KR20040079952A - Increased-dosage nelfinavir tablet and method of making same - Google Patents

Abstract

The present invention is directed to high-dose Nelfinavir tablets having a weight ratio of Nelpinavir to binder of about 3: 1 to about 5: 1. High-dose Nelfinavir tablets are prepared by forming a granulated mixture of the Nelfinavir compound and a binder during the granulation process and then processing to form a tablet. In the granulation process, moisture is added, mechanical energy is added to the mixture, and the mixture is cured without adding moisture or mechanical energy.

Description

INCREASED-DOSAGE NELFINAVIR TABLET AND METHOD OF MAKING SAME}

It has been believed that HIV-infected patients can be treated with HIV-protease inhibitors to prevent or inhibit the virus from proliferating rapidly in the body. HIV-protease inhibitors block important enzyme pathways in the virus, substantially reducing viral load and slowing down the sustained degradation of the immune system. Nelfinavir compounds, particularly Nelfinavir mesylate (Viracept®), appear to be effective protease inhibitors in the treatment of HIV-infected patients. Nelfinavir mesylate and methods for its preparation are incorporated herein by reference and are disclosed in US Pat. No. 5,484,926 to Dressman et al. Intermediates for the preparation of HIV-protease inhibitors, such as nelfinavir mesylate, are disclosed in US Pat. No. 5,705,647, incorporated herein by reference and incorporated by Babu et al.

Nelfinavir mesylate is currently used in tablets to provide doses equivalent to 250 mg of nelpinavir free base. Therefore, because the standard dose is 1250 mg twice a day, the patient must take five tablets twice a day. Since 10 tablets per day is a significant pill burden for the patient, it would be advantageous to reduce this high pill burden and improve compliance. Thus, there is a need for nelpinavir tablets that provide higher doses of nelpinavir than currently available 250 mg tablets.

Summary of the Invention

High-dose Nelfinavir tablets of the present invention comprise a Nelfinavir compound and a binder. Tablets of the present invention have a nelpinavir: binder in a weight ratio of about 3: 1 to about 5: 1. Preferably the weight ratio of nelfinavir to binder is from about 3.5 to 1 to about 5 to 1, more preferably 4 to 1. The nelpinavir compound is preferably present in an amount sufficient to provide an equivalent nelpinavir dose of about 625 mg of nelpinavir free base. The nelpinavir compound is preferably nelpinavir mesylate and the preferred binder is calcium silicate. If the Nelfinavir compound is Nelfinavir mesylate, the compound is preferably present in an amount of about 730 mg per tablet. The tablets of the present invention may further comprise one or more excipients preferably selected from the group consisting of magnesium stearate, crospovidone and colloidal silicon dioxide, and are preferably coated. Each tablet preferably comprises one or more of about 15 to about 20 weight percent crospovidone, about 0.1 to about 0.5 weight percent silicon dioxide, and about 0.5 to about 1.5 weight percent magnesium stearate, based on the total tablet weight It includes. Preferred tablets comprise about 17.5% crospovidone, 0.25% silicon dioxide and about 1% magnesium stearate, based on the total tablet weight.

The coating is preferably hydroxypropyl methylcellulose, which is preferably present in an amount of about 1 to about 3% by weight of the tablet, more preferably about 2% by weight of the tablet.

The method of the present invention comprises the steps of forming a granulated mixture of nelpinavir compound and binder in a granulation process and processing the granulated mixture to form a high-dose nelpinavir tablet, wherein the granules The oxidization process includes adding moisture to the mixture, applying mechanical energy, and curing the mixture with one or more curing steps without adding moisture to the mixture and without adding mechanical energy. Preferably, each curing step has a curing time of at least about 1 minute, more preferably from about 1 minute to about 30 minutes, even more preferably from about 10 minutes to about 15 minutes. The Nelfinavir compound and binder can be dry blended prior to granulating the mixture.

