WO2008091957A2

WO2008091957A2 - Pharmaceutical compositions containing famotidine and ibuprofen and having improved content uniformity

Info

Publication number: WO2008091957A2
Application number: PCT/US2008/051816
Authority: WO
Inventors: Puneet Sharma
Original assignee: Horizon Therapeutics, Inc.
Priority date: 2007-01-24
Filing date: 2008-01-23
Publication date: 2008-07-31
Also published as: WO2008091957A3

Abstract

The invention provides pharmaceutical compositions containing ibuprofen in combination with a second pharmaceutically active ingredient, such as famotidine. The invention also provides unit dosage forms containing ibuprofen and famotidine. Such unit dosage forms have significantly improved content uniformity.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING FAMOTIDINE AND IBUPROFEN AND HAVING IMPROVED CONTENT UNIFORMITY

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U. S. C § 1 19(e) to U.S. Provisional Application No. 60/897,321 , filed 24 January 2007, the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to pharmaceutical compositions containing ibuprofen in combination with a second pharmaceutically active ingredient, such as famotidine. The invention finds use in the fields of pharmacology and medicine.

BACKGROUND

[0003] Descriptions of certain compositions and methods are provided in the section to aid the reader in understanding the present invention. Inclusion of these descriptions in this section is not an indication or admission that the compositions or methods are prior art with regard to the current invention.

[0004] Unpublished U.S. patent application No. 11/489,269, incorporated herein by reference, describes oral unit dosage forms containing ibuprofen and famotidine in an approximately 30:1 ratio (w/w), e.g., 800 mg ibuprofen and 26.6 mg famotidine.

[0005] Ibuprofen [(2RS)-2[4-(2-Methylpropyl)phenyl]ρropanoic acid; CAS No: 15687-27-1] is a widely used nonsteroidal anti-inflammatory drug (NSAID). Ibuprofen for the preparation of pharmaceuticals is available in a variety of forms. Ibuprofen is available in a variety of forms. For example, ibuprofen preparations with mean particle sizes of 25, 38, 50, or 90 microns can be obtained from BASF Aktiengesellschaft (Ludwigshafen, Germany). A particularly useful ibuprofen product is available from BASF under the trade name Ibuprofen DC 85^® ("DC 85"). The DC 85 is quite useful for formulating high content Ibuprofen formulations when compared to either wet or dry granulation processes. The DC 85 form contains approximately 85% ibuprofen and less than 10% each silica (CAS 1 12945-52-5), croscarmellose sodium (CAS 7481 1-65-7), and cellulose (CAS 9004-34-6). DC 85 has a bulk density of 0.55 g/mL and a tapped density of 0.64 g/mL. DC 85 has a mean particle size (D₅₀) of about 700-800 microns. Table 1 shows an exemplary size distribution of DC 85 as analyzed by BASF:

TABLE 1 : Particle Size for Ibuprofen DC 85^*

Source: Ibuprofen DC 85 Technical Information September 2006, Pharma Solutions, BASF.

BRIEF SUMMARY OF THE INVENTION

[0006] In one aspect, the invention provides a pharmaceutical composition comprising: a) ibupro fen-containing particles, wherein at least 80% of the ibuprofen particles are retained by 60 mesh screen and not more than 5% of the ibuprofen particles are retained by 20 mesh screen, and b) famotidine-containing particles, wherein at least 80% of the famotidine- containing particles are retained by 60 mesh screen and not more than 5% of the famotidine- containing particles are retained by 20 mesh screen wherein the ratio of ibuprofen to famotidine (w/w) is at least 20.

