to 20, wherein the subject is a pet or livestock. (Item 22) The method according to any one of items 15 to 21, wherein the subject is a mammal. (Item 23) The method according to item 22, wherein the mammal is a dog, cat, horse, cow, goat, sheep, or pig. (Item 24) The method according to item 22, wherein the mammal is a human. (Item 25) A kit comprising a composition described in any one of items 1 to 14, and instructions for treating xerostomia. (Item 26) The kit according to item 25, further comprising means for delivering the aforementioned composition to a target. (Item 27) The kit according to item 25, further comprising: a first syringe containing a composition comprising a muscarinic agonist encapsulated in an alginate hydrogel; a second syringe containing a solution comprising calcium chloride; and a Luer lock, wherein the second syringe can be connected to the first syringe via the Luer lock. (Item 28) The kit according to item 27, wherein the first syringe containing the composition comprising the muscarinic agonist encapsulated in an alginate hydrogel is frozen. (Item 29) The kit according to any one of items 25 to 28, wherein the muscarinic agonist is cevimeline or pilocarpine. (Item 30) A method for promoting salivary gland regeneration in subjects requiring promotion of salivary gland regeneration, comprising topically administering at least one of a cholinergic or muscarinergic agents to acinar progenitor cells and acinar cells of a salivary gland to promote the proliferation of the acinar progenitor cells and acinar cells, thereby increasing saliva production. (It