HK1116077B - Roflumilast for the treatment of diabetes mellitus - Google Patents
Roflumilast for the treatment of diabetes mellitus Download PDFInfo
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- HK1116077B HK1116077B HK08106441.4A HK08106441A HK1116077B HK 1116077 B HK1116077 B HK 1116077B HK 08106441 A HK08106441 A HK 08106441A HK 1116077 B HK1116077 B HK 1116077B
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Description
Technical Field
The present invention relates to the use of roflumilast, the pharmaceutically acceptable salts thereof, the N-oxides thereof and the pharmaceutically acceptable salts of the latter for the treatment of type 2 diabetes, type 1 diabetes and for the prevention and/or inhibition of the development of diabetic complications.
Furthermore, the invention relates to the combination of roflumilast, the pharmaceutically acceptable salts thereof, the N-oxides thereof and the latter pharmaceutically acceptable salts with one or more other active compounds for the treatment of type 2 and/or type 1 diabetes, to pharmaceutical compositions, combination products and kits comprising these combinations, and to the use of these combinations for the treatment of type 2 and/or type 1 diabetes.
Background
In international patent application WO99/14239, compositions for the treatment of diabetes and obesity are disclosed. The composition contains at least two active ingredients A, B and C, wherein A is at least one hormone that stimulates cAMP production, B is at least one substance that inhibits the breakdown of cyclic nucleosides, and C is at least one hormone that stimulates cGMP production. In international patent application WO01/35979, PDE3 and PDE4 inhibitors are disclosed for the treatment of obesity. In international patent application WO02/13798, the use of selective cGMP PDE5 inhibitors for the treatment of insulin resistance syndrome is disclosed, wherein insulin resistance syndrome is defined as the concomitant presence of two or more disease states selected from dyslipidemia, hypertension, type 2 diabetes, impaired glucose tolerance, a family history of diabetes, hyperuricemia and/or gout, procoalgulant state, atherosclerosis and trunk obesity. Tetrahydropyridin-3-one derivatives are disclosed in the unexamined German application DE 10150517, which are useful, inter alia, for the treatment of diabetes. Pentoxyphylline and rolipram are disclosed to be effective in treating autoimmune diabetes or other conditions that overproduce inflammatory cytokines in diabetes 47, pp.570-575, 1998.
Diabetes is on the rise throughout the world and is considered by the world health organization to be at the epidemic level. The clinical manifestations and progression of diabetes typically alternate between locations and often vary among nationalities of the same country. Diabetes now affects 1.51 million people worldwide, and is estimated to reach 3 million people in 2025. There are two main types of diabetes. Type 1 (insulin-dependent diabetes mellitus, IDDM) is due to a complete deficiency of insulin due to the destruction of pancreatic β -cells initially mediated by autoimmunity. It is the second most common chronic disease in children. In response, type 2 (non-insulin dependent diabetes mellitus, NIDDM) is characterized by insulin resistance and incomplete insulin secretion. A significant portion of individuals who are otherwise diagnosed with type 2 diabetes will develop over time into a type 1 state, which is defined as exhibiting anti-beta-cell autoimmunity.
Since genetic factors contribute to the development of diabetes, the disease exhibits a strong familial aggregation. Although there is a monogenic syndrome of insulin resistance, which has been identified as the exact gene responsible for insulin resistance, they are quite rare. The more commonly occurring forms of diabetes are produced by multiple genes. In addition, there are behavioral lifestyle-related risk factors. Type 2 diabetes is increasingly common due to the prevalence of sedentary lifestyle and obesity. One of the major arguments for the role of behavioral factors in the etiology of diabetes in the population experiencing rapid westernization is the rapid increase in prevalence. This westernization shift is often accompanied by increased obesity, decreased physical activity and dietary intake tending to more changes in calories, fat and non-complex (non-complex) carbohydrates.
Despite wide fluctuations in blood glucose in human supply (e.g., meals) and demand for nutrients (e.g., exercise), blood glucose concentrations are generally maintained within a fairly narrow range. After an overnight fast, insulin-independent tissues, brain (50%) and internal organs (25%) occupy the body to process the maximum amount of total glucose. Insulin-dependent tissue, adipose tissue and major skeletal muscle are responsible for the utilization of the remaining 25% of glucose. These basic glucose intakes are precisely matched by the release of glucose from the liver. In response to postprandial hyperglycemia, insulin secretion from the pancreas is stimulated, and the combination of hyperinsulinemia plus hyperglycemia promotes glucose uptake (through visceral and peripheral, major muscles, tissues) and inhibits hepatic glucose production. Thus, in close time, defects at the beta-cell, muscle, liver levels lead to the development of glucose tolerance and diabetes. All abnormalities in diabetes are essentially due to an imbalance between insulin sensitivity and insulin secretion. The initial stage of diabetes is characterized by impaired glucose tolerance and postprandial hyperglycemia. As the disease progresses, fasting hyperglycemia can be observed.
The earliest detectable abnormality in NIDDM is the impairment of the body's ability to respond to insulin. Since the pancreas can appropriately increase the secretion of insulin to compensate for insulin resistance, glucose tolerance remains normal. But over time, beta cells fail to maintain a high rate of insulin secretion, insulin resistance leads to impaired glucose tolerance and eventually to the development of overt diabetes. The cause of pancreatic "failure" is still unknown. In NIDDM insulin resistance is involved in the liver and peripheral tissues. Failure to normally inhibit hepatic glucose production and reduce uptake by muscle tissue in response to endogenous secretion or exogenous administration of insulin. The accelerated rate of hepatic glucose output is mainly due to an increase in gluconeogenesis. Many cellular defects in muscle in insulin action have been described as including impaired insulin receptor tyrosine kinase activity, reduced glucose turnover, and decreased glycogen synthase and pyruvate dehydrogenase activity. The causes of disorder abnormalities are intracellular glucose clearance, glycogen synthesis and oxidation of glucose in two major pathways. In the earliest days of NIDDM, the major defect involved the inability to promote insulin secretion and glycogen storage. Other potential mechanisms that have been proposed to explain glucose resistance include increased levels of free fatty acids, activation of the chronic low-grade immune system (increased levels of TNF α and IL 6), alterations in skeletal muscle blood flow, increased rates of conversion of dextrins to their insoluble amyloid, and glucose toxicity.
