Title of Invention

PROCESS FOR PREPARING ORAL 2-METHYL-THIENO BENZODIAZEPINE FORMULATION .

Abstract

This invention relates to a process for preparing a stable pharmaceutically elegant solid oral formulation containing olanzapine as an active ingredient and having a polymer coating selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethyl methacrylatemethylacrylate acid ester copolymer, ethylacrylate-methylmethacrylate copolymer, methyl-cellulose and ethylcellulose comprising high shear aqueous wet granulation with fluid bed drying.

Full Text

Field of the Invention The present invention relates to a process for preparing oral 2-methyl-thieno benzodiazepine formulation hereinafter referred to as olanzapine, and process for the preparation thereof. Background and prior art Olanzapine, has shown great promise in the treatment of psychotic patients and is currently being evaluated for that purpose. Certain tablet formulations of olanzapine are known, as described in U.S. Patent No. 5,229,382. However, improved oral formulations were desired in light of the moisture sensitive, metastable nature of olanzapine, the tendency of olanzapine to undesirably discolor in the Known tablet formulation, and due to the surprisingly potent, nature of olanzapine. Statement of the Invention A process for preparing a stable, pharmaceutically elegant, solid oral formulation containing Olanzapine as an active ingredient having a polymer coat selected from the group consisting of hydroxypropyl methyl cellulose, hydroxycthyl cellulose. methylhydroxyethylcellulose, sodium carboxymethylcellulosc. hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethyl methacrylatemethylacrylate acid ester copolymer, ethylacrylate-methylmcthacrylate copolymer, methylcellulose, and ethylcellulose, said process comprising high shear aqueous wet granulation with fluid bed drying process wherein olanzapine is present in an amount of 1 to 3 % by weight provided that the polymer coal is free of polyethylene glycol (PEG). Summay of the Invention The presently claimed invention provides pharmaceutically elegant solid oral formulation for comprising olanzapine intimately mixed with a binder, disintegrant, a dry binder to provide friability, a lubricant; wherein such solid oral formulation is coated with polymer selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose. hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethyl methacrylatemethylacrylate acid ester copolymer, ethylacrylate-methylmethacrylate copolymer, methylcellulose, and ethylcellulose. It is particularly preferred that, the polymer does not contain polyethylene glycol. Further, the invention provides a method lot preparing pharmacutically elegant, stable solid orai the group consisting of hydroxypropyl methyl cellulose. hydroxyethyl cellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose , hydroxypropylcellulose; pyrrolidone, dimethylaminoethyl methacrylatemethylacry acid ester copolymer, ethylacrylate-methylmethacrylate copolymer, methylcellulose, and echylcellulose. comprised of using a high shear aqueous wet granulation with fluid bed drying process. Detailed Description Olanzapine, a potent compound showing promising activity for use in treating psychotic patients, metastable, undergo pharmaceutically undesired discoloration, and demands care to assure homogeniety of the finished solid formulation. Applicants have discovered that certain excipients including powder blends. Further the discoloration is exacerbated by ambient, air conditions elevated temperatures, and by moist. Although the discoloration phenomenon does not produce an increase in the number of total related substance, the browning and mottling appearance is not generally considered pharmaceutically acceptable for porticularly disturbing when a tablet administered to a psychotic patient, which patient may be especially troubled by the changing appearance medication. Applicants have discovered that coating the solid oral formulation with a polymer selected from the group consisting of hydroxypropyl methyl cellulose, hydroxy carboxymethylcellulose , hydroxypropylcellulose, in the formulation. The formulation is most: preferredly tablet form; however, granule formulation and the like are desired as well. Most preferred polymer coats are hydroxypropyl methyl cellulose, hydroxypropylcellulose, methylcelluiose, and ethylcellulose. An especially preferred polymer coat is hydroxypropyl methylcelluiose. It is especially preferred that the formulation contain the most stable anhydrous form of olanzapine, referred to herein as Form II; however, other forms of olanzapine are contemplated. Form II has a typical x-ray powder diffraction pattern as represented by the following interplanar spacings A typical example of an x-ray diffraction pattern for Form II is as follows wherein d represents the interplanar spacing and I/I1 represents the typical relative intensities: The x-ray diffraction patterns set out herein were of tabled using a Siemens D5000 x-ray powder, diflractometed having a copper Kα radiation source of wavelength, The formulation of the invention preferredly contains substantially pure Form II as the active ingredient- . As used herein "substantially pure" refers to Farm associaced with less than about 5% undesired polymorphic form of olanzapine therein referred to