[0007] In one aspect, the invention provides a solid unit dose form comprising ibuprofen and famotidine, wherein said dosage form is prepared by: a) combining and mixing i) ibuprofen- containing particles, wherein at least 80% of the ibupro fen-containing particles are retained by 60 mesh screen and not more than 5% of the ibupro fen-containing particles are retained by 20 mesh screen, and ii) famotidine-containing particles, wherein at least 80% of the famotidine-containing particles are retained by 60 mesh screen and not more than 5% of the famotidine-containing particles are retained by 20 mesh screen thereby producing a mixture containing ibuprofen and famotidine; and b) compressing the mixture into a solid oral dosage form; wherein the amount of ibuprofen in each solid unit dose form exceeds the amount of famotidine by at least 20-fold (w/w). The unit dose form may be a tablet, a caplet, or other forms. In one embodiment the unit dose form contains about 800 mg ibuprofen and about 26.6 mg famotidine. In one embodiment the ibuprofen-containing particles are prepared by controlled milling of larger sized particles, such as IBUPROFEN DC 85. In one embodiment the famotidine-containing particles the unit dose form comprise a) an inert core; b) a famotidine-containing layer coating the core; and c) a barrier layer coating the famotidine- containing layer. In various embodiments the inert core is microcrystalline cellulose and/or the barrier layer coating consists essentially of OPADRY.

[0008] In a related aspect the invention provides a unit dose form of the invention in which the ibuprofen-containing particles and famotidine-containing particles are combined in amounts sufficient to produce a mixture in which the amount of ibuprofen exceeds the amount of famotidine by at least 25-fold, of by at least 30-fold. In one embodiment the unit dose form is prepared with ibuprofen and famotidine wherein at least 90% of the ibuprofen- containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen- containing particles are retained by 20 mesh screen, and at least 90% of the famotidine- containing particles are retained by 60 mesh screen and not more than 5% of the famotidine- containing particles are retained by 20 mesh screen.

[0009] In one aspect, the invention provides a batch of solid unit dosage forms as described above, where the content uniformity for the batch is less than 5% RSD. [0010] In one aspect the invention provides a container containing a plurality of solid unit dosage forms for oral administration, wherein each dosage form contains a) ibuprofen- containing particles, wherein at least 80% of the ibuprofen-containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen-containing particles are retained by 20 mesh screen, and b) particles containing famotidine, wherein at least 80% of the famotidine-containing particles are retained by 60 mesh screen and not more than 5% of the famotidine-containing particles are retained by 20 mesh screen; and wherein the amount of ibuprofen in each dosage form exceeds the amount of famotidine by at least 20-fold, as determined by weight and wherein the content uniformity for the plurality of solid unit dosage forms in the container is less than 5% RSD. The content uniformity for the plurality of solid unit dosage forms in the container is usually less than 4% RSD and sometimes less than 3% RSD. [001 1] In a related aspect the invention provides a process for making the formulation of claim 1 comprising a) milling a composition comprising ibuprofen-containing particles, at least 30% of which have a size greater than 850 microns, to produce a milled composition comprising milled ibuprofen-containing particles, wherein at least 80% of the ibuprofen- containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen- containing particles are retained by 20 mesh screen; and b) combining an amount of said milled ibuprofen-containing particles with famotidine-containing particles, wherein at least 80% of the famotidine-containing particles are retained by 60 mesh screen and not more than 5% of the famotidine -containing particles are retained by 20 mesh screen, wherein the ibuprofen-containing particles and famotidine-containing particles are combined in amounts sufficient to produce a mixture in which the amount of ibuprofen exceeds the amount of famotidine by at least 20-fold, as determined by weight. The ibuprofen-containing particles may be IBUPROFEN DC 85 (BASF). Milling can involve forcing the ibuprofen-containing particles through a 20-mesh screen.

[0012] In some cases, prior to milling, at least 25% of the ibuprofen-containing particles have a particle size greater than 1000 microns. In some cases, prior to milling, the ibuprofen content of the ibuprofen-containing particles is greater than 80%. In some cases, prior to milling, the ibuprofen particles have a bulk density of about 0.55 g/mL and a tap density of about 0.64 g/mL

DETAILED DESCRIPTION

[0013] The invention relates to unit dosage forms containing ibuprofen and famotidine. Ibuprofen-famotidine dosage forms, methods of making and using said forms, and particular forms in which the famotidine portion is provided in the form of a coated particle are described in unpublished U.S. patent application No. 11/489,269 and U.S. provisional patent application No. 60/897371 ("Methods and Medicaments for Administration of Ibuprofen"; filed 24 January 2007; Attorney Docket No. 026057-000310), incorporated herein by reference. Also contemplated in the aforementioned patent application are forms in which the ibuprofen component is DC 85. We have now discovered that in the manufacture of such unit dose forms, significantly improved content uniformity is achieved by changing or selecting the size of the ibuprofen particles. [0014] In one aspect the invention provides a pharmaceutical formulation comprising or made using particles containing ibuprofen and particles containing famotidine, where the ratio of ibuprofen to famotidine (w/w) is at least 20, where the famotidine particles are barrier coated, and where the sizes of the particles fall within a specified profile.

