HRP980155A2 - Pharmaceutical compositions containing propanamine derivatives and cyclodextrin - Google Patents

Description

This invention relates to pharmaceutical ingredients that contain as an active ingredient propanamine derivatives together with cyclodextrin, most preferably in the form of a matching complex.

More specifically, the object of the invention are pharmaceutical ingredients that contain as an active ingredient propanamine of the general formula I - in the formula R represents hydrogen or methyl - or any optical isomer and/or its pharmaceutically acceptable salt together with cyclodextrin, most preferably in the form of a switching complex, as well as new switching complexes, complex preparation processes, pharmaceutical ingredient preparation processes and product use.

In this patent, the specification of substituents, names and abbreviations always represents the following and will therefore not be repeated:

R = hydrogen or methyl

fluoxetine = (±)-N-methyl-γ-[4-(trifluoro-methyl)-phenoxy]benzene-propanamine = FLU

nor-fluoxetine = (±)-γ-[4-(trifluoromethyl)-phenoxy]-benzene-propanamine = N-FLU

CD = cyclodextrin

γ-cyclodextrin = cyclomaltooctose = γCD

β-cyclodextrin = cyclomaltoheptaose = βCD

α-cyclodextrin = cyclomaltohexaose = αCD

CDPSI = ionic water-soluble polymer α, β or γ-cyclodextrin

HPCD = hydroxypropylated α, β or γ-cyclodextrins

HPβCD = hydroxypropyl-β-cyclodextrin (2-8 hydroxypropyl groups per CD-unit)

MECD = methylated α, β or γ-cyclodextrins

DIMEB = heptakis-2,6-di-0-methyl-β-cyclodextrin (average)

TRIMEB = heptakis 2,3,6-tri-0-methyl-β-cyclodextrin

RAMECD = randomly methylated α, β or γ-cyclodextrins

RAMEB = randomly methylated-β-cyclodextrin containing 12 methoxy groups per CD-unit (average)

G2BCD = maltosylated β-cyclodextrin.

More specifically, one object of this invention is a pharmaceutical ingredient containing as an active part propamine of the general formula I or an optical isomer and/or its pharmaceutically acceptable salt together with cyclodextrin, preferably in the form of a matching complex and optionally in further mixtures with the usual auxiliary and additional materials that are used in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical uses.

The ingredients of formula I include the active ingredient known as fluoxetine and its active metabolite known as nor-fluoxetine. Both ingredients contain a chiral carbon atom so that they can appear in the forms of two different stereoisomers depending on the position of the substituents on the chiral carbon atom. This invention relates to any of the pure isomeric forms as well as to any mixture of such pure isomers including racemates.

The ingredients of the general formula I can appear in the form of a free base (these ingredients are called fluoxetine or nor-fluoxetine) and also in the form of their salts. In this specification, the names "fluoxetine" and "nor-fluoxetine" are always used for the free bases and the salts are specifically designated.

Pharmaceutical ingredients according to this invention show significant psychotropic activities, i.e. antidepressant effects.

Fluoxetine is known as a highly selective, serotonin (5-hydroxy-tryptamine) reuptake inhibitor useful in the treatment of depression (Curr. Ther. Res. 37. 115. 1985) and its preparation is known (USP 4314081, DBP 2500110). Commercially available fluoxetine is a racemate labeled under the trade names Prozac®, Potac®, Fontex®.

Cyclodextrins (CDs) are prepared from starch using the CD-glucosyl transferase enzyme. CDs are composed of glucopyranose units linked by α-1,4 glucosidic linkages. Three different types of CDs are known, which differ in molecular weight, water solubility, and cavity diameter: αCD contains 6, βCD contains 7, and γCD contains 8 glucopyranose units. CDs may or may not be able to form inclusion complexes with different types of constituents under appropriate conditions by incorporating all or parts of guest molecules into their cavities. Binding complexes of the same composition successfully formed with different types of CDs can have quite different properties.

There are possibilities to carry out further modifications in the α, β or γ molecules by way of substitution eg methylation to obtain MECDs or hydroxypropylation to obtain HPCDs etc. For example in the case of heptakis-2,6-di-O-methyl -βCD (DIMEB) two hydroxyl groups are methylated at positions 2 and 6 of each glucose unit, while in the case of randomly methylated βCD (RAMEB) the hydroxy groups are substituted by methoxy groups randomly, and the average methylation ratio is about 1.8. Both the solubility and complex formation capacity of such substituted CDs may differ from those corresponding to unsubstituted CDs.