Diabetes is associated with a number of physiological diseases such as hypertension and dyslipidemia. Diabetes also increases the risk of macrovascular (coronary artery disease, stroke, amputation) and microvascular (blindness, renal failure, neuropathy) disease. Myocardial infarction, stroke, or renal failure are the cause of death in 70% of diabetic patients. The massive mortality rate of diabetic-related neuropathy failure indicates the importance of active drug intervention.
There are many ways to combat diabetes. The first is to adjust lifestyle for improvement of endogenous insulin sensitivity. This can be achieved by increasing physical activity and reducing body weight through changes in diet and behavior. Unfortunately, many non-insulin dependent diabetics have never received adequate nutritional education or been unable to follow a strict dietary regimen.
Another treatment method involves increasing the effectiveness of insulin by administering exogenous insulin, insulin analogs, and insulin secretagogues, such as sulfonylureas. The primary mode of action of sulfonylureas is depolarization of pancreatic β -cells by blocking ATP-dependent potassium channels and initiating calcium influx, which can stimulate insulin secretion. The most frequently occurring side effect of insulin, insulin analogs and insulin secretagogues is hypoglycemia. Since insulin not only increases the uptake of blood glucose but also promotes the synthesis and storage of lipids, an increase in body weight is also a concern.
Metformin, the most commonly used of biguanides, has also proven to be effective against hyperglycemia. Metformin reduces hepatic gluconeogenesis and essential hepatic glucose output. A serious side effect is lactic acidosis. Other common side effects of metformin are nausea and anorexia. Oral antidiabetic agents such as thiourea and metformin have been shown to lower fasting blood glucose levels in monotherapy or in combination therapy, but continue postprandial hyperglycemia in 60% of patients and may continue to increase hemoglobin A1CThe level of (c).
Alpha-glucosidase inhibitors, such as acarbose and miglitol, are primarily targeted at postprandial hyperglycemia. The treatment of diabetes with alpha-glucosidase inhibitors is based on delayed intestinal degradation of starch and glucose. These carbohydrates must be hydrolyzed by alpha-glucosidase to monosaccharides before they are transported through the small intestinal mucosa. This reversible inhibition of brush border glucosidase results in a redistribution of carbohydrate absorption from the digestive tract to the upper part of the surface area that covers the greater extension of the entire length of the small intestine. This is achieved by delayed absorption of monosaccharides and reduction of plasma glucose that increases after meals. The most common side effects of α -glucosidase inhibitors are carbohydrate malabsorption and gastrointestinal distress symptoms.
Another class of diabetes drugs are thiazolidinediones, such as rosiglitazone and pioglitazone, which are insulin activators and act through peroxisome activation of the proliferator receptor gamma (PPAR). PPAR γ is mainly expressed in adipose tissue, and plays an important role in adipogenesis and fatty acid synthesis and storage modification. Binding of rosiglitazone to PPAR γ results in decreased endogenous glucose production and increased blood glucose uptake. It increases the sensitivity of skeletal muscle, liver and adipose tissue to insulin. The improved glucose metabolism associated with treatment with rosiglitazone is most likely due to a reduction in free fatty acid metabolism in plasma. Stimulation of PPAR γ rosiglitazone in adipose tissue and subsequently adipose differentiated cells results in more insulin-sensitive adipocytes producing more but very little, and less free fatty acids, TNF α and leptin. The most common side effects of rosiglitazone are anemia, edema and weight gain.
Detailed Description
It is an object of the present invention to overcome some or all of the above mentioned disadvantages, such that a pharmaceutical composition for the treatment of diabetes, in particular type 2 diabetes, is effective.
Treatment of diabetes is surprisingly accomplished using a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof.
Or a pharmaceutically acceptable salt thereof
Or a pharmaceutically acceptable salt thereof
The international non-proprietary name (INN) for the compound of formula 1.1 is roflumilast [ 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloropyridin-4-yl) benzamide ].
The compound of formula 1.2 is roflumilast-N-oxide [ 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloro-1-oxo-pyridin-4-yl) benzamide ].
The preparation of roflumilast, its pharmaceutically acceptable salts and its N-oxides, as well as the use of these compounds as PDE 4-inhibitors, is described in international patent application WO 95/01338.
The term "pharmaceutically acceptable salts" is included to mean non-toxic salts of the compounds of formula 1.1 or 1.2 which are typically prepared by reacting a suitable organic or inorganic acid with the free base or by reacting a suitable organic or inorganic base with an acid. Mention may in particular be made of the pharmacologically acceptable salts of inorganic and organic acids, i.e. the salts used in the pharmaceutical technology. Those suitable are especially water-soluble and water-insoluble acid addition salts with acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, pamoic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid. Examples of pharmaceutically acceptable base salts which may be mentioned are lithium, sodium, potassium, calcium,Aluminium, magnesium, titanium, ammonium, meglumine or guanidineAnd (3) salt.
It will be appreciated that the compounds of formula 1.1 and formula 1.2 and their pharmaceutically acceptable salts may exist in the form of their pharmaceutically acceptable solvates, and in particular their hydrates.
In the term "type 2 and/or type 1 diabetes mellitus and diabetic complications", type 2 diabetes mellitus stands for non-insulin dependent diabetes mellitus (NIDDM) and type 1 diabetes mellitus stands for Insulin Dependent Diabetes Mellitus (IDDM). Commonly associated with type 2 diabetes is one or more of metabolic syndrome, obesity, insulin resistance, dyslipidemia, and pathological glucose tolerance (pathological glucose tolerance). Patients with type 2 and/or type 1 diabetes develop changes in the degree of increase in blood pressure, increased levels of cholesterol and/or triglycerides, increased levels of uric acid, and increased levels of procoagulant factors. Diabetic complications are therefore hypertension, hyperlipidemia, hyperuricemia, gout and hypercoagulability, i.e. an abnormally increased tendency to form blood clots in the blood vessels. These conditions are also considered to be risk factors for atherosclerotic large vessels, as are microvascular diseases. Atherosclerotic macrovascular disease includes myocardial infarction, stroke, and amputation. Microvascular diseases include blindness, kidney disease and neurasthenia.
