Title of Invention	PHARMACEUTICAL DOSAGE FORM OF AMORPHOUS NELFINAVIR MESYLATE
Abstract	A solid unit oral pharmaceutical dosage form of amorphous nelfmavir mesylate is provided comprising amorphous nelfmavir mesylate, and a pharmaceutically acceptable, water soluble, non ionic synthetic block copolymer of ethylene oxide and propylene oxide, said copolymer having a melting point of at least 40°C. A hot melt granulation process for making the dosage form is provided.

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Phanpaceut-ical Dosage Form of Amorphous Nelfinavir Mesylate Nelfinavir mesylate is one of several protease inhibitors used to limit viral replication and improve immune function in HIV-infected individuals. Information regarding nelfinayir mesylate is reported in "Viracept (Nelfinavir Mesylate, AG1343): A Potent, Orally Bioavailable Inhibitor of HlV-1 Protease", Kaldor et a!., J. Med. Chem., 40, 3979-85 (1997), and its use in the treatment of HIV is reported in 'Nelfinavir; An Update on its Use in HIV Infection", Bardsley-Elliot et al., Drugs, 59(3), 581-620 (2000). Nelfinavir mesylate is a white to off-white amorphous powder that is slightly soluble in water at pH less than or equal to 4. Nelfinavir mesylate has a molecular weight of 663.90 (567.79 as the free base). Nelfinavir mesylate is commercially available as a 250 mg tablet (as nelfinavir free base). It is sold under tiie name Viracept® by Agouron Pharmaceuticals, Inc., a Pfizer company. Viracept® tablets are known to additionally contain calcium silicate, crospovidone, magnesium .stearate, FD&C blue #2 powder, hydroxypropyl methylceliulose and triacetin. U.S. Patent No. 6,001,851 to Albizati et a!., assigned to Agouron Pharmaceuticals, Inc, reports a tablet composition (formulation 9) containing 292 mg of an HIV inhibitor which can be nelfinavir mesylate. The patent does not specify the market formulation, Vfracept®, alttiough the reported composition contains calcium silicate, crospovidone and magnesium stearate. Calcium silicate and crospovidone each constitute 25% of the composition reported in the patent. For adult patients, the recommended oral dosage of nelfinavir mesylate (calculated as nelfinavir free base) is 750 mg (3 x 250 mg tablets) 3 times daily or an alternative regimen of 1250 mg (5 x 250 mg tablets) twice daily. Whether a two- or three-times per day dosage program is followed, the tablet burden remains significant over the course of a day. Patient compliance is therefore a real concern. Block copolymers of ethylene oxide and propylene oxide that are listed as poloxamers in the NF Monograph "Poloxamer" are available in a wide range of molecular weights and melting points. They are marketed under the name Lutrol® or Pluronic® by BASF Corporation. Poloxamers have been extensively used as pharmaceutical wetting and solubilizing agents, typically in small amounts. It has also been noted that poloxamers can be used in pharmaceutical formulations to enhance the bioavailability of a drug. U.S. Patent No. 5,834,472 to Sangekar et al., for example, reports that including a non-ionic surfactant that is a block copolymer of ethylene oxide and propylene oxide in a composition of an antifungal compound having extremely low water solubility can enhance the bioavailability of the compound. U.S. Patent No. 5,281,420 to Kelm et al. addresses formulation of the drug tebufelone, an anti-inflammatory, analgesic and/or antipyretic agent that is essentially water-insoluble. Absorption of tebufelone- is quite low from the gastrointestinaF tract. Kelm et al. report a solid dispersion of tebufelone, produced by melting together poloxamer and tebufelone (melting point of 70°C) to form a homogeneous melt mixture. Solid dispersions of the homogeneous melt mixture result from cooling the mixture and allowing it to solidify. The poloxamer surfactant is included to provide the necessary solubilization of the highly insoluble drug in forming the melt mixture. A high dosage strength solid unit oral dosage form, e.g., a tablet, of nelfinavir mesylate having satisfactory dissolution and bioavailability has apparently not been successfully developed prior to the present invention. This may be due In part to the hydrophobic nature of the drug, which accounts for its lov^ aqueous solubility. In addition, nelfinavir mesylate in high dose solid unit dosage forms gels upon exposure to physiological fluid. The gel retards dissolution and bioavailability of the drug. The problem of gelling worsens v\rith increased drug loading. SUMMARY OF THE INVENTION The present invention provides a solid unit oral pharmaceutical dosage form of amorphous nelfinavir mesylate comprising amorphous nelfinavir mesylate and a pharmaceutically acceptable, water soluble, non-ionic synthetic block copolymer of ethylene oxide and propylene oxide, the copolymer having a melting point of at least 40°C. The high dose nelfinavir mesylate