Indian Patents. 225164:SUSTAINED RELEASE FORMULATION

Title of Invention	SUSTAINED RELEASE FORMULATION
Abstract	The present invention is directed towards the presentation of preparation of extended release Alprazolam formulation. The formulation thus obtained provides an efficient mode of delivery of Alprazolam in a continuous manner.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) The Patents Rules, 2000 COMPLETE SPECIFICATIION (See section 10 and rule 13) 1. TITLE OF THE INVENTION "SUSTAINED RELEASE FORMULATION" 2. APPLICANT (S) (a) NAME (b) NATIONALITY (c) ADDRESS :EMCURE PHARMACEUTICALS LTD. :India :12/2, F-II Block, MIDC, Pimpri, Pune-411018 Maharashtra, India FIELD OF THE INVENTION: The present invention provides a novel sustained release composition comprising alprazolam. INTRODUCTION: Benzodiazepines are a class of compounds, commonly known as tranquillizers and sleeping pills. Benzc Jiazepines are minor tranquillizers that affect the central nervous system by slowing down the body physically, mentally and emotionally as referred in patent US 3 849 434. The benzodiazepines act upon the central nervous system to reduce communication between certain neurons, lowering the level of activity in the brain. The benzodiazepines are a class of drugs with sedatives, anticonvulsant, and muscle relaxant properties as referred in patent US 3 109 843 including hypnotic and amnestic properties. Benzodiazepines are often used for short-term relief of severe, disabling anxiety or insomnia. The most common benzodiazepines prescribed are Xanax (Alprazolam), Valium (Diazepam), Serepax (Oxazepam), and Temazepam. Benzodiazepines act as CNS inactivators. Alprazolam i.e. (8-chloro-l-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4]) benzodi-azepine, which has been cited in US 3, 987, 052. According to the USFDA approval of alprazolam is used for the treatment of anxiety disorders and panic attacks. Anxiety disorders are characterized by unrealistic worry and apprehension, causing symptoms of restlessness, aches, trembling, shortness of breath, smothering sensation, palpitations, sweating, cold clammy hands, lightheadedness, flushing, exaggerated startle responses, problems concentrating, and insomnia. Panic attacks occur either unexpectedly or in certain situations (i.e. driving), and can require higher dosages of alprazolam. Xanax is also used in the treatment of panic disorder, which appears as unexpected panic attacks and may by accompanied by a fear of open spaces called agoraphobia. The immediate-release Alprazolam tablet formulation is currently marketed as Xanax ® tablets by PHARMACIA AND UPJOHN. (Ref: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/). Xanax® is delivered as an oral tablet with various strengths like 0.25mg, 0.5 mg, 1 mg and 2 mg. 2 The extended-release Alprazolam tablet formulation is currently marketed as Xanax® XR tablets by PHARMACIA AND UPJOHN. (Ref: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/). These tablets are marketed as an oral tablet in the dose strengths of 0.5 mg, 1 mg, 2 mg, and 3 mg. BACKGROUND OF THE INVENTION: Alprazoalm can be delivered via two methods. The first one being the immediate release mode. The immediate-release Alprazolam (XANAX ®) 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 disorders disclosed in US 2004/0006072 Al. However, such frequency of dosing is bothersome and can adversely affect patient stability. Further, breakthrough anxiety can be a problem in current dosing methods. The non immediate-release delivery systems may be broadly divided into following categories. (Ref: Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Page 1677) a) Delayed release: These release systems are those, which use repetitive, intermittent dosings of a drug from one or more immediate release units incorporated into a single dosage form. This release system provides a patient compliance, however, it does not produce or maintain uniform drug blood levels within the therapeutic range. b) Site-Specific and receptor release: This release system refers to a targeting of a drug directly to a certain biological location. c) Sustained-release: This system includes any drug delivery system that achieves slow release of drug over an extended period of time. If the system is successful at maintaining constant drug levels in the blood or target tissue, it is considered a controlled-release system. If it is unsuccessful at this, but extends the duration of action over that achieved by conventional delivery, it is considered a prolonged release system. Xanax ® tablet, which is an immediate release formulation of Alprazolam, are designated to be divided by the patient into equally sized portions for dose control as disclosed in Physicians Desk Reference, 58th edition (2004), pp 2798-2802. The immediate release tablet needs to be taken at frequent intervals. The shortcoming faced in the immediate release is maintaining the drug concentration in the blood level. As the drug level is not maintained, there exists peaks and trough 3 phenomena. Further, once the drug level descends down, during the trough interval, the panic attacks during this interval might create problems as referred in patent US 2004/0006072 A1. Moreover, the peak and trough delivery pattern provided by known dosage forms results in undesirable effects, such as sedation due to over dose of medication when reached at the peak point in the begining, memory impairment and abuse potential. The dividing of the dose is generally not appropriate for extended release dosage forms that are usually designed to administer as a whole. However, there exists a shortcoming with the alprazolam extended-release dosage form i.e. a wide range of dosage amount is prescribable, depending upon the nature and the severity being treated. Further, certain treatment regimens require different dosage amounts to be administered on different days. Further, extended release products contain a higher drug load and thus any loss of integrity of the release characteristics of the dosage forms has a potential problem as referred in http://www.australianprescriber.com/magazines/vol22no4/oral.htm. The release rate can also be altered by various factors including food and the rate of transit through the gut. Hence, it would be of great benefit to provide a sustained release alprazolam formulation system that is adaptable to a broad range of dosage strengths, yet exhibits substantial bioequivalence, when different dosage strengths are administered in an equal total dosage amount. One approach to solve this problem would be to provide all dosage strengths in an identical formulation, wherein higher dosage strengths are accommodated in proportionally larger dosage units. However, it is found preferable to provide all dosage strengths in tablets of similar total weight. This facilitates the avoidance of excessively small tablets for the lower dosage strengths, and excessively large tablets for higher dosage strengths. A good drug delivery system is expected to provide efficient delivery to target tissue, steady therapeutic concentrations and minimizing exposure to nontarget tissue. It is also possible to reduce the do>e or frequency and to improve compliance. The systems can enhance the therapeutic ratio and regimens of many existing agents that would not be useful in conventional dosage forms because of their toxicity or short half-lives. In this manner, a drug treatment is achieved, whose criteria are (a)better efficacy, (b)selectivity and (c)safety. 4 Further, there remains a need for an effective dosage form that provides a release of alprazolam over a period of time, which would cause a reduction in side effects associated with alprazolam dosings. Thus, a sustained-release formulation system for alprazolam is desired that accommodates dosage strengths over atleast a six fold range from 0.5 mg to 3 mg in substantially the same total dosage form weight, yet exhibits bioequivalence over a corresponding range of excipient/drug weight ratios. An approach to solve this problem would be to identify for a sustained-release dosage form utilizing an HFMC matrix, a suitable amount of mix of HPMC giving substantially equivalent in vivo release and absorption rates over a broad range of alprazolam loadings as referred in patent application US 20040006072. Though mentioned therein, the only exemplified total weight of HPMC is 121.2 mg, having 1:1 ratio only. Surprisingly, in our hand, we found that the in-vitro profile of the composition prepared according to US 2004/0006072 when compared with Xanax XR, the Standard Deviation (SD) as well as % Relative Standard Deviation (%RSD) showed substantially high figures. These substantially high figures relates to the high degree of fluctuations in the said composition comparative to Xanax XR, thus creating a demand for providing a better sustained release composition. Currently available alprazolam compositions do not provide the desired pharmaceutical effect. Hence, there is a need for providing better sustained release compositions. The use of lower quantities of (a) K4M HPMC and (b) KI00LVP HPMC gives comparatively better results with respect to drug release. Due to the same, there are less fluctuations in % related standard deviation. Hence, the pharmaceutical composition prepared according to the current invention is superior to the prior are compositions. The dissolution profile in biological system is reflected from in-vitro dissolution results. It is advisable to have better pharmaceutical composition having less fluctuations, which are inturn dependent on the in-vitro dissolution profile. Thus, the pharmaceutical composition according to the current embodiment is advantageous and better for patients as compared to the prior art compositions. 5 OBJECT OF THE INVENTION: The object of the invention is to provide an efficient mode of delivery of Alprazolam. SUMMARY OF THE INVENTION: According to the present invention, the efficient mode of extended release of Alprazolam is obtained by making use of less quantities of HPMC's. Thus, by making use of the same, Alprazolam formulation is obtained, which has less fluctuations in % related standard deviation as compared to the prior art compositions. BRIEF DESCRIPTION OF THE DRAWING: The subject matter of the invention is described in more detail herein after in connection with the exemplary embodiments illustrated in the drawing. Fig 1: Dissolution Profile of Xanax Xr vs Product of example 13 (3 mg Alprazolam) This figure refers to the dissolution profile of 3 mg tablet (prepared according to experiment discussed in Example 13), which indicates the comparative % dissolution data for 24 hours. The graph of time interval in hours on the X axis vs the % release on the Y axis is plotted. Fig 2: Dissolution Profile of Xanax Xr vs Product of example 10 (2 mg Alprazolam) This figure refers to the dissolution profile of 2 mg tablet (prepared according to experiment discussed in Example 10), which indicates the graphical representation of % dissolution data of Emcure's tablet for 24 hours. The graph of time interval in hours on the X axis vs the % release on the Y axis is plotted. Fig 3: Dissolution Profile of Xanax Xr vs Product of example 11 (0.5 mg Alprazolam) and This figure refers to the dissolution profile of 0.5 mg tablet (prepared according to experiment discussed in Example 11), which indicates the graphical representation of % dissolution data of Emcure's tablet for 24 hours. The graph of time interval in hours on the X axis vs the % release on the Y axis is plotted. 6 Fig 4: Dissolution Profile of Xanax Xr vs Product of example 12 (1 mg Alprazolam) This figure refers to the dissolution profile of 1 mg tablet (prepared according to experiment discussed in Example 12), which indicates the graphical representation of % dissolution data of Emcure's tablet for 24 hours. The graph of time interval in hours on the X axis vs the % release on the Y axis is plotted. DETAILED DESCRIPTION OF THE INVENTION: Alprazolam i.e. (8-chloro-l-methyl-6-phenyl-4/f-s-triazolo [4,3-a] [1,4] ) benzodi-azepine, is cited in US 3, 987, 052. It is well known in the prior art that the alprazolam is used in treatment of anxiety disorders and panic attacks. The immediate release formulation of alprazolam however, has certain disadvantages of peak and trough phenomena. The frequency of dosings is also more in case of immediate release tablets. Accordingly, the invention provides a sustained release pharmaceutical composition comprising: (a) a therapeutically effective amount of alprazolam, (b) a high viscosity hydroxy-propyl-methyl cellulose (HPMC) and low viscosity hydroxy-propyl-methyl cellulose (HPMC) in a ratio of 65:35 to 85:15, and (c) pharmaceutically acceptable excipients. The tablet of present invention contains alprazolam, distributed in a matrix that comprises HPMC(s) and other excipients as discussed herein. Hydroxy propyl methylcellulose, being a semi-synthetic material derived from cellulose, is a linear polymer comprised of etherified anhydrous glucose rings. There are broadly two types of HPMC viz high viscosity polymer and low viscosity polymer. Use of High viscosity polymer retards the rate of release to higher extent, whereas the use of low viscosity polymer retards the rate of release to comparatively lower extent. Furthermore, combination of both types of HPMCs or single type of HPMC is used depending upon the release pattern of interest. To prevent a tablet from immediately disintegrating a fast rate of hydration followed by quick gelation is necessary for a rate controlling polymer to form a protective gelatinous layer around the 7 matrix. The critical parameters of fast polymer hydration and gel layer formation are considered in case of a water-soluble drug and water-soluble excipients. HPMC is commercially available in various grades, under several trade names, including Methocel® E, F, J and K of dow chemicals, HPM of British Celanese Ltd., U.K., and Metalose ® SH of Shin-Etsu Ltd., Japan. The two polymer grades of METHOCEL most commonly used in controlled-release applications are K(HPMC 2208, USP) and E(HPMC 2910, USP). F-chemistry products (HPMC 2906, USP) are used less commonly. The various grades available under a given trade name typically represent differences in methoxy and hydropropoxy content as well as molecular weight of HPMC. The preferred HPMC, used for the retardation purpose 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 one aspect of the present invention, combination of both HPMCs i.e. (a) HPMC having high viscosity and (b) HPMC having low viscosity have been used. The term "high viscosity HPMC" herein refers to HPMC having a viscosity of about 1,500 to about 2,25,000 cP, and the term "low viscosity HPMC" herein refers to HPMC having a viscosity of about 2 to about 400 cP. The high viscosity grade polymers available are METHOCEL K4M Premium, K15M Premium, and K100M Premium. 