[0015] In one embodiment at least 80%, preferably 85%, and most preferably at least 90% of the famotidine particles are retained by 60 mesh screen and not more than 5% of the famotidine particles are retained by 20 mesh screen; and at least 80%, preferably 85%, and most preferably at least 90% of the ibuprofen particles are retained by 60 mesh screen and not more than 5% of the ibuprofen particles are retained by 20 mesh screen.

[0016] In one embodiment the invention provides a pharmaceutical formulation comprising particles containing ibuprofen (at least 90% having a particle size in the range of 300-850 microns) and particles containing famotidine (at least 90% having a particle size in the range of 250-850 microns) where the ratio of ibuprofen to famotidine (w/w) is at least 20.

[0017] Particle size can be determined by microscopy, laser diffraction, dynamic light scanning (DLS), sieve analysis, or other methods. In a preferred embodiment particle size is determined by sieve analysis. Sieve analysis methods are routine in the art. For example, sieve analysis can be preformed using an ATM sonic sifter. The equipment may be set to run for 10 minutes with sift and pulse at amplitude #6. Sieves may be nested in the following order: #20 mesh (850 microns), #40 mesh (420 microns), #60 mesh (250 microns), #120 mesh (125 microns), #200 mesh (75 microns), #325 mesh (45 microns), and fines pan (<45 microns). Samples are run in duplicate and the generated percent retained reflect the average of the two measurements.

[0018] In some embodiments, the ratio of ibuprofen to famotidine is at least 25 or at least 30. In one embodiment the ratio of ibuprofen to famotidine is in the range of 25-35.

Famotidine-containing particles

[0019] Particles containing famotidine, at least 90% having a particle size in the range of 250-850 microns, can be prepared as described in Example 1. Briefly, an inert particulate substrate is coated with a layer of famotidine and then coated with a protective barrier layer (i.e., "barrier coated"). In some embodiments the substrate is microcrystalline cellulose, preferably microcrystalline cellulose having an average particle size less than 100 microns (e.g., less than 75 microns). In a preferred embodiment the substrate is Avicel^® PH-101 (FMC Biopolymer, Philadelphia PA). [0020] Famotidine may be applied to the substrate by spray coating a suspension containing famotidine along with a film-forming polymer. The famotidine may be spray granulated onto the carrier particles in any suitable manner, e.g., in a fluid bed processor, using a solution or suspension of famotidine, an optional film former, an optional anti-static agent, and other optional excipients and diluents. Suitable film formers include Opadry products (Colorcon) such as Opadry II^® White (Colorcon code Y-22-7719), Opadry II^® (Colorcon code 85Fl 8422), Opadry white (Colorcon code YS-I -7003); Kollicoat^® products (BASF) such as Kollicoat IR (a polyvinyl alcohol-polyethylene glycol graft copolymer); Kollicoat Protect^®; polyethylene glycol-HPMC mixtures; and the like. Talc or similar inert material may be used as an anti-static agent. By way of non-limiting example, the famotidine spray mixture may comprise about 75% famotidine, about 20% film former, and about 5% anti-static agent, by weight.

[0021] The famotidine spray mixture is coated onto the inert material until the desired amount of famotidine is added, such as a weight gain per particle or on a batch basis of 20% to 200%. For example, the 1.25 parts famotidine mixture can be sprayed on 1 part microcrystalline cellulose to a weight gain of about 90% to 110% (i.e., about 100%).

[0022] A non-drug containing barrier layer may be applied over the famotidine coated granules to minimize physical and chemical interactions with the ibuprofen component. The barrier layer of the famotidine particles may be made using film-forming compositions as described above, e.g., Opadry^® or Kollicoat^®. In a preferred embodiment the barrier layer is a Opadry^® White layer.

