WO2005044255A1

WO2005044255A1 - Stabilized pharmaceutical compositions

Info

Publication number: WO2005044255A1
Application number: PCT/EP2004/012558
Authority: WO
Inventors: Mark Robert Mecadon; Qin Ji; Abu T. M. Serajuddin; Erika Aina Zannou
Original assignee: Novartis Ag; Novartis Pharma Gmbh
Priority date: 2003-11-06
Filing date: 2004-11-05
Publication date: 2005-05-19
Also published as: AR046320A1; PE20050487A1; TW200529817A

Abstract

A composition comprising a dibenzo-oxepine and an acidulant in an amount effective for stabilization.

Description

Stabilized Pharmaceutical Compositions

The present invention relates to stabilized pharmaceutical compositions, e.g. to the stabilization of pharmaceutically active dibenzo-oxepines in pharmaceutical compositions.

A pharmaceutical composition should ensure high and reproducible stability over a long period. Dibenzo-oxepines which show pharmaceutical activity, e.g. anti-neurodegenerative activity, may be prone to certain types of degradation, e.g. when formulated in pharmaceutical compositions. We have now surprisingly found that dibenzo-oxepines in compositions can be stabilized, e.g. prevented from degradation.

In one aspect the present invention provides a composition, e.g. a pharmaceutical composition, comprising a dibenzo-oxepine, e.g. as an active ingredient, and an acidulant in an amount effective for stabilization, e.g. in an amount effective to decrease or prevent the extent of dibenzo-oxepine degradation, e.g. in comparison with a composition which lacks the presence of an acidulant.

A dibenzo-oxepine comprised in a composition of the present invention is herein also designated as "dibenzo-oxepine of (according to) the present invention".

Dibenzo-oxepines of the present invention include pharmaceutically active dibenzo-oxepines. Pharmaceutically active dibenzo-oxepines of the present invention include e.g. compounds as described in GB1479241 , GB1098347, US3100207, US3928383, GB1449297, US3641056, GB1302624, GB1237386, EP726265, WO9745422. Preferably dibenzo- oxepines of the present invention include 10-aminoaliphatyl-dibenz(b,f)oxepins, such as 10- amino-(Ci.₄)alkylene-dibenz(b,f)oxepins, e.g. as described in EP726265 or WO9745422. Dibenzo-oxepines as described in EP726265 and WO9745422 include a compound of formula

wherein a. alk is a divalent aliphatic radical,

R is an amino group that is unsubstituted or mono- or di-substituted by monovalent aliphatic and/or araliphatic radicals or disubstituted by divalent aliphatic, araliphatic or heteroarylaliphatic radicals, and R-i, R₂, R3, and R independently of each other are hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, e.g. wherein lower alkyl includes

and lower alkoxy includes (C-ι^)alkoxy, b. alk is a divalent aliphatic radical,

R is an amino group that is unsubstituted or mono- or di-substituted by monovalent aliphatic and/or araliphatic radicals or disubstituted by divalent aliphatic radicals, and

Rι, R₂, R₃, and R₄ independently of each other are hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, e.g. wherein lower alkyl includes (Cι.₄)alkyl and lower alkoxy includes (Cι- )alkoxy,

R is amino; which amino is unsubstituted or mono or disubstituted, by an aliphatic, e.g.

(Cι.₈)aliphatic, or araliphatic, e.g. ary d^aliphatic, such as pheny C^aliphatic, group, and

Rι. R2. R3, and R4 independently of each other are hydrogen, (C_1- )alkyl, (C )alkoxy, halogen or trifluoromethyl, d. alk is methylene,

R is selected from the group consisting of

- amino,

- phenyl-(Cm)alkylamino, unsubstituted or substituted by (C^alkyl, (C_1-4)alkoxy, halogen or trifluoromethyl, - N-phenyl-(C_1- )alkyl-N-(Cι_-4)alkylamino, unsubstituted or substituted by (C_1-4)alkyl, (C-..

