Technical Field of the Invention
The present invention relates to a controlled-release oral pharmaceutical composition for alprazolam comprising one or more hydroxypropyl methylcelluloses as a carrier material.
Background of the Invention
Alprazolam, 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine, is prescribed for the management of generalized anxiety disorders, for the treatment of panic disorder, and for short-term relief of symptoms associated with anxiety. Alprazolam is currently marketed as Xanax® tablets by Pharmacia Corporation, as immediate release dosage form and has a dosage regimen 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. Such dosage frequency is inconvenient for patient and also can adversely affect the compliance. In addition, breakthrough anxiety can be a problem with current dosing regimens.
To overcome the disadvantages of Xanax® tablets Pharmacia Corp. developed Xanax XR®, an extended-release tablet that had better patient compliance compared with conventional tablets. In its U.S. Pat. Application. No. 2004/0006072 Pharmacia has reported the use of blend of two different hydroxypropyl methylcellulose's (HPMC) as sustained-release matrix polymer for its extended release tablets. The application also insisted the specific ratio of high to low viscosity HPMC, which should be kept in about 40:60 to about 60:40, and the total amount HPMC should be of about 110mg to about 135mg per tablet. In addition to the sustained release property, the dosage form was capable of housing broad rage of dosage strengths and exhibited substantially bioequivalent results when different dosage strengths are administered in an equal total dosage amount.
Alza Corporation has developed an osmotic dosage form containing alprazolam. Alza in its U.S. Pat. Application. No. 2005/0260268 states that the dosage form

designed to be a once-a-day and to provide continuous delivery of therapeutically effective amount of alprazolam over 24hours. However, osmotic dosage forms have some specific drawbacks, such as the complexity of design, necessary manufacturing processes, and specialized equipment for making complicated laser-drill to produce orifice next to the drug compartment.
U.S. Pat. Application. No. 2005/0163843 by Alpharma describes the sustained-release form in plurality of substrates comprising the alprazolam, in which the substrates are coated with sustained-release coating comprising a release-retarding material. The coated substrates are then packaged in a capsule or compressed with additional excipients to form a tablet. Another process described in U.S. Pat. Application. No. 2005/0163843 mentions, blending or granulating with polymers before coating to provide an additional level of control; these systems appeared as a blend of coated-beads with differing release rates for extended release or pulsitile release formulations. Regardless of the manner of manufacture, coated bead systems are extremely complex to produce, requiring large numbers of excipients, use of solvents and multiple manufacturing steps.
Monolithic matrix systems eliminate the need for costly manufacturing processes such as creating coating membranes with precise release orifices, as in osmotic dosage forms or using large amount of solvents and involving multiple manufacturing steps, as in multi-particulate systems.
Monolithic matrix systems for sustained release of drug comprising as a base hydroxypropyl methylcellulose are well known. Hydroxypropyl methylcelluloses are commercially available in various grades, under several tradenames, including Methocel E, F, J and K (all previously designated as Methocel HG) from The Dow Chemical Co., U.S.A., HPM from British Celanese Ltd., England, and Metalose SH from Shin-Etsu, Ltd., Japan. The various grades available under a

given tradename represent differences in methoxyl and hydroxypropoxyl content as well as molecular weight of the HPMC.
U.S. Pat. No. 4,601,894 describes a controlled release drug delivery system which contains hydroxypropyl methylcellulose (HPMC) and a second polymer such as ethylcellulose, methylcellulose, sodium carboxymethyl cellulose or other cellulose ethers. U.S. Pat. No. 4,680,323 describes a carrier system comprising hydroxypropyl methylcellulose, hydroxypropyl cellulose and a carboxy vinyl polymer. U.S. Pat. No. 4,695,591 describes the use of HPMC for mediating controlled release of pharmaceutically active substances.
Christenson and Dale (U.S. Pat. No. 3,065,143) disclosed the use of certain high molecular weight hydrophilic gums, including hydroxypropyl methylcelluloses, in the preparation of a "sustained release tablet". The tablet consisted essentially of a mixture of a medicament and at least one third part by weight of the weight of the tablet of a hydrophilic gum which rapidly absorbed water and swelled at 37°C to form a "soft mucilaginous gel barrier" on the surface of the tablet when brought into contact with the aqueous fluids of the gastrointestinal tract.
The high molecular weight hydroxypropyl methylcelluloses disclosed by Christenson and Dale and constituting at least one third of the weight of the tablet, include Methocel 60HG 4000 cps, now known as Methocel E4M, having a 28-30 weight-% methoxyl content, a 7.5-12 weight-% hydroxypropoxyl content and a number average molecular weight of 93,000, and Methocel 90HG 4000 cps and Methocel 90HG 15,000 cps, now known as Methocel K4M and Methocel K15M, respectively. The latter have number average molecular weights of 89,000 and 124,000, respectively, and a 19-24 weight-% methoxyl content, and a 4-12 weight-% hydroxypropoxyl content.
U.S. Pat. No. 4,389,393 teaches a carrier base material combined with a therapeutically active medicament and shaped and compressed to a solid unit

