Concentrated injection and infusion solution for intravenous...

Details Concentrated injection and infusion solution for intravenous... Concentrated injection and infusion solution for intravenous...

2000-02-14

2003-10-28

Riley, Jezia (Department: 1637)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S001000, C514S04400A, C514S002600, C530S300000, C530S350000, C536S022100, C424S130100, C424S184100

Reexamination Certificate

active

06638913

ABSTRACT:

SUBJECT OF THE INVENTION
The invention relates to the subjects that are characterized in the claims, i.e., the use of additives to concentrated injection and infusion solutions to mitigate delayed hypersensitivity reactions, as well as injection and infusion solutions that contain these additives.
BACKGROUND OF THE INVENTION
For some therapeutic and diagnostic medical applications, fairly large volumes of concentrated and/or viscous solutions are administered intravascularly. Examples mainly include infusions for administering large amounts of nutrients, substances with an osmotic or colloid-osmotic action, and contrast media. Typically, these solutions are administered at a ratio of 0.5-20 ml/kg of body weight; the solutions contain active ingredients and adjuvants in amounts of 10 or more % by weight and are often more viscous than the blood. These are in part also lower-concentrated, lower-dosed emulsions, suspensions or preparations of complex structures such as micelles or liposomes. The solutions formerly caused a considerable number of different side-effects, among which acute reactions were of most concern. Such effects related to direct metabolic or toxic effects of the substances administered, effects caused to some extent by extremely high and unphysiologic osmolality on the part of solutions, and unphysiologic and harmful solvents, stabilizers and buffers. In addition, acute allergic or allergy-like events occurred. Most of these undesirable effects have now been recognized as regards their causes and have been avoided through the use of better active ingredients and preparations. As a result, the frequency and severity of side-effects have been quite substantially reduced. Studies in recent years have shown, however, that a type of side-effect that used to be rarer and in any case was less noticeable is increasingly receiving attention and causing problems. In this case, these are allergy-like or other less dose-dependent, often unexplainable immediate or delayed (i.e., hours to days) hypersensitivity reactions that occur after administration, can be manifested as reddening of the skin, hives, weals, edemas, swelling of the mucous membrane and other symptoms and can escalate—admittedly in rare cases—to severe breathing difficulties and a state of shock.
The subjects of the invention are therefore additives to highly concentrated and/or viscous solutions as well as microparticle-containing preparations for intravascular administration, which avoid acute or delayed hypersensitivity reactions or mitigate their frequency and intensity. In addition, the use of additives to active-ingredient-containing solutions for the purpose of mitigating acute or delayed hypersensitivity reactions is described.
Prior Art
Additives to injection and infusion solutions are prior art. Electrolytes, sugars, and sugar alcohols such as mannitol are used to match the osmolality of hypotonic active-ingredient solutions to the osmolality of the blood. In exceptional cases, electrolytes have also been added to the active ingredient solutions in instances where this raised the osmolality beyond that of the blood (WO 90/11094). The purpose of these additions is to improve local compatibility in cases where there is contact between the active ingredient solutions in question and blood vessels and tissues, especially in the heart. In addition, stabilizers and buffers are commonly used. X-ray contrast media have been added in some cases before heparin or another clotting inhibiting substance was added to ensure high clotting protection when blood flows back into catheters and syringes that were previously filled with contrast media [Jackson, D. M. A. and P. Dawson: Current Usage of Contrast Agents, Anticoagulant and Antiplatelet Drugs in Angiography and Angioplasty in the U.K., Clinical Radiology 50, 699-704, (1995); Miller, D. L.: Heparin in Angiography: Current Patterns of Use, Radiology 172, 1007-1011, (1989), WO 94/14478]. These mixtures are also used mainly when administration is done into arteries or for x-ray visualization of veins, where it produces a local and nonsystemic protective action of the clotting inhibitor with respect to the formation of clots. The addition of local anesthetics to x-ray contrast media to alleviate pain is rendered unnecessary by the development of less strongly hypertonic preparations. Vasodilators, prostacyclins, urea, and other substances have been used or recommended to improve microcirculation or to enhance the action of contrast media (DE 4 135 193, DE 4 446 694). Finally, therapeutically effective substances or preparations have occasionally been added to contrast medium solutions to make visible their distribution in the tissue or their flowing out into the blood vessel system. Infusion solutions have been used to dilute therapeutic agents. To date, even Na
2
Ca EDTA (as stabilizer, but only up to about 2 mmol), Na citrate, and tris(hydroxymethyl)-methylamine (“tris”)/HCL (as a buffer, in the range of 10 to 20 mmol) and inorganic and organic bases including basic amino acids (as counterions for contrast medium acids) are commonly used as x-ray contrast medium additives. In the past 30 years, efforts have been directed more at cutting back on these additives to avoid possible undesirable physiological effects. Physiologically inorganic ions have been added to match the electrolyte environment, and papaverine and prostacyclins have been added to improve vascular visualization, local anesthesia to alleviate pain and urea to improve the visualization of kidneys and urinary passages by x-ray contrast media. A survey was published by, i.a., S. H. Kim, H. K. Lee and M. C. Han: “Incompatibility of Water-Soluble Contrast Media and Intravascular Pharmacologic Agents,” An In Vitro Study, Investigative Radiology 27, 45-49, (1992). A low level of association of the x-ray contrast medium molecule in the solution to be administered was judged disadvantageous since it results in an unphysiologic increase in osmolality.
Statement of Task
The object to be achieved here has become important only in recent years. The first publications on systematic studies on delayed hypersensitivity reactions after administration of contrast media date from the mid-1980s. The frequency of these reactions obviously increased with the improvement of the acute compatibility of modern preparations. It is noteworthy that the more recent nonionic x-ray contrast media directly trigger even fewer allergy-like acute side-effects than the earlier commonly used and strongly hypertonic ionic contrast media. The increase in the frequency of delayed hypersensitivity reactions, which has led to a growing number of publications and to considerable anxiety among the users, is all the more surprising and incomprehensible. Delayed reactions are defined as those side-effects that occur only one or more hours after administration of the agent in question. To date, there is no conclusive hypothesis on the causes or the mechanism of the occurrence of the delayed reactions. It is also not clear, moreover, whether some of the acute side-effects are caused by a similar mechanism, such as the delayed reactions.
The object of the invention is therefore to make available additives to contrast media that significantly mitigate or even completely avoid acute or delayed hypersensitivity reactions.
DESCRIPTION OF THE INVENTION
The mitigation and avoidance of delayed hypersensitivity reactions are achieved by the addition of substances having physical or pharmacological effects to the otherwise largely unaltered infusion or injection solutions. The actual effective components of the solutions, for example the opacifying substances or structures, are not altered.
As additives, three groups of substances have proven suitable:
a) Substances that reduce the self-association of active ingredient molecules or active ingredient components in highly concentrated infusion solutions.
Physiologically compatible electrolytes such as NaCl, MgCl
2
, sodium acetate, meglumine chloride, Na
2
Ca EDTA, etc., belong to this class o

Affiliated with

Also associated with

Rating

Concentrated injection and infusion solution for intravenous... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Concentrated injection and infusion solution for intravenous..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Concentrated injection and infusion solution for intravenous... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3139576