After granulation, the wet granulated mixture can be dried at a temperature of about 60 to 80 ° C., preferably at a moisture content of about 4 to about 8% LOD (loss on drying). The dried granules can then preferably be milled and blended with one or more excipients, for example magnesium stearate, crospovidone and colloidal silicon dioxide. Preferably, the granule mixture is milled using a round hole screen with a hole size of about 0.024 inches to about 0.045 inches.

The present invention relates to high-dose forms of nelpinavir tablets and methods of making such tablets. More specifically, the present invention relates to nelpinavir tablets having significantly larger doses than are currently used to reduce the pill administration burden of patients.

1 is a flowchart of a process used in Example 1;

2 is a flow chart of the process used in Example 2. FIG.

The present invention relates to high-dose Nelfinavir tablets and methods of making such tablets. As used herein, the term "Nelfinavir compound" refers to (1,1-dimethylethyl) decahydro-2- [2-hydroxy-3-[(3-hydroxy-2-methyl) which is the nelpinavir free base. Benzoyl) amino] -4- (phenyl-thio-butyl)]-3-isoquinolinecarboxamide) or a pharmaceutically acceptable salt such as nelpinavir mesylate ((1,1-dimethylethyl) Decahydro-2- [2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino] -4- (phenyl-thio-butyl)]-3-isoquinolinecarboxamide mono-methanesulfone ). The term "high-dose" means a nelpinavir tablet that effectively provides a higher therapeutic dosage than that provided in a 250 mg tablet. Generally, the dose of the nelpinavir compound in the tablet is equivalent to about 531 mg to about 719 mg, preferably about 593 mg to about 656 mg of nelpinavir free base. More preferably, the dose of the Nelfinavir compound is an amount equivalent to 625 mg of Nelfinavir free base. In other words, the tablets of the present invention provide an amount of nelpinavir compound sufficient to provide the same therapeutic effect as a dose of 625 mg free of nerpinavir free base. For example, in the case of Nelpinavir mesylate, which is the preferred Nelfinavir compound, the amount of drug required to provide the same therapeutic effect as the 625 mg dose of Nelfinavir free base is about 730 mg. Unless otherwise stated, it should be noted that all weights herein relate to anhydrides. Those skilled in the art will understand how to adjust the weight of each component used in the tablet in view of any residual moisture or solvents that may be present.

Tablets of the present invention comprise a nelpinavir compound ("drug") and a binder in a drug / binder weight ratio of about 3: 1 to about 5: 1. Preferably, the drug / binder weight ratio is about 3.5: 1 to about 5: 1, more preferably about 3.5: 1 to about 4.5: 1, even more preferably about 4: 1. Preferably, the nelpinavir compound is nelpinavir mesylate and the binder is calcium silicate (CaSiO ₃ ). The use of calcium silicate as a binder provides optimal solubility and crystallinity for high-dose Nelfinavir tablets.

Commercially available low dose (250 mg) forms of Nelfinavir tablets have a drug / binder ratio of about 2: 1. The higher drug / binder weight ratio of the tablets of the present invention makes water absorption more difficult during the process. As a result, one or more curing steps are required during granulation in order for the moisture to be properly absorbed into the drug-binder matrix. During each curing step of the granulation process, no moisture is added and no mechanical energy is applied during the period referred to herein as "cure time". One or more curing steps during granulation is a suitable time for the moisture to be absorbed in order for the granulation product to be further processed into tablets. In the case of 250 mg Nelfinavir tablets currently on the market, since the ratio of the binder in the tablet is larger, moisture is absorbed without curing, so no curing time is required. Thus, unlike the process of the present invention, in the preparation of 250 mg tablets water is added and mechanical sources of energy such as choppers and / or impellers are used continuously.

In one embodiment, the high dose Nelfinavir tablet of the present invention is prepared by the following procedure. First, any residual humidity and / or solvent is taken into account to determine the amount of Nelfinavir compound and binder required for a given batch size and drug / binder weight ratio. Preferably, the nelpinavir compound and binder are first sieved to remove any lumps.