dosage form having a regular and prolonged release pattern upon administration, the carrier base material being one or more hydroxypropyl methylcelluloses or a mixture of one or more hydroxypropyl methylcelluloses having a methoxy content of 16-24 weight %, a hydroxypropoxyl content of 4-32 weight % and an average molecular weight of at least 50,000.
In the present invention, the inventors have formulated an acceptable dosage form containing alprazolam having controlled-release profile with minimal and simple processing steps.
The above objectives have been achieved by preparing a controlled-release oral pharmaceutical composition for alprazolam comprising one or more hydroxypropyl methylcelluloses as a carrier base and prepared by the direct compression process, which is simple in respect of steps, but the release of alprazolam may be slow and regular upon administration.
Summary of the Invention
The main object of the present invention is to provide a controlled-release oral pharmaceutical composition comprising alprazolam or a pharmaceutically acceptable salt thereof, and one or more hydroxypropyl methylcelluloses (HPMCs), as a carrier base material.
Hence it is one of the aspects to provide a controlled-release oral pharmaceutical composition comprising alprazolam, high viscosity hydroxypropyl methylcellulose having a viscosity from about 1,500 to about 225,000 cP and a low viscosity hydroxypropyl methylcellulose having a viscosity from about 2 to about 400 cP, wherein the high viscosity hydroxypropyl methylcellulose and low viscosity hydroxypropyl methylcellulose are present in a weight ratio ranging from 1:2 to 1:10.

The composition comprises is intended to provide from about 0.1 mg to about 5mg per tablet of alprazolam.
In one embodiment the composition further comprise one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients may be one or more fillers, binders, disintegrants, lubricants, glidants coloring agents and flavoring agents.
The controlled-release oral pharmaceutical composition comprising alprazolam can be made by process comprising one or more conventionally used techniques of direct compression, dry granulation or wet granulation.
According to one of the embodiments, the composition is optionally coated with one or more film forming agents.
It is another aspect to provide a controlled-release oral pharmaceutical composition of alprazolam, which exhibits pharmacokinetic parameters comparable to the commercially available XANAX XR® tablets (Alprazolam extended-release tablets, Pharmacia & Upjohn Company; USA) wherein the composition comprises alprazolam, high viscosity hydroxypropyl methylcellulose having a viscosity from about 1,500 to about 225,000 cP and a low viscosity hydroxypropyl methylcellulose having a viscosity from about 2 to about 400 cP, wherein the high viscosity hydroxypropyl methylcellulose and low viscosity hydroxypropyl methylcellulose are present in a weight ratio ranging from 1:2 to 1:10.
It is yet another aspect to provide a method of treating subject having a central nervous system disorder, more particularly a disorder wherein the alprazolam formulation is indicated, comprising a step of orally administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising alprazolam, high viscosity hydroxypropyl methylcellulose having a viscosity from

about 1,500 to about 225,000 cP and a low viscosity hydroxypropyl methylcellulose having a viscosity from about 2 to about 400 cP, wherein the high viscosity hydroxypropyl methylcellulose and low viscosity hydroxypropyl methylcellulose are present in a weight ratio ranging from 1:2 to 1:10.
The method may further include administering other antianxiety or pharmaceutical agents with alprazolam.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
The inventors have developed a controlled-release oral pharmaceutical composition comprising alprazolam or a pharmaceutically acceptable salt thereof that helps to achieve the desired release profile up to about 24 hours time period. The inventors have surprisingly found that the use of a combination of high and low viscosity hydroxypropyl methylcelluloses (HPMCs), in the weight ratio of other than 40:60 to 60:40 also provides a better control over the rate of release of drug. More precisely, the inventors have found the blend of high and low viscosity HPMCs in the weight ratio ranging from 1:2 to 1:10 provides enhanced release rate of the drug.
The term "controlled-release" as used herein includes any type of controlled-release compositions such as prolonged release, sustained release, modified release and extended release. In particular the controlled-release composition is based on matrix technology. In this technology the alprazolam is embedded in the blend of HPMCs carrier thus making it a non-disintegrating core called matrix. Diffusion of alprazolam occurs through the HPMC(s) matrix.