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. Equivalent products are available from other sources as well. The low viscosity grade polymers available are K3P LV and K 100P LV. The preferred low viscosity HPMC is HPMC 2208 having a viscosity of about 80 to about 120 cP, which is illustratively available as Methocel® K4MP of Dow. Equivalent products are available from other sources as well. Our invention makes use of Methocel ® K4MP of Dow as a high viscosity polymer and a Methocel ® KI00LVP of Dow as a low viscosity polymer. US 2004/0006072 discloses the high viscosity HPMC to low viscosity HPMC to be 60:40 to 40:60. In our embodiment, both high viscosity and low visocity HPMC are present in the particular composition ranging from about 65:35 to 85:15. The preferred ratio being 65:35 to 75:25. The most preferred ratio being 70:30. Further, the total amount 8 of HPMC used is also less as compared to patent application US 2004/0006072. US 2004/0006072 claims the total polymer weight to be of about 110 to 135 mg. However, we use about 70 to 100 mg. of the polymer thus making our invention cost effective. The preferred range for the weight of the polymer in the tablet is 75 to 90 mg. It may be noted that the ratio of mix of HPMC, as well as having different total weight of mix of HPMC gives the interesting results, which are better than the immediate release profile, which eliminates the problems associated with peak and trough issue. The use of lower quantities of (a) K4M HPMC and (lb) K100LVP HPMC gives comparatively better results to the said pharmaceutical composition, such as with respect to drug release. Due to the same, there are less fluctuations in % related standard deviation. Hence, the pharmaceutical composition prepared according to the current invention is superior to the prior art compositions. The dissolution profile in biological system is reflected from in-vitro dissolution results. It is advisable to have better pharmaceutical composition having less fluctuations, which are in turn dependent on the in-vitro dissolution profile. Thus, the pharmaceutical composition according to the current embodiment is advantageous and better for patients. The other excipient used in our tablet invention is lactose. Lactose is used as a preferred diluent. Lactose is widely used as a filler or filler-binder in the manufacture of pharmaceutical tablets and capsules. The general properties of lactose which make a contribution to its usage in formulation are (a) cost effectiveness, (b) easy availability, (c) low hygroscopicity, (d) compatibility with the active ingredients, (e) stability, (f) water solubility etc. Lactose monohydrate is used in one of the embodiment. The amount of lactose used in our invention is about 300 mg for 3 mg of alprazolam. Alprazolam is primarily mixed with lactose and then the further processing is done. Magnesium stearate is an excipient, which is used as a lubricant, to prevent the compacted powder mass from sticking to the equipment during the tabletting or encapsulation process and allow easy ejection of the tablet during tablet formation. However, over lubrication may result into coating of the hydrophobic material on the tablet and thereby retard the release rate. Hence, an appropriate amount of Magnesium Stearate is necessary. 9 In another embodiment colloidal silicon dioxide is used. The most commonly used "glidant" in solid oral dosage form formulations is colloidal silicon dioxide; also know by the trade names of Cab-o-Sil or Aerosil. This material is extremely effective in improving the overall flow characteristics of a blend by coating the surfaces of its' components thereby reducing their inter-particulate friction. The colouring agents optionally can be added at the appropriate stage of preparation of pharmaceutical composition in suitable quantities. It can be along with the lactose. The said colouring agents can be selected from any pharmaceutically acceptable colouring agents. The preferred colouring agents are Lake green blend LB-51426 or D & C Yellow No 10. The ingredients can be sifted independently or in combination with other ingredients, at the appropriate stage. According to the present invention, the strength of sustained release tablets of alprazolam is in the range of 0.5 mg to 3.0 mg equivalent to base. ADVANTAGES: The advantages of the sustained release composition prepared according to the invention are as under: i. The composition provides a convenient method of delivery of alprazolam and avoids the frequency of dosages taken by the patient. ii. The composition provides a mode of release of alprazolam that is adaptable to a broad range of dosage strengths. iii. The composition delivers alprazolam in a continuous manner so that the peak and trough phenomena would be practically inexistent iv. The composition provides alprazolam in such a dosage that the drug concentration in the blood is maintained for a longer period of time v. The composition makes use of the high viscosity and low viscosity HPMC in such a weight ratio so as to avoid bioequivalent fluctuations. 10 vi. The invention provides a process for the preparation of Alprazolam fomulation which is simple, having less number of steps, involving less man power, having smaller time cycle, providing good yields, with a good purity profile, industrially feasible and economical. vii. The invention reduces the total quantities of HPMC and making the process cost effective and industrial friendly. The sustained release tablets according to the instant invention are prepared according to the following process steps comprising of; a) Mixing Alprazolam with lactose and optionally the coloring agents in geometric proportion. b) Sifting the mixture to obtain the homogeneous blend. c) Adding HPMC K-4M and HPMC K-100 LVP to the blend from step (b) and mixing to get a homogenous blend. d) Granulating the blend with water. e) Drying the wet mass. f) Reducing the size of dried granules followed by lubrication and g) compressing to form tablet. The dissolution procedure for the tablets can be carried out as per the procedure known in the art using following parameters. The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, 11 however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention. The present invention is more particularly illustrated in the following example(s), but is not to limit the scope of the present invention. Example 1: (70:30; 90 mg polymer) Tablets having the tabulated composition were prepared by the procedure, mentioned above. Alprazolam was mixed with Lactose* in geometric proportion. The mixture was sifted to obtain the homogeneous blend. HPMC K-4M and HPMC K-100 LVP were added to the above blend and mixed to get a homogenous blend. The blend was granulated with water. The wet mass was dried. The size of dried granules was reduced followed by lubrication and was compressed to form a tablet. "'Optionally the coloring agent(s) are added, if required. In Example 1, the coloring agents are not added. Table-1 SERIAL NUMBER I INGREDIENTS 1 WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydrate USPNF 248.25 3 Hydroxy Propyl Methyl 63.0 Cellulose K-4M 4 Hydroxy Propyl Methyl TLO Cellulose K-100LVP 5 Colloidal Silicon Dioxide 0/75 (Aerosil-200)USPNF 6 Magnesium Stearate USPNF 3XJ0 7 Purified Water q.s. Total weight 345 12 Example 2: (70:30; 90 mg polymer) Tablets having the tabulated composition were prepared by the procedure, mentioned above. Table-2 SERIAL NUMBER I INGREDIENTS I WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydrate 247.19 USPNF 3 Hydroxy Propyl Methyl 63.0 Cellulose K-4M 4 Hydroxy Propyl Methyl 2X0 Cellulose K-100LVP 5 Colloidal Silicon Dioxide 0J5 (Aerosil-200)USPNF 6 Magnesium Stearate 3.00 USPNF 7 Purified Water q.s. 8 Green Color 035 Total weight 344.29 The obtained dissolution profile: Table-3 Time I EMCURE-SR (90 mg, Ratio 70 : 30) _ _ 1 1086 2 17395 4 2836 8 44i82 _ __ 12 5X89 13 14 I 6Z86 18 7051 24~ 78J2 Example 3: (65:35; 80 mg polymer) Tablets having the tabulated composition were prepared by the procedure, as mentioned above. Table-4 SERIAL NUMBER I INGREDIENTS I WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydrate 258.25 USPNF 3 Hydroxy Propyl Methyl 52 Cellulose K-4M 4 Hydroxy Propyl Methyl 28 Cellulose K-100LVP 5 Colloidal Silicon Dioxide 0.75 6 Magnesium Stearate 3.00 7 Purified Water q.s. Total weight 345 The obtained dissolution profile: Table-5 Time I XANAX-SR I EMCURE-SR 0 0 0 1 12JH) 143 ~ 2 21.80 23A 4 35X) 372 8 5T90 608 10 63/7 ■ 731 14 12 \| 704 \| 864 14 __ __ 18 86\8 10L9 24 90/7 T018 Example 4: (70:30; 80 mg polymer) Tablets having the tabulated composition were prepared by the procedure as mentioned above. Table-6 SERIAL NUMBER I INGREDIENTS I WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydrate 258.25 USPNF 3 Hydroxy Propyl Methyl 56 Cellulose K-4M 4 Hydroxy Propyl Methyl 24 Cellulose K-l 00 LVP 5 Colloidal Silicon Dioxide 0/75 6 Magnesium Stearate 3.00 7 Purified Water q.s. Total weight 345 The obtained dissolution profile: Table-7 Time I EMCURE-SR 0 0 1 10.7 2 182 4 293 J\| 8 \| 40 10 605 _ __ 14 TL9 18 842 24 88^0 Example 5: (75:25; 80 mg polymer) Tablets having the tabulated composition were prepared by procedure, as mentioned above. Table-8 SERIAL NUMBER I INGREDIENTS I WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydrate USPNF 258.25 3 Hydroxy Propyl Methyl Cellulose 60 K-4M 4 Hydroxy Propyl Methyl Cellulose 20 K-100LVP 5 Colloidal Silicon Dioxide 0J5 6 Magnesium Stearate 3.00 7 Purified Water q.s. Total weight 345 The obtained dissolution profile: Table-9 Time I EMCURE-SR 0 0 1 13.6 2 2L3 16 * 4 I : 32/7 8 54l 10 654 _ . __ 14 83T8 18 80 24 913 Example 6: (70:30; 100 mg polymer) Tablets having the tabulated composition were prepared by the procedure, as mentioned above. Table-10 SERIAL NUMBER I INGREDIENTS I WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydrate USPNF 238.25 3 Hydroxy Propyl Methyl Cellulose K- 70 4M 4 Hydroxy Propyl Methyl Cellulose K- 30 100 LVP 5 Colloidal Silicon Dioxide 0J5 6 Magnesium Stearate 3.00 7 Purified Water q.s. Total weight 345 The obtained dissolution profile: Table-11 Time I EMCURE-SR ° 0 1 11.42 17 . _ _____ 8 4_T06 10 55^01 12 64^67 14 7Z93 : 18 8536 24 9622 Example 7: (Direct compression experiment) (70:30; 80 mg polymer) Tablets having the tabulated composition were prepared by the procedure, as mentioned above. Table-12 SERIAL NUMBER I INGREDIENT I WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydrate USPNF 258.25 3 Hydroxy Propyl Methyl Cellulose 56 K-4M 4 Hydroxy Propyl Methyl Cellulose 24 K-100LVP 5 Colloidal Silicon Dioxide 0?75 6 Magnesium Stearate 3.00 7 Purified Water q.s. Total weight 345 The obtained dissolution profile: Table-13 Time I EMCURE-SR 0 ~ 0 ~ 1 16.9 18 1 2 I 274 4 44J 8 67\9 10 79^6 12 87l 14 944 18 96J 24 963 Example 8: (Making use of just K4M HPMC) (80:0; 80 mg polymer) Tablets having the tabulated composition were prepared by the procedure, as mentioned above. Table-14 SERIAL NUMBER I INGREDIENTS I WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydralte USPNF 25825 3 Hydroxy Propyl Methyl Cellulose K-4M 80 4 Hydroxy Propyl Methyl Cellulose K-100 - LVP 5 Colloidal Silicon Dioxide 075 6 Magnesium Stearate 3.00 7 Purified Water q.s. Total weight 345 The obtained dissolution profile: Table-15 Time I EMCURE-SR 0 0 1 10.1 19 1 2 \| 1677 4 262 8 404 _ __ 12 55^6 14 65/7 18 712 24 773 Example 9: (Making use of just K100 LVP HPMC) (0:80; 80 mg polymer) Tablets having the tabulated composition were prepared by the procedure as mentioned above. Table-16 SERIAL NUMBER I INGREDIENTS I WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydrate 258.25 USPNF 3 Hydroxy Propyl Methyl