The term "effective amount" refers to a therapeutically effective amount for treating type 2 and/or type 1 diabetes and preventing and/or inhibiting the development of diabetic complications. In the case of combination therapy, an "effective amount" refers to the total amount of the combination subject that is effective in treating type 2 and/or type 1 diabetes.
"patient" includes humans and other mammals.
It has now been found that compounds of formula 1.1 and/or compounds of formula 1.2 reduce postprandial hyperglycemia and fasting hyperglycemia.
It is superior to insulin secretagogues, biguanides and glucosidase inhibitors that improve fasting or postprandial hypertension alone. In contrast to insulin and insulin secretagogues, the compounds of formula 1.1 and/or the compounds of formula 1.2 do not induce hypoglycemia.
Accordingly, a first aspect of the present invention is the use of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of type 2 and/or type 1 diabetes.
A further aspect of the invention is the use of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of type 2 and/or type 1 diabetes and for the prevention and/or inhibition of the development of diabetic complications.
Another aspect of the present invention is the use of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of a disorder selected from metabolism, obesity, insulin resistance, dyslipidemia, and pathological glucose tolerance (pathological glucose tolerance).
The present invention further relates to a method of treating type 2 and/or type 1 diabetes comprising administering to a patient in need thereof an effective amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating type 2 and/or type 1 diabetes and preventing and/or inhibiting the development of diabetic complications, comprising administering to a patient in need thereof an effective amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention relates to a method of treating a disorder selected from metabolism, obesity, insulin resistance, dyslipidemia, and pathological glucose tolerance (pathological), comprising administering to a patient in need thereof an effective amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention is a method of reducing postprandial hyperglycemia comprising administering to a patient in need thereof a prolonged effective amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention is a method for reducing fasting hyperglycemia, comprising administering to a patient in need thereof an effective amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof for an extended period of time.
The present invention also relates to methods of reducing postprandial hyperglycemia and fasting hyperglycemia comprising administering to a patient in need thereof for an extended period of time an effective amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof.
The term "extended time" means at least 3 days of repeated administration of the active ingredient, more preferably at least 5 days, most preferably at least 10 days.
The invention further relates to ready-to-use pharmaceutical compositions containing as active compound(s) (═ therapeutic agent) a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof, and additionally containing evidence of the fact that the ready-to-use pharmaceutical compositions can be used for the treatment of type 2 and/or type 1 diabetes and diabetic complications.
Administration, dosage form and dose of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof for monotherapy:
roflumilast, roflumilast-N-oxide, or a pharmaceutically acceptable salt thereof can be administered in a wide variety of dosage forms. They include, for example, liquid, semisolid dosage forms, such as liquid solutions (injectable and insoluble solutions), dispersions or suspensions, tablets, pills, powders, liposomes or suppositories. The preferred dosage form depends on the intended mode of administration and the subject to which it is to be co-administered.
The most preferred mode of administration of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof is oral. In a preferred embodiment, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof is administered by intravenous infusion or intravenous injection. In a further preferred embodiment, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof is administered by intramuscular injection or subcutaneous injection. Other routes of administration also require observation, including, for example, intranasal and transdermal routes, as well as inhalation.
Typically, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof can be administered in the form of a pharmaceutical composition comprising roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable auxiliary.
The pharmaceutical compositions are prepared using methods known per se and familiar to the person skilled in the art. The pharmaceutical compositions using roflumilast, roflumilast-N-oxide or their pharmaceutically acceptable salts or preferably in combination with at least one pharmaceutically acceptable auxiliary, for example in the form of tablets, coated tablets, capsules, lozenges, suppositories, emulsions, suspensions, gels or solutions, advantageously with an active compound content of between 0.1 and 99.9% by weight, preferably 5 to 95% by weight, more preferably 20 to 80% by weight, can be adapted precisely to the active compound and/or to the desired initial effect by selecting suitable auxiliary agents, the administration form of the medicament (for example sustained-release or enteral).
They are familiar with auxiliaries which are suitable for the desired pharmaceutical preparations on the basis of the expert knowledge of the person skilled in the art. As pharmaceutically acceptable auxiliaries, any auxiliaries known to be suitable for preparing pharmaceutical compositions can be used. Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsions, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrants, buffers, permeation enhancers, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, fragrances, sweeteners, and dyes. In particular, the type of adjuvant used is adapted to the desired dosage form and the desired mode of administration.
Suitable oral formulations of roflumilast or roflumilast-N-oxide are disclosed in International patent application WO 03/70279.
It is known to the person skilled in the art that the optimal dosage of the active compound can vary depending on the body weight, age and general condition of the patient and his/her action on the response behaviour of the active compound. In each case, the optimum dosage required and the mode of administration of the active compound can be readily determined based on the knowledge of the person skilled in the art.
In the case of oral administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloropyrimidin-4-yl) benzamide (roflumilast), the daily dose (for adult patients) ranges from 50 to 1000 μ g per day, preferably from 50 to 500 μ g per day, preferably once daily.
In the case of intravenous administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloropyrimidin-4-yl) benzamide (roflumilast), the daily dose (for adult patients) ranges from 50 to 500 μ g per day, preferably from 150 to 300 μ g per day.
The compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or the compound of formula 1.2 or a pharmaceutically acceptable salt thereof may be administered with one or more other active compounds useful in the treatment of type 2 and/or type 1 diabetes. "one or more" further active compounds in this connection mean preferably 1 or 2 further active compounds.
