Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-09-02
2002-04-30
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S490000, C514S912000, C514S951000, C514S954000
Reexamination Certificate
active
06379692
ABSTRACT:
The present invention relates to a method of preparing pharmaceutical formulations and to pharmaceutical formulations, particularly for ophthalmic use, which may be prepared by that method. In particular, the present invention relates to a method of preparing pharmaceutical formulations wherein the active ingredient is of sparing solubility in pharmaceutically-acceptable solvents.
There is a recurring problem of how to formulate pharmacologically active ingredients which exhibit low solubility in pharmacologically- and pharmaceutically-acceptable solvents at a pH acceptable for the intended use. It is particularly difficult to solve when the formulation is to be administered to a sensitive organ such as the skin or the eye and is required to be at a pH acceptable to the eye. Such ingredients can often only be formulated as ointments in acceptable carriers for pharmaceutical use, such as paraffin or as emulsions with suitable additives. In these instances it has not been found possible to formulate in aqueous and/or non aqueous formulations such as eye drops or gels of wider acceptability.
One such poorly-soluble, active ingredient is the drug aciclovir (formerly acyclovir; 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]6H-purin-6-one or 9-(2-hydroxyethoxymethyl)guanine) which is well-known for its antiviral properties especially against several Herpes viruses. Due to its low lipid and water solubilities, aciclovir is also of low bioavailability, further compounding the formulation problems. It is sold, for topical ocular application, in the form of a paraffin-based ointment, and, for dermal application, as a 5% aqueous emulsion incorporating a high content of propylene glycol.
However, to be of practical use for administration to the eye, an alternative formulation to such an ointment is required. Highly desirable would be a form of eye drops for ease of administration and use, and to increase bioavailability. However, with aqueous solubility of less than 0.1% w/v, it has not been possible to incorporate aciclovir as the active ingredient in eye drop formulations. For an alternative formulation to be medically and commercially successful, it would have to comprise an aqueous carrier in which the aciclovir were bioavailable to a degree that 1% aciclovir by weight of the total formulation could be administered 2-3 times per day, rather than a paraffinic formulation which requires 5 applications per day of a formulation having a high concentration (say, 3% w/w) of aciclovir.
Similar problems exist with other low solubility, low bioavailability antiviral drugs such as ganciclovir (2-amino-1,9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one) which is especially effective in cases of cytomegalo virus retinitis. Penciclovir (9-[4-hydroxy-3-(hydroxymethyl) butyl] guanine) is another effective antiviral having low aqueous (and even lipid) solubility and low bioavailability.
If alternative formulations of these drugs were available which would be suitable, for example, for topical ocular administration, then they could also be modified (e.g. by increasing its viscosity) so as to be suitable for dermal application.
The present invention provides a method of preparing a pharmaceutical formulation suitable for administering to a patient in need thereof a pharmacologically active ingredient which is sparingly soluble in water at the pH acceptable for administration, comprising providing the active ingredient in solution in a pharmacologically-acceptable base and mixing the resulting solution with a pharmacologically-acceptable acid in an amount such that the formulation attains a pH in the range of from about 3.5 to about 8.5 to thereby precipitate out the active ingredients, a viscosity-enhancing agent having been incorporated in the formulation prior to or during the mixing with acid.
Preferably at least one ion-sensitive, hydrophilic polymer is also incorporated in the formulation prior to or during the mixing with acid, which polymer has been found to provide an additional viscosity-enhancer and enchance stability of the formulation.
It has been unexpectedly discovered that, by this method, formulations can be produced which are suspensions of appropriately-sized microparticles of active ingredient, suitably in an aqueous gel, and where the particle size is surprisingly evenly distributed throughout the suspension when compared to formulations prepared by suspending pre-micronized drug in an aqueous gel.
Furthermore, the method has the advantage that sterile conditions are relatively easy to maintain throughout because the microparticles are generated in situ, in contrast to a process involving physical micronization of the active ingredient and subsequent suspension where it is difficult to maintain sterility.
An example of an active ingredient suitable for formulation in accordance with the invention is aciclovir. In the case of aciclovir, using sodium hydroxide and hydrochloric acid as base and acid, on neutralization by the acid of the sodium aciclovir salt initially formed from aciclovir plus base, a precipitate of aciclovir is produced which is suspended in a sodium chloride solution.
However, without the use of a viscosity-enhancing agent, the aciclovir precipitates out as needle-shaped crystals having a length greater than 30 &mgr;m, and without the ion-sensitive polymer has an unacceptable tendency to sedimentation. Particularly for ocular use, the crystals are too long by a factor of about six, and too sharp. It was surprisingly found that incorporating a viscosity-enhancing agent, particularly prior to neutralization, produced acceptable crystal morphology. Furthermore, a formulation having appropriate stability (e.g. which does not sediment on standing to form a ‘cake’ which can not be resuspended or which has an unacceptable resuspension time), was produced by incorporating the ion-sensitive, hydrophilic polymer component, especially a cross-linked polyacrylic acid (also acting as a viscosity-enhancing agent), also preferably prior to the neutralization step.
Therefore, a preferred method in accordance with the invention comprises:
(i) dissolving the active ingredient in base to form a salt solution;
(ii) forming an aqueous suspension or dispersion of the ion-sensitive, hydrophilic polymer(s) and the viscosity-enhancing agent; and
(iii) bringing the salt solution, the aqueous suspension or dispersion and the acid into admixture whereby there is formed a precipitate of microparticles of the active ingredient wherein 90% of the microparticles are of a diameter less than about 10 &mgr;m (number) when measured by a Coulter counter (100 &mgr;m tube).
Step (iii) may be undertaken by first bringing the salt solution into admixture with the aqueous suspension or dispersion followed by addition of the acid. However, preferably, the acid is added to the aqueous suspension/dispersion prior to addition thereto of the salt solution. Preferably, more base is then added to the suspension to neutralize the hydrophilic polymer(s). The resulting formulation is an aqueous gel having fine particles of precipitated active ingredient in aqueous suspension. It has been found that the mean size of particles of active ingredient produced according to the process of the present invention is of the order of 2-10 &mgr;m (number) or 4-16 &mgr;m (volume); preferably around 4 &mgr;m (number) or 8 &mgr;m (volume).
However, in contrast to when pre-micronized active ingredient is used, the process of the present invention whereby such fine particles are produced in situ by precipitation results in a better distribution of particle size, with the D
90
at room temperature being of the order of 5-10 &mgr;m (number), preferably 7-9 &mgr;m (number) or 10-16 &mgr;m (volume), whereas for pre-micronized drug the D
90
is of the order of 5-10 &mgr;m (number) or 21-24 &mgr;m (volume). The formulations of the present invention exhibit similar D
90
values at room temperature for the initial formulation and also after storage for up to 18 months. The term “D
90
” as
Chauvin Pharmaceuticals Limited
Synnestvedt & Lechner LLP
Webman Edward J.
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