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Title:  Biphasic controlled release delivery system for high solubility pharmaceuticals and method

United States Patent:  6,475,521

Issued:  November 5, 2002

Inventors:  Timmins; Peter (Irby, GB); Dennis; Andrew B. (Barnston, GB); Vyas; Kiren A. (Canterbury, GB)

Assignee:  Bristol-Myers Squibb Co. (Princeton, NJ)

Appl. No.:  398107

Filed:  September 16, 1999

Abstract

A biphasic controlled release delivery system for pharmaceuticals which have high water solubility, such as the antidiabetic metformin HCl salt, is provided which provides a dosage form that has prolonged gastric residence so that a dosing regimen of at least one gram metformin, once daily, may be achieved while providing effective control of plasma glucose. The delivery system includes (1) an inner solid particulate phase formed of substantially uniform granules containing a pharmaceutical having a high water solubility, and one or more hydrophilic polymers, one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, and (2) an outer solid continuous phase in which the above granules of inner solid particulate phase are embedded and dispersed throughout, the outer solid continuous phase including one or more hydrophilic polymers, one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, which may be compressed into tablets or filled into capsules. Methods for forming the so-described biphasic controlled release delivery system and using such biphasic controlled release delivery system for treating diabetes are also provided.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, a novel way has been found of formulating drug with high water solubility and a limited window of absorption such as metformin or a salt thereof which has a window of absorption in the upper gastrointestinal tract, to provide a dosage form that inherently has prolonged gastric residence. This is accomplished (a) without need for co-administration of a drug such as propantheline, and (b) without need for low density formulation or gas generation within the formulation. The formulation of the invention (a) achieves extended gastric residence by virtue of size but will degrade in vivo so as not to have potential for causing gastric or intestinal obstruction, and (b) controls drug release adequately where the initial burst of drug is under control. The formulations of the invention will provide for an extended release formulation of drug with minimal interpatient variability in pharmacokinetic parameters.

In the case of metformin, the formulation of the invention allows a patient a dosing regimen of at least one gram metformin, once-daily, preferably from about 1 to about 3 grams, once daily, in the form of one or more tablets and/or one or more capsules, while providing effective control of plasma glucose. The metformin formulations of the invention may be administered once daily at the above dosages to effectively treat diabetes while avoiding problems which may be associated with high plasma metformin levels as may be encountered with conventional metformin formulations, while providing optimum therapeutic control.

The invention is applicable to all drugs having high water solubility and a limited window of absorption.

The biphasic controlled release delivery system of the invention is a heterogeneous two phase system which includes (1) an inner solid particulate phase in the form of individual granules or particles containing (a) drug which has a high water solubility, preferably, metformin or a salt thereof, and a limited window of absorption (such as in the upper gastrointestinal tract), and (b) an extended release material formed of one or more hydrophilic polymers, and/or one or more hydrophobic polymers, and/or one or more other type hydrophobic materials (such as one or more waxes, fatty alcohols and/or fatty acid esters), and (2) an outer solid continuous phase in which granules or particles of inner solid particulate phase are dispersed and embedded, the outer solid continuous phase which primarily is formed of an extended release material formed of one or more hydrophilic polymers, and/or one or more hydrophobic polymers, and/or one or more other type hydrophobic materials (such as one or more waxes, fatty alcohols and/or fatty acid esters).

The biphasic controlled release formulation of the invention is particularly adapted for delivery of high water soluble drugs, such as metformin and pharmaceutically acceptable salts thereof, in controlled and extended manner without significant initial burst of drug, and wherein release of drug (liberated from the individual dispersed particles forming the inner solid particulate phase) is effectively controlled. Drug upon being released from the particles of the inner phase, in effect, migrates through the outer solid continuous phase and then is released from the formulation into the upper gastrointestinal tract to be available for absorption.

As indicated, the inner solid particulate phase will be formed of individual discrete particles or granules each of which contains drug and one or more polymeric materials and/or other hydrophobic-type materials. In effect, the components of the inner solid particulate phase are in particulate association without having a barrier layer around the individual particles or granules.

The outer solid continuous phase is preferably a continuous phase or matrix having the particles or granules including drug (forming the inner solid phase) dispersed throughout and embedded in the continuous outer solid phase.