Non-limiting examples of these other active compounds for use in the treatment of type 2 and/or type 1 diabetes are provided in the following list:
-insulin and insulin analogues
-glucagon-like peptide-1 (GLP-1) receptor agonists
Sulfonylurea substances
Biguanides (biguanides)
-alpha-glucosidase inhibitors
Thiazolidinediones
-meglitinide substances
Inhibitors of dipeptidyl peptidase (DPP) IV
PDE1, PDE5, PDE9, PDE10 or PDE11 inhibitors
-inhibitors of coenzyme A
Anti-obesity substances, such as appetite suppressants, satiety increasing substances and energy expenditure increasing drugs and their pharmaceutically acceptable salts.
Thus a further aspect of the invention is:
a pharmaceutical composition comprising an amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof, an amount of one or more other active compounds or a pharmaceutically acceptable salt thereof for use in the treatment of type 2 and/or type 1 diabetes, wherein the first amount and the second amount together comprise an effective amount for the treatment of type 2 and/or type 1 diabetes, and the above mentioned composition is for use in the treatment of type 2 and/or type 1 diabetes.
In a further aspect the present invention provides the use of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof in combination with one or more other active compounds for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition, combination product or kit for the treatment of type 2 and/or type 1 diabetes.
The compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or the compound of formula 1.2 or a pharmaceutically acceptable salt thereof and one or more other active compounds for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof, may be administered simultaneously, sequentially or separately. To achieve this effect, the active compounds to be combined can be formulated in a single preparation (pharmaceutical composition) or in separate preparations (combination product or kit).
Thus, according to a further aspect of the present invention there is provided a pharmaceutical composition comprising an amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof, an amount of one or more other active compounds useful in the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant in a pharmaceutical formulation, wherein the first amount and the second amount together comprise an effective amount for the treatment of type 2 and/or type 1 diabetes.
The above-mentioned pharmaceutical compositions provide that the compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or the compound of formula 1.2 or a pharmaceutically acceptable salt thereof is administered in admixture with one or more other active compounds for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof, and thus occur as a single formulation.
Alternatively, the compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or the compound of formula 1.2 or a pharmaceutically acceptable salt thereof and one or more other active compounds or pharmaceutically acceptable salts thereof for the treatment of type 2 and/or type 1 diabetes may be present as separate formulations, wherein at least one of those formulations contains the compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or the compound of formula 1.2 or a pharmaceutically acceptable salt thereof and at least one of those formulations contains one or more other active compounds or pharmaceutically acceptable salts thereof for the treatment of type 2 and/or type 1 diabetes.
Further, there is provided:
a combination product comprising the components: (A) an amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof; (B) a suitable amount of an additional active compound for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof; and optionally (C) an amount of another active compound for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof; wherein the first, second and optionally third amounts together comprise an effective amount for the treatment of type 2 and/or type 1 diabetes, and wherein each of components (a), (B) and (C) is formulated in admixture with at least one pharmaceutically acceptable adjuvant.
A kit comprising the components: (A) a pharmaceutical formulation comprising a suitable amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof in admixture with at least one pharmaceutically acceptable auxiliary; (B) pharmaceutical formulations comprising a mixture of a further active compound for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable auxiliary; and (C) a pharmaceutical formulation comprising a suitable amount of a mixture of another active compound for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable auxiliary, wherein the first, second and optionally third amounts together comprise an effective amount for the treatment of type 2 and/or type 1 diabetes.
Simultaneous administration of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof and one or more other active compounds for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof, may be accomplished by administering a composition according to the invention to a patient in need of type 2 and/or type 1 diabetes treatment in one dosage form, e.g., in a single capsule, tablet or injection.
The combination of components (a), (B) and optionally the presence of (C) may also be a kit to be administered continuously or independently of the course of treatment of type 2 and/or type 1 diabetes.
The sequential or separate administration of the compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or the compound of formula 1.2 or a pharmaceutically acceptable salt thereof and one or more further active compounds for the treatment of type 2 and/or type 1 diabetes or a pharmaceutically acceptable derivative thereof may be accomplished by administering a combination product or kit of components (a), (B) and optionally component (C) according to the invention to a patient in need of type 2 and/or type 1 diabetes treatment in multiple separate dosage forms, e.g. in separate capsules, tablets or injections.
Alternatively, one or both of the components (A), (B) and optionally (C) may be formulated as tablets or capsules, and the other administered components may be formulated as, for example, injections or inhalants.
According to the invention, sequential administration between the administration of the combination product or kit of components (a), (B) and optionally (C) (e.g. the time required to swallow a tablet one after the other) involves a relatively short period of time.
According to the invention, the separate administration between the administration of the combination or kit of components (a), (B) and optionally (C) comprises a relatively short and a relatively long period of time. However, for the purposes of the present invention, at least one component is administered while the other component is still effective in the patient being treated. In a preferred embodiment of the invention, the effect of treating the patient is a synergistic effect.
The compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or the compound of formula 1.2 or a pharmaceutically acceptable salt thereof and one or more further active compounds for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof, may be administered in combination in the form of a pharmaceutical composition, combination product or kit according to the invention, such that type 2 and/or type 1 diabetes is effectively treated. And in a preferred embodiment is superior to either substance used alone. Furthermore, in a particularly preferred embodiment, the combined administration of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof and one or more other active compounds for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof, shows a synergistic effect in the treatment of type 2 and/or type 1 diabetes.
The term "synergistic" as used herein means that the compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or the compound of formula 1.2 or a pharmaceutically acceptable salt thereof in combination with one or more other active compounds or a pharmaceutically acceptable salt thereof for the treatment of type 2 and/or type 1 diabetes has an effect on the treatment of type 2 and/or type 1 diabetes which is greater than the sum of their individual effects in a pharmaceutical composition, combination or kit according to the invention. The synergistic effects of the embodiments of the present invention include other unexpected advantages in the treatment of type 2 and/or type 1 diabetes. Such advantages may include, but are not limited to, reducing the dosage of one or more of the co-active compounds required, reducing the side effects of one or more of the co-active compounds, or demonstrating tolerance to one or more of the co-active compounds in a patient in need of treatment for type 2 and/or type 1 diabetes.
The administration of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof in combination with one or more other active compounds or pharmaceutically acceptable derivatives thereof for the treatment of type 2 and/or type 1 diabetes can also be effective in reducing the number of separate doses required, thus improving compliance in patients in need of type 2 and/or type 1 diabetes treatment.
