CZ20011142A3 - Medicamentous form for peroral administration - Google Patents

Abstract

This invention provides discrete oral dosage forms, typically tablets or capsules, containing (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol or a physiologically acceptable salt or solvate thereof, or a solvate of said salt, and an effective stabilizing amount of alginic acid. These dosage forms are useful for preventing or treating attention deficit hyperkinetic disorder or depression, or in the treatment of addiction to nicotine-containing products, especially tobacco-containing products, such as aiding in smoking cessation.

Description

(57)

This solution provides separate oral dosage forms, typically tablets or capsules, containing (2S, 3S, 5R) -2- (3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol, or a physiologically acceptable salt or solvate, or solvate thereof said salts, and an effective stabilizing amount of alginic acid. These dosage forms are suitable for the prevention or treatment of attention deficit hyperactivity disorder or depression, and / or for the treatment of affection for nicotine-containing products, particularly tobacco-containing products, such as smoking cessation aid.

CZ 2001 - 1142 A3

Dosage form for oral administration

Technical field

The invention relates to separate oral dosage forms such as tablets and capsules comprising (2S, 3S, 5R) -2- (3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol (active agent), or salts or solvates.

BACKGROUND OF THE INVENTION

The compound (2S, 3S, 5R) -2- (3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol is most typically prepared and isolated as the hydrochloride salt, which may be depicted as follows:

H ₃ C

HCl

F

This compound, together with certain pharmaceutical products prepared therefrom, is described in U.S. Patent 5,104,870 (Kelley et al.). WO99 / 253 55 discloses the use of this compound for the treatment of dependence on nicotine-containing products and especially tobacco products.

Alginic acid is described in the Handbook of Pharmaceutical Excipients, pages 10-11 (American Pharmaceutical Association 2nd Edition, 1994).

Briefly, in one aspect, the present invention provides a separate oral dosage form comprising a therapeutically active amount of (2S, 3S, 5R) -2- (3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol, or a

-2 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · A pharmaceutically acceptable salt or solvate or solvate of said salt, and an effective stabilizing amount of alginic caseline.

In another aspect, the present invention provides a method of preventing or treating a hyperkinetic disorder of attention deficit or depression.

Depressive conditions for which the separate oral dosage form of the invention is particularly useful are those classified as affective disorders in the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition, American Psychiatry Association, Washington D.C. (1987) (DSM-III-R), including mood disorders (DSM-III-R, 296.2X to 296.6X), other specific affective disorders (301.13 and 300.40), and bipolar and depressive disorders not otherwise specified (296.70 and 311.00).

In another aspect, the present invention provides a method of treating dependence on nicotine-containing products, particularly tobacco-containing products, the method comprising administering a separate oral dosage form of the invention.

In another aspect, the present invention provides the use of a separate oral dosage form as defined above for the preparation of a medicament for the treatment of dependence on nicotine-containing products, and in particular tobacco-containing products.

Nicotine-containing products will include tobacco products (e.g., cigarettes, cigars, pipe tobacco, chewing tobacco, and the like) and tobacco replacement products such as nicotine gums, sprays, patches and inhalers and the like. Treatment of dependence on such nicotine-containing products includes both partial and total alleviation. Thus, with respect to tobacco products, as well as to cessation of activity, such as smoking, treatment will also include reducing the level or frequency of such activity, such as reducing the number of cigarettes smoked in a given period of time. Due to others

For products containing nicotine, treatment will also include both abandoning the use of such products and reducing their levels of use.

In another aspect, the present invention provides a method of treating other conditions set forth in U.S. Patent No. 5,104,870, comprising administering a separate oral dosage form as defined above. Such conditions include the following, with DSM-III-R approved classifications (where listed): anxiety disorders including phobic neuroses (300.00, 300.21, 300.22, 300.23 and 300.29), anxiety disorders (300.01, 300.02 and 300.30) ) and post-traumatic stress disorder (309.89); attention deficit disorders (314.00 and 314.01); eating disorders including anorexia (307.10) and bulimia (307.51); personality disorders including borderline personality disorder (301.83); sexual dysfunction including hypoactive sexual desire disorder (302.71), female sexual arousal disorder or male erective disorder (302.72), inhibited female orgasm (302.73), inhibited male orgasm (302.74), premature ejaculation (302.75), intercourse pain (302.76), vaginism (306.51) and otherwise unspecified sexual dysfunction (302.70); headache including migraine, muscle contractions and mixed (ie, a combination of migraine and muscle contractions) headache; and narcolepsy-cataplexy syndrome, a condition characterized by excessive sleepiness (narcolepsy), often in the form of sleep seizures, episodes of a seemingly irresistible need to sleep, usually lasting about 15 minutes or less, along with short periods (lasting often less than a minute) of muscle loss (cataplexy) ) in conjunction with the expression of excitement.

