Abstract:
A method of treatment of a central nervous system disorder in a human subject comprises administering to the subject by a suitable route a pharmaceutical composition comprising a therapeutically effective amount of alprazolam, wherein the disorder is selected from amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Pick&#39;s disease, psychosocial dwarfism, Lennox-Gastaut syndrome, infantile spasms, and sexual and gender identity disorders.

Description:
[0001]    This application is a continuation-in-part of application Ser. No. 10/179,706, filed on Jun. 25, 2002. This application also claims priority of U.S. provisional application Serial No. 60/391,275, filed on Jun. 25, 2002. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    The present invention relates to use of the benzodiazepine drug alprazolam in treatment of certain disorders of the central nervous system (CNS).  
         BACKGROUND OF THE INVENTION  
         [0003]    Alprazolam, a member of the 1,4-benzodiazepine class of CNS-active compounds, is an effective anxiolytic and anti-panic agent. The immediate-release alprazolam tablet formulation currently marketed as Xanax® tablets by Pharmacia Corporation can be prescribed for administration of up to four doses per day for treatment of anxiety and, in some instances, in excess of four doses per day for treatment of panic disorder.  
           [0004]    Disorders having a major CNS component include amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), Pick&#39;s disease, psychosocial dwarfism, Lennox-Gastaut syndrome, infantile spasms, and sexual and gender identity disorders. To date, alprazolam has not been contemplated for use in therapy for these disorders, which affect thousands of people and, through their effect on the brain and/or neuromuscular system, can lead to severe disability or death.  
           [0005]    The frequency of dosing required for immediate-release alprazolam formulations is inconvenient and can adversely affect patient compliance. This is especially so in the case of the specific disorders mentioned above, in which patient compliance is negatively impacted by neurological and/or psychiatric complications of these disorders.  
           [0006]    Sustained-release alprazolam formulations have been investigated, including formulations wherein alprazolam is dispersed in a polymer matrix, for example a hydroxypropylmethylcellulose (HPMC) matrix. Franz et al. (1987),  Journal of Controlled Release,  5, 159-172, examined effects of several formulation variables on in vitro alprazolam release rate from such a matrix formulation comprising HPMCs of different viscosity grades, sodium carboxymethylcellulose (sodium CMC) and lactose.  
           [0007]    Attempts have also been made to develop a mathematical model to predict relative drug release rate as a function of formulation composition for HPMC-based extended-release alprazolam tablets. Gao et al. (1995),  Pharmaceutical Research  12(7), 965-971, found that the predictive power of their model became poor as drug load increased.  
           [0008]    Busto et al. (2000),  Journal of Clinical Psychopharmacology  20(6), 628-635, have published pharmacokinetic (PK) data derived from single-dose (1.5 mg) administration of an unspecified sustained-release capsule formulation of alprazolam. An essentially constant plasma concentration of alprazolam was observed over a 6-14 hour period.  
           [0009]    Mumford et al. (1995),  Clinical Pharmacology  &amp;  Therapeutics  57(3), 356-365, presented PK data derived from single-dose (2 mg and 3 mg) administration of an unspecified extended-release formulation of alprazolam.  
           [0010]    New and improved methods are needed for treating ALS, CJD, Pick&#39;s disease, psychosocial dwarfism, Lennox-Gastaut syndrome, infantile spasms, and sexual and gender identity disorders.  
         SUMMARY OF THE INVENTION  
         [0011]    It is now contemplated that alprazolam can be used, alone or in combination therapy with other drugs, to provide therapy for the above CNS disorders. Accordingly, a method of treatment of a CNS disorder in a human subject is provided, comprising administering to the subject by a suitable route a pharmaceutical composition comprising a therapeutically effective amount of alprazolam, wherein the CNS disorder is selected from the group consisting of ALS, CJD, Pick&#39;s disease, psychosocial dwarfism, Lennox-Gastaut syndrome, infantile spasms, and sexual and gender identity disorders.  
           [0012]    A “suitable route” herein includes but is not limited to oral, pulmonary, transdermal, parenteral and rectal routes of delivery of the drug. The oral route is preferred.  
           [0013]    In a preferred embodiment, the pharmaceutical composition is a sustained-release alprazolam formulation, preferably in a form of a discrete oral dosage form such as a tablet or capsule.  
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0014]    [0014]FIG. 1 shows in vitro drug release profiles for 0.5 mg, 1 mg, 2 mg and 3 mg sustained-release alprazolam tablets of Examples 1-4 respectively.  
