Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.
U.S. Pat. No. 4,145,434 (the '434 patent), in Example IV therein, describes the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz-[2,3;6,7]oxepino-[4,5c]pyrolle (known also as asenapine, see Merck index monograph no. 832), which has the structure of the compound of Formula I,

The compound of Formula I is known to have activity in the treatment of patients afflicted with central nervous system disorders (CNS disorders). As described in the '434 patent, Col. 1, lines 45 to 50, compounds like the compound of Formula I show in general a marked CNS-depressant activity, which can be used in the treatment of states of tension, excitation and anxiety, and in the treatment of psychotic and schizophrenic conditions and show as well excellent antihistamine and antiserotonin activities. As described in U.S. Pat. No. 5,763,476 (the '476 patent), filed Mar. 9, 1995 as international application. no. PCT/EP95/00765, in Col. 1, lines 43 to 46, sublingual or buccal administration of an asenapine maleic acid salt is useful for use in treating or managing diseases including mental disorders, such as tension, excitation, anxiety, psychosis, and schizophrenia. Each of the afore-mentioned applications and patents are incorporated by reference as if fully set forth herein in their entirety. Treatment of bipolar disorders and associated symptoms with administration of asenapine is described in a U.S. patent application published Apr. 20, 2006 under publication no. 2006/0084692, which application is incorporated by reference as if fully set forth herein in its entirety.
Sublingual administration of a formulation comprising asenapine or a salt thereof to a patient to whom it is administered is effective in providing treatment for many CNS diseases, but requires at least regular daily administration to maintain acceptable therapeutic levels of asenapine in patients.
One serious problem to be overcome in providing effective asenapine therapy is lack of dosing compliance, particularly when the medicament is self-administered and more particularly when it must be administered daily or several times daily. Accordingly, in addressing this compliance issue, it would be preferable to have a medicament administered in a clinical setting to a patient in a form providing a therapeutically effective plasma level in the patient for a sustained period of time, thus eliminating the compliance problems associate with self-administration. This treatment modality would also require fewer dosing treatments in a given period of time.
In an effort to increase the amount of time between, doses of a medicament while maintaining a therapeutically effective plasma level of the active compound, some workers have attempted to administer some CNS active agents by intramuscular injection of a depot (Depot administration) of a composition containing the active pharmaceutical agent (API), which releases a therapeutic compound systemically over time. One example of such a dosage form reported pertains to the pamoate salt of olanzapine, an atypical antipsychotic compound unrelated to asenapine. Olanzapine pamoate has been described in U.S. Pat. Nos. 6,169,084 and 7,303,764 for use in IM administration. Depot administration of a composition containing this salt was tested in clinical trials by Eli Lilly (see for example clinical trial NCT00320489 listed on the U.S. National Institutes of Health, web site at “clinicaltrials.gov”). In these trials a depot of a formulation comprising particles of olanzapine pamoate as an active pharmaceutical agent (API) suspended in a liquid was administered by intramuscular injection (Depot administration). Initially, based on the results of these trials, the FDA declined to approve the formulation for sale citing incidents in the trials of extreme sedation and reversible coma associated with the administration of the formulation. The cause of these adverse events has not been verified, but is believed to be related to unexpectedly rapid dissolution of the suspended API in the injected depot and concomitant rapid systemic absorption of the dissolved material. Subsequently the FDA has approved this formulation for Depot injection subject to strict conditions of patient monitoring. Accordingly, the risks associated with the use of this formulation remain. As this example illustrates, the provision of a salt having apparently suitable characteristics for use in a depot formulation, for example, a pamoate salt, does not necessarily by itself provide a formulation for depot administration which is free of undesirable complications.
In depot administration of a medicament comprising a particle suspension, particle size and particle size distribution of suspended API has been observed to be a factor in the release of drug from the injected depot. This point is illustrated by the study of Miller and Fincher reported in The Journal of Pharmaceutical Sciences, (November 1971) Vol, 60, No. 11, pp. 1733 to 1736. In their study, Miller and Fincher observed plasma levels of phenobarbitol following IM-injections of suspensions of different fractions of classified phenobarbitol particles into dogs. Accordingly, Miller et al. prepared separate suspensions from particle fractions having a mean particle diameter of either 6.63 microns, 10.68 microns, 17.16 microns or 29.96 microns as determined using a Coulter counter. As shown in FIG. 1, plasma concentrations of phenobarbital observed by Miller et al. following depot injection of these suspensions tracked inversely with the mean particle diameter of the phenobarbital particle fraction used to prepare the suspension. This is to say that for equivalent weight percentages of API in a suspension, injection of equal amounts of API in suspensions made with particles having a smaller mean particle size provided higher Cmax in a shorter time post injection than those suspensions prepared from particle fractions having a larger mean particle size.
From the foregoing it can be seen that the attempt to provide a formulation suitable for depot administration implicates issues not addressed by merely identifying a salt form of the drug which has acceptable solubility and melting point properties. As mentioned above, depot formulations are subject to unexpected release profiles due to particle size and other factors described above.
Another aspect of the problem which can interfere with success in the provision of a formulation suitable for use in depot administration, especially in the provision of a depot formulation having extended release properties, is the stability of the active pharmaceutical ingredient (API) used in the formulation. Instability of the formulation can adversely impact the effectiveness of the formulation when subjected to the physiological environment in which it is used as well as impact the ability to store the formulation for long periods or, under ambient conditions. For example, where the API is in a crystalline form, loss of crystallinity or a change in crystalline morphology has been observed to have a profound effect on release rates from a depot injection administered using such a formulation.
As described in Published European application publication no. EP0569096, published Nov. 10, 1993 (the '096 publication), which is incorporated by reference as if fully set for herein in its entirety, pamoate salts of trans-5-chloro-2-methyl-2,3,3a12b-tetrahydro-1H-dibenz-[2,3;6,7]oxepino-[4,5c]pyrolle (asenapine, the compound of Formula I) are known, including 1:1 pamoate salt (comprising equimolar amounts of pamoic acid and asenapine free base reacted together) and, a 2:1 hemipamoate salt (comprising a 2:1 mole ratio of asenapine and pamoic acid reacted together). Published international application no. WO98/5086 (published Dec. 3, 1998, applicant Akzo-Nobel) characterizes the asenapine her salt described in the '096 publication (which is also referred to as “the Form I hemipamoate salt”, as comprising a mixture of amorphous and crystalline material with a melting point of from about 167° C. to about 168° C.
The two aforementioned publications, which describe various depot formulations containing aromatic acid salts of asenapine, do not indicate that the hemipamoate mentioned therein is suitable for use in a depot formulation. The provision of asenapine salts of pamoic acid (pamoate and hemipamoate Form I) has here-to-fore not resulted in the provision of a form of asenapine which is sufficiently stable and possessed of suitable dissolution characteristics for use in a formulation intended for depot administration, particularly for use in the provision of an extended release administration from a depot provided by IM injection of the formulation.