Oral and injectable formulation of tetracycline compound

Abstract

To provide oral formulations of a tetracycline compound suitable for a form of tablet.SOLUTION: There is provided an oral formulation of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, or salt thereof in the form of a tablet, in which 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or salt thereof is present in the amount that exceeds 10 wt.% based on the total weight of formulation. The oral formulation is preferred to contain: 26 to 28 wt.% of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline tosylate salt; 10 to 30 wt.% of lactose; 30 to 50 wt.% of microcrystalline cellulose; 0.05 to 0.35 wt.% of sodium bisulfite; 0.5 to 1.5 wt.% of silicon dioxide; 4.5 to 6.0 wt.% of sodium stearylfumarate or magnesium stearate; and 4 to 6 wt.% of crospovidone.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. §119(e) to pending U.S. Provisional Patent Application No. 61 / 040,398, filed March 28, 2008, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background The development of tetracycline antibiotics was a direct result of the systematic screening of soil samples from around the world for traces of microorganisms capable of producing bactericidal and / or bacteriostatic compounds. The first of these novel compounds was described in 1948 under the name chlortetracycline. Two years later, oxytetracycline became available. Elucidation of the chemical structures of these compounds confirmed their similarity and provided the analytical basis for the production of the third member of this group, tetracycline, in 1952. A new family of tetracycline compounds lacking the ring-attached methyl group present in earlier tetracyclines was prepared in 1957 and became publicly available in 1967; minocycline was in use by 1972.

[0003] In recent years, research efforts have been focused on developing new tetracycline antibiotic compositions that are effective under a variety of therapeutic conditions and administration routes. Novel tetracycline analogs that may prove to be as effective or more effective than the originally published tetracycline compounds are also being investigated. Examples include U.S. Patent Nos. 2,980,584; 2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680 (Patent Documents 1-11). These patents are representative of a wide variety of pharmaceutically active tetracycline and tetracycline analog compositions.

[0004] Historically, shortly after their initial development and publication, tetracyclines proved highly pharmacologically effective against rickettsiae; several Gram-positive and Gram-negative bacteria; and the causative agents of lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis. Tetracyclines were thus recognized as "broad-spectrum" antibiotics. Subsequently, their in vitro antibacterial activity, efficacy in experimental infections, and established pharmacological properties rapidly led to widespread therapeutic use of tetracyclines as a class. However, this widespread use of tetracyclines for both serious and minor illnesses and diseases directly led to the emergence of resistance to these antibiotics, even among highly susceptible bacterial species, both commensal and pathogenic (e.g., Streptococcus pneumoniae and Salmonella). The emergence of tetracycline-resistant bacteria has led to an overall decline in the use of tetracyclines and tetracycline analogues as antibiotics of choice. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 2,980,584 [Patent Document 2] U.S. Patent No. 2,990,331 [Patent Document 3] U.S. Patent No. 3,062,717 [Patent Document 4] U.S. Patent No. 3,165,531 [Patent Document 5] U.S. Patent No. 3,454,697 [Patent Document 6] U.S. Patent No. 3,557,280 [Patent Document 7] U.S. Patent No. 3,674,859 [Patent Document 8] U.S. Patent No. 3,957,980 [Patent Document 9] U.S. Patent No. 4,018,889 [Patent Document 10] U.S. Patent No. 4,024,272 [Patent Document 11] U.S. Patent No. 4,126,680 Summary of the Invention

[0006] In one aspect, the invention pertains, at least in part, to an oral formulation of a 9-aminomethyltetracycline compound, such as 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, or a salt thereof. The composition may be in the form of a tablet or capsule.

[0007] In further embodiments, the present invention also relates to oral formulations comprising about 15% to about 30%, about 16% to about 28%, about 18% to about 25%, about 19% to about 22%, about 19.5% to about 21.5%, or about 20% by weight of an active ingredient, such as 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof (e.g., the tosylate salt).

[0008] In yet another embodiment, the present invention also relates to an oral formulation comprising a tablet having a core weighing about 450 mg to about 550 mg, about 480 mg to about 520 mg, about 490 mg to about 510 mg, about 495 mg to about 505 mg, or about 500 mg.

[0009] In further embodiments, the present invention also relates to oral formulations containing the equivalent of about 70 mg to about 200 mg, about 80 mg to about 180 mg, about 90 mg to about 160 mg, about 100 mg to about 140 mg, about 120 mg to 135 mg, or about 132.8 mg of an active ingredient, e.g., 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt.

[0010] In another embodiment, the present invention also relates to a tablet formulation having an average hardness of about 2 Kp to about 20 Kp, about 3 Kp to about 18 Kp, about 4 Kp to about 16 Kp, about 5 Kp to about 15 Kp, about 6 Kp to about 15 Kp, about 6.3 Kp to about 14.5 Kp, about 6.3 Kp to about 10 Kp, about 6.3 Kp to about 8 Kp, about 6.3 Kp to about 7 Kp, or about 6.3 Kp to about 6.8 Kp. In a further embodiment, the present invention also relates to a tablet formulation having an average hardness of about 6.5 Kp.

[0011] In yet another embodiment, the present invention also relates to tablet formulations having a disintegration time of about 5 minutes to about 30 minutes, about 7 minutes to about 28 minutes, about 8 minutes to about 25 minutes, about 9 minutes to about 23 minutes, about 10 minutes to about 22 minutes, or about 11 minutes to about 21 minutes. In a further embodiment, the present invention also relates to tablet formulations having a disintegration time of more than 30 minutes.

[0012] In a further embodiment, the present invention also relates to a tablet comprising: about 5-40% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof (e.g., the tosylate salt); about 50-90% by weight of a diluent; about 0.01-0.5% by weight of a stabilizer; about 0.2-2.0% by weight of a glidant; about 3-10% by weight of a disintegrant; about 3-10% by weight of a lubricant; optionally about 0.5-3.0% by weight of a buffer; optionally about 0.1-2.0% by weight of an anti-adhesion agent; and optionally about 1-6% by weight of a coating component, such as a coating colorant. It should be recognized that the use of the terms "a" and "an" (e.g., "a diluent" or "an anti-adhesion agent") in the context of excipients and other additives is meant to include instances where multiple different compounds are used to perform the same function. Thus, for example, a formulation having "one diluent" in an amount of 50-90% includes instances where a single compound acts as a diluent and is present in that amount, as well as instances where two, three, or more different compounds act as diluents and are together present in that amount.

[0013] In yet another further embodiment, the present invention includes a tablet comprising: about 13-30% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 10-60% by weight lactose; about 10-50% by weight microcrystalline cellulose; about 0.05-0.25% by weight sodium bisulfite; about 0.4-1.6% by weight silicon dioxide; about 4.5-6.5% by weight magnesium stearate or sodium stearyl fumarate; about 4-6% by weight crospovidone; optionally about 1.0-2.0% by weight citric acid; optionally about 0.7-1.2% by weight talc; optionally about 3-5% by weight Eudragit E100, and about 1-10% by weight OPADRY® AMB Red. It should be recognized that when 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is present as a salt, the weight percent ranges include the weight of the free base and the salt counterion (unless such weight percents are listed separately, as exemplified in Table 1).

