LIPID COMPOSITION FOR ENCAPSULATING AN ACTIVE SUBSTANCE, PERMITTING CONTROL OF THE RATE OF RELEASE OF SAID ACTIVE SUBSTANCE

Abstract

Disclosed is a lipid composition including, per 100% of its weight:—from 40% to 99.9% by weight of a component including, per 100% of its weight, from 90% to 100% by weight of beeswax and up to 10% by weight of at least one other lipid excipient,—from 0.1% to 60% by weight of at least one lipophilic surfactant.

Claims

1. A lipid composition comprising, per 100% of weight: from 40% to 99.9% by weight of a component comprising, per 100% of weight, from 90% to 100% by weight of beeswax and up to 10% by weight of at least one other lipid excipient, from 0.1% to 60% by weight of at least one lipophilic surfactant selected from polyethoxylated fatty acids, esters of fatty diacids and of polyethylene glycols, esters of polyglycerol and of fatty acids, esters of propylene glycol and of fatty acids, mixtures of esters of propylene glycol and of esters of glycerol, fatty acid diglycerides, sterols and derivatives of sterol, esters of fatty acids and of sorbitan, esters of sorbitan, of polyethylene glycols and of fatty acids, ethers of polyethylene glycols and of alkyl, sucrose esters, and polyoxyethylene-polyoxypropylene block copolymers.

2. The lipid composition as claimed in claim 1, wherein the lipid excipient is selected from animal waxes, vegetable waxes, mineral waxes, synthetic waxes or hydrogenated vegetable oils.

3. The lipid composition as claimed in claim 1, wherein the lipophilic surfactant is selected from esters of fatty acids and of sugars.

4. The lipid composition as claimed in claim 1, wherein the lipophilic surfactant is a lipophilic surfactant from the family of the sorbitan esters.

5. The lipid composition as claimed in claim 1, wherein said composition comprises from 0 to 20% of one or more hydrophilic surfactants.

6. The lipid composition as claimed in claim 5, wherein the hydrophilic surfactant or surfactants is/are selected from soya lecithin, ethoxylated sorbitan esters, polyethoxylated alcohols, polyethoxylated acids, polyglycerol esters, glucose ethers and block copolymers of ethylene oxide and of propylene oxide.

7. The lipid composition as claimed in claim 5, wherein the hydrophobic surfactant is a sorbitan ester and the hydrophilic surfactant is selected from polyethoxylated sorbitan esters.

8. The lipid composition as claimed in claim 7, wherein said composition comprises: 75% beeswax, 20% sorbitan stearate, and 5% sorbitan oleate polyethoxylated with 20 moles of ethylene oxide (or polysorbate 80).

9. The lipid composition as claimed in claim 7, wherein said composition comprises: 50% beeswax, 45% sorbitan stearate, and 5% sorbitan oleate polyethoxylated with 20 moles of ethylene oxide (or polysorbate 80).

10. The lipid composition as claimed in claim 1, wherein said composition comprises from 0 to 20% of at least one coating adjuvant.

11. The lipid composition as claimed in claim 8, wherein the coating adjuvant or adjuvants is/are selected from diluents, flavorings, appetizing agents, colorants, antioxidants, plasticizers, antifoaming agents and disintegrants.

12. A controlled-release composition (CA) comprising: at least one composition as defined in claim 1, and at least one active pharmaceutical, prophylactic or food substance.

13. The composition (CA) as claimed in claim 12, wherein the composition is suitable for oral administration in human beings or animals.

14. The composition (CA) as claimed in claim 12, wherein the composition is in solid form.

15. A method for the encapsulation of an active pharmaceutical, therapeutic, prophylactic, or food substance for human beings or animals in a galenical formulation, comprising providing the lipid composition of claim 1, and encapsulating the active pharmaceutical, therapeutic, prophylactic, or food substance within the lipid composition.

16. A process for manufacturing a galenical formulation comprising a composition (CA) as claimed in claim 12, comprising at least: a) a step of preparing the lipid composition, b) a step of mixing and encapsulating an active pharmaceutical, prophylactic or food substance with the lipid composition prepared in step a) so as to obtain a composition (CA) as claimed in claim 12, and c) a step of galenically forming the composition (CA) prepared in step b), involving mechanical stress.