The Nelfinavir compound and binder are then mixed and wet granulated. The drug and binder may be blended dry before granulation or mixed in a granulation device. Preferably, it is granulated in a high-shear granulator.

During granulation, water is added to the drug / binder mixture under the action of a granulator, for example an impeller and / or a whimper. The granulation process also includes one or more curing steps to allow water to be properly absorbed by the Nelfinavir compound / binder mixture. During the curing step, no water or mechanical energy is added to the mixture. That is, the addition of water and the action of any impeller and / or chamfers are stopped. The time for the curing step, ie the curing time, is typically at least about 1 minute, preferably from about 1 to about 30 minutes, more preferably from about 10 to 15 minutes. The granulation process may comprise one or more curing steps. Preferably, the granulation process comprises 1 to about 6 curing steps, more preferably 1 to about 3 curing steps. The granulation process may further include one or more wet agglomeration steps without adding moisture, but with mechanical energy added.

After granulation, the granulated drug / binder mixture is processed into tablets. Processing steps may include, but are not limited to, drying, sieving, milling, blending with excipients, compression, and coating. Useful excipients include, but are not limited to, crospovidone, colloidal silicon dioxide and magnesium stearate.

The following non-limiting examples are examples of preferred embodiments of the invention and are not intended to limit the invention, the scope of the invention being defined by the appended claims.

Example 1

A batch of 117,490 tablets having a capacity equivalent to 625 mg of Nelfinavir free base and having a total weight of 140.6 kg was prepared using the manufacturing process diagram shown in FIG. 1. Each tablet had an average of 730.6 mg of U.S. Spec. Nelfinavir mesylate, 182.7 mg calcium silicate, 196.7 mg crospovidone, NF (Kollidon, CF), 2.8 mg colloidal silicon dioxide, NF and 11.2 mg magnesium stearate, NF . Each tablet was coated with 23.5 mg of Orradry Clear YS-2-19114-A for a total average tablet weight of 1,196 mg. Any water used for processing was essentially removed during the process such that residual humidity of about 4% or less remained in the tablet.

21.47 kg of calcium silicate is equivalent to 88.60 kg (85.85 kg of anhydrous and solvent-free) after sieving through a round-edge impeller and a Quadro Comil with 0.032 inch round-hole sieve Was added to Nelpinavir mesylate, which was sieved through a 20-mesh sieve in a granulation bowl of a Zanchetta Model Roto F900L granulator. The drug and binder were mixed for about 5 minutes, with the impeller set at high speed and the kumper at low speed. Then, the impeller speed was changed low for 1 minute.

Then, the mixture of Nelfinavir mesylate and calcium silicate was granulated as follows. For 5-10 minutes, 30 kg of water at a rate of 3-6 kg / min were added to the mixture with high impeller speed and low kemper speed. Then, the addition of water was stopped and the impeller speed and the whimpers were lowered for 1 minute in the wet agglomeration step. Then, the impeller and wafers were turned off and the wet mixture was cured for a curing time of 10 to 15 minutes. Then, the impeller was turned low again and an additional 6 kg of water was added for 1-2 minutes. The kipper was then turned on and an additional 3 kg of water was added with the speed of both the impeller and the kipper set to low. Again, the addition of water was stopped and the wet agglomeration step was carried out for 30 seconds with both the impeller and the wafer speed set to low. The impeller and chamfer were turned off and the wet mixture was cured for an additional curing time of 10 to 15 minutes. An additional 3.8 kg of water was added for about 1 minute, with the impeller and chamfer speeds set to low. The wet agglomeration step was then carried out for about 1 minute without changing the impeller and chamfer speeds.