A further aspect of the invention is the use of a pharmaceutical composition, a pharmaceutical combination or a kit according to the invention for the preparation of a medicament product for the treatment of type 2 and/or type 1 diabetes.
A further aspect of the invention is a method for the treatment of type 2 and/or type 1 diabetes, comprising administering to a patient in need thereof a pharmaceutical composition in a formulation comprising an amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof, an amount of one or more other active compounds useful in the treatment of type 2 and/or type 1 diabetes or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary.
Another aspect of the invention is a method of treating type 2 and/or type 1 diabetes comprising administering to a patient in need thereof a combination product comprising:
(A) an amount of a compound of formula 1.1 or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2 or a pharmaceutically acceptable salt thereof;
(B) a suitable amount of an additional active compound for the treatment of type 2 and/or type 1 diabetes, or a pharmaceutically acceptable salt thereof; and optionally
(C) A suitable amount of a further active compound for the treatment of type 2 and/or type 1 diabetes mellitus or a pharmaceutically acceptable salt thereof,
wherein the first, second and optionally third amounts together comprise an effective amount for treating type 2 and/or type 1 diabetes; wherein each of components (a), (B) and optionally (C) is prepared in admixture with at least one pharmaceutically acceptable auxiliary; and wherein components (A), (B) and optionally component (C) are administered sequentially or separately.
As examples of other antidiabetic compounds which may be used in the pharmaceutical composition already mentioned above, the combination product and kit according to the invention are selected from the group consisting of:
-insulin and insulin analogues
-glucagon-like peptide-1 (GLP-1) receptor agonists
Sulfonylurea substances
Biguanides (biguanides)
-alpha-glucosidase inhibitors
PPAR agonists
Thiazolidinediones
-meglitinide substances
Inhibitors of dipeptidyl peptidase (DPP) IV
PDE1, PDE5, PDE9, PDE10 or PDE11 inhibitors
-dextrin analogues
-inhibitors of coenzyme A
Anti-obesity substances, such as appetite suppressants, satiety increasing substances and energy expenditure increasing drugs and their pharmaceutically acceptable salts.
In one embodiment of the invention, the further active compound used in the treatment of type 2 and/or type 1 diabetes is selected from:
-insulin and insulin analogues
-glucagon-like peptide-1 (GLP-1) receptor agonists
Sulfonylurea substances
Biguanides (biguanides)
-alpha-glucosidase inhibitors
PPAR agonists
Thiazolidinediones
-meglitinide substances
Inhibitors of dipeptidyl peptidase (DPP) IV
PDE1, PDE5, PDE9, PDE10 or PDE11 inhibitors
-dextrin analogues
-inhibitors of coenzyme A
Anti-obesity substances, such as appetite suppressants, satiety increasing substances and energy expenditure increasing drugs and their pharmaceutically acceptable salts.
In another embodiment of the invention, the other active compound used in the treatment of type 2 and/or type 1 diabetes is insulin. Specific examples of insulin include, but are not limited to, Humulin[ Single-component human insulin injection (rDNA source)]]、Novolin(Single component human insulin injection (rDNA source)]、VelosulinBR[ human buffered regular insulin (rDNA origin)]And Exubera[ Single-component human insulin, inhalation]。
In another embodiment of the invention, the further active compound for use in the treatment of type 2 and/or type 1 diabetes is an insulin analogue or a pharmaceutically acceptable salt thereof. Specific examples of insulin analogs are selected from the group consisting of novaprid, insulin detemir, lispro human insulin, insulin glargine, zinc insulin suspensions, and LYS-Pro insulin.
In another embodiment of the invention, the other active compound used in the treatment of type 2 and/or type 1 diabetes is a glucagon-like peptide-1 receptor agonist or a pharmaceutically acceptable salt thereof. Specific examples of glucagon-like peptide-1 receptor agonists include, but are not limited to, BIM-51077(CAS-No.275371-94-3), EXENATIDE (CAS-No.141758-74-9), CJC-1131(CAS-No.532951-64-7), LIRAGLUTIDE (CAS-No.20656-20-2), and ZP-10(CAS-No. 320367-13-3). A preferred glucagon-like peptide-1 receptor agonist is EXENATIDE.
In another embodiment of the invention, the further active compound used in the treatment of type 2 and/or type 1 diabetes is a sulfonylurea or a pharmaceutically acceptable salt thereof. Specific examples of sulfonylureas include, but are not limited to, tolbutamide (CAS-No.000064-77-7), triazamide mesylate (CAS-No.001156-19-0), glipizide (CAS-No.029094-61-9), butamide sulfamate (CAS-No.000339-43-5), zolpidamide (CAS-No.025046-79-1), glibenclamide (CAS-No.032797-92-5), glibenclamide (CAS-No.026944-48-9), glibenclamide (CAS-No.010238-21-8), gliquidone (CAS-No.033342-05-1), glimepiride (CAS-No.093479-97-1), and gliclazide (CAS-No. 021187-98-4).
In another embodiment of the invention, the pharmaceutically acceptable salt of tolbutamide is the sodium salt of tolbutamide. In another embodiment of the invention, the pharmaceutically acceptable salt of gliquidone is gliquidone sodium salt.
In another embodiment of the invention, the further active compound used in the treatment of type 2 and/or type 1 diabetes is a biguanide or a pharmaceutically acceptable salt thereof. Specific examples of biguanides include, but are not limited to, metformin (CAS-No. 000657-24-9).
In another embodiment of the invention, the pharmaceutically acceptable salt of metformin is the monohydrochloride of metformin.
In another embodiment of the invention, the other active compound used in the treatment of type 2 and/or type 1 diabetes is an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof. Specific examples of alpha-glucosidase inhibitors include, but are not limited to, acarbose (Cas-No.056180-94-0), miglitol (CAS-No.072432-03-2), voglibose (CAS-No. 083480-29-9).