[0014] In yet another further embodiment, the present invention also includes a tablet consisting essentially of the following: about 13-30% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 15-25% by weight of lactose; about 35-45% by weight of microcrystalline cellulose; about 0.17-0.22% by weight of sodium bisulfite; about 0.9-1.1% by weight of silicon dioxide; about 4.5-5.5% by weight of magnesium stearate or sodium stearyl fumarate; about 4.5-5.5% by weight of crospovidone; no citric acid; no talc; no Eudragit E100; and about 3-4.5% by weight of OPADRY® AMB Red. In a further embodiment, the tablet of the present invention consists essentially of the above-listed ingredients.

[0015] In yet another further embodiment, the present invention also includes a tablet consisting essentially of the following: about 15-30% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 15-25% by weight of lactose; about 35-45% by weight of microcrystalline cellulose; about 0.17-0.22% by weight of sodium bisulfite; about 0.4-0.6% by weight of silicon dioxide; about 4.5-5.5% by weight of magnesium stearate; about 4.5-5.5% by weight of crospovidone; and about 0.9-1.1% by weight of talc. In a further embodiment, the tablet of the present invention consists essentially of the ingredients listed above.

[0016] In yet another further embodiment, the present invention also includes a tablet consisting essentially of the following: about 26.56% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 20.00% by weight of lactose; about 41.74% by weight of microcrystalline cellulose; about 0.20% by weight of sodium bisulfite; about 0.50% by weight of silicon dioxide; about 5.00% by weight of magnesium stearate; about 5.00% by weight of crospovidone; and about 1.00% by weight of talc. In a further embodiment, the tablet of the present invention consists essentially of the ingredients listed above.

[0017] In yet another further embodiment, the present invention also includes a tablet consisting essentially of the following: about 13-14% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 45-55% by weight of lactose; about 15-25% by weight of microcrystalline cellulose; about 0.07-0.12% by weight of sodium bisulfite; about 0.4-0.55% by weight of silicon dioxide; about 5.5-6.0% by weight of magnesium stearate or sodium stearyl fumarate; about 4.5-5% by weight of crospovidone; about 1.25-1.75% by weight of citric acid; about 0.7-1.2% by weight of talc; and about 3-5% by weight of Eudragit E100. In a further embodiment, the tablet of the present invention consists essentially of the ingredients listed above.

[0018] In yet another further embodiment, the present invention also includes a tablet comprising: about 195-205 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 155-165 mg of lactose; about 295-310 mg of microcrystalline cellulose; about 1.0-2.0 mg of sodium bisulfite; about 30-50 mg of crospovidone; about 6-8 mg of silicon dioxide; about 30-50 mg of magnesium stearate or sodium stearyl fumarate; optionally about 12.5-17.5 mg of citric acid; optionally about 7.5-12.5 mg of talc; optionally about 30-50 mg of Eudragit E100, and about 20-40 mg of OPADRY® AMB Red.

[0019] The present invention also relates, at least in part, to a tablet consisting of: about 202 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 161 mg of lactose; about 303 mg of microcrystalline cellulose; about 1.5 mg of sodium bisulfite; about 37.5 mg of crospovidone; about 7.5 mg of silicon dioxide; about 37.5 mg of sodium stearyl fumarate; and about 30 mg of OPADRY® AMB Red.

[0020] In yet another further embodiment, the present invention also includes a tablet consisting of about 120-135 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 90-110 mg of lactose; about 190-220 mg of microcrystalline cellulose; about 0.8-1.2 mg of sodium bisulfite; about 20-30 mg of crospovidone; about 2-3 mg of silicon dioxide; about 20-30 mg of magnesium stearate; and about 4-6 mg of talc.

[0021] The present invention also relates, at least in part, to a tablet consisting of: about 132.80 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 100.00 mg of lactose; about 208.70 mg of microcrystalline cellulose; about 1.00 mg of sodium bisulfite; about 25.00 mg of crospovidone; about 2.50 mg of silicon dioxide; about 25.00 mg of magnesium stearate; and about 5.00 mg of talc.

[0022] In yet another further embodiment, the present invention also includes a tablet consisting of about 135-140 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 500-525 mg of lactose; about 200-210 mg of microcrystalline cellulose; about 0.5-1.5 mg of sodium bisulfite; about 40-60 mg of crospovidone; about 4-5 mg of silicon dioxide; about 50-70 mg of magnesium stearate; about 12.5-17.5 mg of citric acid; about 7.5-12.5 mg of talc; and about 30-50 mg of Eudragit E100.

[0023] The present invention also relates, at least in part, to a tablet consisting of: about 138.5 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 515 mg of lactose; about 205.5 mg of microcrystalline cellulose; about 1.0 mg of sodium bisulfite; about 50 mg of crospovidone; about 5.0 mg of silicon dioxide; about 60 mg of magnesium stearate; about 15 mg of citric acid; about 10 mg of talc; and about 40 mg of Eudragit E100.

[0024] In another aspect, the invention also features an oral formulation including 90-120 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base and a pharmaceutically acceptable carrier.

[0025] In a further aspect, the invention features an oral capsule formulation consisting of about 95-115 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base, 0.95-1.15 mg of sodium bisulfite, about 0.09-0.115 mg of colloidal anhydrous silica, and a capsule.

[0026] In yet another embodiment, the invention also relates, at least in part, to an injectable formulation comprising about 90-110 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base and a pharmaceutically acceptable carrier (e.g., an aqueous carrier).

[0027] The present invention also relates, at least in part, to an injectable formulation comprising about 90-110 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base, a lyoprotectant, an antioxidant, and a carrier.

[0028] In a further embodiment, the invention relates, at least in part, to an injectable formulation comprising approximately 90-110 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base, 90-110 mg of sucrose, 0.9-1.1 mg of sodium bisulfite, and an aqueous carrier.

[0029] In another further embodiment, the invention also features an injectable formulation consisting of about 100 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base, 100 mg of sucrose, 1 mg of sodium bisulfite, a pH-adjusting compound, and an aqueous carrier.

[0030] The present invention also features, at least in part, methods for treating a subject with the formulations of the present invention. In certain embodiments, the subject is treated for a bacterial infection. The present invention relates to oral formulations comprising: about 5-40% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline tosylate salt; about 50-90% by weight of a diluent; about 0.01-0.5% by weight of a stabilizer; about 0.2-2.0% by weight of a flow agent; about 1-11% by weight of a lubricant; about 0.5-10% by weight of a disintegrant; and, optionally, 0.5-1.5% of an anti-adhesive agent. For example, the diluent can include lactose, microcrystalline cellulose, or a combination thereof.

[0031] In some embodiments, the oral formulation also includes a buffering agent, an anti-adherent agent, a coating component, or a combination thereof.

[0032] For example, an oral formulation of the present invention may comprise: about 10-30% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof; about 50-90% by weight of a diluent; about 0.01-0.5% by weight of a stabilizer; about 0.2-2.0% by weight of a flow agent; about 3-10% by weight of a lubricant; about 3-10% by weight of a disintegrant; and about 0.01-0.5% by weight of an anti-adhesive agent.

[0033] An example of such an oral formulation comprises: about 26-28% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline tosylate salt; about 10-30% by weight of lactose; about 30-50% by weight of microcrystalline cellulose; about 0.05-0.35% by weight of sodium bisulfite; about 0.5-1.5% by weight of silicon dioxide; about 4.5-6.0% by weight of sodium stearyl fumarate or magnesium stearate; about 4-6% by weight of crospovidone; and about 0.5-1.5% by weight of talc.

