ORAL PHARMACEUTICAL FORMULATION IN THE FORM OF AN AQUEOUS SUSPENSION OF MICROCAPSULES FOR THE MODIFIED RELEASE OF ACTIVE PRINCIPLE(S).

Abstract

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).

Claims

1. Suspension of microcapsules in an aqueous liquid phase that allows the modified release of at least one active principle (excluding amoxicillin) and is intended for oral administration, characterized in that: it comprises a plurality of microcapsules each consisting of a core containing at least one active principle (excluding amoxicillin) and of a film coating that: is applied to the core, controls the modified release of the active principle(s), and has a composition corresponding to one of the following three families A, B and C: Family A 1A—at least one film-forming polymer (P1) insoluble in the tract fluids, present in an amount of 50 to 90 and preferably of 50 to 80% by dry weight, based on the total weight of the coating composition, and consisting of at least one water-insoluble cellulose derivative; 2A—at least one nitrogen-containing polymer (P2) present in an amount of 2 to 25 and preferably of 5 to 15% by dry weight, based on the total weight of the coating composition, and consisting of at least one polyacrylamide and/or poly-N-vinylamide and/or poly-N-vinyllactam; 3A—at least one plasticizer present in an amount of 2 to 20 and preferably of 4 to 15% by dry weight, based on the total weight of the coating composition, and consisting of at least one of the following compounds: glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters and castor oil; 4A—at least one surfactant and/or lubricant present in an amount of 2 to 20 and preferably of 4 to 15% by dry weight, based on the total weight of the coating composition, and selected from anionic surfactants and/or non-ionic surfactants and/or lubricants, it being possible for said agent to comprise only one or a mixture of the above-mentioned products; Family B 1B—at least one hydrophilic polymer carrying groups ionized at neutral pH and preferably selected from cellulose derivatives; 2B—at least one hydrophobic compound different from A; Family C 1C—at least one film-forming polymer insoluble in the gastrointestinal tract fluids; 2C—at least one water-soluble polymer; 3C—at least one plasticizer; 4C—optionally at least one surfactant/lubricant preferably selected from the following group of products: anionic surfactants; and/or non-ionic surfactants, and the liquid phase is saturated or becomes saturated with active principle(s) on contact with the microcapsules.

2. Suspension according to claim 1, characterized in that the families A, B and C from which the constituents of the coating composition are selected are as follows: Family A 1A—ethyl cellulose and/or cellulose acetate; 2A—polyacrylamide and/or polyvinylpyrrolidone; 3A—castor oil; 4A—an alkali metal or alkaline earth metal salt of fatty acids, stearic and/or oleic acid being preferred, a polyethoxylated sorbitan ester, a polyethoxylated castor oil derivative, a stearate, preferably calcium, magnesium, aluminium or zinc stearate, a stearylfumarate, preferably sodium stearylfumarate, or glycerol behenate, taken individually or in a mixture with one another; Family B 1B cellulose acetate-phthalate; hydroxypropyl methyl cellulose phthalate; hydroxypropyl methyl cellulose acetate-succinate; (meth)acrylic acid/(meth)acrylic acid alkyl (methyl) ester copolymer; and mixtures thereof; 2B hydrogenated vegetable waxes; triglycerides; animal and vegetable fats (beeswax, carnauba wax, etc.); and mixtures thereof. Family C 1C water-insoluble cellulose derivatives, ethyl cellulose and/or cellulose acetate being particularly preferred; acrylic derivatives; polyvinyl acetates; and mixtures thereof; 2C water-soluble cellulose derivatives; polyacrylamides; poly-N-vinylamides; poly-N-vinyllactams; polyvinyl alcohols (PVA); polyoxyethylenes (POE); polyvinylpyrrolidones (PVP) (the latter being preferred); and mixtures thereof; 3C glycerol and its esters, preferably from the following subgroup: acetylated glycerides, glycerol monostearate, glyceryl triacetate and glycerol tributyrate; phthalates, preferably from the following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl phthalate and dioctyl phthalate; citrates, preferably from the following subgroup: acetyltributyl citrate, acetyltriethyl citrate, tributyl citrate and triethyl citrate; sebacates, preferably from the following subgroup: diethyl sebacate and dibutyl sebacate; adipates; azelates; benzoates; vegetable oils; fumarates, preferably diethyl fumarate; malates, preferably diethyl malate; oxalates, preferably diethyl oxalate; succinates, preferably dibutyl succinate; butyrates; cetyl alcohol esters; salicylic acid; triacetin; malonates, preferably diethyl malonate; cutin; castor oil (this being particularly preferred); and mixtures thereof; 4C alkali metal or alkaline earth metal salts of fatty acids, stearic and/or oleic acid being preferred; polyethoxylated oils, preferably polyethoxylated hydrogenated castor oil; polyoxyethylene/polyoxypropylene copolymers; polyethoxylated sorbitan esters; polyethoxylated castor oil derivatives; stearates, preferably calcium, magnesium, aluminium or zinc stearate; stearylfumarates, preferably sodium stearylfumarate; glycerol behenate; and mixtures thereof.