[0023] In certain embodiments, the barrier layer may be applied to about a 5.0 - 25% weight gain per particle or on a batch basis, e.g., a 20% weight gain.

[0024] If desired, the coated granules of famotidine may optionally include a further protective coating of a polymeric material to improve compressibility properties or to serve other purposes. The optional polymeric protective coating may be any suitable coating agent or mixtures known in the art, such as, but not limited to, microcrystalline cellulose, polyethylene glycol of suitable molecular weight (e.g., PEG 6000, PEG 8000, etc.), and similar materials. In certain embodiments, the coated famotidine particles may be coated by a suspension of microcrystalline cellulose, PEG 6000/8000, and iron oxide. By way of non- limiting example, the polymeric protective coating suspension may comprise equal parts by weight of microcrystalline cellulose and PEG 6000/8000. [0025] In certain embodiments, the optional polymeric protective coating may be applied to about a 5%, 10%, 20%, or more than 20% weight gain per particle on a batch basis, depending on the degree of protective elastic/compressibility properties desired.

[0026] The resulting famotidine granules are preferably large enough for convenient handling and to maximize content uniformity of the resulting unit dose forms. In some embodiments the famotidine granules are in the size range of 100 microns to 1000 microns, such as in the range of 250-800 microns.

[0027] In one embodiment at least 80%, preferably 85% and most preferably at least 90% of the famotidine particles are retained by 60 mesh screen and not more than 5% of the famotidine particles are retained by 20 mesh screen. In one embodiment at least about 80%, and usually at least 90%, of the famotidine particles are in the size range of 250-800 microns.

[0028] Table 2 shows the size distribution of famotidine particles prepared as described in Example 1 , in which the barriers was Kollicoat^® or Opadry^®.

TABLE 2: Famotidine Granules Particle Size Distribution*

The assay was carried out using an ATM SONIC SIFTER (Settings: Amplitude: 6; Time: 10 min; Pulse: On). lbupr of en-containing particles

[0029] Ibuprofen containing particles having a size in the range of 300-850 microns can be obtained by methods known in the art.

[0030] For use in the present invention it is preferred that at least 80%, preferably 85% and most preferably at least 90% of the ibuprofen particles are retained by 60 mesh screen and not more than 5% of the ibuprofen particles are retained by 20 mesh screen.

[0031 ] In one embodiment, at least 90% of the ibuprofen-containing particles have a size in the range of 300-850 microns).

[0032] In a preferred embodiment the ibuprofen containing particles are milled DC 85.

Commercially available DC 85 was reported by the manufacturer to have the size profile shown in Table 1. The particle size distribution of commercially available DC 85 (BASF) was tested by sieve analysis with the following result:

TABLE 3

[0033] This composition can be converted to a composition with a particle size distribution suitable for use in the invention by controlled milling. In one approach, milling is carried out by passing the commercially available DC 85 composition through a Quadro Comil (Quadro Inc., 55 Bleeker Street, Millburn, NJ, USA) with 20-mesh screen. As is known in the art, the rate of addition of active and speed of the milling equipment affects the particle distribution of milled material.

[0034] It will be appreciated that to avoid melting, milling of ibuprofen should be carried out under conditions in which temperature is maintained below 50°C. Dry ice can be used to cool the temperature of the Comil screen if the temperature is increased above the desired range.

Ibuprofen-famotidine compositions and unit dose forms A. Tablet preparation [0035] Ibuprofen/famotidine unit dose forms can be prepared by combining and mixing coated famotidine particles, ibuprofen particles (e.g., DC 85, or milled DC 85), and optionally excipients, and compressing the resulting mixture into a tablet form. Alternatively the mixture can be compressed into any solid form suitable for oral administration, such as oral dosage capsule, caplet, gelcap, geltab and the like.

[0036] Excipients that may be used include binders, lubricants, diluents, disintegrants, coatings, barrier layer components, glidants, and other components. Excipients are known in the art (see HANDBOOK OF PHARMACEUTICAL EXCIPIENTS, FIFTH EDITION, 2005 edited by Rowe et al., McGraw Hill). Exemplary excipients are microcrystalline cellulose, crosslinked sodium carboxymethylcellulose, silica, Aerosil 200, corn starch, and others. In one embodiment, the table is free of lubricants such as Mg stearate, stearic acid or sodium stearyl fumarate.