[0034] An example of such an oral formulation comprises: about 26-28% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 15-25% by weight of lactose; about 35-45% by weight of microcrystalline cellulose; about 0.15-0.25% by weight of sodium bisulfite; about 0.8-1.2% by weight of silicon dioxide; about 4.8-5.2% by weight of sodium stearyl fumarate or magnesium stearate; about 4.8-5.2% by weight of crospovidone; about 0.15-0.25% by weight of talc, and about 3-5% of OPADRY® AMB Red.

[0035] In one embodiment, the oral formulation contains about 90 to 250 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof.

[0036] For example, the oral formulation is in the form of a tablet containing: about 125-140 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 90-110 mg of lactose; about 200-220 mg of microcrystalline cellulose; about 0.75-1.5 mg of sodium bisulfite; about 20-30 mg of crospovidone; about 2-3 mg of silicon dioxide; about 20-30 mg of magnesium stearate; about 4.5-5.5 mg of talc, and about 20-40 mg of OPADRY® AMB Red.

[0037] The present invention also relates to an oral formulation of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, wherein the formulation is present in an amount greater than 10% by weight based on the total weight of the formulation, e.g., a tablet having a total weight of about 500 mg.

[0038] The present invention also relates to a tableted solid dosage form comprising 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof and at least one pharmaceutically acceptable diluent, wherein the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof is present in an amount that is about 20% by weight based on the total weight of the tableted solid dosage form, for example, the tableted solid dosage form is a tablet with a total weight of about 500 mg.

[0039] The present invention also relates to the use of a formulation of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof described herein in the manufacture of a medicament for treating an infection in a subject. [Claim 1001] An oral formulation of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or its salts. [Claim 1002] The oral formulation of claim 1001, in tablet form. [Claim 1003] The oral formulation of claim 1002, comprising about 5-40% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline tosylate salt, about 50-90% by weight of a diluent, about 0.01-0.5% by weight of a stabilizer, about 0.2-2.0% by weight of a glidant, about 1-11% by weight of a lubricant, about 0.5-10% by weight of a disintegrant, and optionally about 0.5-1.5% of an anti-adhesive agent. [Claim 1004] The oral formulation of claim 1003, wherein the diluent comprises lactose, microcrystalline cellulose, or a combination thereof. [Claim 1005] The oral formulation of claim 1003, further comprising a buffering agent, an anti-adherent agent, a coating component, or a combination thereof. [Claim 1006] The oral formulation of claim 1002, comprising: about 10 to 30% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof; about 50-90% by weight of diluent; about 0.01 to 0.5 wt. % stabilizer; about 0.2 to 2.0 wt. % of a superplasticizer; about 3-10% by weight of a lubricant; about 3-10% by weight of a disintegrant; and Approximately 0.01 to 0.5% by weight of an anti-adhesion agent. [Claim 1007] The oral formulation of claim 1006, comprising: about 26-28% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline tosylate salt; about 10-30% by weight lactose; approximately 30-50% by weight of microcrystalline cellulose; about 0.05 to 0.35% by weight sodium bisulfite; about 0.5 to 1.5% by weight of silicon dioxide; about 4.5 to 6.0% by weight of sodium stearyl fumarate or magnesium stearate; about 4-6% by weight of crospovidone; and Approximately 0.5 to 1.5% by weight of talc. [Claim 1008] The oral formulation of claim 1007, comprising: about 26-28% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 15-25% lactose by weight; approximately 35-45% by weight of microcrystalline cellulose; about 0.15 to 0.25% by weight sodium bisulfite; about 0.8-1.2% by weight of silicon dioxide; about 4.8 to 5.2% by weight of sodium stearyl fumarate or magnesium stearate; approximately 4.8-5.2% crospovidone; about 0.15 to 0.25 weight percent talc; and Approximately 3-5% OPADRY® AMB Red. [Claim 1009] 1002. The oral formulation of claim 1001, comprising about 90 to 250 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof. [Claim 1010] The oral formulation of claim 1009, wherein the formulation is in the form of a tablet, the tablet consisting essentially of: Approximately 125-140 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; Approximately 90-110 mg of lactose; Approximately 200-220 mg of microcrystalline cellulose; Approximately 0.75-1.5 mg of sodium bisulfite; Approximately 20-30 mg of crospovidone; Approximately 2-3 mg of silicon dioxide; Approximately 20-30 mg of magnesium stearate; Approximately 4.5 to 5.5 mg of talc; and Approximately 20-40 mg of OPADRY® AMB Red. [Claim 1011] The oral formulation of claim 1001, comprising 90 to 180 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base and a pharmaceutically acceptable carrier. [Claim 1012] The oral formulation of claim 1002, wherein the formulation is compressed using direct compression, roller compaction, or a combination thereof. [Claim 1013] 1013. The oral formulation of claim 1012, wherein 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof is present in an amount greater than 10% by weight based on the total weight of the formulation. [Claim 1014] A tableted solid dosage form comprising 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof and at least one pharmaceutically acceptable diluent, wherein the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof is present in an amount of about 20% by weight based on the total weight of the tableted solid dosage form. [Claim 1015] An injectable formulation comprising approximately 90-110 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base and a pharmaceutically acceptable carrier. [Claim 1016] 1016. The injectable formulation of claim 1015, further comprising one or more ingredients selected from a lyoprotectant, an antioxidant, and a pH-adjusting compound. [Claim 1017] The injectable formulation of claim 1016, consisting essentially of approximately 100 mg of 9-[(2,2-dimethylpropylamino)-methyl]-minocycline free base, 100 mg of sucrose, 1 mg of sodium bisulfite, a pH-adjusting compound, and an aqueous carrier. [Claim 1018] 1006. Use of the formulation of claim 1001 in the manufacture of a medicament for treating an infectious disease in a subject. [Claim 1019] 1006. A method for preparing a pharmaceutical formulation comprising granulating the oral formulation of claim 1001 to form granules, followed by molding the granules into an oral dosage form, wherein the oral formulation further comprises about 50-90% by weight of a diluent, about 0.01-0.5% by weight of a stabilizer, about 0.2-2.0% by weight of a flow agent, about 1-11% by weight of a lubricant, and about 0.5-10% by weight of a disintegrant. [Claim 1020] The method of claim 1019, wherein the granulation step comprises roller compaction and the granules comprise greater than 10% by weight of 9-[(2,2-dimethylpropylamino)-methyl]-minocycline. [Brief explanation of the drawings]

[0040] [Figure 1] The percentage of particles retained by sieves of various sizes prior to granulation is shown. [Figure 2] The percentage of particles retained by sieves of various sizes after granulation is shown. DETAILED DESCRIPTION OF THE INVENTION

[0041] Detailed Description of the Invention The present invention relates, at least in part, to oral and injectable formulations of 9-aminomethyltetracycline compounds, such as 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, or salts thereof. The formulations of the invention have been found to be useful for treating bacterial infections in subjects, such as humans.