It is also known that due to the chiral character of the cavities of CDs, some of the CDs may be suitable for use in the identification of individual isomers in racemic mixtures of individual ingredients. Thus, β-CD is used in aqueous solutions and bound to a solid phase for the analytical identification of + and - enantiomers of fluoxetine and nor.fluoxetine. (J. Chromatogr. A 700, 59-67. 1995; 5-th Intl. Symp. on Chiral Discrimination, Stockholm, Sweden, Sept. 25-28 1994; Chirality 7 . 257-266 1995). The presence of the two isomers was detected by UV on the chromatograms in the solution that was subjected to treatment with βCD. However, until now none of the CD complexes of the ingredients of formula I have been isolated and used in pharmaceuticals, nor were they specific isomers.

The aim of this invention was to improve the properties of the ingredients of formula I by combining them with cyclodextrins if possible.

For this reason, solubility isotherm experiments were performed according to known methods (Adv. in Anal. Chem. and Instr. Ed. C. N. 1965, vol 4. pp. 117-212). This invention is based on the recognition that some of the CDs have a favorable effect on the solubility properties of the ingredients of the general formula I. Table I and Table II show by way of example the change in the solubility of representatives of some ingredients according to the invention.

Table legends:

Table I: Solubility of fluoxetine.HCl with cyclodextrins as a function of cyclodextrin concentration in water (mg/ml)

Table II: Solubility of nor-fluoxetine oxalate with cyclodextrins as a function of CD concentration in water (mg/ml)

Table I

[image] Table II

[image]

It can be concluded from the data of Tables I and II that among the studied non-substituted CDs was γ-cyclodextrin, which was found to noticeably improve the water solubility of the tested salts and therefore has a high affinity towards drugs. Among highly soluble βCD derivatives, methylated-β-cyclodextrin appears as the most powerful solvent of fluoxetine and nor-fluoxetine salts, while hydroxypropylated βCD derivatives were found to be less effective.

Based on the above and further experiments, one object of the present invention are pharmaceutical ingredients containing as an active ingredient propanamine of the general formula I or any optical isomer and/or its pharmaceutically acceptable salt together with cyclodextrin, most preferably in the form of a coupling complex and optionally in further mixtures with the usual auxiliary and additional materials used in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical uses.

Preferred embodiments of the invention are pharmaceutical ingredients containing as an active ingredient propanamine of the general formula I or any optical isomer and/or its pharmaceutically acceptable salt together with γ-cyclodextrin, methylated α-, β- or γ-cyclodextrin, ionic water-soluble polymer α-, β- or γ-cyclodextrin, β-cyclodextrin or α-cyclodextrin most preferably in the form of a coupling complex and optionally in further mixtures with the usual auxiliary and additional materials used in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical uses.

It was found that in the ingredients according to the invention it is preferable to use a molar ratio of propanamine of formula I to cyclodextrin, which is in the range of 1:1 to 1:6, most preferably 1:1 and 1:2.

The compound of formula I can appear as a "free base" in the coupling complex or they can form, for example, the following salts with the corresponding acids: chloride, bromide, methane sulfonate, tosylate, besylate, pivalate, caproate, etc.

Preferred excipients to be used in the ingredients include carriers, diluents, surfactants, colorants, flavorings, and the like which are acceptable in the pharmaceutical art and which are compatible with the active ingredient.

Further objects of this invention are novel coupling complexes of propanamine of formula I and any optical isomer and salt thereof formed with γ-cyclodextrin, wherein the molar ratio of propanamine of formula I to γ-cyclodextrin is within the range of 1:1 to 1:6 preferably 1:1 and 1:2. Such complexes can be prepared and isolated in the solid state and are ready for handling and use in the laboratory or production in the pharmaceutical industry.

Further objects of this invention are novel inclusion complexes of propanamine of formula I and any optical isomer and salt thereof formed with methylated α, β or γ-cyclodextrin or hydroxypropylated α, β or γ-cyclodextrin, wherein the molar ratio of propanamine to cyclodextrin is within the range of 1 :1 to 1:6 preferably 1:1 and 1:2. Such complexes can be prepared and isolated in the solid state and are ready for handling and use in the laboratory or production in the pharmaceutical industry.

