MXPA01000310A - Thixotropic formulations for filling capsules - Google Patents

Abstract

The invention concerns liquid or pasty thixotropic compositions containing an active substance for filling capsulesat room temperature. The compositions become fluid by the effect of shearing when they pass through the filling nozzle, then recover their consistency with sufficient intensity and rapidity to prevent, after filling, any leak between the two capsule parts. Said compositions are characterised in that their rheological properties are specially adapted for filling and for optimal thixotropic recovery of consistency. They are preferably in the form of dispersions supporting amphiphilic excipients. Said compositions enable the formulation of active liquid, pasty and even solid substances.

Description

TIXOTROPIC FORMULATIONS FOR FILLING CAPSULES DESCRIPTIVE MEMORY The present invention relates to pharmaceutical or veterinary, food or cosmetic thixotropic compositions containing one or more active substances for filling hard case capsules, called hard capsules, at room temperature. The term "room temperature" is understood as a temperature substantially between 15 and 30 ° C. Two types of capsule are used for medicinal products of oral, rectal or vaginal administration called soft case capsules and hard case capsules. Individual liquid or pasty pharmaceutical compositions are conventionally presented in soft capsules. However, the process for making soft capsules requires the use of complex plants and custom molds, so the use, for economic reasons, of hard capsules is preferred. Hard capsules are conventionally used to pack solid substances such as powders and granules. In some cases, the filling of hard capsules with solid substances involves certain technical problems such as, on the one hand, the generation of polluting dust when handling active and toxic substances (anticancer, hormones), something that can active and toxic substances (anticancer, hormones ), which can be particularly dangerous, and, on the other hand, the non-uniform filling of one hard capsule to another when the active substance or substances are dosed in small amounts. This is why a solid active substance must be combined with a liquid vehicle before being packaged in hard capsules (US H 672). The use of a liquid vehicle for the filling of hard capsules also causes some problems, since the liquid can leak between the body and the upper part of the hard capsule. Dripping is generally prevented by sealing the hard capsules (EP 488 181 and WO-91/02520). This sealing operation requires a particular expertise and an additional step that incurs a significant additional cost. An alternative to sealing hard capsules has been proposed.

It consists of filling the hard capsules with a composition containing the active principle in the dissolved or dispersed state. This same composition is liquid or pasty and of low viscosity during filling and then thickens inside the hard capsules. According to a first filling mode, called "hot filling", the composition, which is pasty at room temperature, is thickened with heat (EP-49 909). This method can not be applied to heat-sensitive active ingredients such as certain anticancer agents, vitamins and antibiotics.

According to a second filling mode, called "room temperature filling", GB-1 590 864 provides compositions such that: its viscosity at 20 ± 1 ° C is between 500 and 5000 mPa.s, preferably between 1000 and 3000 mPa.s, measured at 450 revolutions per minute in a Haake viscometer, and such that its surface tension is greater than 20 dynes / cm, preferably greater than 30 dynes / cm. However, GB-1 590 864 does not specify what the viscosity of the compositions at rest should be. In addition, a third filling mode, combining the first two, has been described in EP-49 909. According to this method, a slimming shear composition, containing liquid paraffin, hydrogenated castor oil and colloidal silica , it is heated to 40 ° C. The Applicant has demonstrated that the slimming shear nature of the hard capsule filling compositions of the aforementioned technique, although it is necessary to ensure adequate filling of the hard capsule, however, proves to be insufficient. This is because it is also imperative to check that the formulation at rest in the hard capsule is restructured sufficiently strong and especially fast enough, after filling, to avoid dripping between the two parts of the hard capsule.

It is therefore absolutely essential for the consistency of the composition at rest to be sufficient to avoid any filtration of the composition between the two parts of the hard capsule. Among the starting materials used in conventional filling compositions are polyethylene glycols.