[0042] The term "9-aminomethyl tetracycline compound" includes compounds having a four-ring core structure similar to that of tetracycline and its analogs (e.g., minocycline, sancycline, doxycycline, methacycline, etc.), substituted at the 9-position with an aminomethyl moiety (e.g., -CH2-NR'R'', where R' and R'' are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, or linked to form a ring, etc.). Preferably, the tetracycline compound is 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof. The structure of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is The file is TIFF2025137721000001.tif35130.

[0043] In a further embodiment, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally as the free base or as the tosylate salt, or injected as the free base.

[0044] In further embodiments, the formulations described herein are administered to a patient in need of treatment with the formulation, including, for example, a patient in need of treatment who has, is suspected of having, is at risk of, or has previously been infected with an infection, such as a bacterial infection.

[0045] As used herein, the term "patient" (also "subject") includes any animal in need of treatment with the formulations described herein. Examples include livestock animals, such as cattle, sheep, goats, and humans.

[0046] The term "treat" or "treatment" refers to the amelioration, eradication, or reduction of one or more symptoms of the disorder being treated, such as a bacterial infection. In certain embodiments, the disorder includes the eradication or elimination of most of the bacteria associated with the infection being treated. In some instances, the compositions of the present invention are administered prior to infection, i.e., as a preventative treatment.

[0047] In further embodiments, the infection is caused by a gram-positive pathogen (e.g., Staphylococcus aureus (MSSA), Staphylococcus aureus (MRSA), Enterococcus faecalis, Enterococcus faecium, Enterococcus faecium (VRE), Streptococcus pneumoniae, Streptococcus pneumoniae (PRSP), Streptococcus pyogenes, Streptococcus agalactiae, etc.), a gram-negative pathogen (e.g., Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Escherichia coli, Shigella spp., etc.), or a gram-negative pathogen (e.g., Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Escherichia coli, Shigella spp., etc.). spp., Salmonella spp., Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae, Serratia marcescens, Acinetobacter baumannii, Stenotrophomonas maltophilia, etc.), anaerobic pathogens (e.g., Bacteroides fragilis, Clostridium perfringens, etc.), and / or atypical pathogens (e.g., Chlamydia pneumoniae, Legionella pneumophila, etc.). It can be an infection caused by bacteria such as pneumophila.

[0048] Oral tablet formulation In one aspect, the invention relates, at least in part, to an oral formulation of a 9-aminomethyltetracycline compound or a salt thereof in tablet form. Advantageously, the 9-aminomethyltetracycline compound is 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline and the salt is the tosylate salt.

[0049] In further embodiments, the formulation comprises about 5% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 27% by weight, about 12% to about 25% by weight, about 13% to about 25% by weight, about 14% to about 25% by weight, about 15% to about 24% by weight, about 16% to about 24% by weight, about 16% to about 23% by weight, about 16% to about 22% by weight, about 18% to about 22% by weight, about 19% to about 21% by weight, or about 20.0% by weight of an active ingredient, such as 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base.

[0050] In further embodiments, the formulation contains about 50% to about 90% diluent or inactive ingredients. Examples of such diluents include, but are not limited to, lactose and microcrystalline cellulose. In further embodiments, the formulation contains about 10% to about 60%, about 10% to about 30%, about 11% to about 29%, about 12% to about 28%, about 13% to about 27%, about 14% to about 26%, about 15% to about 25%, about 16% to about 24%, about 17% to about 23%, about 18% to about 22%, about 19% to about 22%, about 20% to about 22%, or preferably about 21.5% lactose.

[0051] In another further embodiment, the formulation comprises about 10% to about 50% by weight, about 30% to about 50% by weight, about 31% to about 49% by weight, about 32% to about 48% by weight, about 33% to about 47% by weight, about 34% to about 46% by weight, about 35% to about 45% by weight, about 36% to about 44% by weight, about 37% to about 43% by weight, about 38% to about 42% by weight, about 39% to about 41% by weight, about 40% to about 41% by weight, or preferably about 40.4% by weight of microcrystalline cellulose.

[0052] In another further embodiment, the formulation includes a stabilizer. The stabilizer may be an antioxidant. Examples of stabilizers include sodium bisulfite. In one embodiment, the formulation includes about 0.01% to about 0.5% by weight, about 0.02% to about 0.45% by weight, about 0.04% to about 0.4% by weight, about 0.05% to about 0.35% by weight, about 0.10% to about 0.3% by weight, about 0.15% to about 0.25% by weight, about 0.16% to about 0.24% by weight, about 0.17% to about 0.23% by weight, about 0.18% to about 0.22% by weight, about 0.19% to about 0.21% by weight, or about 0.2% by weight of sodium bisulfite.

[0053] In another further embodiment, the formulation comprises a fluidizing agent such as colloidal silicon dioxide, hi one embodiment, the formulation comprises about 0.1% to about 2.0%, about 0.3% to about 1.9%, about 0.5% to about 1.5%, about 0.7% to about 1.4%, about 0.8% to about 1.2%, or about 1.0% by weight of colloidal silicon dioxide.

[0054] In yet another further embodiment, the formulation also includes a lubricant such as magnesium stearate or sodium stearyl fumarate. In one embodiment, the formulation includes about 1% to about 11%, about 2% to about 10%, about 3% to about 9%, about 4% to about 8%, about 4% to about 7%, about 4.5% to about 6%, or about 5.0% by weight of magnesium stearate or sodium stearyl fumarate.

[0055] In yet another further embodiment, the formulation also includes a disintegrant such as crospovidone. In one embodiment, the formulation includes about 0.5% to about 10%, about 1% to about 10%, about 2% to about 9%, about 3% to about 8%, about 4% to about 7%, about 4% to about 6%, or about 5.0% by weight of crospovidone.

[0056] In yet another further embodiment, the tablet formulation may also include a buffering agent such as citric acid, which, when present, may be present at about 0.9% to about 2.0%, about 1.0% to about 1.9%, about 1.1% to about 1.8%, about 1.2% to about 1.7%, about 1.3% to about 1.6%, about 1.4% to about 1.5%, or about 1.44% by weight.

[0057] In yet another further embodiment, the tablet formulation may also include an anti-adherent agent such as talc. When present, the talc may be present in an amount of about 0.1% to about 2.0%, about 0.2% to about 1.9%, about 0.3% to about 1.8%, about 0.4% to about 1.7%, about 0.4% to about 1.6%, about 0.5% to about 1.5%, about 0.6% to about 1.4%, about 0.7% to about 1.3%, about 0.8% to about 1.2%, about 0.9% to about 1.1%, or about 0.96% by weight.

[0058] The oral formulation may also include a coating. If present, the coating may optionally include Eudragit El 00 and optionally include trace amounts of solvent (preferably less than about 0.1% ethanol). In one embodiment, the formulation contains about 1% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 3% to about 4%, or about 3.4% by weight of Eudragit E 100.

[0059] The oral formulation may also include a coating colorant, such as OPADRY® AMB Red. In one embodiment, the formulation includes about 1% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 3% to about 4%, or about 3.85% by weight of OPADRY® AMB Red.

[0060] In another embodiment, the invention relates to a tablet containing about 190 to about 205 mg of a 9-aminomethyltetracycline compound, e.g., 9-[(2,2-dimethylpropylamino)-methyl]-minocycline, tosylate salt. Preferably, the tablet contains about 201.6 mg of 9-[(2,2-dimethylpropylamino)-methyl]-minocycline, tosylate salt (i.e., 150 mg of 9-[(2,2-dimethylpropylamino)-methyl]-minocycline and 51.6 mg of tosylate counterion).