Cellulose K-4M 4 Hydroxy Propyl Methyl 80 Cellulose K-100 LVP 5 Colloidal Silicon Dioxide 0?75 6 Magnesium Stearate 3.00 7 Purified Water q.s. Total weight 345 20 Time I EMCURE-SR 0 0 1 17.3 2 315 4 65~1 8 882 _ _ 12 90J 14 8^9 ""18 89l) "~ 24 8X4 Example 10: (70:30; 80 mg polymer; 2.00 mg Alprazolam) Tablets having the tabulated composition were prepared by the procedure, as mentioned above. Table-18 SERIAL NUMBER I INGREDIENTS j WEIGHT (mg) 1 Alprazolam 2.0 2 Lactose monohydrate 259.25 USPNF 3 Hydroxy Propyl Methyl 56.00 Cellulose K-4M 4 Hydroxy Propyl Methyl 24.00 Cellulose K-100LVP 5 Colloidal Silicon Dioxide 0?75 6 Magnesium Stearate 3.00 Total weight 345 21 Time I EMCURE-SR 0 ~ o 1 13.3 2 20J 4 323 8 516 10 65~!6 12 : 75l) 16 ; 873 20 9L7 24 93J8 Example 11: (70:30; 80 mg polymer; 0.50 mg Alprazolam) Tablets having the tabulated composition were prepared by the procedure as mentioned above. Table-20 SERIAL NUMBER \| INGREDIENTS I WEIGHT (mg) 1 Alprazolam 0.50 2 Lactose monohydrate 260.75 USPNF 3 Hydroxy Propyl Methyl 56.00 Cellulose K-4M 4 Hydroxy Propyl Mtethyl 24.00 Cellulose K-l 00 LVP 5 Colloidal Silicon Dioxide 0?75 6 Magnesium Stearate 3.00 Total weight 345 22 Time I EMCURE-SR 0 0.0 1 24.6 _ _ _ _ 6 73~7 8 843 _ __ 12 97.6 20 9L7 24 9T8 Conclusion: The dissolution profile when compared with Xanax showed a comparable release pattern. Example 12: (70:30; 80 mg polymer; 1.00 mg Alprazolam) Tablets having the tabulated composition were prepared by the procedure, as mentioned above. Color was mixed with some part of lactose and sifted through 100#mesh Alprazolam was mixed with lactose in geometric proportion and sifted through 40 mesh. HPMC K-4M and HPMC K-100 LVP are sifted through 40 mesh and mixed with above blend. This homogenous blend was granulated with water to form wet mass. Wet mass was dried and then crushed to form dried granules. Dried granules were lubricated and compressed to tablet with suitable punches. Tahle-22 SERIAL NUMBER I INGREDffiNTS I WEIGHT (mg) 1 Alprazolam 1.0 2 Lactose monohydirate USPNF 260.00 23 f 3 I Hydroxy Propyl Methyl Cellulose K-4M I 56.00 4 Hydroxy Propyl Methyl Cellulose K-100 LVP 24.00 5 Colloidal Silicon Dioxide 0/75 6 Magnesium Stearate 3.00 7 D&C Yellow No. 10 025 ~~ 8 Purified Water q.s. Total weight 345 The obtained dissolution profile: Table-23 Time I EMCURE-SR 0 0 1 17.3 2 28^2 __ __ _ __ 10 '■ 793 12 86^6 14 __ 18 94^ _ __ According to the instant invention, the Alprazolam ER tablets are prepared as per Example Number 4. The dissolution experiments of the said tablets was carried out. Exactly similar dissolution experiment was carried out with respect to the Alprazolam ER tablets obtained from the public domain i.e Xanax XR of Pharmacia Upjon ; Batch No. 63 MCX. The experimental procedure and results of the above experiments is provided below in Table-25 and Table-26. 24 Experimental procedure for the preparation of product of Example 13 Table-24 SERIAL NUMBER I INGREDIENTS I WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydrate USPNF 257.9 3 Hydroxy Propyl Methyl Cellulose K-4M 56\0 4 Hydroxy Propyl Methyl Cellulose K-100 LVP 24l) 5 Colloidal Silicon Dioxide 0/75 6 Magnesium Stearate 3.0 7 Lake Green Blend LB-51426 035 Total weight 345 Example 13: Color was mixed with some part of lactose and sifted through 100#mesh Alprazolam was mixed with lactose in geometric proportion and sifted through 40 mesh. HPMC K-4M and HPMC K-100 LVP are sifted through 40 mesh and mixed with above blend. This homogenous blend was granulated with water to form wet mass. Wet mass was dried and then crushed to form dried granules. Dried granules were lubricated and compressed to tablet with suitable punches. Three tablets under study were prepared with the above procedure. The tablets according to Example 13 are exactly similar to that of Example 4, except the addition of colour, which is optional. The colour is non-functional excipient with respect to the sustained release profile. Thus, for SR purposes, the Example 4 and Example 13 are same. Experimental procedure of dissolution test for the comparative study The dissolution is carried out by using following parameters Medium : Mixed Phosphate Buffer pH 6.0 ±0.1 Volume : 500 ml Apparatus \| : USPI (Basket) ~ 25 Speed : 100 rpm Temperature : 37.0° C Time Interval : lHr, 4Hr, 8Hr, lOHr, 12Hr, 14Hr, 18Hr, 24Hr. Withdrawal volume : 5 ml Table-25 Dissolution results of Xanax XR of Pharmacia Upjohn. Batch Number 63MCX; % Drug release. Time Interval Minimum Maximum Average S.D. %R.S.D. lHour 11.52 12.75 12.32 0.46 3.73 4 Hour 28.47 35.25 33.10 2.53 7.65 8 Hour 48.41 57.54 55.01 3.42 6.22 10 Hour 63.85 71.31 66.64 2.53 3.79 12 Hour 70.25 77.41 72.98 2.48 3.40 14 Hour 75.13 80.20 78.09 1.86 2.38 18 Hour 82.55 94.45 87.70 4.37 4.98 24 Hour 1 88.18 \| 98.92 \| 94.16 \| 4.10 \| 4.35 TabIe-26 Dissolution results of Alprazolam Extended Release (Emcure) Batch Number FD/1616/05; % Release Time Interval Minimum Maximum Average S.D. %R.S.D. lHour 10J8 11.23 10.99 0.23 2.06 4 Hour 29.88 30.49 30.13 9.32 1.07 8 Hour 48/73 50.13 49.60 0.76 1.53 10 Hour 6035 62.07 61.37 0.91 1.48 12 Hour 69,21 71.44 70.39 1.12 1.59 14 Hour 76^06 78.30 77.05 1.15 1.49 i 8 Hour 8152 85.99 84.81 1.24 1.46 24 Hour 1 91.69 \| 93.59 \| 92.91 \| 1.06 \| 1.14 Comparitive data of bioavailability of Alprazolam 3 mg extended release tablets of Pharmacia and Upjohn (Xanax XR) vs Alprazolam 3 mg extended-release tablets of Emcure Pharmaceuticals. Example 14 Products Evaluated: 26 Test Product: Alprazolam extended release tablet 3 mg according to the present invention (Example 4): Batch/Lot No: EM 5Y009 Reference Product: XANAX XR tablets 3 mg-Pharmacia Upjohn Company, USA Batch/Lot No: 95 MMJ The experiment was carried out on 12 human subjects. One dose of either test or reference was administered orally. After the period of seven days, the another respective dose was administered orally such that the volunteer gets the dose of both test and reference. Comparitive data for concentration of Alprazolam in human plasma. Table-27 Time Standard Deviation of Standard Deviation of Mean concentration of Data Emcure's Test Sample Xanax XR (95 MMJ) of Emcure's test sample (Product of Example 4) Pharmacia Upjohn (EM 5Y 009) r\gfmblJO 0.139 (U82 0.040 3l)0 5l41 4^877 19.323 (TOO 5T890 6463 23.452 9M TMl " 7359 26.171 12.00 5282 5lS4 25.510 16^00 4.818 5398 22.429 20.00 5TT2I 5734 19728 24.00 5369 574(5 18.547 36.00 4.086 51)83 10.924 48.00 3.491 4385 6.819 72.00 2lT0 2233 2T823 It may be evident from examples 1-12 that the composition of examples 1-7 and 10-12 exhibit a release pattern, wherein the composition comprising alprazolam is released over a period of about 24 27 hours, i.e. between 20-40% in 4 hours to more than 70% in 40 hours of the total dose. Usually the Cmax is reached 3 hours after administration. In examples 8 & 9, where only high viscosity HPMC or low viscosity HPMC are used, the release pattern varies and is below the desirable standard. Further, from table 25 it is clear that Xanax XR exhibits a large standard deviation in its release profile. Comparatively, the composition of the invention exhibits much less deviation, which shows that the peak-trough effect in case of the composition of the invention is negligible or non-existent. According to the instant invention, the Alprazolam SR tablets are prepared as per Experiment Number 4. The dissolution experiments of the said tablets was carried out and compared with the tablets prepared as per the compositions known in the prior art. The experimental procedure and results of the above experiments is provided below in Table-28 and Table-29. Table-28 (Compositions known in prior art) SERIAL NUMBER I INGREDIENTS I WEIGHT (mg) 1 Alprazolam 3.0 2 Lactose monohydrate (Lactose DCL 11) 221.7 3 Hydroxy Propyl Methyl Cellulose K-4M 60JO 4 Hydroxy Propyl Methyl Cellulose K-100 60li LVP 5 Colloidal Silicon Dioxide 075 6 Magnesium Stearate 1.5 7 D&CYellow#10 024 8 FD&C Blue # 2 Aluminum Lake 0M Total weight 348.6 Example 15: Color was mixed with some part of lactose and sifted through 100 # mesh Alprazolam was mixed with lactose in geometric proportion and sifted through 40 mesh. This was added to the above blend. HPMC K-4M and HPMC K-100 LVP are sifted through 40 mesh and 28 mixed with above blend. Colloidal silicon dioxide was sifted through 40 #. Magnesium stearate was also sifted through 40 # and both were mixed to the above blend. The entire blend was compressed to tablet with suitable punch. Three tablets under study were prepared with the above procedure. Experimental procedure of dissolution test for the comparative study. The dissolution is carried out by using following parameters Medium : Mixed Phosphate Buffer pH 6.0 + 0.1 Volume : 500 ml Apparatus : USPI (Basket) Speed : 100 rpm Temperature : 37.0° C Time Interval : lHr, 4Hr, 8Hr, lOHr, 12Hr, 14Hr, 18Hr, 24Hr. Withdrawal volume \| : 5 ml Table-25 Dissolution results of Xanax XR of Pharmacia Upjohn. Batch Number 63MCX; % Drug release. Time Interval Minimum Maximum Average S.D. %R.S.D. 1 Hour 11.52 12.75 12.32 0.46 3.73 4 Hour 28.47 35.25 33.10 2.53 7.65 8 Hour 48.41 57.54 55.01 3.42 6.22 10 Hour 63.85 71.31 66.64 2.53 3.79 12 Hour 70.25 77.41 72.98 2.48 3.40 14 Hour 75.13 80.20 78.09 1.86 2.38 18 Hour 82.55 94.45 87.70 4.37 4.98 24 Hour 1 88.18 \| 98.92 \| 94^16 [ 4.10 \| 4.35 Table-26 Dissolution results of Alprazolam Extended Release (Emcure) Batch Number FD/1616/05; % Release Time Interval Minimum Maximum Average S.D. %R.S.D. lHour 10J8 11.23 10.99 0.23 2.06 4 Hour 29.88 30.49 30.13 0.32 1.07 8 Hour I 48.73 \| 50.13 \| 49.60 \| 0.76 \| 1.53 29 10 Hour 1 60.35 I 62.07 I 61.37 1 0.91 I 1.48 12 Hour 6921 71.44 70.39 1.12 1.59 14 Hour 76.06 78.30 77.05 1.15 1.49 18 Hour 83.52 85.99 84.81 1.24 1.46 24 Hour I 91.69 \| 93.59 \| 92.91 \| 1.06 \| 1.14 Table-27 Dissolution results of Alprazolam Extended Release (Prior art US 2004/0006072) Batch Number AZM/05/029; % Release Time Interval Minimum Maximum Average S.D. %R.S.D. lHour 12J0O 14.10 13.60 0.40 3.00 4 Hour 3L00 36.10 34.90 0.80 2.30 8 Hour 47.90 59.30 57.20 4.70 8.20 10 Hour 59,40 73.00 68.40 6.80 9.90 12 Hour 68.30 80.50 77.10 8.30 10.00 14 Hour 8T70 90.00 86.40 8.30 10.00 18 Hour 90.50 98.10 92.90 3.60 3.90 24 Hour 1 95.40 1 101.50 \| 95.00 \| 3.30 \| 3.50 WE CLAIM: 1. A sustained release pharmaceutical composition comprising: (a) a therapeutically effective amount of alprazolam, (b) a high viscosity hydroxy-propyl-methyl cellulose (HPMC) and low viscosity hydroxy-propyl-methyl cellulose (HPMC) in a ratio of 65:35 to 85:15, and (c) pharmaceutically acceptable excipients. 2. A composition as claimed in claim 1, wherein the amount of alprazolam is between lmg and 5mg. 3. A composition as claimed in claim 1, wherein the alprazolam is a pharmaceutically acceptable salt of alprazolam. 4. A composition as claimed in claim 1, wherein the high viscosity HPMC has about 19% to about 24% by weight of methoxy substituent, and about 4% to about 12% by weight of hydroxypropoxy substituent. 5. A composition as claimed in claim 1, wherein the high viscosity HPMC has a viscosity of about 1500 to about 2,25,000 cp. 6. A composition as claimed in claim 1, wherein the low viscosity HPMC has a viscosity of about 2 to about 400 cp. 7. A composition as claimed in claim 1, wherein the high viscosity HPMC is selected from the group comprising of K4M Premium, K15 M Premium and K100 M premium. 8. A composition as claimed in claim 1, wherein the high viscosity HPMC preferably used is K4M Premium. 9. A composition as claimed in claim 1, wherein the low viscosity HPMC is selected from the group comprising of K3 P LV and K 100P LV. 10. A composition as claimed in claim 1, wherein the high viscosity HPMC preferably used is K 100LVP. 31 11. A composition as claimed in claim 1, wherein the preferable ratio of high viscosity HPMC to low viscosity HPMC is 65:35 to 75:25. 12. A composition as claimed in claim 1, wherein the more preferable ratio of high viscosity HPMC to low viscosity HPMC is 70:30. 13. A composition as claimed in claim 1, wherein the composition provides a total daily dose of about 0.5 mg to about 3 mg of alprazolam. 14. A composition as claimed in claim 1, wherein the composition is configured to release alprazolam at a rate that ranges between 20% to 40% in 4 hours to more than 70% in 14 hours of the total dose of alprazolam after the exposure to phosphate buffer having pH 6.0 + 0.1. 15. A composition as claimed in claim 1, wherein the Cmax occurs more than 3 hours after administration. 16. The process for the preparation of sustained release composition of Alprazolam, comprising the steps of: Mixing Alprazolam with lactose and optionally the coloring agents in geometric proportion Sifting the mixture to obtain the homogeneous blend. Adding HPMC K-4M and HPMC K-100 LVP to the blend from step (b) Granulating the blend with water to form wet mass. Drying the wet mass Forming granules and Compressing to form tablet. 17. The process for the preparation of sustained release composition of Alprazolam, as described herein with respect to the foregoing examples. 32 ABSTRACT The present invention is directed towards the preparation of extended release Alprazolam formulation. The formulation thus obtained provides an efficient mode of delivery of Alprazolam in a continuous manner. 33