3. Suspension according to claim 1 or 2, characterized in that the film coating consists of a single layer.

4. Suspension according to claim 1, characterized in that it contains: 30 to 95% by weight and preferably 60 to 85% by weight of liquid phase (advantageously water); and 5 to 70% by weight and preferably 15 to 40% by weight of microcapsules.

5. Suspension according to claim 1, characterized in that the amount of solvent liquid phase (preferably water) for the active principle(s) is such that the proportion of dissolved active principle(s) originating from the microcapsules is less than or equal to 15% and preferably less than or equal to 5% by weight, based on the total weight of the active principle(s) contained in the microcapsules.

6. Suspension according to claim 1, characterized in that the liquid phase is at least partially and preferably totally saturated with active principle(s) following the incorporation of the microcapsules into this liquid phase.

7. Suspension according to claim 6, characterized in that it is the active principle(s) contained in the microcapsules that saturate the liquid phase.

8. Suspension according to claim 1, characterized in that the liquid phase is at least partially and preferably totally saturated with active principle(s) by means of non-encapsulated active principle(s) prior to the incorporation of the microcapsules into this liquid phase.

9. Suspension according to any one of claims 1 to 8, characterized in that the microcapsules have a particle size less than or equal to 1000 microns, preferably of between 200 and 800 microns and particularly preferably of between 200 and 600 microns.

10. Suspension according to any one of claims 1 to 9, characterized in that the film coating represents from 1 to 50% and preferably from 5 to 40% of the total weight of the coated microcapsules.

11. Suspension according to claim 10, characterized by an in vitro release profile obtained using a type II apparatus according to the European Pharmacopoeia 3rd edition, in a phosphate buffer medium of pH 6.8 and at a temperature of 37° C., such that: the proportion PI of active principle(s) released during the first 15 minutes of the dissolution test is such that:
PI≦15
preferably PI≦5; the remaining active principle(s) is (are) released over a period such that the release time of 50% by weight of AP (t.sup.1/2) is defined as follows (in hours):
0.5≦t.sub.1/2≦30
preferably 0.5≦t.sub.1/2≦20.

12. Suspension according to any one of claims 1 to 11, characterized in that: the initial in vitro release profile Pfi obtained just after suspension of the microcapsules in the solvent (preferably aqueous) phase, 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., and the in vitro release profile Pf.sub.10 obtained 10 days after suspension of the microcapsules in the solvent (preferably aqueous) phase, using a type H apparatus according to the European Pharmacopoeia 3rd edition, in a phosphate buffer medium of pH 6.8, at a temperature of 37° C., are similar.

13. Suspension according to any one of claims 1 to 12, characterized in that its pH is arbitrarily acidic or neutral.

14. Suspension according to any one of claims 1 to 13, characterized in that it comprises at least one rheology modifier.

15. Suspension according to any one of claims 1 to 14, characterized in that it comprises at least one agent for modifying the solubility of the active principle(s) in the solvent (preferably aqueous) liquid phase.