         [0015]    [0015]FIG. 2 shows mean alprazolam plasma concentration profiles in human subjects administered a total of 6 mg alprazolam in the form of 1, 2 and 3 mg sustained-release alprazolam tablets of Examples 2-4 respectively.  
         [0016]    [0016]FIG. 3 shows mean alprazolam plasma concentration profiles in human subjects administered a total of 1 mg alprazolam in the form of 0.5 and 1 mg sustained-release alprazolam tablets of Examples 1 and 2 respectively. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0017]    Illustrative methods for preparation of alprazolam, 8-chloro-1-methyl-6-phenyl-4H-s-triazolo-[4,3-α]-1,4-benzodiazepine (I), are disclosed in the patents individually listed below and incorporated herein by reference.  
         [0018]    U.S. Pat. No. 3,709,898 to Hester.  
         [0019]    U.S. Pat. No. 3,879,413 to Hester.  
         [0020]    U.S. Pat. No. 3,980,789 to Hester.  
         [0021]    U.S. Pat. No. 3,987,052 to Hester.  
                         
 
         [0022]    Any pharmaceutically acceptable form of alprazolam can be used, including any suitable crystalline or other solid state form, enantiomer or tautomer thereof  
         [0023]    The invention is illustrated herein by reference to a particular orally deliverable sustained-release tablet formulation of alprazolam. However, it win be understood that other formulations, including immediate-release, intermediate-release, sustained-release, delayed-release and dual-release formulations, can be substituted if desired. A preferred formulation is a sustained-release formulation having a pharmacokinetic (PK) profile substantially similar to the illustrative tablet formulation described herein, more particularly one that is substantially bioequivalent to that illustrative tablet formulation.  
         [0024]    In an illustrative tablet useful in the method of the invention, alprazolam is present in an amount of about 0.1 mg to about 5 mg, preferably about 0.5 to about 3 mg, for example about 0.5 mg, about 1 mg, about 2 mg or about 3 mg.  
         [0025]    The alprazolam is distributed in a matrix that comprises HPMC, optionally but preferably together with other excipients as detailed below. HPMC is believed to function as a release-controlling agent and a binder in the formulation of the invention. The HPMC is present in a total amount of about 110 mg to about 135 mg, for example about 120 mg, per tablet. It has surprisingly been found that in such an amount, the HPMC provides in vivo release, as determined by PK data, that is substantially unaffected by alprazolam loading in the range provided above, even where in vitro release data would predict a significant effect of alprazolam loading on in vivo release rates.  
         [0026]    HPMC is commercially available in various grades, under several trade names, including Methocel® E, F, J and K (all previously designated as Methocel® HG) of Dow Chemical Co., U.S.A., HPM of British Celanese Ltd., U.K., and Metalose® SH of Shin-Etsu Ltd., Japan. The various grades available under a given trade name typically represent differences in methoxy and hydroxypropoxy content as well as molecular weight of the HPMC.  
         [0027]    A preferred type is HPMC 2208, which contains about 19% to about 24% by weight of methoxy substituents, and about 4% to about 12% by weight of hydroxypropoxy substituents, calculated on a dry basis.  
         [0028]    Viscosity of commercial HPMCs ranges from about 2 to about 225,000 cP (centipoise), as measured in a 2% aqueous solution at 20° C. The term “high viscosity HPMC” herein refers to HPMC having a viscosity of about 1,500 to about 225,000 cP, and the term “low viscosity HPMC” herein refers to HPMC having a viscosity of about 2 to about 400 cP.  
         [0029]    A preferred high viscosity HPMC is HPMC 2208 having a viscosity of about 3000 to about 5600 cP, which is illustratively available as Methocel® K4MP of Dow. A preferred low viscosity HPMC is HPMC 2208 having a viscosity of about 80 to about 120 cP, which is illustratively available as Methocel® K100LVP of Dow. Equivalent products are available from other manufacturers.  
         [0030]    Both a high viscosity and a low viscosity HPMC are present in the composition. In one embodiment, both high and low viscosity HPMCs conform to the preferred types described above. The weight ratio of high to low viscosity HPMC is about 40:60 to about 60:40, preferably about 45:55 to about 55:45, for example about 1:1. Each of the high and low viscosity HPMCs can be present in an amount of about 50 mg to about 70 mg per tablet, for example about 60 mg per tablet.  
         [0031]    Preferably the tablet comprises one or more additional pharmaceutically acceptable excipients other than the high and low viscosity HPMCs. Such excipients include conventional pharmaceutical tablet excipients, for example diluents, binders, disintegrants, glidants, lubricants, pH modifying agents, coloring agents, antioxidants, etc.  