₄)alkoxy, halogen or trifluoromethyl, or

- (C_2-7)alkenylamino, (C₂.₇)alkynylamino, N-(C_2-7)alkenyl-N-(Cι_-4)alkylamino or N-(C_2- ₇)alkynyl-N-(Cι.₄)alkylamino, and

Rι, R21 R3, and R independently of each other are hydrogen, (C_M)alkyl, (C_1- )alkoxy, halogen or trifluoromethyl, and e. alk is a divalent aliphatic radical,

R is an amino group that is mono or di-substituted by monovalent aliphatic groups at least one monovalent radical being a substituted or unsubstituted lower alkynyl group, and R-i, R₂, R₃, and R₄ independently of each other are hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, e.g. wherein lower alkyl includes (C_1-4)alkyl and lower alkoxy includes (C_1-4)alkoxy, such as the compound N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine of formula

A dibenzo-oxepine of the present invention includes a dibenzo-oxepine in any form, e.g. in free form, in the form of a salt, in the form of a solvate and in the form of a salt and a solvate.

A salt includes a metal salt or an acid addition salt, preferably an acid addition salt. Acid addition salts include salts of a dibenzo-oxepine with inorganic or organic acids. Salts of compounds of formula I are, for example, the pharmaceutically acceptable acid addition salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with pharmaceutically acceptable organic acids, such as

- optionally hydroxylated (Cι_-7)alkanoic acids, e.g. including acetic acid, propionic acid, pivalic acid, glycolic acid, pyroacemic acid, lactic acid, gluconic acid,

- optionally hydroxylated, aminated and/or oxo-substituted (C₂.₇)alkane dicarboxylic acids, e.g. including oxalic acid, malonic acid, succinic acid, glutamic acid, aspartic acid, tartaric acid, malic acid,

- optionally hydroxylated and/or oxo-substituted (C .₇)alkane tricarboxylic acids, e.g. including citric acid, aconitic acid,

- optionally hydroxylated and/or oxo-substituted (C₄.₇)alkene dicarboxylic acids, e.g. including fumaric acid, maleic acid, itaconic acid,

- optionally hydroxylated and/or oxo-substituted (C .₇)alkyne dicarboxylic acids, e.g. including acetylene dicarboxylic acid,

- benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, nicotinic acid, - aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, e.g. including methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamates (cyclamates).

Preferably a dibenzo-oxepine of the present invention is in the form of a salt, e.g. a compound of formula I, including a compound of formula la, is in the form of a salt with maleic acid (maleate).

A dibenzo-oxepine of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa. A dibenzo-oxepine of the present invention in free form or in the form of a salt and in the form of a solvate may be converted into a corresponding compound in free form or in the form of a salt in non- solvated form; and vice versa.

A dibenzo-oxepine of the present invention may exist in the form of pure isomers or mixtures thereof; e.g. optical isomers, diastereoisomers, cis/trans isomers. A dibenzo-oxepine of the present invention may e.g. contain asymmetric carbon atoms and may thus exist in the form of enantiomers or diastereoisomers and mixtures thereof, e.g. racemates.

Isomeric mixtures may be separated as appropriate, e.g. according, e.g. analogously, to a method as conventional, to obtain pure isomers. A dibenzo-oxepine of the present invention includes a dibenzo-oxepine in any isomeric form and in any isomeric mixture, e.g. also including tautomers, where tautomers can exist.

In another aspect the present invention provides a composition of the present invention wherein the dibenzo-oxepine is a compound of formula I, wherein alk, R, R_t, R₂, R₃ and R₄ are as defined above, e.g. a compound of formula la. optionally in the form of a salt, such as a salt with maleic acid, e.g. a compound of formula I in the form of a maleate.

A dibenzo-oxepine of the present invention may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional. A dibenzo-oxepine of the present invention may also be present in micronized form prepared e.g. according, e.g. analogously, to a method as conventional, such as e.g. reducing particle size by milling. ln another aspect the present invention provides a composition of the present invention wherein the dibenzo-oxepine, e.g. a compound of formula I, including a compound of formula la, is present in micronized form.

An appropriate acidulant useful in a composition of the present invention includes an organic carboxylic acid, e.g. including carboxylic acids such as disclosed above, preferably

- optionally hydroxylated, aminated and/or oxo-substituted (C₂.₇)alkane dicarboxylic acids, such as optionally hydroxylated (C_2-7)alkane dicarboxylic acids, e.g. including succinic acid, tartaric acid,

- optionally hydroxylated and/or oxo-substituted (C_4-7)alkane tricarboxylic acids, such as hydroxylated (C₄.₇)alkane tricarboxylic acids, e.g. including citric acid,

- optionally hydroxylated and/or oxo-substituted (C₄.₇)alkene dicarboxylic acids, such as (C_4- ₇)alkene dicarboxylic acids, e.g. including maleic acid, such as citric acid, maleic acid, tartaric acid and succinic acid, preferably citric acid.