Preferred new complexes according to the invention include the following:

coupling complexes (±)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts with γ cyclodextrin;

coupling complexes (+)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts with γ cyclodextrin;

coupling complexes (-)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts with γ cyclodextrin;

coupling complexes (±)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts with γ cyclodextrin;

coupling complexes (+)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts and methylated α, β or γ cyclodextrin;

coupling complexes (-)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts and methylated α, β or γ cyclodextrin;

coupling complexes (+)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts and hydroxypropylated α, β or γ cyclodextrin;

coupling complexes (-)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts and hydroxypropylated α, β or γ cyclodextrin;

coupling complexes (+)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts and methylated α, β or γ cyclodextrin;

coupling complexes (-)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts and methylated α, β or γ cyclodextrin;

coupling complexes (+)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts and hydroxypropylated α, β or γ cyclodextrin;

coupling complexes (-)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and its salts and hydroxypropylated α, β or γ cyclodextrin;

A further object of this invention are processes for the preparation of novel coupling complexes of propanamine of the general formula I or any optical isomer or its pharmaceutically acceptable salt formed with γ-cyclodextrin, methylated α, β or γ-cyclodextrin, ionically water-soluble polymer α-, β- or γ -cyclodextrin or hydroxypropylated α-, β- or γ-cyclodextrin or maltosylated α-, β- or γ-cyclodextrin or β-cyclodextrin or α-cyclodextrin such that the propanamine of the general formula I or any optical isomer or a pharmaceutically acceptable salt thereof reacts with γ-cyclodextrin, methylated α, β or γ-cyclodextrin, ionically water soluble polymer of α-, β- or γ-cyclodextrin, hydroxypropylated α-, β- or γ-cyclodextrin or maltosylated α, β or γ-cyclodextrin or β-cyclodextrin or with α-cyclodextrin, whereby the molar ratio of applied propanamine to applied cyclodextrin takes values within the range of 1:1 to 1:6, preferably 1:1 and 1:2. The following methods can be used to implement the above processes alone or in combination:

a) reacting propanamine with cyclodextrin in a solution of water or water and water-miscible organic solvents, cooling the solution and isolating the complex by freeze-drying;

b) thoroughly mix (crushing, grinding, kneading) solid propanamine with optional cyclodextrin in the presence of or after adding an organic solvent or water or an aqueous organic solvent followed by granulation and drying;

c) reacting propanamine with cyclodextrin in a solution of water or water and water-miscible organic solvents and isolation of the complex by spray drying;

d) reacting propanamine with cyclodextrin in a solution of water or water and water-miscible organic solvents with heating to about 60°C, cooling the solution and isolation of the complex by crystallization.

When carrying out process variants a), c) or d) according to the invention, the ingredients of formula I or its isomers or their salts react with cyclodextrins and derivatives in an aqueous medium. A small amount of suitable, pharmaceutically acceptable organic solvents or detergents can be used as the third component.

When carrying out method b) according to this invention, the best laboratory method seems to be to knead the ingredients according to formula I and the cyclodextrins used can be added in the presence of a small amount of water and some other solvent, preferably after some degree of mixing has been achieved. Grinding and crushing are the methods that are preferably used for the preparation of larger quantities on a production scale. The products thus obtained appear as fatty materials which can be further treated to achieve a stable solid isolated complex.

Using methylated- and hydroxypropylated-cyclodextrins for the formulation of the ingredients of formula I or any isomer thereof or their salts, powder products can be isolated.

Isolation from the reaction mixture can be achieved by known methods, such as evaporation, spray-drying, freeze-drying.

A further object of the invention is a method of treating depression by administering to a patient in need of such treatment an effective dose of a pharmaceutical ingredient containing as an active component propanamine of the general formula I or any optical isomer and/or its pharmaceutically acceptable salt together with cyclodextrin optionally in the form of a coupling complex a said ingredient optionally further contains auxiliary and additional materials used in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical uses.

It is preferable for the treatment of depression to give the patient an effective dose of a pharmaceutical ingredient that contains as an active ingredient the coupling complex of propanamine of general formula I and cyclodextrin, wherein the molar ratio of propanamine of formula I to cyclodextrin is within the range of 1:1 to 1:6, preferably 1 :1 and 1:2. Specifically, such cyclodextrin ingredients or complexes show good results where an effective dose of a pharmaceutical ingredient comprising the coupling complexes of propanamine of general formula I or any optical isomer and its salt formed with γ-cyclodextrin is administered to a patient wherein the molar ratio of propanamine of formula I to γ-cyclodextrin is within the range of 1:1 to 1:6 or 1:1 and 1:2. The preferred ingredients for such a treatment are those that contain an effective dose of matching complexes

(±)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or

(+)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or

(-)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or

(±)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or

(+)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or

(-)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine with γ-cyclodextrin or with methylated α, β or γ-cyclodextrin.

The effective doses of the ingredients according to the invention depend very much on the patient being treated and on the severity of the case. Doses are within the range corresponding to about 10 to 20 mg/kg body weight per day of γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine. For less serious cases, daily doses of 5 mg or about 10 to 20 mg doses every two or three days are sufficient. Administration of the drug may be achieved by oral, parenteral, transdermal, rectal, or nasal routes, or by any conventional medical route that may be used in the treatment of depression or anxiety, either by inpatient or outpatient treatment. It is preferable to take the medicine in capsule form of 10 - 20 mg or liquid of 20 mg/5 ml.