In addition, in accordance with the present invention, a method for lowering insulin resistance or treating diabetes is provided wherein the biphasic controlled release formulation of the invention containing an antidiabetic pharmaceutical is administered to a patient in need of treatment.

The term "diabetes" as employed herein refers to type 2 diabetes and type 1 diabetes, usually type 2 diabetes.

The antidiabetic pharmaceutical employed is preferably a biguanide, preferably metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride, hydrobromide, fumarate, succinate, p-chlorophenoxy acetate or embonate, all of which are collectively referred to as metformin. The fumarate and succinate salts are preferably the metformin (2:1) fumarate, and the metformin (2:1) succinate disclosed in U.S. application Ser. No. 09/262,526 filed Mar. 4, 1999. Metformin hydrochloride salt is preferred.

In another aspect of the present invention, a method is provided for lowering insulin resistance or treating diabetes wherein the biphasic controlled release formulation of the invention contains metformin and is administered in a dosing regimen of at least one gram metformin, once daily, preferably from about 1 to about 3 grams, once daily, to a patient in need of treatment.

The term "extended release material" as present in the inner solid particulate phase and the outer solid continuous phase refers to one or more hydrophilic polymers and/or one or more hydrophobic polymers and/or one or more other type hydrophobic materials, such as, for example, one or more waxes, fatty alcohols and/or fatty acid esters. The "extended release material" present in the inner solid particulate phase may be the same as or different from the "extended release material" present in the outer solid continuous phase. However, it is preferred that the "extended release material" present in the inner solid particulate phase be different from the "extended release material" present in the outer solid continuous phase.

The term "high water solubility" or similar term when characterizing a drug, medicament or pharmaceutical for use in the formulation of the invention refers to a solubility in water at ambient temperature of at least about 50 mg/ml H2O, preferably at least about 100 mg/ml H2 O or more, and more preferably greater than 150 mg/ml.

The term "limited window of absorption" or similar term when characterizing a drug, medicament or pharmaceutical for use in the formulation of the invention refers to an oral bioavailability of less than about 75%, usually less than about 60%, usually decreasing with increasing dose, and almost invariably having permeability/transit time limited absorption.

The biphasic controlled release system of the invention will include the inner solid particulate phase in a weight ratio to the outer solid continuous phase within the range from about 0.5:1 to about 4:1, preferably from about 0.8:1 to about 2:1.

The inner solid particulate phase will contain drug in an amount within the range from about 10 to about 98% by weight, preferably from about 15 to about 95% by weight, and extended release material in the form of hydrophilic polymers and/or hydrophobic polymers and/or other hydrophobic material in an amount within the range from about 5 to about 95% by weight, preferably from about 7 to about 85% by weight, the above % being based on the weight of the inner solid particulate phase. Where mixtures are employed, the hydrophilic polymer will be employed in a weight ratio to hydrophobic polymer and/or other hydrophobic material within the range from about 0.05:1 to about 19:1, preferably from about 0.1:1 to about 10:1.

The particles or granules of the inner solid particulate phase will have a mean particle size within the range from about 30 .mu.m to about 0.8 mm, and preferably from about 50 .mu.m to about 0.5 mm.

The outer solid continuous phase will contain extended release material (preferably different from that employed in the inner solid particulate phase) in the form of one or more hydrophilic polymers and/or hydrophobic polymers and/or other hydrophobic material in an amount within the range from about 40 to about 100%, preferably from about 60 to about 100% (based on the weight of the outer solid continuous phase).

The outer solid continuous phase may contain mixtures of two or more extended release materials in the form of one or more hydrophilic polymer and/or hydrophobic polymer and/or other hydrophobic material in a weight ratio of hydrophilic polymer to hydrophobic polymer or other hydrophobic material within the range from about 200:1 to about 0.05:1, preferably from about 100:1 to about 0.1:1.

The pharmaceutical formulation of the invention will have a total polymer extended release material content (including hydrophilic polymers and/or hydrophobic polymers and/or other hydrophobic material present in the inner solid particulate phase and hydrophilic polymer and/or hydrophobic polymers and/or other hydrophobic material present in the outer solid continuous phase) within the range from about 25 to about 75% by weight, preferably from about 30 to about 65%, more preferably from about 35 to about 60% by weight based on the total weight of the pharmaceutical formulation.

Hydrophilic polymers which may be employed in the inner solid particulate phase and/or outer solid continuous phase include, but are not limited to hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, polyvinyl alcohol, povidone, carbomer, potassium pectate, potassium pectinate, and the like.