[0037] Mixing is carried out using conventional methods. A geometric mixing process is used to improve uniformity. Typically the components are screened and added to a suitable- size V-blender. The materials charged are mixed for 10 minutes.

[0038] Tabletting is carried out using methods well known in the art. Briefly, tablets are usually formed by pressure applied to the material to be tabletted on a tablet press (e.g., DC16 with 0.3750"x0.8125" capsule-shaped tooling). A tablet press includes a lower punch which fits into a die from the bottom and an upper punch having a corresponding shape and dimension, which enters the die cavity from the top after the tabletting material fills the die cavity. The tablet is formed by pressure applied on the lower and upper punches. Tablets are produced in batches of 15,000-160,000.

[0039] In some embodiments the tablet includes an "over-coating" added to improve appearance, taste, swallowability, or other characteristics of the table. Suitable over-coatings are soluble in, or rapidly disintegrate in water, and, for purposes of this invention, are not enteric coatings. An exemplary over-coating material is Opadry II available from Colorcon (Westpoint, PA).

B. Content uniformity

[0040] We have discovered that in the manufacture of ibuprofen/famotidine unit dose forms containing DC 85 and coated famotidine, significantly improved content uniformity is achieved by changing (e.g., milling) or selecting the size of the DC 85 particles. [0041] For example, Table 4 below, illustrate the effect of DC 85 size on content uniformity of ibuprofen and famotidine in the blend. Left columns show content uniformity achieved using commercially available DC 85 in the process described in Example 1. Right columns shows content uniformity achieved when the DC 85 milled by passing DC 85 through a Quadro Comil with 20-mesh (0.841 mm opening) screen. Content uniformity is determined by the analysis ibuprofen and famotidine contents in the test samples assayed by HPLC. The multi-stage content uniformity criteria are defined according to United States Pharmacopoeia (USP) which includes 1) assaying ten samples to ensure that the relative standard deviation (RSD) of active content is less than or equal to 6.0%, no value is outside 85-1 15%; and 2) assaying twenty more tablets to ensure that the RSD for all thirty tablets is less than or equal to 7.8%, no more than one value is outside 85-115% and no value is outside 75-125% of stated content.

Table 4 Effect of DC85 Milling on the Content Uniformity of the Ibuprofen/Famotidine

[0042] In one respect, the present invention provides a container containing a plurality of solid unit dosage forms for oral administration, wherein each dosage form contains (a) ibuprofen-containing particles, wherein at least 80% of the ibuprofen-containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen-containing particles are retained by 20 mesh screen, and (b) particles containing famotidine, wherein at least 80% of the famotidine -containing particles are retained by 60 mesh screen and not more than 5% of the famotidine -containing particles are retained by 20 mesh screen; and wherein the amount of ibuprofen in each dosage foπn exceeds the amount of famotidine by at least 20- fold, as determined by weight and wherein the content uniformity for the batch is less than 5% RSD, usually less than 4% RSD, most often less than 3% RSD. The container may be provided to a patient, a pharmacy, a hospital or other provider. In certain embodiments the plurality may consist of 50-100 tablets, 100-500 tablets, 100-1000 tablets or more than 1000 tablets.

Ibuprofen DC 85 Combination Forms

[0043] Combination therapies are known in which ibuprofen is combined with a second active pharmaceutical ingredient are known. The discovery that use of milled Ibuprofen DC 85 results in superior content uniformity when the ibuprofen is used to manufacture a coated famotidine-ibuprofen combination dose in which the ratio of ibuprofen to famotidine (w/w) is at least 20 can be extended to other combinations.

[0044] Accordingly, in one aspect the present invention provides a pharmaceutical formulation containing (a) ibuprofen-containing particles, where at least 80% of the ibuprofen particles are retained by 60 mesh screen and not more than 5% of the ibuprofen particles are retained by 20 mesh screen, and (b) particles containing an active pharmaceutical ingredient (API) other than ibuprofen, where at least 80% of the API- containing particles are retained by 60 mesh screen and not more than 5% of the API- containing particles are retained by 20 mesh screen where the ratio of ibuprofen to the API (w/w) is at least 20.