[0061] In another further embodiment, the tablet contains about 140 mg to about 180 mg, about 145 mg to about 175 mg, about 150 mg to about 170 mg, 155 mg to about 165 mg, or about 161.1 mg of a diluent, e.g., lactose.

[0062] In another further embodiment, the tablet comprises about 290 mg to about 315 mg, about 295 mg to about 310 mg, about 295 mg to about 305 mg, about 300 mg to about 305 mg, or about 303.3 mg of additional diluent, such as microcrystalline cellulose.

[0063] The tablet composition may further comprise a stabilizer. The stabilizer may be sodium bisulfite, which is also an antioxidant. In one embodiment, the composition contains about 0.1 mg to about 2 mg, about 0.2 mg to about 2 mg, about 0.3 mg to about 2 mg, about 0.4 mg to about 2 mg, about 0.5 mg to about 1.9 mg, about 0.6 mg to about 1.8 mg, about 0.7 mg to about 1.7 mg, about 0.8 mg to about 1.6 mg, about 0.9 mg to about 1.5 mg, about 1.0 mg to about 1.5 mg, about 1.0 mg to about 2.0 mg, about 1.1 mg to about 1.9 mg, about 1.2 mg to about 1.8 mg, about 1.3 mg to about 1.7 mg, about 1.4 mg to about 1.6 mg, or about 1.5 mg of sodium bisulfite per tablet.

[0064] In still another further embodiment, the tablet contains from about 10 mg to about 100 mg, from about 20 mg to about 80 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, from about 35 mg to about 45 mg, from about 35 mg to about 40 mg, or about 37.5 mg of a disintegrant, e.g., crospovidone.

[0065] In yet another embodiment, the tablet contains a glidant such as colloidal silicon dioxide. The tablet may contain about 1.0 mg to about 12.0 mg, about 2.0 mg to about 11.0 mg, about 3.0 mg to about 10.0 mg, about 4.0 mg to about 9.0 mg, about 5.0 mg to about 8.0 mg, about 6.0 mg to about 8.0 mg, about 7.0 mg to about 8.0 mg, or about 7.5 mg of a glidant, such as colloidal silicon dioxide.

[0066] In still another further embodiment, the tablet contains about 10 mg to about 110 mg, about 20 mg to about 90 mg, about 25 mg to about 70 mg, about 30 mg to about 50 mg, about 35 mg to about 40 mg, or about 37.5 mg of a lubricant, such as magnesium stearate or sodium stearyl fumarate.

[0067] In yet another embodiment, the tablet may contain a buffering agent such as citric acid, although other acids can be used. If present, the buffering agent may be present in an amount of about 10 mg to about 20 mg, about 11 mg to about 19 mg, about 12 mg to about 18 mg, about 13 mg to about 17 mg, about 14 mg to about 16 mg, or about 15 mg of buffering agent, e.g., citric acid.

[0068] The tablets may also contain an anti-adhesion agent to prevent the tablets from sticking together. In one embodiment, the anti-adhesion agent is talc. When present, the composition contains about 1 mg to about 20 mg, about 2 mg to about 19 mg, about 3 mg to about 18 mg, about 4 mg to about 17 mg, about 5 mg to about 16 mg, about 6 mg to about 15 mg, about 7 mg to about 14 mg, about 8 mg to about 13 mg, about 9 mg to about 12 mg, about 9 mg to about 11 mg, or about 10 mg of an anti-adhesion agent, such as talc, per tablet.

[0069] In yet another embodiment, the tablet may include a coating component. Examples of coating components include colorants and coating polymers. Specific examples include OPADRY® AMB Red and Eudragit E100.

[0070] In yet another embodiment, the tablet may contain a coating colorant such as OPADRY® AMB Red, although other colorants can be used. The tablet may contain about 10 mg to about 50 mg, or about 15 mg to about 45 mg, or about 20 mg to about 40 mg, or about 25 mg to about 35 mg, or about 30 mg of colorant.

[0071] The coating may be applied to the tablet using a solvent such as ethanol. The composition may also contain trace amounts of ethanol. In a further embodiment, the coating comprises Eudragit E100. Eudragit E100 may be present in an amount of about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, or about 40 mg per tablet.

[0072] In further embodiments, the formulation comprises 15% to about 30%, about 16% to about 28%, about 18% to about 25%, about 19% to about 22%, about 19.5% to about 21.5%, or about 20% by weight of the active ingredient, e.g., 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline tosylate salt.

[0073] In further embodiments, the formulation contains about 50% to about 90% diluent or inactive ingredients. Examples of such diluents include, but are not limited to, lactose and microcrystalline cellulose. In further embodiments, the formulation contains about 10% to about 60%, about 10% to about 30%, about 11% to about 29%, about 12% to about 28%, about 13% to about 27%, about 14% to about 26%, about 15% to about 25%, about 16% to about 24%, about 17% to about 23%, about 18% to about 22%, about 19% to about 22%, about 19.5% to about 21.5%, or preferably about 20% lactose.

[0074] In another further embodiment, the formulation comprises about 30% to about 50% by weight, about 31% to about 50% by weight, about 32% to about 49% by weight, about 33% to about 48% by weight, about 34% to about 47% by weight, about 35% to about 46% by weight, about 36% to about 45% by weight, about 37% to about 44% by weight, about 38% to about 43% by weight, about 39% to about 42% by weight, about 40% to about 42% by weight, or preferably about 41.74% by weight of microcrystalline cellulose.

[0075] In another further embodiment, the formulation includes a stabilizer. The stabilizer may be an antioxidant. Examples of stabilizers include sodium bisulfite. In one embodiment, the formulation includes about 0.01% to about 0.5% by weight, about 0.02% to about 0.45% by weight, about 0.04% to about 0.4% by weight, about 0.05% to about 0.35% by weight, about 0.10% to about 0.3% by weight, about 0.15% to about 0.25% by weight, about 0.16% to about 0.24% by weight, about 0.17% to about 0.23% by weight, about 0.18% to about 0.22% by weight, about 0.19% to about 0.21% by weight, or about 0.2% by weight of sodium bisulfite.

[0076] In another further embodiment, the formulation comprises a fluidizing agent such as colloidal silicon dioxide, hi one embodiment, the formulation comprises about 0.1% to about 1.5%, about 0.2% to about 1.0%, about 0.3% to about 0.8%, about 0.4% to about 0.6%, or about 0.5% by weight of colloidal silicon dioxide.

[0077] In yet another further embodiment, the formulation also includes a lubricant such as magnesium stearate. In one embodiment, the formulation includes about 1% to about 11%, about 2% to about 10%, about 3% to about 9%, about 4% to about 8%, about 4% to about 7%, about 4.5% to about 6%, or about 5.0% by weight of magnesium stearate.

[0078] In yet another further embodiment, the formulation also includes a disintegrant such as crospovidone. In one embodiment, the formulation includes about 0.5% to about 10%, about 1% to about 10%, about 2% to about 9%, about 3% to about 8%, about 4% to about 7%, about 4% to about 6%, or about 5.0% by weight of crospovidone.