17. The manufacturing process as claimed in claim 16, wherein the mixing and encapsulation step b) comprises: a first sub-step of heating the lipid composition prepared in step a) to a temperature 10 to 15° C. greater than the highest melting point of the various ingredients of said lipid composition so as to melt said lipid composition, a second sub-step of mixing the molten lipid composition with the active substance in dispersed or molten form, and a third sub-step of spraying the composition obtained in the second sub-step into ambient or cooled air or into a cooled liquid in order to obtain solidified particles of composition (CA).

18. The manufacturing process as claimed in claim 16, wherein the galenical forming step involving mechanical stress is selected from compression, forming into hard capsules, compacting, packaging, placing into sachets, forming into sticks, extrusion, granulation, and pelletization.

19. The lipid composition as claimed in claim 2, wherein the lipophilic surfactant is selected from esters of fatty acids and of sugars.

20. The lipid composition as claimed in claim 2, wherein said composition comprises from 0 to 20% of one or more hydrophilic surfactants.

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Examples

[0116] The qualification of the encapsulation compositions as described above inducing properties of resistance to the mechanical stresses of the downstream galenical steps is established by setting up analyses as described below.

[0117] An active agent is chosen as a principal model active agent. Note that the term “active agent” is understood to mean an active substance. This active substance is caffeine, with an average solubility at ambient temperature (25° C.) in water of 20-25 g/I. Molecular formula: C8H10N4O2; molecular weight: 194.194 g/mol.

[0118] This active agent is encapsulated with the compositions which are the subject matter of the present invention at a rate of 20% to 30% by rotating disk prilling technology. Rotating disk prilling technology: process for preparing composition M1

[0119] For each test, a waxy liquid dispersion is prepared. This waxy liquid dispersion consists of: [0120] the composition which is a subject matter of the present invention, in molten form; [0121] the model active agent in dispersed solid form. In the general case, it should be remembered that an active agent may be present in dispersed or liquid form depending on the value of its melting point.

[0122] For this, a “pre-dispersion”—the result of the melting and/or mixing in the liquid state of the various elements of the composition which is a subject matter of the present invention—is produced beforehand: mixture preparation M0.

[0123] The temperature at which this pre-dispersion, and then the reconstituted dispersion, is kept should be adjusted so as to be 10 to 15° C. greater than the highest melting point of the various ingredients of the composition. Before starting the manufacturing process, the active agent is added, dispersed in this case, with mechanical stirring while maintaining the previously established temperature.

[0124] The rotating disk prilling process is then performed. The dispersion is conveyed by means of heat-insulated pipes to a spray nozzle located in a space/tower resulting, after spraying, to the creation of fine droplets. These fine droplets are then solidified in a stream of cold ambient air, leading to the formation of small spherical beads characterized in that 50% by volume of these beads have a diameter of between 300 and 500 μm. It will be noted that the particle size profile of the beads is measured by virtue of a Mastersizer 3000 laser particle sizer from Malvern, used in the dry route, at a pressure of 1 bar.

[0125] Silicon dioxide or another flow/anti-stick agent can optionally be added beforehand to the microbeads thus produced in order to facilitate later handling thereof.

[0126] Likewise, sieving on a 500 μm sieve may be performed in order to remove any undesired agglomerate/residue having a particle diameter greater than or equal to 500 μm.

[0127] The microbeads thus obtained are then incorporated into a mixture of excipients of grades compatible with a tablet-type galenical forming process. The tablet form is chosen as model final galenical forming process since it represents one of the most extreme cases for induced mechanical stress.

[0128] The tableting is carried out on an instrumented Dott Bonapace reciprocating single-punch press or an instrumented Riva Piccola rotary 8-punch press with application of a compression force which can vary between 5 and 20 kN; 500 mg tablets with breaking strengths of between 80 and 120 N are thus manufactured.

[0129] Demonstration of the technical effect:

[0130] The release profile of the active agent, coated in the composition which is a subject matter of the present invention and then incorporated into a tablet format, is established by means of an Erweka dissolution tester following the recommendations of the European Pharmacopoeia, version 7.3, paragraph 2.9.3.