pharmaceutical dosage form of the invention exhibits satisfactory dissolution and bioavailability. The present invention also provides a process for preparing a solid unit oral pharmaceutical dosage fonn of amorphous nelfinavir mesylate, comprising: (a) heating a blend of amorphous nelfinavir mesylate and a pharmaceutically acceptable, water soluble, non-ionic synthetic block copolymer of ethylene oxide and propylene oxide, the copolymer having a melting point of at least 40°C at a temperature of from the melting point temperature of the copolymer to below the decomposition temperature of nelfinavir mesylate, (b) mixing the blend to form a melt granulation, and (c) processing the melt granulation into the solid unit oral dosage form of amorphous nelfinavir mesylate. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 presents dissolution profiles of 625 mg tablets of nelfinavir mesylate (Examples 11 and 111) compared to that of the 250 mg market (tablet) formulation (Example I), Figure 2 presents dissolution profiles of 625 mg nelfinavir mesylate tablets in accordance with the invention (Examples IV and V) compared to other 625 mg nelfinavir mesylate tablets (Examples II and III). Figure 3 shows the effect of Poloxamer 188 concentration on the dissolution profiles of 625 mg tablets of nelfinavir mesylate (Examples VI, Vll, Vlll and IX). Figure 4 shows mean plasma concentration versus time profiles after administration of 2 x 625 mg nelfinavir mesylate tablets of the invention (Example IV) compared to administration of 5 x 250 mg tablets of the market formulation (Example I), DETAILED DESCRIPTION OF THE INVENTION It has surprisingly been found that when amorphous nelfinavir mesylate is melt granulated with a pharmaceutically acceptable, water-soluble, non-ionic synthetic block copolymer of ethylene oxide and propylene oxide in accordance with the invention, a significant improvement in the dissolution rate of the drug is shown with resulting satisfactory bioaivailability. The nelfinavir mesylate used for the solid unit dosage form of the invention is amorphous. Dosage amounts are calculated as nelfinavir free base, unless specified othenA/ise. The pharmaceutical dosage form of the invention is a high per unit dosage of the nelfinavir mesylate as compared to the 250 mg market formulation, and is amenable to oral administration. For patient compliance and acceptability, the maximum weight of a solid unit oral pharmaceutical dosage form is typically from 1.0 g to 1.5 g. The present invention encompasses solid unit oral dosage forms having the nelfinavir mesylate in a dose from 400 mg, the dose at which the gelling potential of the nelfinavir mesylate begins to be problematic when formulated using conventional pharmaceutical excipients and processes, to 700 mg. The dosage fomn comprises nelfinavir mesylate in an amount of from 400 mg to 700 mg, preferably from 500mg to 700 mg. A preferable dosage amount is, for example, 625 mg. The pharmaceutically acceptable, water-soluble, non-ionic synthetic block copolymer of ethylene oxide and propylene oxide in accordance with the present invention as a rule has a molecular weight of from 6,000 D to 18,000 D, preferably from 6800 D to 17500 D and a melting point of preferably 40°C to 60°C, more preferably from 49°C to 57°C. The hydrophil/lipophil balance ("HLB") value at 25°C expediently is at least 14, preferably 14 to 29, more preferably 22 to 29. The copolymer is readily water soluble. Typically, the copolymer of the present invention has an ethylene oxide content (percentage of oxyethylene-groups) of at least 70% by weight, preferably 70% to 85% by weight. Suitable pharmaceutically acceptable water-soluble, non-ionic synthetic block copolymers of ethylene oxide and propylene oxide are listed in the NF Monograph "Poloxamer". Preferred copolymers in accordance with the invention include Lutrol® or Pluronic F68, F87, F108 and F127 (BASF Corporation). Very good results have been achieved with Pluronic® F68. The coplymers have the following characteristics: The pharmaceutical dosage form of the invention expediently contains the block copolymer in an amount of from 40% to 65% by weight of the nelfmavir mesylate, preferably from 45% to 60%, and more preferably from 50% to 55% by weight of the neffinavir mesylate. The nelfinavir mesylate dosage form of the present invention is advantageously produced by a hot melt granulation process. The hot melt granulation process of the present invention comprises blending the nelfinavir mesylate and the copolymer, and heating the blend to a temperature of from the copolymer melting point temperature to below the decomposition temperature of nelfinavir mesylate. The hot melt granulation process results in a meit granulation which comprises granules of the drug embedded in the copolymer. The heated blend is mixed until such melt granules are obtained. Preferably, the blend is heated to