In a preferred aspect, the present invention provides a method of preventing or treating a hyperkinetic attention deficit disorder comprising administering a separate oral dosage form of the invention.

In another preferred aspect, the present invention provides the use of a separate oral dosage form as defined above in the manufacture of a medicament for the prevention or treatment of a hyperkinetic attention deficit disorder.

In another aspect, the separate oral dosage form may further be used in human medicine: to alleviate withdrawal symptoms resulting from the cessation of illicit drug abuse; to enhance analgesia induced by morphine or a similar opioid analgesic, for example in the treatment and care of end-stage cancer patients; for the prevention of functional impairment and drowsiness after administration of a sleep-inducing benzodiazepine tranquilizer - suitable indications for concomitant administration of said compound or salt thereof and such benzodiazepine include: (a) treating mixed anxiety and depression in situations where functional weakness or apathy is undesirable; in situations where functional weakness or inertia are undesirable; to prevent memory loss following administration of a benzodiazepine soothing agent; to restore mental function acutely impaired as a result of ethanol ingestion; for suppressing the release or secretion of prolactin, for example in suppressing lactation of post parts or in treating spontaneous milk outflow (galactorrhoea), excessive milk excretion, amenorrhea from excessive milk excretion, and prolactin-sensitive breast cancer; or to treat memory loss and other memory deficiencies associated with benign senility.

The separate oral dosage form of the invention is typically a tablet or capsule and can be manufactured by standard procedures. For example, a tablet of the invention may be made by wet granulation or direct compression.

The separate oral dosage form of the invention comprises a therapeutically effective amount of the active agent, or a physiologically acceptable salt thereof, or a solvate thereof, or a solvate of said salt. In general, the amount required to be therapeutically effective is calculated based on the weight of the active agent itself and not on any attached counterions or solvent. For example, the active agent is typically produced in the form of its hydrochloride salt, but the amount required is usually based on the amount of active agent excluding the weight of concomitant HCl.

The active agent (2S, 3S, 5R) -2- (3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol, like its hydrochloride salt, is known and can be produced by known techniques, in particular according to as described in U.S. Patent No. 5,104,870 to Kelley et al.

The discrete oral dosage form of the invention generally comprises at least 0.1 mg of active agent, or a salt or solvate thereof, in an amount calculated to provide at least 0.1 mg of active agent.

In general, the discrete oral dosage form of the present invention comprises at least 0.1 wt. % alginic acid based on the total weight of the tablet or capsule, preferably at least 2% by weight, and most preferably at least 5% by weight. alginic acid. A particularly preferred form of alginic acid is alginic acid of national pharmacopoeial quality.

As used herein, the terms% by weight,% by weight,% by weight. or% w / w. or similar percentages by weight based on the total weight of the composition. Unless otherwise indicated, the percentages given herein are by weight based on the total weight of the separate oral dosage form.

Alginic acid can be obtained from any suitable source, such as from Mendell. Generally, the molecular weight is not a critical parameter, but is typically in the range of 20,000 to 200,000. A typical pH of alginic acid is 1.5 to 3.5 for a 3% (w / v) aqueous dispersion.

The discrete oral dosage form of the invention preferably further comprises standard additives such as a binder, filler, lubricant, disintegrant or glidant. The separate oral dosage forms of the invention may also contain other stabilizers in addition to alginic acid.

The filler, sometimes referred to as a carrier, may be any suitable filler. Preferably, the filler is selected from the group consisting of mannitol, sucrose, lactose and microcrystalline cellulose fillers: Most preferred is lactose, and in particular its monohydrate. The separate oral dosage forms preferably contain 40 to 95 wt. % and more preferably 55 to 90 wt. % filler.