[0131] The dissolution medium mainly chosen is a pH 7.2 phosphate buffer maintained at a temperature of 37° C. Samples are taken periodically for up to 6 hours. The samples are then analyzed by reversed-phase HPLC assay with UV detection in order to determine the amount of active agent present in each sample and thus to establish a dissolution profile per sample to be evaluated.

[0132] The dissolution profiles, from composition to composition or comparison before/after application of a mechanical stress, are compared in order to determine the yes/no difference of two profiles with each other or of one profile with respect to a control profile.

[0133] Two profiles are thus judged to be similar or not very different, and hence the composition is judged to improve the resistance to mechanical stress, when: [0134] The time-to-time difference, the calculation of which is as follows:

abs[% released(Txi)tab−% released(Txi)μbeads]≤y % [0135] where: [0136] % released(Txi)tab=% of active agent released at the sampling point Txi when the formulation has undergone a tableting process. [0137] % released(Txi)μbeads=% of active agent released at the sampling point Txi when the formulation has not undergone mechanical stress [0138] and in terms of value y is less than or equal to 30+/−2% for up to 2 hours of dissolution time and less than or equal to 20+/−2% over the remaining evaluation time. [0139] The profile can be judged to be similar when the difference throughout the dissolution test is less than or equal to 15%. [0140] The rate of change between the values before and after application of a mechanical stress is less than or equal to 30% as from 3 hours of dissolution time. The calculation is as follows:

[00001]$\frac{\%\mathrm{released}\left(\mathrm{Txi}\right)\mathrm{tab}-\%\mathrm{released}\left(\mathrm{Txi}\right)\mathrm{\mu beads}}{\%\mathrm{released}\left(\mathrm{Txi}\right)\mathrm{\mu beads}}\le 30\%\mathrm{as}\mathrm{from}180\min$ [0141] where:

Txi>=180 minutes [0142] % released(Txi)tab=% of active agent released at the sampling point Txi when the formulation has undergone a tableting process(involving a compression step). [0143] % released(Txi)μbeads=% of active agent released at the sampling point Txi when the formulation has not undergone mechanical stress

Example 1

[0144] In this example, lipid compositions containing as component A the same beeswax, the same amount of polysorbate 80, and the same proportion of various lipophilic surfactants as component B. The constitution of the lipid compositions prepared is recorded in table 1 below. These lipid compositions are used for the coating according to the prilling process as described above with caffeine as the active ingredient. The aim of this example is to show the validity of the combination of beeswax with certain lipophilic surfactants for the coating by the prilling process of the active agent caffeine, by observing the maintenance or non-maintenance of a release profile over the course of time, so as to possibly not consider as appropriate certain combinations of beeswax and lipophilic surfactants before they are subjected to a compression step.

TABLE-US-00001 TABLE 1 Identification of the composition CL 1 CL 2′ CL 3′ Beeswax 80.0% 80.0% 80.0% Sorbitan stearate 19.6% (Montane 60 SEPPIC) Glycerol distearate 19.6% (EP name) Glycerol Monostearate 19.6% (EP name) Polysorbate 80  0.4%  0.4%  0.4% (Montanox 80 SEPPIC)  100%  100%  100%

[0145] The active agent is dispersed at 20% in the composition. The prilling process is implemented. Microbeads having a median diameter of between 350 and 400 μm are obtained.

[0146] These microbeads are stabilized at ambient temperature, protected from light, for a minimal duration of 28 months.

[0147] The dissolution profiles of the microbeads after the manufacturing process or after a minimal shelf life of 28 months are studied. Various sampling times are realized; the comparison of the profile is carried out at the 120 minute point.

