Synergistic association of amantadine and selegiline

Amantadine is a Virusstatikum and an anti-Parkinson drug. The chemical name is 1-amino-adamantane.

Selegiline is an antidepressant and an appetite suppressant. The chemical name is N- (2-phenylisopropyl) -N-methyl-N-propyne (2) -yl-amine.

It has now been found that the effect of amantadine and its salts is synergistically increased surprisingly by combination with selegiline or salts of selegiline.

The object of the invention is to provide an improved pharmaceutical composition for the treatment of Parkinsonism.

The invention relates to the combination of the active compounds, amantadine and selegiline, and these active compounds can also be in the form of their salts with physiologically acceptable acids. The given in the description and in the claims amounts by weight or parts by weight are each based on the pure active compounds, that is not to salts of these active ingredients.

Amantadine and selegiline are preferably used as acid addition salts, in particular the salts with hydrohalic acids (for example the hydrochloride) or organic acids (for example, the citrate) coming into question.

The combination of the invention is, for example, in Parkinson's disease a surprising synergism of action which is synergistically increased compared to the effect of pure amantadine. The selegiline alone in contrast has almost no anti-Parkinson effects.

As experimental model for antiparkinsonian effect, for example, the following are suitable:

Animal experiments:

The substances which are used as anti-Parkinson drug in question are based on the increase in dopamine concentration or of the dopamine turnover (for example, dopamine DOPAC = to 3,4-dihydroxyphenylacetic acid or homovanillic acid to dopamine = 3-methoxy-4-hydroxyphenylacetic acid) in the striatum (brain area in the extrapyramidal motor system; name for a part of the basal ganglia) reviewed by Mongolian gerbils. The prepared Striatumproben be on dopamine high pressure liquid chromatography (HPLC-ESA-ECD; see Felice et al, J., Neurochemistry 31 (1978) page 1461) and homovanillic acid and DOPAC high pressure liquid chromatography (HPLC-BAS-ECD; see Sperk, J. Neurochemistry 38 (1982) page 840) analyzed. 80 g - In this test animals of both sexes selected weighing 70^,

The substances are the animals intraperitoneally (into the abdominal cavity) in concentrations 0.8 - 200 mg per ml or Selegininhydrochlorid 3 - injected 40 mg amantadine hydrochloride per ml. Groups of 5 mice each receive Amantadindosen 0.5 to 400 mg / kg, for example, 1-100 mg / kg and Selegilindosen 0.04 to 200 mg / kg, for example 0.1 to 50 mg / kg to determine the ED 50 values.

For the determination of the synergistic effect each different fractions or multiples (for example, from 0.01 times to 2 times) of selegiline combined ED 50 dose. At various times (for example, in 0.5 - 6 hours) after administration of the individual substances or the combination of the individual substances, the animals are sacrificed and the striatum samples.

By means of HPLC, the content of the homogenized samples of dopamine, DOPAC and homovanillic acid is determined.

A synergistic effect can be shown by the fact that the values ​​for dopamine, DOPAC and homovanillic acid to the values ​​are increased when the individual substances.

Research methodology in humans:

The effect of antiparkinsonian effect, for example by Webster, DD, Med. Treat. (NY) 5, 257-282 (1968) found. Here, after application of a single agent amantadine or the combination, the different symptoms are assigned and weighted:<ul><li>1. slowed motor skills of hands</li><li>2. Rigor (increase in muscle tone)</li><li>3. stooped posture</li><li>4. resonance of the upper extremities</li><li>5th gear</li><li>6. tremor (shaking)</li><li>7. Facial Expression</li><li>8. seborrhea</li><li>9. language</li><li>10 independence.</li></ul>

A antiparkinsonian effect is present when is lowered the sum of the resulting from the Webster-scale values ​​(the so-called disability-score) compared to the baseline without medication, "30). The synergistic effect of the combination results from the fact that with the additional use of selegiline, the sum of the disability-scores compared with those who would be obtained by the sole use of amantadine, is lower and / or the duration of the effectiveness of amantadine is extended.

The synergistic increase in humans is particularly pronounced when at least 20 mg amantadine and at least 1 mg selegiline are present in the combination.

Synergistic effect when applying the combination of the invention in the early stages of the disease Parkinsons:

The earliest possible administration of monoamine oxidase B inhibitor selegiline, for reasons of progression inhibiting Erkran kung sense. Because selegiline alone does not have sufficient effect in terms of improvement of parkinsonian symptoms, there is a surprise that after simultaneous administration of amantadine its efficacy is synergistically increased (decrease of Webster Buzz course). In order for a treatment option, the patient is first opened in the early stages of his illness, which slows the progression of the disease Parkinsons, improves the total symptoms satisfactorily and simultaneously holds astonishingly low the rate of side effects.