Hydrophobic polymers which may be employed in the inner solid particulate phase and/or outer solid continuous phase include, but are not limited to ethyl cellulose, hydroxyethylcellulose, ammonio methacrylate copolymer (Eudragit RL.TM. or Eudragit RS.TM.), methacrylic acid copolymers (Eudragit L.TM. or Eudragit S.TM.), methacrylic acid-acrylic acid ethyl ester copolymer (Eudragit L 100-5.TM.), methacrylic acid esters neutral copolymer (Eudragit NE 30D.TM.), dimethylaminoethylmethacrylate-methacrylic acid esters copolymer (Eudragit E 100.TM.), vinyl methyl ether/maleic anhydride copolymers, their salts and esters (Gantrez.TM.).

Other hydrophobic materials which may be employed in the inner solid particulate phase and/or outer solid continuous phase include, but are not limited to waxes such as beeswax, carnauba wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty acid esters such as glyceryl monostearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated castor oil.

Where hydrophilic polymers and/or hydrophobic polymers are used in the inner solid particulate phase and/or the outer solid continuous phase, such polymers can be ionic or non-ionic, preferably ionic for the inner solid particulate phase and preferably non-ionic for the outer solid continuous phase.

Preferred ionic polymers for use in the inner solid particulate phase include sodium alginate, carbomer (Carbopol.TM.), calcium carboxymethylcellulose, or sodium carboxymethylcellulose, xanthan gum, methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethylmethacrylate-methacrylic acid esters copolymer, cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, hydroxypropylmethylcellulose trimellitate, and hydroxypropylmethylcellulose maleate, with sodium carboxymethylcellulose being particularly preferred.

Preferred non-ionic polymers for use in the outer solid continuous phase are those which assure rapid hydration of the outer solid continuous phase to minimize a variable and significant burst of drug, yet effectively control the release of drug being liberated from the discrete particles or granules forming the inner solid particulate phase. The liberated drug will migrate through the non-ionic polymers forming the outer solid continuous phase before being released from the dosage form and being available for absorption. Preferred polymers for the outer solid phase with the appropriate hydration characteristics include hydroxypropylmethyl cellulose 2208 USP (hydroxypropylmethylcellulose with a methoxyl content of 19-24% and a hydroxypropyl content of 4-12%), viscosity grades ranging from about 4000 to about 100,000 cps and hydroxypropylmethylcellulose 2910 USP (hydroxypropyl-methylcellulose with a methoxyl content of 28-30% and a hydroxypropyl content of 7-12%), viscosity grades ranging from about 3 to about 150 cps. In particular preferred embodiments of the outer solid phase, the above preferred polymers are used in admixture in weight ratios of hydroxypropylmethylcellulose 2208 USP:hydroxypropylmethylcellulose 2910 USP within the range from about 25:1 to about 50:1, preferably from about 30:1 to about 40:1.

Preferred biphasic controlled extended release delivery systems in accordance with the present invention are as follows.

                                           % by Weight of Inner
     A.   Inner Solid Particulate Phase    Solid Particulate Phase
          (1) Metformin HCl (or other           55 to 98
          salt such as succinate or
          fumarate)
          (2) Polymer or Hydrophobic             5 to 95
          Material
          Preferred: ethylcellulose and/or       5 to 45
          sodium carboxymethylcellulose
          and/or glyceryl monostearate
    (Average Particle Size of granules
    forming inner solid particulate
    phase: 0.05 to 2.0 mm)
                                           % by Weight of Outer
     B.   Outer Solid Continuous Phase     Solid Continuous Phase
          Polymer and/or Hydrophobic            40 to 100
          Material:
          Preferred
          (1) Hydroxypropylmethyl-              60 to 100
          cellulose 2208 USP
          (100,000 cps)
          (2) Hydroxypropylmethyl                1 to 30
          cellulose 2910 USP (5 cps)
    Weight Ratio of Inner Solid Phase:       0.5:1 to 1.5:1
    Outer Solid Phase
                                           % by Weight of Outer
     C.   Optional Ingredients             Solid Continuous Phase
          Lubricant (e.g. Mg Stearate)          0.02 to 1
          Compression aid (e.g.                    0 to 30
          Microcrystalline cellulose)



The preferred drug (having high water solubility) for use herein is metformin or pharmaceutically acceptable salts thereof, including the hydrochloride salt and dibasic salts such as metformin (2:1) fumarate and metformin (2:1) succinate as described in pending U.S. application Ser. No. 09/262,526 filed Mar. 4, 1999, now U.S. Pat. No. 6,031,004, which is incorporated herein by reference.