a temperature at which the nelfinavir mesylate remains in solid form in the nelfinavir mesylate-copolymer mixture. A jacketed mixer or a hot melt extruder can be used to prepare a melt granulation. One or more excipients can be included in the mixture of nelfinavir mesylate and copolymer. The excipient can be selected from the group of stabilizers, wetting agents, binders, disintegrants, diluents and solubiiizers. Examples of additives for inclusion in the nelfinavir mesylate-copolymer mixture are povidone, polyethylene glycol, and polyoxyethylene sorbitan esters of C8-C-18 fatty acids, (e.g., Tween® 20, Tween® 60, and Tween® 80), etc. The heated blend is mixed and melt granules are formed, thus resulting in a melt granulation that includes one or more pharmaceutically acceptable excipients. The melt granulation can then be milled and mixed with one or more pharmaceutical excipients. The excipient added to the milled granulation can be selected from the group of lubricants, disintegrants and diluents. The pharmaceutical excipient may be, for example, microcrystalline cellulose, corn starch, magnesium stearate, etc. The hot melt granulation process of the present invention comprises hot melt granulating the nelfinavir with a phanmaceutically acceptable, water soluble, non-ionic synthetic block copolymer of ethylene oxide and propylene oxide, the copolymer having a melting point of at least 40°C , at a temperature of from the melting point temperature of the copolymer to below the decomposition temperature of nelfinavir mesylate. Preferably, the temperature is from 50-C to 85-C, with the proviso that the temperature be at least at the melting point temperature of the copolymer. The melt granulation, prepared with or without any additional pharmaceutical excipients, is then processed into a solid unit oral dosage form. For preparing tablets, the melt granulation can be processed into a solid unit oral dosage form by milling, lubricating, compressing (tabletting),"'and, typically, aqueous film coating. In an embodiment of the present invention, tablets are prepared as follows: a) blend amorphous nelfinavir mesylate in an amount of from 400 mg to 700 mg (calculated as free base) per unit dosage with the copolymer of the invention in an amount from 40% to 65% by weight of the nelfinavir mesylate; b) mix the powder blend from step (a) in a jacketed high shear granulator at 60+10°C with the proviso that the temperature be at least at the melting point temperature of the copolymer, or in a jacketed hot melt extruder at 80+50°C, until melt granules are obtained; cool the melt granulation to room temperature; c) mill the granulation from step (b) into a fine powder; d) blend the milled granulation from step (c) with other suitable tablet diluents, such as corn starch and microcrystailine cellulose; e) lubricate the granulation from step (d) with a suitable lubricant, such as magnesium stearate; f) compress the final blend from step (e) on a tablet press; g) aqueous film coat the tablet from step (f). A pharmaceutical dosage form of the invention, can alternatively be prepared by hot melt extrusion. Hot melt extrusion can be used to make molded tablets. The solid oral unit dosage form can be a tablet, capsule or caplet. The pharmaceutical composition can include one or more pharmaceutically acceptable excipients selected from the group of stabilizers, wetting agents, binders, disintegrants, diluents, solubilizers and lubricants. For example, the excipient can be microcrystailine cellulose, com starch, magnesium stearate, povidone, polyethylene glycol, and polyoxyethylene sorbitan esters of C8-C18 fatty acids (e.g., Tween®20, Tween® 60 and Tween® 80), etc. EXAMPLES Example 1: 250 mq Nelfinavir Mesylate Tablet (Market Formulation) Commercial Viracept® tablets were used in the present Example. Example II: 625 mo Nelfinavir Mesylate Tablet The tablet formulation of Example II was produced by a conyentional aqueous wet granulation process. Example III: 625 mq Nelfinavir Mesylate Tablet The tablet formulation of Example ill was produced by a conventional aqueous wet granulation process. The tablet formulation of Example IV was produced using a hot melt granulation process, as follows: step 1) Nelfmavir mesylate and Lutrol® F68 were mixed in a jacketed high shear granulator with a temperature setting at 25°+5*'C for 5 minutes using impeller at low speed and chopper at low speed. Step 2) The jacketed temperature was raised to 60°+10°C with the proviso that the temperature was at least at the melting point temperature of the Lutrol® F68, while mixing of the powder blend {step 1) in the high shear granulator was continued using impeller at low speed and chopper at low speed until a suitable granulation was obtained, at which time the impeller and chopper were turned off. Step 3) The heat to the jacket was turned off. The product was cooled to room temperature by passing tap