16. Suspension according to any one of claims 1 to 15, characterized in that it contains at least one additive selected from the group comprising surfactants, colourants, dispersants, preservatives, taste improvers, flavourings, sweeteners, antioxidants and mixtures thereof.

17. Suspension according to any one of claims 1 to 16, characterized in that the active principle(s) belongs (belong) to at least one of the following families of active substances: antiulcer drugs, antidiabetics, anticoagulants, antithrombics, hypolipidaemics, antiarrhythmics, vasodilators, antiangina drugs, antihypertensives, vasoprotectors, fertility promoters, labour inducers and inhibitors, contraceptives, antibiotics, antifungals, antivirals, anticancer drugs, anti-inflammatories, analgesics, antiepileptics, antiparkinsonism drugs, neuroleptics, hypnotics, anxiolytics, psychostimulants, antimigraine drugs, antidepressants, antitussives, antihistamines and antiallergics.

18. Suspension according to claim 17, characterized in that the AP is selected from the following compounds: pentoxifylline, prazosin, aciclovir, nifedipine, diltiazem, naproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, fentiazac, oestradiol valerate, metoprolol, sulpiride, captopril, cimetidine, zidovudine, nicardipine, terfenadine, atenolol, salbutamol, carbamazepine, ranitidine, enalapril, simvastatin, fluoxetine, alprazolam, famotidine, ganciclovir, famciclovir, spironolactone, 5-asa, quinidine, perindopril, morphine, pentazocine, metformin, paracetamol, omeprazole, metoclopramide, atenolol, salbutamol morphine, verapamil, erythromycin, caffeine, furosemide, cephalosporins, montelukast, valaciclovir, ascorbic acid salts, diazepam, theophylline, ciprofloxacin, vancomycin, aminoglycosides, penicillins (except for amoxicillin) and mixtures thereof.

19. Drug, characterized in that it comprises a suspension according to any one of claims 1 to 18.

20. Drug, characterized in that it comprises a kit for preparing the suspension according to any one of claims 1 to 18, said kit containing: microcapsules in substantially dry form containing the active principle(s) for saturating the liquid phase with active principle(s) once the two solid and liquid phases have been brought into contact; and/or a mixture of microcapsules in substantially dry form containing the active principle(s) in the dose that is just necessary for modified release, together with immediate-release uncoated active principle(s) in a necessary and sufficient dose to saturate the liquid phase with active principle(s) once the saturation dose of active principle(s) and the liquid phase have been brought into contact; and the liquid phase and/or at least part of the ingredients useful for its preparation, and/or the protocol for preparation of the suspension.

Description

DESCRIPTION OF THE FIGURES

[0208] FIG. 1 shows the initial dissolution profile and the dissolution profile after 10 days' storage of the suspension according to Example 1, in % dissolved (D) as a function of the time (t) in hours.

[0209] FIG. 2 shows the initial dissolution profile and the dissolution profile after 19 days' storage of the suspension according to Example 2, in % dissolved (D) as a function of the time (t) in hours.

[0210] FIG. 3 shows the initial dissolution profile and the dissolution profile after 12 days' storage of the suspension according to Example 3, in % dissolved (D) as a function of the time (t) in hours. This suspension combines 29% of free metformin with 71% of encapsulated metformin.

EXAMPLE 1

[0211] Preparation of Microcapsules of Aciclovir:

[0212] 1000 g of aciclovir and 30 g of povidone® are mixed dry for 5 minutes. The mixture is granulated with water. The granules are dried at 40° C. in a ventilated oven and then graded on a 500 μm screen. The 200-500 μm fraction is selected.

[0213] 700 g of granules obtained above are coated with 27.3 g of ethyl cellulose, 3.7 g of castor oil, 3.7 g of magnesium stearate and 2.9 g of povidone® dissolved in a 60/40 w/w acetone/isopropanol mixture, in a Glatt GPC-G1 fluidized air bed apparatus. Temperature of product: 40° C.

[0214] Preparation of the Suspension:

[0215] 0.58 g of microcapsules obtained above is placed in 37 ml of phosphate buffer of pH 6.8.

[0216] Test:

[0217] The above suspension is stored for 10 days at room temperature. After 10 days the suspension is analysed for dissolution using a type II apparatus according to the European Pharmacopoeia 3rd edition, phosphate buffer medium of pH 6.8, volume of 900 ml, temperature of 37° C., blade stirring at 100 rpm, UV detection at 252 nm.

[0218] The result is shown in FIG. 1 attached.

[0219] The profiles are apparently identical: similarity factor f.sub.2 greater than 50. The microcapsules remain highly effective in aqueous suspension.

EXAMPLE 2

[0220] Preparation of Microcapsules of Spironolactone:

[0221] Step 1: Granules

[0222] 45 g of spironolactone, 25 g of PEG 40—hydrogenated castor oil and 30 g of povidone are first solubilized in a water/acetone/isopropanol mixture (5/57/38 w/w). This solution is then sprayed onto 800 g of cellulose spheres (of diameter between 300 and 500 □m) in a Glatt GPC-G1 fluidized air bed apparatus.

[0223] Step 2: Coating

[0224] 50 g of granules obtained above are coated with 1.44 g of ethyl cellulose, 0.16 g of castor oil, 0.64 g of poloxamer 188 and 0.96 g of povidone dissolved in an acetone/isopropanol mixture (60/40 w/w), in a miniGlatt fluidized air bed apparatus.

[0225] Preparation of the Suspension:

[0226] 0.07 g of microcapsules obtained above is placed in 0.165 ml of phosphate buffer of pH 6.8.

[0227] Test:

[0228] The above suspension is stored for 19 days at room temperature. After 19 days the suspension is analysed for dissolution using a type II apparatus according to the European Pharmacopoeia 3rd edition, phosphate buffer medium of pH 6.8, volume of 1000 ml, temperature of 37° C., blade stirring at 100 rpm, UV detection at 240 nm.

[0229] The result is shown in FIG. 2 attached.

[0230] The profiles are apparently identical: similarity factor f.sub.2 greater than 50. The microcapsules remain very effective in aqueous suspension.

EXAMPLE 3

[0231] Preparation of Microcapsules of Metformin:

[0232] 740 g of metformin crystals (200-500 μm fraction) are coated with 192.4 g of ethyl cellulose, 26 g of castor oil, 26 g of magnesium stearate and 20.8 g of povidone® dissolved in a 60/40 w/w acetone/isopropanol mixture, in a Glatt GPC-G1 fluidized air bed apparatus. Temperature of product: 40° C.

[0233] Preparation of the Suspension (29% of Free Form and 71% of Encapsulated Form):

[0234] 50 g of microcapsules obtained above are mixed dry with 15 g of metformin crystals and 0.7 g of xanthan gum in a 100 ml glass flask. 34.3 g of purified water are then added to the powder mixture. After manual stirring, a suspension is obtained which produces a sediment very slowly.

[0235] The total metformin titre in the suspension is 0.52 g/ml.

[0236] Stability Test:

[0237] The above suspension is stored for 12 days at room temperature. After 12 days the suspension is analysed for dissolution using a type H apparatus according to the European Pharmacopoeia 3rd edition, phosphate buffer medium of pH 6.8, volume of 900 ml, temperature of 37° C., blade stirring at 100 rpm, UV detection at 232 nm.

[0238] The result is shown in FIG. 3 attached.

[0239] The profiles are apparently identical: similarity factor f.sub.2 greater than 50. The microcapsules remain very effective in aqueous suspension.

[0240] Homogeneity Test:

[0241] The above suspension is stirred manually and then six 5 ml samples are taken with a graduated syringe. The metformin content of each sample is determined by HPLC and is shown below:

TABLE-US-00001 Metformin content for 5 ml Sample no. of suspension (in g) 1 2.58 2 2.60 3 2.62 4 2.59 5 2.60 6 2.63

[0242] It is seen that the samples are very homogeneous and that the dosage corresponds to the expected value of 2.60 g for 5 ml.

[0243] This formulation can therefore be administered without risk of overdosing or underdosing.