The separate oral dosage forms of the invention preferably contain from 1 to 10 percent of a disintegrant, which may be any suitable disintegrant. Preferred disintegrants are glucopyranose compounds. Suitable glucopyranose compounds are typically poly- or poly-3-glucopyranose compounds in which some of the hydroxyl groups have been converted to carboxyalkyl ether groups (e.g., carboxymethyl-). Some of the carboxyalkyl ether groups may be in the form of a pharmaceutically acceptable salt (eg, sodium salt). The glucopyranose compound is preferably sodium starch glycolate. Sodium starch glycolate is described in Handbook of Pharmaceutical Excipients ”at pages 462-466 (American Pharmaceutical Association, 2nd Edition, 1994). The glucopyranose compound is preferably in the form of a low pH glucopyranose compound. Low pH is generally understood to mean that a 3.3% aqueous dispersion of a compound exhibits a pH of from 1 to 5. The molecular weight is not critical, but is typically in the range of 500,000 to 1,000,000. An example of a suitably low pH compound is available as EXPLOTAB® LOW pH from Mendell (Penwest Company, 2981 Route 22, Patterson, NY, USA 12563-9970). See also EXPLOTAB® LOW pH Sodium Starch Glycolate Product Brochure (Mendell 1996). Other suitable glucopyranose compounds including low pH sodium croscarmellose see, for example, in the Handbook of Pharmaceutical Excipients on page 141.

The separate oral dosage forms of the invention preferably contain 0.1 to 5 percent of a lubricant, a lubricant. Lubricants that can be used in the practice of the present invention include, but are not limited to, glyceryl behenate, magnesium stearate, and stearic acid. Glyceryl behenate and magnesium staerate are preferred. Magnesium stearate is particularly preferred.

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- 4 ··· 4 ·····

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The separate oral dosage form can be manufactured by any suitable pharmaceutical method, including the step of associating the active agent, alginic acid and any other ingredients. Typically, a filler or carrier is used and is first mixed with alginic acid and with one or more optional ingredients such as a lubricant, stabilizer and / or disintegrant. In general, the compositions of the invention are prepared by uniformly and intimately mixing the hydrochloride salt of the active agent with a solid particulate carrier, alginic acid and optionally added ingredients and then, if desired, shaping the resulting mixture. For example, a tablet may be made by compressing or forming a powder or granules containing the active compound, with one or more of the active ingredients. Compressed tablets may be made in a suitable machine by compressing the compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersing agent (s). Molded tablets may be made by molding a powdered compound moistened with an inert liquid binder in a mold on a suitable machine. Capsules can be made by filling a two-piece hard gelatin capsule with an active agent, a carrier, and excipients.

The oral dosage forms of the present invention are useful as antidepressants for the prevention or treatment of depression, obesity and attention deficit disorder, or for helping to quit smoking in subjects, particularly people in need thereof and for all purposes described in U.S. Patent No. 5,104 870.

The present invention is illustrated by the following working examples, where NF stands for National Formulas Grade and mg is milligrams.

DETAILED DESCRIPTION OF THE INVENTION

The hydrochloride salt of the active agent may be prepared as described in U.S. Patent No. 5,104,870.

• φ · φ · · φ φ φ φ φ φ · · · · · · · · · · · · · · · ·

- 8φ · φφ φφ φφ φφ φφφ

The active agent, (2S, 3S, 5R) -2- (3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol, is unstable in the presence of conventional additives used in the manufacture of oral dosage forms. The rate of decomposition of the active agent may be unacceptably high. Stability was determined by measuring (analyzing) the amount by weight of the active ingredient and the amount of impurities by the amount of area% in the analysis using HPLC. The weight% remaining active ingredient is reported as% label claim or LC. Instability is generally expressed by measurement values less than 90% of the labeled part and 3% or higher impurity levels. The compositions will preferably be stable for more than 3 months and more preferably for more than 6 months.

Comparative Example C1

Tablets containing equivalent to 1 mg of active agent were prepared. The hydrochloride salt as an active agent was weighed to give a calculated amount of 1 mg free base per tablet. Tablets were made by sieving each ingredient, except for magnesium stearate and silica, with a 20 mesh mesh screen. The sieved ingredients were added to a V-jacketed mixer and mixed for 15 minutes. Magnesium stearate and silica were passed through a 20 mesh mesh screen and added to the same mixer. The contents of the mixer were mixed for an additional 5 minutes. The mixture was compressed in a rotary tablet press, supplemented with a 8.6 mm round tool, scoring the top surface and smoothing the bottom, at about 250 mg per tablet. The composition of the tablets is summarized below in Table 1.