In particular embodiment the controlled-release composition of alprazolam of the present invention comprises a controlled-release oral pharmaceutical composition comprising alprazolam, high viscosity hydroxypropyl methylcellulose having a viscosity from about 1,500 to about 225,000 cP and a low viscosity hydroxypropyl methylcellulose having a viscosity from about 2 to about 400 cP, wherein the high viscosity hydroxypropyl methylcellulose and low viscosity hydroxypropyl methylcellulose are present in a weight ratio ranging from 1:2 to 1:10.
The term "pharmaceutically acceptable salt" as used herein includes any form of salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and, as such, they are the pharmacological equivalents of the bases of the alprazolam compound. Examples of pharmaceutically acceptable acids that are useful for the purposes of salt formation include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, mandelic, phosphoric, nitric, mucic, isethionic, palmitic, and others.
In the present invention alprazolam may be 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.
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.
In particular high viscosity HPMC have a viscosity of about 3000 to about 5600 cP, which is illustratively available as Methocel K4M of Dow. A particular low viscosity HPMC have a viscosity of about 80 to about 120 cP, which is

illustratively available as Methocel K100LV CR of Dow. Equivalent products available from other manufacturers having similar viscosity profiles may also be used. Both the high viscosity and low viscosity HPMCs present in the composition conform to the particular types described above.
More particularly, the type is hydroxypropyl methylcellulose used 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.
In addition to the active and the hydroxylpropyl methylcellulose polymers, the composition comprises pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients are those known to the skilled in the art and may be selected from fillers, binders, disintegrants, lubricants, glidants coloring agents and flavoring agents.
Examples of fillers include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch and starch pregelatinized.
Examples of binders include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate and propylene glycol.
Examples of disintegrants include, but are not limited to, starch, cross-linked carboxy methyl cellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate and low substituted hydroxy propyl cellulose.

Examples of lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax and white beeswax.
The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.
In general the process of preparing controlled-release oral pharmaceutical composition comprises blending alprazolam, high and low viscosity HPMCs and one or more pharmaceutically acceptable excipients, under low-shear conditions, granulating the blend, sizing the granules, lubricating and compressing the granules into tablets or pellets. Alternatively the granules or pellets can be filled into capsules. The blending can be carried out using a mixer such as planetary or using conventional powder mixers such as double cone blenders, V-shell blenders, ribbon and paddle mixers. The granulation step can be wet or dry.
For example, composition of the present invention can be prepared, e.g. by a wet granulation of a mixture of alprazolam, high and low viscosity HPMCs and one or more pharmaceutically acceptable excipients, with the aid of a granulating solvent such as water or ethanol; drying the wet granulate; sieving the granulate; blending with extra-granular excipients if any, and compressing into solid dosage forms.
Yet another suitable process comprises direct compression of the blend of alprazolam and high and low viscosity HPMCs with one or more pharmaceutically acceptable excipients. In this process, the ingredients are blended together to form a compressible blend composition that is subsequently compressed into solid dosage forms.

The composition prepared by the present invention optionally coated with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
Coating may be performed by applying one or more film forming polymers with or without other pharmaceutically inert excipients. This may be done as a solution or suspension using any conventional coating technique known in the prior art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip coating.
Suitable film forming polymers include one or more of ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes, methacrylic acid polymers such as Eudragit® RL and RS, and mixtures thereof. The coating can also be performed using any commercially available ready to coat preparations such as opadry-AMB, opadry-white, opadry-clear, etc.
Suitable solvents used for making a solution/suspension of film forming polymer include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.
The controlled-release alprazolam composition according to the present invention may be used to treat central nervous system disorder, more particularly a disorder wherein the alprazolam formulation is indicated. The composition may be administered in combination with other medicines, for example, other antianxiety agents.
The present invention is illustrated below by reference to the following example. However, one skilled in the art will appreciate that the specific methods and
results discussed are merely illustrative of the invention, and not to be construed as limiting the invention.
EXAMPLE: PREPARATION OF ALPRAZOLAM EXTENDED RELEASE 3mg TABLETS