Synergistic effect of the combination of the invention in crisis-deteriorations of disease Parkinsons:

The relatively slow onset of improvement of akinetic crisis after intravenous administration of amantadine was surprisingly accelerated by addition of selegiline. The subsequently observed effect is more pronounced and longer lasting than in the sole administration of the individual components.

For the combinations of the invention the following indications may for example be considered: Parkinson's disease in all stages of the disease, depression, narcolepsy, brain organic mental syndrome.

The daily doses of the combination according to the invention consist, for example of from 20 to 4000 mg, preferably 50 to 3000 mg and particularly 100 to 2000 mg amantadine and 1 to 250 mg, preferably 3 to 200 mg, particularly 4 to 150 mg of selegiline.

The daily doses can be used in the form of a single administration of the total amount or in form of 1 to 5, in particular 1 to 4 part doses per day. In general, an administration 1 to 3 times, particularly preferably 1 to 2 times daily. For example, the preferred dosage for the combination of amantadine and selegiline is preferably 100 to 400 mg amantadine and 4 to 30 mg selegiline from 1 to 3 times daily. In particular, this dose is about 250 mg amantadine and about 10 mg selegiline from 1 to 3 times daily.

Amantadine and selegiline are in a unit dose, for example, in the following weight ratio before:

1 part by weight selegiline, for example, 0.4 - 800 parts by weight amantadine, preferably 1 part by weight selegiline with 1.2 - 200 parts by weight amantadine, especially 1 part by weight selegiline with 3.3 - -100 parts by weight amantadine combined.

For example, can be used for the combination of 20-800 mg amantadine and 1-50 mg selegiline, preferably 50-600 mg amantadine and 3 - 40 mg of selegiline, particularly 100-400 mg amantadine and 4-30 mg selegiline, especially 200-300 mg amantadine and 5-15 mg selegiline easily formulate the drug.

These previously indicated weight amounts only apply to homogeneous mixtures of amantadine and selegiline (eg suppositories or monolayer tablet). In other formulations, such as capsules and two-layer tablets, the components may of course be combined in other weight amounts.

The dosage unit of the combination of the invention may include, for example:<ul><li>a) In oral dosage forms:<ul><li>20-800 mg amantadine, preferably 50-600 mg, especially 100-400 mg amantadine and 1-50 mg, preferably 3-40 mg, especially 4-30 mg selegiline.</li><li>These doses may be administered 1 to 4, in particular 1 to 3 times a day for example 1 to 5, preferably.</li></ul></li><li>b) In the case of parenteral medicinal forms (for example intravenous, intramuscular):<ul><li>20-800 mg amantadine, preferably 50-600 mg, especially 100-400 mg amantadine and 1-50 mg, preferably 3-40 mg, especially 4-30 mg selegiline.</li><li>These doses may be administered 1 to 4, in particular 1 to 3 times a day for example 1 to 5, preferably.</li></ul></li><li>c) For medicinal forms for rectal or vaginal application:<ul><li>20-800 mg amantadine, preferably 50-600 mg, especially 100-400 mg amantadine and 1-50 mg, preferably 3-40 mg, especially 4-30 mg selegiline.</li><li>These doses may be administered 1 to 4, in particular 1 to 3 times a day for example 1 to 5, preferably.</li></ul></li><li>d) In the case of medicinal forms for application to the skin and mucous membranes (for example as solutions, lotions, emulsions, ointments, plasters and so on):<ul><li>20-800 mg amantadine, preferably 50-600 mg, especially 100-400 mg amantadine and 1-50 mg, preferably 3-40 mg, especially 4-30 mg selegiline.</li><li>These doses may be administered 1 to 4, in particular 1 to 3 times a day for example 1 to 5, preferably.</li></ul></li></ul>

Of course, pharmaceutical preparations may be prepared containing the above dosage units 2 to, for example, 6 times.

The above doses and weight parts that relate to the use in humans are, in each case based on the free bases.

The acute toxicity of the combination of the invention in the mouse (expressed by the LD 50 mg / kg; method: Litchfield and Wilcoxon, J. Pharmacol Exper Ther 95: 99 in 1959...) Is, for example, for the combination amantadine (HCl salt) and selegiline (HCl salt) (weight ratio 10: 1) in oral application between 600-700 mg / kg.