         [0032]    In one embodiment, a diluent is present. A preferred diluent is lactose. Either lactose monohydrate or anhydrous lactose can be used. A suitable amount of lactose is about 150 mg to about 300 mg, preferably about 180 mg to about 260 mg, more preferably about 200 mg to about 240 mg per tablet.  
         [0033]    In another embodiment, a disintegrant is present. For example, sodium CMC (carmellose sodium) can be used as a disintegrant in a composition of the invention, but preferably the amount of sodium CMC is zero to about 50 mg per tablet. More preferably substantially no sodium CMC is present.  
         [0034]    In yet another embodiment, a glidant is present. A preferred glidant is colloidal silicon dioxide, suitably in an amount of about 0.3 mg to about 1.5 mg, preferably about 0.6 mg to about 0.9 mg, per tablet.  
         [0035]    In yet another embodiment, a lubricant is present. A preferred lubricant is magnesium stearate, suitably in an amount of about 1 mg to about 2 mg, preferably about 1.3 mg to about 1.7 mg, per tablet.  
         [0036]    Optionally, one or more coloring agents can be present in the composition. Selection of coloring agents can be made, for example, so that tablets of different dosage strengths can be easily distinguished. Illustratively, D&amp;C Yellow #10 can be present in an amount of about 0.2 mg to about 0.3 mg per tablet, and/or FD&amp;C Blue #2 can be present in an amount of about 0.05 mg to about 0.09 mg per tablet. In one embodiment, D&amp;C Yellow #10 and FD&amp;C Blue #2 are used in combination as a coloring agent.  
         [0037]    The phrase “pharmaceutically acceptable” is employed herein to refer to compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with tissues of human beings and animals and without excessive toxicity, irritation, allergic response, or any other problem or complication, commensurate with a reasonable benefit/risk ratio.  
         [0038]    Amounts of excipient ingredients specified herein for the illustrative tablet are consistent with a tablet size that is neither inconveniently small nor so large as to present difficulty in swallowing by most subjects, it being noted that to obtain the full benefit of the sustained-release properties of the illustrative tablet it should be swallowed whole. Typically, total tablet weight is about 200 mg to about 500 mg, preferably about 250 mg to about 450 mg, more preferably about 300 mg to about 400 mg, for example about 350 mg.  
         [0039]    In a preferred embodiment, the tablet is a member of a series having different amounts of alprazolam in the range from about 0.1 mg to about 5 mg, members of the series having substantially equal total tablet weight. For example, tablets in the series can have amounts of alprazolam of about 0.5 mg, about 1 mg, about 2 mg and about 3 mg per tablet respectively.  
         [0040]    Surprisingly, members of such a series, when formulated according to the invention, are substantially bioequivalent. The term “substantially bioequivalent” herein means that a first composition exhibits a mean value of the important PK parameters C max  (maximum plasma concentration of alprazolam) and/or AUC (area under the plasma concentration/time curve, a measure of overall bioavailability) that is about 80% to about 125% of the corresponding mean value exhibited by a second composition, in a standard PK study in adult humans wherein equal doses of the two compositions are administered. Preferably members of the series exhibit substantially similar mean plasma concentration/time curves in a standard PK study in adult humans.  
         [0041]    The invention also provides a method of treating a CNS disorder in a subject. The method comprises orally administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising alprazolam, as illustrated by the sustained-release composition illustratively provided herein. Preferably the composition provides an alprazolam release rate that is acceptable for once or twice daily dosing in humans, thus in a preferred method a composition of the invention is orally administered in a therapeutically effective amount to a human subject one or two times per day.  
         [0042]    In a first embodiment, the CNS disorder is ALS.  
         [0043]    In a second embodiment, the CNS disorder is CJD, including any variant of CJD contracted via consumption of products of animals having bovine spongiform encephalitis (BSE) or counterpart diseases in non-bovine species.  
         [0044]    In a third embodiment, the CNS disorder is Pick&#39;s disease.  
         [0045]    In a fourth embodiment, the CNS disorder is psychosocial dwarfism.  
         [0046]    In a fifth embodiment, the CNS disorder is Lennox-Gastaut syndrome.  
         [0047]    In a sixth embodiment, the CNS disorder is infantile spasms.  
         [0048]    In a seventh embodiment, the CNS disorder is a sexual or gender identity disorder.  
