MXPA96003713A - Sublingual pharmaceutical composition or bu - Google Patents

Abstract

The present invention relates to a sublingual or buccal pharmaceutical composition characterized in that the composition comprises trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dib enz [2,3: 6,7] oxepino [4,5-c] pyrrole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliaries for use in sublingual or buccal compositions

Description

SUBLINGUAL OR BUCAL PHARMACEUTICAL COMPOSITION DESCRIPTION OF THE INVENTION The invention relates to a sublingual or buccal pharmaceutical composition, and more specifically to a sublingual or buccal composition for the treatment of various mental disorders.

The compound trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2, 3: 6, 7] oxepino [4,5-c] pyrrole and the preparation thereof is describe in USP No. 4, 145,434. The compound described has sedative-CNS activity and antihistaminic and antiserotinic activities. The pharmacological profile of trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2, 3: 6,7] oxepino [4,5-c] pyrrole, its kinetics and Metabolism, as well as the first safety and efficacy studies in humans, volunteers, and schizophrenic patients were reviewed by Boer et al. (Drugs of the Future 1993, 18 (12), 1 1 17-1 123). It has been established that Org 5222 [5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino [4,5-c] pyrrole maleate ( 1: 1)] is a very important dopamine and serotonin antagonist with potential antipsychotic activity. However, Phase I clinical studies on the effects of a personal administration of trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino [4,5-c] pyrrole, revealed that serious cardiotoxic effects occurred, v. gr. , postural hypotension and / or damage to baroreceptor function. Surprisingly, it has been found that under sublingual or buccal administration, trans-5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino [4, 5-c] pyrrole has substantially minor cardiovascular side effects. The invention, therefore, relates to a sublingual or buccal pharmaceutical composition comprising trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7 ] oxepino [4,5-c] pyrrole or a pharmaceutically acceptable salt thereof, and pharmaceutically suitable auxiliaries for use in sublingual or buccal compositions. The compositions of the invention are useful in the treatment of mammals, including humans, that suffer from diseases that are susceptible to treatment with trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H- dibenz [2, 3: 6,7] oxepino [4l 5-c] pyrrole. Such diseases include mental disorders, such as, tension, excitement, anxiety, psychosis, and schizophrenia. The compositions can also be used for diseases related to antihistamine or antiserotonin. In its simplest form, the pharmaceutical composition of the invention consists of an aqueous solution, for example, comprising 0.9% (w / v) of sodium chloride and the active compound 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino [4,5-c] pyrrole, or a pharmaceutically acceptable salt thereof. The maleate salt (Org 5222) is a preferred salt. The active compound is rapidly absorbed from these aqueous, pharmaceutical compositions, when they are kept under the tongue or in the mouth of a patient. Preferred pharmaceutical compositions are solid pharmaceutical compositions, which disintegrate rapidly in the mouth of a subject, when introduced into the buccal sac or when placed under the tongue. Rapid disintegration means that the pharmaceutical composition disintegrates in 30 seconds in water at 37 ° C, and preferably in 10 seconds, as measured according to the procedure described in Remington's Pharmaceutical Sciences, 18th. Edition (De A. A. Genaro), 1990, pp. 1640-1641; see also US Pharmacopeia, Chapter < 701 > . In a preferred embodiment, the pharmaceutical compositions of the invention are tablets or lozenges, which comprise a rapidly disintegrating composition of a pharmaceutically acceptable, water-soluble, water-dispersible carrier material. Tablets or tablets comprising a rapidly disintegrating composition of a water soluble, water dispersible, pharmaceutically acceptable carrier material are well known in the art., for example, as described in USP 4, 371, 516. Said tablets can be prepared by freeze drying an aqueous solution comprising 5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2, 3: 6,7] oxepino [4, 5-c] pyrrole, a water soluble vehicle material, dispersible in water and, optionally, pharmaceutically acceptable excipients. In the art, such excipients are known, see for example, Remington's Pharmaceutical Sciences, 18th. Edition (De A. A. Genaro), 1990, pp. 1635-1638, and are commonly used in pharmaceutical compositions, for example, surfactants, coloring agents, flavoring agents, preservatives, and the like. The water soluble or water dispersible carrier material is preferably water soluble. Suitable water-soluble carrier materials are (poly) saccharides, such as dextran hydrolyzate, dextrin, mannitol and alginates, or mixtures thereof, or mixtures thereof with other carrier materials such as polyvinyl alcohol, polyvinyl pyrrolidone and derivatives thereof. * Cellulose soluble in water, such as hydroxypropyl cellulose. A preferred carrier material is gelatin, in particular, partially hydrolyzed gelatin. The partially hydrolyzed gelatin can be prepared by heating a gelatin solution in water, for example, in an autoclave at about 120 ° C for up to 2 hours. The hydrolyzed gelatin is used in concentrations of about 1 to 6% (w / v), and preferably in concentrations of about 2 to 4% (w / v). Preferred dosage forms of the composition of the invention, i.e., tablets or lozenges, can be prepared by methods well known in the art. For example, according to a method described in British Patent 2, 1111, 423, an aqueous composition comprising a predetermined amount of 5-chloro-2-methyl-2, 3,3a, 12b-tetrahydro-1H- dibenz [2, 3: 6,7] oxepino [4, 5-c] pyrrole, a pharmaceutically acceptable, water-soluble or water-dispersible vehicle material, and, optionally, pharmaceutically acceptable auxiliaries and excipients, is transferred to a mold , after which, the composition is cooled and the solvent is sublimated, preferably by freeze drying. The composition preferably contains a surfactant, for example, Tween 80 (polyoxyethylene (20) sorbitan mono-oleate), which can help prevent the product, freeze-dried, from adhering to the surface of the mold. The mold may comprise a series of cylindrical depressions or other shapes, each having a size corresponding to the desired size of the dosage form. Alternatively, the mold may have a size larger than the desired size of the dosage form, and after the contents have been freeze-dried, the product may be cut to the desired size. Preferably, the dosage form is freeze-dried in the form of a lyosphere, which is a spherical freeze-dried drop containing the active ingredient. A preferred mold could correspond to a depression in a sheet of film material, as for example described in USP 4, 305,502 and USP 5,046,618. The film material may be similar to that used in conventional blister packages.