Most preferred are the metformin hydrochloride salt, metformin (2:1) succinate salt, and metformin (2:1) fumarate salt.

Where desired, metformin or a salt thereof may be used in combination with another antihyperglycemic agent and/or a hypolipidemic agent which may be administered orally in the same dosage form in accordance with the invention, a separate oral dosage form or by injection. The metformin or salt thereof will be employed in a weight ratio to the other antihyperglycemic agent and/or hypolipidemic agent within the range from about 0.01:1 to about 300:1, preferably from about 0.05:1 to about 250:1.

It is believed that the use of the metformin or salt thereof in combination with another anti-hyperglycemic agent produces antihyperglycemic results greater than that possible from each of these medicaments alone and greater than the combined additive anti-hyperglycemic effects produced by these medicaments.

In addition, in accordance with the present invention a method is provided for lowering insulin resistance or treating hyperglycemia including type 2 diabetes (NIDDM) and/or type 1 diabetes (IDDM) wherein a therapeutically effective amount of the biphasic formulation of the invention containing metformin or a salt thereof, optionally in combination with another antihyperglycemic agent and/or a hypolipidemic agent, is administered to a patient in need of treatment.

The other antihyperglycemic agent may be an oral antihyperglycemic agent preferably a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas or other antihyperglycemic agents which act on the ATP-dependent channel of the .beta.-cells, with glyburide being preferred.

The metformin or salt thereof will be employed in a weight ratio to the sulfonyl urea in the range from about 300:1 to about 50:1, preferably from about 250:1 to about 75:1.

The oral antihyperglycemic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosed in U.S. Pat. No. 4,639,436), which may be administered in a separate oral dosage form.

The metformin salt thereof will be employed in a weight ratio to the glucosidase inhibitor within the range from about 300:1 to about 2:1, preferably from about 200:1 to about 25:1.

The metformin or salt thereof may be employed in combination with a thiazolidinedione oral anti-diabetic agent (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner-Lambert's Rezulin.RTM., disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016) Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer).

The metformin or salt thereof will be employed in a weight ratio to the thiazolidinedione in an amount within the range from about 75:1 to about 0.1:1, preferably from about 5:1 to about 0.5:1.

The sulfonyl urea and thiazolidinedione in amounts of less than about 150 mg oral anti-diabetic agent may be incorporated in a single tablet with the biphasic controlled release formulation of the invention as a separate rapidly dissolving layer.

The metformin or salt thereof may also be employed in combination with a non-oral antihyperglycemic agent such as insulin or with glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of which is incorporated herein by reference), which may be administered via injection, or by transdermal or buccal devices.

Where present, the sulfonyl ureas, such as glyburide, glimepiride, glipyride, glipizide, glipizide, chlorpropamide and gliclazide and the glucosidase inhibitors acarbose or miglitol may be employed in formulations as described above and in amounts and dosing as indicated in the Physician's Desk Reference.

Where present, the thiazolidinedione anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.

Where present insulin may be employed in formulations, amounts and dosing as indicated by the Physician's Desk Reference.

Where present GLP-1 peptides may be administered in oral buccal formulations, by nasal administration or parenterally as described in U.S. Pat. No. 5,346,701 (TheraTech), U.S. Pat. Nos. 5,614,492 and 5,631,224 which are incorporated herein by reference.

The hypolipidemic agent which may be optionally employed in combination with metformin or a salt thereof may include MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, cholesterol absorption inhibitors, ileal Na+ /bile acid cotransporter inhibitors, bile acid sequestrants, and/or nicotinic acid and derivatives thereof.

MTP inhibitors employed herein include MTP inhibitors disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No. 5,885,983 and U.S. Application Ser. No. 09/175,180 filed Oct. 20, 1998, now U.S. Pat. No. 5,563,440. Preferred are each of the preferred MTP inhibitors disclosed in each of the above patents and applications.

All of the above U.S. Patents and applications are incorporated herein by reference.