The details of the invention that follow in the Examples are for purposes of illustration and not for reasons of limitation.

Examples

I. Complexation

The interaction between propanamine and cyclodextrin was studied by registering phase solubility diagrams in distilled water at 25°C after 48 hours of equilibration with stirring (mixing of 2 ingredients). Quantitative determination of the dissolved amount of propanamine molecules was performed by UV-spectrophotometry on a Hewlett Packard 8452A diode-array spectrophotometer. Calibration was performed on the substance in 50% (v/v) aqueous ethanol at an analytical wavelength of 264-266 nm in a concentration range of 0.05-0.5 mg/ml of the drug. It was not found that any of the applied cyclodextrins affect the UV absorption of the drug, therefore the method can be used reliably.

Example I.1

70.12 g (0.054 mol) of crystalline γ-CD was intensively mixed in 150 ml of water at room temperature for 30 minutes. Then 18.6 g (0.06 mol) of fluoxetine.HCl was added to the aqueous solution of γ-CD, and the reaction mixture was further stirred for 8 hours at room temperature with 600 revolutions per minute. The resulting opalescent solution was freeze-dried to yield 82.65 g (93.28%) of fluoxetine.HCl/γCD as a white, amorphous solid containing 21.5% fluoxetine by weight. Loss on product drying is 4.55%.

Re-dissolving properties of the product:

The solid formulation dissolves easily in water at room temperature resulting in a stable, clear solution of 1.00 g/100ml.

Characteristics of the solid state of the product:

X-ray diffraction on the powder: a new solid phase of amorphous character was formed as compared to the crystalline structure of the initial γ-CD hydrate (Figure 1). DSC comparison of the product with fluoxetine.HCl (Figures 2 and 3): absence of endothermic heat flow in the graph of the product in the region of the melting point of fluoxetine.HCl is evidence of the formation of a complex between γ-cyclodextrin and fluoxetine.HCl.

Example I.2

120 g of γ-Cyclodextrin is mixed with 500 ml of water at room temperature for 10 minutes resulting in a slightly sparkling solution. 15.6 g of fluoxetine (free base, oily substance) are dissolved in 25 ml of 96% ethanol and added drop by drop to the γ-CD solution. The reaction mixture is stirred at room temperature with 600 approx. min. through 8 hours. A white precipitate forms, which is filtered off and air-dried to constant weight. Product: 114.9 g fluoxetine/CD as a white, odorless, microcrystalline solid. Fluoxetine content: 12.7% by weight. Losses during drying: 13.35% by weight.

Powder X-ray Diffraction: The diffraction pattern of the complex differs significantly from that of γCD, and possesses a high degree of crystallinity (see Figure 4). The oily, non-crystalline base forms a well-defined crystalline complex. Dissolution characteristics: Improved wettability and dissolution rate were found compared to free fluoxetine (Table III).

Table III

[image]

Example I.3

13.35 g (0.01 mol) of heptakis-2,6-di-O-methyl-β-cyclodextrin is intensively mixed with 2.5 ml of water and 3.1 g (0.01 mol) of fluoxetine.HCl for 30 minutes at room temperature in a twin-screw mixer. The wet solid formulation is air-dried to constant weight resulting in 16.47 g of microcrystalline fluoxetine.HCl/DIMEB in solid form containing 18.23% fluoxetine.

Example I.4.

15 g of maltosylated β-CD were dissolved in 100 ml of water. 3.1 g of fluoxetine.HCl was dissolved in 5 ml of 50% aqueous ethanol and added drop by drop to the CD solution. The slightly shimmering reaction mixture is stirred for an additional 4 hours and the solution is removed by lipophilization.

Product: 17.78 g of white, foamy amorphous solid containing 17.09% (b.w.) fluoxetine.

Example I.5.

15 g of 2-hydroxypropylated-β-cyclodextrins were dissolved in 50 ml of deionized water at ambient temperature. 3.0 g of fluoxetine hydrochloride was added to the clear solution and the reaction mixture was stirred for 6 hours to obtain a slightly sparkling solution. By removing the solution by spray-drying, a white amorphous powder was obtained. Product: 15.55 g fluoxetine.HCl/HPβCD. Fluoxetine content: 16.45% b.w.