In another aspect the present invention provides a composition of the present invention, wherein the acidulant is an organic carboxylic acid, e.g. citric acid.

in another aspect the present invention provides a composition of the present invention wherein the dibenzo-oxepine is a compound of formula la in the form of a salt with maleic acid and wherein the acidulant is citric acid.

In a composition of the present invention the amount of the dibenzo-oxepine of the present invention is as appropriate in a pharmaceutical composition, e.g. including

- from about 0.25% w/w to about 30% w/w, such as from 0.25% w/w to 30% w/w,

- from about 0.75% w/w to about 25% w/w, such as from 0.75% w/w to 25% w/w,

- from about 0.75% w/w to about 20% w/w, such as from 0.75% w/w to 20%, w/w

- from about 0.75% w/w to about 15% w/w, such as from 0.75% w/w to 15% w/w, based on the total weight of the composition.

In a composition of the present invention the amount of the acidulant is not critical, although the amount must be at least sufficient to stabilize, e.g. to decrease or prevent degradation, of a dibenzo-oxepine in a composition of the present invention, and is preferably at least around 0.5% w/w, such as 0.5% w/w, based on the total weight of the composition, e.g.

- from about 0.5% w/w to about 25% w/w, such as from 0.5%o w/w to 25% w/w,

- from about 1 % w/w to about 20% w/w, such as 1 % w/w to 20% w/w,

- from about 1% w/w to about 15% w/w, such as 1% w/w to 15% w/w,

- from about 1 % w/w to about 10% w/w, such as 1 % w/w to 10% w/w,

- from about 1 % w/w to about 5% w/w, such as 1 % w/w to 5% w/w, based on the total weight of the composition.

An appropriate stabilizing amount may be found by pre-testing.

The weight ratio of a dibenzo-oxepine of the present invention to the acidulant may be determined as conventional and includes a weight ratio of a dibenzo-oxepine of the present invention to the acidulant

- from about 5.5:1 to about 1:7, such as 5.5:1 to 1:7, - from about 2: 1 to about 1 :2, such as 2: 1 to 1 :2.

in another aspect the present invention provides a composition of the present invention wherein

- a dibenzo-oxepine of the present invention is present in an amount from about 0.25% w/w to about 30% w/w, %, based on the total weight of the composition; and/or

- the acidulant is present in an amount from about 0.5% to about 25%, based on the total weight of the composition; and/or

- the weight ratio of a dibenzo-oxepine of the present invention to the acidulant is from about 5.5:1 to about 1:7.

A composition of the present invention may further comprise appropriate excipient, e.g. including pharmaceutical excipient, such as appropriate carrier and/or diluent, which excipient is pharmaceutically acceptable. Such excipient must be compatible with the selected acidulant so as not to interfere with their stabilizing function of a dibenzo-oxepin of the present invention and e.g. includes

- lubricants, e.g., talc and alkaline earth metal stearates, such as magnesium stearate and calcium stearate and hydrogenated vegetable oils, such as hydrogenated cottonseed oil and hydrogenated castor oil;

- binders, such as polyvinylpyrrolidone and gelatin; - disintegrants, such as microcrystalline cellulose, cross-linked polyvinylpyrrolidone and alginic acid,

- fillers, flow conditioners, wetting agents and/or emuisifiers, water scavengers, buffers, preservatives, antioxidants, colorants, flavoring agents (fragrances), sugars and sweeteners, solubilizers, and/or salts for regulating osmotic pressure.

Interference of such excipient with the stabilizing function of the acidulant on a dibenzo- oxepin of the present invention may be determined in pre-testing. Generally, appropriate excipient includes compounds which do not contain groups which would significantly interfere with either a dibenzo-oxepin of the present invention, or the acidulant, and optionally the lubricant, as the stabilizing components. For example, sugars, such as lactose, sucrose, mannitol and sorbitol are quite suitable; as are starches, such as corn starch and tapioca starch; cellulose and derivatives thereof, such as sodium carboxymethyl cellulose and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate; sodium sulfate; and polyvinyl alcohol. Excipient may be present in a composition of the present invention in amounts from about 5% w/w to about 90% w/w, such as 5% w/w to 90% w/w, preferably from about 10% w/w to about 80% w/w, such as from 10% w/w to 80% w/w, based on the total weight of the pharmaceutical composition.