In another embodiment of the invention, the other active compound used in the treatment of type 2 and/or type 1 diabetes is a PPAR-agonist or a pharmaceutically acceptable salt thereof. Specific examples of PPAR-agonists include, but are not limited to, MURAGLITAZAR (CAS-No.331741-94-7), rosiglitazone (CAS-No.122320-73-4), pioglitazone (CAS-No.111025-46-8), RAGAGLITAZAR (CAS-No.222834-30-2), Faglitazar (CAS-No.196808-45-4), TESAGLIZAR (CAS-No.251565-85-2), NAVEGLITAZAR (CAS-No.476436-68-7), NETOGLITAZONE (CAS-No.161600-01-7), RIVOGLITAZONE (CAS-No.185428-18-6), K-111(CAS-No.221564-97-2), GW-677954(CAS-No.622402-24-8), FK-614 (CAS-No. 193012-35-0), and (-) -lipoamide (CAS-No. 024136-23-0). Preferred PPAR-agonists are rosiglitazone and pioglitazone.
In another embodiment of the invention, the pharmaceutically acceptable salt of rosiglitazone is rosiglitazone maleate. In another embodiment of the invention, the pharmaceutically acceptable salt of ritoglitazone is a monohydroxylated salt of ritoglitazone. In another embodiment of the invention, the pharmaceutically acceptable salt of K-111 is K-111 sodium salt. In another embodiment of the present invention, the pharmaceutically acceptable salt of pioglitazone is pioglitazone dihydrochloride.
In another embodiment of the invention, the other active compound used in the treatment of type 2 and/or type 1 diabetes is a meglitinide substance or a pharmaceutically acceptable salt thereof. Specific examples of meglitinide substances include, but are not limited to, repaglinide (CAS-No.135062-02-1), nateglinide (CAS-No.105816-04-4), and mitiglinide (CAS-No. 145375-43-5).
In another embodiment of the invention, the pharmaceutically acceptable salt of mitiglinide is the mono-potassium or calcium salt of mitiglinide.
In another embodiment of the invention, the other active compound used in the treatment of type 2 and/or type 1 diabetes is a dipeptidyl peptidase IV inhibitor or a pharmaceutically acceptable salt thereof. Specific examples of dipeptidyl peptidase IV inhibitors include, but are not limited to, SITAGLIPTIN (CAS-No.486460-32-6), SAXAGLIPTIN (CAS-No.361442-04-8), VILDAGLIPTIN (CAS-No.274901-16-5), DENA-GLIPTIN (CAS-No.483369-58-0), P32/98(CAS-No.251572-70-0), and NVP-DPP-728(CAS-No. 247016-69-9).
In another embodiment of the invention, the pharmaceutically acceptable salt of SITAGLIPTIN is SITAGLIPTIN phosphate. In another embodiment of the invention, the pharmaceutically acceptable salt of P32/98 is P32/98 hydrochloride.
In another embodiment of the invention, the other active compound used in the treatment of type 2 and/or type 1 diabetes is a PDE5 inhibitor or a pharmaceutically acceptable salt thereof. Specific examples of PDE5 inhibitors include, but are not limited to, sildenafil (CAS-No.139755-83-2), VARDENAFIL (CAS-No.224785-90-4), and TAdAALAFIL (CAS-No. 171596-29-5).
In another embodiment of the invention, the pharmaceutically acceptable salt of sildenafil is sildenafil hemi-citrate, citrate or mesylate. Sildenafil citrate is particularly preferred. In another embodiment of the invention, the pharmaceutically acceptable salt of VARDENAFIL is VARDENAFIL monohydrochloride or VARDENAFIL dihydrochloride.
In another embodiment of the invention, the further active compound used in the treatment of type 2 and/or type 1 diabetes is a PDE1, PDE9, PDE10 or PDE11 inhibitor or a pharmaceutically acceptable salt thereof. PDE1, PDE9, PDE10 or PDE11 inhibitors for use according to the invention may be found in US20020160939, WO2003037432, US2004220186, WO2005/003129, WO2005012485, WO2O05120514 and WO 03077949.
In another embodiment of the invention, the other active compound used in the treatment of type 2 and/or type 1 diabetes is a dextrin analogue or a pharmaceutically acceptable salt thereof. Specific examples of dextrin analogues include, but are not limited to, pramlintide (CAS-No. 151126-32-8).
In another embodiment of the invention, the pharmaceutically acceptable salt of pramlintide is pramlintide acetate.
In another embodiment of the invention, the other active compound used in the treatment of type 2 and/or type 1 diabetes is a coenzyme a inhibitor or a pharmaceutically acceptable salt thereof. Specific examples of coenzyme A inhibitors include, but are not limited to, Etomoken (CAS-No. 082258-36-4).
In another embodiment of the invention, the further active compound for use in the treatment of type 2 and/or type 1 diabetes is an anti-obesity agent or a pharmaceutically acceptable salt thereof. Specific examples of anti-obesity drugs include, but are not limited to, HMR-1426(CAS-No.262376-75-0), CETILISTAT (CAS-No.282526-98-1), sibutramine (CAS-No. 106650-56-0).
In another embodiment of the invention, the pharmaceutically acceptable salt of HMR-1426 is HMR-1426 hydrochloride. In another embodiment of the present invention, the pharmaceutically acceptable salt of sibutramine is sibutramine hydrochloride.