Example I.6

18.54 g (0.06 mol) of fluoxetine was ground with 77.80 g (0.06 mol) of crystalline γ-cyclodextrin in a ceramic burr for 5 minutes. Then, 10 ml of deionized water was added to the mixture and the resulting fine sludge was thoroughly mixed for 45 minutes. The wet paste was then passed through a 2.0 mm sieve and the wet grains were allowed to dry in an air stream. The resulting dry granules can be ground and sieved to the desired particle size. Product: 93.8 g of white granules of fluoxetine/γCD, with a fluoxetine content of 18.9% by weight. Molar ratio in the complex: 1:1.

Example I.7

15.5 g of maltosylated β-CD (approximately 0.01 mol) was milled with 1.54 g (0.005 mol) of fluoxetine in a ceramic burr for 5 minutes. The homogeneous mixture was moistened with 2.5 ml of 50% (vol/vol) aqueous ethanol. The wet slurry was mixed for 30 minutes at room temperature to obtain a sticky wet material. This paste was allowed to dry in an oven at 40°C to a constant weight. The dry formulation was ground in a ball mill resulting in a white amorphous solid. Product: 16.78 g of white powder with a fluoxetine content of 9.0%. Molar ratio in the complex: 1:2.

Example I.8

16.0 g (about 0.01 mol) of hydroxypropylated β-CD were dissolved in 40 ml of deionized water at 25°C by ultrasonication. To this clear solution was added 3.1 g (0.01 mol) of fluoxetine previously dissolved in 5 ml of 96% ethanol with intense cherry. The reaction mixture was further stirred for 4 hours at 25°C and then cooled with a dry ice/ethanol mixture to -56°C and lyophilized. 18.8 g of the fluoxetine/hydroxy-propylated-β-cyclodextrin complex was obtained as a white amorphous powder containing 16.0% fluoxetine by weight. Molar ratio in the complex: about 1:1.

Example I.9

1.2 g of crystalline γ-cyclodextrins (0.93 mM) were dissolved in 5.2 ml of deionized water at ambient temperature by ultrasonification for 5 minutes and then stirred at 600 rpm. The slightly hazy γ-CD solution has a pH of 5.3. 0.125 g (0.45 mM) of nor-fluoxetine previously dissolved in 2 ml of 96% ethanol was added dropwise to this solution. After addition, the reaction mixture became cloudy. The milky reaction mixture was further stirred for 8 hours at 600 rpm. and it was left to stand at 4°C for 12 hours in a refrigerator. The formed white precipitate was filtered off and dried under vacuum at 25°C to constant weight. 1.28 g of the nor-fluoxetine/γ-cyclodextrin complex was obtained. Nor-fluoxetine content: 9.3% by weight (determined by UV spectrophotometry). Norfluoxetine molar ratio: γCD ≈ 1:2.

II. FORMULATIONS

Example II.1

Foamed bags with 20 mg of fluoxetine each from the product of Example I.1 were prepared in a known manner.

Composition:

- Fluoxetine/γCD (Example I.1) 93 mg

- citric acid 50 mg

- baking soda 85 mg

- sucrose 120 mg

- orange flavor 30 mg

- Mg-stearate 465 mg

Example II.3 Tablets of 20 mg fluoxetine

Tablets are prepared from the fluoxetine.HCl/γCD complex of Example I.2 in a known manner. Composition:

- Fluoxetine.HCl/γCD (diameter I.2) 170 mg

- Magnesium stearate 13 mg

- lactose 10 mg

- Esma Spreng 4 mg

III. BIOLOGICAL EXAMPLES

Example III.1.

Effect of oral drug administration on the electroactivity of serotoninergic neurons of the dorsal suture in vivo.

The aim of the study is to compare the influence of fluoxetine.HCl and fluoxetine.HCl/γCD on the electrical activity of serotoninergic cells of the dorsal suture. Two active products and a control (saline) were given orally to live anesthetized rats (each group n = 8). The given dose corresponds to 10 mg/kg of fluoxetine base.

In the case of control animals receiving drinking water, the frequency of bursts of serotoninergic neurons decreases slightly with time. After 30 minutes, a slight but significant drop of about 7% can be observed (p = 0.047).

Oral administration of 10 mg/kg fluoxetine in the form of fluoxetine.HCl or Fluoxetine.HCl/γCD causes a progressive decrease in the firing frequency of RD serotoninergic neurons. This reduction is of the order of 45% after 30 minutes.

The effect of both substances becomes significant after 10 minutes of drug administration. Between the 10th and 15th minutes, the degree of significance is more pronounced for fluoxetine.HCl/γCD (p<0.005 and 0.0005) than for fluoxetine. HCl (p<0.05 and 0.005).