[0079] In yet another further embodiment, the tablet formulation may also include an anti-adherent agent such as talc. When present, the talc may be present at about 0.1% to about 2.0% by weight, about 0.2% to about 1.9% by weight, about 0.3% to about 1.8% by weight, about 0.4% to about 1.7% by weight, about 0.4% to about 1.6% by weight, about 0.5% to about 1.5% by weight, about 0.6% to about 1.4% by weight, about 0.7% to about 1.3% by weight, about 0.8% to about 1.2% by weight, about 0.9% to about 1.1% by weight, or about 1.00% by weight.

[0080] In another embodiment, the present invention relates to a tablet containing about 70 mg to about 200 mg, about 80 mg to about 180 mg, about 90 mg to about 160 mg, about 100 mg to about 140 mg, or about 120 mg to about 135 mg of 9-[(2,2-dimethylpropylamino)-methyl]-minocycline, tosylate salt. Preferably, the tablet contains about 132.8 mg of 9-[(2,2-dimethylpropylamino)-methyl]-minocycline, tosylate salt.

[0081] In another further embodiment, the tablet contains about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, 80 mg to about 120 mg, 90 mg to about 110 mg, or about 100 mg of a diluent, such as lactose.

[0082] In another further embodiment, the tablet comprises about 150 mg to about 250 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, or about 208.70 mg of additional diluent, such as microcrystalline cellulose.

[0083] The tablet composition may further comprise a stabilizer. The stabilizer may be sodium bisulfite, which is also an antioxidant. In one embodiment, the composition contains about 0.1 mg to about 2 mg, about 0.2 mg to about 1.9 mg, about 0.3 mg to about 1.8 mg, about 0.4 mg to about 1.7 mg, about 0.5 mg to about 1.6 mg, about 0.6 mg to about 1.5 mg, about 0.7 mg to about 1.4 mg, about 0.8 mg to about 1.3 mg, about 0.9 mg to about 1.2 mg, about 0.95 mg to about 1.1 mg, or about 1.0 mg of sodium bisulfite per tablet.

[0084] In still another further embodiment, the tablet contains from about 5 mg to about 80 mg, from about 10 mg to about 60 mg, from about 15 mg to about 40 mg, from about 18 mg to about 35 mg, from about 20 mg to about 30 mg, from about 22 mg to about 28 mg, or about 25.0 mg of a disintegrant, e.g., crospovidone.

[0085] In yet another embodiment, the tablet contains about 0.5 mg to about 10.0 mg, about 0.7 mg to about 8.0 mg, about 1.0 mg to about 6.0 mg, about 1.3 mg to about 4.0 mg, about 1.8 mg to about 3.0 mg, about 2.1 mg to about 2.8 mg, about 2.4 mg to about 2.6 mg, or about 2.5 mg of a fluidizing agent, such as colloidal silicon dioxide.

[0086] In yet another further embodiment, the tablet comprises from about 5 mg to about 80 mg, from about 10 mg to about 60 mg, from about 15 mg to about 40 mg, from about 18 mg to about 35 mg, from about 20 mg to about 30 mg, from about 22 mg to about 28 mg, or about 25.0 mg of a lubricant, such as magnesium stearate.

[0087] The tablets may also contain an anti-adhesion agent to prevent the tablets from sticking together. In one embodiment, the anti-adhesion agent is talc. The composition contains about 1 mg to about 10 mg, about 1.5 mg to about 9 mg, about 2.0 mg to about 8 mg, about 2.5 mg to about 7 mg, about 3.0 mg to about 6 mg, about 3.5 mg to about 5.8 mg, about 4.0 mg to about 5.6 mg, about 4.5 mg to about 5.4 mg, about 4.8 mg to about 5.3 mg, about 4.9 mg to about 5.1 mg, or about 5 mg of an anti-adhesion agent, such as talc, per tablet.

[0088] It should be appreciated that the components of diluents, stabilizers, disintegrants, glidants and lubricants can also be referred to herein as pharmaceutically acceptable carriers in the formulations described herein.Therefore, the formulations can also be said to comprise, for example, sodium bisulfite, silicon dioxide, lactose, sodium stearyl fumarate, microcrystalline cellulose, or a combination thereof, as pharmaceutically acceptable carriers.

[0089] In a further embodiment, the present invention also relates to a tablet comprising: about 10-15% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof (e.g., the tosylate salt); about 50-90% by weight of a diluent; about 0.01-0.5% by weight of a stabilizer; about 0.2-1.0% by weight of a glidant; about 3-10% by weight of a disintegrant; about 3-10% by weight of a lubricant; about 0.5-3.0% by weight of a buffering agent; about 0.1-2.0% by weight of an anti-adhesive agent; and about 1-6% by weight of a coating component.

[0090] In yet another further embodiment, the present invention also includes a tablet consisting essentially of the following: about 15-30% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 15-25% by weight of lactose; about 35-45% by weight of microcrystalline cellulose; about 0.17-0.22% by weight of sodium bisulfite; about 0.4-0.6% by weight of silicon dioxide; about 4.5-5.5% by weight of magnesium stearate; about 4.5-5.5% by weight of crospovidone; and about 0.9-1.1% by weight of talc. In a further embodiment, the tablet of the present invention consists essentially of the ingredients listed above.

[0091] In a further embodiment, the present invention also includes a tablet consisting essentially of the following: about 26.56% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 20.00% by weight of lactose; about 41.74% by weight of microcrystalline cellulose; about 0.20% by weight of sodium bisulfite; about 0.50% by weight of silicon dioxide; about 5.00% by weight of magnesium stearate; about 5.00% by weight of crospovidone; and about 1.00% by weight of talc. In a further embodiment, the tablet of the present invention consists essentially of the ingredients listed above.

[0092] In yet another embodiment, the present invention also relates to an oral formulation comprising a tablet having a core weighing about 450 mg to about 550 mg, about 480 mg to about 520 mg, about 490 mg to about 510 mg, about 495 mg to about 505 mg, or about 500 mg.

[0093] In yet another further embodiment, the present invention includes a tablet comprising: about 13-14% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 40-60% by weight lactose; about 10-30% by weight microcrystalline cellulose; about 0.05-0.15% by weight sodium bisulfite; about 0.4-0.6% by weight silicon dioxide; about 5-6.5% by weight magnesium stearate; about 4-6% crospovidone; about 1.0-2.0% by weight citric acid; about 0.7-1.2% by weight talc; and about 3-5% Eudragit E100.

[0094] In yet another further embodiment, the present invention also includes a tablet consisting essentially of the following: about 13-14% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 45-55% by weight of lactose; about 15-25% by weight of microcrystalline cellulose; about 0.07-0.12% by weight of sodium bisulfite; about 0.4-0.55% by weight of silicon dioxide; about 5.5-6.0% by weight of magnesium stearate; about 4.5-5% by weight of crospovidone; about 1.25-1.75% by weight of citric acid; about 0.7-1.2% by weight of talc; and about 3-5% of Eudragit E100. In a further embodiment, the tablet of the present invention consists essentially of the ingredients listed above.