The polyethylene glycols dissolve the water-soluble active principle of the filling composition, thanks to its hydrophilic properties (EP-276 116, EP-488 181 and EP-49 909). It has been discovered that the incorporation, as a continuous phase, of polyethylene glycols, and more particularly of polyethylene glycols of low average molecular mass, in the filling composition can involve serious problems of physicochemical interaction and therefore stability problems. In particular, these polyethylene glycols are hygroscopic and attract water from the gelatin in the continuous phase causing the case to become brittle and weak during storage. The filler compositions of the present invention are favorably free of any polyethylene glycol, and in particular of polyethylene glycol of low average molecular mass, which would represent the risk of weakening the hard capsule case. The purpose of the present invention is to provide so-called "thixotropic" compositions containing one or more active substances that allow easy filling of the hard capsules at room temperature and which guarantees the absence of filtrations between the two parts of the hard capsule without being necessary to make use of the sealing generally recommended for this type of pharmaceutical dosage form. The rheological properties of the formulations of the invention ensure an effective filling at room temperature and the absence of drips in the hard filled capsules. It should be remembered that a liquid or pasty thixotropic composition has a shear thinning character which is manifested by a reduction in apparent viscosity under the effect of increasing shear stress. In addition, any variation in the shear conditions causes a structural modification delayed with time. In this way, in particular a recovery of gradual, total or partial consistency is observed after stopping the shear stress. The rheological parameters chosen as particularly representative of the consistency of the formulations are: the G * complex module whose value is greater while the thicker is the product under study, whose complex module is a synthesis of the elastic and viscous properties of the material, and the phase shift d, between 0 and 90 °, knowing that a phase shift greater than 45 ° characterizes a predominantly viscous nature and, conversely, a phase shift of less than 45 ° shows a predominantly elastic nature characteristic of a structured material.

The present invention relates to thixotropic liquid or paste compositions containing one or more active substances, for filling hard capsules at room temperature, such that: their G * complex module is greater than about 100 Pa. Their phase shift d is less than about 45 °, its viscosity decreases as the shear rate increases, under the effect of a constant shear rate? or, the viscosity of said compositions decreases in a delayed manner over time and stabilizes at the equilibrium value ? eq between 100 mPa.s and approximately 10,000 mPa.s, when? o is between 100 and 1000 s "1 after setting said shear rate to 0, the complex modulus and the phase shift of said compositions are recovered, after a time t of less than 1 hour, the G * and d values of more than about 100 Pa and less of approximately 45 °, respectively. The compositions according to the invention are thus defined, on the other hand, by their nature of slimming shearing stress, that is to say that their viscosity decreases when the intensity of the shearing stress increases and, on the other hand, by the decrease in their viscosity over time for a given cutting effort.

The formations of the invention are thus thinned in the hard capsule filling machine due to the effect of the shear stress induced by the agitation occurring from the feed hopper to the distributor nozzle. This property makes it particularly easy to fill hard capsules. For each shear rate, the viscosity of the compositions of the invention decreases with time and is finally stabilized at an equilibrium value called? Eq. The compositions according to the invention have equilibrium viscosities? Eq of 100s "1 and 1000 s" 1 of between 100 mPa.s and 1500 mPa.s. It is completely unnecessary to make use of a heating operation as required in certain prior art processes (E.U.A. 4450 877). The compositions according to the invention are also defined by a significant recovery in consistency delayed with time. The compositions of the invention, thinned in the hard capsule filling machine, recover their initial consistency after a sufficient time of rest, to avoid any risk of leakage of the filled capsule. The formulations according to the invention are characterized by G * values greater than 100 Pa, preferably greater than 1000 Pa, and / or d values of less than 45 °, preferably less than 25 °, and / or a recovery time t less than one hour and preferably less than 30 minutes, and / or values? eq of between 100 mPa.s and 1500 mPa.s when the shear rate is between 100 and 1000 s "1. recovery, the G * eq value is greater than 100 Pa, preferably 1000 Pa, and deq is less than 45 °, preferably less than 25 ° C. The hard capsules used within the context of the present invention consist of gelatin, a polymer of cellulose (such as hydroxypropylmethylcellulose) or of any other polymer capable of fulfilling the functions of using gelatin in the form of a hard capsule In accordance with a preferred embodiment, the thixotropic compositions of the present invention are dispersions containing a digestion phase. continuous liquid or pasty spersion, a dispersed phase of modulating viscosity in the particle or micellar state and at least one active substance present in the dissolved and / or dispersed state. The dispersion phases of the invention are characterized by their wide polarity scale in terms of hydrophilic / lipophilic equilibrium (HLB). The raw materials used in the formulation of these dispersing phases of the invention have hydrophilic, lipophilic or amphiphilic properties of HLB variables, which allows the dissolution or dispersion of active liquid and solid principles that are themselves hydrophilic, lipophilic or amphiphilic. The continuous phase of these compositions consists favorably of at least one vehicle such as oils, their derivatives, and very particularly amphiphilic esters having an HLB of between 3 and 15, such as polyglycolized amphiphilic glycerides, such as LABRASOL® and LABRAFIL® sold by Gattefosse . The use of amphiphilic vehicles having a hydrophilic tendency represents a good alternative for the hydrophilic polyethylene glycols of the prior art. In addition to polyethylene glycols, the products conventionally used in the formulation of liquid or pasty thixotropic preparations for a hard capsule are rather lipophilic (GB-1 590 864, US-4 450 877, US-H672, EP-461 290) . The amphiphilic continuous phases having a hydrophilic tendency used within the context of the present invention, unlike the excipients of the prior art, prove to be ideally suited for active hydrophilic, lipophilic or amphiphilic principles whether they are dissolved or dispersed respectively. The dispersed viscosity modulating phase of the compositions according to the invention can be chosen from hydrophilic or hydrophobic pyrogenic silica particles, the average size of which should be between 5 and 50 nm, preferably between 7 and 20 nm, and the surface area specific between 10 and 450 m2 / g, preferably between 70 and 410 m2 / g, such as AEROSIL® sold by Degussa, and copolymers of ethylene oxide and propylene oxide, such as SYNPERONIC® products sold by ICI, and their mixtures . The dispersed phase combined with the continuous phase makes it possible to achieve HLB values ranging up to about 20.