Each dosage form of the pharmaceutical composition of the present invention comprises a dosage unit of 5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino [4,5-c] pyrrole as an active ingredient. A dose unit may contain between 0.005 mg and 15 mg of the active ingredient. Preferably, the dose unit contains 0.03-0.50 mg of 5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino [4, 5-c ] pyrrole. The invention further relates to the use of trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6I7] oxepino [4,5-c] pyrrole for the manufacture of a sublingual or buccal pharmaceutical composition for the treatment of mental disorders, such as psychosis and schizophrenia. A method of providing therapy, using the pharmaceutical composition of the present invention, comprises inserting a dosage form, according to this invention, into the buccal sac or below the tongue of a subject, such as a human being. The final dose to provide relief to the patient depends, in addition to the individual characteristics, of the patient's weight, condition and age. Usually, the administration of 1-4 dose units of the pharmaceutical composition of the invention, per day, is sufficient to obtain a therapeutic effect. The therapy can be continued as long as it is necessary or desired. The invention is further illustrated by the following examples.

EXAMPLE 1 a: Preparation of hydrolyzed gelatin (3% w / v) Gelatin (30 g) was dissolved in 1 liter of distilled water under heating and constant stirring. The resulting solution was autoclaved at 121 ° C (10sPa) for one hour, after which the solution was allowed to cool to room temperature to give hydrolyzed gelatin (3% w / v). b: Preparation of a pharmaceutical solid dosage form A polyvinyl chloride (PVC) sheet containing cylindrical depressions was cooled with solid carbon dioxide. 0.2 g of Org 5222 [5-chloro-2-methyl-2, 3,3a, 12b-tetrahydro-1 H-dibenz [2, 3: 6, 7] oxepino [4,5-c] pyrrole maleate was dissolved. (1: 1)] in 1 liter of hydrolyzed gelatin under mixing. While mixing was continuing, 0.5 ml of the solution was placed in each of the depressions. When the contents of the depressions were frozen, the PVC sheet was placed in a freeze drying system. An aluminum sheet was finally sealed to the sheet to close the depressions containing the pharmaceutical dosage forms, dried by freezing. Each of the depressions contains a pharmaceutical unit dose comprising 0.10 mg of 5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino maleate [ 4,5-c] pyrrole (1: 1).

EXAMPLE 2 In the manner as described in Example 1b, a pharmaceutical composition was prepared comprising: 0.2 g of 5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz maleate [2,3: 6,7] oxepino [4,5-c] pyrrole (1: 1) (Org 5222), 0.50 g of Tween 80 (polyoxyethylene mono-oleate (20) sorbitan), 30 g of sucrose and 1 liter of hydrolysed gelatin (3% p / v).

EXAMPLE 3 In the manner as described in Example 1b, a pharmaceutical composition was prepared comprising: 2 g of 5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz maleate [2,3: 6,7] oxepino [4,5-c] pyrrole (1: 1) (Org 5222), 0.50 g of Tween 80 (polyoxyethylene mono-oleate (20) sorbitan), 30 g of sucrose and 1 liter of hydrolysed gelatin (3% w / v), 1 liter of hydrolyzed gelatin (3% w / v).

EXAMPLE 4 A pharmaceutical composition comprising: 0.2 g of 5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino maleate [4,5-c] was prepared. ] pyrrole (1: 1) (Org 5222), 17 g of sodium alginate, 35 g of dextran (MW approximately 40,000), 17.5 g of dextrose, and distilled water at a volume of 1 liter, said composition was cooled by Freezing to dosage unit forms.

EXAMPLE 5 A pharmaceutical composition was prepared comprising: 0.4 g of 5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino maleate [4,5-c] ] pyrrole (1: 1) (Org 5222), 50 g of dextrin, 0.20 G of Teewn 80 (polyoxyethylene mono-oleate (20) sorbitan), 30 g of polyvinyl pyrrolidone and distilled water at a volume of 1 liter, said composition it was cooled by freezing to unit dosage forms.

EXAMPLE 6 Lyospheres were prepared by dissolving 138.9 g of sucrose, 40.8 g of sodium citrate and 11.1 mg of polysorbate 20, in 300 ml of distilled water, adjusting the pH to 7 using 1 N hydrochloric acid and 1 N sodium hydroxide and adding water at 500 mi. The solution was homogenized by stirring and filtered through a sterile 0.22 μm filter, after which the solution was cooled to 0.1 ml drops, said drops were transferred to the frozen state in a freeze dryer and then dried by freezing to lyophilized, spherical, uncharged dose units (lyospheres). 120 mg of maleate of 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1 H-dibenz [2,3: 6I7] oxepino [4I5-c] pyrrole (1: 1) was dissolved (Org 5222), in 1 ml of ethanol and 83 μl of this solution were added to one of the lyospheres, after which, the ethanol was removed by moderate heating, to obtain a lyosphere containing 10 mg of Org 5222. The lyospheres containing 1 and 0.1 mg of Org 5222, respectively, were prepared in a similar manner, by dissolving 60 or 6 mg of Org 5222, respectively, in 1 ml of ethanol, after which 16.6 μl of this solution was added to a lyosphere.

EXAMPLE 7 A pharmaceutical composition comprising: 0.094 g of 5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino maleate [4,5-c] was prepared. ] pyrrole (1: 1) (Org 5222), 30 g of mannitol, 40 g of gelatin, and distilled water at a volume of 1 liter, said composition was freeze-cooled according to the method of Example 1 to unit dosage forms, each of which comprises 10 μg of Org 5222.