water (25'*+5°C) into the jacketed vessel, with intemnittent jogging of both impeller and chopper at low speed. Step 4) The granulation from step 3 was passed through a mill. Step 5) Approximately 50% of the milled granulation from Step 4 was placed into a twin shell blender. Corn starch and magnesium stearate (passed through a 30 mesh stainless steel screen) were added into the blender. The remainder of TT the milled granulation from step 4 was added to the blender and mixed for 8 minutes. Step 6) The granulation from step 5 was compressed into a tablet containing nelfmavir mesylate, 625 mg (as free base). Step 7) The coating suspension was prepared as follows: In a stainless steel container, triacetin and Aquacoat ECD-30 were dispersed in purified water using a propeller mixer, mixing for 45 minutes. HPMC 2910-6 cps, Phanmacoat 603, talcum, titanium dioxide, yellow iron oxide and red iron oxide were added and slowly dispersed, while mixing gently to avoid air entrapment. Mixing was continued for anotlier 60 minutes or until a uniform suspension was obtained. Step 8) The kernels from step 6 were placed into a perforated coating pan. They were heated with warm inlet air of 50°+3°C with intermittent jogging until the outlet air temperature reached 38°±3°C. Step 9) The inlet air temperature was increased to 60%3°C. The kemels from step 8 were sprayed with the coating suspension from step 7, stirred continuously, using an air spray system and maintaining the outlet air temperature at 38%3°C. The film coat, 38 mg per tablet, was applied (range 35-41 mg on a dry basis). Step 10) The inlet air temperature was reduced to 40°'±3°C and the coated tablets were dried by jogging until the loss on drying of the tablets at 90°C was less than 1.8%, The heat was turned off and the tablets were cooled to room temperature by occasional jogging. Example V: 625 mg Nelfinavir Mesylate Tablet of the Invention The melt granulation method set forth In Example IV was used with the composition amounts set forth in the table above for the present example. Differences in the tablet coating are reflected in the following steps numbered 7 and 9 that here replace steps 7 and 9 of Example IV. The coating suspension, was prepared as follows: In a stainless steel container, triacetin and Aquacoat ECD-30 were dispersed in purified water using a propeller mixer, mixing for 45 minutes. HPMC 2910-6 cps, talcum, titanium dioxide and FD&C Blue #2 were added and slowly dispersed, while mixing gently to avoid air entrapment. Mixing was continued for another 60 minutes or until a unifomn suspension was obtained. The inlet air temperature was increased to 60°±3°C. The kernels from step 8 were sprayed with the coating suspension from step 7, then stirred continuously, using an air spray system and maintaining the outlet air temperature at 38°±3°C. The film coat, 28 mg per tablet, was applied (range 25-31 mg on a dry basis). The tablet formulation of Example Vi was produced by hot melt granulation, as follows: Nelfinavir mesylate and Lutrol® F68 were blended in a mixer for 10 minutes. The powder mixture from step 1 was added to a jacketed hot melt extruder set at 80+5°C while thorough mixing was continued until a uniform melt mixture was obtained. Steps 3 to 6 under Example (V were then followed as steps 3 to 6 of the present example. The same hot melt granulation procedure was followed as described in Example VI. The same hot melt granulation procedure was followed as described in Example VI. The same hot melt granulation procedure was followed as described in Example VI. Example X: Dissolution Testing Tablet formulations containing nelfinavlr mesylate (Examples I-IX) were evaluated for dissolution in 900 mL of 0.1 N hydrochloric acid solution equilibrated at 37°±0.5°C using a paddle method (USP Apparatus 2) at 50 rpm. Sample aliquots were taken at different time intervals and analyzed by UV spectrophotometry. Figure 1 presents dissolution profiles of 625 mg tablet formulations of nelfinavlr mesylate which do not contain the block copolymer of the present invention (Examples 11 and 111) compared to that of the 250 mg market (tablet) formulation (Example I). The dissolution profiles of 625 mg nelfinavir mesylate tablets without block copolymer (Examples 11 and 111) were significantly slower and less complete than that of the 250 mg market (tablet) formulation (Example 1). The tablet formulations of Examples II and 111 contain conventional excipients and were produced by a conventional aqueous wet granulation process. As shown in Figure 2, the results of the dissolution evaluation indicate that the dissolution profiles of 625 mg nelfinavir mesylate tablets in accordance with the invention (Examples IV and V) were significantly faster and essentially complete compared to the dissolution profiles of the 625 mg nelfinavir mesylate tablets which were prepared using conventional pharmaceutical excipients and