Table 1

component % in tablet, wt. active agent, HCl 0.463 anhydrous lactose 76.9 microcrystalline cellulose PH 102 20.0

-9 0 9 9 9 9 9 9 9 9

9 9 9 9 9 9 99 ♦ 99 00 »00 09 * 0 000 00 9 9 9 ·

0 0 »00 ·· 00 • 0 00 00 00 00

0

magnesium stearate 0.400 crospovidone 2,0 silica 0.200

The tablets were tested for% of label and impurities immediately and after 1 month under three different conditions: at 30 ° C, at 40 ° C and 75% relative humidity and at 50 ° C. The results of the stability determination are shown in Table 2 below.

Table 2

test moment % of the label,% wt. total impurities,% area initial 95.7 1.9 Deň: 29 ° C 90.8 6.5 40 ° C / 75% Rt. humidity 76.5 17.7 Deň: 32 ° C 78.8 15.0

The data show that the stability of these tablets is satisfactory.

Comparative Examples C2 and C3

Tablets containing 1.25 mg of active agent were prepared as in Comparative Example C1 except that stearic acid and sodium starch glycolate were used as a lubricant and disintegrant, and Comparative Example C2 contained 4.8 wt. % of ascorbic acid and Comparative Example C3 contained 4.8 wt. citric acid. In theory, the pH and / or antioxidant effects of these carboxylic acids should stabilize the compositions. The results of the stability determination are given in Table 3 below.

- 10λ ·· · * · ♦ ▼? · «♦ ί: ·:

·· · * ··

Table 3

test moment cf. Example C2 cf. Example C3 marked part, % wt. total impurities% area marked part, % wt. total impurities % areas initial 85.2 2.96 90.1 2.89

As shown by the data, the stability at the initial time of testing was so low that there was no need to store the tablets under faster disintegration conditions. These mixtures were currently less stable than those without carboxylic acid.

Examples 1 to 4

Tablets were prepared containing 4 different amounts of the active agent. The HCl salt active agent was weighed to give 0.25 mg, 0.5 mg, 1.25 mg, and 5 mg of active agent per tablet in Examples 1-4, when converted from the active agent salt to the active agent. Each tablet contained 5 wt. alginic acid.

The hydrochloride salt of the active agent (HCl salt of the active agent) was first passed through a 30 mesh 30.4 mesh US mesh screen to remove any larger clusters. Thereafter, the HCl salt of the active agent was ground in a 0.5 mm spin mill.

The required amount of ground HCl salt of the active agent was then sieved on a 14 mesh mesh 14.4 mesh (14 mesh US Standard) vibration screen. The HCl salt of the active agent was then filled into a V-mixer. A blender of 0.141 m (5 cubic feet) was used to produce tablets containing 1.25 mg of active α agent, while a blender of ··· was used to produce tablets containing 0.25 mg and 0.5 mg of active agent.

-11 ♦ · content 0.084 m ³ (3 cubic feet). A blender containing 0.0283 m ³ (1 cubic foot) was used to make tablets containing 5 mg of active agent. The required amounts of modified spray dried lactose monohydrate, low pH alginic acid and sodium starch glycolate were also passed through a 14 mesh mesh 14.4 mesh US mesh vibration screen and added to mixers. The V-mixer was rotated for 20 minutes. The correct amount of glyceryl behenate was sieved on a vibratory screen supplemented with 14 mesh stainless steel mesh and added to the blender. It was then rotated for another 5 minutes.

Tablets containing the HCl salt of the active agent were compressed on a rotary tablet press. For compression, a round tool with a diameter of 5 mm, with a straight face, was standardly concave. The target compressed weight was 75 mg. Finally, dust was removed from the tablets. The composition of the tablets is summarized in Table 4 below.