The granulated mixture was then dried at 60 ± 5 ° C. until the humidity content reached 4-8% LOD (target is 6% LOD). The dried mixture was then milled using Quadro Comil 196-S with a round-edge impeller, a 0.032 inch round-hole sieve and a 0.2 inch spacer.

Then, about half of the total dried and milled granulate was placed in a 30 cubic foot "V" type blender using a vacuum load and 23.11 kg of crospovidone, NF (Kollidon CL) was added to the blender. It was. The remaining granulation mixture was then added to the blender and the combined materials were mixed for 30 minutes. A mixture of 1.32 kg magnesium stearate, NF and 0.32 kg colloidal silicon dioxide, NF is mixed and passed through a 20-mesh stainless steel sieve and mixed for 5 minutes before adding the other ingredients to the blender, resulting in a final blend. Formed.

The final blend was then compressed into a white oval 0.750x0.425 inch (19.1x10.8 mm) tablet core with "V" on one hand and "625" on the other. The tablets had a weight of 1.144 g to 1.202 g and a target of 1.173 g. The thickness of the tablets ranged from 0.322 inches (8.18 mm) to 0.342 inches (8.69 mm), the target was 0.332 inches (8.43 mm), the hardness ranged from 22 Kp to 35 Kp, and the target was 28 Kp. Fracture property was less than 1.0%, and decomposition was 15 minutes or less.

The tablet cores were then coated with 2.76 kg of Opadry Clear YS-2-19114-S in purified water on a Glat PC 1500 60 inch coater and dried. The tablet was found to be biologically equivalent to a commercial 250 mg Nelfinavir tablet.

Example 2

Nelfinavir mesylate tablet of the present invention was prepared using the manufacturing process shown in FIG. Nelfinavir mesylate and calcium silicate were blended in a 500-liter bin-blender for 15 minutes to form a 60 kg Nelfinavir mesylate and calcium silicate blend with a drug / binder weight ratio of 4: 1. It was. The correction factor was applied to nelpinavir mesylate taking into account the presence of 3.1% volatiles. The height of the blended powder was monitored for changes to determine if aeration occurred, but no significant changes were observed. The blended powder was placed in a fiber drum lined with a polyethylene bag and showed a characteristic fluid flow.

Within a few minutes of release, a volume reduction greater than 10% was observed and almost 50% reduction was observed after overnight storage. It is believed that the powder blend was vented during release to increase the volume. Thus, as the air in the blend exited during storage, the volume was reduced.

The powder blend was fed to a biaxial wet granulator (34 mm Leistriz granulator) through a side stuffer. The components of the screw design of the type used are described below. The screw granulator comprises the following compartments according to the flow direction: spacer, first transport compartment, first mixing compartment, second transport compartment, second mixing compartment, third transport compartment, chopper compartment, spacer compartment and tor Fedo. Water for granulation was injected into the first transport compartment and the first mixing compartment. The granulation screw was operated at 300 rpm and the side stuffer at 200 rpm. The powder blend had a feed rate of 7.8 kg per hour and water was injected at 47 ml / min to provide a constant wet yield of at least 10 kg per hour.

The dry powder blend of bulk density had a moisture content of 2.2% LOD, a bulk density of 0.15 g / ml and a tapped density of 0.25 g / ml. The wet granulation had a moisture content of 27.88% LOD, a bulk density of 0.45 g / ml and a tapped density of 0.75 g / ml.

During granulation, the blend was once passed through the second transport compartment and once through the third transport compartment to cure the drug / binder blend twice.

The wet granulation was dried in two parts of A and B at a humidity level of 4-8% LOD in a fluid-bed drier at an inlet temperature of 60 ° C. at 750 cfm (ft ³ / m). The final humidity level in part A was 4.81% LOD and the final humidity in part B was 3.7% LOD, below the target level. Both dried parts were transported in the direction of the process, but only part B was used for the compression study.

The dried granulation was passed through a Quadro Comil 197S equipped with a 0.032 inch screen and a 0.150 inch screen using an impeller speed of 2300 rpm.