Ingredients
Alprazolam Lactose
Hydroxypropyl methylcellulose Type 2208 DSP, 4000 cP
Hydroxypropyl methylcellulose Type 2208 USP, 100cP
Colloidal silicon dioxide
Magnesium stearate
Coloring agent

Example Percent (%) w/w
0.85
40.68
7.04
50.70
0.23
0.42
0.09

PROCEDURE:
1. Alprazolam, lactose, hydroxypropyl methylcellulose high viscosity,
hydroxypropyl methylcellulose low viscosity, colloidal silicon dioxide and
coloring agent were blended in a suitable V-blender and passed through
suitable mesh.
2. Magnesium stearate was mixed with the above mixture and compressed
using suitable punch.

In Vitro Dissolution Studies:
In vitro dissolution studies of the tablets prepared as per example was conducted in different release mediums using USP-I (rotating basket type) dissolution apparatus. The drug release from tablets of the present invention is steady, stable and reproducible. The release rate does not change with the pH of the dissolution medium. The release profiles in comparison with XANAX XR ® 3 mg tablets are shown in Fig. 1 to Fig. 4.
(Figure Removed)
In vivo bioequivalence study
In vivo performance of alprazolam controlled-release tablets prepared as per the composition of example was evaluated with respect to the XANAX XR® 3 mg tablets in healthy male volunteers under fasting and fed conditions. Pharmacokinetic parameters Cmax (Maximum plasma concentration), AUCt(Area under the plasma concentration vs. time curve from 0 hours to the time of last sample collected) and AUCinf (Area under the plasma concentration vs time curve from 0 hours to infinity) were calculated from the data obtained. Statistical analysis was carried out at 90% interval using "SAS" software package. The results of the study are given in the following table.

Pharmacokinetic data for tablets of example (T) vs. XANAX XR® 3mg tablets (R)

(Table Removed)

While there has been shown and described what are the preferred embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the formulations and process can be made without departing from the scope of the invention as it is defined by the appended claims.

WE CLAIM:
1. A controlled-release oral pharmaceutical composition comprising
alprazolam, high viscosity hydroxypropyl methylcellulose having a viscosity
from about 1,500 to about 225,000 cP and a low viscosity hydroxypropyl
methylcellulose having a viscosity from about 2 to about 400 cP, wherein
the high viscosity hydroxypropyl methylcellulose and low viscosity
hydroxypropyl methylcellulose are present in a weight ratio ranging from 1:2
to 1:10.
2. The composition according to claim 1 wherein the composition comprises
different amounts of alprazolam in the range from about 0.1 mg to about
5mg per tablet.
3. The composition according to claim 1 wherein the composition further
comprises one or more pharmaceutically acceptable excipients.
4. The composition according to claim 3 wherein the pharmaceutically
acceptable excipients comprise at least one or more of fillers, binders,
disintegrants, lubricants, glidants, coloring agents and flavoring agents.
5. The composition according to any of the preceding claims prepared by
process comprising one or more techniques of direct compression, dry
granulation and wet granulation.
6. The process according to claim 5 wherein the process comprise
compressing into solid dosage form.
7. A composition according to claim 6 wherein the composition is optionally
coated with one or more film forming agents.

8. A controlled-release alprazolam composition according to claim 1 exhibits
pharmacokinetic parameters comparable to the commercially available
XANAX XR® tablets (Alprazolam extended-release tablets, Pharmacia &
Upjohn Company; USA) and is complying with the USFDA criteria set for
bioequivalence.
9. A method of treating subject having a central nervous system disorder,
more particularly a disorder wherein the alprazolam formulation is indicated,
comprising a step of orally administering to the subject a therapeutically
effective amount of a pharmaceutical composition comprising alprazolam,
high viscosity hydroxypropyl methylcellulose having a viscosity from about
1,500 to about 225,000 cP and a low viscosity hydroxypropyl
methylcellulose having a viscosity from about 2 to about 400 cP, wherein
the high viscosity hydroxypropyl methylcellulose and low viscosity
hydroxypropyl methylcellulose are present in a weight ratio ranging from 1:2
to 1:10.
10. A controlled-release alprazolam composition comprising alprazolam and
one or more hydroxypropyl methylcelluloses (HPMCs) substantially as
described and illustrated herein.