[0095] In a further embodiment, the present invention also relates to a tablet comprising: about 10-30% by weight of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof (e.g., the tosylate salt); about 50-90% by weight of a diluent; about 0.01-0% by weight of a stabilizer; about 0.2-2.0% by weight of a glidant; about 3-10% by weight of a disintegrant; about 3-10% by weight of a lubricant; about 0-3.0% by weight of a buffer; about 0-2.0% by weight of an anti-adhesive agent; and about 1-6% by weight of a coating component, such as a coating colorant.

[0096] In yet another further embodiment, the present invention also includes a tablet consisting essentially of the following: about 13-30% by weight 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 15-25% by weight lactose; about 35-45% by weight microcrystalline cellulose; about 0.17-0.22% by weight sodium bisulfite; about 0.9-1.1% by weight silicon dioxide; about 4.5-5.5% by weight magnesium stearate or sodium stearyl fumarate; about 4.5-5.5% crospovidone; no citric acid; no talc; no Eudragit E100; and about 3-4.5% OPADRY® AMB Red. In a further embodiment, the tablet of the present invention consists essentially of the above-listed ingredients.

[0097] In yet another further embodiment, the present invention also includes a tablet comprising: about 195-205 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 155-165 mg of lactose; about 295-310 mg of microcrystalline cellulose; about 1.0-2.0 mg of sodium bisulfite; about 30-50 mg of crospovidone; about 6-8 mg of silicon dioxide; about 30-50 mg of magnesium stearate or sodium stearyl fumarate; optionally about 12.5-17.5 mg of citric acid; optionally about 7.5-12.5 mg of talc; optionally about 30-50 mg of Eudragit E100, and about 20-40 mg of OPADRY® AMB Red.

[0098] In yet another further embodiment, the present invention also includes a tablet consisting of about 135-140 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 500-525 mg of lactose; about 200-210 mg of microcrystalline cellulose; about 0.5-1.5 mg of sodium bisulfite; about 40-60 mg of crospovidone; about 4-6 mg of silicon dioxide; about 50-70 mg of magnesium stearate; about 12.5-17.5 mg of citric acid; about 7.5-12.5 mg of talc; and about 30-50 mg of Eudragit E100.

[0099] The present invention also relates, at least in part, to a tablet consisting of: about 138.5 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 515 mg of lactose; about 205.5 mg of microcrystalline cellulose; about 1.0 mg of sodium bisulfite; about 50 mg of crospovidone; about 5.0 mg of silicon dioxide; about 60 mg of magnesium stearate; about 15 mg of citric acid; about 10 mg of talc; and about 40 mg of Eudragit E100.

[0100] The tablets of the present invention can be formed using direct compression, for example, using a pressure of about 20 kPa, and can be coated tablets, such as oval tablets.

[0101] The tablets of the present invention can be formed using roller compaction. For example, the tablets formed by roller compaction can have a hardness of about 2 Kp to about 20 Kp, about 3 Kp to about 18 Kp, about 4 Kp to about 16 Kp, about 5 Kp to about 15 Kp, about 6 Kp to about 15 Kp, about 6.3 Kp to about 14.5 Kp, about 6.3 Kp to about 10 Kp, about 6.3 Kp to about 8 Kp, about 6.3 Kp to about 7 Kp, or about 6.3 Kp to about 6.8 Kp. For example, the average hardness of the tablets is about 6.5 Kp.

[0102] In one embodiment, the formulation process uses roller compaction to increase the particle size of the mixture, e.g., in some embodiments, roller compaction results in a higher drug loading in the formulation, e.g., a drug loading of greater than 10% by weight.

[0103] In one embodiment, the tablets are formulated according to the amounts in Table 1 below.

[0104] [Table 1]

[0105] In another embodiment, the tablets are formulated according to the amounts in Table 2 below.

[0106] [Table 2]

[0107] Oral capsule formulation In another embodiment, the invention also features an oral formulation including about 90 to 120 mg of a 9-aminomethyltetracycline compound, such as 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, and a pharmaceutically acceptable carrier. In a further embodiment, the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is the free base.

[0108] In another embodiment, the invention also features an oral formulation containing about 70 to 200 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt.

[0109] In another further embodiment, the pharmaceutically acceptable carrier includes a stabilizer and / or antioxidant, e.g., sodium bisulfite. The composition also includes a fluidizing agent, such as silica, e.g., colloidal anhydrous silica.

[0110] The formulation may be placed in a capsule, such as a size 0 white HPMC opaque capsule.

[0111] In further embodiments, the oral capsule formulation contains about 95 mg to about 115 mg, about 100 mg to about 110 mg, or about 105 mg of 9-[(2,2-dimethylpropylamino)-methyl]-minocycline free base.

[0112] The formulation may also include about 0.95 to about 1.15 mg, about 0.10 mg to about 1.10 mg, or about 1.05 mg of sodium bisulfite and about 0.09 mg to about 0.115 mg, about 0.10 mg to about 0.11 mg, or about 0.105 mg of colloidal anhydrous silica. It should be recognized that colloidal anhydrous silica may also be referred to as a pharmaceutically acceptable carrier in the formulations described herein.

[0113] In a further aspect, the invention features an oral capsule formulation consisting of about 95-115 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base, 0.95-1.15 mg of sodium bisulfite, about 0.09-0.115 mg of colloidal anhydrous silica, and a capsule.

[0114] In another embodiment, the oral capsule formulation contains about 70 mg to about 200 mg, about 80 mg to about 180 mg, about 90 mg to about 160 mg, about 100 mg to about 140 mg, or about 120 mg to about 135 mg of 9-[(2,2-dimethylpropylamino)-methyl]-minocycline, tosylate salt. Preferably, the capsule contains about 132.8 mg of 9-[(2,2-dimethylpropylamino)-methyl]-minocycline, tosylate salt.

[0115] In further embodiments, the capsule formulation may also include: about 120-135 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 90-110 mg of lactose; about 190-220 mg of microcrystalline cellulose; about 0.8-1.2 mg of sodium bisulfite; about 20-30 mg of crospovidone; about 2-3 mg of silicon dioxide; about 20-30 mg of magnesium stearate; and about 4-6 mg of talc.

[0116] In a further embodiment, the capsule formulation comprises: about 132.80 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 100.00 mg of lactose; about 208.70 mg of microcrystalline cellulose; about 1.00 mg of sodium bisulfite; about 25.00 mg of crospovidone; about 2.50 mg of silicon dioxide; about 25.00 mg of magnesium stearate; and about 5.00 mg of talc. In a further embodiment, the tablet of the present invention consists essentially of the ingredients listed above.

[0117] The capsules can be manufactured using the following process. First, each of the components listed in Table 3 below is prepared separately. The tetracycline compound 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, free base, is passed through a 500-micron sieve and weighed out in the appropriate amount. Sodium bisulfite is placed in a mortar and crushed to break up crystals. Next, sodium bisulfite is passed through a 300-micron sieve and weighed out in the appropriate amount. Colloidal anhydrous silica (AEROSIL) is passed through a 710-micron sieve and similarly weighed out in the appropriate amount shown in Table 3.

[0118] [Table 3] a A small amount of variation (±10%) may occur during the drug production process. b Correction amount

[0119] After both 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, free base, and sodium bisulfite were passed through separate sieves, the free base was placed in a stainless steel container and sodium bisulfite was added. The mixture was blended for 10 minutes, after which colloidal anhydrous silica (AEROSIL) was added. After the silica was added, the mixture was blended for 5 minutes. HPMC capsules were then hand filled and the weight of each was recorded.

