Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
2000-08-03
2003-04-01
Walczak, David J. (Department: 3751)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C366S162400
Reexamination Certificate
active
06540715
ABSTRACT:
The aim of developing infusion solutions which can be administered intravenously is always good tolerability of the preparation. To ensure this it is necessary for the formulation to be approximated as closely as possible to physiological circumstances, that is to say it should be in the form of an aqueous formulation with isotonic (osmolarity) and isohydric (pH) properties.
Some active pharmaceutical ingredients have the disadvantage that they are difficult to formulate or convert into a form ready for use owing to their low solubility, sensitivity to hydrolysis or oxidation or owing to their photosensitivity. This can in the final analysis be attributed to the fact that the active ingredients are not in thermodynamic equilibrium under usual formulating conditions, that is to say that they either precipitate or decompose under physiological conditions. Thus the formulation possibilities and, in the final analysis, the provision of such active ingredients are greatly restricted.
Active pharmaceutical ingredients, especially those of the more recent generation, often have the disadvantage of low solubility in aqueous medium at physiologically tolerated pH values. This applies in particular to active ingredients from the group of dihydropyridines, anaesthetics, antibiotics, antimycotics, immunosuppressants, CNS-active drugs, oncologicals, steroids, barbiturates and vitamins. Slightly soluble active ingredients have, according to the definition in current pharmacopoeias, a solubility in water of less than 1 percent by weight. Slightly soluble active ingredients frequently confront the pharmaceutical technologist with the problem of developing a sufficiently well tolerated aqueous infusion solution when the volume administered by infusion is strictly limited. The patient in particular in intensive care units (ICU) frequently receives several infusion solutions administered in parallel, in which case the acceptable daily volume depends on the kidney function of the individual. One priority of pharmaceutical development is to minimize the infusion volume, this parameter showing a contrary behaviour to the solubility of the substance. Formulating additions such as isotonicizing agents, antioxidants etc. moreover reduce the dissolving capacity of water. The active ingredient also frequently has a solubility or stability optimum outside the physiological pH range of 7.2-7.6, so that the formulation possibility is further restricted at the optimum pH.
Because of the poor solubility in aqueous media, the active ingredient is dissolved in an organic or aqueous/organic solvent or at strongly acidic/alkaline pH values in aqueous or aqueous/organic medium (active ingredient concentrate). In order to ensure tolerability, administration of this active ingredient concentrate must be preceded by dilution with an aqueous medium (diluting medium) or adjustment to physiologically tolerated pH values. This may result in supersaturated solutions. These are characterized in that the dissolved active ingredient is present in a concentration higher than is possible in the solvent at the given temperature by dissolving the active ingredient crystals. Such solutions are, as a consequence of the kinetic inhibition of crystallization, initially optically clear and virtually free of particles. However, the solutions are thermodynamically unstable. Thus, over the course of time, they lead to the active ingredient crystallizing out and thus particles being formed. Since relatively long times, which include at least the duration of the infusion, frequently elapse for example after preparation of such solutions in hospitals until they are completely infused into the patients, formation of particles in the solution is possible during this. Particles injected into the bloodstream may, however, depending on their size and shape lead inter alia to vascular occlusion and thus to serious harm to the patient. This risk can be reduced either by ensuring the stability of the supersaturation also over a lengthy period and under all environmental conditions, demonstrating this with certainty, or by minimizing the time the supersaturated solution stands after its preparation. The latter object is achieved by the present invention, namely by preparing the supersaturated solution from an active ingredient concentrate and a diluting medium with use of a special mixer immediately before administration—on the patient's arm—and only seconds up to a few minutes elapsing until the solution enters the bloodstream.
On simultaneous parenteral administration of different solutions by intravenous infusion so-called connecting pieces or Y pieces (for example Codan Art. No. C87/2R) have been used to date. Connection to other infusion equipment takes place, for example, via so-called Luer-Lock connectors complying with DIN 13090 Part 2 (disposable medical articles: medical products; standards and other documents; Beuth Verlag 1989). The infusion solutions having viscosities in the region of a few mPas are fed from different containers to the relevant connecting piece and combined therein simply by being conducted together before the mixture reaches the patient. An infusion device of this type is described, for example, in DE-3228595-C2. In this case, 2 solutions from infusion bottles are combined by gravity through a Y piece and infused. Disposable articles of this type are commercially available in a variety of forms. The disadvantage of the available devices is that it is impossible to mix fluid media with very different viscosities at the available low flow rates (5-500 ml/h) sufficiently and quickly enough because the commercially available connecting pieces are not optimal in terms of their function as mixers. In particular at low flow velocities there is sometimes a back-flow of the solutions, and components of the solution spend some time in regions of low flow (dead spaces). This can lead to crystallization inside the administration system. Organic solvents which can be administered parenterally may have viscosities above 100 mPas (for example macrogol 400). When the organic active ingredient concentrate and the aqueous diluting medium are mixed there is a risk that the active ingredient will crystallize out of the supersaturated solution after a certain time. The time up to the onset of crystallization decreases with increasing content of aqueous phase. However, at the same time, the tolerability increases with increasing content of aqueous phase.
The result of the problems described is that no such concentrate/dilution systems have yet been developed for a marketable product. On the contrary, the only solution presentations marketed are those whose system is not supersaturated. This is achieved, for example, by adding relatively large amounts and relatively high concentrations of organic solvents (ethanol, macrogol, propylene glycol etc.) or solubilizers and surfactants (Tween, Cremophor), which have an adverse effect on the local and systemic tolerability of the formulation.
GB-A-1472793 describes such formulations for the anaesthetic propofol, in which surface-active substances and water-miscible, nonaqueous solvents are added to the aqueous base. A concentration of 20-30% of organic medium should not be exceeded as limits for the local tolerability of organic solvents in infusions. The systemic tolerability of the solvents varies in a substance-specific manner. In general, solvents lead to irritation and inflammation of veins and to haemolysis. Surfactants have even stronger haemolytic activity and, moreover, may cause an anaphylactic shock reaction with a fatal outcome. It is therefore necessary to examine such formulations particularly critically, and a precondition for a decision in their favour is an appropriate benefits/risk assessment.
Another possibility, for which the possible uses are, however, only limited, is to develop presentations such as, for example, lipid emulsions or liposome formulations, but these are considerably more complicated and thus more costly than conventional solution formulations. The formu
Herrmann Erhard
Klein Jürgen
Krumbach Bernd
Kühn Bernd
Rupp Roland
Bayer Aktiengesellschaft
deVore Peter
Walczak David J.
LandOfFree
Method and device for in-situ formulation of a medicinal... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method and device for in-situ formulation of a medicinal..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method and device for in-situ formulation of a medicinal... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3042528