The combination according to the invention is suitable for producing pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredient, the inventive combination in a formulation. The individual active ingredients of the combination can also be present in separate formulations, wherein the amounts of active ingredient be already received will be used for each of the dosing unit in question. The active substances or combinations are optionally present in a mixture with other pharmacologically or pharmaceutically active substances.

The medicaments in a known manner, whereby the known and commonly used pharmaceutical adjuvants and other commonly used vehicles and diluents can be used.<ul><li>As such vehicles and adjuvants, for example, those substances that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmann's Encyclopedia of Industrial Chemistry, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 u.ff.,</li><li>HvCzetsch-Lindenwald, auxiliary substances for pharmacy and related fields; Pharm. Ind., No. 2, 1961, page 72 u.ff .; Dr. HP Fiedler, Lexikon der adjuvants for pharmaceutics, cosmetics and related fields Cantor KG, Aulendorf in Württemberg 1981st</li></ul>

Examples thereof are gelatine, natural sugars such as raw sugar or lactose, lecithin, pectin, starch (for example corn starch), cyclodextrins and cyclodextrin derivatives, polyvinylpyrrolidone, gelatin, gum arabic, alginic acid, tylose, talcum, lycopodium, silica (for example colloidal), cellulose , cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and / or lower saturated aliphatic oxyalcohols, for example methyloxypropyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate), stearates, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, in particular saturated (for example stearates), emulsifiers, oils and fats, in particular vegetable (for example, peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod-liver oil, mono-, di- and triglycerides of saturated fatty acids C)₂H₂₄0₂ to ClBH3602 and mixtures thereof), pharmaceutically acceptable mono- or multivalent alcohols and polyglycols such as polyethylene glycols and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 C-atoms, in particular 10 to 18 carbon atoms) with monovalent aliphatic alcohols ( 1 to 20 C-atoms) or polyhydric alcohols such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol or mannitol, which can also be etherified, if appropriate, esters of citric acid with primary alcohols and acetic acid, benzyl benzoate, dioxolanes, glycerol formals, tetrahydrofurfuryl alcohol, polyglycol ether with C -C₁₂-alcohols, Dimethylacetamide, Lactamide, lactates, ethyl carbonates, silicones (in particular medium-viscosity polydimethylsiloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate and magnesium carbonate.

Other auxiliary substances come into consideration which cause the disintegration (so called disintegrants) such as:<ul><li>crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, Natrlumcarboxymethylcellulose or microcrystalline cellulose. Conventional coating substances may be used, such as polyacrylates or cellulose ethers.</li></ul>

For the preparation of solutions, for example water or physiologically acceptable organic solvents, such as, for example, ethanol, 1,2-propylene glycol, polyglycols and their derivatives, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerol and paraffins. For injectable solutions or suspensions, for example, non-toxic parenterally acceptable diluents or solvents, such as, for example: water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols in mixture with water, Ringer's solution, isotonic saline or hardened oils, including synthetic mono- or diglycerides or fatty acids such as oleic acid.

In preparing the preparations, known and conventional solubilizers or emulsifiers are used. Solubilizers and emulsifiers, for example: polyvinyl pyrrolidone, sorbitan such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolisierte oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3- (2-hydroxyethyl) -imidazolidon- (2). Context, polyoxyethylated means that the substances in question contain polyoxyethylene chains whose degree of polymerization generally ranges from 2 to 40 and especially from 10 to 20th<ul><li>Such polyoxyethylated materials for example, by reaction of hydroxyl-containing compounds (for example mono- or diglycerides or unsaturated compounds such as those that contain Olsäurereste) with ethylene oxide (for example, 40 moles of ethylene oxide per mol glyceride). Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil.</li></ul>

See also Dr. HP Fiedler "Lexikon der adjuvants for pharmaceutics, cosmetics and related fields" 1971, pp 191-195.

Moreover, the addition of preservatives, stabilizers, buffer substances, such as calcium hydrogen phosphate, colloidal aluminum hydroxide, flavor, sweeteners, colorants, antioxidants and complex formers (for example, ethylenediaminetetraacetic acid) possible. If necessary, the stabilization of the drug molecule adjust with physiologically acceptable acids or buffers to a pH range of about 3 to 7th In general, a possible neutral to weakly acidic (up to pH 5) pH value is preferred.

