CONTROLLED RELEASE OF ACTIVE SUBSTANCES

Abstract

A water-insoluble composition, solid in appearance at a temperature of less than or equal to 20° C., comprising, for 100% of the mass of same:—X1% by mass of at least one lipophilic surfactant having a value HLB, H1, greater than or equal to 1 and less than 10;—X2% by mass of at least one hydrophilic surfactant having a value HLB, H2, greater than or equal to 10 and less than or equal to 20; characterised by the fact that the HLB of same=X1.H1+X2.H2, X1 and X2 varying from 2 to 60, and characterised in that it is free of acrylic polymer and/or of acetate succinate.

Claims

1. A water-insoluble composition, of solid appearance at a temperature less than or equal to 20° C., comprising for 100% of its weight: X1 wt % of at least one lipophilic surfactant having an HLB value, H1, greater than or equal to 1 and below 10; X2 wt % of at least one hydrophilic surfactant having an HLB value, H2, greater than or equal to 10 and less than or equal to 20; characterized in that its HLB=X1.H1+X2.H2, X1 and X2 varying from 2 to 60, and characterized in that it is free from acrylic polymer and/or succinate acetate.

2. The composition as claimed in the preceding claim, characterized in that H1 is greater than or equal to 3.4 and less than or equal to 6 and H2 is greater than or equal to 14 and less than or equal to 16.

3. The composition as claimed in claim 1, characterized in that it comprises from two to five surfactants each having an HLB, Hi, and a proportion by weight Xi such that the HLB value of said composition is equal to ΣXi.Hi, with i between 2 and 5, xi between 2% and 60% and ΣXi≦100%.

4. The composition as claimed in claim 1, characterized in that said at least one hydrophilic surfactant is selected from ethoxylated sorbitan esters, ethoxylated alcohols or acids, polyglycerol esters, glucose ethers, the block copolymers of ethylene oxide and propylene oxide.

5. The composition as claimed in claim 1, characterized in that said at least one lipophilic surfactant is selected from esters of fatty acids and sugars; said fatty acids being selected from stearic, palmitic, ketostearic, arachidic, and behenic acids; said sugars being for example glucose, sorbitol, mannitose, mannitol, sucrose, mannose, xylitol or xylose; esters of fatty acids and glycerol, said fatty acids being selected from stearic, palmitic, ketostearic, arachidic, and behenic acids; ethers of fatty alcohols and sugars, the fatty alcohols being stearic, palmitic, ketostearic, arachidic, and behenic alcohols; said sugars being for example reducing sugars, and more particularly glucose, xylose, arabinose, mannose, or sucrose; divalent salts of fatty acids such as the magnesium, zinc or calcium salts of stearic, palmitic, ketostearic, arachidic, and behenic acids; fatty alcohols condensed with propylene oxide and/or butylene oxide; block copolymers of alkoxides (ethylene, propylene, butylene, etc.), rich in propylene oxide or butylene oxide.

6. The composition as claimed in claim 1, characterized in that said at least one lipophilic surfactant is a sorbitan stearate.

7. The composition as claimed in claim 1, characterized in that it further comprises, to 100% of its weight, an amount of additives such as a perfume, a flavoring, a palatabilizer, a dye, a pigment, or a solid diluent at a temperature less than or equal to 20° C. such as a hydrogenated vegetable oil such as soybean oil, castor oil, colza oil or hydrogenated palm oil, shea butter, a wax such as beeswax or carnauba wax.

8. A controlled-release galenical formulation comprising for 100% of its weight: from 20 to 95 wt % of at least one pharmaceutical, food or veterinary active substance; and from 5 to 80 wt % of a composition as defined in claim 1.