Table 4

component Example 1 Example 2 Example 3 Example 4 active agent per tablet (mg) 0.25 0.5 1,25 5.0 ground HCl salt act. Reagents (wt.%) 0.383 0,767 1.92 7.67 lactose monohydrate, NF, dried mod. Spray (% wt) 87.61 87.23 86.08 80.33 alginic acid, NF, (wt.%) 5 5 5 5 sodium starch glycolate, NF, low pH (% w / w) 5 5 5 5 glyceryl behenate, NF, (wt%) 2 2 2 2

Tablet stability was evaluated under three different conditions, at 25 ° C

60% relative humidity (RH), at 40 ° C at 75% RH and at 50 ° C at ambient humidity · 4 4 «44 44

4 4 4 445 4

4,444 4 4,444 4 4

44,444 44,444 4 «444 4444 · 4

43 4 «43 44 4

- 12 (ΑΜΗ). The results of the stability determination are summarized below in Table 5. Data for the labeled part, L.C. are given in% by weight in Table 5 and data for total impurities are given in% area.

Table 5

Example 1 Example 2 Example 3 Example 4 25 ° C, 60% RH tot. impurities L.C. tot. impurities L.C. tot. impurities L.C. tot. impurities L.C. the beginning of the ratings. 0.53 99.0 0.44 100.0 0.27 98.0 0.18 98.0 1 month 0.73 98.9 NT NT 0.29 98.5 0.18 98.3 3 months 0.68 98.9 NT NT 0.30 98.5 0.25 98.3 5 months NT NT NT NT 0.21 97.8 0.19 98.1 6 months 0.46 99.1 NT NT 0.25 97.3 0.24 98.7 9 months 0.45 96.9 NT NT 0.20 97.4 0.18 97.4 40 ° C, 75% RH the beginning of the ratings. 0.53 99.0 0.44 100.0 0.27 98.0 0.18 98.0 1 month 0.31 98.5 NT NT 0.19 97.5 0.15 97.2 3 months 0.28 97.9 NT NT 0.21 97.7 0.25 99.7 6 months 0.20 99.3 NT NT 0.30 98.2 0.16 97.7 50 [deg.] C., AMH the beginning of the ratings. 0.53 99.0 0.44 100.0 0.27 98.0 0.18 98.0 1 měcíc 0.28 97.7 NT NT 0.18 96.8 0.47 98.9 3 months 0.22 97.7 NT NT 0.19 98.2 0.20 98.4

NT = Not tested

The data show that alginic acid stabilizes the HCl salt of the active agent in these tablets at different active agent strengths and under different temperature and humidity conditions.

- 13 · · · · · · <* * * * * * * * * * * * * * * * * * * * * * 13 ♦ * · «99 99 99 99 99 99 99 999

Examples 5 and 6

Tablets containing 2 different amounts of active agent were prepared.

The HCl salt active agent was weighed to give 0.25 mg and 0.5 mg of active agent per tablet in Examples 5 and 6, respectively. Each tablet contained 10 wt. alginic acid.

The tablets were made as in Examples 1-4, except that they were film coated using standard techniques. The thin film coating was Opadry, White, YS-1-18034 (a patented polymer, plasticizer, or even pigment in the form of a dry concentrate).

The tablet weight was 75 mg. The tablet composition is summarized below in Table 6.

Table 6

component Example 5 Example 6 active agent per tablet (mg) 1,25 5 ground HCl salt act. Reagents (wt.%) 0.383 7.66 lactose monohydrate, NT, dried modifier. Spray (% wt) 87.61 80.84 alginic acid, NF, (wt.%) 10 10 glyceryl behenate, NF, (wt%) 2 1.5

The stability of the tablets was evaluated at baseline, after 2 weeks and after 1 month, at 40 ° C and 75% RH. Both tablets (with different amounts of active substance) were packed in foil / foil blisters. Stability was evaluated by determining the level of total impurities and active agent content in both types of tablets. The results of the stability determination are summarized below in Table 7, data for the labeled part, L.C. are given in% by weight in Table 7 and data for total impurities are given in% by area.

··> 4 ·· ·· • 9 · • · · · • 9 · t · • 9 • · ·· • «999 • · 9 9 · · · · »« · 9 · 99 9

Table 7

Example 5 Example 6 40 ° C, 75% RH total impurities L.C. total impurities L.C. start of evaluation 0.21 107 0.19 100 ALIGN! 2 weeks 0.60 110 0.26 99 1 month 1.48 105 0.33 99

Examples 7 and 8

Tablets containing 2 different amounts of active agent were prepared. The HCl salt active agent was weighed to give 10 mg and 5 mg of active agent per tablet in Examples 7 and 8, respectively. Each of the tablets contained

2.5 wt. alginic acid.

