Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-05
2004-12-21
Jones, Dwayne (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S059000, C514S626000
Reexamination Certificate
active
06833377
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions and methods useful for potentiating the activity of drugs affecting the Central Nervous System.
BACKGROUND OF THE INVENTION
The following is a list of references which may be important in understanding the background of the invention:
1. U.S. Pat. No 5,942,241;
2. Mancusi L. et al., Minerva Anestesiol, 53(1-2) 19-26, 1987;
3. Huang KS et al., Ma Tsui Hsueh Tsa Chi, 31(4), 245-8, 1993;
4. Goyagi T et al., Anesth Analg. 81(3), 508-13, 1995;
5. Niemi G et al., Acta Anaesthesiol Scand, 42(8), 897-909, 1998;
6. Russian Patent No. SU 2,088,233
7. 8
th
Sardinian Conference on Neuroscience.
Anxiety and depression neurobiology pharmacology; and clinic
. Tanka Village, Villasimius, May 24-28
th
1995. Behavioral Pharmacology, Vol. 6 (Supplement 1), 1995, P.152.
The references are referred to in the specification by their respective numbers.
Currently, two principal methods of potentiation of the effect of central nervous system (CNS) active drugs (potentiated synergism) are known: (1) pharmacokinetic; and (2) pharmacodynamic.
The pharmacokinetic method provides potentiation by creating a maximum concentration of the drug at the site of the primary pharmacological response due to improved absorption, increased bioavailability, accelerated distribution and retarded elimination of the drug (Goodman & Gilman's
The Pharmacological Basis of Therapeutics
9th ed. Hardman Paperback, McGraw-Hill Book Company, 1996). The known methods of pharmacokinetic potentiation are connected, as a rule, with the development of new and improved dosage forms and ways of drug administration.
In recent years, the method of controlled extended release of active ingredients from micro-particles and microcapsules (e.g. U.S. Pat. No. 6,022,562) has been considered the most popular and promising of these methods. Each micro-particle generally represents a matrix of nontoxic polymer containing a drug and osmotically active polyatomic alcohols (e.g. U.S. Pat. No. 5,431,922). Micro-particles are included in traditional dosage forms for oral administration. (tablets, capsules, suspensions, granules), which most frequently contain polymers such as polyvinylpyrilidone (PVP) or polyethylene oxide (PEO), and osmotically active alcohols such as sorbitol, xylitol and mannitol.
The main drawback of this method is the necessity for permanent administration of a high dose of the active ingredient. This may lead, in the case of long-term administration, to the potentiation not only of its therapeutic action, but also of side effects in case of poor selectivity of the drug effect. In addition, the production of traditional oral dosage forms on the basis of micro-particles and microcapsules leads to a manifold increase in their cost, which often greatly exceeds the cost of the active ingredient. Despite its numerous advantages the aforementioned pharmacokinetic method does not achieve a manifold intensification of the effect of drugs.
Osmotically active polymers (PVP, PEO) and polyatomic alcohols (xylitol, sorbitol, mannitol), included in the composition of both traditional monolithic dosage forms as well as forms intended for controlled release of active ingredients, play an important role in pharmacokinetic potentiation of CNS active drugs (e.g. U.S. Pat. Nos. 4,952,402 and 5,552,429). However, they are not active components of the compositions but rather they only provide optimal conditions for the pharmacokinetics of a CNS active drug.
A combined application of the &agr;-1-adrenomimetics phenylephrine or midodrine, as well as the nonselective adrenomimetic adrenaline together with narcotic analgesics and local anesthetics has been found to lead to a pharmacokinetic potentiation of analgesic and anesthetic effect. However, these compositions were only administered locally to intensify local anesthesia (1) or intrathecally to intensify spinal anesthesia (2-5). intensification and prolongation of the effect of analgesics and anesthetics was caused by an increase in their local concentration, which is due to a decrease in the amount of analgesics and anesthetics entering the blood as a result of a local spasm of vessels caused by the adrenomimetics.
The pharmacodynamic method also provides potentiation by a joint administration of active ingredients causing unidirectional pharmacological effects, but affecting different molecular substrates (having different mechanisms) (Goodman & Gilman's The Pharmacological Basis of Therapeutics, op. cit.)
Two main types of pharmacodynamic methods of the potentiation of CNS active drugs are known:
(1) Potentiation of the effects of CNS active drugs caused by joint administration of CNS active drugs only;
(2) Potentiation of the effects of CNS active drugs caused by joint administration of a CNS active drug and a peripherally active drug.
The well-known first method consists in joint administration of two CNS active drugs that act unidirectional and mutually potentate each other's effect. In cases of grave depressions, pain syndrome, parkinsonism, epilepsy and psychoses, potentiation of the maximal effect of antidepressants, neuroleptics, analgesics, psychostimulants, anti-parkinson and anticonvulsive agents is required. As a rule, potentiation is possible only by joint administration of CNS active drugs in submaximal doses. Potentiating of submaximal doses effects of CNS active drugs results in maximum possible intensification of their therapeutic activity On the other hand potentiating of their central toxic effect is also caused resulting in multiple side effects and complications. (e.g. U.S. Pat. No. 4788189; Winter J. C. et al., Pharmacol Biochem Behav, 63(3). 507-13, 1999; Sills T S et al., Behav Pharmacol, 11(2), 109-16, 2000); Fredriksson A. et al., J Neural Transm Cen Sect, 97(3), 197-209, 1994).
U.S. Pat. No. 3,947,579 discloses a method for potentiating the neuroleptic activity of drugs such as butyrophenone derivatives by administrating them together with an amino acid known to cross the blood brain barrier and have muscle relaxant properties useful in the treatment of spinal origin spasticity.
At mild and moderate severity (or stage) of a disease, maximal or even submaximal effect caused by CNS active drug is quite sufficient. In this case therapeutic activity may usually be achieved by potentiating threshold doses of CNS active drugs. (e.g. U.S. Pat. No. 5,891,842; Freedman G. M., Mt. Sinai J Med, 62(3), 221-5, 1995; Kaminsky R et al., Pharmacol Res, 37(5), 375-81, 1998). The potentiation of the effect of threshold doses significantly reduces the probability of the development of side effects and complications inherent to CNS active drugs at maximal doses, as well as the development of tolerance and dependence due to their prolonged administration. However, even this, the safest of all known methods of pharmacodynamic potentiation has its own drawbacks:
1) The effect achieved by potentiating low doses of drugs does not exceed, as a rule, the maximal effect of the drug itself
2) When the elimination of active ingredients is decelerated (childhood age, diseases of liver or kidneys) or the permeability of the hematoencephalic barrier is increased, threshold dosages of CNS active drugs can become submaximal and even toxic in their effect. Therefore, their combined administration even at such threshold doses becomes impossible due to the potentiation of their CNS side effects.
3) The risk of potentiating not only therapeutic, but also toxic effects of CNS active drugs by even small doses of other safe CNS active drugs.
The potentiation of the effects of threshold doses of CNS active drugs can also be realized by a combined administration of a CNS active and a peripherally osmotically active drug. It is known that oral or intramuscular administration of osmotically active copolymers of N-vinyl-pyrrolidone with N,N,N,N, triethylmethacryloidoxyethylammonium iodide (6), which do not penetrate the Blood Brain Barrier, potentiate the effects of threshold doses of analgesics, antidepressant, antishock and antihypoxic
Browdy and Neimark PLLC
Gevys Pharmaceuticals Ltd.
Jones Dwayne
LandOfFree
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