In another aspect the present invention provides a composition of the present invention, further comprising at least one pharmaceutical excipient.

It has surprisingly been found that the use of hydrogenated castor oil as a lubricant may optimize the stabilizing effect of the acidulant e.g. if hydrogenated castor oil as a lubricant is used in a composition of the present invention, the formation of oxidation degradation products of a dibenzo-oxepin upon processing and storage may be decreased.

In another aspect the present invention provides a composition of the present invention further comprising a lubricant, such as hydrogenated castor oil.

An appropriate amount of a lubricant in a composition of the present may be found by pretesting and includes an amount

- from about 0.5% w/w to about 10%) w/w, such as 0.5% w/w to 10% w/w , - from about 1 % w/w to about 5% w/w, such as 1 % w/w to 5% w/w, based on the total weight of the composition.

The total amount of optional excipient in a composition of the present invention is consistent with the amount of the dibenzo-oxepine of the present invention, the acidulant, optionally the lubricant and optionally a pharmaceutically acceptable carrier, i.e. the total amount will be equivalent to the remainder of the compositions.

In another aspect the present invention provides a composition of the present invention wherein the dibenzo-oxepine is a compound of formula la in the form of a salt with maleic acid, wherein the acidulant is citric acid, further comprising

- a lubricant, such as hydrogenated castor oil and/or

- a binder, and/or

- a disintegrant; e.g. further comprising fillers, flow conditioners, wetting agents and/or emulsifiers, water scavengers, buffers, preservatives, antioxidants, colorants, flavoring agents (fragrances), sugars and sweeteners, solubilizers, and/or salts for regulating osmotic pressure.

in a further aspect the present invention provides a composition comprising a compound of formula la, citric acid, mannitol, microcrystalline cellulose, polyvinylpyrrolidone and hydrogenated castor oil.

Although the dibenzo-oxepine containing compositions, including pharmaceutical compositions, of the present invention may be in any form, solid forms are preferred, such as tablets, capsules, pellets or sachets.

In a further aspect the present invention provides a composition of the present invention e.g. a pharmaceutical composition, in solid form, e.g. in the form of a tablet, capsule, pellet or sachets, optionally a coated tablet, such as e.g. a tablet coated with an hydroxypropyl methylcellulose (HPMC) coating.

A composition of the present invention may be prepared as appropriate, e.g. by any processing techniques, e.g. such as conventional. ln order to achieve homogenous distribution of the dibenzo-oxepine of the present invention and a homogenous distribution of the acidulant over or among the dibenzo-oxepine particles preferably wet granulation is used. Conveniently, the acidulant is used as a granulating liquid, e.g. in the form of an aqueous solution which is processed with the dibenzo-oxepine particles, e.g. in a high shear granulation process.

The granulated particles comprising the dibenzo-oxepine of the present invention and the acidulant may be further processed with appropriate excipient as appropriate, e.g. as conventional, e.g. by mixing, granulating, blending, coating, tableting or encapsulation processes, e.g. to obtain tablets, capsules, pellets or sachets.

In another aspect the present invention provides

- the use of an acidulant for stabilizing a dibenzo-oxepine in a composition, such as a pharmaceutical composition.

- a method for stabilizing a dibenzo-oxepine in a composition, such as a pharmaceutical composition comprising adding an acidulant in an amount effective for stabilization.

A composition of the present invention may be useful as a pharmaceutical, e.g. for the treatment of diseases for which dibenzo-oxepines of the present invention may be useful, e.g. including diseases for which dibenzo-oxepines are known to be useful. Such diseases include e.g. neurodegenerative disorders cerebral ischemia, glaucoma, Huntington's disease, Alzheimer^'s disease, Parkinson^'s disease, Amyotrophic Lateral Sclerosis, multiple sclerosis, retina degradation, such as e.g. retinitis pigmentosa, general or diabetic peripheral neuropathy, bipolar disorders and schizophrenia, preferably neurodegenerative diseases, such as e.g. Amyotrophic Lateral Sclerosis, Parkinson^'s disease and Alzheimer^'s disease. For pharmaceutical use a dibenzo-oxepine present in the composition of the present invention includes one or more, preferably one, dibenzo-oxepines, e.g. a combination of two or more dibenzo-oxepines.