Most preferred MTP inhibitors to be employed in accordance with the present invention include preferred MTP inhibitors as set out in U.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

The most preferred MTP inhibitor is

9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2 ,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

The hypolipidemic agent may be an HMG CoA reductase inhibitor which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivatives thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application No.0,142,146 A2, as well as other known HMG CoA reductase inhibitors.

In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.

The squalene synthetase inhibitors suitable for use herein include, but are not limited to, .alpha.-phosphono-sulfonates disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinylmethyl)phosphonates as well as other squalene synthetase inhibitors as disclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R. W. et al, J. A. C. S., 1987, 109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary.

Other hypolipidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secholex.RTM., Policexide.RTM.), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterol lowering agents.

The hypolipidemic agent may be an ACAT inhibitor such as disclosed in, "The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters", Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; "RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor", Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; "ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals", Krause et al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; "Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N'-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity", Stout et al, Chemtracts: Org. Chem. (1995), 8(6), 359-62.

The cholesterol absorption inhibitor may be Schering-Plough's SCH 48461 or as disclosed in Atherosclerosis 115, 45-63 (1995) or J. Med. Chem. 41, 973 (1998).

The ileal Na+ /bile acid cotransporter inhibitor may be as disclosed in Drugs of the Future, 24, 425-430 (1999).

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin.

The above-mentioned U.S. patents are incorporated herein by reference. The amounts and dosages employed will be as indicated in the Physician's Desk Reference and/or in the patents set out above.

The compounds of formula I of the invention will be employed in a weight ratio to the hypolypidemic agent (were present), within the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

The dosages and formulations for the hypolipidemic agent will be as disclosed in the various patents, papers and applications discussed above.

The dosages and formulations for the other hypolipidemic agent to be employed, where applicable, will be as set out in the latest edition of the Physicians' Desk Reference.

For oral administration, a satisfactory result may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg to about 75 mg/kg, one to four times daily.

A preferred oral dosage form, such as tablets or capsules, will contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.

For parenteral administration, the MTP inhibitor will be employed in an amount within the range of from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.005 mg/kg to about 8 mg/kg, one to four times daily.

For oral administration, a satisfactory result may be obtained employing an HMG CoA reductase inhibitor, for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin in dosages employed as indicated in the Physician's Desk Reference, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.

The squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 40 mg.

A preferred oral dosage form, such as tablets or capsules will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.

The metformin or salt thereof and the hypolipidemic agent may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.

The compositions described above may be administered in the dosage forms as described above in single or divided doses, once daily and up to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.

The preferred hypolipidemic agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.

The following additional type high water soluble drugs may be employed in the biphasic controlled release delivery system of the invention:

pravastatin;

antihypertensives and antidepressants related to guanethidine (as disclosed in U.S. Pat. No. 2,928,829) and related to guanoxyfen (as disclosed in BE612362);

antibiotics and viricides such as related to amidinomycin (as disclosed in JP 21,418);

stallimycin (as disclosed in DE 1,039,198);

Arphamenine B (as disclosed in published European Patent Application 85/133550A2);

chitinovorin-A (as disclosed in published European Patent Application 85/150,378A2 and U.S. Pat. No. 4,723,004);

streptomycin (as disclosed in U.S. Pat. No. 2,868,779);

SB-59 (as disclosed in Justus Liebigs, Ann. Chem. (1973) 7, 1112-1140);

TAN-1057-A (as disclosed in U.S. Pat. No. 4,971,965);

streptoniazid (as disclosed in J. Am. Chem. Soc. (1953) 75, 2261);

immunostimulants related to ST-789 (as disclosed in published European Patent Application 88/260588);

peptide hydrolase inhibitors related to nafamastat (as disclosed in U.S. Pat. No. 4,454,338);

gabexate (as disclosed in U.S. Pat. No. 3,751,447);

sepimostat (as disclosed in U.S. Pat. Nos. 4,777,182 and 4,820,730);

Factor Xa inhibitors related to DX-9065a (as disclosed in published European Patent Application 92/0540051);

anti-inflammatory agents related to paranyline as disclosed in U.S. Pat. No. 2,877,269;

peptidyl aldehydes (as disclosed in W094/13693);

antianaphylactics related to GMCHA-TBP (Batebulast) (as disclosed in U.S. Pat. No. 4,465,851);

anti-ulcer agents related to benexate (as disclosed in U.S. Pat. No. 4,348,410);

deoxyspergualin (as disclosed in U.S. Pat. Nos. 4,518,532, 4,658,058 and 4,983,328); and arginine.

