Compositions and methods for treating metabolic disorders
阅读说明：本技术 用于治疗代谢性病症的组合物和方法 (Compositions and methods for treating metabolic disorders ) 是由 A.D.贝伦 M.S.芬曼 N.R.A.比利 于 2013-01-05 设计创作，主要内容包括：本发明提供了用于改善双胍化合物的胃肠道耐受性和用于治疗有需要的患者、特别是患有使用双胍化合物治疗的禁忌症的个体的代谢性病症和/或诱导重量减轻的方法,所述方法包括施用靶向小肠的包括二甲双胍的此类双胍化合物的延迟释放制剂。(The present invention provides methods for improving the gastrointestinal tolerance of biguanide compounds and for treating metabolic disorders and/or inducing weight loss in a patient in need thereof, in particular in an individual suffering from contraindications to treatment with a biguanide compound, said methods comprising administering a delayed-release formulation of such biguanide compounds including metformin targeted to the small intestine.)
1. Use of a biguanide compound in the manufacture of a medicament for the treatment of a diabetic patient suffering from hyperglycemia and contraindications for said biguanide compound, wherein said medicament comprises a delayed-release formulation comprising an enteric coating that begins release of said biguanide compound at a pH of about 6.5 or above about 6.5, wherein said delayed-release formulation is adapted to release said biguanide compound in the distal small intestine and provides reduced systemic bioavailability in said delayed-release formulation compared to an immediate-release formulation having an equivalent amount of said biguanide compound, and administration of said delayed-release formulation results in a circulating plasma concentration of said biguanide compound in said patient of less than about 1.0 μ g/ml.
2. The use according to claim 1, wherein the patient suffers from a contraindication selected from the group consisting of: hypoxic condition, impaired lactic acid clearance and impaired clearance of the biguanide compound.
3. The use of claim 2, wherein the patient has a hypoxic condition.
4. The use of claim 2, wherein the patient has impaired lactate clearance.
5. The use according to claim 2, wherein the patient suffers from impaired clearance of the biguanide compound.
6. The use of claim 2, wherein the patient has moderate renal impairment, severe renal impairment or advanced renal disease that causes impaired clearance of the biguanide compound.
7. The use of claim 2, wherein the patient has chronic kidney disease.
8. The use according to any one of claims 1-7, wherein the hyperglycemia is chronic.
9. The use of claim 8, wherein the hyperglycemia is caused by type II diabetes.
10. Use of a biguanide compound in the manufacture of a medicament for the treatment of a patient suffering from diabetes and moderate or severe renal impairment, wherein said medicament comprises a delayed-release formulation comprising an enteric coating that begins to release the biguanide compound at a pH of about 6.5 or above about 6.5, wherein the delayed-release formulation is adapted to release the biguanide compound in the distal small intestine and provides reduced systemic bioavailability in the delayed-release formulation compared to an immediate-release formulation having an equivalent amount of the biguanide compound, and administration of the delayed-release formulation results in a circulating plasma concentration of the biguanide compound in the patient of less than about 1.0 μ g/ml.
Technical Field
The present invention relates generally to the treatment of metabolic disorders with biguanide compounds and to improving the gastrointestinal tolerance of biguanide compounds by administering such compounds to a patient using a delayed release formulation.
Background
Hyperglycemia (Hyperglycemia), Hyperglycemia
Hyperglycemia may be caused by or associated with: dysfunction of the thyroid, adrenal and pituitary glands, pancreatic disease, severe sepsis, and intracranial diseases (e.g., encephalitis, brain tumors, and meningitis). By far, the most common cause of chronic hyperglycemia is diabetes, which is widely recognized by many as an imminent health care epidemic. In diabetes, hyperglycemia is often caused by low insulin levels (type I diabetes) and/or insulin resistance at the cellular level (type II diabetes).
Many type II diabetes drugs are designed to lower blood glucose levels. The first line of first choice drug for the treatment of type II diabetes and the most commonly prescribed antidiabetic drug worldwide is metformin. In contrast to most diabetic drugs, hypoglycemia with metformin is rare; it also controls weight (weight neutral) and is associated with reduced cardiovascular events and reduced mortality.
Metformin (dimethylbiguanide) belongs to a class of biguanide drugs developed on the basis of hypoglycemic extracts containing guanidines from the plant of the goat bean (Galega officinalis). (Bailey & Turner Metformmin. N Engl JMed.1996Feb 29; 334 (9): 574-9; Bailey et al. Metformmin. its cosmetic Diabetes Iht. 2004; 21 (3): 115-7). Initially in 1921 as a byproduct, (Werner E, Bell J. the preparation of methylguanidine, and of β -methylguanidine by the interaction of cyanodiamides, and Methalaminium and hylalaminium chloride reactivity J Chem Soc, transactions.1921; 121: 1790-5), metformin and other biguanides were found to reduce blood glucose in animals. Studies on the hypoglycemic effects of metformin, phenformin and buformin in humans were published in the 50 s of the 20 th century. Initially, the greater potency of phenformin and buformin led to its wider use; however, their relationship to lactic acidosis has ultimately led to cessation of use in most countries in the 70's of the 20 th century.
Metformin improves glucose tolerance in patients by lowering both basal and postprandial blood glucose. Metformin monotherapy reduces fasting glucose by substantially 20% and HbA1c levels by approximately 1.5%. (Bailey & Turner, supra; Fronzo & Goodman efficiency of methods in tissues with non-insulin-dependent diabetes mellitis. the Multicenter Metal Study group. NEngl J Med.1995, month 8 31; 333 (9): 541-9). Metformin has been shown to improve serum lipids, reduce triglycerides, free fatty acids and LDL-cholesterol and moderately increase HDL-cholesterol. (Bailey & Turner, supra)
It is postulated that the antihyperglycemic effects of metformin are caused by a variety of systemic biochemical interactions including, for example, inhibition of hepatic glucose production, increased insulin sensitivity, increased peripheral glucose uptake (by phosphorylating GLUT-4 enhancers), increased fatty acid oxidation and/or decreased absorption of glucose from the gastrointestinal tract. (Hundal & Inzuc chi Metformin: new understandings, new uses. drugs. 2003; 63 (18): 1879-94). Recently, researchers have focused on their apparent effect on glucagon-like peptide-1 (GLP-1) secretion, apparently determining that metformin does not act directly on intestinal L cells to induce G LP-1 secretion or to enhance L cell sensitivity to several known secretagogues. (Mulherin et al, mechanics understanding method for min-induced therapy of glucose-like peptide-1 from the expression L cell Endocrinology 152: 4610-19 (12 months 2011)). These researchers suggest that metformin stimulates GLP-1 release by an indirect mechanism involving muscarinic (M3) receptor dependent and gastrin-releasing peptide (GRP) pathways independent of intestinal L cells, such that the systemic bioavailability of metformin is critical for therapeutic efficacy.
Unfortunately, however, systemic exposure to metformin still carries a serious risk of lactic acidosis for several patient populations. Lactic acidosis is a potentially fatal metabolic complication that occurs when lactic acid levels in the blood stream increase. Thus, metformin is contraindicated in patients with any condition that may increase the risk of lactic acidosis, including renal disorders, pulmonary disorders and liver diseases. According to the prescription information, heart failure, in particular unstable or acute congestive heart failure, also increases the risk of lactic acidosis with metformin. Thus, metformin remains unusable for treating hyperglycemia in patients suffering from these contraindications.
In addition, conventional metformin formulations often produce dose-limiting adverse Gastrointestinal (GI) complications, including diarrhea, nausea, vomiting, dizziness, headache, and dyspepsia. Thus, patient administration is typically titrated up to the maximum tolerated dose over a period of time, based in part on any resulting patient-specific adverse GI effects, which are not trivial. The development of extended release formulations is desired to solve this problem, but this does not completely solve the problems.
Clearly, there remains a need for better and safer compositions and methods for delivering biguanide compounds that address these tolerability and safety issues. Ideally, these also provide a more effective treatment option for metabolic disorders in patients with metformin and/or other biguanide contraindications.
Summary of The Invention
As demonstrated herein for the first time, the present inventors have surprisingly found that the systemic bioavailability of biguanides, such as metformin, can be minimized without compromising its therapeutic efficacy. Accordingly, methods and compositions are provided for treating metabolic disorders in patients, including patient populations with other contraindications, by minimizing the systemic bioavailability of biguanide compounds in patients by administering Delayed Release (DR) formulations.
The first time herein also demonstrates the surprising discovery that GI complications, typically caused by biguanide administration, can be significantly reduced using the subject compositions and methods. Thus, patient comfort and compliance are greatly improved, as well as treatment efficacy. Accordingly, methods and compositions are provided for improving GI tolerance and/or reducing GI complications resulting from biguanide administration by administering a delayed-release formulation comprising a biguanide compound to minimize systemic bioavailability of the compound in a patient.
The disclosed biguanide compounds can be administered to a subject in need thereof to treat a variety of metabolic disorders, including obesity, dyslipidemia or other lipid metabolism disorders, as well as hyperglycemic conditions and histopathological diseases associated with hyperglycemia, including type II diabetes, prediabetes, gestational diabetes, and polycystic ovary syndrome. The effective use of biguanide compounds for the prevention and prophylaxis of such diseases and conditions and for more general weight loss purposes in overweight or mildly obese to heavily obese individuals is also specifically contemplated, particularly in view of the surprising and unexpected decoupling of systemic bioavailability from therapeutic efficacy and the subsequent improvement in toxicity and safety profiles achieved herein.
Accordingly, in one aspect, provided herein is a method of treating a metabolic disorder in a patient in need thereof (including patients with contraindications), the method comprising administering to the patient a therapeutically effective amount of a biguanide compound in a delayed-release formulation, wherein the administration minimizes the systemic bioavailability of the biguanide compound in the patient. In another aspect, there is provided a method of improving GI tolerance of a biguanide compound and/or reducing GI complications resulting from biguanide administration, said method comprising administering to a subject a therapeutically effective amount of a biguanide compound in a delayed-release formulation, wherein said administration minimizes the systemic bioavailability of the biguanide compound in a patient. Suitable biguanide compounds for use in the subject methods include, for example, metformin, phenformin, buformin, or imeglimin, including analogs, salts, solvates, polymorphs, hydrates, N-oxides, and prodrugs of such compounds.
In preferred embodiments, the biguanide compound in a subject delayed release formulation has a reduced relative bioavailability of 70%, 60%, 50%, 40%, 30%, 20% or 10% compared to a conventional Immediate Release (IR) or extended release (XR) composition having an equivalent amount of the biguanide compound. In particular embodiments, administration of the subject delayed release formulation results in a mean plasma AUC, mean plasma C of the biguanide compound in said patient compared to the same regimen with administration of an IR or XR formulation having an equivalent amount of the biguanide compoundmaxAnd/or circulating plasma concentrations are minimized. In a preferred embodiment, the biguanide compound is metformin and the IR composition isAnd the XR composition is
In one embodiment, the mean plasma AUC of the biguanide compound when administered at a total dose of 2000mg per day (TDD) or 1000mg twice per day (bis in die); abbreviated "b.i.d" or "BID")0-36Less than about 15,000ng h/mL or 14,000ng h/mL, preferably less than about 12,000ng h/mL, more preferably less than about 11,000ng h/mL or 10,500ng h/mL, and most preferably less than about 10,000ng h/mL. In another embodiment, the mean plasma AUC of the biguanide compound when administered at an effective dose of 1000mg TDD, 500mg BID or less0-36Less than about 10,000ng h/mL, preferably less than about 9,000ng h/mL, more preferably less than about 8,000ng h/mL or 7,000ng h/mL, and most preferably less than about 6,000ng h/mL or 5,00 ng h/mL0ng*h/mL。
In one embodiment, the mean plasma Cmax of the biguanide compound when administered at 2000mg TDD or 1000mg BIDmaxLess than about 1100ng/mL, preferably less than about 1000ng/mL, more preferably less than about 950ng/mL, and most preferably less than about 900 ng/mL. In another embodiment, the mean plasma Cmax of the biguanide compound when administered at an effective dose of 1000mg TDD, 500mg BID or lessmaxLess than about 800ng/mL, preferably less than about 700ng/mL, more preferably less than about 600ng/mL, and most preferably less than about 600ng/mL or 500 ng/mL.
In one embodiment, the resulting circulating plasma concentration of the biguanide compound in a patient is less than about 5 μ g/ml or4 μ g/ml, preferably less than about 3 μ g/ml or 2.5 μ g/ml, more preferably less than about 2 μ g/ml, 1 μ g/ml, 0.5 μ g/ml or 0.25 μ g/ml.
The methods and compositions disclosed herein are particularly suitable for use in patients with contraindications for biguanide compounds (e.g., metformin, phenformin, or buformin). Such contraindications may be hypoxic conditions, impaired lactate clearance, and/or impaired biguanide compound clearance, such as impaired metformin clearance.
For example, in one embodiment, the methods disclosed herein may be used to treat a patient who may suffer from hypoxic conditions, such as, but not limited to, respiratory failure and heart failure. In another embodiment, the patient may suffer from impaired lactate clearance. In another embodiment, the patient may suffer from liver failure, which may result in impaired lactate clearance. In another embodiment, the patient may have impaired clearance of the biguanide compound, which may be caused, for example, by renal impairment and/or renal disease. Thus, in one embodiment, the patient may have renal impairment. Such renal impairment may be moderate or severe renal impairment or end-stage renal disease. In another embodiment, the patient may have renal disease, which may be chronic. In another embodiment, the patient may have hyperglycemia, which may be chronic and may be caused by type II diabetes.