The dispersive viscosity modulating phase of the compositions according to the invention preferably represent from 1 to 30% m / m, most preferably from 5 to 15% m / m, of the preparation. The excipients used in the formulation of thixotropic compositions according to the invention are chosen from pharmaceutically acceptable excipients which are inert with respect to the active substances which it is desired to formulate. In addition, these excipients are chosen from excipients that are compatible with the hard capsule case. The excipients which are used in the formulation of thixotropic compositions according to the invention are conveniently endowed with hydrophilic, lipophilic or amphiphilic properties with, for these, a variable lipophilic hydrophilic balance (HLB), which allows the dissolution or dispersion of both the substances active hydrophilic as lipophilic. Vehicle HLB can vary from 4 ± 1 for a combination of LABRAFIL® M1944CS and AEROSIL® to 20 ± 1 for a combination of LABRASOL® and SYNPERONIC®. The compositions according to the invention contain an active substance which can be liquid or pasty but also solid, for example milnacipran hydrochloride (solubility in water of 600 g / l), baquimast (solubility in water of 0.23 g / l), nifedipine , triamterene, aluminum hydroxychloride, sodium salicylate, vancomycin, parametadone and griseofulvin.

The hard capsules used within the context of the present invention consist of gelatin or any other cellulose polymer capable of fulfilling the functions of using gelatin in the form of a hard capsule, such as hydropropylmethylcellulose. The invention is not limited to these examples and one skilled in the art will easily be able to include any active substance of their choice whether liquid, pasty or even solid, in the compositions described. The present invention also relates to the use of compositions described above in a cosmetic, food, pharmaceutical or veterinary preparation. The present invention is illustrated with the following examples with reference to the accompanying drawings: Figure 1 shows the rheogram of a formulation of Example 4 of the invention and the rheogram of a composition of Example 5, whose rheological properties do not meet the criteria of the invention. The stress (in passages) is marked on the y-axis and the shear velocity (in s "1) is marked on the x-axis; Figure 2 gives the time dependence of the consistency recovery of two formulations of the invention, that of example 2 and that of example 4. The complex module, expressed in passages, is marked on the y-axis and the time is marked on the x-axis; Figures 3 and 4 represent the degree of dissolution as a percentage (on the y-axis) of a formulation of Example 1 and of a formulation of Example 2, respectively, as a function of time (on the x-axis) expressed in hours and minutes, representatively.

EXAMPLES 1 TO 7 a) Preparation of the dispersions Seven dispersions were prepared, each containing a continuous phase, a dispersed phase and an active phase. The continuous phase consisted of an amphiphilic ester such as LABRAFIL M1944CS® (HLB = 4 ± 1) or LABRASOL® (HLB = 14 + 1). It should be mentioned at this stage that the amphiphilic esters that can be used within the context of the invention can have HLB values between 3 and 15. The dispersed phase was chosen from AEROSIL 200 V® (a hydrophilic pyrogenic silica), AEROSIL R 974® (a hydrophobic pyrogenic silica) and SYNPERONIC PE / F 68® (a copolymer of ethylene oxide / propylene oxide having an HLB of 29 + 1). When the dispersed phase chosen was SYNPERONIC® the HLB of the dispersing phase increased to approximately 20. The active substance was chosen from milnacipran hydrochloride (a solid whose solubility in water is 600 g / l) a basquimast (a solid whose solubility in water it is 0.23 g / l).