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
The Patents Rules, 2000
COMPLETE SPECIFICATIION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
"SUSTAINED RELEASE FORMULATION"

2. APPLICANT (S)
(a) NAME
(b) NATIONALITY
(c) ADDRESS

:EMCURE PHARMACEUTICALS LTD.
:India
:12/2, F-II Block, MIDC, Pimpri,
Pune-411018 Maharashtra, India

FIELD OF THE INVENTION:
The present invention provides a novel sustained release composition comprising alprazolam.
INTRODUCTION:
Benzodiazepines are a class of compounds, commonly known as tranquillizers and sleeping pills. Benzc Jiazepines are minor tranquillizers that affect the central nervous system by slowing down the body physically, mentally and emotionally as referred in patent US 3 849 434. The benzodiazepines act upon the central nervous system to reduce communication between certain neurons, lowering the level of activity in the brain. The benzodiazepines are a class of drugs with sedatives, anticonvulsant, and muscle relaxant properties as referred in patent US 3 109 843 including hypnotic and amnestic properties. Benzodiazepines are often used for short-term relief of severe, disabling anxiety or insomnia. The most common benzodiazepines prescribed are Xanax (Alprazolam), Valium (Diazepam), Serepax (Oxazepam), and Temazepam. Benzodiazepines act as CNS inactivators.
Alprazolam i.e. (8-chloro-l-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4]) benzodi-azepine, which has been cited in US 3, 987, 052. According to the USFDA approval of alprazolam is used for the treatment of anxiety disorders and panic attacks. Anxiety disorders are characterized by unrealistic worry and apprehension, causing symptoms of restlessness, aches, trembling, shortness of breath, smothering sensation, palpitations, sweating, cold clammy hands, lightheadedness, flushing, exaggerated startle responses, problems concentrating, and insomnia. Panic attacks occur either unexpectedly or in certain situations (i.e. driving), and can require higher dosages of alprazolam. Xanax is also used in the treatment of panic disorder, which appears as unexpected panic attacks and may by accompanied by a fear of open spaces called agoraphobia.