Further details regarding preferred combinations of compounds of formula 1.1 and/or formula 1.2 are set forth in table 1:
table 1:
| INN or research code | Structural/chemical name |
| BIM-51077 | L-histidinyl-2-methyllactoyl-L-glutamyl-glycyl-L-threonyl-L-phenyllactoyl-L-threonyl-L-seryl-L-aspartyl-L-valyl-L-seryl-L-tyrosyl-L-leucyl-L-glutamyl-glycyl-L-glutaminyl-L-lactoyl-L-lysyl-L-glutamyl-L-phenyllactoyl-L-isoleucyl-L-lactoyl-L-tryptophanyl-L-leucyl-L-valyl -L-lysyl-2-methyllactoyl-L-argininamide |
| EXENATIDE | L-histidyl-L-glutamyl-L-threonyl-L-phenyllactoyl-L-threonyl-L-seryl-L-aspartyl-L-leucyl-L-seryl-L-lysyl-glutaminyl-L-methionyl-L-glutamyl-L-lactoyl-L-valyl-L-arginyl-L-leucyl-L-phenyllactoyl-L-isoleucyl-L-glutamyl-L-tryptophanyl-L-leucyl-L-lysyl-L-asparaginyl glycyl aminoacyl-L-prolyl-L-seryl glycyl-L-lactoyl-L-prolyl-L-serine amide |
| INN or research code | Structural/chemical name |
| CJC-1131 | L-histidinyl-D-lactoyl-L-alpha-glutamylglycyl-L-threonyl-L-phenyllactoyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-valyl-L-seryl-L-tyrosyl-L-leucyl-L-alpha-glutamylglycyl-L-glutaminyl-L-lactoyl-L-lysyl-L-alpha-glutamyl-L-phenyllactoyl-L-isoleucine-L-lactoyl-L-tryptophanyl-L-leucyl-L-isoleucine -valyl-L-lysylglycyl-L-arginyl-N6- [2- [2- [2- [3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propanamidoethoxy]Ethoxy radical]Acetyl group]-L-lysin-amide |
| LIRAGLUTIDE | L-histidinyl-L-lactoyl-L-glutamyl-glycyl-L-threonyl-L-phenyllactoyl-L-threonyl-L-seryl-L-aspartyl-L-valyl-L-seryl-L-tyrosyl-L-leucyl-L-glutamyl-glycyl-L-glutaminyl-L-lactoyl-Nepsilon- (Nalpha-hexadecanal-gamma-L-glutamyl) -L-lysyl-L-glutamyl-L-phenyllactoyl-L-isoleucyl-L-lactoyl-L-lactoyl -tryptophanyl-L-leucinyl-L-valyl-L-arginyl-glycyl-L-arginyl-glycine |
| ZP-10 | H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-1le-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2 |
For additional information on the formulation, suitable dosage forms and dosage ranges for the glucagon-like peptide receptor agonists listed in table 1 can be found in the following patents/patent applications: WO0334331, EP0981611, EP1180121, WO9808871 and WO 0104156.
The sulfonylureas listed in Table 1 are tolbutamide, tolazamide, glipizide, amisulbutamide, tolazamide; glibenclamide, gliquidone, glimepiride and gliclazide are commercially available. Those skilled in the art are familiar with suitable dosage forms and dosage ranges for these compounds.
The biguanides listed in table 1, metformin, are commercially available. Those skilled in the art are familiar with suitable dosage forms and dosage ranges for these compounds.
The α -glucosidase inhibitors acarbose, miglitol and voglibose listed in table 1 are commercially available. Those skilled in the art are familiar with suitable dosage forms and dosage ranges for these compounds.
Additional information on the formulation, suitable dosage forms and dosage ranges for the PPAR-agonists listed in table 1 can be found in the following patents/patent applications: WO0121602, EP03306228, EP0658161, EP0193256, WO9919313, WO9731907, WO9962870, WO0140169, WO02100813, EP0604983, EP0745600, WO9615784, WO0259098, EP0882718 and EP 1183020.
The metformin substances repaglinide, nateglinide and mitiglinide listed in table 1 are commercially available. Those skilled in the art are familiar with suitable dosage forms and dosage ranges for these compounds.
Additional information on the formulation, suitable dosage forms and dosage ranges for the DPP IV inhibitors listed in table 1 may be found in the following patents/patent applications: WO03004498, WO0168603, WO0034241, WO0302531, WO9961431 and WO 9919998.
For additional information on the formulation, suitable dosage forms and dosage ranges for the PDE5 inhibitors listed in table 1 can be found in the following patents/patent applications: WO0213798, WO0260422 and WO 2004082667.
For additional information on the formulation, suitable dosage forms and dosage ranges for the dextrin analogue pramlintide listed in table 1 can be found in EP 0567626.
Additional information regarding the formulation, suitable dosage forms and dosage ranges for ETOXOMIR, HMR-1426, CETILISTAT, and sibutramine listed in table 1 can be found in the following patents/patent applications: EP0046590, WO0018749, EP1144395 and EP 0397831.
"pharmaceutically acceptable salts" of other active compounds for use in the treatment of type 2 and/or type 1 diabetes mellitus are not limited to the specific examples given above. The term refers to non-toxic salts of these compounds. These pharmaceutically acceptable salts are typically prepared by reacting a suitable organic or inorganic acid with the free base or by reacting a suitable organic or inorganic base with the free acid. Mention may in particular be made of the pharmacologically acceptable salts of inorganic and organic acids, i.e. the salts used in the pharmaceutical technology. Those suitable are, in particular, acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acidWater-soluble and water-insoluble acid addition salts of acids, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, pamoic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid. Examples of pharmaceutically acceptable base salts which may be mentioned are lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidineAnd (3) salt.
It will be appreciated that the other active compounds and their pharmaceutically acceptable salts for use in the treatment of type 2 and/or type 1 diabetes may exist in the form of their pharmaceutically acceptable solvates, and in particular in the form of their hydrates.
Mode of administration, dosage form and dose combination:
the combination according to the invention may be administered by any suitable route, for example by oral, sublingual, buccal, intravenous, arterial, intramuscular, subcutaneous, intradermal, topical, transdermal, intranasal, intraperitoneal, rectal or vaginal route, by inhalation or insufflation.
Tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are examples of suitable oral administration. In particular, the dosage form may be adapted for use in, for example, an enteric dosage form, an immediate release dosage form, a sustained release dosage form, a multi-dose dosage form, a delayed release dosage form, or a sustained release dosage form. The dosage form may be prepared, for example, by coating the tablet, by separating the tablet into different compartments by layers that disintegrate under different conditions (e.g., pH conditions), or by combining the active ingredient with a biodegradable polymer.
Preferably used in inhalation administration is an aerosol. The aerosol is liquid-vapor dispersed, solid-vapor dispersed, or liquid/solid mixed-vapor dispersed.