The tablets were made as in Examples 1-4, except that the diameter was increased to 6.5 mm and the tablet weight was increased to 150 mg for Example 7 and 135 mg for Example 8. The tablets were not film coated. The tablet composition is summarized below in Table 8.

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Table 8

component Example 7 Example 8 active agent per tablet (mg) 10 5 ground HCl salt act. Reagents (wt.%) 7.66 4.26 lactose monohydrate, NF, spray-dried (% w / w) 83.84 57.74 microcrystalline. cellulose PH 113, NF, (wt.%) 0 30 algmic acid, NF, (wt.%) 2 5 2.5 sodium starch glycolate, NF, low pH (wt.%) 5 5 magnesium stearate, NF, (wt.%) 1 0.5

The tablets were stored in open and closed vials to determine stability in both arrangements. The results of the stability determination are summarized below in Table 9, data for the labeled part, L.C. are given in% by weight and data for total impurities are given in% by area.

Table 9

Example 7, open. bottle Example 7, cl. bottle Example 8, open. bottle Example 8, cl. bottle 40 ° C 75% RH tot. impurities L.C. tot. impurities L.C. tot. impurities L.C. tot. impurities L.C. beginning of values 0.39 100.1 0.39 100.1 0.51 98.0 0.51 99.7 2 weeks 0.34 99.3 0.44 99.3 0.36 98.5 0.48 100.0 1 month 0.31 99.9 0.45 99.8 0.35 98.5 0.53 97.8 3 months 0.35 98.9 0.46 99.7 0.37 97.8 0.64 98.8

- 16 · ♦ ·· ·· ·· φφ · ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 99 · * 99 ·· φφφ

Examples 9 and 10

Tablets containing 2 different amounts of microcrystalline cellulose were prepared. The HCl salt active agent was weighed to give 7.5 mg of the active agent per tablet in Examples 10. Each tablet contained 5 wt. alginic acid.

The tablets were made as above, the tablet diameter was

6.5 mm and weight 135 mg. The tablets were not film coated. The composition of the tablets is summarized below in Table 10.

Table 10

component. Example 9 Example 10 active agent per tablet (mg) 7.5 7.5 ground HCl salt act. Reagents (wt.%) 6.39 6.39 lactose monohydrate, NF, spray-dried (% w / w) 78.11 73.11 microcrystalline. cellulose PH 102 NF, (wt.%) 5 10 alginic acid, NF, (wt.%) 5 5 sodium starch glycolate, NF, low pH (wt.%) 5 5 magnesium stearate, NF, (wt.%) 0.5 0.5

The tablets were stored in open and closed vials to determine stability in both arrangements. The results of the stability determination are summarized below in Table 11, data for labeled part, L.C. are given in% by weight and data for total impurities are given in% by area.

Φ ♦ ♦ · ·· · «·· φ

Φφφφ φφφ. φ φ · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Table 11

Example 9, open. bottle Example 9, cl. bottle Example 10, open. bottle Example 10 zavř. bottle 40 ° C 75% RH tot. impurities L.C. tot. impurities L.C. tot. impurities L.C. tot. impurities L.C. beginning of values 0.04 100.9 0.04 100.9 0.06 98.9 0.06 98.9 1 month 0.05 100.0 0.08 100.4 0.05 97.3 0.07 98.7 3 months 0.12 99.5 0.13 100.6 0.14 98.8 0.19 98.5

Examples 11 and 12

Tablets containing 2 different amounts of microcrystalline cellulose were prepared. The HCl salt active agent was weighed to give 1.25 mg of active agent per tablet in both Examples 11 and 12. Each tablet contained 5 wt. alginic acid.

The tablets were made as above, the diameter of the tablets was

6.5 mm and weight 135 mg. The tablets were not film coated. The tablet composition is summarized below in Table 12.

Table 12

component Example 11 Example 12 active agent per tablet (mg) 1,25 1,25 ground HCl salt act. Reagents (wt.%) 1.06 1.06 lactose monohydrate, NF, spray-dried (% w / w) 83.44 78.44 microcrystalline. cellulose PH 102 NF, (wt.%) 5 10

- 18 · · 18 18 18 · · · ·

alginic acid, NF, (wt.%) 5 5 sodium starch glycolate, NF, low pH (wt.%) 5 5 magnesium stearate, NF, (wt.%) 0.5 0.5

The tablets were stored in open and closed vials to determine stability in both arrangements. The results of the stability determination are summarized below in Table 13, data for the labeled part, L.C. are given in% by weight and data for total impurities are given in% by area.