The immediate-release Alprazolam tablet formulation is currently marketed as Xanax ® tablets by PHARMACIA AND UPJOHN. (Ref: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/). Xanax® is delivered as an oral tablet with various strengths like 0.25mg, 0.5 mg, 1 mg and 2 mg.
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The extended-release Alprazolam tablet formulation is currently marketed as Xanax® XR tablets by PHARMACIA AND UPJOHN. (Ref: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/). These tablets are marketed as an oral tablet in the dose strengths of 0.5 mg, 1 mg, 2 mg, and 3 mg.
BACKGROUND OF THE INVENTION:
Alprazoalm can be delivered via two methods. The first one being the immediate release mode. The immediate-release Alprazolam (XANAX ®) 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 disorders disclosed in US 2004/0006072 Al. However, such frequency of dosing is bothersome and can adversely affect patient stability. Further, breakthrough anxiety can be a problem in current dosing methods.
The non immediate-release delivery systems may be broadly divided into following categories. (Ref: Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Page 1677)
a) Delayed release: These release systems are those, which use repetitive, intermittent dosings of a drug from one or more immediate release units incorporated into a single dosage form. This release system provides a patient compliance, however, it does not produce or maintain uniform drug blood levels within the therapeutic range.
b) Site-Specific and receptor release: This release system refers to a targeting of a drug directly to a certain biological location.
c) Sustained-release: This system includes any drug delivery system that achieves slow release of drug over an extended period of time. If the system is successful at maintaining constant drug levels in the blood or target tissue, it is considered a controlled-release system. If it is unsuccessful at this, but extends the duration of action over that achieved by conventional delivery, it is considered a prolonged release system.
Xanax ® tablet, which is an immediate release formulation of Alprazolam, are designated to be divided by the patient into equally sized portions for dose control as disclosed in Physicians Desk Reference, 58th edition (2004), pp 2798-2802. The immediate release tablet needs to be taken at frequent intervals. The shortcoming faced in the immediate release is maintaining the drug concentration in the blood level. As the drug level is not maintained, there exists peaks and trough
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phenomena. Further, once the drug level descends down, during the trough interval, the panic attacks during this interval might create problems as referred in patent US 2004/0006072 A1. Moreover, the peak and trough delivery pattern provided by known dosage forms results in undesirable effects, such as sedation due to over dose of medication when reached at the peak point in the begining, memory impairment and abuse potential.
The dividing of the dose is generally not appropriate for extended release dosage forms that are usually designed to administer as a whole. However, there exists a shortcoming with the alprazolam extended-release dosage form i.e. a wide range of dosage amount is prescribable, depending upon the nature and the severity being treated. Further, certain treatment regimens require different dosage amounts to be administered on different days. Further, extended release products contain a higher drug load and thus any loss of integrity of the release characteristics of the dosage forms has a potential problem as referred in http://www.australianprescriber.com/magazines/vol22no4/oral.htm. The release rate can also be altered by various factors including food and the rate of transit through the gut.
Hence, it would be of great benefit to provide a sustained release alprazolam formulation system that is adaptable to a broad range of dosage strengths, yet exhibits substantial bioequivalence, when different dosage strengths are administered in an equal total dosage amount. One approach to solve this problem would be to provide all dosage strengths in an identical formulation, wherein higher dosage strengths are accommodated in proportionally larger dosage units. However, it is found preferable to provide all dosage strengths in tablets of similar total weight. This facilitates the avoidance of excessively small tablets for the lower dosage strengths, and excessively large tablets for higher dosage strengths.
A good drug delivery system is expected to provide efficient delivery to target tissue, steady therapeutic concentrations and minimizing exposure to nontarget tissue. It is also possible to reduce the do>e or frequency and to improve compliance. The systems can enhance the therapeutic ratio and regimens of many existing agents that would not be useful in conventional dosage forms because of their toxicity or short half-lives. In this manner, a drug treatment is achieved, whose criteria are (a)better efficacy, (b)selectivity and (c)safety.
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Further, there remains a need for an effective dosage form that provides a release of alprazolam over a period of time, which would cause a reduction in side effects associated with alprazolam dosings.
Thus, a sustained-release formulation system for alprazolam is desired that accommodates dosage strengths over atleast a six fold range from 0.5 mg to 3 mg in substantially the same total dosage form weight, yet exhibits bioequivalence over a corresponding range of excipient/drug weight ratios.
An approach to solve this problem would be to identify for a sustained-release dosage form utilizing an HFMC matrix, a suitable amount of mix of HPMC giving substantially equivalent in vivo release and absorption rates over a broad range of alprazolam loadings as referred in patent application US 20040006072. Though mentioned therein, the only exemplified total weight of HPMC is 121.2 mg, having 1:1 ratio only. Surprisingly, in our hand, we found that the in-vitro profile of the composition prepared according to US 2004/0006072 when compared with Xanax XR, the Standard Deviation (SD) as well as % Relative Standard Deviation (%RSD) showed substantially high figures. These substantially high figures relates to the high degree of fluctuations in the said composition comparative to Xanax XR, thus creating a demand for providing a better sustained release composition.
Currently available alprazolam compositions do not provide the desired pharmaceutical effect. Hence, there is a need for providing better sustained release compositions.
The use of lower quantities of (a) K4M HPMC and (b) KI00LVP HPMC gives comparatively better results with respect to drug release. Due to the same, there are less fluctuations in % related standard deviation. Hence, the pharmaceutical composition prepared according to the current invention is superior to the prior are compositions.
The dissolution profile in biological system is reflected from in-vitro dissolution results. It is advisable to have better pharmaceutical composition having less fluctuations, which are inturn dependent on the in-vitro dissolution profile. Thus, the pharmaceutical composition according to the current embodiment is advantageous and better for patients as compared to the prior art compositions.
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OBJECT OF THE INVENTION:
The object of the invention is to provide an efficient mode of delivery of Alprazolam.
SUMMARY OF THE INVENTION:
According to the present invention, the efficient mode of extended release of Alprazolam is obtained by making use of less quantities of HPMC's. Thus, by making use of the same, Alprazolam formulation is obtained, which has less fluctuations in % related standard deviation as compared to the prior art compositions.
BRIEF DESCRIPTION OF THE DRAWING:
The subject matter of the invention is described in more detail herein after in connection with the exemplary embodiments illustrated in the drawing.
Fig 1: Dissolution Profile of Xanax Xr vs Product of example 13 (3 mg Alprazolam)
This figure refers to the dissolution profile of 3 mg tablet (prepared according to experiment discussed in Example 13), which indicates the comparative % dissolution data for 24 hours. The graph of time interval in hours on the X axis vs the % release on the Y axis is plotted.
Fig 2: Dissolution Profile of Xanax Xr vs Product of example 10 (2 mg Alprazolam)
This figure refers to the dissolution profile of 2 mg tablet (prepared according to experiment discussed in Example 10), which indicates the graphical representation of % dissolution data of Emcure's tablet for 24 hours. The graph of time interval in hours on the X axis vs the % release on the Y axis is plotted.
Fig 3: Dissolution Profile of Xanax Xr vs Product of example 11 (0.5 mg Alprazolam) and
This figure refers to the dissolution profile of 0.5 mg tablet (prepared according to experiment discussed in Example 11), which indicates the graphical representation of % dissolution data of Emcure's tablet for 24 hours. The graph of time interval in hours on the X axis vs the % release on the Y axis is plotted.
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Fig 4: Dissolution Profile of Xanax Xr vs Product of example 12 (1 mg Alprazolam)
This figure refers to the dissolution profile of 1 mg tablet (prepared according to experiment discussed in Example 12), which indicates the graphical representation of % dissolution data of Emcure's tablet for 24 hours. The graph of time interval in hours on the X axis vs the % release on the Y axis is plotted.
DETAILED DESCRIPTION OF THE INVENTION:
Alprazolam i.e. (8-chloro-l-methyl-6-phenyl-4/f-s-triazolo [4,3-a] [1,4] ) benzodi-azepine, is cited in US 3, 987, 052. It is well known in the prior art that the alprazolam is used in treatment of anxiety disorders and panic attacks. The immediate release formulation of alprazolam however, has certain disadvantages of peak and trough phenomena. The frequency of dosings is also more in case of immediate release tablets.
Accordingly, the invention provides a sustained release pharmaceutical composition comprising:
(a) a therapeutically effective amount of alprazolam,
(b) a high viscosity hydroxy-propyl-methyl cellulose (HPMC) and low viscosity hydroxy-propyl-methyl cellulose (HPMC) in a ratio of 65:35 to 85:15, and
(c) pharmaceutically acceptable excipients.
The tablet of present invention contains alprazolam, distributed in a matrix that comprises HPMC(s) and other excipients as discussed herein.
Hydroxy propyl methylcellulose, being a semi-synthetic material derived from cellulose, is a linear polymer comprised of etherified anhydrous glucose rings. There are broadly two types of HPMC viz high viscosity polymer and low viscosity polymer. Use of High viscosity polymer retards the rate of release to higher extent, whereas the use of low viscosity polymer retards the rate of release to comparatively lower extent. Furthermore, combination of both types of HPMCs or single type of HPMC is used depending upon the release pattern of interest.
To prevent a tablet from immediately disintegrating a fast rate of hydration followed by quick gelation is necessary for a rate controlling polymer to form a protective gelatinous layer around the
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matrix. The critical parameters of fast polymer hydration and gel layer formation are considered in case of a water-soluble drug and water-soluble excipients.
HPMC is commercially available in various grades, under several trade names, including Methocel® E, F, J and K of dow chemicals, HPM of British Celanese Ltd., U.K., and Metalose ® SH of Shin-Etsu Ltd., Japan. The two polymer grades of METHOCEL most commonly used in controlled-release applications are K(HPMC 2208, USP) and E(HPMC 2910, USP). F-chemistry products (HPMC 2906, USP) are used less commonly. The various grades available under a given trade name typically represent differences in methoxy and hydropropoxy content as well as molecular weight of HPMC. The preferred HPMC, used for the retardation purpose 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 one aspect of the present invention, combination of both HPMCs i.e. (a) HPMC having high viscosity and (b) HPMC having low viscosity have been used. The term "high viscosity HPMC" herein refers to HPMC having a viscosity of about 1,500 to about 2,25,000 cP, and the term "low viscosity HPMC" herein refers to HPMC having a viscosity of about 2 to about 400 cP.
The high viscosity grade polymers available are METHOCEL K4M Premium, K15M Premium, and K100M Premium. 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. Equivalent products are available from other sources as well.
The low viscosity grade polymers available are K3P LV and K 100P LV. The preferred low viscosity HPMC is HPMC 2208 having a viscosity of about 80 to about 120 cP, which is illustratively available as Methocel® K4MP of Dow. Equivalent products are available from other sources as well.
Our invention makes use of Methocel ® K4MP of Dow as a high viscosity polymer and a Methocel ® KI00LVP of Dow as a low viscosity polymer. US 2004/0006072 discloses the high viscosity HPMC to low viscosity HPMC to be 60:40 to 40:60. In our embodiment, both high viscosity and low visocity HPMC are present in the particular composition ranging from about 65:35 to 85:15. The preferred ratio being 65:35 to 75:25. The most preferred ratio being 70:30. Further, the total amount
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of HPMC used is also less as compared to patent application US 2004/0006072. US 2004/0006072 claims the total polymer weight to be of about 110 to 135 mg. However, we use about 70 to 100 mg. of the polymer thus making our invention cost effective. The preferred range for the weight of the polymer in the tablet is 75 to 90 mg.
It may be noted that the ratio of mix of HPMC, as well as having different total weight of mix of HPMC gives the interesting results, which are better than the immediate release profile, which eliminates the problems associated with peak and trough issue.
The use of lower quantities of (a) K4M HPMC and (lb) K100LVP HPMC gives comparatively better results to the said pharmaceutical composition, such as with respect to drug release. Due to the same, there are less fluctuations in % related standard deviation. Hence, the pharmaceutical composition prepared according to the current invention is superior to the prior art compositions.
The dissolution profile in biological system is reflected from in-vitro dissolution results. It is advisable to have better pharmaceutical composition having less fluctuations, which are in turn dependent on the in-vitro dissolution profile. Thus, the pharmaceutical composition according to the current embodiment is advantageous and better for patients.
The other excipient used in our tablet invention is lactose. Lactose is used as a preferred diluent. Lactose is widely used as a filler or filler-binder in the manufacture of pharmaceutical tablets and capsules. The general properties of lactose which make a contribution to its usage in formulation are (a) cost effectiveness, (b) easy availability, (c) low hygroscopicity, (d) compatibility with the active ingredients, (e) stability, (f) water solubility etc. Lactose monohydrate is used in one of the embodiment. The amount of lactose used in our invention is about 300 mg for 3 mg of alprazolam. Alprazolam is primarily mixed with lactose and then the further processing is done.
Magnesium stearate is an excipient, which is used as a lubricant, to prevent the compacted powder mass from sticking to the equipment during the tabletting or encapsulation process and allow easy ejection of the tablet during tablet formation. However, over lubrication may result into coating of the hydrophobic material on the tablet and thereby retard the release rate. Hence, an appropriate amount of Magnesium Stearate is necessary.
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In another embodiment colloidal silicon dioxide is used. The most commonly used "glidant" in solid oral dosage form formulations is colloidal silicon dioxide; also know by the trade names of Cab-o-Sil or Aerosil. This material is extremely effective in improving the overall flow characteristics of a blend by coating the surfaces of its' components thereby reducing their inter-particulate friction.
The colouring agents optionally can be added at the appropriate stage of preparation of pharmaceutical composition in suitable quantities. It can be along with the lactose. The said colouring agents can be selected from any pharmaceutically acceptable colouring agents. The preferred colouring agents are Lake green blend LB-51426 or D & C Yellow No 10.
The ingredients can be sifted independently or in combination with other ingredients, at the appropriate stage.
According to the present invention, the strength of sustained release tablets of alprazolam is in the range of 0.5 mg to 3.0 mg equivalent to base.
ADVANTAGES:
The advantages of the sustained release composition prepared according to the invention are as under:
i. The composition provides a convenient method of delivery of alprazolam and avoids the frequency of dosages taken by the patient.
ii. The composition provides a mode of release of alprazolam that is adaptable to a broad range of dosage strengths.
iii. The composition delivers alprazolam in a continuous manner so that the peak and trough
phenomena would be practically inexistent
iv. The composition provides alprazolam in such a dosage that the drug concentration in the blood is maintained for a longer period of time
v. The composition makes use of the high viscosity and low viscosity HPMC in such a weight ratio so as to avoid bioequivalent fluctuations.
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vi. The invention provides a process for the preparation of Alprazolam fomulation which is simple, having less number of steps, involving less man power, having smaller time cycle, providing good yields, with a good purity profile, industrially feasible and economical.
vii. The invention reduces the total quantities of HPMC and making the process cost effective and industrial friendly.
The sustained release tablets according to the instant invention are prepared according to the following process steps comprising of;
a) Mixing Alprazolam with lactose and optionally the coloring agents in geometric proportion.
b) Sifting the mixture to obtain the homogeneous blend.
c) Adding HPMC K-4M and HPMC K-100 LVP to the blend from step (b) and mixing to get a homogenous blend.
d) Granulating the blend with water.
e) Drying the wet mass.
f) Reducing the size of dried granules followed by lubrication and
g) compressing to form tablet.
The dissolution procedure for the tablets can be carried out as per the procedure known in the art using following parameters.
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein,
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however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The present invention is more particularly illustrated in the following example(s), but is not to limit the scope of the present invention.
Example 1: (70:30; 90 mg polymer)
Tablets having the tabulated composition were prepared by the procedure, mentioned above.
Alprazolam was mixed with Lactose* in geometric proportion. The mixture was sifted to obtain the homogeneous blend. HPMC K-4M and HPMC K-100 LVP were added to the above blend and mixed to get a homogenous blend. The blend was granulated with water. The wet mass was dried. The size of dried granules was reduced followed by lubrication and was compressed to form a tablet.
"'Optionally the coloring agent(s) are added, if required. In Example 1, the coloring agents are not added.
Table-1
SERIAL NUMBER I INGREDIENTS 1 WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydrate USPNF 248.25
3 Hydroxy Propyl Methyl 63.0 Cellulose K-4M
4 Hydroxy Propyl Methyl TLO Cellulose K-100LVP
5 Colloidal Silicon Dioxide 0/75 (Aerosil-200)USPNF
6 Magnesium Stearate USPNF 3XJ0
7 Purified Water q.s. Total weight 345
12