In a further aspect the present invention provides a pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment of neurodegenerative disorders, cerebral ischemia, glaucoma, Huntington's disease, Alzheimer's disease, Parkinson^'s disease, Amyotrophic Lateral Sclerosis, multiple sclerosis, retina degradation, such as e.g. retinitis pigmentosa, general or diabetic peripheral neuropathy, bipolar disorders and schizophrenia, preferably for the treatment of a neurodegenerative disease, such as e.g. Amyotrophic Lateral Sclerosis, Parkinson's disease and Alzheimer^'s disease.

In a further aspect the present invention provides a method of treatment of neurodegenerative disorders, cerebral ischemia, glaucoma, Huntington's disease,

Alzheimer's disease, Parkinson^'s disease, Amyotrophic Lateral Sclerosis, multiple sclerosis, retina degradation, such as e.g. retinitis pigmentosa, general or diabetic peripheral neuropathy, bipolar disorders and schizophrenia, preferably for the treatment of a neurodegenerative disease, such as e.g. Amyotrophic Lateral Sclerosis, Parkinson's disease and Alzheimer^'s disease, comprising administering to a subject in need of such treatment a pharmaceutical composition of the present invention, in which composition the dibenzo- oxepine is present in an effective amount.

Treatment includes treatment and prophylaxis. For such treatment, the appropriate dosage will, of course, vary depending upon, for example, the chemical nature and the pharmacokinetic data of a dibenzo-oxepine of the present invention employed, the individual host, the mode of administration and the nature and severity of the conditions being treated. However, in general, for satisfactory results in larger mammals, for example humans, an indicated daily dosage is in the range from (about) 0.01 g to (about) 1.5 g, such as (about) 0.03 g to (about) 1.0 g of a compound present in a pharmaceutical composition of the present invention; conveniently administered, for example, in divided doses up to four times a day. As indicated above, dibenzo-oxepins of the present invention and their use in treating diseases, such as neurodegenerative diseases, is known and the mode of administration and appropriate dosages are documented in the literature.

A pharmaceutical composition of the present invention may be administered by any conventional route, for example enterally, e.g. including nasal, buccal, rectal, oral, administration; parenterally, e.g. including intravenous, intramuscular, subcutanous administration; or topically; e.g. including epicutaneous, intranasal, intratracheal administration; e.g. in form of coated or uncoated tablets, capsules, pellets or sachets; injectable solutions or suspensions, e.g. in the form of ampoules, vials, in the form of creams, gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops, sprays, or in the form of suppositories, preferably in solid form.

A pharmaceutical composition of the present invention may be administered in the form of a pharmaceutically acceptable salt, e.g. an acid addition salt or metal salt; or in free form; optionally in the form of a solvate. The dibenzo-oxepines of the present invention present in a composition or pharmaceutical composition of the present invention in the form of a salt exhibit the same order of activity as the dibenzo-oxepines present in a composition or pharmaceutical preparation of the present invention in free form; optionally in the form of a solvate.

A composition or pharmaceutical preparation of the present invention may be used for pharmaceutical treatment according to the present invention alone or in combination with one or more other pharmaceutically active agents.

Combinations include fixed combinations, in which two or more pharmaceutically active agents are in the same formulation; kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g. with instruction for co- administration; and free combinations in which the pharmaceutically active agents are packaged separately, but instruction for simultaneous or sequential administration are given.

The compositions of the present invention may have several advantages over compositions which do not contain an acidulant (and optionally a lubricant such as hydrogenated castor oil). Principally, the dibenzo-oxepine, such as a compound of formula la may be virtually preserved from any type of degradation. In addition a composition of the present invention

- may exhibit an extended shelf-life under normal storage conditions; - may be insensitive to moisture;

- may exhibit minimal, if any, discoloration over a significant period of time;

- may exhibit minimal, if any, instability when used in the presence of colorants.