The analysis of variance between the mean value ± deviation (4.39-13.19 action potential/10 sec) regarding the maximum homogenization of the groups during the control period shows that fluoxetine.HCl/γCD is significantly different from the controls at the 25th minute (p=0.023) and at the 30th. minutes (p=0.004). Sl. 5 shows the change in mean action potential/10 sec as a function of time measured every minute; and as a function of pharmacological treatment in the ANOVA test (all groups n = 8), standard deviation NS p>0.05, significant deviations *p<0.05, highly significant deviations **p<0.01 compared to the saline group. N= number of groups. The signs on the graph indicate the following groups:

-- salty,

-O- fluoxetine.HCl,

--- fluoxetine.HCl/γCD.

Fluoxetine.HCl does not show significant differences compared to the control under these conditions (p = 0.16 and 0.06).

Example III.2

Swimming test

Comparative study of fluoxetine.HCl and fluoxetine.HCl/γCD in the forced swimming test (Porsolt model 1977) in mice. A statistical comparison of mean immobilization times as a function of drug and dose was made using analysis of variance followed by a post hoc Newman-Keuls test. The method is one way of determining antidepressant activity.

III.2.1. Comparing salt groups with each other:

[image]

Thus, the Student's test for the independence of the groups showed an insignificant difference between the groups (t<1.00, p = 0.946).

III.2.2. Fluoxetine.HCl:

Analysis of variance with the dose factor as a classification criterion showed a significant difference between the groups (F = 11.99, p<0.0001).

The post-hoc Newman-Keul test showed that some doses of fluoxetine.HCl induced a significant decrease (p<0.05) in immobilization time.

[image]

III.2.3. Fluoxetine.HCl/γCD :

[image]

Analysis of variance with the dose factor as a classification criterion shows a significant difference between the groups (F = 55.58, p<0.0001). The post-hoc Newman-Keuls test shows that fluoxetine.HCl/γCD doses induce a significant decrease (p<0.05) in immobilization time.

III.2.4. Comparison between two oral fluoxetine products:

[image]

Pairwise comparisons for each given dose, using the student's t test for independent groups, show that at a dose of 16 mg/kg, the γCD ingredient is significantly more effective (p<0.0001).

III.2.5. Determination of oral ED50 and/or ED30

[image]

III.2.6. Findings:

The greatest reduction in immobility was observed at a dose of 24 mg/kg for fluoxetine.HCl and at a dose of 16 mg/kg fluoxetine.HCl/γCD. Fluoxetine.HCl reduces immobility by 48% and fluoxetine.HCl/γCD by 68%. No clear dose-effect relationship was observed in the case of fluoxetine.HCl, while a U-shaped dose-effect relationship was measured for fluoxetine.HCl/γCD. ED50 and ED30 decrease in the case of fluoxetine.HCl/γCD.

Example III.3. Bioavailability study in humans

Materials:

Fluoxetine.HCl [Prozac®] and fluoxetine.HCl/γCD - prepared according to Example 1 - were administered in a single dose [each containing 20 mg of fluoxetine] to healthy male subjects (Subj.).

The aim of the research was to compare the bioavailability of fluoxetine.HCl (FLU), fluoxetine.HCl/γCD (FLU/γCD), nor-fluoxetine (NFLU), nor-fluoxetine/γCD (NFLU/γCD).

Methods

a. Patient selection

Twelve healthy male subjects (white, between 18 and 45 years old) participated after giving written consent. They were within ± 10% of the ideal body weight for their age and height calculated according to the Broca index. They were judged to be in good health based on their previous medical history, physical examination, hematological and blood chemistry profiles, blood pressure and electrocardiogram. Table I presents their physical data.

b. Experimental design

A double-blind randomized trial was conducted. According to the protocol, which was accepted by the Local Ethics Committee, the treatment was performed randomly on volunteers (Table V). During the study, six subjects received treatment A (using FLU) and six received treatment B (using FLU/γCD). The medicine was given with 200 ml of water. After drug administration, 10 ml of heparized blood samples were collected using butterfly catheters at the following times: T0, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8, 9, 24h, 36, 48h and 3, 4, 7, 9, 11, 14, 16, 18, 21, 23 and 25 days after taking the medicine. The tubes were centrifuged for 5 minutes at 300 rpm, the plasma was separated and cooled to -20°C until the experiment. Usual breakfast, lunch and dinner are allowed at times 2, 5 and 8 hours after taking the medicine.

c. Determination of plasma level

Fluoxetine and norfluoxetine levels were measured by LO-MS-MS (high pressure liquid chromatography coupled to tandem mass spectrometer) method after solid phase extraction procedure. The accuracy of the method was determined on each measurement day.

d. Pharmacokinetic parameters

The relative bioavailability of the two active ingredients was compared using the following parameters obtained using non-compartmental analysis (TOPFIT 2.0 program):

Cmax: maximum plasma level (ng/ml);

tmax: time C max (h);

AUC (0-48h): area under the curve calculated by the trapezoidal rule between T 0h and T 48h (ng*h/ml);

AUC (0-∞): area under the curve extrapolated to ∞ (ng*h/ml);

MRT: mean drug retention time (h);

t1⁄2β: terminal half-life (h);

volume of distribution (l);

C1T: Complete removal (ml/min).