Accordingly, provided herein is a method of treating a kidney-impaired subject having diabetes, the method comprising administering to the subject a therapeutically effective amount of a biguanide compound, for example metformin, phenformin, buformin or imeglimin, in a delayed-release formulation. In certain embodiments, the subject has moderate renal impairment, severe renal impairment, or advanced renal disease. In other embodiments, the subject has a serum creatinine concentration greater than 1.2mg/dL when the subject is male or greater than 1.1mg/dL when the subject is female. In another embodiment, the subject has a decreased Glomerular Filtration Rate (GFR) as compared to a normal baseline level. In another embodiment, the subject has an increase in urine protein as compared to a normal baseline level.
Also provided herein are methods of treating a diabetic subject suffering from congestive heart failure, a hypoxic state, and/or advanced liver disease, comprising administering to the subject a therapeutically effective amount of a biguanide compound, e.g., metformin, phenformin, buformin, or imeglimin, in a delayed-release formulation.
Another treatment method provided herein is a method of reducing the onset of diabetes in a subject with pre-diabetes, the method comprising administering to the subject a therapeutically effective amount of a biguanide compound, for example metformin, phenformin, buformin or imeglimin, in a delayed-release formulation.
Also provided herein are methods of inducing weight loss in a subject, comprising administering to the subject a therapeutically effective amount of a biguanide compound in a delayed-release formulation. In some embodiments, the induced weight loss causes the subject to lose more than 5 pounds, for example, more than 10 pounds, preferably more than 25 pounds, and even more preferably more than 50 pounds. In other embodiments, the induced weight loss causes the subject to have a body mass index between 18.5 and 24.9. In another embodiment, the induced weight loss causes a reduction in waist circumference of at least 0.5 inches.
The application of the formulation of the invention may be twice daily (b.i.d.) (in the morning and in the evening) or once daily (omni in die, abbreviated as "OD"). In certain preferred embodiments, administration may be once a day in the morning, e.g., before 1pm, preferably before 12am or 11am at noon, more preferably before 10am or 9am, or at breakfast. In other preferred embodiments, administration may be once a day in the evening, for example after 5pm, more preferably after 6pm or 7pm, or at dinner. In another preferred embodiment, administration may be once daily at bedtime.
The subject methods administer a therapeutically effective amount of one or more biguanide compounds. It is noteworthy, however, that the inventive methods provided herein advantageously allow for lower therapeutic doses than prior art formulations, both on a per unit basis and/or on a daily dosage basis. In certain embodiments of the methods disclosed herein, the biguanide compound is administered twice daily in an oral dosage form per unit dose of greater than 500mg BID, e.g., 600mg BID or 800mg BID. In certain preferred embodiments of the methods disclosed herein, the oral dose twice daily is less than 500mg BID, e.g., less than 400mg BID, e.g., less than 300mg BID, e.g., about 150mg BID, 200mg BID, or 250mg BID. In alternative preferred embodiments, the biguanide compound is administered once daily at a unit dose of 75mg OD, 125mg OD, 250mg OD, 300mg OD, 500mg OD, 600mg OD, 750mg OD, 800mg OD. or 1000mg OD. In further embodiments, the Total Daily Dose (TDD) of the biguanide compound is less than 2000 mg/day, preferably less than 1500 mg/day, more preferably less than 1000 mg/day or 750 mg/day, most preferably less than 500 mg/day, 400 mg/day, 300 mg/day or 200 mg/day.
In any of the methods disclosed herein, the delayed release formulation can be enteric coated. In one embodiment, the biguanide compound is targeted for delivery to the small intestine and the formulation comprises an oral dosage form that is enterically coated at one pH, at pH 5.0, pH5.5 or pH6.0 or greater than pH 5.0, pH5.5 or pH6.0, e.g., pH 5.0 enteric coating, pH5.5 enteric coating, pH6.0 enteric coating, pH 6.5 enteric coating or pH7.0 enteric coating, or a combination thereof. In another embodiment, the oral dosage form may further comprise a delayed release component for the biguanide compound. In a preferred embodiment, the biguanide compound is targeted for delivery to the distal small intestine and the formulation comprises an orally administered dosage form enterically coated at one pH, at pH6.0 or pH 6.5 or greater than pH6.0 or pH 6.5.
In the methods disclosed herein, the biguanide compound may be or may include metformin, a metformin salt, a metformin solvate, a metformin polymorph, a metformin hydrate, a metformin N-oxide, or a metformin prodrug. In a preferred embodiment, the biguanide compound is a metformin salt selected from the group consisting of: hydrochloride, phosphate, sulfate, hydrobromide, salicylate, maleate, benzoate, succinate, ethanesulfonate, fumarate, glycolate, pamoate, orotate, acetate, isobutyrate, acetylsalicylate, nicotinate, adamantine, chlorophyllin zinc salt, carboxylate, benzoate, dichloroacetate, theophylline-7-acetate, clofibrate, tartrate, oxalate, tannate, and glycolate. In a particularly preferred embodiment, the biguanide compound is metformin hydrochloride.
The methods disclosed herein may further comprise administering an immediate-release formulation, an extended-release formulation, or a delayed-release formulation of one or more additional therapeutic agents, such as a DPP-IV inhibitor (e.g., sitagliptin, saxagliptin, berberine, vildagliptin, linagliptin, alogliptin, etc.), a chemosensory receptor ligand (e.g., a sweet receptor ligand, a bitter receptor ligand, an umami receptor ligand, an acidic receptor ligand, a fat receptor ligand, or a bile acid receptor ligand), an anti-obesity agent, or an anti-diabetic agent, or a chemosensory receptor antagonist (e.g., lactitol). Non-limiting examples include embodiments further comprising: 100mg sitagliptin OD or 50mg sitagliptin BID was administered. The delayed release formulation may be a bilayer tablet or a capsule having both components as encapsulated mini-tablets. The delayed release formulation may further comprise an immediate release component having an enteric coating of pH 5.0 for another therapeutic agent.
Brief Description of Drawings
Figure 1 shows the design of the study described in example 1.
Figure 2 shows events during the treatment period of the study described in example 1.
Figure 3 shows plasma concentrations (x-axis; ng/mL) of immediate release of metformin (metformin IR) (●) and delayed release of metformin (metformin DR) (■) as a function of time (y-axis; min) after ingestion of t-240 and after a meal of t-0 min.
Figure 4A shows PYY plasma concentrations (x-axis; pg/mL) as a function of time (y-axis; min) in subjects at baseline (□, ○) or after ingestion of metformin IR (●) or metformin DR (■) and after a meal at T-0 min figure 4B shows active GLP-1 plasma concentrations (x-axis; GLP-1A pmol/L) in subjects as a function of time (y-axis; min) at baseline (□, ○) or after ingestion of metformin IR (●) or metformin DR (■) and after a meal at T-0 min figure 4C shows the increase in plasma concentrations (GLP-1A pmol/L) as a function of time (y-axis; GLP-1A pmol/L) in subjects at baseline (□, ○) or after ingestion of metformin (●) or of DR ■) and after a meal at T-0 min in subjects as a function of time (y-axis; GLP-1-pmol/L) versus AUC 4C for the graph of the percentage increase in plasma concentrations (abx-1-min) to baseline.
Fig. 5A shows glucose plasma concentration (x-axis; mg/dL) as a function of time (y-axis; min) in subjects at baseline (□, ○) or after ingestion of metformin IR (●) or metformin DR (■) and after a meal at t-0 min fig. 5B shows insulin plasma concentration (x-axis; pmol/L) as a function of time (y-axis; min) in subjects at baseline (□, ○) or after ingestion of metformin IR (●) or metformin DR (■) and after a meal at t-0 min, the percentage decrease in Abs AUC is relative to baseline values for fig. 5A-5B.
Figure 6 is a graph showing the area under the PYY curve (x-axis; log-transformed) as a function of the area under the metformin curve (ng/mL min) after ingestion of metformin IR (●) and metformin DR (■).
Figure 7A shows plasma concentrations (x-axis; ng/mL) of metformin IR (●) and metformin DR (■) as a function of time (y-axis; min) after an intake of t-240 and after a meal of t-0 min figure 7B shows PYY plasma concentrations (x-axis; pg/mL) as a function of time (y-axis; min) in subjects at baseline (□, ○) or after intake of metformin IR (●) or metformin DR (■) and after a meal of t-0 min.
Figure 8 shows the mean plasma metformin concentration (x-axis; ng/mL) on day 5 as a function of time (y-axis; min) at 500mg (◆) and 1000mg (■) metformin DR, 1000mg metformin IR (○) and 500mg metformin IR +1000mg metformin DR (a), doses administered at t-1 min.
FIG. 9 shows the 11 hour plasma metformin AUC (y-axis;% AUC) based on day 5(0-11h)) The steady state relative bioavailability of 500mg BID and 1000mg BID metformin DR in subjects with type 2diabetes compared to 1000mg BID metformin IR. These levels of 500mg BID and 1000mg BID metformin DR constituted 45% and 57% reduction in total plasma metformin exposure compared to 1000mg BID metformin IR.
FIG. 10 shows mean total plasma PYY concentrations (x-axis; pg/mL) as a function of time (y-axis; min) in subjects at baseline (○) or on day 5 of indicated treatment (●).
Figure 11 shows mean plasma active GLP-1 concentrations (x-axis; pmol/L) as a function of time (y-axis; min) in subjects at baseline (○) or on day 5 of prescribed treatment (●). breakfast was administered at t 0min, dose was administered at t-1 min, and lunch was administered at
FIG. 12 shows mean blood glucose concentrations (x-axis; mg/dL) as a function of time (y-axis; min) in subjects at baseline (○) or on day 5 of prescribed treatment (●).
FIG. 13 shows by scatter plot the individual change in fasting glucose concentration (x-axis; mg/dL) as a function of time (y-axis; min) from baseline to day 5 (y-axis) in subjects treated with 500mg (◆) and 1000mg (■) metformin DR, 1000mg metformin IR (●), and 500mg metformin IR +1000mg metformin DR (. tangle-solidup.) (y-axis) the lines in the plot mark the mean change in glucose LS (mg/dL) for each treatment.
Figure 14 shows mean plasma metformin concentrations (x-axis; ng/mL) as a function of time (y-axis; hours) of 500mg (◆) and 1000mg (■) metformin DR, 1000mg metformin IR (○), and 2000mg metformin XR extended release (metformin XR). the dose was administered at t-0 hours.a second dose of the BID regimen was administered at t-12 hours.meals/snacks were provided at t-42 hours, 2.08 hours, 11.5 hours, 18 hours, and 24 hours.
FIG. 15 shows C given 1000mg BID metformin IR, 500mg BID and 1000mg BID metformin DR and 2000mg QD metformin XR a daymax(left panel) and AUC0-36(right panel). Indicates a statistically significant reduction in exposure compared to both metformin IR and metformin XR (all p < 0.0001)
FIG. 16 shows the relative bioavailability of 500mg and 1000mg BID metformin DR administered one day compared to 1000mg BID metformin IR (left panel) and 500mg and 1000mg BID metformin DR administered one day compared to 2000mg QD metformin XR (right panel)
Detailed description of the invention
Methods and compositions are contemplated herein that minimize the systemic bioavailability of biguanide compounds (e.g., metformin) in a subject, yet provide significant beneficial metabolic effects (e.g., reducing hyperglycemia). Contrary to conventional understanding (see, e.g., Mulherin et al, supra), the disclosed biguanide compounds actually cause GLP-1 release through a mechanism of action that may include interaction with the luminal or epithelial aspects of enteroendocrine cells (i.e., the gastrointestinal tract side), and systemic bioavailability may thus be minimized while still achieving meaningful therapeutic efficacy. Advantageously, the methods and compositions of the present invention significantly improve GI tolerance and also reduce the likelihood of side effects (such as lactic acidosis) so that patients with other contraindications can now be effectively treated.
Accordingly, provided herein is a method of improving GI tolerance and/or reducing GI complications resulting from biguanide compound administration, comprising administering to a subject in need thereof a therapeutically effective amount of a biguanide compound in a delayed-release formulation; wherein the delayed release formulation minimizes systemic compound levels in the subject. Also provided herein are methods of treating a metabolic disorder in a subject, and in particular a subject suffering from a contraindication for one or more biguanide compounds, the method comprising administering to a subject in need thereof a therapeutically effective amount of a biguanide compound in a delayed-release formulation; wherein the delayed release formulation minimizes systemic compound levels in the subject. In a preferred embodiment, the biguanide compound is selected from the group consisting of metformin, buformin, phenformin and imeglimin, and is administered at a lower dose and/or lower bioavailability than currently indicated while still achieving the desired metabolic improvement.
Definition of
The terms "gastrointestinal tract" and "intestine" as used herein refer to the stomach and intestine. The "small" or "upper" intestine includes the duodenum, jejunum, and ileum and the "large" or "lower" intestine includes the cecum, colon, and rectum. The "distal" small intestine includes the jejunum and ileum.
In some embodiments, "treating" or "treating" any condition, disease, or disorder refers to ameliorating the disease, disorder, or condition (i.e., arresting or reducing the development of the disease, disorder, or condition, or at least one clinical symptom thereof). In other embodiments, "treated" or "treating" refers to improving at least one physical parameter that may or may not be discernible by the subject, including undesirable but not clinically significant physical parameters. In other embodiments, "treating" or "treatment" refers to inhibiting the disease, disorder, or condition, either physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset of the disease, disorder, or condition.
By "therapeutically effective amount" or "effective amount" is meant an amount of a composition, compound, therapy or course of treatment sufficient to effect such treatment of a disease, disorder or condition when administered to a subject for treatment of such disease, disorder or condition. The "therapeutically effective amount" will vary depending on the composition, compound, therapy, course of treatment, disease, disorder or condition, and its severity, as well as the age, weight, etc., of the subject to be treated.