EXAMPLE 8 Orthostatic hypotension (inclination test) and the hemodynamic and electrophysiological effects were determined as follows: Method: "Beagle" dogs (10-20 kg, Harian, France) were instrumented under anesthesia. A micromanometer (Konigsberg Instruments) was placed in the aorta near the aortic arch and another in the left ventricle. A pair of segmental length piezoelectric crystals (Triton Technology) were sutured into the endocardial left ventricular wall, at a distance of approximately 1 cm between each. All connection cables were inserted subcutaneously and exteriorized in the back of the neck. Two weeks after the operation the dogs were placed in a Pavlov pavilion and transducers were connected to an eight-channel register (Gould ES3000). An electrocardiogram (normal I I lead) was also recorded using bipolar limbus conductors. Org 5222 (or placebo) was administered either orally (1, 2.5, 5, 10 or 50 mg / kg) or sublingually (0.10, 0.1, or 1 mg / kg) to conscious dogs. The aortic, diastolic, and mean blood systolic (mmHg) pressures, heart rates (beats / minutes), segmental ventricular systoletal reductions (mm), and QT intervals were continuously recorded and automatically analyzed every 15 minutes for a period of observation of 5 hours, after the administration of Org 5222. The Qts (which reflects the cardiac repolarization time) was calculated according to the Bazett formula.

The dogs were inclined to a straight 90 ° position for periods of 30 seconds by raising their front limbs. Tilt responses refer to the maximum changes observed in aortic blood pressure and heart rate during the observation period of 30 seconds, and were analyzed both 30 minutes and just before administration of Org 5222 and then 15, 30, 60, 90, 120, 180, 240, and 300 minutes after administration. Blood samples were taken just before administration of the drug and at 15, 30, 60, 90, 120, 240, 300, 360 minutes and at 21 hours after administration, in each case just after the tilt test. Plasma, prepared from blood samples, was added to internal normal (cis-5-chloro-2-methyl-2 maleate, 3,3a, 12b-tetrahydro-1 H-dibenz- [2,3: 6 , 7] oxepino [4,5-c] -pyrrole (1: 1); Org 5033) and Org 5222 and the internal normal were isolated by extracting the alkalized plasma with n-hexane. The concentration of Org 5222 was determined by capillary gas chromatography (cGC) with detection of NPD.

Results: The hypotensive response to the inclination was modestly increased and dependent on the dose per Org 5222, regardless of the route of administration. However, for equivalent plasma levels of Org 5222, the accompanying tachycardia was always more marked after oral administration of Org 5222 than after sublingual administration (Table 1).

Table 1: mean change in heart rate due to inclination (corrected for placebo effects), calculated by concentration scale (ng / ml) and for each of the two routes, oral (po) and sublingual (if) .

Conclusions: Orthostatic hypotension accompanied by tachycardia was more pronounced after oral administration than by suglingual administration of Or? 5222. Hemodynamic and electrophysiological effects were also less marked after sublingual administration than oral administration with respect to negative ionotropy and Qtc prolongation.

In addition, orally treated dogs showed marked side effects, such as long-duration excitation, whereas sublingually treated dogs only showed short periods of excitation followed by long-term sedation.

Claims (4)

1. - A sublingual or buccal pharmaceutical composition characterized in that the composition comprises trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino [4,5 -c] pyrrole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliaries for use in sublingual or buccal compositions.

2. The pharmaceutical composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable water-soluble or water-dispersible carrier material.

3. The pharmaceutical composition of claim 2, wherein the carrier material is partially hydrolysed gelatin.

4. A use of trans-5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1 H-dibenz [2,3: 6,7] oxepino [4,5-c] pyrrole for the manufacture of a sublingual or buccal pharmaceutical composition for the treatment of mental disorders.