Thermostable quick-dissolving thin film
The present invention relates to thermostable quick-dissolving thin films comprising a biological moiety and an excipient mix which are suitable for the formulation of biological moieties such as viral vaccines, to methods for manufacturing such thermostable quick-dissolving thin films, and to their use in therapy. The excipient mix comprises one or more water-soluble polymer(s), a sugar selected from sucrose, trehalose and a combination thereof, a metal ion, a carboxylate, and a buffering agent.
1. A quick-dissolving thin film comprising a virus and an excipient mix, wherein said excipient mix comprises
one or more water-soluble polymer(s),
trehalose,
a metal ion,
a carboxylate, and
a buffering agent,
wherein said quick-dissolving thin film is thermostable, and
wherein said quick-dissolving thin film does not comprise any animal derived product or gelatin.
2. The quick-dissolving thin film of claim 1 , wherein said virus is selected from a live virus, a live attenuated virus, an inactivated virus or a reassortant virus.
3. The quick-dissolving thin film of claim 2 , wherein the virus is a rotavirus, wherein the rotavirus is a live attenuated rotavirus.
4. The quick-dissolving thin film of claim 1 , wherein said metal ion is selected from Zn 2+ and Mn 2+ .
5. The quick-dissolving thin film of claim 1 , wherein the carboxylate is citric acid.
6. The quick-dissolving thin film of claim 1 , wherein said buffering agent is selected from phosphate buffer and histidine base.
7. The quick-dissolving thin film of claim 1 , wherein said excipient mix further comprises one or more amino acids, selected from at least one of glycine and arginine.
8. The quick-dissolving thin film of claim 1 , wherein the virus is present in the quick-dissolving thin film of the invention at a titer ranging from about 1×10 5 to about 1×10 11 ffu per dose, and wherein the excipient mix comprises or consists of
between 30% and 90% by weight of the water-soluble polymer(s),
between 10% and 60% by weight of trehalose,
between 0.01% and 1% by weight of the metal ion or salt,
between 0.5% and 5% by weight of the carboxylate,
between 0.5% and 5% by weight of the buffering agent, and
between 0% and 20% by weight of one or more amino acids.
9. The quick-dissolving thin film of claim 1 , wherein in the excipient mix,
the water-soluble polymer is PVA,
the sugar is trehalose,
the metal ion is in the form of ZnCl 2 ,
the carboxylate is citric acid,
the buffering agent is selected from K 2 HPO 4 and histidine base, and
the one or more amino acids, if present, are selected from arginine and/or glycine.
10. The quick-dissolving thin film of claim 9 , wherein the virus is a rotavirus.
11. The quick-dissolving thin film of claim 10 , wherein the rotavirus is present in the quick-dissolving thin film of the invention at a titer ranging from about 1×10 5 to about 1×10 8 ffu per dose.
12. The quick-dissolving thin film of claim 9 , wherein the excipient mix comprises or consists of
a. between 30% and 90% by weight of PVA,
b. between 10% and 60% by weight of trehalose,
c. between 0.01% and 1%, by weight of ZnCl 2 ,
d. between 0.5% and 5% by weight of citric acid,
e. between 0.5% and 5% by weight of K 2 HPO 4 or histidine base,
f. between 0% and 10% by weight of arginine and,
g. between 0% and 5%, by weight of glycine.
13. The quick-dissolving thin film of claim 1 , wherein said quick-dissolving thin film further comprises an antacid.
14. The quick-dissolving thin film of claim 13 , wherein the excipient mix: antacid ratio (w/w) is from about 1:3 to about 2:1, from about 1:2 to 1.5:1, or from about 1:1.5 to 1:1.
15. The quick-dissolving thin film of claim 1 , wherein said quick-dissolving thin film has a surface pH between 5 and 9.
16. The quick-dissolving thin film of claim 1 , wherein said quick-dissolving thin film has a thickness of less than 500 μm.
17. The quick-dissolving thin film of claim 1 , wherein said quick-dissolving thin film has a moisture content lower than about 10% by weight.
18. A method for the treatment of an infectious disease in a subject comprising administering the quick-dissolving thin film of claim 1 to a subject.
19. A kit comprising the quick-dissolving thin film of claim 1 in a sterile packaging and instructions for use of the kit.
20. A method for preparing a thermostable quick-dissolving thin film comprising:
a) preparing an aqueous solution comprising or consisting of
a virus,
one or more water-soluble polymer(s),
trehalose,
a metal ion,
a carboxylate, and
one or more buffering agents,
wherein said aqueous solution does not comprise any animal derived product or gelatin,
b) adjusting the pH of the aqueous solution to a value comprised between 5 and 9,
c) applying the aqueous solution on a drying surface,
d) drying the aqueous solution to obtain a thin film, and
e) removing the dried thin film from the drying surface,
thereby obtaining said thermostable quick-dissolving thin film.