When the biguanide compounds described herein contain one or more chiral centers, the stereochemistry of such chiral centers may be independently in the R or S configuration or a mixture of the two. The chiral center may further be indicated as R or S or R, S, or D, L or D, L, D, L. Accordingly, if the biguanide compounds of the present invention can be present in optically active form, they may in fact be present as a racemic mixture of enantiomers or as one of the individual enantiomers in a substantially isolated and purified form or as a mixture containing the enantiomers in any relative proportion.
When the biguanide compounds described herein contain two or more chiral centers, then diastereomers are possible. Such diastereomers may exist as pure diastereomers, as pure racemic mixtures of diastereomers, or as diastereomeric mixtures which may themselves be racemic or may be optically active due to the complex arrangement of the enantiomeric diastereomers in the remaining mixture.
If the biguanide compounds of the present invention can exist as geometric isomers around, for example, the guanidine bond, they can exist as a mixture of geometric isomers comprising isomers in virtually any relative proportion or, in some cases, as one of the individual geometric isomers in substantially isolated and purified form.
When the biguanide compounds described herein contain one or more isolated or linearly conjugated double bonds, the geometry surrounding such double bonds may independently be cis/trans, an E/Z mixture, or an E or Z geometric isomer thereof.
"alkyl" means a straight or branched chain saturated monovalent hydrocarbon radical. As examples, the hydrocarbon chain can have one to twenty carbons, one to sixteen carbons, one to fourteen carbons, one to twelve carbons, one to ten carbons, one to eight carbons, one to six carbons, one to four carbons, and the like. "lower alkyl" may refer to alkyl groups having, for example, one to six carbons, one to four carbons, and the like. In certain examples, a straight chain alkyl group can have one to six carbon atoms and a branched alkyl group can have three to six carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like. "Me" means methyl, "Et" means ethyl, and "iPr" means isopropyl.
"aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical, e.g., having 6 to 20 or 6 to 10 ring atoms, such as phenyl or naphthyl.
"alkylaryl" means an (alkylene) -R group, wherein R is aryl as defined above.
"cycloalkyl" means a cyclic saturated or partially saturated monovalent hydrocarbon group (or alicyclic group). As examples, a cycloalkyl group can have three to twenty carbon atoms, three to sixteen carbon atoms, three to fourteen carbon atoms, three to twelve carbon atoms, three to ten carbon atoms, three to eight carbon atoms, three to six carbon atoms, and the like, wherein one or two carbon atoms can be replaced with an oxy group, e.g., adamantyl (admantanyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, indanyl, and the like.
"alkylcycloalkyl" means an (alkylene) -R group, wherein R is cycloalkyl as defined above; such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl or cyclohexylmethyl, and the like.
"Heterocyclyl" or "heterocycloalkyl" means a saturated or unsaturated monovalent monocyclic radical in which one or two ring atoms are heteroatoms selected from N, O or S and the remaining ring atoms are C. The heterocyclyl ring is optionally fused to a (one) aryl or heteroaryl ring as defined herein. In this application, a heterocyclyl ring fused to a monocyclic aryl or heteroaryl ring is referred to as a "bicyclic heterocyclyl" ring. Furthermore, one or two ring carbon atoms in the heterocyclyl ring may optionally be replaced by a-CO-group. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino and the like. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds. When a heterocyclyl contains at least one nitrogen atom, it is also referred to herein as a heterocyclic amino group and is a subset of heterocyclyl. When a heterocyclyl is a saturated ring and is not fused to an aryl or heteroaryl ring as illustrated above, it is also referred to herein as a saturated monocyclic heterocyclyl.
"Alkylheterocycloalkyl" means a- (alkylene) -R group, wherein R is a heterocyclyl ring as defined above, e.g., tetrahydrofurylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
"heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical in which one or more, preferably one, two or three ring atoms are heteroatoms selected from N, O or S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, triazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl, and the like.
"oxo" or "carboxy" means an ═ O group or a C ═ O group, respectively.
The term "substituted" means that the reference group is individually substituted with one or more additional groups and is independently selected from the groups described herein. In some embodiments, the optional substituents are selected from: oxo, halogen, -CN, -NH2、-OH、-NH(CH3)、-N(CH3)2Alkyl (including straight, branched and/or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, fluoroalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy, -S-alkyl, -S (o)2-alkyl, -CONH ((substituted or unsubstituted alkyl) or (substituted or unsubstituted phenyl)), -CON (H or alkyl)2-OCON (substituted or unsubstituted alkyl)2NHCONH ((substituted or unsubstituted alkyl) or (substituted or unsubstituted phenyl)), -NHCO alkaneA group, -N (substituted or unsubstituted alkyl) CO (substituted or unsubstituted alkyl), -NHCOO (substituted or unsubstituted alkyl), -C (OH) (substituted or unsubstituted alkyl)2and-C (NH)2) (substituted or unsubstituted alkyl)2. In some embodiments, as an example, the optional substituent is selected from oxo, fluoro, chloro, bromo, iodo, -CN, -NH2、-OH、-NH(CH3)、-N(CH3)2、-CH3、-CH2CH3、-CH(CH3)2、-CF3、-CH2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCF3、-OCH2CF3、-S(O)2-CH3、-CONH2、-CONHCH3、-NHCONHCH3、-COCH3-COOH, etc. In some embodiments, a substituted group is substituted with one, two, or three of the foregoing groups. In some embodiments, a substituted group is substituted with one or two of the foregoing groups. In some embodiments, a substituted group is substituted with one of the aforementioned groups. Furthermore, unless indicated to the contrary, a formula having a chemical bond shown only as a solid line and not as a solid or dashed line encompasses each possible isomer (e.g., each enantiomer and diastereomer) as well as mixtures of isomers (e.g., racemic and non-racemic mixtures).
In some embodiments, the disclosed biguanide compounds are present in the composition as a salt. In some embodiments, the salts are obtained by reacting the disclosed compounds with an acid. In some other embodiments, pharmaceutically acceptable salts are obtained by reacting the disclosed compounds with a base. In other embodiments, the compounds are used as the free acid or free base form in the manufacture of the compositions described herein. Types of salts include, but are not limited to: (1) an acid addition salt formed by reacting the free base form of the compound with the following pharmaceutically acceptable acids: inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or an organic acid, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-enyl-1-carboxylic acid, glucoheptonic acid, 4' -methylenebis- (3-hydroxy-2-enyl-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts are formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth metal ion (e.g., magnesium or calcium), or an aluminum ion. In some cases, the biguanide compounds described herein are reacted with an organic base such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris (hydroxymethyl) methylamine. In other instances, the compounds described herein form salts with amino acids, such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases for forming salts with compounds (including acidic protons) include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
The term "amino acid" includes any of the twenty naturally occurring amino acids or the D-form of any naturally occurring amino acid. Furthermore, the term "amino acid" also includes other non-naturally occurring amino acids other than D-amino acids, which are functional equivalents of the naturally occurring amino acids. Such non-naturally occurring amino acids include, for example, norleucine ("Nle"), pentanine ("Nva"), L-or D-naphthylamine, ornithine ("Orn"), homoarginine (homoArg), and other amino acids well known in the peptide art, such as those described below: M.Bodanzsky, "Principles of PeptideSeynthesis,"
Amino acids or amino acid analogs can be commercially purchased (Sigma Chemical Co.; Advanced Chemtech) or synthesized using methods known in the art.
Within the scope of the embodiments, the biguanide compounds described herein include other forms of the compound, such as pharmaceutically acceptable salts, solvates (including hydrates), amorphous phases, partially crystalline and crystalline forms (including all polymorphs), prodrugs, metabolites, N-oxides, isotopically labeled, epimers, pure epimers, mixtures of epimers, enantiomers (including but not limited to individual enantiomers and diastereoisomers of enantiomers), meso compounds, stereoisomers, racemic mixtures and mixtures of diastereomers. Biguanide compounds described herein having one or more double bonds include cis/trans isomers, E/Z isomers, and stereoisomers. The biguanide compounds described herein may be prepared as pharmaceutically acceptable salts when the acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminium ion; or form the salt when coordinated to an organic base. In addition, salts of the starting materials or intermediates can be used to prepare salt forms of the disclosed compounds.
In some embodiments, the biguanide compounds described herein include solvent addition forms or crystalline forms thereof, particularly solvates or polymorphs. Solvates comprise stoichiometric or non-stoichiometric amounts of solvent and may be formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
As described above, in some embodiments, the biguanide compounds described herein have one or more stereogenic centers and each center is independently present in the R or S configuration. The biguanide compounds provided herein include all diastereomeric, enantiomeric and epimeric forms and suitable mixtures thereof.
In some embodiments, the sites on the biguanide compounds disclosed herein are susceptible to various metabolic reactions. Thus, incorporation of appropriate substituents at the site of a metabolic reaction will reduce, minimize or eliminate metabolic pathways. In particular embodiments, suitable substituents that reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, or alkyl.
In some embodiments, the biguanide compounds described herein are isotopically labeled, which are the same as those described in the various formulae and structures provided herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. In some embodiments, one or more hydrogen atoms are replaced with deuterium. In some embodiments, the metabolic site on a compound described herein is deuterated. In some embodiments, substituents with deuterium provide some therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Throughout the specification, groups and substituents thereof may be selected by one skilled in the art to provide stabilizing moieties and compounds.
Biguanides
The compositions and methods disclosed herein relate to metformin and other biguanides. By way of background, metformin is one of the simplest structural variants of a class of compounds known as biguanides. From a structural perspective, metformin resembles a pharmacophore or fragment of a chemical structure with greater biological activity.
In one embodiment, the biguanide compounds of the present invention include the following:
wherein:
R1、R2、R3、R4、R5、R6and R7Independently selected from:
H、OH；
O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;
optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)2NH-alkyl substituted C1To C12Straight or branched chain alkyl); cycloalkyl (e.g. C)3To C7Cycloalkyl groups); alkylcycloalkyl (e.g. C)4To C12Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)2To C6Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)3To C11Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)2NH-alkyl substituted C1To C12Straight or branched alkenyl); optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH)2NH-alkyl substituted C1To C12Straight or branched alkynyl);
optionally substituted aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); optionally substituted alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); optionally substituted heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); optionally substituted alkylheteroaryl; and
or R6And R7May be linked together to form a bond, thereby together forming a ring containing the nitrogen atom to which they are attached;
or R1And R2May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;
or R4And R5May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.
In certain embodiments, O-Rx may be selected from: O-C1To C8A linear or branched alkyl group; O-C3To C7A cycloalkyl group; O-C4To C8An alkyl cycloalkyl group; an O-acyl group; an O-ester; and an O-thioester.
In other embodiments, optional substituents may include, for example, OH, O-alkyl, SH, S-alkyl, NH2NH-alkyl. In addition, alkyl, alkenyl, alkynyl, and the like can be substituted with oxygen, silicon, sulfur, and the like to form heteroalkyl, heteroalkenyl, heteroalkynyl, and the like.
In certain embodiments, R3、R6And R7(ii) a Or R3、R4、R5And R7(ii) a Or R3、R4、R5And R7(ii) a Or R3、R4、R5、R6And R7(ii) a Or R2、R3、R4、R5、R6And R7Each of which is independently selected from:
H. methyl, ethyl, propyl or isopropyl;
and the remaining substituents R1、R2、R4And R5(ii) a Or R1、R2And R6(ii) a Or R1、R2And R6(ii) a Or R1And R2(ii) a Or R1Each of which is independently selected from:
h; optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)2NH-alkyl substituted C1To C12Straight or branched chain alkyl); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)2NH-alkyl substitutionC of (A)1To C12Straight or branched alkenyl); optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)2NH-alkyl substituted C1To C12Straight or branched alkynyl); cycloalkyl (e.g. C)3To C7Cycloalkyl groups); alkylcycloalkyl (e.g. C)4To C12Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S, or N, including C)2To C6Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S, or N, including C)3To C11Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); an alkyl heteroaryl group;
or R1And R2May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;
or R4And R5May together form a ring comprising the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.
Exemplary compounds and substituents R having formula I1、R2、R3、R4、R5、R6And R7As shown below. Substituents R are foreseen1、R2、R3、R4、R5、R6And R7And is disclosed in co-pending U.S. patent application serial No.13/547,022, the disclosure of which is incorporated by referenceThe formulae are expressly incorporated herein.
In certain embodiments, the biguanide compounds of formula I may comprise one or more asymmetric centers and may be in the form of a composition of a racemic mixture, a mixture of diastereomers, a single enantiomer, a diastereomer of an enantiomer, a meso compound, a pure epimer, or a mixture of epimers thereof, and the like. In addition, the biguanide compounds may have one or more double bonds and may be in the form of cis/trans, E/Z mixtures or E or Z geometric isomers thereof.
The biguanide compounds of formula I may also be prepared in salt form, for example as a pharmaceutically acceptable salt, including a suitable acid form, for example as a salt selected from: hydrochloride, hydrobromide, acetate, propionate, butyrate, sulfate, bisulfate, sulfite, carbonate, bicarbonate, phosphate, phosphinate, oxalate, hemi-oxalate, malonate, hemi-malonate, fumarate, hemi-fumarate, maleate, hemi-maleate, citrate, hemi-citrate, tartrate, hemi-tartrate, aspartate, glutamate and the like.
Alternative embodiments specifically contemplated for biguanide compounds for use in the present invention include the related heterocyclic compounds described in co-pending U.S. patent application serial No.13/547,022, the disclosure of which is expressly incorporated herein by reference. The phrase "biguanide compounds" as used herein includes these related heterocyclic compounds, exemplary embodiments of which include the following:
triazole:
triazine:
bis-hydrogen triazine:
7-membered cyclic biguanide:
in one embodiment, the disclosed compounds can be prepared as a three component salt form comprising component A, B and C, wherein:
a is the protonated form of a natural or unnatural amino acid;
b is a divalent anion of an acid; and is
C is a protonated form of the compound having formula I.
In certain aspects, a stoichiometric amount of A, B, and C may be included, wherein:
a is a protonated form of a natural amino acid selected from: alanine, aspartic acid, asparagine, arginine, glycine, glutamine, glutamic acid lysine, phenylalanine, tyrosine, serine, threonine, tryptophan, leucine, isoleucine, histidine, methionine, proline, cysteine, or cystine;
b is a divalent anion of an acid selected from: oxalic acid, malonic acid, citric acid, maleic acid, fumaric acid, tartaric acid, aspartic acid, glutamic acid, and the like; and is
C is a protonated form of the compound having formula I.
Contraindications for biguanide compounds including metformin
Since systemic biguanides including metformin have been reported to be substantially excreted by the kidney, the risk of biguanide compound accumulation and lactic acidosis increases with the degree of renal function impairment. Other contraindications for biguanide compounds (e.g., metformin) include impaired lactate clearance and hypoxic conditions. Thus, patients suffering from these contraindications are currently not treatable with conventional biguanide compounds.
However, as demonstrated herein, the therapeutic efficacy of metformin and other biguanide compounds does not require increased systemic levels of metformin, which presents an increased risk of lactic acidosis. Thus, the risk of metformin accumulation and lactic acidosis is significantly reduced and the methods provided herein may therefore be used to treat patients in need thereof, even in cases where said patients suffer from metformin contraindications. For example, the methods provided herein can be used to treat a patient in need thereof, wherein the patient has a hypoxic condition (e.g., respiratory failure and/or heart failure), impaired lactic acid clearance (e.g., due to liver failure), impaired metformin clearance, and/or renal damage, which can be moderate, severe, or advanced damage and can be the result of chronic kidney disease.
Metabolic disorders
The compositions and methods of the invention are advantageously used to treat and/or prevent metabolic disorders, including overweight, obesity, prediabetes, polycystic ovary syndrome, dyslipidemia or a lipid metabolic disorder, as well as hyperglycemic conditions, such as insulin-dependent diabetes mellitus (type 1) or non-insulin-dependent diabetes mellitus (type 2) diabetes, and physiological conditions or disorders associated with or caused by hyperglycemic conditions. Thus, the hyperglycemic conditions treatable by the methods of the invention also include histopathological changes associated with chronic or acute hyperglycemia (e.g., diabetes). Specific examples include pancreatic islet degeneration (β -cell destruction), renal tubular calcification, liver degeneration, eye damage (diabetic retinopathy), diabetic foot, mucosal (e.g., mouth and gums) ulceration, excessive bleeding, delayed blood clotting or wound healing, and increased risk of coronary heart disease, stroke, peripheral vascular disease, dyslipidemia, hypertension, and obesity.
The term "hyperglycemic" or "hyperglycemia" as used herein, when used in relation to a condition of a patient, means an abnormally high glucose level, transient or chronic, that is present in the blood of the patient. The condition may be caused by a delay in glucose metabolism or absorption, such that the patient exhibits glucose intolerance or a high glucose state is not typically seen in normal patients (e.g., in sub-diabetic patients with glucose intolerance at risk of developing diabetes or in diabetic patients). Normoglycemic fasting glucose (FPG) levels are less than about 110mg/dl, impaired glucose metabolism FPG is between about 110mg/dl and 126mg/dl, and diabetic FPG is greater than about 126 mg/dl.
Metabolic disorders also include obesity or unwanted body mass. Leptin, cholecystokinin, PYY and GLP-1 reduce hunger, increase energy expenditure, induce weight loss or provide normal glucose homeostasis. Thus, in various embodiments, a method of the invention for treating obesity or unwanted body mass or hyperglycemia involves the topical administration of metformin to agonize enteroendocrine cells to produce cholecystokinin, oxyntomodulin, GIP, GLP-2, PYY or GLP-1. Treatable conditions also include those commonly associated with obesity, e.g., abnormally high serum/plasma LDL, VLDL, triglycerides, cholesterol, plaque formation leading to narrowing or blockage of blood vessels, increased hypertension/stroke, coronary heart disease risk, and the like.
Synthesis of Compounds
The compounds described herein can be synthesized using standard synthetic techniques known to those skilled in the art, or using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures, and other reaction conditions provided herein may be varied according to the practice and knowledge of those skilled in the art.
Starting materials for the synthesis of the compounds described herein are available from commercial sources, such as Aldrich Chemical Co, (Milwaukee, Wis.), Sigma Chemical Co, (st. The compounds described herein and other related compounds having different substituents can be synthesized using techniques and materials known to those skilled in the art, as described, for example, in: march, ADVANCED ORGANIC CHEMISTRY 4 th edition (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th edition, volumes A and B (Plenum2000, 2001); and Green and Wuts, technical GROUPS IN ORGANIC SYNTHESIS 3 rd edition (Wiley 1999) (all of which are incorporated herein by reference IN their entirety). The general methods for preparing compounds as disclosed herein may be derived from reactions known in the art, and the reactions may be modified by the use of appropriate reagents and conditions, as recognized by the skilled artisan, for the introduction of various moieties appearing in the formulae provided herein.
Other biguanide synthesis methods and protocols for the compounds described herein are found in U.S. application No.12/593,479 (published as u.s.2010/0130498); U.S. application serial No.12/593,398 (published as u.s.2010/0184796); U.S. patent nos. 7,829,299; U.S. application serial No.11/578,013 (published as u.s.2010/0056621); U.S. Pat. Nos. 7, 416,867; U.S. application Ser. No.11/455,693 (published as U.S. 2007/0037212); U.S. application serial No.13/059,730 (published as u.s.2011/0143376); U.S. application serial No.12/996,670 (published as u.s.2011/0311991); U.S. patent nos. 7,811,788; U.S. application Ser. No.11/182,942 (published as U.S. 2006/0019346); U.S. application serial No.12/993,542 (published as u.s.2011/0086138); U.S. application serial No.12/373,235 (published as u.s.2010/0055209); international application No. PCT/IL2007/000454 (published as WO 2007/116404); U.S. application Ser. No.10/472,056 (published as U.S. 2004/0138189); U.S. patent nos. 5,891,919; U.S. patent nos. 6,376,657; U.S. application Ser. No.11/554,982 (published as U.S. 2007/0104805); U.S. application serial No.11/926,745 (published as u.s.2008/0108604); international application No. pct/CA2009/001688 (published as WO 2010/060198); U.S. application serial No.12/735,557 (published as u.s.2010/0330205); international application No. PCT/CA2007/001066 (published as WO 2008/000063); U.S. application Ser. No.11/438,204 (published as U.S. 2006/0269617); U.S. application Ser. No.10/563,713 (published as U.S. 2006/0172020); U.S. application Ser. No.10/902,352 (published as U.S. 2006/0024335); U.S. application Ser. No.10/538,038 (published as U.S. 2006/0275765); U.S. application serial No.11/555,617 (published as u.s.2008/0187936); U.S. application serial No.12/739,264 (published as u.s.2010/0316736); U.S. application serial No.12/215,609 (published as u.s.2009/0042813); U.S. application serial No.11/893,088 (published as u.s.2008/0050499); U.S. patent nos. 7,807,204; U.S. application serial No.11/811,166 (published as u.s.2008/0003268); U.S. patent nos. 6,376,657; international application No. pct/US2011/041183 (published as WO 2011/163183); international application No. pct/EP2011/059814 (published as WO 2011/157692); U.S. application serial No.12/790,292 (published as u.s.2011/0293753); international application No. pct/JP2009/071700 (published as WO 2010/076879); U.S. application serial No.13/032,530 (published as u.s.2011/0217394); international application No. pct/EP2011/000110 (published as WO 2011/085979); international application No. pct/US2010/058467 (published as WO 2011/068814); U.S. application serial No.13/060, 996 (published as u.s.2011/0152361); U.S. application serial No.12/09,253 (published as u.s.2011/0124609); U.S. application serial No.12/687,962 (published as u.s.2011/0119499); and international application No. pct/EP2010/004623 (published as WO 2011/012298); each of these applications is incorporated by reference herein in its entirety.
Administration and methods
The disclosed biguanide compounds (including analogs, salts, solvates, polymorphs, hydrates, N-oxides, and prodrugs of such compounds) can be administered to a subject in need thereof to treat a variety of metabolic disorders, including obesity, dyslipidemia or other disorders of lipid metabolism, as well as hyperglycemic conditions and histopathological diseases associated with hyperglycemia (including type II diabetes). Effective use of such compounds for the prevention and prophylaxis of such diseases and conditions, as well as for more general weight loss purposes, is also expressly contemplated herein, particularly in view of the surprising and unexpected decoupling of systemic bioavailability from therapeutic efficacy achieved herein, and the subsequent improvement in toxicity and safety.
In a preferred embodiment, the compound is metformin. Existing formulations of metformin are reported to have an average bioavailability of 30% to 60%, while many comparable small molecules have a bioavailability of greater than 60%. See, for example, Tucker et al, "Metformin kinetics in health subjects and in properties with catalysis mellitis" Br. J. Clin. Pharmacol.1981, 12(2) -. Notably, metformin administration increased GLP-1 plasma concentrations in normal, diabetic and DPP-IV-deficient rodents, as well as in patients with and without type II diabetes, but this increase was reported to occur indirectly and independently of direct effects on intestinal L cells. Mulherin et al, supra.
However, as demonstrated herein and contrary to established practice in the art, enteroendocrine cell activation by metformin can be triggered by luminal signaling on the epithelial aspect of the intestine, and thus increased systemic bioavailability of metformin is virtually unnecessary after oral ingestion in order to stimulate the release of gastrointestinal hormones such as GLP-1. Thus, effective treatment of patients with other contraindications can now be performed by administering compositions comprising biguanide compounds (including analogs, salts, solvates, polymorphs, hydrates, N-oxides, and prodrugs thereof) suitable for minimizing the systemic bioavailability of said compounds. In preferred embodiments, the subject compositions and methods are formulated to minimize and most preferably avoid initial release in the stomach and/or proximal small intestine (the region with the greatest absorption) in order to reduce systemic bioavailability upon oral administration.
Delivery to specific intestinal locations
Embodiments described herein provide a method of treatment comprising administering a delayed release composition comprising a biguanide compound (including any analog, salt, solvate, polymorph, hydrate, N-oxide and prodrug thereof) formulated for delivery to one or more sites of the small and/or lower and preferably distal small intestine, so as to treat a condition by avoiding absorption in the stomach and proximal small intestine and corresponding CmaxRapidly increasing to minimize systemic bioavailability.
The biguanide compound is targeted across the stomach to one or more regions of the small intestine and is preferably targeted to the downstream or distal duodenum. In preferred embodiments, the compounds are delivered to the jejunum, ileum, caecum and colon or combinations thereof. In preferred embodiments, the compounds are delivered to the jejunum, ileum and caecum or combinations thereof. In a preferred embodiment, the compound is preferably delivered to the ileum. In further embodiments, the compound is delivered downstream or distal of the jejunum or separately to the lower intestine.
In other embodiments, the biguanide compound (including analogs, salts, solvates, polymorphs, hydrates, N-oxides, and prodrugs thereof) is delivered to one or more regions of the upper intestine and one or more regions of the lower intestine. For example, the compounds may be delivered to the duodenum and colon. In another non-limiting example, the compounds can be delivered to the duodenum, jejunum, ileum, and colon.
Administration of a biguanide, such as metformin, to a preferred region or location of the intestine may be achieved by any known means. In a preferred embodiment, the biguanide compound is formulated in a delayed release composition for oral delivery of the compound to a targeted area or location of the intestine. When delivery of the biguanide compounds is targeted to two or more regions of the gastrointestinal tract, the compounds may be delivered in any ratio and manner.
Minimizing systemic exposure
As noted above, the methods disclosed herein minimize the systemic bioavailability of biguanide compounds in patients suffering from contraindications. In some embodiments, the biguanide compound has a reduced average systemic bioavailability. In some embodiments, the reduced average systemic bioavailability is a lower average systemic bioavailability compared to an immediate release or extended release formulation having an equivalent amount of the biguanide compound. In other embodiments, the reduced average systemic bioavailability is less than 30%, less than 25%, less than 15%, less than 10% and less than 5% compared to an immediate release or extended release formulation having an equivalent amount of the biguanide compound. In some cases, the average systemic bioavailability is less than 15%.
In some embodiments, the subject methods provide a mean plasma Cmax of the biguanide compound in a patient suffering from a contraindicationmaxAnd/or averagingAUC levels are minimized. In some embodiments, the method of administration results in minimal plasma absorption, mean C, of the biguanide compound in the patientmaxAnd/or mean AUC levels. In other embodiments, the mean plasma Cmax of the biguanide compoundmaxAnd/or average AUC levels with reports C for conventional immediate and extended release formulations with equivalent amounts of metforminmaxAnd/or AUC levels compared to that considered as sub-treatment of the composition. For example, negligible or sub-therapeutic metformin plasma CmaxAnd/or AUC levels include known metformin formulations (e.g.,
In particular embodiments, the inventive compositions and methods involving metformin produce no more than an equal dose of an immediate release metformin formulation after oral ingestion (e.g.,
Thus, in particular embodiments, administration of the subject delayed release formulations results in a mean plasma AUC, mean plasma C of the biguanide compound in a patient suffering from a contraindication as compared to the same regimen with an IR or XR formulation having an equivalent amount of the biguanide compoundmaxAnd/or circulating plasma concentrations are minimized. In one embodiment, the mean plasma AUC of the biguanide compound resulting from the administration0-∞Less than about 15,000ng h/mL or 14,000ng h/mL, preferably less than about 12,000ng h/mL, 11,000ng h/mL or 10,000ng h/mL, more preferably less than about 9,000ng h/mL, 8,000ng h/mL or 7,000ng h/mL. In one embodiment, the resulting biguanide compound has a mean plasma CmaxmaxLess than about 1000ng/mL, preferably less than about 900ng/mL or 800ng/mL, more preferably less than about 700ng/mL, 600ng/mL or 500 ng/mL. In one embodiment, the resulting circulating plasma concentration of the biguanide compound in a patient is less than about 5 μ g/ml or4 μ g/ml, preferably less than about 3 μ g/ml or 2.5 μ g/ml, more preferably less than about 2 μ g/ml, 1 μ g/ml, 0.5 μ g/ml or 0.25 μ g/ml. In a preferred embodiment, the biguanide compound is metformin and the IR composition isAnd the XR composition isXR。
Preparation
To limit its systemic bioavailability, the compositions comprising the biguanide compounds are suitable for delayed release in order to minimize plasma absorption. Delivery of biguanide compounds, such as metformin, to enteroendocrine cells is by any known method including, for example, oral, rectal, nasogastric tube, parenteral injection (e.g., intraluminal enteral injection). In a preferred embodiment, an oral dosage form is administered. Oral delivery of biguanide compounds is described in the delayed release formulation section and includes timed release systems, enteric coatings, and pH dependent systems among others. In some embodiments, the compositions comprising the compounds described herein utilize a multi-component system, wherein the biguanide compounds are delivered to several locations within the gastrointestinal tract, such as the duodenum, jejunum, ileum, lower intestine, or combinations thereof, following administration. For example, delayed release formulations comprising biguanide compounds may be delivered to the lower intestine by the use of timed or delayed (enteric) release components. The multicomponent system of such compounds may be in unit dosage form, e.g. in the form of a bi-or tri-or multi-layer tablet or multiparticulate form, e.g. encapsulated mini-tablets, granules or in separate dosage forms, e.g. separate tablets taken together or at periodic intervals.
In some embodiments, the delayed release formulation releases the biguanide compound after the onset of the desired pH due to the enteric coating. Contemplated phs include about pH 5.0 or about pH5.5, more preferably about pH6.0, about pH 6.5, and about pH 7.0. After the desired pH has started, the compound begins to be released. Such compositions may release the biguanide compound within about 15 minutes, about 20 minutes, about 25 minutes, or about 30 minutes after the onset of the desired pH and/or may have a timed, extended or slow release aspect that releases the biguanide compound over an extended period of time, such as about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours. In some embodiments, an exemplary two component delivery system can be a bilayer tablet. Three, four, and additional components are encompassed within the embodiments.
For delayed release formulations comprising a biguanide compound, the dose of the compound may range from about 1mg to about 2000mg, about 10mg to about 1500mg, about 50mg to about 1000mg or about 100mg or about 500mg per day. In some cases, the dose of the compound is about 2000mg, about 1500mg, about 1000mg, about 800mg, about 600mg, about 500mg, about 400mg, about 300mg, about 250mg, about 200mg, about 150mg, about 100mg, about 75mg, about 50mg, about 25mg, about 10mg, or about 1mg per day. In some embodiments, the dose of the compound is less than 400 mg. In some embodiments, the dose of the compound is 250 mg.
Salts of biguanide compounds include, but are not limited to, hydrochlorides, phosphates, sulfates, hydrobromides, salicylates, maleates, benzoates, succinates, ethanesulfonates, fumarates, glycolates, pamoates, orotates, acetates, isobutyrates, acetylsalicylates, nicotinates, amantades, zinc chlorophyllins, carboxylates, benzoates, dichloroacetates, theophylline-7-acetate, clofibrate, tartrates, oxalates, tannins, and hydroxy acid salts. In a preferred embodiment, the salt is metformin hydrochloride.
The biguanide compounds of the present invention may be advantageously administered or combined with other therapeutic agents, such as the anti-obesity and/or anti-diabetic agents described herein. Important agents for combination with the metformin compositions described herein include DPP-IV inhibitors (e.g., sitagliptin, saxagliptin, berberine, vildagliptin, linagliptin, alogliptin, etc.), SGLT-2 and/or SGLT-1 inhibitors (e.g., dapaflagliflozin, canaflozin, LX4211), GPR40, GPR120, GPR119, GPR41, GPR43, etc., agonists of thiazolidinediones (e.g., pioglitazone), rivoglitazone, rosiglitazone, troglitazone, etc.), ureas (e.g., pyrazine, gliclazide), gliclazide (gliclazide), gliclazide, chlorpyrizide, gliclazide, chlorpyride, chlorpyridazide, gliclazide, glibenclamide, gli, Dual PPAR agonists (aleglitazar, muraglitazar, tegaser, etc.), lipid lowering agents (e.g. statins) and antihypertensive agents.
Formulations for the compositions provided herein include those suitable for oral or rectal administration, and administration by the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more required ingredients.
Formulations suitable for oral administration may be presented as discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or anhydrous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
Formulations of the compositions which can be used orally include tablets made of gelatin, push-fit capsules and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, crospovidone, croscarmellose sodium) or lubricant, surfactant or dispersant. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may be optionally coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Tablets may optionally be provided with an enteric coating to provide release in parts of the intestine other than the stomach. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings for the purpose of identifying or characterizing different active compound dose combinations.
It will be appreciated that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may contain other agents conventional in the art having regard to the type of formulation in question, for example those compositions suitable for oral administration may contain flavouring agents.
The compositions described herein may also comprise the biguanide compound in a form suitable for oral use, for example, as tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents, as non-limiting examples, in order to provide pharmaceutically elegant and palatable preparations.
Delayed release formulation
Many strategies may be pursued to obtain delayed release, wherein the position of release is controlled in order to minimize systemic absorption. For example, delayed release may be achieved by appropriate selection of formulation parameters and ingredients (e.g., appropriate controlled release compositions and coatings). Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, and liposomes. Where an early release of the other combination therapeutic agent is preferred over the other, the release mechanism may be controlled such that the biguanide compound is released at certain time intervals or the site of release is controlled, the release of the combination agents may be simultaneous or a delayed release of the biguanide compound in the combination may be effected. The different delivery systems described herein may also be combined with release initiated at multiple time intervals (e.g., about 30 minutes, about 120 minutes, about 180 minutes, and about 240 minutes after oral administration) or at different locations (e.g., release at the lower intestine, upper intestine, jejunum, ileum, cecum, colon, and/or rectum), or combinations thereof. For example, a pH-dependent system may be combined with a timed release system or any other system described herein to achieve a desired release profile.
In certain embodiments, the biguanide compound is provided in a delayed release formulation in combination with a biguanide compound and/or an extended release component of an additional therapeutic agent in a unit dosage form. The extended release component may be formulated by any known method, such as a layer surrounding a portion of the delayed release component or the like. Exemplary ratios of extended release additional therapeutic agent to delayed release biguanide compound are about 10% XR to about 90% DR, about 15% XR to about 85% DR, about 20% XR to about 80% DR, about 25% XR to about 75% DR, about 30% XR to about 70% DR, about 35% XR to about 65% DR, about 40% XR to about 60% DR, about 45% XR to about 55% DR, or about 50% XR to about 50% DR. In certain embodiments, the ratio of extended release active agent to modified release active agent is about 25% XR to about 75% DR. In certain embodiments, the ratio of extended release active agent to modified release active agent is about 20% XR to about 80% DR. Unit dosage forms having XR and DR components include any known formulation, including bilayer tablets, coated pills, and the like.
In certain embodiments, the biguanide compound is provided in a unit dosage form in a delayed-release formulation in combination with an immediate-release component of an additional therapeutic agent. The immediate release component may be formulated by any known method, such as a layer surrounding a delayed release component or the like. Exemplary ratios of immediate release additional therapeutic agent to delayed release biguanide compound are about 10% IR to about 90% DR, about 15% IR to about 85% DR, about 20% IR to about 80% DR, about 25% IR to about 75% DR, about 30% IR to about 70% DR, about 35% IR to about 65% DR, about 40% IR to about 60% DR, about 45% IR to about 55% DR, or about 50% IR to about 50% DR. In certain embodiments, the ratio of immediate release active agent to delayed release active agent is about 25% IR to about 75% DR. In certain embodiments, the ratio of immediate release active agent to delayed release active agent is about 20% IR to about 80% DR. Unit dosage forms having IR and DR components include any known formulation, including bilayer tablets, coated pills, and the like.
Timed release system
In one embodiment, the delayed release mechanism is a "timed" or temporary release ("TR") system that releases the active agent, e.g., a biguanide compound, at some point after administration. Timed release systems are well known in the art and suitable timed release systems may comprise any known excipient and/or coating. For example, excipients in a matrix, layer, or coating may delay the release of the active agent by slowing the diffusion of the active agent into the environment. Suitable time-release excipients include, but are not limited to, acacia (gum arabic), agar, magnesium aluminum silicate, alginate (sodium alginate), sodium stearate, fucus, bentonite, carbomer, carrageenan, carbopol, cellulose, microcrystalline cellulose, carob gum, carrageenan, dextrose, furcellaran, gelatin, gum ghatti, guar gum, galactomannan, hectorite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, karaya gum, xanthan gum, glyceryl behenate (e.g., Compritol 888ato), glyceryl distearate (e.g., precrol ato 5), polyethylene glycol (e.g., PEG 200-4500), polyethylene oxide, adipic acid, tragacanth, ethylcellulose (e.g., ethylcellulose 100), Ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl methyl cellulose (e.g., KlOOLV, K4M, K15M), hydroxypropyl cellulose, poly (hydroxyethyl methacrylate), cellulose acetate (e.g., cellulose acetate CA-398-10NF), cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate butyrate, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, cellulose butyrate, cellulose nitrateOxidized polygelatins, pectins, polygeline, povidone, propylene carbonate, polyanhydrides, methyl vinyl ether/maleic anhydride copolymers (PVM/MA), poly (methoxyethyl methacrylate), poly (methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose (CMC), silicon dioxide, vinyl polymers (e.g., polyvinylpyrrolidone (PVP: povidone)), polyvinyl acetate, or polyvinyl acetate phthalates and mixtures, Kollidon SR, acryloyl derivatives (e.g., polyacrylates, such as crosslinked polyacrylates, methacrylic acid copolymers), and mixtures thereof,(dextrose, maltodextrin, and sucralose), or a combination thereof. The time release excipient may be in the matrix with the active agent, in another compartment or layer of the formulation, as part of a coating, or any combination thereof. Different amounts of one or more time release excipients may be used to achieve a specified release time.
One non-limiting example includesFormulation of the system. The controlled release formulation system provides modified temporary release (SyncroDose (TM)) as well as biphasic release
In some embodiments, the timed release system is formulated to begin release of the compound at about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 130 minutes, about 140 minutes, about 150 minutes, about 160 minutes, about 170 minutes, about 180 minutes, about 190 minutes, about 200 minutes, about 210 minutes, about 220 minutes, about 230 minutes, about 240 minutes, about 250 minutes, about 260 minutes, about 270 minutes, about 280 minutes, about 290 minutes, about 300 minutes, about 310 minutes, about 320 minutes, about 330 minutes, about 340 minutes, about 350 minutes, about 360 minutes, about 370 minutes, about 380 minutes, about 390 minutes, about 400, about 410, or about 420 minutes after administration. In embodiments with multiple releases, the timed release system is formulated to release at more than one time point. In certain embodiments, the timed release system is formulated to begin release at about 10 minutes, about 30 minutes, about 120 minutes, about 180 minutes, and about 240 minutes after administration. In certain embodiments, the timed release system is formulated to begin release at about 5 minutes to about 45 minutes, about 105 minutes to about 135 minutes, about 165 minutes to about 195 minutes, about 225 minutes to about 255 minutes, or a combination thereof, after administration to a patient.
Enteric coating and pH dependent system
The formulation may also be coated with an enteric coating, which may protect the active agent (e.g., biguanide compound) from degradation in acidic environments such as the stomach and allow delayed release into the targeted area (e.g., ileum) for ingestion.
Enteric coatings may be, as non-limiting examples, waxes or waxy materials such as carnauba wax, fatty alcohols, hydrogenated vegetable oils, zein, shellac, sucrose, gum arabic, gelatin, dextrin, psyllium husk powder, polymethacrylates, anionic polymethacrylates, mixtures of poly (methacrylic acid, methyl methacrylate), polymers or copolymers derived from acrylic acid and/or methacrylic acid esters, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose hexahydrophthalate, polyvinyl acetate phthalate, mixtures of poly (methacrylic acid, ethacrylic acid), mixtures of poly (methacylic acid, and, Ethyl cellulose, methyl cellulose, propyl cellulose, chitosan succinate, polyvinyl acetate phthalate (PVAP), polyvinyl acetate polymer carboxymethyl ethyl cellulose, and compatible mixtures thereof. In addition, an inactive intermediate film may be provided between the biguanide compound and the enteric coating to prevent the biguanide compound from interacting with the enteric coating.
In another non-limiting example, silicone microspheres for pH controlled gastrointestinal drug delivery have been manufactured by Carelli et al, int.j. pharmaceuticals 179: 73-83, 1999. The microspheres are prepared from different ratios of poly (methacrylic acid-co-methyl methacrylate) encapsulated in silicone microspheresL100 or
Enteric coatings may be formulated to release the biguanide compound at a desired pH using a combination of enteric polymers. It is well known that different locations of the gastrointestinal system have a specific pH. For example, the duodenum may correspond to a pH5.5 environment and the jejunum may correspond to a pH6.0 environment. In a preferred embodiment, the enteric coating is formulated to begin release of the compound at a desired pH, for example, in the distal small intestine and lower intestine (i.e., about pH6, about pH 6.5, or about pH 7). In embodiments with multiple releases, the enteric coating is formulated to begin release at two or more pH values. In certain embodiments, the enteric coating is formulated to begin release at pH6.0, pH 6.5, and pH 7.0. In certain embodiments, the enteric coating is formulated to begin release at pH 6.5 and pH 7.0. In certain embodiments, the enteric coating is formulated for release in the jejunum, ileum, and lower intestine. In other embodiments, the enteric coating is used in combination with other release systems, such as timed release systems.
In other embodiments, enteric coatings are used in combination with immediate release/extended release unit dosage forms. For example, a unit dosage form such as a bi-layer tablet of a biguanide compound with 20% IR/80% MR component may be coated with an enteric coating which releases at e.g. pH5.5, pH6.0, pH 6.5, pH7.0 such that the release is delayed until the dosage form reaches e.g. pH5.5, pH6.0, pH 6.5, pH7.0, thereby releasing the IR component immediately and the MR component according to its MR release properties. In some cases, enteric coatings are used in combination with immediate release/timed release unit dosage forms.
The microcapsule gastric retention systems described in U.S. patent nos. 6,022,562, 5,846,566, and 5,603,957 may be used in the delayed release delivery methods described herein. Microparticles of active agent or drug are coated by spraying with a material consisting of a mixture of a film-forming polymer derivative, a hydrophobic plasticizer, a functional agent, and a nitrogen-containing polymer. The resulting microcapsules have a size of less than or equal to 1000 micrometers (gm) and in some cases such microcapsules are between 100 micrometers and 500 micrometers. These microcapsules remain in the small intestine for at least 5 hours.
Film-forming polymer derivatives used in such microcapsules include, but are not limited to, ethyl cellulose, cellulose acetate, and water-insoluble cellulose derivatives. Nitrogen-containing polymers include, but are not limited to, polyacrylamides, poly-N-vinyl amides, poly-N-vinyl lactams, and polyvinylpyrrolidones. Plasticizers used in such microcapsules include, but are not limited to, glycerides, phthalates, citrates, sebacates, cetyl alcohol esters, castor oil, and cutin. Surfactants and/or lubricants used in such microcapsules include, but are not limited to, anionic surfactants, such as alkali or alkaline earth metal salts of fatty acids, stearic acid and/or oleic acid; nonionic surfactants, such as polyoxyethylene esters of sorbitan and/or polyoxyethylene derivatives of castor oil; and/or lubricants, such as stearates, e.g., calcium stearate, magnesium stearate, aluminum stearate, zinc stearate, stearyl fumarate, sodium stearyl fumarate, and glyceryl behenate.
One non-limiting example of a lower GI delivery formulation includes a tablet for lower GI delivery. The inner composition of the tablet comprises from about 0.01% to about 10.0% by weight of a suitable active ingredient; from about 50% to about 98% by weight of hydrocolloid gum, obtainable from higher plants; and about 2% to about 50% by weight of a pharmaceutically acceptable excipient, such as a binder. Other optional materials may be present which will help establish the desired characteristics of the pharmaceutical composition. These include materials that enhance absorption of the active ingredient in the lower GI, protect the active ingredient from degradation, prevent dissolution, and the like. Optionally surrounding the inner composition of the tablet is a coating of preferably enteric polymer material.
The formulation is designed to take advantage of: (1) protective characteristics of hydrocolloids obtainable from higher plants in the upper GI and (2) disintegrating characteristics of hydrocolloids in the lower GI. Thus, the inner composition of the tablet can be one of several designs: (a) it can be a matrix of a total homogeneously dispersed therapeutically effective amount of the active ingredient in combination with a high percentage of hydrocolloids and usually minor amounts of other excipients; (b) it may have a core in which the active ingredient is concentrated, surrounded by a layer of material free of active ingredient and having a high percentage of hydrocolloids and generally lesser amounts of other excipients; (c) it may have a concentration gradient of the active ingredient such that there is a greater amount in the core of the tablet, a lesser amount in the layers surrounding the core and little or no active ingredient in the outer layers. Regardless of whether the design of the tablet is of the above (a), (b) or (c), specificity for topical delivery into the lower GI is enhanced by enteric coating the tablet with an appropriate enteric coating material.
Suitable hydrocolloids are well known in the art. See, for example, "The chemistry of Plant Gums and Mucilages" by Smith and Montgomery, from A.C.S. monograph sequences, #141, 1959, Reinhold Publishing Co., and eighteenth edition of The Merck Index. Generally, the amount of hydrocolloid that can be used is that amount which allows the composition to pass through the upper GI tract without significantly disintegrating and without releasing significant amounts of the active ingredient in the upper GI tract (i.e., so as to provide a delayed release profile). Typically, the amount of hydrocolloid will be greater than about 50% but less than about 98%. Depending on individual variability (whether the patient is eating or fasting) and other factors, the tablet will pass through the stomach and upper intestinal tract in about 3 to 6 hours. During this time, a small amount of active ingredient (less than 20%, preferably less than 10%) is released from the tablets of the invention. Once the tablet reaches the lower GI, release of the active ingredient is triggered by enzymatic degradation of the galactomannan gum.
Modified release formulation
In other embodiments, the methods and compositions relating to biguanide compound delivery may further employ controlled-release, sustained-release or extended-release formulations, collectively referred to as "modified-release" formulations. The composition may be administered by a modified release system or by a delivery device known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809, respectively; 3,598,123, respectively; 4,008,719, respectively; 5,674,533, respectively; 5,059,595, respectively; 5,591,767, respectively; 5,120,548, respectively; 5,073,543, respectively; 5,639,476, respectively; 5,354,556, respectively; and those described in U.S. Pat. No.5,733,566. Such dosage forms may be used to provide the desired release profile using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof in varying proportions to provide modified release of one or more active ingredients. Suitable modified release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the present invention. The present invention thus encompasses single unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps (gelcaps), and caplets (caplets) that are further suitable for modified release.
In some embodiments, the modified-release system is formulated to release the compound over a sustained period of about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 130 minutes, about 140 minutes, about 150 minutes, about 160 minutes, about 170 minutes, about 180 minutes, about 190 minutes, about 200 minutes, about 210 minutes, about 220 minutes, about 230 minutes, about 240 minutes, about 250 minutes, about 260 minutes, about 270 minutes, about 280 minutes, about 290 minutes, about 300 minutes, about 310 minutes, about 320 minutes, about 330 minutes, about 340 minutes, about 350 minutes, about 360 minutes, about 370 minutes, about 380 minutes, about 390 minutes, about 400, about 410, or about 420 minutes after initiation of release. In embodiments with multiple releases, the modified release system is formulated to release over more than one duration at different time points.
In one non-limiting example, chitosan and mixtures of chitosan and sodium carboxymethyl cellulose (CMC-Na) have been used as vehicles for sustained release of active ingredients, such as Inouye et al, Drug Design and Delivery 1: 297, 305, 1987. Mixtures of these compounds with the combination agents of the present invention form tablets when compressed at 200kg/cm2 from which the active agent is slowly released upon administration to a patient. The release profile can be modified by varying the ratio of chitosan, CMC-Na and one or more active agents. Tablets may also contain other additives including lactose, CaHPO4 dihydrate, sucrose, crystalline cellulose or croscarmellose sodium.
In another non-limiting example, Baichwal, in U.S. patent No.6,245,356, describes a sustained release oral solid dosage form comprising agglomerated particles of an amorphous therapeutically active drug, a gelling agent, an ionizable gel strength enhancer, and an inert diluent. The gelling agent may be a mixture of xanthan gum and locust bean gum capable of crosslinking with the xanthan gum when the xanthan gum is exposed to an environmental fluid. Preferably, the ionizable gel enhancer is used to enhance the strength of the cross-linking between xanthan gum and locust bean gum and thus prolong the release of the pharmaceutical components of the formulation. In addition to xanthan gum and locust bean gum, acceptable gelling agents can be used, including those well known in the art. Examples include naturally occurring or modified naturally occurring gums such as alginates, carrageenans, pectins, guar gum, modified starches, hydroxypropylmethyl cellulose, methyl cellulose, and other cellulosic materials or polymers, such as sodium carboxymethyl cellulose and hydroxypropyl cellulose, and mixtures of the foregoing.
In another non-limiting formulation of a combination suitable for use in the present invention, Baichwal and stanifforth in U.S. patent No.5,135,757 describe free-flowing slow-release granules for use as pharmaceutical excipients comprising: from about 20% to about 70% by weight or more of a hydrophobic material comprising a heteropolysaccharide (e.g., xanthan gum or a derivative thereof) and a polysaccharide material capable of crosslinking with the heteropolysaccharide in the presence of an aqueous solution (e.g., galactomannan and most preferably locust bean gum); and from about 30% to about 80% by weight of an inert pharmaceutical filler (e.g., lactose, dextrose, sucrose, sorbitol, xylitol, fructose, or mixtures thereof). After mixing the excipients with the tricyclic compound/corticosteroid combination or combination of the present invention, the mixture is directly compressed into a solid dosage form such as a tablet. The tablets thus formed are capable of slow release of the drug when ingested and exposed to gastric fluid. By varying the amount of excipient relative to the drug, a slow release profile can be achieved.
Slow release formulations may also include coatings that are not readily soluble in water but are slowly attacked and removed by water or through which water can slowly permeate. Thus, for example, the combinations of the present invention may be spray coated with a binder solution under continuous fluidization conditions, as described by Kitamori et al, U.S. Pat. No.4,036,948. Examples of the water-soluble binder include pregelatinized starch (e.g., pregelatinized corn starch, pregelatinized white potato starch), pregelatinized modified starch, water-soluble cellulose (e.g., hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, dextrin, gum arabic and gelatin, and a binder soluble in an organic solvent (e.g., a cellulose derivative such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, ethyl cellulose).
In another non-limiting example, Villa et al, in U.S. Pat. No.6,773,720, describe a modified release system comprising an inner lipophilic matrix in which the active ingredient is entrapped and an outer hydrophilic matrix in which the lipophilic matrix is dispersed. The active ingredient, such as a biguanide or related heterocyclic compound, is first encapsulated within a low melting lipophilic excipient or mixture of excipients while heating to soften and/or melt the excipient itself for incorporation into the active ingredient by simple dispersion. After cooling at room temperature, an inert matrix is formed, the size of which can be reduced to obtain matrix granules containing active ingredient particles. The inert matrix particles are then mixed with one or more hydrophilic water-swellable excipients. In this regard, when the composition is contacted with a biological fluid, a highly viscous swelling layer is formed that coordinates with solvent molecules and acts as a barrier to penetration of the aqueous fluid itself into the new structure. The barrier antagonizes the initial "burst effect" caused by the dissolution of the active ingredient encapsulated within an inert matrix, which in turn is within a hydrophilic matrix. One commercially available system of this type is available from Cosmo Technologies Limited (italy) under the trade name Cosmo Technologies Limited
Formulations for upper intestinal delivery, lower intestinal delivery, or both are known in the art. Targeting of the active ingredient to different regions of the intestine is described, for example, below: the Encyclopedia of Pharmaceutical Technology, James Swarbrick and James Boylan, Inrma Health Care, 1999, p.287-308. Any suitable formulation for gastrointestinal delivery for site-specific delivery and/or specific temporal delivery (i.e., delayed, controlled, extended, or sustained release) may be used in the present invention and is included herein.
Any of the delivery systems described herein can be used in combination with other systems to achieve multiple releases and/or specific release profiles. In some embodiments, the biguanide compound is in a formulation that achieves multiple release at a site in the gastrointestinal tract after administration. In certain embodiments, the biguanide compound is in a multiple release formulation that begins release at about 10 minutes, about 30 minutes, about 120 minutes, about 180 minutes, about 240 minutes, or a combination thereof after administration. In certain embodiments, the biguanide compound is in a multiple release formulation that begins release at about 5 minutes to about 45 minutes, about 105 minutes to about 135 minutes, about 165 minutes to about 195 minutes, about 225 minutes to about 255 minutes, or a combination thereof after administration.
In certain embodiments, the biguanide compound is in a multiple release formulation that is released into the duodenum, jejunum, ileum, lower intestine, or a combination thereof following administration. In other embodiments, the biguanide compound is in a multiple release formulation that begins release at about pH5.5, about pH6.0, about pH 6.5, about pH7.0, or a combination thereof after administration. In other embodiments, the biguanide compound is in a multiple release formulation that releases after administration in the range of about pH 5.0 to about pH6.0, about pH6.0 to about pH7.0, about pH7.0 to about pH 8.0, or a combination thereof. In other embodiments, the biguanide compound is in a multiple release formulation that releases a small portion or a portion of the biguanide as an immediate release and the remainder of the compound by a delayed manner as described herein.
Oral dosage form
Oral dosage forms suitable for use in the subject compositions and methods include tablets, hard gelatin capsules, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol), as well as lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups or elixirs. Suitable oral dosage forms may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from, by way of non-limiting example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
Tablets contain the active ingredient in admixture with pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactic acid, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, crospovidone, croscarmellose sodium) or lubricant, surfactant or dispersant. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets are coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby minimize systemic bioavailability as more fully described herein.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier, for example polyethylene glycol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Alternatively, the push-fit capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings for the purpose of identifying or characterizing different active compound dose combinations.
It will be appreciated that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may contain other agents conventional in the art having regard to the type of formulation in question, for example those compositions suitable for oral administration may contain flavouring agents.