In another aspect the present invention a method of stabilizing a pharmaceutical composition containing a dibenzo-oxepine compound subject to degradation comprising incorporating therein a stabilizing effective amount of an acidulant. ln another aspect the present invention provides a method of stabilizing a pharmaceutical composition containing a dibenzo-oxepine compound subject to degradation comprising incorporating therein a stabilizing effective amount of an acidulant, e.g. wherein the dibenzo-oxepine compound has the structural formula (I)

wherein alk is a divalent aliphatic radical;

R is an amino group that is mono- or di-substituted by a monovalent aliphatic radical, at least one of said monovalent radicals being an unsubstituted or substituted lower alkynyl group; and each of R-j, R₂, R₃ and R , independently, is hydrogen, lower alkyl, lower alkoxy, halo or trifluoromethyl; or a pharmaceutically acceptable salt.

The following examples illustrate the present invention.

Example 1 in TABLE 1 are listed the components of a composition in accordance with the present invention in tablet core form.

TABLE 1

Component Amount (mg) I

Compound of formula la in the form of a maleate, 3.55 micronized

Mannitol M 200 90.70

Microcrystalline cellulose 19.50

Polyvinylpyrroiidone K-30 2.60

Citric acid 2.60

*Purified water a.n.

Polyvinylpyrroiidone XL 5.20

Hydrogenated castor oil 5.85

TOTAL = 130.00 *Used to disperse the acidulant during the wet granulation process and is removed after fluid bed drying a.n. as necessary

For preparation of a tablet is carried out as follows: A compound of formula I in the form of a maleate and micronized by milling is pre-blended with mannitol, microcrystalline cellulose and polyvinylpyrroiidone K-30 in a high shear mixer so that a pre-blend is obtained. Citric acid is dissolved in H₂O and this solution is added is added to the pre-blend in a high shear mixer. The wet granulated product obtained is dried in a fluid bed dryer, granules obtained are sized via a suitable screen and the screened granulate is blended with polyvinylpyrroiidone XL a d hydrogenated castor oil. The granules obtained are compressed into tablets. The above composition has a total degradation of 0.56% at 40°C / 75% relative humidity for

180 days.

Example 2

The following compositions 2A and 2B in TABLE 2 represent compositions in accordance with the present invention in tablet core form (= not film coated), prepared according to the method as described in Example 1 , Composition 2C in TABLE 2 is prepared as described for compositions 2A and 2B, but does not contain an acidulant of the present invention.

TABLE 2

Amount (mg) Component 2A 2B 2C

Compound of formula (la) in the form of a maleate, 3.55 3.55 3.55 micronized

91.35 91.35 106.0

Mannitol M 200 0

Microcrystalline cellulose 19.50 19.50 21.00 Polyvinylpyrroiidone K-30 2.60 2.60 2.80 Citric acid 2.60 2.60 — *Purified water a.n. a.n. a.n. Polyvinylpyrroiidone XL 5.20 5.20 5.60 Magnesium stearate — 0.98 1.05 Hydrogenated castor oil 5.20 — —

^" 130.0 125.7 140.0 TOTAL = 0 8 0 *Used to disperse the acidulant during the wet granulation process and is removed after fluid bed drying.

Example 3

Tablets 2A, 2B and 2C of Example 2 are tablet cores stored for 3 months at 40°C and 75% relative humidity, the content in these compositions of a compound of formula la in the form of a maleate is determined at the beginning of storage and after three months by HPLC. The % assay and % of degradation of a compound of formula la in the tablet cores after 3 months are calculated. Results are set out in TABLE 3.

TABLE 3

2A 2B 2C

*Assay loss (%) 0.00 0.25 7.44

Total degradation (%) 0.13 0.60 1.51 *Difference between the content of the maleate salt of the compound of formula (la) at initial assay time zero and after 3 month as percentage From TABLE 3 it is evident that there is already about 7.5% assay loss after 3 months 40/75 from tablet cores 2C which does not contain an acidulant according to the present invention, whereas there is practically no degradation in case of tablet cores 2A and only a small amount of degradation in case of tablet 2B, which both are tablets according to the present invention. Furthermore from TABLE 3 it is evident that degradation during storage in case of tablet core 2C is more than ten-fold as in tablet core 2A and more than double as in tablet core 2B.

Example 4

In TABLE 4 are listed the components of a composition in accordance with the present invention in film coated tablet form prepared according to the method as described in Example 1 and then further processed by aqueous film coating with HPMC.

