Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1998-10-16
2001-02-27
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C424S680000, C424S717000
Reexamination Certificate
active
06194456
ABSTRACT:
BACKGROUND OF THE INVENTION
a) Field of the Invention
The invention is directed to a drug which is preferably usable for inhibiting inflammation in chronic and autoimmune inflammatory processes and/or produces vasodilating and sympathicolytic effects.
b) Description of the Related Art
The pharmacological characteristics of ester type and amide type local anesthetics are well known. Procaine hydrochloride (Procaine, Procaine-N-glucoside-hydrochloride, chemical designation: 2-diethylaminoethyl-4-aminobenozate) is a basic ester type local anesthetic; it inhibits the function of excitable structures such as sensory, motor and autonomic nerve fibers, influences the stimulus conduction of the heart, and is applied clinically for local and regional nerve blockade.
Procaine hydrochloride cancels the conduction capacity of the sensory nerve fibers in a reversible and locally delimited manner. After reducing sensitivity to pain, in descending order, sensitivity to cold or heat, touch and pressure are reduced. Procaine hydrochloride acts on smooth muscles as an antiarrhythmatic and tone reducer. Further, it has a mild antihistaminic and parasympatholytic effect.
The action of procaine hydrochloride is known to the extent that procaine hydrochloride reduces membrane permeability to cations, especially to sodium ions and, in higher concentrations, also potassium ions. Because of this, a reduced excitability of nerve fibers can be achieved, depending on the concentration, because the sudden rise in sodium permeability necessary for the development of action potential is reduced. Membrane stabilization is based on the storing of lipophilic local anesthetics in the cellular membrane, so that ion channels, especially sodium channels, are blocked.
However, it is also known that the resorption of local anesthetics, and therefore also the resorption of procaine hydrochloride, is problematic and their usefulness is therefore limited. The resorption of procaine hydrochloride depends on the vascularization and blood flow at the site of injection, insofar as procaine hydrochloride is administered by injection. The latent period prior to the onset of action is 1-2 minutes in the case of infiltration and 15-20 minutes in the case of epidural anesthesia. The duration of action is 1-2 hours. In general, due to the low resorbability of procaine hydrochloride, only the smallest dose by which the desired adequate nerve blockade can be achieved may be administered. Dosage is determined on the basis of the peculiarities of the individual case (see the monograph “Procaine as Injection Solution”, published in the German Federal Gazette No. 144 of 8/3/1994, Bundesinstitut fur Arzneimittel and Medizinprodukte). It is recommended herein that, when applied in tissues from which a rapid resorption of substances is carried out, an individual dose may not exceed 500 mg of procaine hydrochloride without addition of vasoconstrictors or 600 mg of procaine hydrochloride with addition of vasoconstrictors. Numerous additional precautionary indications must be taken into consideration. In this connection, its high osmolarity is of 290 mOsmol and the low pH between 4.0 and 6.0 are disadvantageous.
As a result, it was formerly supposed that procaine hydrochloride is not suitable for continuous application. When administered in the conventional manner, pain, redness, heat buildup and swelling occur at the injection site within a short period following injection. When injected subcutaneously, liquid chambers occur 20 along with the above-mentioned complaints, likewise as a result of the insufficient resorption rate for procaine hydrochloride in the subcutaneous tissue. When injected in peripheral veins, thrombophlebitic complications develop in addition after about 48 hours.
The anti-inflammatory action of procaine hydrochloride is also known. However, it has not been possible so far to take advantage of the full potential of this anti-inflammatory action with the current maximum possible dosages and discontinuous administration. Although it has long been desirable to administer procaine hydrochloride in large doses and in a continuous manner in order to permit the development of this action, it is still assumed by those skilled in the art that continuous injection of procaine hydrochloride is impossible in view of the described side effects, limitations and risks.
It has been attempted to administer procaine amide orally in the form of tablets or capsules, but this method is difficult to control because of broad individual tolerances of the resorption rates. In view of this uncertainty, the pronounced effect of procaine hydrochloride on the stimulus conduction of the cardiac muscle results in corresponding risks. It follows, inversely, that safe application presupposes good controllability of the active ingredients level.
OBJECT AND SUMMARY OF THE INVENTION
According to the invention, this object is met through a drug from a mixture containing at least one local anesthetic of the ester type or amide type, water, and at least one substance for adjusting the pH of the mixture in the range of 7.6 to 8.6. It is possible by means of this drug to significantly increase the injectable amount compared with commercially available and known drugs containing a local anesthetic as active ingredient. The mixture can be applied continuously by subcutaneous or intravenous injection. In comparison to previously available possibilities, a decisive increase in the daily dosage can be achieved, resulting in the potentiation of the strength and duration of action especially with respect to the development of potential for anti-inflammatory effects. Also, the undesirable side effects such as pain, redness, heat buildup, etc. do not occur when the daily dosage or duration of injection are increased.
A particularly preferred embodiment of the invention provides procaine hydrochloride as local anesthetic. In further embodiments, the following can be provided as local anesthetics: lidocaine, bupivacaine, mepivacaine, benzocaine, cocaine, butacaine, tetracaine, isocaine, proparacaine, metabutoxycaine, prilocaine, pyrocaine, dibucaine, piridocaine and/or eucaine.
It has therefore been shown surprisingly that local anesthetics administered within this mixture have a substantially higher resorption rate. Procaine hydrochloride in particular can now be applied in substantially greater scope with extremely positive results for blocking inflammations, especially of chronic and autoimmune inflammatory processes. A very promising possibility of application is for the treatment of chronic spondylitis until the decay of the illness can no longer be detected by bone scintigraphy. The advantageous effect appears to be based on a heretofore unknown influence on the immune system, especially on T lymphocytes and B lymphocytes.
Another substantial advantage consists in that the increased resorption rate can be well and reliably controlled, so that the influence on the stimulus conduction at the cardiac muscle and the related risk can be monitored in a very favorable manner because the serum concentration is directly proportional to the dosage.
In a clinical test based on n=400 injections, the pH range of 7.2 to 7.6 of a first group and the pH range of 7.8 to 8.6 in a second group were compared. In the first group, redness, swelling and sometimes burning pain occurred in every case over an injection period of 24 hours. In the second group, none of the above-mentioned side effects occurred.
In an embodiment of the invention, sodium bicarbonate is provided as means for adjusting the pH. The mixture can contain 1.8 parts by weight of sodium bicarbonate for every part by weight of procaine hydrochloride. Accordingly, a resorption rate can be achieved which, under normal circumstances, enables a long-term application at increased daily doses without risk and, in so doing, develops in particular the anti-inflammatory action of procaine hydrochloride.
REFERENCES:
patent: 4748022 (1988-05-01), Busciglio
patent: 5149320 (1992-09-01), Dhaliwal et al.
patent: 5209724 (1
Oettmeir Ralf
Reuter Uwe
Weber Carsten
Medicur Pharma GmbH
Reed Smith LLP
Weddington Kevin E.
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