Table 13

Example 11, open bottle. Example 11, closed bottle. Example 12, open bottle. Example 12, bottle closed. 40 ° C 75% RH tot. impurities L.C. tot. impurities L.C. tot. impurities L.C. tot. impurities L.C. beginning of values 0.05 980, 0.05 98.0 0.05 98.8 0.05 98.8 1 month 0.04 99.3 0.19 98.3 0.06 99.8 0.16 98.4 3 months 0.10 98.2 0.28 97.6 0.11 96.3 0.32 98.6

The foregoing Examples are illustrative of the present invention and are not to be construed as limiting the invention. The invention is defined by the following claims, the equivalents of which are incorporated herein.

Claims (23)

PATENT CLAIMS A separate oral dosage form comprising a therapeutically effective amount of (2S, 3S, 5R) -2- (3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol or a physiologically acceptable salt or solvate thereof , or a solvate of said salt, and an effective stabilizing amount of alginic acid. A separate oral dosage form according to claim 1, wherein said salt is the hydrochloride salt. A separate oral dosage form according to claim 1 or 2, wherein said therapeutically effective amount is at least 0.25 mg. A separate oral dosage form according to any one of claims 1 to 3, characterized in that it comprises at least 0.2 wt. alginic acid. 5. A separate oral drug knows algin. A mold according to any one of claims 1 to 3 comprising at least 2 wt. acid 6. Separate oral drug designation of alginic. A mold according to any one of claims 1 to 3 comprising at least 5 wt. % acid form according to any one of claims 1 to 6, further comprising 40 to 95 wt. fillers. 7. Separate drug A separate oral dosage form according to claim 7, wherein said filler is selected from the group consisting of mannitol, sucrose, lactose and microcrystalline cellulose. • And ti 9 9 9 9 9 9 9 9 9 -20-. A separate oral dosage form according to any one of claims 1 to 8, further comprising 0.1 to 5 wt. lubricants. A separate oral dosage form according to claim 9, wherein said lubricant is selected from the group consisting of glyceryl behenate, magnesium stearate and stearic acid. A separate oral dosage form according to any one of claims 1 to 10, further comprising 1 to 10 percent of a low pH poly-α-glucopyranose or poly-β-glucopyranose compound. A separate oral dosage form according to claim 11, wherein said glucopyranose compound is a low pH sodium starch glycolate. A separate oral dosage form according to claim 1 comprising 0.1 to 25 mg of (2S, 3S, 5R) -2- (3,5-difluorophenyl) -3,5-dimethyl-2 hydrochloride. % morpholinol, 40 to 95 wt. 0.1 to 15 percent by weight of a filler, 0.1 to 15 percent of a low pH poly-.alpha.-glucopyranose or poly-.beta.-glucopyranose compound in which some hydroxy groups have been converted to carboxyalkyl ethers; lubricants. A separate oral dosage form according to any one of claims 1 to 13, wherein the form is a tablet. A separate oral dosage form according to claim 14, wherein said tablet is a film coated tablet. 4 · • 4 4 « • 4 44 4 • · • • 4 4 4 «4 • 4 • · 4 · 4 · 444 4 · 4 • · • 4 4 4 4 • 4 • 4 · • • · • 4 4 · • 4 • 4 • • 4 44 44 4 4 • 4 • 4 A separate oral dosage form according to any one of claims 1 to 13, wherein the form is a capsule. A separate oral dosage form according to any one of claims 1 to 16 for use in therapy. A method of preventing or treating a hyperkinetic disorder of attention deficit or depression, comprising administering a separate oral dosage form according to any one of claims 1 to 16. Use of a separate oral dosage form according to any one of claims 1 to 16 for the preparation of a medicament for the prevention or treatment of hyperkinetic attention deficit disorder or depression. A method of treating affection for nicotine-containing products, comprising administering a separate oral dosage form according to any one of claims 1 to 16. The method of claim 20, wherein the nicotine-containing product is a tobacco-containing product. Use of a separate oral dosage form according to any one of claims 1 to 16 for the preparation of a medicament for the treatment of affection for nicotine-containing products. Use according to claim 22, characterized in that the nicotine-containing product is a tobacco-containing product.