Example 2: (70:30; 90 mg polymer)
Tablets having the tabulated composition were prepared by the procedure, mentioned above.
Table-2
SERIAL NUMBER I INGREDIENTS I WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydrate 247.19
USPNF
3 Hydroxy Propyl Methyl 63.0
Cellulose K-4M
4 Hydroxy Propyl Methyl 2X0
Cellulose K-100LVP
5 Colloidal Silicon Dioxide 0J5
(Aerosil-200)USPNF
6 Magnesium Stearate 3.00
USPNF
7 Purified Water q.s.
8 Green Color 035
Total weight 344.29
The obtained dissolution profile: Table-3
Time I EMCURE-SR (90 mg, Ratio 70 : 30)
_ _
1 1086
2 17395
4 2836
8 44i82
_ __
12 5X89

13

14 I 6Z86
18 7051
24~ 78J2
Example 3: (65:35; 80 mg polymer)
Tablets having the tabulated composition were prepared by the procedure, as mentioned above.
Table-4
SERIAL NUMBER I INGREDIENTS I WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydrate 258.25
USPNF
3 Hydroxy Propyl Methyl 52
Cellulose K-4M
4 Hydroxy Propyl Methyl 28
Cellulose K-100LVP
5 Colloidal Silicon Dioxide 0.75
6 Magnesium Stearate 3.00
7 Purified Water q.s.
Total weight 345
The obtained dissolution profile: Table-5
Time I XANAX-SR I EMCURE-SR
0 0 0
1 12JH) 143
~ 2 21.80 23A
4 35X) 372
8 5T90 608
10 63/7 ■ 731

14

12 | 704 | 864
14 __ __
18 86\8 10L9
24 90/7 T018
Example 4: (70:30; 80 mg polymer)
Tablets having the tabulated composition were prepared by the procedure as mentioned above.
Table-6
SERIAL NUMBER I INGREDIENTS I WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydrate 258.25
USPNF
3 Hydroxy Propyl Methyl 56
Cellulose K-4M
4 Hydroxy Propyl Methyl 24
Cellulose K-l 00 LVP
5 Colloidal Silicon Dioxide 0/75
6 Magnesium Stearate 3.00
7 Purified Water q.s.
Total weight 345
The obtained dissolution profile: Table-7
Time I EMCURE-SR
0 0
1 10.7
2 182 4 293

J| 8 | 40
10 605
_ __
14 TL9
18 842
24 88^0
Example 5: (75:25; 80 mg polymer)
Tablets having the tabulated composition were prepared by procedure, as mentioned above.
Table-8
SERIAL NUMBER I INGREDIENTS I WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydrate USPNF 258.25
3 Hydroxy Propyl Methyl Cellulose 60
K-4M
4 Hydroxy Propyl Methyl Cellulose 20
K-100LVP
5 Colloidal Silicon Dioxide 0J5
6 Magnesium Stearate 3.00
7 Purified Water q.s.
Total weight 345
The obtained dissolution profile: Table-9
Time I EMCURE-SR
0 0
1 13.6
2 2L3

16

* 4 I : 32/7
8 54l
10 654
_ . __
14 83T8
18 80
24 913
Example 6: (70:30; 100 mg polymer)
Tablets having the tabulated composition were prepared by the procedure, as mentioned above.
Table-10
SERIAL NUMBER I INGREDIENTS I WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydrate USPNF 238.25
3 Hydroxy Propyl Methyl Cellulose K- 70
4M
4 Hydroxy Propyl Methyl Cellulose K- 30
100 LVP
5 Colloidal Silicon Dioxide 0J5
6 Magnesium Stearate 3.00
7 Purified Water q.s.
Total weight 345
The obtained dissolution profile: Table-11
Time I EMCURE-SR
° 0
1 11.42