as "Undesired Form" preferably less than ,about 2% Undesired Form, and more preferably less than about 1% Undesired Form. Further, "substantially pure" Form II will contain less than about undesired chemical impurities or residual solvent water. In particular, "substantially pure" Form II contain less than about 0.05% content of more preferably, less than about 0.0059 of acetonitrile. Additionally, Form II preferredly contain less than 0.5% of associated water. As used herein, the term "mammal" shall refer to the Mammalia class of higher vertebrates. The term "mammal includes, but" is not- limited to, a human. The term "treating" as used herein includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established. Form II is the most stable anhydrous form of olanzapine known and is therefore important for the commercial development of pharmaceutically elegant formulations. Olanzapine may form an undesired crystal form in the presence of certain solvents and excipients, therefore, in making the compositions of the invention it is most desired to prepare the formulation using a method which does not require dissolution of the olanzapine substance. The desired Form II can be converted to less desirable polymorphic forms by contact with methylene chloride, for example. Additionally, for example, 'i polyethylene glycol contact with the olanzapine substance produces undesir.ed discoloration, particularly under moist conditions. Applicants believe that a dry blend direct compression proc'ess or dry granulated processes for preparing solid oral formulations create a greater chance that poor dose uniformity will occur. In light of the potent nature of olanzapine, consistent dose uniformity is imperitive. In accordance with this invention, Applicants have discovered that a high shear aqueous wet granulation with fluid bed drying is the most effective method for preparing pharmaceutically elegant, stable, oral formulations. Uncoated tablets stored at ambient conditions (approximately 23°C and 40% relative humidity) in amber, high density polyethylene bottles do not show signs of discoloration after 24 months; however, if the bottle opened such chat the tablets are exposed to open ambient conditions then discoloration occurs within 5 days A new solid oral formulation was prepared un- used a hydroxypropropyl methylcellulose subcoating and white color coating. The new formulation did not discolor after 90 days of open dish storage at 40°C, 60°C, 40°C. %RH, ambient temperature with 75% RH, or at ambient, temperature with 85% RH. The hydroxypropyl methylcellulose coating which is free of polyethylene glycol is much preferred to ensure that discoloration does not occur on the tablet surface. It provides an effective barrier between the white color coat which provides an acceptable medium for imprinting and color dressing ot the product. The hydroxypropylmethylcellulose coating provides sufficient barrier to prevent discoloration attribute the polyethylene glycol in the white color coat. Alternative white film coat formulas containing alter plasticizers were evaluated; however, none were prevent discoloration in all test conditions after of storage. Therefore, the hydroxypropy 1 methyl coat or subcoating is a surprising and important component of pharmaceutically elegant solid oral formulations of olanzapine. A diluent or bulking agent should be selected provide an increase in tablet size. The artisan can utilize known methods to select a bulking agent whir!, provides hardness, friability, and disintegration time is satisfactory for pharmaceutical usage. The bulking agent should be selected to provide a tablet that has characterstics desired by the patient as well as comply with applicable regulatory guidelines. One lespecially preferred diluent or bulking agent is lactose. Various forms of lactose are for such formulations including anhydrous, hydrous spray dried forms. The most desired form of lactase selected based on desired dissolution, content hardness, friability, and disintegration time. artisan is aware; of the regulatory requirements for hardness, friability, and disintegration time and can adjust the diluent or bulking agents using known techniques. i to achieve the desired physical characteristics. The formulation should include a binder for use in the granulation step. The artisan can choose an appropriate binder based on the acceptable viscosity, and desired hydration. Hydroxypropyl cellulose is especially preferred for use as a binder in the granulation step. The hydroxypropyl cellulose may vary in particle size. Fine grade hydroxypropyl cellulose is especially preferred for most claimed formulations. The desired formulation includes a disintegrant. for use in the granulation as well as in the running powders to facilitate the disintegration process. There are a variety of grades available, and the grade may de- selected based on the acceptable batch variability. A particularly prefered disintegrant is crospovidone. A fine grade of crospovidone provides particularly desirable consistency between batches. The artisan may choose appropriate dry using known methods. Such binders should be selected to assure that satisfactory friability is attained. Most preferably, dry binder is microcrystalline cellulose; however, other appropriate dry binders may be selected. Such