Oral pharmaceutical formulation in the form of an aqueous suspension of microcapsules for the modified release of active principle(s)
The invention relates to liquid pharmaceutical formulations for oral administration with the modified release of active principle(s), excluding amoxicillin, said formulations consisting of suspensions of coated particles of active principles (microcapsules). According to the invention, the microcapsules constituting the disperse phase of the suspension are designed to allow the modified release of the active principle(s) according to a profile that does not change during the storage of the liquid suspension. To do this the inventors propose the selection of a specific coating composition for the microcapsules which consists of at least four components that allow these microcapsules to be stored in water without modifying their properties of modified release of the active principle, this liquid phase furthermore being saturated with active principle(s).
1 . A composition comprising:
a suspension of microcapsules in an aqueous liquid phase, wherein the suspension of microcapsules comprises a plurality of microcapsules and an aqueous liquid phase, and wherein each microcapsule comprises:
(a) a core comprising at least one active principle, wherein the at least one active principle is ibuprofen; and
(b) a film coating applied to the core, wherein the film coating comprises:
(1) at least one film-forming polymer (P1) insoluble in gastrointestinal tract fluids, present in an amount of 50 to 90% by dry weight based on the total weight of the coating composition, and wherein at least one of said at least one film-forming polymer (P1) is ethylcellulose;
(2) at least one nitrogen-containing polymer (P2) present in an amount of 2 to 25% by dry weight based on the total weight of the coating composition, and wherein at least one of said at least one nitrogen-containing polymer (P2) is polyvinylpyrrolidone;
(3) at least one plasticizer present in an amount of 2 to 20% by dry weight based on the total weight of the coating composition, and wherein at least one of said at least one plasticizer is castor oil; and
(4) at least one surfactant or lubricant present in an amount of 2 to 20% by dry weight based on the total weight of the coating composition, and wherein at least one of said at least one surfactant or lubricant is polyethoxylated hydrogenated castor oil,
wherein the film coating provides modified release of the at least one active principle in gastrointestinal fluids,
wherein the suspension of microcapsules is for oral administration,
wherein the aqueous liquid phase is saturated or becomes saturated with the at least one active principle on contact with the microcapsules, and
wherein the in vitro release profile of the suspension of microcapsules in an aqueous liquid phase on day ten is similar to the release profile on day zero, as measured using a type II apparatus according to the European Pharmacopoeia 3rd edition, in a phosphate buffer medium of pH 6.8, at a temperature of 37° C.
2 . The composition of claim 1 , wherein the film coating comprises:
the at least one film-forming polymer (P1) present in an amount of 50 to 80% by dry weight based on the total weight of the coating composition;
the at least one nitrogen-containing polymer (P2) present in an amount of 5 to 15% by dry weight based on the total weight of the coating composition;
the at least one plasticizer present in an amount of 4 to 15% by dry weight based on the total weight of the coating composition; and
the at least one surfactant or lubricant present in an amount of 4 to 15% by dry weight based on the total weight of the coating composition.
3 . The composition of claim 1 , wherein each microcapsule has only one coating layer.
4 . The composition of claim 1 , wherein the suspension of microcapsules comprises 30 to 95% by weight of liquid phase and 5 to 70% by weight of microcapsules.
5 . The composition of claim 4 , wherein the suspension of microcapsules comprises 60 to 85% by weight of liquid phase.
6 . The composition of claim 4 , wherein the suspension of microcapsules comprises 15 to 40% by weight of microcapsules.
7 . The composition of claim 1 , wherein a proportion of dissolved at least one active principle originating from the plurality of microcapsules is less than or equal to 15% by weight of the total weight of the at least one active principle contained in the plurality of microcapsules.
8 . The composition of claim 7 , wherein a proportion of dissolved at least one active principle originating from the plurality of microcapsules is less than or equal to 5% by weight of the total weight of the at least one active principle contained in the plurality of microcapsules.
9 . The composition of claim 1 , wherein the at least one active principle contained in the plurality of microcapsules saturates the aqueous liquid phase.
10 . The composition of claim 1 , wherein the aqueous liquid phase is at least partially saturated with active principle by non-encapsulated active principle prior to the incorporation of the plurality of microcapsules into the aqueous liquid phase.
11 . The composition of claim 1 , wherein the plurality of microcapsules have a particle size less than or equal to 1000 microns.
12 . The composition of claim 11 , wherein the plurality of microcapsules have a particle size between 200 and 800 microns.
13 . The composition of claim 12 , wherein the plurality of microcapsules have a particle size between 200 and 600 microns.
14 . The composition of claim 1 , wherein 1 to 50% of the total weight of the coated microcapsules is film coating.
15 . The composition of claim 14 , wherein 5 to 40% of the total weight of the coated microcapsules is film coating.
16 . The composition of claim 1 , wherein the in vitro release profile of the suspension of microcapsules, as measured using a type II apparatus according to the European Pharmacopoeia 3rd edition, in a phosphate buffer medium of pH 6.8, at a temperature of 37° C., is such that the proportion, PI, of the at least one active principle released during the first 15 minutes of the dissolution test is not greater than 15%, and the remaining at least one active principle is released over a period such that the release time of 50% by weight of active principle (t 1/2 ) is not lower than 0.5 hour and not greater than 30 hours.
17 . The composition of claim 16 , wherein the proportion, PI, of the at least one active principle released during the first 15 minutes of the dissolution test is not greater than 5%, and the remaining at least one active principle is released over a period such that the release time of 50% by weight of active principle (t 1/2 ) is not lower than 0.5 hour and not greater than 20 hours.