[0045] In one respect, the present invention provides a solid unit dose form containing ibuprofen and active pharmaceutical ingredient (API) other than ibuprofen, where the dosage form is prepared by: (a) combining and mixing (i) ibuprofen-containing particles, where at least 80% of the ibuprofen-containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen-containing particles are retained by 20 mesh screen, and (ii) API- containing particles, where at least 80% of the API-containing particles are retained by 60 mesh screen and not more than 5% of the API-containing particles are retained by 20 mesh screen thereby producing a mixture containing ibuprofen and API; and (b) compressing the mixture into a solid oral dosage form; where the amount of ibuprofen in each solid unit dose form exceeds the amount of API by at least 20-fold (w/w). The ibuprofen-containing particles may be prepared by milling larger sized particles, e.g., IBUPROFEN DC 85 (BASF).

[0046] In some embodiments the API-containing particles contain (a) an inert core (e.g., microcrystalline cellulose); (b) a API-containing layer coating the core; and (c) a barrier layer (e.g., KOLLICOAT or OPADRY) coating the API-containing layer.

[0047] In some embodiments, the at least 90% of the ibuprofen-containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen-containing particles are retained by 20 mesh screen, and at least 90% of the API-containing particles are retained by 60 mesh screen and not more than 5% of the API-containing particles are retained by 20 mesh screen.

[0048] In one respect, the present invention provides a container containing a plurality of solid unit dosage forms for oral administration, where each dosage form contains (a) ibuprofen-containing particles, where at least 80% of the ibuprofen-containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen-containing particles are retained by 20 mesh screen, and (b) particles containing API, where at least 80% of the API- containing particles are retained by 60 mesh screen and not more than 5% of the API- containing particles are retained by 20 mesh screen; and where the amount of ibuprofen in each dosage form exceeds the amount of API by at least 20-fold, as determined by weight and where the content uniformity for the batch is less than 5% RSD, usually less than 4% RSD, most often less than 3% RSD.

[0049] In one aspect the invention provides a process for making the formulation of claim 1 containing (a) milling a composition containing ibuprofen-containing particles, at least 30% of which have a size greater than 850 microns, to produce a milled composition containing milled ibuprofen-containing particles, where at least 80% of the ibuprofen-containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen-containing particles are retained by 20 mesh screen; and (b) combining an amount of the milled ibuprofen-containing particles with particles containing an active pharmaceutical ingredient (API) other than ibuprofen, where at least 80% of the API-containing particles are retained by 60 mesh screen and not more than 5% of the API-containing particles are retained by 20 mesh screen, where the ibuprofen-containing particles and API-containing particles are combined in amounts sufficient to produce a mixture in which the amount of ibuprofen exceeds the amount of API by at least 20-fold, as determined by weight.

[0050] Examples of APIs used in combination with ibuprofen include, for example and not limitation, hydrocodone, codine, and cyclobenzaprine hydrochloride.

Examples

Example 1 : Producing Famotidine-Containing Particles

[0051] In one approach, coated famotidine particles are prepared by spray famotidine suspension onto a carrier particles, coating the resulting granule with a barrier layer, and optionally a further protective layer. In certain embodiments, the carrier particles may be αu inert material such as microcrystalline cellulose (fine grade; e.g., Avicel PHlOl [FMC Corp.]), or the like. The famotidine may be spray coated onto the carrier particles in any suitable manner, e.g., in a fluid bed processor, using a solution of famotidine, an optional film former, an optional anti-static agent, and other optional excipients and diluents. For instance, Opadry II^® or similar materials, e.g., as described in U.S. Patent No. 4,802,924, herein incorporated by reference, may be used as a film former, and talc or similar inert material may be used as an anti-static agent. By way of non-limiting example, the famotidine spray mixture may comprise about 75% active, about 20% film former, and about 5% anti-static agent, by weight.

[0052] The famotidine spray mixture is coated onto the inert material until the desired amount of famotidine is added, such as a weight gain per particle or on a batch basis of 20% to 200%. For example, the 1.25 parts famotidine mixture can be sprayed on 1 part microcrystalline cellulose to a weight gain of about 90% to 110% (i.e., about 100%).