Antioxidants that may for example sodium metabisulfite, ascorbic acid, gallic acid, gallic acid alkyl ester, butylhydroxyanisole, nordihydroguaiaretic acid, tocopherols as well as tocopherols + synergists (substances which bind heavy metals through complex formation, for example lecithin, ascorbic acid, phosphoric acid). The addition of synergists increases antioxygenic activity of tocopherol.<ul><li>Suitable preservatives are, for example sorbic acid, p-hydroxy (for example lower), benzoic acid, sodium benzoate, trichloroisobutyl, phenol, cresol, benzethonium chloride and formalin derivatives.</li></ul>

The pharmaceutical and galenic treatment of the active ingredients according to the usual standard methods. For example, active substance (s) and auxiliary or carrier substances by stirring or homogenizing (for example using conventional mixing devices) well mixed, generally at temperatures between 20 and 80_° C, preferably 20 to 50_° C, is carried out particularly at room temperature. Reference is also made to the following standard work: Sucker, Fuchs, Speiser, Pharmazeutische Technologie, Thieme-Verlag, Stuttgart., 1978

It can be applied to the skin or mucous membrane or inside the body, such as oral, peroral, enteral, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intracardiac, intramuscular, intraperitoneal, intracutaneous, subcutaneous. The parenteral forms of preparation are in particular sterile or sterilized products.

The combination of the invention may also be present as a product in which in each case the two individual active substances are present in separate formulations, so that a separate or sequential administration is possible.

If such separate formulations are present, they are compatible and contain the respective active ingredients in the dosage unit in the same amounts and corresponding weight ratios in which they may be present in the combined mixture.

In separate application, it is also possible that both combination partners are not administered simultaneously. In such cases, for example, the selegiline 1 times given per day (dose, for example, 5-30 mg) and the amantadine simultaneously (dose, for example 50 to 200 mg) and then 3 to 4 more doses (for example between 50-200 mg) at intervals of 4 hours.

In the liquid preparations the amantadine is, for example, in concentrations of 2-10, preferably 4-6, more preferably 5 weight percent and the selegiline in concentrations from 0.1 to 1, preferably from 0.3 to 0.5, in particular 0.375 weight percent.

For preparations in which the combination of the invention is suspended and homogenized in the molten hard fat, for example, per 1 part by weight amantadine (in the combination) or per 1 part by weight selegiline (if the selegiline is present as separate formulation) 10 - used 50 parts by weight of hard fat, where appropriate also 0.01 to 1 parts by weight (based on 1 part by weight amantadine) soya lecithin may be admixed additionally.

For the preparation of compositions in the form of tablets or capsules, for example, per 1 part by weight amantadine (in the combination) or per 1 part by weight selegiline (if the selegiline is present as separate formulation) 0.01 to 0.5 parts by weight of starch or gelatin or 0.005 - 0.3 parts by weight of vinylpyrrolidone-vinyl acetate copolymer used for the granulation. Optionally previously per 1 part by weight amantadine (in the combination), or per 1 part by weight selegiline (if the selegiline is present as a separate formulation) from 0.01 to 10, preferably 0.05 to 1 parts by weight of calcium hydrogen phosphate are admixed. The resulting granules are, for example, with air whose temperature is between 50 - 70 ° C is dried.

The dry granules, for example, even with 0.005 to 0.1 parts by weight magnesium stearate 0.001 - 0.1 part by weight silicon dioxide and / or 0.05 - to 2 parts by weight of starch are homogeneously mixed (the parts by weight given above relate in each case per 1 part by weight amantadine (in the combination) or per 1 part by weight selegiline (if the selegiline is present as separate formulation).

Examples

example 1

Injectable Solution Containing 100 mg amantadine hydrochloride and 7.5 mg selegiline

25 g amantadine hydrochloride and 1.875 g selegiline hydrochloride are dissolved successively in 450 ml nitrogen-gassed water for injections. The solution is made up with nitrogen-gassed water for injection to 500 ml and after careful mixing and additional nitrogen to sterile filtration through a membrane filter of pore size 0.2 with glass fiber. The filtrate is aseptically and under nitrogen into colorless ampoules, content 2 ml bottled. 2 ml of solution containing 100 mg amantadine hydrochloride and 7.5 mg selegiline hydrochloride.

example 2

Capsules with 100 mg amantadine hydrochloride and 7.5 mg selegiline

10 kg amantadine hydrochloride are intensively mixed using a suitable mixer with 0.75 kg selegiline. Thereafter, the mixture in a fluidized bed is Sprühgranulationsapparatur granu lines with a solution of 0.25 kg of gelatin in 2.25 kg of water in a known manner. After admixture of 0.85 kg of corn starch 0.1 kg of magnesium stearate and 0.05 kg of colloidal silica, the mixture in a capacity of 120 mg is filled into hard gelatin capsules of size. 2 One capsule contains 100 mg Amantadinhydrochforid and 7.5 mg selegiline hydrochloride.