[0148] Table 2 below gives percentage values of caffeine released at the 120 minute sampling point:

TABLE-US-00002 TABLE 2 CL 1′ - at a CL 2′ - at a CL 3′ - at a minimum of minimum of minimum of CL1′ - at T0 T28 months CL2′ - at T0 T28 months CL3′ - at T0 T28 months Identification from the from the from the from the from the from the of the obtaining obtaining obtaining obtaining obtaining obtaining composition // of the of the of the of the of the of the sampling time microbeads microbeads microbeads microbeads microbeads microbeads 120 minutes 71% 75% 73% 64% 100% 75%

[0149] Table 3 below gives the values of the time-to-time differences* at the 120 minute sampling point:

TABLE-US-00003 TABLE 3 Identification of CL1′ - CL2′ - CL3′ - the composition // time-to- time-to- time-to- sampling time time difference time difference time difference 120 minutes 4% 9% 25%
(*): a specific definition of the time-to-time difference should be noted here, in the case of a comparison of the release profile at T0 and after a period of stabilization. Therefore, the time-to-time difference is redefined here as resulting from the following calculation:

abs[% released(120x′i)μbeads−% released(120xi)μbeads]y % [0150] where: [0151] % released (120x′i)μbeads=% of active agent released at the 120 minute sampling point, when the formulation has been stored for a defined duration at ambient temperature. [0152] released (120xi)μbeads=% of active agent released at the 120 minute sampling point, when the formulation has not been stored, i.e. the value at T0 from the production of the microbead.

[0153] Two profiles are judged to be of the same order when the time-to-time difference in terms of value y is less than or equal to 20+/−2% at the sampling point considered.

[0154] The profile can be judged to be similar when the time-to-time difference is less than or equal to 15%.

[0155] For this example, it can be observed that the compositions CL1′ and CL2′ make it possible to maintain over time the release profile of the active agent caffeine contained in the microbeads resulting from the prilling process. The composition CL3′ containing glycerol monostearate as component B can already be discounted.

Example 2

[0156] In this example, lipid compositions containing as component A waxes and oils from various sources which are used for the coating by the prilling process of the active agent caffeine as described above. The aim of this example is to demonstrate the specificity of beeswax, combined with the other components, for making it possible to maintain a similar/not greatly different, or otherwise, release profile of the coated active agent after the galenical forming process/following mechanical stress.

[0157] The following compositions are thus used in parallel (table 4):

TABLE-US-00004 TABLE 4 Identification of the composition CL 1 CL 2 CL 3 CL 4 Beeswax 80.0% Palm oil 80.0% Candelilla wax 80.0% Carnauba wax 80.0% Sorbitan stearate 19.6% 19.6% 19.6% 19.6% (Montane 60 SEPPIC) Polysorbate 80  0.4%  0.4%  0.4%  0.4% (Montanox 80 SEPPIC)  100%  100%  100%  100%

[0158] The active agent is dispersed at 20% in the composition. The prilling process is implemented. Microbeads having a median diameter of between 350 and 400 μm are obtained.

[0159] These microbeads are then introduced into a mixture for tablets. 500 mg tablets having a diameter of 11 mm are thus produced according to the following composition: for 40% by weight of microbeads, 27% by weight of microcrystalline cellulose, 29% by weight of calcium hydrogen phosphate dihydrate, 3% by weight of crospovidone and 1% by weight of magnesium stearate are added.

[0160] The dissolution profiles of the microbeads before and after compression process are studied. The sampling times are as follows: 60, 120, 180, 240, 300 and 360 minutes.

[0161] Table 5 below gives the percentage values of caffeine released as a function of time:

TABLE-US-00005 TABLE 5 CL1 - CL2 - CL3 - CL4 - Identification before before before before of the galenical CL 1 - galenical CL 2 - galenical CL 3 - galenical CL 4 - composition // forming after forming after forming after forming after sampling time process tableting process tableting process tableting process tableting  60 minutes  40%  49% 3% 24%  6% 26%  9% 23% 120 minutes  71%  73% 5% 29%  8% 32% 10% 28% 180 minutes  87%  86% 6% 33%  9% 36% 10% 30% 240 minutes >90% >90% 7% 36% 11% 39% 11% 32% 300 minutes >90% >90% 7% 38% 12% 42% 11% 33% 360 minutes >90% >90% 8% 40% 12% 44% 11% 34%

[0162] Table 6 below gives the values of the time-to-time differences and the rates of change at 180 minutes and beyond:

[0163] For this example, it can be seen that only composition CL1 allows an improvement in the resistance to mechanical stress, this stress being illustrated here by a tablet-type galenical forming process.