[0053] A drug-free barrier layer may be applied over the famotidine coated granules. Again, the barrier layer of the famotidine particles may be made as described above (e.g., using Opadry^®, Kollicoat^®, or similar materials). In certain embodiments, the barrier layer may be applied to about a 5.0 - 50% weight gain per particle or on a batch basis, e.g., a 20% weight gain. [0054] If desired, the coated granules of famotidine may include a further protective coating of a polymeric material to improve compressibility properties. The optional polymeric protective coating may be any suitable coating agent or mixtures known in the art, such as, but not limited to, microcrystalline cellulose, polyethylene glycol of suitable molecular weight (e.g., PEG 6000, PEG 8000, etc.), and similar materials. In certain embodiments, the coated famotidine particles may be coated by a suspension of microcrystalline cellulose, PEG 6000/8000, and iron oxide. By way of non-limiting example, the polymeric protective coating suspension may comprise equal parts by weight of microcrystalline cellulose and PEG 6000/8000.

[0055] In certain embodiments, the optional polymeric protective coating may be applied to about a 5%, 10%, 20%, or more than 20% weight gain per particle on a batch basis, depending on the degree of protective elastic/compressibility properties desired.

[0056] The resulting famotidine granules are preferably large enough for convenient handling and to maximize content uniformity of the resulting unit dose forms. In some embodiments the famotidine granules are in the size range of 100 microns to 1000 microns, such as in the range of 350-800 microns. Particle size is usually determined based on the ability of particles to pass through an opening (e.g., using a US sieve series, or Tyler equivalent mesh). In one embodiment at least about 80%, and usually at least 90%, of the famotidine particles are in the size range of 350-800 microns. In one embodiment, at least 80% of the famotidine- containing particles are retained by 60 mesh screen and not more than 5% of the famotidine- containing particles are retained by 20 mesh screen.

Example 2: Milling DC 85

[0057] Ibuprofen DC85 is passed through Quadro Comil 194 with a number 20 mesh screen and round impeller. Mill speed is controlled at low speed. The milled DC85 particles are collected in polyethylene bags.

Example 3 : Mixing and Tabletting

[0058] The famotidine particles and ibuprofen particles may then be blended and compressed into tablets, or other suitable form, using methods known in the art. Optionally a lubricant, such as magnesium stearate, may be added to the ibuprofen-famotidine mixture prior to the compression step.

[0059] Tablets are formed by direct compression with tablet press machine (e.g. DC 16) and compression tooling (0.3750" x 0.8125" capsule-shaped). The target weight is controlled at 3% of theoretical weight with acceptance limit set at 95% to 105% of target weight.

[0060] In one version, the unit dose form contains coated famotidine granules, DC 85 ibuprofen and a lubricant such as magnesium stearate.

[0061 ] A final coating (e.g., Opadry^®, Opadry II^®, Kollicoat^® or similar materials) optionally may be applied using tablet coating system (e.g., Accella Coata with a 24" or 48" pan) according to manufacturer's instructions, as generally recognized by those skilled in the art.

***

[0062] All publications and patent documents (patents, published patent applications, and unpublished patent applications) cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any such document is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description and example, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples are for purposes of illustration and not limitation of the following claims.

Claims

1. A pharmaceutical composition comprising: a) ibuprofen-containing particles, wherein at least 80% of the ibuprofen particles are retained by 60 mesh screen and not more than 5% of the ibuprofen particles are retained by 20 mesh screen, and b) famotidine-containing particles, wherein at least 80% of the famotidine-containing particles are retained by 60 mesh screen and not more than 5% of the famotidine-containing particles are retained by 20 mesh screen wherein the ratio of ibuprofen to famotidine (w/w) is at least 20.

2. A solid unit dose form comprising ibuprofen and famotidine, wherein said dosage form is prepared by: a) combining and mixing i) ibuprofen-containing particles, wherein at least 80% of the ibuprofen- containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen- containing particles are retained by 20 mesh screen, and ii) famotidine-containing particles, wherein at least 80% of the famotidine- containing particles are retained by 60 mesh screen and not more than 5% of the famotidine- containing particles are retained by 20 mesh screen thereby producing a mixture containing ibuprofen and famotidine; and b) compressing the mixture into a solid oral dosage form; wherein the amount of ibuprofen in each solid unit dose form exceeds the amount of famotidine by at least 20-fold (w/w).