Preparations containing fumed silica as dispersed phase were obtained by gradually adding silica to the amphiphilic ester with vigorous stirring, favorably at between 10 and 3000 revolutions per minute. The mixture was then placed under vacuum and agitation was continued after incorporating the silica until homogeneous. The preparations containing SYNPERONIC® as dispersed phase were obtained by gradually adding SYNPERONIC® to the amphiphilic ester with moderate agitation, favorably at between 400 and 800 revolutions per minute. The mixture was then placed under vacuum and stirring was continued until homogeneous. Regardless of whether the preparations contained AEROSIL® or SYNPERONIC® as dispersed viscosity modulating phase, the chosen active substance was always added to the amphiphilic ester / dispersed phase mixture at room temperature with moderate agitation. The composition of each dispersion is shown in detail in Table 1 below. b) Rheological properties The rheological properties of the seven preparations were studied in terms of slimming shear and recovery of consistency. b1) The slimming shear stress was characterized at 25 ° C in terms of flow rheology in a rotating controlled rheometer (Carri-Med CSL100).

The rheogram of "effort as a shear rate function" is marked for each of the dispersions. The rheogram makes it possible to review the ability of a preparation to undergo a thinning when the intensity of the shearing stress increases. Since the viscosity is defined as the ratio of the stress to the shear rate, a convex curve is the expression of a decrease in viscosity with shear rate, this means a shear thinning behavior, while a curve Concave is the expression of an increase in viscosity with shear rate, ie a shear stress behavior. Figure 1 shows the rheogram for two dispersions, dispersion 4 and dispersion 5, whose compositions are shown in table 1. The line of the reogram for dispersion 4, which is convex, means that dispersion 4 is of slimming shear and meets with the criteria of the compositions of the invention, while for the preparation 5, which is concave, its character of thickening shear stress is demonstrated. Table 1 specifies the character of slimming shear stress or thickener shear observed in the light of the rheogram of each dispersion. The formulations were also subjected to constant shear rates of the same order of magnitude as those that occur in a hard capsule filling machine of the conventional type (100 s "1 for lines in the machine and 1000 s" for narrowing at the outlet of the injection nozzle). For each shear rate, it should be noted that there is a reduction in viscosity over time, which finally stabilizes at an equilibrium value called? Eq. The results are given in table 1. The seven dispersions have equilibrium viscosities, at a shear rate of 100 s "1 or 1000 s" 1, between 100 mPa.s and 5000 mPa.s. These viscosity values prove, therefore, to be suitable for the automatic filling of hard capsules. It is completely unnecessary to lose weight more our thixotropic dispersions by raising the filling temperature, as recommended by the authors of the patent of USES. 4450 877. b2) The rheological conditions in relation to the recovery of thixotropy, and that guarantee that there is no long-term drip, was determined at 25 ° C, in dynamic rheology, in a Couette rotary rheometer controlled effort (Carri -Med CSL 100). This mode of study, unlike the flow rheology, allows the consistency of a material "at rest" is calculated since it is possible to apply considerably lower pressures to the material than in flow. The seven dispersions were pre-cut for 15 minutes at 1000 sA The parameters used to characterize the consistency recovery are the magnitude of the recovery (expressed as a percentage) the G * complex module (in passages) after the recovery and the phase shift (in degrees) 1 hour after stopping the shear stress and the time t50% for the recovery to reach 50% with respect to G * eq. The results are added in table 1. Percent recovery of the consistency of slimming shear dispersions 1, 2, 3, 4, 6 and 7 is equal to 100%. The recovery is, therefore, total. The values of recovery G * after 1 hour are total and greater than 100 Pa with respect to preparations 1, 4 and 7, but less than 100 Pa with respect to preparations 5 and 6, which reach values of 5 and 70 Pa respectively . After recovery, d is less than 25 ° for all dispersions, with the exception of dispersion 5 (equal to 71 °). For the five dispersions of slimming shear, t5o% is less than 30 minutes. The dispersions 1, 2, 3, 6 and 7 pass, therefore, by a rapid and total recovery of their consistency, which is even more considerable. Figure 2 shows the change in G * as a function of time for dispersions 2 and 4. It can be seen that the consistency recovery of dispersion 2 is very fast (t50% = 1 s) and considerable (after recovery G * = 1400 Pa), that of dispersion 4 is slower (tdo% = 23 min) and considerable (after recovery G * = 900 Pa). c) Hard capsule stability study Having studied the rheological properties of the dispersions, these were deposited in size 1 conventional hard gelatin capsules at room temperature using an industrial type filling machine. The filling was carried out with a coefficient of variation in the mass of the filled hard capsule that was systematically less than 1.5%. The filled hard capsules were stored for 12 months in an oven (25 ° C ± 2 ° C) and 60% RH ± 5% RH) in order to confirm that there were no leaks or deformations in the capsule case. Only the capsules containing preparations 5 and 6 had leaks during storage. d. In vitro release study of hard capsule In vitro release studies were carried out, carried out in "Dissolutes" (water at 37 + 0.5 ° C, 100 tpm). The results for preparations 1 and 2 are given in Figures 3 and 4, respectively. The release of milnacipran hydrochloride (a water soluble solid active ingredient) is faster the more hydrophilic the continuous phase.