microcrystalline cellulose may be in a granular The artisan can choose an appropriate to prevent sticking and picking of the tablets to the compression tooling. One preferred lubricant is stearate. The artisan can readily choose other aqueous dispersion film coats (color mix) for over the hydroxypropyl methylcellulose layer. The color mixture is a dry blend of ingredients be dispersed in water and used as an aqueous dispersion film coat solid formulations. One example of a typical color mixture is comprised of hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80, and titianium dioxide. A variety of edible inks known to the artisan are appropriate for imprinting the finished formulation For example, one typical edible ink is comprised of shellac, ehtyl alcohol, isopropyl alcohol, n-butyl propylene glycol, ammonium hydroxide, and FD&C Blue. The solid formulation is most preferably subcoated with hydroxypropyl methylcellulose, coated with a color coat, and imprinted with an edible ink. The solid formulation may be polished using standard methods such is carnauba wax polishing, if desired. Olanzapine is effective over a wide dosage range, the actual dose administered being dependent on the condition being treated. For example, in the treatment of adult humans, dosages of from about 0.25 to 50 mg, preferably from 1 to 30 mg, and most preferably 1 to 20 mg per day may be used A once a day dosage is normally although divided doses may be administered. For treatment of central nervous system disorders, a dose range of from 1 to 20 mg, preferably 1 to 20 mg per day suitable. Radiolabelled Form II 2-methyl-4 -(4-methyl-1 piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepine, can be detected in the saliva and thus the compound can potentially be monitored in patients to assess compliance. A preferred formulation of the invention is a solid oral formulation comprising from about 1 to about 20 :ng olanzapine as an active ingedient, wherein such solid oral formulation is coated with hydroxypropyi methylcellulose. Especially preferred is an oral formulation comprising from 1 to 20 mg of provided that such solid oral formulation is coated with hydroxypropyl methylcellulose. Most preferably, the solid oral formulation is contained in pacKaging materials which protect the formulation from moisture and light. For example, suitable packaging materials include amber colored high density polyethylene bottles, amber colored glass bottles, and other containers made of a material which inhibits the passage of light. Most preferably, the packaging will include a desiccant pack. The container may be sealed with an aluminium foil blister to provide the desired protection and maintaing prcduct stability. A study of the hydroxypropyl methyl cellulose coated tablets in an amber colored bottle having a pack stored at harsh, 40°C/75% RH conditions for six months showed pharmaceutically acceptable stability with a 0.4 about 1.2% increase in total related substances. The materials for the present invention can be purchased or prepared by a variety of procedures well known tc those of ordinary skill in the art. Olanzapine can be prepared as desdribed by Chakrabarti in U.S. Patent No 5,229,382 ('382), herein incorporated by reference in its entirety. It is most desirable to prepare a rapidly dissolving formulation comprising substantially pure crystalline Form II. Such substantially pure crysta1ine Form II olanzapine may be prepared using the techniques described herein by the Preparation section herein Compound characterization methods include, for analysis (TGA), differential scanning calorimetery titrametric analysis for water, and H1-NMR analysis for solvent content. The formulations were studied to assure that the Form II polymorph was substantially pure using polarization / magic angle spinning (CP/MAS) NMR. were obtained using a Varian Unity 400 MHz spectromer or operating at a carbon frequency of 100.577 MHz and equipped with a complete solids accessory and Varian 5 mm or mm VT CP/MAS probes. Measurement conditions were optimized for Olanzapine Form II and were as follows: 90° proton, pulse 4.5 ms, contact time 1.1 ms, pulse repetition time MAS frequency 7.0 kHz, spectral width 50 kHz, and time 50 ms. Chemical shifts were referenced co the i hexamethylbenzene (d = 17.3 ppm) by sample replacement was determined that the substantially pure Form II is retained throughout the formulation process claimed herein. Therefore, the formulations of this invention provide substantially pure Form II olanzapine polymorphic pharmaceutically elegant formulation without producing undesired polymorphic transformation. The following examples are provided for purpose illustration and are not to be construed as limiting the scope of the claimed invention. Preparation 1 Intermediate 1 In a suitable three neck flask the following was added Dimethylsulfoxide (analytical): 6 volumes Intermediate 1 : 75 g N-Methhylpiperazine (reagent) : 6 equivalents Intermediate 1 can be prepared using methods known to the skilled artisan. For example, the preparation of the Intermediate 1 is taught in the '382 patent. A sub-surface nitrogen sparge line was added to remove the ammonia formed during the reaction. The reaction was to 120°C and maintained at that temperature through duration of the reaction. The reactions were followed