         [0049]    According to any of the above embodiments, the alprazolam can optionally be administered in combination therapy with one or more other drugs having therapeutic utility in the particular disorder to be treated. Preferably such other drug or drugs are not benzodiazepines.  
         [0050]    The alprazolam can be especially useful in treatment or management of anxiety and panic associated with any of the above disorders.  
       EXAMPLES  
     Example 1  
       [0051]    Tablets having the composition shown in Table 1 were prepared in a lot of 187,500 tablets. These were nominally 0.5 mg alprazolam tablets, but with a calculated alprazolam content of 0.525 mg per tablet.  
                                                   TABLE 1                           Composition of 0.5 mg alprazolam sustained-release tablets                Amount   Weight   Weight/tablet       Component   (kg)   (%)   (mg)                    alprazolam   0.0984   0.15   0.525       lactose   41.57   64.14   221.7       HPMC type 2208 USP, 4000 cP   11.36   17.53   60.6       HPMC type 2208 USP, 100 cP   11.36   17.53   60.6       colloidal silicon dioxide   0.1406   0.22   0.75       magnesium stearate   0.2813   0.44   1.5       total   64.81   100   345.7                  
 
         [0052]    The alprazolam and all excipients except the magnesium stearate were passed through a screen using a Quick Sieve equipped with a 0.8 mm sieve drum and stator #1 and charged into a 40 cu. ft. Patterson-Kelley V-Blender, where they were mixed together for approximately 20 minutes until uniformly blended. If a uniform blend was not achieved, the mixture was passed through a screen and mixed together again in the blender. Next, the magnesium stearate was passed through a #20 mesh screen with 3-5 kg of the blended alprazolam material. The resulting magnesium stearate mixture was charged into the V-Blender containing the balance of the blended alprazolam material, and mixed for approximately 3 minutes. The resulting tableting mixture was compressed into tablets using a Manesty Mark IV rotary tablet press.  
       Example 2  
       [0053]    Tablets having the composition shown in Table 2 were prepared in a lot of 187,500 tablets, by the process described in Example 1. These were nominally 1 mg alprazolam tablets, but with a calculated alprazolam content of 1.05 mg per tablet.  
                                                   TABLE 2                           Composition of 1 mg alprazolam sustained-release tablets                Amount   Weight   Weight/tablet       Component   (kg)   (%)   (mg)                    alprazolam   0.1969   0.30   1.05       lactose   41.57   64.00   221.7       HPMC type 2208 USP, 4000 cP   11.36   17.49   60.6       HPMC type 2208 USP, 100 cP   11.36   17.49   60.6       colloidal silicon dioxide   0.1406   0.22   0.75       magnesium stearate   0.2813   0.43   1.5       D&amp;C Yellow #10   0.045   0.07   0.24       total   64.95   100   346.4                  
 
       Example 3  
       [0054]    Tablets having the composition shown in Table 3 were prepared in a lot of 187,500 tablets, by the process described in Example 1. These were nominally 2 mg alprazolam tablets, but with a calculated alprazolam content of 2.1 mg per tablet.  
                                                   TABLE 3                           Composition of 2 mg alprazolam sustained-release tablets                Amount   Weight   Weight/tablet       Component   (kg)   (%)   (mg)                    alprazolam   0.3938   0.60   2.1       lactose   41.57   63.84   221.7       HPMC type 2208 USP, 4000 cP   11.36   17.44   60.6       HPMC type 2208 USP, 100 cP   11.36   17.44   60.6       colloidal silicon dioxide   0.1406   0.22   0.75       magnesium stearate   0.2813   0.43   1.5       FD&amp;C Blue #2 Aluminum Lake   0.015   0.02   0.08       total   65.12   100   347.3                  
 
       Example 4  
       [0055]    Tablets having the composition shown in Table 4 were prepared in a lot of 187,500 tablets, by the process described in Example 1. These were nominally 3 mg alprazolam tablets, but with a calculated alprazolam content of 3.15 mg per tablet.  