17
. _ _____
8 4_T06
10 55^01
12 64^67
14 7Z93
: 18 8536
24 9622
Example 7: (Direct compression experiment) (70:30; 80 mg polymer)
Tablets having the tabulated composition were prepared by the procedure, as mentioned above.
Table-12
SERIAL NUMBER I INGREDIENT I WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydrate USPNF 258.25
3 Hydroxy Propyl Methyl Cellulose 56
K-4M
4 Hydroxy Propyl Methyl Cellulose 24
K-100LVP
5 Colloidal Silicon Dioxide 0?75
6 Magnesium Stearate 3.00
7 Purified Water q.s.
Total weight 345
The obtained dissolution profile: Table-13
Time I EMCURE-SR
0 ~ 0 ~
1 16.9

18
1 2 I 274
4 44J
8 67\9
10 79^6
12 87l
14 944
18 96J
24 963
Example 8: (Making use of just K4M HPMC) (80:0; 80 mg polymer)
Tablets having the tabulated composition were prepared by the procedure, as mentioned above.
Table-14
SERIAL NUMBER I INGREDIENTS I WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydralte USPNF 25825
3 Hydroxy Propyl Methyl Cellulose K-4M 80
4 Hydroxy Propyl Methyl Cellulose K-100 -
LVP
5 Colloidal Silicon Dioxide 075
6 Magnesium Stearate 3.00
7 Purified Water q.s.
Total weight 345
The obtained dissolution profile: Table-15
Time I EMCURE-SR
0 0
1 10.1

19

1 2 | 1677
4 262
8 404
_ __
12 55^6
14 65/7
18 712
24 773
Example 9: (Making use of just K100 LVP HPMC) (0:80; 80 mg polymer)
Tablets having the tabulated composition were prepared by the procedure as mentioned above.
Table-16
SERIAL NUMBER I INGREDIENTS I WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydrate 258.25
USPNF
3 Hydroxy Propyl Methyl
Cellulose K-4M
4 Hydroxy Propyl Methyl 80
Cellulose K-100 LVP
5 Colloidal Silicon Dioxide 0?75
6 Magnesium Stearate 3.00
7 Purified Water q.s.
Total weight 345

20

Time I EMCURE-SR
0 0
1 17.3
2 315
4 65~1
8 882
_ _
12 90J
14 8^9
""18 89l) "~
24 8X4
Example 10: (70:30; 80 mg polymer; 2.00 mg Alprazolam)
Tablets having the tabulated composition were prepared by the procedure, as mentioned above.
Table-18
SERIAL NUMBER I INGREDIENTS j WEIGHT (mg)
1 Alprazolam 2.0
2 Lactose monohydrate 259.25
USPNF
3 Hydroxy Propyl Methyl 56.00
Cellulose K-4M
4 Hydroxy Propyl Methyl 24.00
Cellulose K-100LVP
5 Colloidal Silicon Dioxide 0?75
6 Magnesium Stearate 3.00
Total weight 345

21

Time I EMCURE-SR
0 ~ o
1 13.3
2 20J
4 323
8 516
10 65~!6
12 : 75l)
16 ; 873
20 9L7
24 93J8
Example 11: (70:30; 80 mg polymer; 0.50 mg Alprazolam)
Tablets having the tabulated composition were prepared by the procedure as mentioned above.
Table-20
SERIAL NUMBER | INGREDIENTS I WEIGHT (mg)
1 Alprazolam 0.50
2 Lactose monohydrate 260.75
USPNF
3 Hydroxy Propyl Methyl 56.00
Cellulose K-4M
4 Hydroxy Propyl Mtethyl 24.00
Cellulose K-l 00 LVP
5 Colloidal Silicon Dioxide 0?75
6 Magnesium Stearate 3.00
Total weight 345

22

Time I EMCURE-SR
0 0.0
1 24.6
_ _
_ _
6 73~7
8 843
_ __
12 97.6
20 9L7
24 9T8
Conclusion: The dissolution profile when compared with Xanax showed a comparable release pattern.
Example 12: (70:30; 80 mg polymer; 1.00 mg Alprazolam)
Tablets having the tabulated composition were prepared by the procedure, as mentioned above.
Color was mixed with some part of lactose and sifted through 100#mesh
Alprazolam was mixed with lactose in geometric proportion and sifted through 40 mesh. HPMC K-4M and HPMC K-100 LVP are sifted through 40 mesh and mixed with above blend. This homogenous blend was granulated with water to form wet mass. Wet mass was dried and then crushed to form dried granules. Dried granules were lubricated and compressed to tablet with suitable punches.
Tahle-22
SERIAL NUMBER I INGREDffiNTS I WEIGHT (mg)
1 Alprazolam 1.0
2 Lactose monohydirate USPNF 260.00
23

f 3 I Hydroxy Propyl Methyl Cellulose K-4M I 56.00
4 Hydroxy Propyl Methyl Cellulose K-100 LVP 24.00
5 Colloidal Silicon Dioxide 0/75
6 Magnesium Stearate 3.00
7 D&C Yellow No. 10 025 ~~
8 Purified Water q.s.
Total weight 345
The obtained dissolution profile: Table-23
Time I EMCURE-SR
0 0
1 17.3
2 28^2
__ __
_ __
10 '■ 793
12 86^6
14 __
18 94^
_ __
According to the instant invention, the Alprazolam ER tablets are prepared as per Example Number 4. The dissolution experiments of the said tablets was carried out. Exactly similar dissolution experiment was carried out with respect to the Alprazolam ER tablets obtained from the public domain i.e Xanax XR of Pharmacia Upjon ; Batch No. 63 MCX.
The experimental procedure and results of the above experiments is provided below in Table-25 and Table-26.
24

Experimental procedure for the preparation of product of Example 13
Table-24
SERIAL NUMBER I INGREDIENTS I WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydrate USPNF 257.9
3 Hydroxy Propyl Methyl Cellulose K-4M 56\0
4 Hydroxy Propyl Methyl Cellulose K-100 LVP 24l)
5 Colloidal Silicon Dioxide 0/75
6 Magnesium Stearate 3.0
7 Lake Green Blend LB-51426 035
Total weight 345
Example 13*: Color was mixed with some part of lactose and sifted through 100#mesh Alprazolam was mixed with lactose in geometric proportion and sifted through 40 mesh. HPMC K-4M and HPMC K-100 LVP are sifted through 40 mesh and mixed with above blend. This homogenous blend was granulated with water to form wet mass. Wet mass was dried and then crushed to form dried granules. Dried granules were lubricated and compressed to tablet with suitable punches.
Three tablets under study were prepared with the above procedure.
* The tablets according to Example 13 are exactly similar to that of Example 4, except the addition of colour, which is optional. The colour is non-functional excipient with respect to the sustained release profile. Thus, for SR purposes, the Example 4 and Example 13 are same.
Experimental procedure of dissolution test for the comparative study
The dissolution is carried out by using following parameters
Medium : Mixed Phosphate Buffer pH 6.0 ±0.1
Volume : 500 ml
Apparatus | : USPI (Basket) ~
25

Speed : 100 rpm
Temperature : 37.0° C
Time Interval : lHr, 4Hr, 8Hr, lOHr, 12Hr, 14Hr, 18Hr, 24Hr.
Withdrawal volume : 5 ml
Table-25 Dissolution results of Xanax XR of Pharmacia Upjohn. Batch Number 63MCX; % Drug release.
Time Interval Minimum Maximum Average S.D. %R.S.D.
lHour 11.52 12.75 12.32 0.46 3.73
4 Hour 28.47 35.25 33.10 2.53 7.65
8 Hour 48.41 57.54 55.01 3.42 6.22
10 Hour 63.85 71.31 66.64 2.53 3.79
12 Hour 70.25 77.41 72.98 2.48 3.40
14 Hour 75.13 80.20 78.09 1.86 2.38
18 Hour 82.55 94.45 87.70 4.37 4.98
24 Hour 1 88.18 | 98.92 | 94.16 | 4.10 | 4.35
TabIe-26
Dissolution results of Alprazolam Extended Release (Emcure) Batch Number FD/1616/05; % Release
Time Interval Minimum Maximum Average S.D. %R.S.D.
lHour 10J8 11.23 10.99 0.23 2.06
4 Hour 29.88 30.49 30.13 9.32 1.07
8 Hour 48/73 50.13 49.60 0.76 1.53
10 Hour 6035 62.07 61.37 0.91 1.48
12 Hour 69,21 71.44 70.39 1.12 1.59
14 Hour 76^06 78.30 77.05 1.15 1.49
i 8 Hour 8152 85.99 84.81 1.24 1.46
24 Hour 1 91.69 | 93.59 | 92.91 | 1.06 | 1.14
Comparitive data of bioavailability of Alprazolam 3 mg extended release tablets of Pharmacia and Upjohn (Xanax XR) vs Alprazolam 3 mg extended-release tablets of Emcure Pharmaceuticals.
Example 14
Products Evaluated:
26

Test Product: Alprazolam extended release tablet 3 mg according to the present invention (Example
4):
Batch/Lot No: EM 5Y009
Reference Product: XANAX XR tablets 3 mg-Pharmacia Upjohn Company, USA
Batch/Lot No: 95 MMJ
The experiment was carried out on 12 human subjects. One dose of either test or reference was administered orally. After the period of seven days, the another respective dose was administered orally such that the volunteer gets the dose of both test and reference.
Comparitive data for concentration of Alprazolam in human plasma.
Table-27
Time Standard Deviation of Standard Deviation of Mean concentration of
Data Emcure's Test Sample Xanax XR (95 MMJ) of Emcure's test sample
(Product of Example 4) Pharmacia Upjohn (EM 5Y 009) r\gfmblJO 0.139 (U82 0.040
3l)0 5l41 4^877 19.323
(TOO 5T890 6463 23.452
9M TMl " 7359 26.171
12.00 5282 5lS4 25.510
16^00 4.818 5398 22.429
20.00 5TT2I 5734 19728
24.00 5369 574(5 18.547
36.00 4.086 51)83 10.924
48.00 3.491 4385 6.819
72.00 2lT0 2233 2T823
It may be evident from examples 1-12 that the composition of examples 1-7 and 10-12 exhibit a release pattern, wherein the composition comprising alprazolam is released over a period of about 24
27