[0120] Injectable formulations In another embodiment, the invention also features an injectable formulation including about 90-110 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base and a pharmaceutically acceptable carrier (e.g., an aqueous carrier).

[0121] In further embodiments, the injectable formulation may comprise approximately 90-110 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline and one or more ingredients selected from a free base, a lyoprotectant, an antioxidant, a pH-adjusting compound, and a carrier.

[0122] Examples of lyoprotectants include sugars such as sucrose. The formulations may contain about 90 to about 110 mg, about 95 mg to about 105 mg, or about 100 mg of sucrose (e.g., for a vial containing about 100 mg of a tetracycline compound).

[0123] Examples of antioxidants include, but are not limited to, sodium bisulfite. The injectable formulations may contain about 0.9 to about 1.1 mg, about 0.95 to about 1.05 mg, or about 1.0 mg of sodium bisulfite (e.g., for a vial containing about 100 mg of a tetracycline compound).

[0124] The formulation may also include acids and bases that can be used to adjust the pH of the composition to 4.2. Examples of such compounds include hydrochloric acid and sodium hydroxide.

[0125] In a further embodiment, the invention relates, at least in part, to an injectable formulation comprising approximately 90-110 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base, 90-110 mg of sucrose, 0.9-1.1 mg of sodium bisulfite, and an aqueous carrier.

[0126] In another further embodiment, the invention also features an injectable formulation consisting of about 100 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base, 100 mg of sucrose, 1 mg of sodium bisulfite, a pH-adjusting compound, and an aqueous carrier.

[0127] The composition of one batch of injectable formulation of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base for 100 mg vials is set forth in Table 4 below.

[0128] [Table 4]

[0129] The injectable formulation may be prepared by first adding water (4.662 liters) and 174.8 grams of sucrose to a container. 372 grams of 1 M hydrochloric acid and 1.75 g of sodium bisulfite were also added. 174.8 g of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline free base was then added. After the tetracycline compound was added, the pH was adjusted to 4.0-4.5 with 0.1 M sodium hydroxide or 0.1 M hydrochloric acid, as needed. The weight of the resulting solution was adjusted to 5.82 kg with additional water. The mixture was then filtered through a 0.22 pm sterile filter. The solution was then filled into Type 1 glass vials at 3.5 g per vial.

[0130] Injectable formulations using the tosylate salt of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline can also be prepared. Table 5 shows an example formulation.

[0131] [Table 5]

[0132] Roller compaction In another aspect, the invention features an oral tablet formulation consisting of: about 120-135 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, tosylate salt; about 90-110 mg lactose; about 190-220 mg microcrystalline cellulose; about 0.8-1.2 mg sodium bisulfite; about 20-30 mg crospovidone; about 2-3 mg silicon dioxide; about 20-30 mg magnesium stearate; and about 4-6 mg talc.

[0133] In a further aspect, the invention features an oral tablet formulation comprising a tablet weighing about 450 mg to about 550 mg, about 480 mg to about 520 mg, about 490 mg to about 510 mg, about 495 mg to about 505 mg, or about 500 mg.

[0134] In a further aspect, the invention features an oral tablet formulation comprising a tablet having an average hardness of about 2 Kp to about 20 Kp, about 3 Kp to about 18 Kp, about 4 Kp to about 16 Kp, about 5 Kp to about 15 Kp, about 6 Kp to about 15 Kp, about 6.3 Kp to about 14.5 Kp, about 6.3 Kp to about 10 Kp, about 6.3 Kp to about 8 Kp, about 6.3 Kp to about 7 Kp, or about 6.3 Kp to about 6.8 Kp. In a preferred aspect, the invention also features a tablet formulation having an average hardness of about 6.5 Kp.

[0135] In a further aspect, the invention features an oral tablet formulation comprising a tablet prepared by a roller compaction process.

[0136] The roller compaction process is illustrated in Scheme 1 below. Scheme 1 TIFF2025137721000007.tif148130

[0137] The roller compaction process significantly improved drug loading. The physical properties of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or its salts (API), such as low particle size, poor flow properties, and tendency to adhere to the surfaces of tableting dies, and therefore the need for large amounts of fillers and lubricants, resulted in a drug loading of 10% (e.g., 100 mg per gram of tablet) in the direct compression process. The roller compaction process overcame these limitations, resulting in a mixture with larger particle size and better flow properties, and increased drug loading to 20%.

[0138] Phase 1: Tablet formulation The target core tablet weight is 500 mg. The dose is 100 mg free base equivalent active substance, API, with an assay of 75.3%. Formulation data is presented in Table 2.

[0139] Stage 2: Mixing and Granulation The blends were manufactured and sampled before lubrication to determine uniformity. Five samples were taken from the entire blend. The pre-lubrication data is presented in Table 6.

[0140] [Table 6]

[0141] A uniform blend was achieved. The blend was then lubricated with 5% magnesium stearate and granulated using an Alexanderwerk WP120 roller compactor with the following settings: TIFF2025137721000009.tif36157

[0142] Following the lubrication and granulation process, the particles were sampled to measure uniformity. Five samples were taken from the entire mixture. The sampling data after lubrication and granulation are presented in Table 7. Uniform particles were obtained.

[0143] [Table 7]

[0144] Particle sizing was evaluated before and after granulation. Figures 1 and 2 show the percentage retained versus mesh size. The granulation process significantly reduced the fine content. This change in particle size improved the flow properties and reduced adhesion tendency of the API, thus increasing drug loading.

[0145] Step 3: Tableting The particles were compressed using a Riva Piccola tablet press. The particles flowed well from the hopper. 10 mm diameter round standard concave tooling was used. A tablet weight of 500 mg was achieved. The tablets were compressed to obtain the hardest tablets without applying pressure to the machine. A softer variety of tablets was then compressed. The resulting tablets were subjected to disintegration. Both the tablet weight and hardness values ​​showed low variability. The particles flowed well during compression. Tablet properties are presented in Table 8.

[0146] [Table 8]

[0147] The remaining granules were compressed to a hardness of approximately 6.5 Kp (actual hardness 6.66 Kp SD 0.52). The mean tablet weight was 494.0 mg, with an RSD of 0.51%.

[0148] Step 4: Coating The tablet batch was split into two sublots. One lot was coated with Eudragit E100 using an ethanol-based solution. A weight gain of 4% was achieved in 2 hours.

[0149] A second tablet lot was coated using the aqueous Opadry® AMB moisture barrier system. The required 4% weight gain was achieved in less than one hour. The tablets produced had little or no visible edge erosion.

[0150] It should be understood that, wherever values ​​and ranges are provided herein, e.g., for amounts, dosages, etc., all values ​​and ranges encompassed by these amounts and ranges are meant to be encompassed within the scope of the invention. Moreover, all values ​​within these values ​​and ranges may also include the upper and lower limits of the range.

[0151] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures, embodiments, appended claims, and examples described herein. Such equivalents are considered to be within the scope of the invention and encompassed by the claims appended hereto. The contents of all references, issued patents, and published patent applications cited throughout this application are hereby incorporated by reference.

Claims

[Claim 1] The invention described in the specification of this application.

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