In various embodiments, the compositions provided herein are in liquid form. Liquid forms include, by way of non-limiting example, pure liquids, solutions, suspensions, dispersions, gums, foams, and the like. In some cases, the liquid form also contains a nutritional component or base (e.g., derived from milk, yogurt, milkshakes, or fruit juices). In some aspects, the compound is micronized or as nanoparticles in liquid form. In some cases, the compounds are coated to mask taste characteristics. In other cases, the compounds are coated to alter delivery to the intestine and colon.
Aqueous solutions or suspensions contain one or more active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide (e.g. lecithin), or a condensation product of an alkylene oxide with a fatty acid (e.g. polyoxyethylene stearate), or a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g. heptadecacyclooxyethyl hexadecanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g. polyoxyethylene sorbitol monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g. polyethylene sorbitan monooleate). The aqueous solution or suspension may also contain one or more preservatives (e.g., ethyl or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., sucrose, saccharin, or aspartame). In some cases, a flavoring agent is the compound.
Oily suspensions may be formulated by suspending the active ingredient or ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be prepared by adding an antioxidantAn oxidizing agent such as butylated hydroxyanisole or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous solution or suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already listed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
The composition may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil (for example, olive oil or arachis oil) or a mineral oil (for example, liquid paraffin or mixtures of these). Suitable emulsifying agents may be naturally-occurring phosphatides (e.g. soy bean lecithin), and esters or partial esters derived from fatty acids and hexitol anhydrides (e.g. sorbitan monooleate) and condensation products of the partial esters with ethylene oxide (e.g. polyoxyethylene sorbitan monooleate). The emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidants.
The compositions may also be formulated, for example, as rectal compositions such as suppositories or retention enemas, containing conventional suppository bases such as cocoa butter, polyethylene glycols or other glycerides. These compositions can be prepared by mixing the inhibitor with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of different molecular weights, and fatty acid esters of polyethylene glycols.
Accordingly, there is also provided a pharmaceutical composition comprising a biguanide compound in a delayed-release formulation suitable for oral administration, e.g. a tablet, capsule, cachet, pill, lozenge, powder or granule, solution, liquid or suspension. The pharmaceutical composition is preferably in unit dosage form suitable for single administration of a precise dose (e.g. 100mg, 200mg, 250mg, 300mg, 400mg, 500mg, 600mg, 750mg, 800mg or 1000mg) of the desired biguanide compound, in particular metformin, phenformin, buformin or imeglimin or a salt thereof. The pharmaceutical compositions may comprise the biguanide compounds according to the present invention in combination with a conventional pharmaceutical carrier or excipient and a crop active ingredient. They may further comprise other drugs or agents, carriers, adjuvants, etc.
Suitable carriers may include inert diluents or fillers, water, and various organic solvents. The composition may contain additional ingredients such as flavoring agents, binders, excipients, and the like, if desired. Thus, for oral administration, tablets containing various excipients such as citric acid may be employed together with various disintegrants (such as starch or other fibrous materials, alginic acid and certain complex silicates) and binding agents (such as sucrose, gelatin and acacia). Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are generally suitable for tableting purposes. Other agents such as inhibitors, surfactants or solubilizers, plasticizers, stabilizers, thickeners or film formers may also be added. Solid compositions of a similar type may be used in soft-filled and hard-filled gelatin capsules. The materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof.
Excipient
Any of the compositions or formulations described herein comprise any of the usual excipients in pharmacy and are selected based on compatibility with one or more active agents and the desired release profile properties of the dosage form. Excipients include, but are not limited to, binders, fillers, flow aids/glidants, disintegrants, lubricants, stabilizers, surfactants, and the like. A summary of the excipients described herein can be found, for example, in Remington: the Science and Practice of Pharmacy, nineteenth edition (Easton, PA: Mack Publishing Company, 1995); hoover, John E., Remington's pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975); liberman, H.A. and Lachman, L. eds., Pharmaceutical document Forms (New York, NY: Marcel Decker 1980); and Pharmaceutical document Forms and Drug Delivery Systems, seventh edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entirety.
The binder imparts adhesive properties and includes alginic acid and salts thereof; cellulose derivatives, such as carboxymethyl cellulose, methyl cellulose (e.g.,
Disintegrants help to break up or disintegrate oral solid dosage forms after administration. Examples of disintegrants include starches, e.g. native starches (e.g. corn or potato starch), pregelatinized starches (e.g. National 1551 or
A lubricant is a compound that prevents, reduces, or inhibits the adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid; calcium hydroxide; talc; sodium stearyl fumarate; hydrocarbons, e.g. mineral oil, hydrogenated castor oil or hydrogenated vegetable oil (e.g. hydrogenated soybean oil)
Flow aids or glidants improve the flow characteristics of the powdered mixture. Such compounds include, for example, colloidal silica, e.g.Tricalcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and micronized amorphous silicon dioxide
Plasticizers aid in coating of oral solid dosage forms. Exemplary plasticizers include, but are not limited to, triethyl citrate, triacetin (triacetin), acetyl triethyl citrate, polyethylene glycol (PEG 4000, PEG 6000, PEG 8000), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, diethyl sebacate, acetyl triethyl citrate, oleic acid, glyceryl monostearate, tributyl citrate, acetylated monoglycerides, glycerin, fatty acid esters, polypropylene glycol, dibutyl phthalate, and the like.
The above excipients are given as examples only and are not intended to include all possible options. Other suitable classes of excipients include colorants, granulating agents, preservatives, antifoaming agents, solubilizing agents, and the like. In addition, many excipients may have more than one role or function, or may be classified into more than one group; the categories are merely descriptive and are not intended to limit any use of a particular excipient.
Combination therapy
The compositions of the embodiments described herein can be co-administered with known therapeutic agents for the treatment of any of the conditions described herein. Co-administration may also provide an additive or synergistic effect, thereby causing a need for lower doses of known therapeutic agents, the compositions described herein, or both. Additional benefits of co-administration include reduced toxicity associated with any known therapeutic agent.
Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present. Thus, in some embodiments, the compositions described herein and known therapeutic agents are administered in a single treatment. In some embodiments, the resulting composition is mixed with a composition described herein and a known therapeutic agent. In some embodiments, the compositions described herein and known therapeutic agents are administered in separate compositions or administrations.
Administration of the compositions described herein and the known therapeutic agents described herein can be carried out by any suitable means. Administration of the compositions and second compounds described herein (e.g., a diabetes drug or an obesity drug) can be performed by any suitable means. If the composition described herein and the second compound are administered as separate compositions, they may be administered by the same route or by different routes. If the composition described herein and the second compound are administered in a single composition, they can be administered by any suitable route (e.g., oral administration). In certain embodiments, a combination of metformin or its analogs (including salts, solvates, polymorphs, hydrates, N-oxides or prodrugs thereof) and a second compound may be administered to the same region or to different regions of the gastrointestinal tract. For example, metformin or its analogs (including salts, solvates, polymorphs, hydrates, N-oxides or prodrugs thereof) may be administered in combination with an antidiabetic drug to be delivered to the duodenum, jejunum, ileum or colon.
Therapeutic agents, drugs, and compounds useful for treating hyperglycemia and/or diseases or conditions associated therewith (e.g., diabetes) may be administered with the compositions disclosed herein. Diabetes drugs and compounds include, but are not limited to, those that reduce triglyceride concentrations, reduce glucose concentrations, and/or modulate insulin (e.g., stimulate insulin production, mimic insulin, increase glucose-dependent insulin secretion, inhibit glucagon secretion or action, increase insulin action or insulin sensitizers, or in the form of exogenous insulin).
Drugs that reduce triglyceride levels include, but are not limited to, ascorbic acid, asparaginase, clofibrate, colestipol (colestipol), fenofibrate (fenofibrate) mevastatin (mevastatin), pravastatin (pravastatin), simvastatin (simvastatin), fluvastatin (fluvastatin), or omega-3 fatty acids. Drugs that reduce LDL cholesterol levels include, but are not limited to, clofibrate, gemfibrozil (gemfibrozil), and fenofibrate, nicotinic acid, mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, lovastatin, cholestyramine (cholestyrine), colestipol, or probucol.
In another aspect, the compositions of the embodiments described herein may be administered in combination with a hypoglycemic compound.
The drug classes of thiazolidinediones (also known as glitazones), sulphonylureas, meglitinides, biguanides, alpha-glucosidase inhibitors, DPP-IV inhibitors, and incretin mimetics have been used as adjunctive treatments for hyperglycemia and diabetes (type 2) and related diseases.
Drugs that lower glucose levels include, but are not limited to, glipizide, glibenclamide, exenatide
When administered sequentially, the combination may be administered in two or more administrations. In an alternative embodiment, it is possible to administer one or more biguanide compounds and one or more further active ingredients by different routes. The skilled artisan will also recognize that a variety of active ingredients may be administered in combination with one or more biguanide compounds, which compounds may be used to augment or synergistically enhance the controlled prevention, amelioration, palliation or treatment of obesity or an eating disorder or condition.
According to the methods provided herein, the disclosed compounds, when co-administered with at least one other obesity (or anti-obesity) or weight-reducing agent, can be: (1) co-formulated in a combined preparation and administered or delivered simultaneously; (2) delivered as separate formulations, alternately or in parallel; or (3) by any other combination treatment regimen known in the art. When delivered in alternation therapy, the provided methods may include administering or delivering the active ingredients sequentially, e.g., in the form of separate solutions, emulsions, suspensions, tablets, pills, or capsules, or by different injections through separate syringes. Typically, an effective dose of each active ingredient is administered sequentially (i.e., consecutively) during alternating treatments, while in simultaneous treatments, effective doses of two or more active ingredients are administered together. Intermittent combination therapies in various sequences may also be used.
In certain embodiments, the compositions provided herein may be used with other commercially available dietary supplements or other weight loss and/or anti-obesity agents, such as, by way of example, PYY and PYY agonists, GLP-1 and GLP-1 agonists, DPP-IV inhibitors, CCK and CCK agonists, exendin and exendin peptide agonists, GIP and GIP agonists, amylin and amylin agonists, ghrelin modulators (e.g., inhibitors), and leptin agonists. In certain instances, the compositions comprising the biguanide compounds provided herein are used in combination with an amylin, an amylin agonist, or a mimetic. Exemplary amylin agonists or mimetics include pramlintide and related compounds. In certain instances, the compounds and compositions provided herein are used in combination with leptin, a leptin agonist, or a mimetic. Additional leptin agonists or mimetics may be identified using the methods described in U.S. patent No.7,247,427, which is incorporated herein by reference. In other instances, the compounds and compositions provided herein increase leptin sensitivity and increase the efficacy of leptin, leptin agonists, or mimetics.
Other anti-obesity agents suitable for use in the subject methods include those agents currently being developed. Other anti-obesity agents include phentermine, fenfluramine, sibutramine, rimonabant, topiramate, zonisamide, bupropion, naltrexone, lorcaserin (lorcaserin) or related sympathomimetic agents, and orlistat or other intestinal lipase inhibitors, alone or in combination. Therapeutic agents, drugs, and compounds useful for the treatment of weight loss, binge eating, food addiction, and craving may be administered with the compositions described herein. For example, the patient may be further administered at least one other medication known to suppress hunger or control appetite. Such therapeutic agents and compounds include, but are not limited to, phentolamine (phenteramine), e.g.
As such, in one aspect, the compounds may be used as part of a combination therapy for the control, prevention, or treatment of obesity or an eating disorder or condition. Compounds useful as part of a combination therapy for treating obesity or weight loss include, but are not limited to: central nervous system agents that affect neurotransmitter or neuroion channels, including antidepressants (bupropion), norepinephrine reuptake inhibitors (GW320659), selective 5HT 2c receptor agonists, antiepileptics (topiramate, zonisamide), some dopamine antagonists, and cannabinoid-1 receptor antagonists (CB-1 receptor antagonists) (rimonabant); leptin/insulin/central nervous system pathway agents including leptin analogs, leptin transport and/or leptin receptor agonists, ciliary neurotrophic factor (Axokine), neuropeptide Y and agouti-related peptide antagonists, proopiomelanocortin and ***e and amphetamine-regulated transcription promoters,. alpha. -melanocyte-stimulating hormone analogs, melanocortin-4 receptor agonists, and agents affecting insulin metabolism/activity, such agents include protein-tyrosine phosphatase-1B inhibitors, peroxisome proliferator activated receptor-gamma receptor antagonists, short acting bromocriptine (ergoset), somatostatin agonists (octreotide), and adiponectin/Acrp 30(Famoxin or inducers of oxidative fatty acid metabolism); gastrointestinal nerve pathway agents including those that increase the pancreatic secretase peptide activity (CCK), PYY activity, NPY activity, and PP activity, increase glucagon-like peptide-1 activity (insulinotropic peptide 4, liraglutide, dipeptidyl peptidase IV inhibitors), and those that decrease ghrelin activity, and amylin analogs (pramlintide); agents that increase the rate of resting metabolism (selective 3-3 stimulators/agonists, uncoupled protein homologs, and thyroid receptor agonists); other more diverse agents including hormone antagonists of melanin concentration, phytostanol analogs, functional oils, P57, amylase inhibitors, growth hormone fragments, synthetic analogs of dehydroepiandrosterone sulfate, antagonists of adipocyte 11B-hydroxysteroid dehydrogenase type 1 activity, corticotropin releasing hormone agonists, inhibitors of fatty acid synthesis (cerulenin and C75), carboxypeptidase inhibitors, indanone/indanol, aminosterols (trodusquine)/troducamine), and other gastrointestinal lipase inhibitors (ATL 962); amphetamines, such as dextroamphetamine; other sympathomimetics include phentermine, benzyltolylpropylamine, phendimetrazine, mazindol, and diethylpropion.