hours, i.e. between 20-40% in 4 hours to more than 70% in 40 hours of the total dose. Usually the Cmax is reached 3 hours after administration.
In examples 8 & 9, where only high viscosity HPMC or low viscosity HPMC are used, the release pattern varies and is below the desirable standard. Further, from table 25 it is clear that Xanax XR exhibits a large standard deviation in its release profile. Comparatively, the composition of the invention exhibits much less deviation, which shows that the peak-trough effect in case of the composition of the invention is negligible or non-existent.
According to the instant invention, the Alprazolam SR tablets are prepared as per Experiment Number 4. The dissolution experiments of the said tablets was carried out and compared with the tablets prepared as per the compositions known in the prior art.
The experimental procedure and results of the above experiments is provided below in Table-28 and Table-29.
Table-28 (Compositions known in prior art)
SERIAL NUMBER I INGREDIENTS I WEIGHT (mg)
1 Alprazolam 3.0
2 Lactose monohydrate (Lactose DCL 11) 221.7
3 Hydroxy Propyl Methyl Cellulose K-4M 60JO
4 Hydroxy Propyl Methyl Cellulose K-100 60li LVP
5 Colloidal Silicon Dioxide 075
6 Magnesium Stearate 1.5
7 D&CYellow#10 024
8 FD&C Blue # 2 Aluminum Lake 0M Total weight 348.6
Example 15: Color was mixed with some part of lactose and sifted through 100 # mesh
Alprazolam was mixed with lactose in geometric proportion and sifted through 40 mesh. This was added to the above blend. HPMC K-4M and HPMC K-100 LVP are sifted through 40 mesh and
28

mixed with above blend. Colloidal silicon dioxide was sifted through 40 #. Magnesium stearate was also sifted through 40 # and both were mixed to the above blend. The entire blend was compressed to tablet with suitable punch.
Three tablets under study were prepared with the above procedure.
Experimental procedure of dissolution test for the comparative study.
The dissolution is carried out by using following parameters
Medium : Mixed Phosphate Buffer pH 6.0 + 0.1
Volume : 500 ml
Apparatus : USPI (Basket)
Speed : 100 rpm
Temperature : 37.0° C
Time Interval : lHr, 4Hr, 8Hr, lOHr, 12Hr, 14Hr, 18Hr, 24Hr.
Withdrawal volume | : 5 ml
Table-25
Dissolution results of Xanax XR of Pharmacia Upjohn.
Batch Number 63MCX; % Drug release.
Time Interval Minimum Maximum Average S.D. %R.S.D.
1 Hour 11.52 12.75 12.32 0.46 3.73
4 Hour 28.47 35.25 33.10 2.53 7.65
8 Hour 48.41 57.54 55.01 3.42 6.22
10 Hour 63.85 71.31 66.64 2.53 3.79
12 Hour 70.25 77.41 72.98 2.48 3.40
14 Hour 75.13 80.20 78.09 1.86 2.38
18 Hour 82.55 94.45 87.70 4.37 4.98
24 Hour 1 88.18 | 98.92 | 94^16 [ 4.10 | 4.35
Table-26
Dissolution results of Alprazolam Extended Release (Emcure) Batch Number FD/1616/05; % Release
Time Interval Minimum Maximum Average S.D. %R.S.D.
lHour 10J8 11.23 10.99 0.23 2.06
4 Hour 29.88 30.49 30.13 0.32 1.07
8 Hour I 48.73 | 50.13 | 49.60 | 0.76 | 1.53
29

10 Hour 1 60.35 I 62.07 I 61.37 1 0.91 I 1.48
12 Hour 6921 71.44 70.39 1.12 1.59
14 Hour 76.06 78.30 77.05 1.15 1.49
18 Hour 83.52 85.99 84.81 1.24 1.46
24 Hour I 91.69 | 93.59 | 92.91 | 1.06 | 1.14
Table-27
Dissolution results of Alprazolam Extended Release (Prior art US 2004/0006072) Batch Number AZM/05/029; % Release
Time Interval Minimum Maximum Average S.D. %R.S.D.
lHour 12J0O 14.10 13.60 0.40 3.00
4 Hour 3L00 36.10 34.90 0.80 2.30
8 Hour 47.90 59.30 57.20 4.70 8.20
10 Hour 59,40 73.00 68.40 6.80 9.90
12 Hour 68.30 80.50 77.10 8.30 10.00
14 Hour 8T70 90.00 86.40 8.30 10.00
18 Hour 90.50 98.10 92.90 3.60 3.90
24 Hour 1 95.40 1 101.50 | 95.00 | 3.30 | 3.50

WE CLAIM:
1. A sustained release pharmaceutical composition comprising:
(a) a therapeutically effective amount of alprazolam,
(b) a high viscosity hydroxy-propyl-methyl cellulose (HPMC) and low viscosity hydroxy-propyl-methyl cellulose (HPMC) in a ratio of 65:35 to 85:15, and
(c) pharmaceutically acceptable excipients.

2. A composition as claimed in claim 1, wherein the amount of alprazolam is between lmg and 5mg.
3. A composition as claimed in claim 1, wherein the alprazolam is a pharmaceutically acceptable salt of alprazolam.
4. A composition as claimed in claim 1, wherein the high viscosity HPMC has about 19% to about 24% by weight of methoxy substituent, and about 4% to about 12% by weight of hydroxypropoxy substituent.
5. A composition as claimed in claim 1, wherein the high viscosity HPMC has a viscosity of about 1500 to about 2,25,000 cp.
6. A composition as claimed in claim 1, wherein the low viscosity HPMC has a viscosity of about 2 to about 400 cp.
7. A composition as claimed in claim 1, wherein the high viscosity HPMC is selected from the group comprising of K4M Premium, K15 M Premium and K100 M premium.
8. A composition as claimed in claim 1, wherein the high viscosity HPMC preferably used is K4M Premium.
9. A composition as claimed in claim 1, wherein the low viscosity HPMC is selected from the group comprising of K3 P LV and K 100P LV.
10. A composition as claimed in claim 1, wherein the high viscosity HPMC preferably used is K
100LVP.
31

11. A composition as claimed in claim 1, wherein the preferable ratio of high viscosity HPMC to low viscosity HPMC is 65:35 to 75:25.
12. A composition as claimed in claim 1, wherein the more preferable ratio of high viscosity HPMC to low viscosity HPMC is 70:30.
13. A composition as claimed in claim 1, wherein the composition provides a total daily dose of about 0.5 mg to about 3 mg of alprazolam.
14. A composition as claimed in claim 1, wherein the composition is configured to release alprazolam at a rate that ranges between 20% to 40% in 4 hours to more than 70% in 14 hours of the total dose of alprazolam after the exposure to phosphate buffer having pH 6.0 + 0.1.
15. A composition as claimed in claim 1, wherein the Cmax occurs more than 3 hours after administration.
16. The process for the preparation of sustained release composition of Alprazolam, comprising the steps of:
Mixing Alprazolam with lactose and optionally the coloring agents in geometric proportion
Sifting the mixture to obtain the homogeneous blend.
Adding HPMC K-4M and HPMC K-100 LVP to the blend from step (b)
Granulating the blend with water to form wet mass.
Drying the wet mass
Forming granules and
Compressing to form tablet.
17. The process for the preparation of sustained release composition of Alprazolam, as described
herein with respect to the foregoing examples.

32

ABSTRACT
The present invention is directed towards the preparation of extended release Alprazolam formulation. The formulation thus obtained provides an efficient mode of delivery of Alprazolam in a continuous manner.
33

Documents:

880-mum-2005-abstract (complete).doc

880-mum-2005-abstract (complete).pdf

880-mum-2005-cancelled pages(20-07-2006).pdf

880-mum-2005-claims (complete).doc

880-mum-2005-claims (complete).pdf

880-mum-2005-claims(granted)(20-07-2006).doc

880-mum-2005-claims(granted)(20-07-2006).pdf

880-mum-2005-correspondence(ipo)-(04-09-2008).pdf

880-mum-2005-correspondence-received-09092005.pdf

880-mum-2005-correspondence-received-12092006.pdf

880-mum-2005-correspondence-received-20072006.pdf

880-mum-2005-correspondence-received-21072005.pdf

880-mum-2005-correspondence-received.pdf

880-mum-2005-correspondence1(25-03-2008).pdf

880-mum-2005-correspondence2(14-02-2006).pdf

880-mum-2005-description (complete).pdf

880-mum-2005-description (provisional).pdf

880-mum-2005-drawings.pdf

880-mum-2005-form 1(22-07-2005).pdf

880-mum-2005-form 1(25-03-2008).pdf

880-mum-2005-form 18(21-07-2006).pdf

880-mum-2005-form 2(granted)-(20-07-2006).doc

880-mum-2005-form 2(granted)-(20-07-2006).pdf

880-mum-2005-form 26(14-02-2006).pdf

880-mum-2005-form 26(24-02-2005).pdf

880-mum-2005-form 26(25-03-2008).pdf

880-mum-2005-form 26(25-07-2005).pdf

880-mum-2005-form 3(20-07-2006).pdf

880-mum-2005-form 3(22-07-2005).pdf

880-mum-2005-form 3(30-01-2005).pdf

880-mum-2005-form 5(22-07-2005).pdf

880-mum-2005-form 5(25-03-2008).pdf

880-mum-2005-form 5(30-01-2006).pdf

880-mum-2005-form-1.pdf

880-mum-2005-form-2 (complete).doc

880-mum-2005-form-2 (complete).pdf

880-mum-2005-form-2 (provisional).doc

880-mum-2005-form-2 (provisional).pdf

880-mum-2005-form-3.pdf

880-mum-2005-form-5.pdf

880-mum-2005-other documents(04-11-2008).pdf

880-mum-2005-petition under rule 137(25-03-2008).pdf

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Patent Number

225164

Indian Patent Application Number

880/MUM/2005

PG Journal Number

02/2009

Publication Date

09-Jan-2009

Grant Date

04-Nov-2008

Date of Filing

22-Jul-2005

Name of Patentee

EMCURE PHARMACEUTICALS LTD.

Applicant Address

12/2 F-II BLOCK, M.I.D.C. PIMPRI, PUNE-4110018,

Inventors:

#	Inventor's Name	Inventor's Address
1	MANJUSHA JOSHI	R&D CENTRE II, 12/2 F-II BLOCK, M.I.D.C. PIMPRI, PUNE - 4110 018
2	GANESH VINAYAK GAT	R&D CENTRE II, 12/2 F-II BLOCK, M.I.D.C. PIMPRI, PUNE - 4110 018
3	SATISH RAMANLAL MEHTA	R&D CENTRE II, 12/2 F-II BLOCK, M.I.D.C. PIMPRI, PUNE - 4110 018

PCT International Classification Number

A61K31/5513 A61K9/22

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA