Patent Application
20080014228
The present invention will now be further described with reference to specific examples which are illustrative of the invention.
In this specification, all parts and percentages are by weight unless otherwise noted.
Fill material: The ibuprofen and theohylline active powders were sieved through a 24 mesh screen (710 microns) prior to weighing. The Rhodapap® acetaminophen active powder was sieved through a 35 mesh screen (425 microns) prior to weighing. Powders were weighed out and blended for 15 to 20 minutes in a Turbula TF2 shaker mixer, a PharmaTech V-blender or in a Speedmixer DAC150FVZ-K for 5 seconds at 3000 rpm. The powder fill material was stored in a plastic bottle or double plastic bags until use. Ibuprofen granulate was prepared using a 4M8 granulator from Pro-Cept: Ibuprofen and Avicel were weighed out and blended in the granulator for 5 minutes at 500 rpm, 145 ml of a solution of 8.8 g/ml Docusate Sodium in DI water was added at a speed of 11 ml/min in the 297 mg powder blend, which was mixed at 1000 rpm. The granules were then dried in an oven at 50° C. for 12 hours and screened through a #12 sieve thereafter. Ibuprofen and ketoconazole are practically insoluble in water (1 g in more than 10,000 g of water), acetaminophen is sparingly soluble in water (1 g in 30 to 100 g of water), aspirin and theophylline are slightly soluble in water (1 g in 100 to 1000 g water).
Powder compacts: Powder compacts of varying densities were prepared by compressing the powder fill material in an ESH compaction simulator (ESH Testing Ltd, Dudley, UK) with flat round punches having a diameter of 13 millimeters. The upper punch speed was 100 mm/sec giving a 0.36 second cycle. The upper punch displacement was adjusted to vary the compaction force. The maximum applied force was chosen to be lower than a force that would result in mechanical failure (“capping”) of the compressed fill formulation. Six compacts were prepared for each test condition. The amount of powder fill used was 250 milligrams for compaction pressures of 30 MPa or less and 500 milligrams for compaction pressures of more than 30 MPa. The upper punch force and compact weight were recorded. The compaction pressure reported was based on the upper punch force divided by the punch area (132.73 square millimeters). Compacts were stored in double plastic bags. The compact thickness measured prior to the beginning of the dissolution testing was used to calculate the apparent density.
Enrobed solid form: A soluble film known as XGEL UNO and supplied by Bio Tec Films LLC was cut into strips 6 centimeters by 20 centimeters. The lower film had a thickness of about 120 microns and the upper film had a thickness of about 80 microns or 120 microns. The lower film was heated sufficiently to thermoform under vacuum into dose cups about 2 to 4 millimeters in height to conform to cavities (7.5 millimeters width by 16.75 length millimeters) with the cavity depth determined by height-adjustable dose-shaped lower pistons within the stainless steel die. The film strip was placed over the die and brought in contact with a heated TEFLON® coated surface by means of upward vacuum. The film was then drawn into the stainless steel die cavities by inverting the vacuum to form a strip of twelve thermoformed dose cups with 3.0 millimeters separation between adjacent dose cups. Some unused portion of the filmstrip was cut and removed. The fill composition was dosed (by volume) into the dose cups, then the fill was lightly compacted in the dose cups with upper pistons, and the lower film was cut to separate the individual solid forms. The solid forms were then lifted by the lower pistons to expose a portion of the solid form sidewalls for application of the upper film to complete the enrobing of the solid form. An adhesive composed of 5% Methocel E15LV Premium, 45% Benzyl alcohol and 50% Triacetin, [was applied (by transfer roller) to the upper filmstrip on the side to be pressed against the exterior sidewall of the dose cup. This adhesive and application method is referred to as “Adhesive 1” in the examples. Alternatively, an adhesive composed of 62% Benzyl alcohol, 31% Ethanol, 5% Potassium Acetate, 2% Deionised Water and Erythrosine was sprayed on the upper portion of the exterior sidewall of the lower film prior to the upper thermoforming step. This adhesive and application method is referred to as “Adhesive 2” in the examples. The upper film was placed over the solid forms containing the compressed powder fill and the film was heated by contact with the heating element using upper vacuum. The heated upper film was formed around the solid forms using the lower vacuum enclosing the fill material within the solid form by overlapping the upper film onto the sidewall of the solid forms. The top film was cut to separate the completed enrobed solid forms and the unused film was removed. Each solid form was ironed by forcing it through a heated die under low pressure so that the cut film overlapping the sides was pressed smooth. Examples 1, 5, 6, 7-1, 8-1, 8-2, 11-2, 11-3 and 11-4 below used the apparatus set forth in WO 2005/030115, and examples 7-2, 7-3, 7-4, 9-1, 9-2, 9-3, and 11-1 below used the apparatus set forth in WO 2005/030116.
Dissolution tests were carried out according to USP 24 and USP 28 with dissolution apparatus 2, paddles. Disintegration tests were carried out according to USP 28, with disks.
A powder fill was prepared with the following composition: 74.5% Ibuprofen, 20% AVICEL® PH 200, 4.0% AC-DI-SOL®, 1.0% talc and 0.5% magnesium stearate. The ibuprofen, Avicel and Ac-Di-Sol were mixed together for 20 minutes in a V-blender. The talc and magnesium stearate were then added and mixed for 10 minutes. This powder fill material was used to fill two types of commercial hard shell capsules: gelatin hard shell capsules (Capsugel size 0) and hydroxypropyl methylcellulose hard shell capsules (Shionogi size 0); and to prepare an enrobed solid form of the present invention. The capsules were filled by hand with a semi-automatic capsule filling machine. Both the upper and lower films were 120 microns in thickness. The thermoforming steps were at 140° C. for 2 seconds. Adhesive 1 was used. The ironing step was 30 seconds at 45° C. Table 1 shows the weights of the solid form and its components (the shell or film, and the fill material), the mean ibuprofen content of the powder fill material, the disintegration time, and the percentage of ibuprofen released at 5 minutes in the dissolution test at 37° C. according to USP 24 for Ibuprofen immediate release tablets using 900 ml of phosphate buffer at pH 7.2 in dissolution apparatus 2, paddles.
The release of the ibuprofen using the same powder fill material was significantly faster from the enrobed solid form of the present invention than from the commercial gelatin or HPMC hard capsules as shown in Table 1 and
Dissolution of compacted and non-compacted powder fill compositions containing 76% ibuprofen with and without AC-DI-SOL® croscarmellose sodium was measured in phosphate buffer at pH 7.2 as specified in USP 24 for ibuprofen. USP specifications for Ibuprofen tablets for immediate release are: not less than 85% of the drug dissolved after 60 minutes (Q). This is referred to as the “Q-time.”
The powder fill compositions were: (1) 76% ibuprofen, 23% AVICEL® PH200 microcrystalline cellulose, and 1% talc and (2) 76% ibuprofen, 20% AVICEL® PH200, 3% AC-DI-SOL® and 1% talc. The powder compacts were prepared using 250 mg of powder fill when the compaction pressure was 30 MPa or less and 500 mg when the compaction pressure was greater than 30 MPa. The non-compacted powders were tested for dissolution using 500 mg of the powder fill composition.
Table II shows the percentage of ibuprofen released during dissolution at 5 minutes as a function of density for samples with and without the AC-DI-SOL® croscarmellose sodium. The samples containing 3% Ac-Di-Sol in Table II are all examples within the scope of the invention.
Powder compacts containing 76% ibuprofen were prepared using fill formulations as in Example 2 except replacing the microcrystalline cellulose (a viscoelastic, insoluble filler) with lactose (a brittle, soluble filler) or dicalcium phosphate dihydrate (a brittle, insoluble filler). The dissolution data for the microcrystalline cellulose are from Table II in Example 2. All Ibuprofen compacts were tested for dissolution at 37° C. according to USP 24 for Ibuprofen immediate release tablets using 900 ml of phosphate buffer at pH 7.2 in dissolution apparatus 2, paddles. USP specifications for Ibuprofen tablets for immediate release are: not less than 85% of the drug dissolved after 60 minutes (Q). The samples containing 3% Ac-Di-Sol in Table III are all examples within the scope of the invention.
Powder compacts containing 76% ibuprofen were prepared using the fill material formulations of Example 2 but with varying amounts of AC-DI-SOL® croscarmellose sodium. As the amount of AC-DI-SOL® was decreased in the formulation, it was replaced with additional AVICEL® PH 200 microcrystalline cellulose. Compacts containing all levels of AC-DI-SOL® tested had an increased amount of ibuprofen released at 5 minutes of dissolution when tested for dissolution at 37° C. according to USP 24 for Ibuprofen immediate release tablets using 900 ml of phosphate buffer at pH 7.2 in dissolution apparatus 2, paddles compared to the powder compact without AC-DI-SOL® as shown in Table IV. All samples in Table IV are examples within the scope of the present invention.
Commercial solid forms containing 200 milligrams of ibuprofen were tested for dissolution. The commercial products tested were NUROFEN® sugar coated tablets, NUROFEN® liquid filled gelatin softgel capsules, and ADVIL® (bicolored) gelatin dipped caplets.
Table V shows that the ibuprofen release was significantly faster from the enrobed solid form (Example 1) of the present invention than from the tested commercial solid forms.
The Ibuprofen solid forms were tested for dissolution at 37° C. according to USP 24 for Ibuprofen immediate release tablets using 900 ml of phosphate buffer at pH 7.2 in dissolution apparatus 2, paddles.
Commercial solid forms containing 500 mg dose of acetaminophen were tested for dissolution at 37° C. according to USP 24 for acetaminophen using 900 ml of phosphate buffer at pH 5.8 in dissolution apparatus 2, paddles. The commercial solid forms were hard shell gelatin capsules manufactured by Boots, TYLENOL RAPID RELEASE® gelcaps, PANADOL ACTIFAST® film coated tablets, and bicolored gelatin-coated capsule-shaped tablets (“geltabs”) manufactured by Banner Pharmacaps. Enrobed solid forms of the present invention containing acetaminophen were prepared as in Example 1 using 441 mg of COMPAP® L as the powder fill material.
Enrobed solid forms were prepared with acetaminophen in the powder fill material using COMPAP® L, a commercial directly compressible, fast disintegrating powder containing 90% acetaminophen in addition to starch, polyvinylpyrrolidone, stearic acid and CrosPovidone, used as the superdisintegrant, according to its MSDS sheet. Examples 7-1, 7-2, 7-3, 7-4 and 7-5 are examples within the scope of the invention.
For example 7-1: The lower film thickness was about 120 microns, and the upper film thickness was about 90 microns prior to thermoforming. The lower film thermoforming step (140° C., 2 second) produced a solid form of 3 millimeters in height. The upper film thermoforming step (140° C., 2 seconds) gave a film overlap of 2 millimeters. Adhesive 1 was used. The ironing process was by passing the solid form through a hole in a die at 40° C. with a transit time 20 seconds. The enrobed solid form had an average weight of 480 mg (19 mg upper film, 19 mg lower film and 442 mg of fill).
For example 7-2 and 7-5: the lower film thermoforming step (140° C., 1 second) produced a solid form of 2 millimeters in height. The upper film thermoforming step (160° C., 1 second) resulted in a film overlap of 1 millimeter. Adhesive 2 was used. The enrobed solid forms were ironed at 60° C. for 110 seconds. The enrobed solid form 7-2 had an average weight of 314 mg (18.5 mg upper film, 18.5 mg lower film and 277 mg of fill). The enrobed solid form 7-5 had an average weight of 313 mg (18.5 mg upper film, 18.5 mg lower film and 276 mg of fill). 7-2 and 7-5 were taken form the same manufacturing batch. 7-2 were tested immediately after manufacture, 7-5 were tested after 20 months storage at room conditions. The results in table VII show that the release profile of the drug from the solid form of the present invention is stable with time.
For examples 7-3 and 7-4: the lower and upper film thicknesses were about 120 microns prior to thermoforming. The lower film thermoforming step (155° C., 2 seconds) produced a dose cup 3 millimeters in height. The upper film thermoforming step (150° C., 3 seconds) gave a film overlap of 1.5 millimeters. No adhesive was applied on these solid forms. The ironing process was by passing the solid form 7-4 through a hole in a die at 60° C. with a transit time 13.2 seconds. Solid form 7-3 was not passed through the ironing step. The enrobed solid form 7-3 had an average weight of 656 mg (19 mg upper film, 19 mg lower film and 618 mg of fill). The enrobed solid form 7-4 had an average weight of 377 mg (19 mg upper film, 19 mg lower film and 339 mg of fill).
Examples 7-1, 7-2, 7-3 and 7-4 were tested for dissolution at 37° C. according to USP 24 for acetaminophen using 900 ml of phosphate buffer at pH 5.8 in dissolution apparatus 2, paddles. USP specifications for Acetaminophen tablets for immediate release are: not less than 85% of the drug dissolved after 30 minutes (Q). All samples in the following Table VII are examples within the scope of the invention.
Enrobed solid forms were prepared with powder fill materials using high drug loadings of 98% and 99% of RHODAPAP® acetaminophen powder. The two formulations tested were (1) 99% acetaminophen and 1% colloidal silica and (2) 98% acetaminophen, 1% AC-DI-SOL® and 1% colloidal silica. The thermoforming step (145° C., 2 seconds) formed a dose cup with a 3 millimeter height. The upper film thermoforming step (160° C., 4 seconds) gave a film overlap of 1 millimeter. Adhesive 1 was used. The ironing process used a 20 second dwell (40° C.). Example 8-1 is a comparative example, and Example 8-2 is an example within the scope of the invention.
Examples 8-1 and 8-2 were tested for dissolution at 37° C. according to USP 24 for acetaminophen using 900 ml of phosphate buffer at pH 5.8 in dissolution apparatus 2, paddles. USP specifications for Acetaminophen tablets for immediate release are: not less than 85% of the drug dissolved after 30 minutes (Q). 8-1 in the Table below is a comparative example, and 8-2 in the Table below is an example of the present invention.
Enrobed solid forms were prepared with acetaminophen in the powder fill material using COMPAP® L, a commercial directly compressible, fast disintegrating powder containing 90% acetaminophen in addition to starch, polyvinylpyrrolidone, stearic acid and CrosPovidone, used as the superdisintegrant, according to its MSDS sheet. Example 9-1, 9-2, 9-3 are examples within the scope of the invention.
The lower and upper film thicknesses were about 120 microns prior to thermoforming. The lower film thermoforming step (155° C., 2 seconds) produced a dose cup 2.7 millimeters in height. The upper film thermoforming step (165° C., 3 seconds) gave a film overlap of 1.5 millimeters for example 9-3, and 1.3 mm for examples 9-1 and 9-2. No adhesive was applied on these solid forms. The ironing process was by passing the solid form through a hole in a die at 60° C. with a transit time 79.2 seconds. The enrobed solid form 9-1 had an average weight of 553 mg (19 mg upper film, 19 mg lower film and 515 mg of fill). The enrobed solid form 9-2 had an average weight of 494 mg (19 mg upper film, 19 mg lower film and 456 mg of fill). The enrobed solid form 9-3 had an average weight of 403 mg (19 mg upper film, 19 mg lower film and 365 mg of fill). All samples in the Table below are examples within the scope of the invention.
Dissolution of compacted powder fill compositions containing ibuprofen with and without the superdisintegrant AC-DI-SOL® croscarmellose sodium and with and without the wetting agent Docusate sodium (DS) or Sodium Lauryl Sulfate (SLS) was measured in phosphate buffer at pH 7.2 as specified in USP 24 for ibuprofen tablets for Immediate Release. The powder fill compositions were: (1) 76% ibuprofen, 22.6% AVICEL® PH101 microcrystalline cellulose, 0.4% Docusate sodium and 1% talc in a granulate form, (2) 76% ibuprofen, 20.6% AVICEL® PH101 microcrystalline cellulose, 0.4% Docusate sodium, 2% Ac-Di-Sol and 1% talc in a granulate form, (3) 76% ibuprofen, 23% AVICEL® PH200 microcrystalline cellulose, and 1% talc in a powder form (formulation from example 2 (1), (4) 50% ibuprofen, 48% AVICEL® PH102, 1% Sodium lauryl sulfate and 1% talc, (5) 50% ibuprofen, 46% AVICEL® PH102, 2% AC-DI-SOL®, 1% Sodium lauryl sulfate and 1% talc. The powder compacts were prepared using 250 mg of powder fill.
Example 10-4 is a comparative example, and examples 10-1, 10-2, 10-3, 10-5 and 10-6 are examples within the scope of the invention.
Table X shows the % ibuprofen released during dissolution at 5 minutes at 37° C. according to USP 24 for Ibuprofen immediate release tablets using 900 ml of phosphate buffer at pH 7.2 in dissolution apparatus 2, paddles as a function of density for samples with and without the AC-DI-SOL® croscarmellose sodium and with or without the wetting agent. 10-4 is a comparative example and all other samples in the Table below are examples of the present invention.
Enrobed solid forms were prepared with the following blends: (1) 95% Aspirin, 3% talc and 2% Ac-Di-Sol (2) 98% Ketoconazole and 2% Ac-Di-Sol (3) 98% Theophylline and 2% Ac-Di-Sol. Example 11-1, 11-2, 11-3 and 11-4 are examples within the scope of the invention.
The lower and upper film thicknesses were about 120 microns prior to thermoforming.
In examples 11-1, the lower film thermoforming step (155° C., 2 seconds) produced a dose cup 3.1 millimeters in height. The upper film thermoforming step (165° C., 4.5 seconds) gave a film overlap of 1.5 millimeters. No adhesive was applied. In examples 11-2 and 11-3, the lower film thermoforming step (155° C., 3 seconds) produced a dose cup 2.5 millimeters in height. The upper film thermoforming step (165° C., 3 seconds) gave a film overlap of 1.5 millimeters. Adhesive 1 was used. In examples 11-4, the lower film thermoforming step (165° C., 2 seconds) produced a dose cup 2.5 millimeters in height. The upper film thermoforming step (165° C., 3 seconds) gave a film overlap of 1.5 millimeters. Adhesive 1 was used.
In example 11-1 the ironing process was by passing the solid form through a hole in a die at 60° C. with a transit time of 14.5 seconds. In examples 11-2, 11-3 and 11-4 the ironing process was by passing the solid form through a hole in a die at 40° C. with a transit time of 20 seconds.
The enrobed solid form 11-1 had an average weight of 783 mg (19 mg upper film, 19 mg lower film and 745 mg of fill). The enrobed solid form 11-2 had an average weight of 580 mg (19.5 mg upper film, 19.5 mg lower film and 541 mg of fill). The enrobed solid form 11-3 had an average weight of 540 mg (19.5 mg upper film, 19.5 mg lower film and 501 mg of fill). The enrobed solid form 11-4 had an average weight of 421 mg (19.5 mg upper film, 19.5 mg lower film and 382 mg of fill).
Aspirin solid forms were tested for dissolution at 37° C. using 900 ml of acetate buffer at pH 4.5 in dissolution apparatus 2, paddles. USP specifications for Aspirin tablets for immediate release are: not less than 85% of the drug dissolved after 30 minutes (Q). Ketoconazole solid forms were tested for at 37° C. according to USP 28 for Ketoconazole immediate release tablets using 900 ml of 0.1N hydrochloric acid in dissolution apparatus 2, paddles. USP specifications for Ketoconazole immediate release tablets are: not less than 85% of the drug dissolved after 30 minutes (Q). Theophylline solid forms were tested for at 37° C. according to USP 28 for Theophylline immediate release tablets using 900 ml of water in dissolution apparatus 2, paddles. USP specifications for Theophylline immediate release tablets are: not less than 85% of the drug dissolved after 45 minutes (Q). The samples in the Table below are all examples within the scope of the invention.
The invention has been illustrated by detailed description and examples of the preferred embodiments. Various changes in form and detail will be within the skill of persons skilled in the art. Therefore, the invention must be measured by the claims and not by the description of the examples or the preferred embodiments.
This application claims priority from U.S. Application No. 60/830,912 filed on Jul. 14, 2006, which is herein incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 60830912 | Jul 2006 | US |