3. The solid unit dose form of claim 2 that is in the form of a tablet or caplet.

4. A batch of solid unit dosage forms of claim 2, wherein the content uniformity for the batch is less than 5% RSD.

5. The unit dose form of claim 2 that contains about 800 mg ibuprofen and about 26.6 mg famotidine.

6. The unit dose form of claim 2 wherein the ibupro fen-containing particles are prepared by controlled milling of larger sized particles.

7. The unit dose form of claim 6 wherein the larger sized particles are IBUPROFEN DC 85 (BASF).

8. The unit dose form of claim 2 wherein the famotidine-containing particles comprise a) an inert core; b) a famotidine-containing layer coating the core; and c) a barrier layer coating the famotidine-containing layer.

9. The unit dose form of claim 8 wherein the inert core is microcrystalline cellulose.

10. The unit dose form of claim 9 wherein the barrier layer coating consists essentially of OPADRY.

11. The unit dose form of claim 2 wherein the ibuprofen-containing particles and famotidine-containing particles are combined in amounts sufficient to produce a mixture in which the amount of ibuprofen exceeds the amount of famotidine by at least 25-fold.

12. The unit dose form of claim 2 wherein the ibuprofen-containing particles and famotidine-containing particles are combined in amounts sufficient to produce a mixture in which the amount of ibuprofen exceeds the amount of famotidine by at least 30-fold.

13. The unit dose form of claim 2 wherein at least 90% of the ibuprofen-containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen-containing particles are retained by 20 mesh screen, and at least 90% of the famotidine-containing particles are retained by 60 mesh screen and not more than 5% of the famotidine-containing particles are retained by 20 mesh screen.

14. A container containing a plurality of solid unit dosage forms for oral administration, wherein each dosage form contains a) ibuprofen-containing particles, wherein at least 80% of the ibuprofen-containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen-containing particles are retained by 20 mesh screen, and b) particles containing famotidine, wherein at least 80% of the famotidine-containing particles are retained by 60 mesh screen and not more than 5% of the famotidine-containing particles are retained by 20 mesh screen; and wherein the amount of ibuprofen in each dosage form exceeds the amount of famotidine by at least 20-fold, as determined by weight and wherein the content uniformity for the plurality of solid unit dosage forms in the container is less than 5% RSD.

15. The container of claim 13 wherein the content uniformity for the plurality of solid unit dosage forms in the container is less than 4% RSD.

16. The container of claim 14 wherein the wherein the content uniformity for the plurality of solid unit dosage forms in the container is less than 3% RSD.

17. A process for making the formulation of claim 1 comprising a) milling a composition comprising ibuprofen-containing particles, at least 30% of which have a size greater than 850 microns, to produce a milled composition comprising milled ibuprofen-containing particles, wherein at least 80% of the ibuprofen-containing particles are retained by 60 mesh screen and not more than 5% of the ibuprofen-containing particles are retained by 20 mesh screen; and b) combining an amount of said milled ibuprofen-containing particles with famotidine-containing particles, wherein at least 80% of the famotidine-containing particles are retained by 60 mesh screen and not more than 5% of the famotidine -containing particles are retained by 20 mesh screen, wherein the ibuprofen-containing particles and famotidine-containing particles are combined in amounts sufficient to produce a mixture in which the amount of ibuprofen exceeds the amount of famotidine by at least 20-fold, as determined by weight.

18. The process of claim 17 wherein, prior to milling, at least 25% of the ibuprofen- containing particles have a particle size greater than 1000 microns.

19. The process of claim 18 wherein, prior to milling, the ibuprofen content of the ibuprofen-containing particles is greater than 80%.

20. The process of claim 19 wherein, prior to milling, the ibuprofen particles have a bulk density of about 0.55 g/mL and a tap density of about 0.64 g/mL

21. The process of claim 20 wherein the ibuprofen-containing particles are IBUPROFEN DC 85 (BASF).

22. The process of claim 17 wherein milling comprises forcing the ibuprofen-containing particles through a 20-mesh screen.