Example 3

[0164] In this example, lipid compositions containing as component A a ratio of beeswax and candelilla wax which are used for the coating by prilling process of the active agent caffeine. The aim of this example is to demonstrate the possibility of mixing beeswax with another lipid compound up to a certain ratio, combined with the other components, while still making it possible to maintain a similar/not greatly different, or otherwise, release profile of the coated active agent after the galenical forming process/following mechanical stress.

[0165] The following compositions are thus used in parallel:

TABLE-US-00006 TABLE 7 Identification of the composition CL 1 CL 5 CL 6 Beeswax 80.0% 76.0% 68.0% Candelilla wax  4.0% 12.0% Sorbitan stearate 19.6% 19.6% 19.6% (Montane 60 SEPPIC) Polysorbate 80  0.4%  0.4%  0.4% (Montanox 80 SEPPIC)  100%  100%  100%

[0166] The active agent is dispersed at 20% in the composition. The prilling process is implemented. Microbeads having a median diameter of between 350 and 400 μm are obtained.

[0167] These microbeads are then introduced into a mixture for tablets prepared according to the procedure described in example 2. 500 mg tablets having a diameter of 11 mm are thus produced.

[0168] The dissolution profiles of the microbeads before and after compression process are studied. The sampling times are as follows: 60, 120, 180, 240, 300 and 360 minutes.

[0169] The table below gives the percentage values of caffeine released as a function of time:

TABLE-US-00007 TABLE 8 CL1 - CL5 - CL6 - Identification before before before of the galenical CL 1 - galenical CL 5 - galenical CL6 - composition // forming after forming after forming after sampling time process tableting process tableting process tableting  60 minutes  40%  49% 27%  59% 10% 48% 120 minutes  71%  73% 52%  79% 22% 67% 180 minutes  87%  86% 71%  89% 35% 77% 240 minutes >90% >90% 83% >90% 46% 84% 300 minutes >90% >90% 90% >90% 56% 87% 360 minutes >90% >90% >90%  >90% 64% 90%

[0170] The table below gives the values of the time-to-time differences and the rates of change at 180 minutes and beyond:

TABLE-US-00008 TABLE 9 Identification CL1 - CL5- CL6 - of the time-to- CL 1 - time-to- CL 5 - time-to- CL6 - composition // time rate of time rate of time rate of sampling time difference change difference change difference change  60 minutes 9% 31% 38% 120 minutes 2% 26% 45% 180 minutes 0% 0% 19% 26% 43% >100%  240 minutes N/A N/A N/A N/A 37% 80% 300 minutes N/A N/A N/A N/A 31% 56% 360 minutes N/A N/A N/A N/A 25% 39%

[0171] In this example, compositions CL1 and CL5 allow an improvement in the resistance to mechanical stress, with a similar profile for composition CL1 and a not greatly different profile for composition CL5.

Example 4

[0172] In this example, lipid compositions having a component A (beeswax) and a component B (hydrophobic surfactant of sorbitan ester type) which are used for the coating by prilling process of the active agent caffeine.

[0173] The aim of this example is to demonstrate the possibility of mixing component A and component B, for a certain ratio, with regard to maintaining a similar/not greatly different, or otherwise, release profile of the coated active agent after the galenical forming process/following mechanical stress.

[0174] The following compositions are thus used in parallel:

TABLE-US-00009 TABLE 10 Identification of the composition CL7 CL8 CL9 Beeswax 100.0% 80.0% 60.0% Sorbitan stearate 20.0% 40.0% (Montane 60 SEPPIC) .sup. 100%  100%  100%

[0175] The active agent is dispersed at 20% in the composition. The prilling process is implemented. Microbeads having a median diameter of between 350 and 400 μm are obtained.

[0176] These microbeads are then introduced into a mixture for tablets prepared according to the procedure described in example 2. 500 mg tablets having a diameter of 11 mm are thus produced.

[0177] The dissolution profiles of the microbeads before and after compression process are studied. The sampling times are as follows: 30, 60, 120, 180, 240, 300 and 360 minutes.

[0178] Table 11 below gives the percentage values of caffeine released as a function of time:

[0179] The table below gives the values of the time-to-time differences and the rates of change at 180 minutes and beyond:

[0180] In this example, compositions CL8 and CL9 allow an improvement in the resistance to mechanical stress. Via composition CL7, it is observed that a minimal amount of component B is required.