Tables X and XI present the pharmacokinetic parameters (individual values, mean, standard deviation (SD) and standard error (SE)) of FLU after treatment A with FLU and treatment B with FLU/γCD.

Tables XII and XIII present the pharmacokinetic parameters (individual values, mean, standard deviation (SD) and standard error (SE)) of N-FLU after treatment with A FLU and treatment with B FLU/γCD.

A Student's test was performed to compare the pharmacokinetic parameters of FLU and N-FLU, calculated with non-compartmental analysis with treatment A or treatment B. Tables XIV and XV present the obtained results.

Table legends:

Table IV Physical data of subjects

Table V Random arrangement

Table VI Plasma levels of FLU upon treatment A with FLU

Table VII Plasma levels of FLU upon treatment B with FLU/γCD

Table VIII Plasma levels of N-FLU upon treatment of A with FLU

Table IX Plasma levels of N-FLU upon treatment B with FLU/γCD

Table X Pharmacokinetic parameters of FLU after treatment with FLU

Table XI Pharmacokinetic parameters of FLU after treatment with FLU/γCD

Table XII Pharmacokinetic parameters of N-FLU after treatment with FLU

Table XIII Pharmacokinetic parameters of N-FLU after treatment with FLU/γCD

Table XIV Summary of FLU and FLU/γCD pharmacokinetic parameters

Table XV Summary of norfluoxetine and norfluoxetine/CD pharmacokinetic parameters.

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Figure 6: FLU plasma level curves (mean ± SE); time in hours after drug administration as a function of concentration. Round signs FLU, square signs FLU/γCD.

Figure 7: N-FLU plasma level curves (mean ± SE); time in hours after drug administration as a function of concentration. Round signs N-FLU, square signs N-FLU/γCD.

Table IV

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Table V

[image] Table VI

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Table VII

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Table VIII

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Table IX

[image] Table X

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Table XI

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Table XII

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Table XIII

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Table XIV

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Table XV

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Claims (21)