a conventional aqueous wet granulation process (Examples !l and III). The dissolution profiles of tablets of Examples VI through IX are shown in Rgure 3. The results indicate that the concentration of block copolymer plays a significant role with respect to the rate and completeness of dissolution of nelfinavir mesylate. Examples VI and VII contain Poloxamer 188 in an amount of 25% and 33% by weight of nelfinavir mesylate, respectively. Examples Vlll and IX, which contain Poloxamer 188 in an amount of 47%, and 61% by weight of nelfinavir mesylate, respectively, show faster and more complete release. Example XI: Pharmacokinetic Testing Nelfinavir mesylate 250 mg tablets of the market formulation (Example I) and nelfinaw mesylate 625 mg tablets of the invention (Example IV) were evaluated for bioavailability in man. Each subject was administered a number of tablets of the given formulation totaling 1250 mg of nelfinavir mesylate (calculated as free base). In this study, 13 blood samples were drawn for each pharmacokinetic profile, i.e. at pre-dose, and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, and 24, hours after administration of the drug. Venous blood samples of approximately 5 ml were collected into heparinized tubes. Plasma was separated by centrifugation at 1500 g and 4°C for 10 minutes, within 60 minutes of drawing the blood. Plasma samples were subsequently stored at -20°C until analysis. Nelfinavir content in the plasma samples was determined by liquid chromatography - tandem mass spectrometry (LC-MS/MS). The limit of quantification was set to 4 ng/ml. The plasma concentration versus time profiles were used for the estimation of phannacoldnetic parameters. Standard non-compartmental methods were applied using the software WinNonlin 3.1. The pre-dose sampling time of a profile was set to zero and the post-dose sampling times were used as actual times. The following parameters were estimated: Cmax, maximum observed plasma concentration tmax, time of maximum observed plasma concentration AUCo-24h, calculated using WinNonlin computational rules for partial AUCs and the linear trapezoidal rule AUCo.int, calculated by AUClast + (Clast)/k), where an assessment of k (terminal elimination rate constant) was feasible t1/2, tenninal half-life, calculated by Ln (2) / k, where an assessment of k was feasible The results of this bioavailability evaluation are given in Table 1 below. The data reported in Table 1 and plotted in Figure 4 indicate that the bioavailability in man of 2 x 625 mg nelfinavir mesylate tablets of the invention (Example IV) was comparable to that of 5 x 250 mg tablets .of the market formulation (Example I) when administered with food. The present invention advantageously provides high dosage solid unit oral pharmaceutical compositions of nelfinavir mesylate having satisfactory dissolution and bioavailability. WE CLAIM : 1. A solid unit oral pharmaceutical dosage form of amorphous nelfinavir mesylate comprising amorphous nelfinavir mesylate , and a pharmaceutically acceptable, water soluble, non-ionic synthetic block copolymer of ethylene oxide and propylene oxide, said copolymer having a melting point of at least 40oC. 2. The dosage form according to claum 1, wherein said copolymer is present from 40% to 65% by weight of the nelfinavir mesylate. 3. The dosage form according to claims 1 or 2, wherein said copolymer has a melting point of 40°C to 60°C. 4. The dosage form according to claims 1 to 3, wherein said copolymer has a HLB value at 25°C of at least 14 . 5. The dosage form according to claim 4, wherein said copolymer has a HLB value at 25°C of 14 to 29 . 6. The dosage form according to claims 1 to 5, wherein said copolymer has an ethylene oxide content of at least 70 % by weight. 7. The dosage form according to claims 1 to 6, having a content of nelfinavir mesylate, calculated as nelfinavir base of 400 mg to 700 mg. 8. The dosage form according to claims 1 to 7, further comprising a pharmaceutically acceptable excipient selected from the group consisting of stabilizers, wetting agents, binders, disintegrants, diluents, solubilizers, and lubricants. 9. The dosage form according to claims 1 to 8, which is a tablet, a capsule or a caplet. 10. A process for making a solid unit oral pharmaceutical dosage form according to claims 1 to 9, comprising the steps of: (a) heating a blend comprising amorphous nelfinavir mesylate and the pharmaceutlcally acceptable, water soluble, non-ionic synthetic block copolymer of ethylene oxide and propylene oxide, said copolymer having a melting point of at least 40°C, at a temperature of from the melting point temperature of the copolymer to below the decomposition temperature of nelfinavir mesylate, (b) mixing the blend to form a melt granulation, and (c) processing the melt granulation into said dosage form of amorphous nelfinavir mesylate.

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