by HPLC until After the reaction was complete, the mixture was allowed to cool slowly to 20°C (about 2 hours). The reaction mixture was then transferred to an appropriate three neck round bottom flask and water bath. To this solution with agitation was added 10 volumes reagent grade methanol and the reaction was stirred at 20°C for 30 minutes. Three volumes of water was added slowly, over about 30 minutes. The reaction slurry was cooled to zero to 5°C and stirred for 30 minutes. The product was filtered and the wet cake was washed with methanol. The wet cake was dried in vacuo at 45°C over. The product was identified as technical olanzapine. Yieid: 76.7%; Potency: 98.1% Preparation 2 Form II A 270 g sample of technical grade 2-methyl-4-4- was suspended in anhydrous ethyl acetate (2.7 Li . The mixture was heated to 76°C and maintained at 7 6°C for 30 minutes. The mixture was allowed to cool to 25°C. The resulting product was isolated using vacuum filtration. The product was identified as Form II using x-ray powder analysis. Yield: 197 g. The process described above for preparing provides a pharmaceutically elegant product having 97%, total related substances • 73%. EXAMPLE 1 A portion of the hydroxypropyl cellulose was dissolved in purified water to form a solution for granulation; The remaining hydroxypropyl cellulose (total of 4.0% w/w final tablet weight), which was an extra fine grade. was combined with the olanzapine (1.18% w/w), lactose (79.32% w/w) and a portion of the crospovidone (5% w/w) in a high shear granulator. All ingredients were security sieved prior to addition and dry blended in the granulator. This mixture was then granulated with the hydroxypropyl cellulose solution in the high shear granulator. The granulation was wet sized using standard methods. The wet granulation was then dried in a fluidized bed dryer and sized. The material was then added to a tumble bin mixer. The running powders consisting of microcrystaliine cellulose (granular) (10% w/w), magnesium stearate (0.5% w/w), and the remainder of the crospovidone were added to the sized granulation. The mixture was blended and compressed with the appropriate tooling on tablet compression equipment. Hydrbxypropyl methylcellulose (10% w/w) was mixed with purified water to form a solution. Core tablets were divided into approximately equal sections and spray coated with the hydroxypropyl methylcellulose solution. The operation was performed in a perforated coating Coating of Core Tablets: Color Mixture white (hydroxypropy) methyl polyethylene glycol, polysorbate 80, and titanium was mixed with purified water to form the coating Subcoated tablets were divided into approximately equal described above. The operation was performed in a perforated coating pan. The coated tablets were lightly dusted with carnauba wax and imprinted with appropriate identification. The process substantially as described above in Example 1 was repeated using the following ingredients to provide pharmaceutically elegant tablet formulations containing 1, 2.|5, 5, 7.5, and 10 mg olanzapine, respectively, per tablet: 1 mg olanzapine per tablet: We Claim: 1. A process for preparing a stable, pharmaceutically elegant, solid oral formulation containing Olanzapine as an active ingredient having a polymer coat selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethyl methacrylatemethylacrylate acid ester copolymer, ethylacrylate-methylmethacrylate copolymer, methylcellulose, and ethylcellulose, said process comprising high shear aqueous wet granulation with fluid bed drying process wherein olanzapine is present in an amount of 1 to 3 % by weight provided that the polymer coat is free of polyethylene glycol (PEG). 2. A process as claimed in claim 1, wherein the Olanzapine is substantially pure form II polymorph having a typical X-ray powder diffraction pattern as represented by the following interplanar spacing: 3. A process as claimed in claim 1, wherein the Olanzapine in the range of 1.1-2.5% w/w. 4. A solid oral formulation containing olanzapine whenever prepared by the process of any one of claims 1 to 4. 5. A process for preparing and/or a solid oral formulation herein described with reference to the foregoing examples and description. This invention relates to a process for preparing a stable pharmaceutically elegant solid oral formulation containing olanzapine as an active ingredient and having a polymer coating selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethyl methacrylatemethylacrylate acid ester copolymer, ethylacrylate-methylmethacrylate copolymer, methyl-cellulose and ethylcellulose comprising high shear aqueous wet granulation with fluid bed drying.

Documents:

416-CAL-1999-CORRESPONDENCE 1.1.pdf

416-CAL-1999-CORRESPONDENCE.pdf

416-CAL-1999-FORM 27.pdf

416-cal-1999-granted-abstract.pdf

416-cal-1999-granted-claims.pdf

416-cal-1999-granted-correspondence.pdf

416-cal-1999-granted-description (complete).pdf

416-cal-1999-granted-examination report.pdf

416-cal-1999-granted-form 1.pdf

416-cal-1999-granted-form 13.pdf

416-cal-1999-granted-form 18.pdf

416-cal-1999-granted-form 2.pdf

416-cal-1999-granted-form 26.pdf

416-cal-1999-granted-form 3.pdf

416-cal-1999-granted-form 5.pdf

416-cal-1999-granted-gpa.pdf

416-cal-1999-granted-reply to examination report.pdf

416-cal-1999-granted-specification.pdf