Other water-soluble drugs suitable for use herein include peptides preferably have a molecular weight from about 100 to 10,000, more preferably from about 100 to about 6,000 and having from 2 to 35 amino acid moieties. Higher molecular weight peptides, even those with a molecular weight of above 10,000, up to about 50,000, may also be accommodated in biphasic formulations of the present invention.

Suitable small peptides have from about 2 to about 10, more preferably from about 2 to about 6 amino acid moieties. Preferred small peptides include the fibrinogen receptor antagonists (RGD containing peptides) which are tetrapeptides with an average molecular weight of about 600. These peptide antagonists are highly potent platelet aggregation inhibitors at plasma levels as low as 1 pmol/mL. Preferred fibrinogen antagonists include the peptide cyclo(S,S)-Na-acetyl-Cys-(Na -methyl)Arg-Gly-Asp-Pen-NH2 (Ali et al, EP 0341915, whose disclosure is herein incorporated by reference) and the peptide cyclo(S,S)-(2-mercapto)benzoyl-(Na -methyl)Arg-Gly-Asp-(2-mercapto)-phenylamide (EP 0423212, whose disclosure is herein incorporated by reference). Other fibrinogen antagonists useful in the present invention are those peptides disclosed by Pierschbacher et al, WO 89/05150 (U.S. Pat. No.8,804,403); Marguerie, EP 0275748; Adams et al, U.S. Pat. No. 4,857,508; Zimmerman et al, U.S. Pat. No. 4,683,291; Nutt et al, EP 0410537, EP 0410539, EP 0410540, EP 0410541, EP 0410767, EP 0410833, EP 0422937 and EP 0422938; Ali et al, EP 0372486; Ohba et al, WO 90/02751 (PCT/JP89/00926); Klein et al, U.S. Pat. No. 4,952,562; Scarborough et al, WO 90/15620 (PCT/US90/03417); Ali et al, PCT/US90/06514 and PCT/US92/00999; the peptide-like compounds disclosed by Ali et al, EP 0381033 and EP 0384362; and the RGD peptide cyclo-Na -acetyl-Cys-Asn-Dtc-Amf-Gly-Asp-Cys-OH (in which Dtc is 4,4'-dimethylthia-zolidine-5-carboxylic acid and Amf is 4-aminomethylphenyl-alanine).

The RGD peptide may be usefully included in the formulation of the invention in an amount up to about 600 mg/g of the hydrophilic phase or from 0.1 to 60 mg/g of the formulation.

Other peptides useful in the present invention include, but are not limited to, other RGD containing peptides such as those disclosed by Momany, U.S. Pat. No. 4,411,890 and U.S. Pat. No. 4,410,513; Bowers et al, U.S. Pat. No. 4,880,778, U.S. Pat. No. 4,880,777, U.S. Pat. No. 4,839,344; and WO 89/10933 (PCT/US89/01829); the peptide Ala-His-D-Nal-Ala-Trp-D-Phe-Lys-NH2 (in which Nal represents b-naphthyl-alanine) and the peptides disclosed by Momany, U.S. Pat. No. 4,228,158, U.S. Pat. No. 4,228,157, U.S. Pat. No. 4,228,156, U.S. Pat. No. 4,228,155, U.S. Pat. No. 4,226,857, U.S. Pat. No. 4,224,316, U.S. Pat. No. 4,223,021, U.S. Pat. No. 4,223,020, U.S. Pat. No. 4,223,019 and U.S. Pat. No. 4,410,512.

Other suitable peptides include hexapeptides such as the growth hormone releasing peptide (GHRP) His-D-Trp-Ala-Trp-D-Phe-Lys-NH2, (Momany, U.S. Pat. No. 4,411,890, the disclosure of which is herein incorporated by reference in its entirety). This may usefully be included in an amount up to about 250 mg/g of the hydrophilic phase or from 0.1 to 25 mg/kg of the formulation.