TABLE 4

Component Amount (mg)

Compound of formula (la) in the form of a maleate, 3.55 micronized

Mannitol M 200 90.70

Microcrystalline cellulose 19.50

Polyvinylpyrroiidone K-30 2.60

Citric acid 2.60

*Purified water a.n.

Polyvinylpyrroiidone XL 5.20

Hydrogenated castor oil 5.85

HPMC coating 6.00

TOTAL = 136.00

*Used to disperse the acidulant during the wet granulation process and is removed after fluid bed drying.

Example 5 The tablet of Example 4 is stored for 6 months at various temperatures and various relative humidity (RH) as set out in TABLE 5. The content of a compound of formula la in the form of a maleate in that tablet is determined at the beginning of storage and after 3 and 6 months by HPLC and the degradation of a compound of formula la in the tablet is calculated. Results are set out in TABLE 5.

TABLE 5

25°C / 60% RH 30°C / 70% RH 40°C / 75% RH

Period (months) DP DP DP

0 < 0.05 < 0.05 < 0.05

3 < 0.05 0.05 0.22

6 < 0.05 0.24 0.63

From TABLE 5 it is evident that, after 6 months a compound of formula la in the form of a maleate,

- under normal environmental conditions (25°C and 60% RH) is practically not degraded,

- at 30°C and 70% RH is only degraded to a small extent of below 0.3%, and

- at 40°C and 75% RH is still only degraded to an extent which is below 0.7%.

Claims

Patent claims

1. A composition comprising a dibenzo-oxepine and an acidulant in an amount effective to decrease or prevent the extent of dibenzo-oxepine degradation.

2. A composition of claim 1 wherein the dibenzo-oxepine is a compound of formula

wherein alk is a divalent aliphatic radical, R is an amino group that is unsubstituted or mono- or di-substituted by monovalent aliphatic and/or araliphatic radicals or disubstituted by divalent aliphatic, araliphatic or heteroarylaliphatic radicals, and

Rι, R₂, R₃, and R₄ independently of each other are hydrogen, (Cι^)alkyl, (C^alkoxy, halogen or trifluoromethyl.

A composition of any one of claims 1 or 2, wherein the dibenzo-oxepine is the compound N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine of formula

4. A composition of any one of claims 1 to 3, wherein the dibenzo-oxepine is in the form of a salt.

5. A composition of any one of claims 1 to 4, wherein the dibenzo-oxepine is in the form of a salt with maleic acid.

6. A composition of any one of claims 1 to 5, wherein the acidulant is an organic carboxylic acid.

7. A composition of any one of claims 1 to 6, wherein the acidulant is citric acid.

8. A composition of any one of claims 1 to 7, further comprising at least one pharmaceutical excipient.

9. A composition of claim 8, wherein the pharmaceutical excipient is hydrogenated castor oil.

10. A composition of any one of claims 1 to 9, which is a pharmaceutical composition, wherein the active ingredient is a benzo-oxepine as defined in any one of claims 2 to 5.

11. A composition of any one of claims 1 to 10 in solid form.

12. A composition of any one of claims 1 to 11 comprising a compound of formula la as defined in claim 3, citric acid, mannitol, microcrystalline cellulose, polyvinylpyrroiidone and hydrogenated castor oil.

13. A composition of any one of claims 1 to 12 in the form of a tablet, capsule, pellet or sachets.

14. A pharmaceutical composition of any one of claims 9 to 13 for the manufacture of a medicament for the treatment of neurodegenerative disorders, cerebral ischemia, glaucoma, Huntington^'s disease, Alzheimer's disease, Parkinson^'s disease, Amyotrophic Lateral Sclerosis, multiple sclerosis, retina degradation, such as e.g. retinitis pigmentosa, general or diabetic peripheral neuropathy, bipolar disorders and schizophrenia.

15. A method of treatment of neurodegenerative disorders, cerebral ischemia, glaucoma, Huntington^'s disease, Alzheimer^'s disease, Parkinson^'s disease, Amyotrophic Lateral Sclerosis, multiple sclerosis, retina degradation, such as e.g. retinitis pigmentosa, general or diabetic peripheral neuropathy, bipolar disorders and schizophrenia, preferably for the treatment of a neurodegenerative disease, comprising administering to a subject in need of such treatment a pharmaceutical composition of any one of claims 9 to 13, in which composition the dibenzo-oxepine is present in an effective amount.