The milled granulate is blended with an external excipient in a 250 liter empty blender, first with crospovidone for 15 minutes, then with a mixture that has removed the previous blend and agglomerates of colloidal silicon dioxide and magnesium stearate Blend for an additional 10 minutes. The amounts of crospovidone, silicon dioxide and magnesium stearate used were 16.44%, 0.23% and 0.94%, respectively, based on the total weight of the final tablet formulation.

The final blend was compressed on a 19-station Kikusui Virgo tablet press using an elliptical deep concave punch of 0.750 × 0.425 inch (19.1 × 10.8 mm). The press was run with a minimum press speed of 22 rpm and a paddle feeder of 55 rpm. The precompression was 0.90 tons (818 kg) and the main compression was 1.0 tons (909 kg).

A 10 kg batch of tablet cores was coated with an Opadry Clear film using a 24 inch perforation pan to increase the theoretical weight by 2% in an Accela Cota coating system. The fan speed was maintained at 10 rpm and the spray rate was 20-40 ml / min. As a result of the loss of moisture by the core during the coating, no weight increase was observed.

The dissolution profile of the obtained 625 mg tablets was compared with 250 mg of commercially available tablets. The dissolution time of a 625 mg tablet of 17.1 minutes is several times longer than 1.75 minutes of a 250 mg tablet. However, within 15 minutes, the solubility of 625 mg in simulated gastrointestinal fluid without pepsin is 68%, comparable to 78% of 250 mg tablets, and within 45 minutes 88% solubility of 625 mg tablets is comparable to 89% solubility of 250 mg tablets. be worth.

The invention is not limited by the disclosed embodiments. It is intended that the appended claims cover all such changes and aspects as fall within the true spirit and scope of this invention.

Claims (15)

A tablet comprising a Nelfinavir compound and a binder having a Nelfinavir to binder weight ratio of about 3: 1 to about 5: 1. The method of claim 1, Tablets wherein the Nelfinavir compound is nerpinavir mesylate. The method of claim 1, A tablet wherein the Nelfinavir compound is present in an amount sufficient to provide an elpinavir dose equivalent to about 625 mg of nelpinavir free base. The method of claim 3, wherein A tablet wherein the Nelfinavir compound is Nelfinavir mesylate and is present in an amount of about 730 mg. The method of claim 1, Tablets further comprising one or more excipients. The method of claim 1, Further comprising at least one of about 15 to about 20 weight percent crospovidone, about 0.1 to about 0.5 weight percent silicon dioxide, about 0.5 to about 1.5 weight percent magnesium stearate, and a coating, based on the total weight of the tablet refine. Forming a granulated mixture of the nlpinavir compound and the binder in the granulation process; And Processing the granulated mixture to form a high-dose Nelfinavir tablet, comprising adding moisture to the granulated mixture, applying mechanical energy and at least one that does not add moisture to the mixture and does not add mechanical energy A tablet forming step comprising curing the granulated mixture in a curing step, Method of Making High-Dose Nelfinavir Tablets. The method of claim 7, wherein At least one curing step has a curing time of at least about 1 minute. The method of claim 7, wherein Further dry-blending the nlpinavir compound and binder before granulating the mixture. The method of claim 7, wherein Wherein the weight ratio of nelpinavir compound to binder in the mixture is from about 3: 1 to about 5: 1 The method of claim 7, wherein And drying the granulated mixture at a temperature of about 60 ° C to about 80 ° C. The method of claim 7, wherein And drying the granulated mixture to a moisture content of about 4 to about 8% LOD. The method of claim 7, wherein Milling the granulated mixture. The method of claim 7, wherein Further comprising blending the granulated mixture with one or more excipients. The method of claim 7, wherein Further comprising blending the granulated mixture with one or more excipients selected from the group consisting of magnesium stearate, crospovidone and colloidal silicon dioxide.