Other compounds include ecopipam (ecopipam); gastrointestinal hormone (OM); a glucose-dependent insulinotropic polypeptide (GIP) inhibitor; gastrin releasing peptide; neuromedin B; enterostatin; bupropion, SR-58611; CP-045598; AOD-0604; QC-BT 16; rGLP-1; 1426 (HMR-1426); n is a radical of
In some embodiments, compounds for use in combination with the biguanide compound-containing compositions provided herein include rimonabant (rimonabant), sibutramine, orlistat, PYY or an analog thereof, a CB-1 antagonist, leptin, phentermine, and an insulinotropic peptide analog. Exemplary dosage ranges include phentermine resin (30 mg in the morning), fenfluramine hydrochloride (20mg, three times daily), and a combination of phentermine resin (15 mg in the morning) and lorcaserin (30 mg before the evening meal), and sibutramine (10mg-20 mg). Weintraub et al (1984) ara. lnn. med.144: 1143-1148.
In further embodiments, compounds for use in combination with the compositions provided herein include
In some embodiments, the compositions provided herein are used as an adjunct to bariatric surgical procedures. Bariatric surgery is a procedure for reducing weight and involves alterations of the gastrointestinal tract, and includes such procedures as: gastric banding, sleeve gastric volume reduction, GI bypass procedures (e.g., roux Y, biliary-duodenal, gastric bypass), intragastric balloon, vertical banding, gastroplasty, endoluminal sleeve placement, pancreaticobiliary diversion, and the like. In certain instances, the compositions provided herein are an adjunct to gastric banding. In some cases, the composition is an adjunct to the GI bypass procedure. In other instances, the compositions provided herein are adjuncts to gastric sleeve volume reduction. In certain embodiments, the compositions provided herein are administered prior to an obesity treatment procedure as an adjunct to obesity treatment surgery. In certain embodiments, the compositions provided herein are administered after an obesity treatment procedure as an adjunct to obesity treatment surgery. In certain instances, when used as an adjunctive therapeutic agent, the dosages and amounts of the compositions provided herein can be adjusted as needed for the obesity treatment procedure. For example, the amount of a composition provided herein administered as an adjunctive therapeutic to an obesity treatment procedure may be reduced by half the normal dose or as directed by a pharmaceutical specialist.
Combination therapy can be used, for example, to modulate metabolic syndrome (or to treat metabolic syndrome and its associated symptoms, complications, and conditions), wherein the compositions provided herein can be effectively used, in combination with an active agent, such as discussed above, to modulate, prevent, or treat diabetes, obesity, hyperlipidemia, atherosclerosis, and/or their corresponding associated symptoms, complications, and conditions.
Methods for evaluating treatment
Evaluation of diabetes treatment
The effect of biguanide compound therapy of the present invention on the aspects of diabetes can be assessed according to methods of treatment of diabetic patients known in the art and generally practiced by physicians.
The efficacy of treatment of diabetes/metabolic syndrome and diabetes-related conditions using the compositions and methods described herein can be assessed using assays and methods known in the art. As an example, quantitative determination of renal function and parameters of renal dysfunction are well known in the art. Examples of assays for determining renal function/dysfunction include serum creatinine levels; creatinine clearance; cysteine protease inhibitor (cystatin) C clearance rate, 24-hour urinary creatinine clearance, 24-hour urinary protein secretion; glomerular Filtration Rate (GFR); urinary Albumin Creatinine Ratio (ACR); albumin Excretion Rate (AER); and renal biopsy.
The quantitative determination of pancreatic function and parameters of pancreatic dysfunction or pancreatic insufficiency are well known in the art. Examples of assays for determining pancreatic function/pancreatic dysfunction include assessing pancreatic function using biological and/or physiological parameters, such as assessing size, growth and/or secretory activity, beta-cell size, growth and/or secretory activity, insulin secretion and circulating blood levels, blood glucose levels, pancreatic imaging, and pancreatic biopsy, glucose uptake studies by oral glucose challenge, assessment of cytokine properties, blood gas analysis, tissue blood perfusion range, and angiogenesis within tissues.
Other assays for treating diabetes and diabetes-related conditions are known in the art and are included herein.
Evaluation of treatment of weight loss, obesity and eating disorders
In the treatment of obesity, it is desirable to have a reduction in the weight and/or fat of the patient. By weight loss is meant that the patient loses a portion of his/her total body weight during the course of treatment (whether the course of treatment is daily, weekly, monthly or yearly). Alternatively, weight loss may be defined as a decrease in the ratio of fat mass to lean mass (in other words, the patient has reduced fat mass but maintained lean mass or increased lean mass without a corresponding reduction in total body weight). The therapeutically effective amount of the biguanide compound administered in this embodiment is an amount effective to reduce the weight of the patient during the course of therapy or alternatively an amount effective to reduce the percentage of the fat mass of the patient during the course of therapy. In certain embodiments, the patient's body weight is reduced by at least about 1%, at least about 5%, at least about 10%, at least about 15%, or at least about 20% during the course of treatment. Optionally, the mass percentage of fat in the patient is reduced by at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% during the treatment.
Total body weight and fat content can be measured at the end of the meal time. In rats, a frequently used method of determining total fat is to surgically remove the retroperitoneal fat pad, which is the body of fat located in the retroperitoneal cavity, which is the area between the posterior abdominal wall and the posterior peritoneal wall layer, and weigh the retroperitoneal fat pad. Pad weight is believed to be directly related to the body fat percentage of the animal. Since the relationship between body weight and body fat in rats is linear, obese animals have a correspondingly higher percentage of body fat and retroperitoneal fat pad weight.
In embodiments in which methods of treating, reducing, or preventing a patient's cravings are provided, cravings may be measured by using questionnaires known in the art or established by those studying cravings. This questionnaire preferably ranks the level of craving on a numerical scale, where the ranking is 0 if the patient has no craving, and 10 if the patient has severe craving (if the scale is 1 to 10). The questionnaire also preferably includes questions such as the type of food desired by the patient. Binge eating may be determined or measured by using a questionnaire and Binge Eating Scale (BES). Binge severity can be divided into three categories (mild, moderate and severe) based on the total BES score (calculated by summing the scores for each individual item). Accordingly, methods are provided for reducing the patient's BES score comprising administering to a patient in need thereof a compound treatment in an amount effective to reduce the patient's BES score. In some embodiments, administration of the compound treatment alters the patient's BES category, e.g., from severe to moderate, severe to mild, or moderate to mild.
Pre-treatment evaluation of hormonal characteristics of a patient
In some embodiments, the expression of metabolic hormones in a patient is previously assessed using the methods described herein. Thus, a therapeutic agent provided to an individual may target his or her particular needs. In embodiments, the hormonal characteristics of the patient are pre-evaluated and certain defined amounts of the compound/metabolite combination are administered according to the changes that the physician desires to achieve. The evaluation process can be repeated and the treatment adjusted accordingly during or at any time after the treatment.
Hormone assay
In embodiments, the level of hormones determined in conjunction with the methods of the invention, including but not limited to GLP-1, GLP-2, GIP, gastrointestinal hormone, PYY, CCK, active glucagon, insulin, glucagon, ghrelin, amylin, uroguanylin, C-peptide and/or combinations thereof, is measured according to standard methods described in the literature. For example, proteins can be measured by immunological assays and transcripts measured by nucleic acid amplification techniques. Functional assays as described in the art may also be used where appropriate. In embodiments, the sample assayed includes cultured cells, a patient cell or tissue sample, a patient bodily fluid (e.g., blood or plasma), and the like. Similarly, the level of an analyte (e.g., glucose, triglycerides, HDL, LDL, apoB, etc.) determined in conjunction with the methods of the invention is detected according to any known method.
For example, immunofluorescence can be used to measure GLP-1. Cells can be grown to confluent monolayers on matrigel-covered coverslips in 12-well plates at 37 ℃, fixed in 4% paraformaldehyde in Phosphate Buffered Saline (PBS) and incubated with primary antisera (e.g., rabbit anti-alpha gustducin, 1: 150; Santa Cruz Biotechnology, and rabbit anti-GLP-1, Phoenix) overnight at 4 ℃, followed by permeabilization with 0.4% Triton-X in PBS for 10 minutes and blocking at room temperature for 1 hour. Three washing steps were then performed with blocking buffer and the appropriate secondary antibody (AlexaFluor488 anti-rabbit immunoglobulin, 1: 1000; Molecular Probes) was applied for 1 hour at room temperature. After three washing steps, cells can be fixed in Vectashield medium and immunofluorescence can be seen.
GLP-1RNA isolated from cells can be determined using RT-PCR. Isolation of RT-PCR RNA from cells can be performed using standard methods. RT-PCR reactions can be carried out in a Peltier thermal Cycler (PTC-225DNA Engine tetra Cycler; MJ Research) in 50pl volumes using published primer sequences (Integrated DNA Technologies). Reverse transcription can be performed at 50 ℃ for 30 minutes; after an initial activation step at 95 ℃ for 15 minutes. PCR was performed by 40 cycles of denaturation at 94 ℃ for 1min, annealing at 55 ℃ for 1min and extension at 72 ℃ for 1min, followed by a final extension step at 72 ℃ for 10 min. Negative controls may be included where appropriate, for example by replacing omitted reverse transcriptase or template with water. The control may be RNA isolated from, for example, rat tongue epithelial cells. The PCR product could be isolated in a 2% agarose gel with ethidium bromide and be visible under UV light.
In the art, there may be mentioned, for example, Laferre et al, 2007, "increasing Levels and Effect Markedly Enhanced 1 Month after Roux-en-Y gaming Bypass Surgery in Obese Patients with Type 2Diabetes, Diabetes Care30 (7): 1709A Radioimmunoassay (RIA) of total GLP-1 in patient blood samples was performed as described in 1716 (using commercially available materials from PhoenixPharmaceutical, Belmont, Calif.). The authors describe measuring the effect of GIP and GLP-1 on insulin secretion by measuring the difference in insulin secretion (area under the curve or AUC) in response to the oral glucose tolerance test and the heteroglycemic venous blood glucose test.
By e.g. Toft-Nielsen et al, 2001, "derivatives of the amplified characterization of glucose-Like Peptide-1in Type 2diabetes Patients," J.Clin.End.Met.86 (8): 3717-3723 describe plasma concentration measurements of GLP-1, GIP, glucagon, insulin, C-peptide, pancreatic peptide, unesterified fatty acids, glutamate decarboxylase antibodies, and islet antigen antibodies. The authors describe the use of a radioimmunoassay for GLP-1 to measure the plasma concentration of amidated GLP-1- (7-36) with antibody number 89390. This assay measures the total amount of GLP-1- (7-36) and its metabolite GLP-1- (9-36). The authors describe GIP measurements using the C-terminal directed antibody number R65(RIA) which is 100% reactive with human GIP and not 100% reactive with 8-kDA GIP.
GLP-1 and PYY can be determined directly in the supernatant from the venous effluent as described, for example, by Claustre et al (1999, "Stulantory effect of (3-acquired antibodies on the L cell section correlation and modulation by a-acquired interaction, J.Endocrins.162: 271-8) (see also, Plaisance 'et al, 1994," Regulation of glucose-lipid-1- (7-36) amino secretion by intracellular secretion peaks and isolated peptide in the isolated peptide reaction, Endocrinology: 135 2398-2403 and isolated peptide' et al, 1995, "polypeptide by assay Y1-9) antibody was used in the dilution of GLP-peptide 31-37, Glycine-11-199 in the assay peptide reaction, Glycine-1-199, Glycine-11-1-11-9-1-11-9-1-37-11-1-7-37-11-2-1-7-9-11-1-7-1-7-9-one-1-one-1-7-one, 84% with GLP-1- (1-36) amide and less than 0.1% with GLP-1- (1-37), GLP-1- (7-37), GLP-2, and pancreatic hyperglycemia. PYY was determined using A4D anti-porcine PYY antiserum in a 1: 800000 dilution.
Methods for determining GLP-1 and GIP are also described elsewhere in the art, for example by Jong et al, PNAS, 2007, etc.
Radioimmunoassays can also be used to determine PYY in blood, such as, for example, by Weickert et al, 2006, "Soy isovitamins in capillary precursor YY (PYY), but have no effect on ghrelin and body weight in height postbiological gene, Journal of biological resources in BioMedicine, 5: 11, as described above. Blood was collected in ice-cold EDTA tubes for analysis of glucose, ghrelin, and PYY. Followed by centrifugation at 1600g for 10 min at 4 ℃ and aliquots were immediately frozen at-20 ℃ until assayed. All samples from individual patients were measured in the same assay. The total amount of immunoreactive ghrelin measured as described by the authors was measured by a commercially available radioimmunoassay (Phoenix Pharmaceuticals, Mountain View, Calif., USA). (see also, Weickert et al, 2006, "real fiber improves hold-body inertia in overhead and organism watch," Diabetes Care 29: 775-780). The total amount of immunoreactive human PYY was measured by a commercially available radioimmunoassay (LINCO Research, Missouri, USA), using 125I-labelled bioactive PYY as tracer and PYY antiserum to determine the level of active PYY via the diabody/PEG technique. PYY antibodies in guinea pigs raise and recognize both PYY 1-36 and PYY 3-36 (active) forms of human PYY.
SGLT-1 (intestinal sodium-dependent glucose transporter 1) is a protein involved in supplying glucose to the body. It has been reported that it is expressed in response to sugars in the intestinal lumen by a pathway involving T1R3 (Margolskee et al, 2007 "T1R 3 and gustducin in gut sense sugar to regulation expression of Na + -
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