Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-03-05
2004-03-23
Lovering, Richard D. (Department: 1712)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S455000, C424S456000, C424S453000, C514S937000, C516S099000
Reexamination Certificate
active
06709675
ABSTRACT:
The present invention relates to thixotropic pharmaceutical or veterinary, dietary or cosmetic compositions containing one or more active substances intended for filling capsules with a hard casing, called hard capsules, at room temperature.
The term “room temperature” is understood to mean a temperature substantially between 15 and 30° C.
Two types of capsules are used for medicinal products intended for oral, rectal or vaginal administration, namely capsules with a soft case and capsules with a hard case.
Individual liquid or pasty pharmaceutical compositions are conventionally presented in soft capsules. However, the process for manufacturing soft capsules requires the use of complex plants and specialized custom molders, so that the use of hard capsules may, for economic reasons, be preferred.
Hard capsules are conventionally used for packaging solid substances such as powders and granules. In some cases, filling hard capsules with solid substances poses certain technical problems such as, on the one hand, the generation of contaminating dust when handling active and toxic substances (anticancers, hormones)—something which may prove to be particularly dangerous—and, on the other hand, the nonuniform filling from one hard capsule to another when the active substance or substances are lightly dosed.
This is why a solid active substance may 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 raises problems, since the liquid can flow out between the body and the top of the hard capsule. Leaks are generally avoided by sealing the hard capsules (EP 488 181 and WO-91/02520). This sealing operation requires a particular know-how and an additional step incurring a not insignificant additional cost.
An alternative to sealing the hard capsules has been proposed. It consists in 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 the filling and it then thickens inside the hard capsules.
According to a first filling mode, called “hot filling”, the composition, which is pasty at room temperature, is thinned by heating (EP-49 909). This method cannot be applied to heat-sensitive active principles 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
their 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 on a Haake viscosimeter,
and such that
their 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 must be.
Moreover, a third filling mode, combining the first two, has been described in EP-49 909. According to this method, a shear-thinning composition, containing liquid paraffin, hydrogenated castor oil and colloidal silica, is heated to 40° C.
The Applicant has demonstrated that the shear-thinning nature of the compositions for filling hard capsules of the prior art, although necessary for ensuring proper filling of the hard capsule, nevertheless proves to be insufficient.
This is because it is also imperative to check that the formulation at rest in the hard capsule restructures sufficiently strongly and above all sufficiently quickly, after filling, to avoid any leakage 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 flow of the composition between the two parts of the hard capsule.
Among the raw materials that are used in conventional filling compositions are polyethylene glycols. Polyethylene glycols are intended to dissolve the water-soluble active principle of the filling composition, by virtue of their hydrophilic properties (EP-276 116, EP-488 181 and EP-49 909).
It has been found that the incorporation, as continuous phase, of polyethylene glycols, and more particularly of polyethylene glycols of low average molecular masses, in the filling composition may pose serious physicochemical interaction problems and therefore stability problems.
In particular, these polyethylene glycols are hygroscopic and attract water from the gelatin into the continuous phase making the case brittle and weak during storage.
The filling compositions of the present invention are advantageously free of any polyethylene glycol, and in particular of polyethylene glycol of low average molecular mass, which would run the risk of weakening the case of the hard capsules.
The objective of the present invention is to provide compositions termed “thixotropic” compositions containing one or more active substances which allow any filling of the hard capsules at room temperature and which ensure the absence of leaks between the two parts of the hard capsule without it being necessary to make use of the sealing usually recommended for this type of pharmaceutical dosage form.
The rheological properties of the formulations of the invention ensure effective filling at room temperature and the absence of leaks from the filled hard capsules.
It will be recalled that a liquid or pasty thixotropic composition has a shear-thinning character which is manifested by a reduction in the apparent viscosity under the effect of increasing shear. Furthermore, any variation in the shear conditions causes a structural modification delayed over time. Thus, in particular a gradual, total or partial recovery in consistency is observed after the shear has stopped.
The rheological parameters chosen as being particularly representative of the consistency of the formulations are:
the complex modulus G*, the value of which is greater the thicker the product under study, which complex modulus is a synthesis of the elastic and viscous properties of the material, and
the phase shift &dgr;, of between 0° and 90°, knowing that a phase shift of greater than 45° characterizes a predominantly viscous nature and, conversely, a phase shift of less than 45° demonstrates a predominantly elastic nature characteristic of a structured material.
The present invention relates to liquid or pasty thixotropic compositions containing one or more active substances, intended for filling hard capsules at room temperature, such that:
their complex modulus G* is greater than about 100 Pa,
their phase shift &dgr; is less than about 45°,
their viscosity decreases with increasing shear rate,
under the effect of a constant shear rate &ggr;
0
, the viscosity of the said compositions decreases in a delayed manner over time and stabilizes at the equilibrium value &eegr;
eq
of between 10 mPa.s and about 10 000 mPa.s, when &ggr;
0
is between 100 and 1000 s
−1
and
after making the said shear rate 0, the complex modulus and the phase shift of the said compositions resume, after a time t of less than 1 hour, G* and &dgr; values of greater than about 100 Pa and of less than about 45°, respectively.
The compositions according to the invention are therefore defined, on the one hand, by their shear-thinning nature, that is to say that their viscosity decreases when the intensity of the shear increases and, on the other hand, by the decrease in their viscosity over time for a given shear.
The formations of the invention thus thin in the hard-capsule filling machine due to the effect of the shear induced by the agitation present from the feed hopper right to the dispensing nozzle. This property makes it particular easy to fill the hard capsules.
For each shear rate, the viscosity of the compositions of the invention decreases over time and finally stabilizes at an equilibrium value denoted &eegr;
eq
. The compositions according to the invention have equilibrium viscosities &eegr;
eq
at 100 s
−1
and 1000 s
−1
of between 10 mPa.s and 10 000 mPa.s, preferably between 100 mPa.s and 1500 mPa.s. It is entirely
Bougaret Joël
Goutay Eric
Grossiord Jean-Louis
Leverd Elie
Lombardin Pascal
Lovering Richard D.
Pierre Fabre Medicament
The Firm of Hueschen and Sage
LandOfFree
Thixotropic formulations for filling capsules does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Thixotropic formulations for filling capsules, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Thixotropic formulations for filling capsules will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3206033