Suitable larger polypeptides and proteins for use in the controlled release formulations of the present invention include insulin, calcitonin, elcatonin, calcitoningene related peptide and porcine somatostatin as well as analogs and homologs thereof. Other suitable larger polypeptides include those disclosed by Pierschbacher et al, U.S. Pat. No. 4,589,881 (>30 residues); Bittle et al, U.S. Pat. No. 4,544,500 (20-30 residues); and Dimarchi et al, EP 0204480 (>34 residues).

Other type of compounds useful in the present invention include analogs or homologs of LHRH which display potent LH releasing activity or inhibit the activity of LHRH; analogs or homologs of HP5 which possesses hematopoetic activity; analogs or homologs of endothelin which possess hypotensive activity; analogs or homologs of enkephalin which have antinociceptive activity; analogs or homologs of chlorecystokinin; analogs or homologs of cyclosporin A which have immunosuppressive activity; analogs or homologs of atrial natriuretic factor; peptidergic antineoplastic agents; analogs or homologs of gastrin releasing peptide; analogs or homologs of somatostatin; gastrin antagonists; bradykinin antagonists; neurotensin antagonists; bombesin antagonists; oxytocin agonists and antagonists; vasopressin agonists and antagonists; hirudin analogs and homologs; analogs and homologs of the cytoprotective peptidecyclolinopeptide; alpha MSH analogs; analogs, and homologs of MSH releasing factor (Pro-Leu-Gly-NH2); peptides which inhibit collagenase; peptides which inhibit elastase, peptides which inhibit renin; peptides which inhibit HIV protease; peptides which inhibit angiotensin converting enzyme; peptides which inhibit chymases and tryptases and peptides which inhibit blood coagulation enzymes.

Other suitable drugs include non-peptide therapeutic agents such as antibiotics, antimicrobial agents, antineoplastic agents, cardiovascular and renal agents, such as captopril, anti-inflammatory, immunosuppressive and immunostimulatory agents and CNS agents.

Preferably, the water-soluble drug is metformin or salt thereof as described above.

The biphasic controlled release formulation of the present invention can be administered to various mammalian species, such as dogs, cats, humans, etc., in need of such treatment.

The biphasic controlled release system of the invention can be incorporated in a conventional systemic dosage form, such as a tablet or capsule. The above dosage forms may also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid or sodium bisulfite) or the like.

The dose administered must be carefully adjusted according to the age, weight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result. In general, the dosage forms of formulation containing metformin or salt thereof (whether by itself or with another antihyperglycemic agent and/or a hypolipidemic agent) described above may be administered in amounts as described for metformin hydrochloride (Bristol-Myers Squibb Company's Glucophage.RTM.) as set out in the Physician's Desk Reference.

The combination of the metformin or salt thereof and the other antihyperglycemic agent and/or hypolipidemic agent may be formulated separately or, where possible, in a single formulation employing conventional formulation procedures.

The various formulations of the invention may optionally include one or more fillers or excipients in an amount within the range of from about 0 to about 90% by weight and preferably from about 1 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose (also referred to as a compression aid).

One or more binders may be present in addition to or in lieu of the fillers in an amount within the range of from about 0 to about 35% and preferably from about 0.5 to about 30% by weight of the composition. Examples of such binders which are suitable for use herein include polyvinylpyrrolidone (molecular weight ranging from about 5000 to about 80,000 and preferably about 40,000), lactose, starches such as corn starch, modified corn starch, sugars, gum acacia and the like as well as a wax binder in finely powdered form (less than 500 microns) such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax.

Where the composition is to be in the form of a tablet, it will include one or more tableting lubricants in an amount within the range of from about 0.2 to about 8% and preferably from about 0.5 to about 2% by weight of the composition, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and the like. Other conventional ingredients which may optionally be present include preservatives, stabilizers, anti-adherents or silica flow conditioners or glidants, such as Syloid brand silicon dioxide as well as FD&C colors.

Tablets of the invention may also optionally include an optional coating layer which may comprise from 0 to about 15% by weight of the tablet composition. The coating layer which is applied over the outer solid phase containing particles of inner solid phase embedded therein may comprise any conventional coating formulations and will include one or more film-formers or binders, such as a hydrophilic polymer like hydroxypropylmethylcellulose, and/or a hydrophobic polymer like methacrylic acid esters neutral polymer, ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, .beta.-pinene polymers, glyceryl esters of wood resins and the like and one or more plasticizers, such as triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthalate, castor oil and the like. Both core tablets as well as coating formulations may contain aluminum lakes to provide color.