1. Pharmaceutical ingredients characterized by the fact that they contain as an active ingredient propanamine of the general formula I - where in the formula R represents hydrogen or methyl - or any optical isomer and/or its pharmaceutically acceptable salt together with cyclodextrin, most preferably in the form of a matching complex, and said ingredient optionally in further mixtures contains the usual auxiliary and additional materials used in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical use. 2. Pharmaceutical ingredients characterized by the fact that they contain as an active ingredient propanamine of the general formula I - where in the formula R represents hydrogen or methyl - or any optical isomer and/or a pharmaceutically acceptable salt thereof together with γ-cyclodextrin, methylated α-, β- or γ-cyclodextrin, hydroxypropylated α-, β- or γ-cyclodextrin, ionic water-soluble polymer α-, β- or γ -cyclodextrin, maltosylated α-, β- or γ-cyclodextrin or β-cyclodextrin or α-cyclodextrin, most preferably in the form of a matching complex, and the aforementioned ingredient optionally in further mixtures contains the usual auxiliary and additional materials acceptable in pharmaceuticals for oral, parenteral, transdermal, rectal or other medicinal uses. 3. Pharmaceutical ingredients according to any of claims 1 and 2, characterized by the fact that they contain as an active ingredient a propanamine coupling complex of the general formula I - in the formula R represents hydrogen or methyl - wherein the molar ratio of propanamine of formula I to cyclodextrin is within the range of 1:1 to 1:6 preferably 1:1 and 1:2. 4. Compound complexes of propanamine of formula I - indicated by the fact that in the formula R represents hydrogen or methyl - and any optical isomer and salt thereof formed with γ-cyclodextrin, wherein the molar ratio of propanamine of formula I to γ-cyclodextrin within the range of 1:1 to 1:6 is preferably 1:1 and 1:2. 5. Compound complexes of propanamine of formula I - indicated by the fact that in the formula R represents hydrogen or methyl - and/or any optical isomers and/or salts thereof formed with methylated α, β or γ-cyclodextrin or hydroxypropylated α, β or γ-cyclodextrin, wherein the molar ratio of propanamine to cyclodextrin is within the range of 1: 1 to 1:6 preferably 1:1 and 1:2. 6. Indicated by this, that the coupling complexes are (±)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and γ cyclodextrin. 7. Indicated by this, that the coupling complexes are (±)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and γ cyclodextrin. 8. Indicated that the coupling complexes are (+)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and methylated α, β or γ cyclodextrin. 9. Indicated by this, that the coupling complexes are (-)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and methylated α, β or γ cyclodextrin. 10. Indicated that the coupling complexes are (+)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and hydroxypropylated α, β or γ cyclodextrin. 11. Indicated by this, that the coupling complexes are (-)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and hydroxypropylated α, β or γ cyclodextrin. 12. Indicated that the coupling complexes are (+)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and methylated α, β or γ cyclodextrin. 13. Indicated that the coupling complexes are (-)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and methylated α, β or γ cyclodextrin. 14. Indicated that the coupling complexes are (+)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and hydroxypropylated α, β or γ cyclodextrin. 15. Indicated by this, that the coupling complexes are (-)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and hydroxypropylated α, β or γ cyclodextrin. 16. Processes for the preparation of new coupling complexes of propanamine of the general formula I - in the formula R represents hydrogen or methyl - or any optical isomer or a pharmaceutically acceptable salt thereof formed with γ-cyclodextrin, methylated α, β or γ-cyclodextrin, ionic water-soluble polymer of α-, β- or γ-cyclodextrin, hydroxypropylated α-, β- or γ-cyclodextrin, maltosylated α-, β- or γ-cyclodextrin or β-cyclodextrin or α-cyclodextrin characterized in that the propanamine of the general formula I - in the formula R represents hydrogen or methyl - or any optical isomer or a pharmaceutically acceptable salt thereof reacts with γ-cyclodextrin, methylated α, β or γ-cyclodextrin, ionic water-soluble polymer of α-, β- or γ-cyclodextrin, hydroxypropylated α-, β- or γ-cyclodextrin, maltosylated α, β or γ-cyclodextrin or β-cyclodextrin or α-cyclodextrin, wherein the molar ratio of applied propanamine to applied cyclodextrin takes values within the range of 1:1 to 1:6, preferably 1:1 and 1:1 2. 17. The process according to claim 16 characterized in that the propanamine of the general formula I - in the formula R represents hydrogen or methyl - or any optical isomer or a pharmaceutically acceptable salt thereof reacts with γ-cyclodextrin, methylated α, β or γ-cyclodextrin, ionic water-soluble polymer of α-, β- or γ-cyclodextrin, hydroxypropylated α-, β- or γ-cyclodextrin or β-cyclodextrin or α-cyclodextrin wherein the molar ratio of applied propanamine to applied cyclodextrin takes values within the range of 1:1 to 1:6 preferably 1:1 and 1:2 using any of the following methods alone or in combination: a) reacting propanamine with cyclodextrin in a solution of water or water and water-miscible organic solvents, cooling the solution and isolating the complex by freeze-drying; b) thorough mixing (crushing, grinding, kneading) in the solid state of propanamine with cyclodextrin optionally in the presence of or after the addition of an organic solvent or water or an aqueous organic solvent followed by granulation and drying; c) reacting propanamine with cyclodextrin in a solution of water or water and water-miscible organic solvents and isolation of the complex by spray drying; d) reacting propanamine with cyclodextrin in a solution of water or water and water-miscible organic solvents with heating to about 60°C, cooling the solution and isolation of the complex by crystallization. 18. A method of treating depression indicated by giving the patient an effective dose of a pharmaceutical ingredient containing as an active component propanamine of the general formula I - in the formula R represents hydrogen or methyl - or any optical isomer and/or its pharmaceutically acceptable salt together with cyclodextrin optionally in the form of a fitting complex and the said ingredient optionally further contains auxiliary and additional materials which are acceptable in pharmaceuticals for oral, parenteral, transdermal, rectal or other medicinal uses. 19. A method of treating depression indicated by giving the patient an effective dose of a pharmaceutical ingredient that contains as an active component propanamine coupling complexes of the general formula I - in the formula R represents hydrogen or methyl - and cyclodextrin, wherein the molar ratio of propanamine of formula I to cyclodextrin is within the range of 1:1 to 1:6, preferably 1:1 and 1:2. 20. A method of treating depression indicated by giving the patient an effective dose of a pharmaceutical ingredient that contains as an active component propanamine coupling complexes of the general formula I - in the formula R represents hydrogen or methyl - and any optical isomer and its salt formed with γ-cyclodextrin, wherein the molar ratio of propanamine of formula I to γ-cyclodextrin is within the range of 1:1 to 1:6 or 1:1 and 1:2. 21. A method of treating depression characterized by giving the patient an effective dose of the compound complex (±)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or (+)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or (-)-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or (±)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or (+)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine or (-)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzene-propanamine with γ-cyclodextrin or with methylated α, β or γ-cyclodextrin.