18 . The composition of claim 1 , wherein the pH of the suspension of microcapsules is acidic or neutral.
19 . The composition of claim 1 , wherein the suspension of microcapsules further comprises at least one rheology modifier.
20 . The composition of claim 19 , wherein the at least one rheology modifier is xanthan.
21 . The composition of claim 19 , wherein the at least one rheology modifier is carboxymethylcellulose.
22 . The composition of claim 1 , wherein the suspension of microcapsules further comprises at least one agent for modifying the solubility of the at least one active principle in the aqueous liquid phase.
23 . The composition of claim 1 , wherein the suspension of microcapsules further comprises at least one additive selected from the group consisting of: surfactants, colorants, dispersants, preservatives, taste improvers, flavorings, sweeteners, antioxidants, and mixtures thereof.
24 . The composition of claim 1 , further comprising at least one active principle in an immediate release form.
25 . The composition of claim 24 , further comprising ibuprofen in an immediate release form.
26 . The composition of claim 1 , wherein the aqueous liquid phase comprises at least 20% by weight of water.
27 . The composition of claim 26 , wherein the aqueous liquid phase comprises at least 50% by weight of water.
28 . A suspension of microcapsules in an aqueous liquid phase that allows modified release of at least one active principle and is intended for oral administration, wherein said suspension comprises a plurality of microcapsules and an aqueous liquid phase,
wherein the aqueous liquid phase is saturated or becomes saturated with active principle(s) on contact with the microcapsules,
wherein each microcapsule comprises:
(a) a core comprising at least one active principle(s), wherein the at least one active principle is ibuprofen, and
(b) a film coating that: (i) is applied to the core, (ii) controls the modified release of the active principle(s) in gastrointestinal tract fluids, and (iii) comprises:
(1) 50 to 90% by dry weight based on the total weight of the coating composition of a film-forming polymer insoluble in gastrointestinal tract fluids selected from the group consisting of:
water-insoluble cellulose derivatives,
water-insoluble acrylic polymers,
polyvinyl acetates,
and mixtures thereof;
(2) 2 to 25% by dry weight based on the total weight of the coating composition of a water-soluble polymer selected from the group consisting of:
water-soluble cellulose derivatives,
polyacrylamides,
poly-N-vinylamides,
poly-N-vinyllactams,
polyvinyl alcohols (PVA),
polyoxyethylenes (POE),
polyvinylpyrrolidones (PVP),
and mixtures thereof;
(3) 2 to 20% by dry weight based on the total weight of the coating composition of a plasticizer; and
wherein the in vitro release profile of the suspension of microcapsules in an aqueous liquid phase on day ten is similar to the release profile on day zero, as measured using a type II apparatus according to the European Pharmacopoeia 3rd edition, in a phosphate buffer medium of pH 6.8, at a temperature of 37° C.
29 . The composition of claim 28 , wherein:
at least one of the at least one film-forming polymer (P1) is selected from the group consisting of ethylcellulose and cellulose acetate;
at least one of the at least one nitrogen-containing polymer (P2) is selected from the group consisting of polyacrylamide and polyvinylpyrrolidone;
at least one of the at least one plasticizer is castor oil is selected from the group consisting of glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters and castor oil
30 . A composition comprising:
a suspension of microcapsules in an aqueous liquid phase, wherein the suspension of microcapsules comprises a plurality of microcapsules and an aqueous liquid phase, and wherein each microcapsule comprises:
(a) a core comprising at least one active principle, wherein the at least one active principle is ibuprofen; and
(b) a film coating applied to the core, wherein the film coating comprises:
(1) at least one film-forming polymer (P1) insoluble in gastrointestinal tract fluids, present in an amount of 50 to 90% by dry weight based on the total weight of the coating composition, and wherein at least one of said at least one film-forming polymer (P1) is a water-insoluble cellulose derivative;
(2) at least one nitrogen-containing polymer (P2) present in an amount of 2 to 25% by dry weight based on the total weight of the coating composition, and wherein at least one of said at least one nitrogen-containing polymer (P2) is selected from the group consisting of polyacrylamide, poly-N-vinylamine and poly N-vinyllactam;
(3) at least one plasticizer present in an amount of 2 to 20% by dry weight based on the total weight of the coating composition, and wherein at least one of said at least one plasticizer is selected from the group consisting of glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters and castor oil; and
(4) at least one surfactant or lubricant present in an amount of 2 to 20% by dry weight based on the total weight of the coating composition, and wherein at least one of said at least one surfactant or lubricant is selected from the group consisting of: an alkali metal salt of fatty acids, stearic acid, oleic acid, a polyethoxylated sorbitan ester, a polyethoxylated castor oil derivative, a stearate, a stearylfumarate, sodium strearlyfumarate, glycerol behenate, and mixtures thereof.
wherein the film coating provides modified release of the at least one active principle in gastrointestinal fluids,
wherein the suspension of microcapsules is for oral administration,
wherein the aqueous liquid phase is saturated or becomes saturated with the at least one active principle on contact with the microcapsules, and
wherein the in vitro release profile of the suspension of microcapsules in an aqueous liquid phase on day ten is similar to the release profile on day zero, as measured using a type II apparatus according to the European Pharmacopoeia 3rd edition, in a phosphate buffer medium of pH 6.8, at a temperature of 37° C.