9. (canceled)

10. The formulation as claimed in claim 8, characterized in that the active substance is selected from the antiulcer drugs, antidiabetic drugs, anticoagulants, antithrombotics, hypolipemic drugs, antiarhythmic drugs, vasodilators, antiangina drugs, antihypertensives, vasoprotective agents, antibiotics, antifungals, antivirals, anticancer drugs, anti-inflammatories, analgesics, antiepileptics, antiparkinsonian drugs, neuroleptics, hypnotics, anxiolytics, psychostimulants, antimigraine drugs, antidepressants, antitussives, antihistamines or antiallergic drugs.

11. The formulation as claimed in the preceding claim, characterized in that the active substance is selected from the following compounds: metformin, acetylsalicylic acid, pentoxifylline, prazosin, acyclovir, nifedipine, diltiazem, naproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, fentiazac, estradiol valerate, metoprolol, sulpiride, captopril, cimetidine, zidovudine, nicardipine, terfenadine, atenolol, salbutamol, carbamazepine, ranitidine, enalapril, simvastatin, fluoxetine, alprazolam, famotidine, ganciclovir, famciclovir, spironolactone, 5-ASA, quinidine, morphine, pentazocine, paracetamol, omeprazole, metoclopramide and mixtures thereof.

12. The formulation as claimed in claim 8, characterized in that the active substance is selected from a list of nutraceuticals: tonics, antioxidants, and stimulants such as mineral salts, notably iron salts, vitamins, urea, caffeine.

13. The use of a composition as defined in claim 1 for encapsulation of a pharmaceutical, food or veterinary active substance in a controlled-release galenical formulation.

14. (canceled)

Description

EXAMPLE 1: CONTROLLED RELEASE AND TASTE MASKING OF A HYDROPHILIC METAL Powder

[0086] In this example, the active substance to be encapsulated is a hydrophilic powder consisting of a metal sulfate. It is used for restoring the metal balance if there is a deficiency, notably in young children.

[0087] Its taste is a very astringent taste typical of the metal salts and in particular its hydrophilic character is such that the product dissolves in less than an hour in the stomach, making continuous administration over the day impossible and suddenly increasing the content of metal in the blood.

[0088] Said hydrophilic powder for example consists of a calcium, manganese, zinc or iron sulfate.

[0089] Description of the Operations:

[0090] A 5-ml glass syringe equipped with a 20 G needle for dropping beads of the surfactant/metal powder mixture molten at 75° C. into cold water is used. Then the molten mixture is held in the syringe.

[0091] Beads are prepared with a diameter of about 2 mm containing, for 100% of their weight, 50 wt % of hydrophilic powder and 50 wt % of an intimate Montane 60/Montanox 60 mixture in a weight ratio of 90/10.

[0092] The release kinetics was evaluated by monitoring the conductivity. A result that meets the requirement is obtained (80 to 100% of active substance released between six hours and eight hours).

[0093] Two 30 g samples of beads are prepared, and the following table gives their composition by weight for 100% of their weight.

TABLE-US-00001 Hydrophilic powder 50% 50% Montane 60* 50% 45% Montanox 60**  5% *Sorbitan monostearate manufactured by SEPPIC **Ethoxylated sorbitan monostearate with 20 moles of ethylene oxide manufactured by SEPPIC.

[0094] Evaluation of the Rate of Release of the Metal Ion:

[0095] 1 g of beads are dispersed in 100 g of water. The variation of conductivity is monitored as a function of time. The results are illustrated in FIG. 1.

[0096] Control: solution with 0.5 g of powder alone in 100 g of water: 3560 mS/cm.

EXAMPLE 2: ENCAPSULATION AND TASTE MASKING OF A VETERINARY ACTIVE SUBSTANCE

[0097] In this example the active substance to be protected and encapsulated is a veterinary antiparasitic agent (API). This active principle, administered mainly by the oral route, is very bitter, it is easily detected by felines, whose smell and taste are very sensitive. It is in the form of a white powder of high melting point (135° C.) with very low solubility in water (200 mg/l at 20° C.).

