Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-25
2003-09-30
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S349000, C514S408000, C514S631000, C514S810000, C514S811000, C424S444000, C424S484000, C424S447000, C424S449000, C604S890100
Reexamination Certificate
active
06627631
ABSTRACT:
DESCRIPTION
Deoxypeganine and its pharmaceutically acceptable acid addition salts can be used for the treatment of alcoholism. These substances are preferably administered in a continuous and controlled manner. The pharmaceutical administration form makes controlled release possible for, for example, oral, transdermal or alternatively parenteral administration.
The invention relates to the use of deoxypeganine and its pharmaceutically suitable acid addition salts for the treatment of alcoholism. These compounds are released in a continuous and controlled manner from appropriate pharmaceutical formulations, which are administered, for example, orally, transdermally or otherwise parenterally.
In particular, the present invention makes pharmaceutical formulations available which release suitable compounds for the treatment of alcoholism in a controlled manner.
While acute withdrawal in alcohol-dependent patients and the treatment of life-endangering withdrawal delirium in special wards is no longer a medical problem today, there is still no satisfactory treatment of chronic alcoholism. About 80% of the treated alcoholics relapse within a year. They need help by means of a reliably acting and highly tolerable agent against the desire for alcohol which leads to the relapse.
In spite of the human problems and of the immense national economic damage associated with the problem of chronic alcoholism, innovation in the medicinal treatment of chronic alcoholism is stagnating worldwide and very particularly in the Federal Republic of Germany.
In the case of the pharmaceuticals which are employed for the control of the effects of alcohol and of alcoholism, the following must be differentiated:
1. Sobering-up agents (amethysts).
2. Agents for the treatment of life-threatening alcohol intoxication, e.g. naloxone (Narcanti), physostigmine.
3. Pharmaceuticals for making acute alcohol withdrawal easier, e.g. neuroleptics (Neurocil, Melleril), piracetam, clonidine, carbamazepine, and withdrawal delirium: clomethiazole (Distraneurin).
4. Substances which block the degradation of alcohol at the acetaldehyde stage and as a result produce an artificial alcohol intolerance. Disulfiram (Antabuse), the main representative of this group, is the medicament which is employed most frequently for the treatment of alcoholism. Antabuse, however, is not a therapeutic, as this and related substances decrease neither the desire for alcohol nor influence the causes of the condition.
5. Agents which are intended to satisfy the compulsive desire for alcohol (the craving) and thus to prevent the relapse of the treated alcoholics. There is an urgent need, in particular, for these agents, but an efficacious medicament for the treatment of chronic alcoholism has still not been found.
Clinical trials with fenfluoramine and bromocriptine have not been repeated and confirmed.
The great hopes which had been placed in the lithium therapy of chronic alcoholism have not been fulfilled.
The best results yet have been achieved with zimelidine, but this serotonin reuptake inhibitor, which was marketed as an antidepressant under the name Normud, had to be withdrawn because of serious side effects and is no longer available. Galanthamine, an alkaloid from Amaryllidaceae, is still being clinically tested at present.
The object of the invention is therefore the provision of a pharmaceutical which, by controlled release of an oral, transdermal or otherwise parenteral formulation, makes an efficacious and practical treatment of alcoholism possible by decreasing the desire for alcohol.
This object is achieved according to the invention by a formulation and its use for the treatment of alcoholism, which formulation comprises an efficacious amount of the active compound deoxypeganine (1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline) and/or one of its pharmaceutically tolerable acid addition salts.
This achievement is all the more surprising as the pharmacological actions of deoxypeganine have in fact been intensively investigated in the former USSR, but the action of a deoxypeganine-containing formulation, attributed to deoxypeganine, of decreasing the desire of alcoholics for alcohol has not been described up to now.
Deoxypeganine is obtained by isolation from the harmel peganum (Peganum harmala) or by synthesis.
On account of its pharmacological properties, deoxypeganine belongs to the group of reversibly acting cholinesterase inhibitors. It is closely related in its actions to physostigmine, neostigmine and galanthamine, but also has specific properties. Deoxypeganine inhibits not only the degradation of acetylcholine, but also that of dopamine.
This advantage offsets its somewhat lower dose-related cholinesterase inhibitory action. Deoxypeganine was intended in the former Soviet Union as an antidote and prophylactic in poisoning by organic thiophosphoric acid esters.
In contrast to neostigmine, deoxypeganine crosses the blood-brain barrier and antagonizes the cerebral action of cholinergic toxins.
The present invention is directed at formulations by means of which deoxypeganine or one of its pharmaceutically acceptable acid addition salts are released in a continuous, controlled manner.
Pharmaceutical forms which release active compounds in a controlled manner are known in the prior art. The administration of pharmaceutically active compounds by means of such formulations can be carried out orally, transdermally or otherwise parenterally.
The formulations for oral administration suitable in the context of the present invention are described below.
In such a formulation, the pharmaceutical active compound is encapsulated in a semipermeable membrane, e.g. of cellulose acetate. A tiny hole is drilled in the capsule material using a drill or a laser. Water is absorbed by the capsule material in the body of the patient who is being treated. The pharmaceutical active compound is gradually driven through the small opening by osmotic pressure in the desired, constant and controlled manner. Such systems are described in U.S. Pat. Nos. 3,760,805, 3,760,806, 3,764,984, 3,845,770, 3,916,899 and 3,987,790. In these systems, the pharmaceutical active compounds can be present in solid form or absorbed on ion exchanger resins.
Another system for oral administration according to the present invention is described by Sheth and Leeson in U.S. Pat. No. 4,137,300. This patent describes a formulation which comprises a wax matrix.
The active compounds of the present invention are administered in a fitting and suitable manner by means of appropriate formulations. The solid active compounds can be administered in solution or as a dispersion. The solution or dispersion medium can be inorganic or organic. Suitable solution or suspension media for deoxypeganine are, for example, water, silicone oil or mineral oil.
Silicone oils are understood here as meaning linear-polymeric dimethylsiloxanes and mineral oils are understood as meaning the distillation products obtained from mineral raw materials (petroleum, lignite tar and coal tar, wood, peat), which essentially consist of mixtures of saturated hydrocarbons.
In order to make the administration of a compound by means of a formulation as described above possible, the following additives can be added to the system:
antioxidants, synergists, stabilizers,
preservatives,
flavor corrigents,
colorants,
solvents, solubilizers,
surfactants (emulsifiers, solubilizers, wetting agents, antifoams),
viscosity- and consistency-influencing agents, gel-forming agents,
absorption accelerators,
adsorption agents,
moisture retention agents,
lubricants (e.g. flow-regulating agents),
disintegration- and solution-influencing agents,
fillers (extenders),
peptizing agents,
release-delaying agents.
This list makes no claim to completeness. Many substances fulfil not only one function, they are therefore to be assigned to a number of the excipient groups mentioned. Thus, for example, types of starch are used as fillers in tablet and powder production. However, at the same time they are flow-regulating agents, adsorption agents, h
Asmussen Bodo
Hille Thomas
Hoffmann Hans-Rainer
Opitz Klaus
Frommer & Lawrence & Haug LLP
Krass Frederick
LTS Lohmann Therapie-Systeme AG
Ostrup Clinton
LandOfFree
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