The film formers are applied from a solvent system containing one or more solvents including water, alcohols like methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones like acetone, or ethylmethyl ketone, chlorinated hydrocarbons like methylene chloride, dichloroethane, and 1,1,1-trichloroethane.

Where a color is employed, the color will be applied together with the film former, plasticizer and solvent compositions.

It will be recognized by one of skill in the art that the amount of drug required for therapeutic effect on administration will, of course, vary with the agent chosen, the nature and severity of the condition and the animal undergoing treatment, and is ultimately at the discretion of the physician. Furthermore, the optimal quantity and spacing of individual dosages of a drug will be determined by the nature and extent of the condition being treated, the form, route and site of administration, the particular patient being treated and that such optima can be determined by conventional techniques. It will also be appreciated that the optimal course of treatment, this is, the number of doses given, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

As indicated, the preferred highly water-soluble drug will be metformin or a salt thereof, which will be employed in a dosage range from about 2 to about 43 mg/kg, preferably about 3 to about 36 mg/kg and more preferably from about 4.5 to about 30 mg/kg (or from about 150 to about 3000 mg, preferably from about 250 to about 2500 mg) on a regimen in single daily dose or 2 to 4 divided daily doses, 1 to 4 times daily.

Where metformin is to be administered once daily, metformin will be employed in an amount of at least one gram, preferably from about one to about 3 grams and more preferably from about 1 to about 2.5 grams, in one, two or more tablets and/or one, two or more capsules.

The biphasic controlled release formulation of the invention may be prepared in accordance with the following method of the invention.

A mixture of medicament (preferably metformin HCl) and hydrophilic polymer and/or hydrophobic polymer and/or other hydrophobic material are dispersed/dissolved in a suitable solvent such as water or an inert organic solvent such as ethanol, isopropanol, acetone or dichloromethane or appropriate mixtures of two or more thereof, to produce a substantially uniform granulation. The granulation is dried and passed through a 0.5 to 2 mm aperture screen to break down agglomerates.

The resulting dry granules are blended with hydrophilic polymer and/or hydrophobic polymer and/or other hydrophobic material. The resulting mix usually with lubricant is pressed into tablets or filled into capsules.

The finished dosage form is either a compressed tablet or a hard gelatin capsule, preferably a tablet. The tablet may be optionally film coated. The total amount of drug per dosage unit would be such as to offer a dosage form of convenient size for patients, but following ingestion would remain (or swell to, by hydration of the polymers used in the fabrication of the tablet) a size that does not easily pass through the pylorus (15 mm or greater) when taken with a meal. As the tablet swells up to approximately three times its dry size following hydration, drug loads of up to 750 mg and more are possible, dependent upon the actual characteristics of the individual drug. Gradual erosion of the polymers of the formulation over a period of up to 15 hours ensures that the dosage form does not produce a gastrointestinal obstruction.

Useful metformin formulations of the invention show the following drug release characteristic when tested in vitro.

                  Time (hours)             % released
                       1                    28-39
                       2                    43-57
                       3                    53-70
                       5                    70-88
                       7                    80-98
                      10                    >85

In addition, in accordance with the present invention, the controlled release metformin formulation of the invention (relative to the rapid-release marketed Glucophage.RTM. tablets) reduces maximum attained plasma-metformin concentration (Cmax) by at least about 15% (preferably from about 15 to about 30%), and increases time to reach maximum metformin plasma concentration (Tmax) by at least about 30% (preferably from about 30 to about 100%), while having an insignificant effect on area under the plasma-metformin concentration time curve (AUC) and % urinary recovery (UR) of the dose of metformin. Thus, the controlled-release metformin formulation of the invention can be employed for once daily dosing of metformin in the treatment of diabetes.

Claim 1 of 50 Claims

What is claimed is:

1. A pharmaceutical formulation comprising (1) an inner solid particulate phase, and (2) an outer solid continuous phase in which particles of the inner solid particulate phase are dispersed and embedded, the particles of the inner solid particulate phase comprising (a) a pharmaceutical having a high water solubility selected from metformin or a pharmaceutically acceptable salt thereof; and (b) an extended release material, and the outer solid continuous phase comprising an extended release material, wherein the total extended release material content in both the inner solid particulate phase and the outer solid continuous phase is within the range from about 25 to about 75% by weight of the pharmaceutical formulation.
 


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