[0098] As a veterinary antiparasitic agent, we may mention for example insect repellents for external use: essential oils such as geraniol or lavender extract. Insecticides for internal use: Fiproli, avermectin.

[0099] Other examples are anthelmintics and acaricides such as febantel, niclosamide, pyrantel. A very good example is praziquantel.

[0100] Encapsulation has the aim of masking the taste of the active principle for about 15 minutes. This means very little release of the API (an amount not exceeding 10 wt % of the API) during this minimum interval of time of 15 minutes, but it must be released completely in a time of one to two hours after administration, in the animal's stomach at pH 4 to 5.

[0101] The concentration of active principle in the encapsulating matrix has to approach 40 wt %.

[0102] Different mixtures of hydrophilic and lipophilic surfactants were evaluated, combined with 40 wt % of the active substance. The formulations have the following composition, for 100% of their weights:

[0103] Active principle: 40%

[0104] Lipophilic surfactant: 30%-60%

[0105] Hydrophilic surfactant: 0%-30%

TABLE-US-00002 Table of the surfactants used for the tests Nature Trade name HLB Character Glycerol dibehenate Compritol 888  1.8 lipophilic (Gattefossé) Glycerol Essai Seppic  2 lipophilic monobehenate Sorbitan stearate Montane 60  4.7 lipophilic (Seppic) Ethoxylated Simulsol 58 PHA 15.7 hydrophilic ketostearyl alcohol (Seppic) (8 EO) Ethoxylated sorbitan Montanox 60 14.9 hydrophilic stearate (20 EO) (Seppic)

[0106] Experimental Protocol for Microbead Manufacture

[0107] All the utensils used are put in a stove at 100° C. The excipients are melted in the stove at 100° C. The molten excipients are introduced with stirring into a hot 500-mL reactor on a water bath on a magnetic stirrer with thermostatic control at 145° C. The active substance is added and homogenized until an oily liquid of yellowish or brown appearance is obtained. The molten mixture is cooled and then ground and sieved to obtain solid microbeads.

[0108] The granulometry of the microbeads is characterized by laser diffraction from their Dv90 (maximum size of 90% of the particles) and their Dv50 (average diameter of the particles), using a MALVERN Mastersizer granulometer.

[0109] Experimental Protocol for Release of the Active Substance

[0110] The dissolution protocol described in the US pharmacopeia was followed. 100 g of microbeads are dispersed in one liter of aqueous solution at pH 5, maintained at 37° C. Samples are taken periodically and analyzed by HPLC for their concentration of active principle.

TABLE-US-00003 Composition and characterization of the microbeads produced Composition by weight Granulometry Refer- Active Lipophilic Hydrophilic HLB (μm) ence principle TA TA microbead Dv90 DV50 1 40% Glycerol 0 1.8 900 ND dibehenate 60% 2 40% Glycerol 0 1.8 493 ND dibehenate 60% 3 50% Glycerol 0 1.8 872 ND dibehenate 50% 4 40% Glycerol Ketostearyl 4.3 494 250 dibehenate alcohol 50% 8 EO 10% 5 40% Glycerol Ketostearyl 6.6 514 266 dibehenate alcohol 40% 8 EO 20% 6 40% Glycerol Ketostearyl 8.9 496 248 dibehenate alcohol 30% 8 EO 30% 7 40% Glycerol 0 2 555 284 monobehenate 60% 8 40% Glycerol Sorbitan 6.3 498 252 dibehenate stearate 20 40% EO 20%

[0111] Results for Release of the Active Substance in the Various Tests Performed

[0112] It can be seen from the curves in FIG. 2 that the different compositions tested alter the release profiles of the active principle completely.

[0113] Tests 1 and 2, with identical compositions, give release profiles that can be superimposed, showing the reproducibility and robustness of the method. They only allow release of a tiny fraction of the active substance (up to 4 wt % in 30 minutes) and therefore effective taste masking. Test 3 with the same qualitative composition but a higher load of active principle displays a slightly quicker release profile, in accordance with the principles of the laws of diffusion.

[0114] The curves also show that the higher the HLB value of the microbead, the quicker the release of the active substance.

[0115] The compositions not containing hydrophilic surfactant (and which therefore do not correspond to the invention), such as 7, 1, 2 and 3, effectively release very little active substance in the first quarter of an hour but do not release much more of it thereafter. The active substance therefore remains largely trapped in the capsule and is no longer effective. The composition with the highest HLB value (test 6) releases practically all the active substance in one hour but also a lot of the active substance in fifteen minutes, which means it has limited taste masking properties. It is therefore a question of finding a good compromise, which is the case with compositions such as 4, 5 and 8. The compositions aimed at are those that release less than 10% of active substance in 15 minutes to provide the taste masking effect and more than 30% of active substance in 45 minutes to provide efficacy of the active principle in the alimentary canal.

[0116] This correlation can also be seen in the graph in FIG. 3, showing the percentage by weight of active substance released after 15 minutes as a function of the HLB value of the microbeads.

[0117] During production of the finished product, a palatabilizer for cats was added to the solution for encapsulation by prilling of surfactants to make the product even more attractive for animals.

[0118] Addition of the palatabilizer at a dose of 0.5% did not alter the “prilling” conditions or the release profiles.

EXAMPLE 3: CASE OF A VETERINARY ADDITIVE FOR RUMINANTS

[0119] In this example we are interested in a hydrophilic active principle for feeding bovines, soluble in thirty seconds in the ruminant's rumen.

[0120] The objective is to encapsulate it so that it is released in the bovine rumen gradually in about six to eight hours.

[0121] The aim is to encapsulate this active substance in mixtures involving at least two surfactants having different HLB values to obtain a targeted release profile, characterized by the release of about 20% of the active substance administered after one hour, 40% after four hours and 50% after six hours.

[0122] The composition adopted comprises: [0123] Two surfactants: Sorbitan stearate-lipophilic surfactant of HLB 4.7 and ethoxylated sorbitan stearate (20 EO)−hydrophilic surfactant of HLB 15. [0124] A diluent: hydrogenated palm oil

[0125] The HLB of the composition is 5.1; the proportions by weight of its constituents are given below for 100% of the weight of said composition:

[0126] Hydrogenated palm oil: 74%

[0127] Sorbitan stearate: 25%

[0128] Ethoxylated sorbitan oleate 20 EO: 1%.

[0129] Encapsulation of the active substance is carried out by spraying the molten composition at 70° C. on the active substance in a film-coating turbine, the temperature of which is kept close to 50° C. Spraying is effected with Accucoat® apparatus equipped with a gun of the Airless type.

[0130] Dissolution of the active substance is carried out in a dissolution bench according to the European Pharmacopeia. 2.5 g of microcapsules are dispersed in one liter of an aqueous solution at pH 6, maintained at 37° C. with a stirring speed of 100 rev/min. The release of the active substance is monitored by taking regular samples for analysis of said active substance by spectrophotometry at 420 nm.

[0131] The curves in FIG. 4 show that the targeted release profile can be achieved by encapsulating 88 wt % of active substance in 12% of the composition adopted and that the release profile can be adjusted as a function of the amount of the composition deposited on the active substance: the greater the amount deposited, the slower the dissolution of the active substance.

EXAMPLE 4: EFFECT OF THE HLB OF THE ENCAPSULATING COMPOSITION ON THE RELEASE OF A VETERINARY ADDITIVE FOR RUMINANTS

[0132] Different compositions of hydrophilic and lipophilic surfactants diluted in a hydrogenated vegetable oil were studied for encapsulating the veterinary active substance from example 3.

[0133] The active substance is for example an amino acid such as choline, urea, vitamins (for example vitamin C), or a mineral salt (of calcium or of iron).

[0134] Sorbitan stearate is a lipophilic surfactant with HLB 4.7. Ethoxylated sorbitan oleate with 20 moles of ethylene oxide is a hydrophilic surfactant with HLB 15.

[0135] The release kinetics of the active substance was measured in the same conditions as described above in example 3.

[0136] The compositions by weight of the fatty phases employed for encapsulating the active substance are given below, for 100% of the weight of the compositions formed.

TABLE-US-00004 Hydrogenated Sorbitan Sorbitan vegetable oil stearate oleate 20 EO HLB of the Reference (%) (%) (%) composition 9 47.5 47.5 5 5.7 10 50 50 0 4.7

[0137] The curves in FIG. 5 show the release kinetics of the active substance determined in the same experimental conditions as those described above. Once again it is found that the rate of release increases with the HLB of the coating composition.

[0138] In another series of tests, we formulated capsules comprising, for 100% of their weight, 90 wt % of active substance and 10 wt % of coating, having the following compositions for 100 wt % of said coating.

TABLE-US-00005 Hydrogenated Sorbitan Sorbitan vegetable oil stearate oleate 20 EO HLB of the Reference (%) (%) (%) composition 11 75 25 0 4.7 12 74.3 24.7 1 5.1 13 72.8 24.2 3 5.8

[0139] The curves of release of the active substance presented in FIG. 6 show that a targeted profile may be achieved by adjusting the concentration of hydrophilic surfactant to 1% in the coating composition.

EXAMPLE 5: ENTERIC MICROBEADS COMPRISING TWO SURFACTANTS

[0140] The objective is to develop a composition that is in the form of microbeads and contains an active pharmaceutical ingredient, diclofenac sodium, that does not dissolve in the stomach at acid pH, but allows release of the active principle in the intestine (for a pH value greater than or equal to 5 and less than or equal to 8).

[0141] To achieve this objective, we formulated a composition comprising a combination of two surfactants: a lipophilic surfactant (sorbitan stearate, HLB=4.7) and a surfactant whose HLB value varies as a function of the pH. Stearic acid is lipophilic in an acid environment and hydrophilic in a neutral or basic environment (HLB close to 20).

[0142] The waxy mixture (sorbitan stearate/stearic acid) is heated to 85° C. on a water bath. The diclofenac sodium is added while stirring with a deflocculator/Rayneri.

[0143] When the mixture is homogeneous, it is put in the prilling machine.

[0144] Experimental Protocol:

[0145] A liquid formula is obtained at 85° C., which sets at room temperature and has the following composition by weight for 100% of its weight: [0146] 21% A sorbitan stearate (Montane™ 60), [0147] 49% stearic acid, [0148] 30% diclofenac sodium.

[0149] The molten formula is put in the tank of a rotating-disk prilling device made by SPRAI.

[0150] The operating parameters for formation of the microbeads are as follows: [0151] tank heating temperature: 85° C., [0152] heating temperature of the feed pipe for the disk: 85° C., [0153] disk rotary speed: 50 rev/s, [0154] pressure in the tank: 0.6 bar.

[0155] In these conditions, spherical microbeads are obtained with a diameter under 500 μm.

[0156] The release of the diclofenac is measured in a dissolution bench according to the European Pharmacopeia: [0157] release medium: solution of HCl at pH=1 (750 mL) for two hours then addition of 250 mL of phosphate buffer and then pH adjustment to 6.8 with 5% NaOH solution. Beads left at pH=6.8 for four hours, [0158] 150 g of beads placed directly in the dissolution medium, [0159] amount of the release medium per bowl: 1 L, [0160] amount of medium taken each time: 3 mL, [0161] temperature of the release medium: 37° C.

[0162] The curve in FIG. 7 shows the release kinetics obtained. It shows that the active substance is not released from the microbeads in acid medium but dissolves quickly as soon as the pH of the dissolution medium is increased to a value of 6.8. The reproducibility of the release kinetics evaluated in four identical tests is good.