                                                   TABLE 4                           Composition of 3 mg alprazolam sustained-release tablets                Amount   Weight   Weight/tablet       Component   (kg)   (%)   (mg)                    alprazolam   0.5906   0.90   3.15       lactose   41.57   63.60   221.7       HPMC type 2208 USP, 4000 cP   11.36   17.38   60.6       HPMC type 2208 USP, 100 cP   11.36   17.38   60.6       colloidal silicon dioxide   0.1406   0.22   0.75       magnesium stearate   0.2813   0.43   1.5       D&amp;C Yellow #10   0.045   0.07   0.24       FD&amp;C Blue #2 Aluminum Lake   0.0113   0.02   0.06       total   65.36   100   348.6                  
 
       Example 5  
       [0056]    In vitro drug release rates were determined for the tablets of Examples 1-4 using USP apparatus 1 (rotating basket) at 100 rpm and 500 ml of 0.07M phosphate buffer at pH 6 as dissolution medium. Samples of the medium were removed at 1, 2, 4, 8, 12, 16 and 20 hours after immersion. Alprazolam concentrations were determined by HPLC using conventional UV absorbance detectors at 254 nm.  
         [0057]    Data are shown in FIG. 1. It will be noticed that, consistent with data published by Franz et al., op. cit., as alprazolam loading in the tablet increased, release rate significantly decreased. That is, increasing the amount of alprazolam in the matrix while maintaining constant HPMC content decreased the percentage release rate of alprazolam from the matrix. These results are not suggestive of a formulation system that meets a major objective of the present invention, namely to provide bioequivalence over a wide range of alprazolam loadings.  
       Example 6  
       [0058]    Bioequivalence of the 1 mg, 2 mg and 3 mg sustained-release alprazolam tablets of Examples 2-4 was evaluated by measuring mean alprazolam plasma concentration in human subjects over a predetermined period of time following oral administration of equal 6 mg doses in a PK study. The study involved 24 healthy male volunteers, as determined by physical examination and standard clinical laboratory tests, who received each of three treatments listed below as single oral doses according to a three-way crossover design with a seven day washout period between phases.  
         [0059]    The first treatment was administration of two 3 mg alprazolam tablets of Example 4, the second treatment was administration of three 2 mg alprazolam tablets of Example 3 and the third treatment was administration of six 1 mg alprazolam tablets of Example 2.  
         [0060]    After receiving a cupcake and a caffeine-free beverage, subjects were required to fast from 10 p.m. the night before dosing until 4 hours after drug administration. During the fasting period no food or beverage other than water were consumed. Treatments were administered at 7 a.m., with 180 ml of water. Standard meals were consumed at 11 a.m. and 5 p.m. on the day of dosing. Subjects were allowed to remain sedentary during the study period.  
         [0061]    Venous blood samples were collected immediately prior to drug administration and at 20 minutes, 40 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30 and 36 hours after drug administration. Blood samples (10 ml) were collected into heparinized vacutainers at each sampling time. Plasma was harvested from the samples after centrifugation and frozen at −20° C. until analyzed. Determinations of alprazolam in plasma were performed by HPLC. The analytical method involved liquid-solid extraction of alprazolam and triazolam (internal standard) on an end-capped cyano-column with acetonitrile. The samples were chromatographed under isocratic conditions on a silica column using a sensitive ultraviolet detector for quantitation.  
         [0062]    Mean plasma concentrations of alprazolam are shown in FIG. 2.  
         [0063]    Effects of treatment on PK parameters among the three treatments were assessed by analysis of variance (ANOVA), with group, treatment and period as fixed effects and subject within group as a random effect. Differences between treatments were determined by Waller-Duncan K-ratio test and least squares means analysis. Statistical analysis was performed using SAS. The bioequivalence (on a potency-corrected basis) of the 1 mg, 2 mg and 3 mg sustained release alprazolam tablets was also assessed by 90% confidence interval analysis (two-one sided t-tests).  
         [0064]    No significant differences were observed in plasma alprazolam concentrations between any of the treatments at any sampling time, leading to the conclusion that the 1 mg, 2 mg and 3 mg sustained release alprazolam tablet dosage formulations are bioequivalent.  
       Example 7  
       [0065]    Bioequivalence of the 0.5 mg and 1 mg sustained-release alprazolam tablets of Examples 1 and 2 respectively was evaluated in a PK study conducted according to a similar protocol to that of Example 6. Results are shown in Table 3.  
         [0066]    The 0.5 mg and 1 mg alprazolam tablets were found to be bioequivalent. By reference to Example 6, it can be concluded that the 0.5 mg tablet is also bioequivalent to the 2 mg and 3 mg tablets because all are bioequivalent to the 1 mg tablet.  
         [0067]    It is particularly surprising, in view of the unpromising in vitro data of Example 5, as shown in FIG. 1, that in vivo release and absorption of alprazolam, as illustrated in Examples 6 (FIG. 2) and 7 (FIG. 3), are substantially unaffected by alprazolam loading, at least where the amount of HPMC in the matrix is as provided herein.