Under the operating conditions employed, preparation 2 (FIG. 4) containing an amphiphilic ester having a hydrophilic tendency (HLB = 14) released the active ingredient much more rapidly than preparation 1 (FIG. 3) containing an amphiphilic ester which it has a lipophilic tendency (HLB = 4 ± 1). The choice of the continuous phase, therefore, makes it possible to adjust the rate of release of the active principle.

TABLE I: Compositions and critical reolóqicos parameters of the dispersion examples? tsJ O

Claims (10)

1. NOVELTY OF THE INVENTION CLAIMS 1. - Liquid or pasty thixotropic compositions containing one or more active substances, for filling hard capsules at room temperature in such a way that: their G * complex module is greater than about 100 Pa, their phase shift d is less than about 45 °, its viscosity decreases when its shear rate increases, under the effect of a constant shear rate? 0 > the viscosity of said compositions decreases in a delayed manner with time and stabilizes at an equilibrium value? eq between 10 mPa.s and approximately 10,000 mPa.s, when? o is between 100 and 1000 s "1 and after setting the speed of shear stress mentioned at 0, the complex modulus and phase displacement of said compositions recover, after a time t less than 1 hour, the G * and d values greater than 100 Pa and less than 45 ° respectively. according to claim 1, further characterized in that: G * is greater than 1000 Pa, and / od is less than 25 ° and / or? eq is between 100 and 1500 mPa.s when? 0 is between 100 and 1000 s "1 y / ot is less than 30 minutes. 3. - The compositions according to claim 1 or 2, further characterized in that they are preparations containing a continuous dispersing phase, a dispersed phase and at least one active substance. 4. The compositions according to claim 3, further characterized in that the continuous phase consists of at least one vehicle such as amphiphilic esters having an HLB between 3 and 15 and very particularly polyglycolized glycerides. 5. The compositions according to claim 3 or 4, further characterized in that the dispersed phase is chosen from hydrophilic or hydrophobic pyrogenic silica particles and copolymers of ethylene oxide propylene oxide, the latter making it possible to achieve, when combined with the continuous phase, HLB values which amount to up to about 20. The compositions according to one of claims 3 to 5, further characterized in that the active substance is liquid, pasty or solid. 7. The compositions according to claim 6, further characterized in that the active substance is chosen from milnacipran hydrochloride, baquimast, nifedipine, triamterene, aluminum hydrochloride, sodium salicylate, vancomycin, parametadone and griseofulvin. 8. The compositions according to one of claims 3 to 7, further characterized in that the dispersed phase of the preparations according to the invention represent from 1 to 30% m / m of the preparation. 9. - The compositions according to claim 8, further characterized in that the dispersed phase of the dispersions according to the invention represent from 5 to 15% m / m of the preparation. 10. The compositions according to one of the preceding claims, further characterized in that the hard capsules consist of gelatin or any other cellulose polymer capable of fulfilling the functions of using gelatin in the form of a hard capsule such as hydroxypropylmethylcellulose.