Aerosols can be generated by aerosol generating devices such as dry powder inhalation Devices (DPIs), pressurized metered dose aerosols (PMDIs), and nebulizers. Depending on the type of active ingredient to be administered, the aerosol-generating device may contain the active compound in the form of a powder, a solution or a dispersion. The powder may contain one or more of the following adjuvants, such as carriers, stabilizers and fillers. In addition to the solvent, the solution may contain one or more of the following auxiliaries, for example: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and fragrances. In addition to the dispersing agent, the dispersion may contain one or more of the following auxiliaries, for example: propellants, surfactants, stabilizers, buffers, preservatives and fragrances. Examples of carriers include, but are not limited to, sugars such as lactose and glucose. Examples of propellants include, but are not limited to, hydrofluorocarbons such as 1, 1, 1, 2-tetrafluoroethylene and 1, 1, 1, 2, 3, 3, 3-heptafluoropropane.
The aerosol particles (solid, liquid or solid/liquid particles) preferably have a particle size of less than 100 μm, more preferably in the range from 0.5 to 10 μm, in particular in the range from 2 to 6 μm (D50 value, measured by laser diffraction).
Parenteral administration is, for example, intravenous, arterial, intramuscular, subcutaneous, intradermal and intraperitoneal administration, preferably using solutions (e.g., sterile solutions, isotonic solutions). Administration by injection or infusion techniques is preferred.
Pharmaceutical compositions (formulations) containing roflumilast, roflumilast-N-oxide or their pharmaceutically acceptable salts and/or one or more other active compounds for the treatment of type 2 and/or type 1 diabetes mellitus and at least one pharmaceutically acceptable auxiliary can be prepared by methods known to the person skilled in the art, for example by dissolving, mixing, granulating, dragee-making, grinding, emulsifying, encapsulating, entrapping or lyophilizing.
As pharmaceutically acceptable auxiliaries, any auxiliaries known to be suitable for preparing pharmaceutical compositions (preparations) can be used. Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel-forming agents, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrants, buffers, permeation enhancers, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, fragrances, sweeteners, and dyes. In particular, the type of adjuvant used is adapted to the desired dosage form and the desired mode of administration.
Preferred modes of administration of the combination according to the invention depend on the subject to which the particular combination is to be administered.
The roflumilast, roflumilast-N-oxide or pharmaceutically acceptable salts thereof mentioned above can be administered in a wide variety of dosage forms. They include, for example, liquid, semisolid dosage forms, such as liquid solutions (injectable and insoluble solutions), dispersions or suspensions, tablets, pills, powders, liposomes or suppositories. The preferred dosage form depends on the intended mode of administration and the subject to which it is to be co-administered.
The most preferred mode of administration of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof is oral. In a preferred embodiment, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof is administered by intravenous infusion or intravenous injection. In a further preferred embodiment, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof is administered by intramuscular injection or subcutaneous injection. Other routes of administration also require observation, including, for example, intranasal and transdermal routes, as well as inhalation.
The preferred mode of administration of the other active ingredients in combination with roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof depends on the particular substance. For example, EXENATIDE, BIM-51077, CJC-1131, ZP-10 or pramlintide are preferably administered by subcutaneous injection. Preferred modes of administration for the compounds like tolbutamide, tolazamide, glipizide, amisulbutamide, zolpidem, glibenclamide, gliquidone and gliclazide, metformin, acarbose, miglitol and voglibose, rosiglitazone, pioglitazone, RAGAGLITAZAR, faglitazar, NAVEGLITAZAR, NETOGLITAZONE, rivitazone, K-111, GW-677954, FK-614, (-) -lipoamide, repaglinide, nateglinide and miglitide, SITAGLIPTIN, SAXAGLIPTIN, VILDAGLIPTIN, DENAGLIPTIN, P32/98, NVP-DPP-728, sildenafil, vardenafil, TADALAFIL, etoxazel, HMR-1426, CETILISTAT and sibutramine are oral. Further information on preferred modes of administration of the other active ingredients in combination with roflumilast, roflumilast-N-oxide or pharmaceutically acceptable salts thereof is summarized in table 2 below.
As part of the combination therapy, roflumilast-N-oxide or their pharmaceutically acceptable salts and/or one or more other active compounds for the treatment of type 2 and/or type 1 diabetes mellitus according to the invention are generally of the order of magnitude used for monotherapy, so that it is more likely that the respective dose of the combined administration of roflumilast, roflumilast-N-monoxide or their pharmaceutically acceptable salts and one or more other active compounds usually used for the treatment of type 2 and/or type 1 diabetes mellitus will be reduced on the basis of interacting and mutually enhancing individual behaviors.
In the case of oral administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloropyridin-4-yl) benzamide (roflumilast), as mentioned above, the daily dose of the single treatment (for adult patients) ranges from 50 to 500 μ g per day, preferably once daily. In the case of intravenous administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloropyridin-4-yl) benzamide (roflumilast), the daily dose (for adult patients) ranges from 50 to 500 μ g per day, preferably from 150 to 300 μ g per day.
Further information on the preferred mode of administration and typical dosages (for a single treatment) of the active compounds used in combination with roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt thereof is summarized in table 2 below.
Table 2: preferred routes of administration and dosages:
| INN or research code | Preferred treatment | Preferred routes of administration | Typical daily dose (dose range) for a single treatment |
| Insulin/insulin analogues | Type I diabetes mellitus type II diabetes mellitus | Subcutaneous injection | When required |
| EXUBERA | Type I diabetes mellitus type II diabetes mellitus | Inhalation | When required |
| BIM-51077 | Type II diabetes | Subcutaneous injection | |
| EXENATIDE | Type II diabetes | Subcutaneous injection | 10-20μg |
| CJC-1131 | Type II diabetes | Subcutaneous injection | ≈200μg |
| ZP-10 | Type II diabetes | Subcutaneous injection | |
| Tolbutamide | Type II diabetes | Is administered orally | 0.5 to 2.0g |
| Methanesulfonamidothion | Type II diabetes | Is administered orally | 100 to 150mg |
| Glipizide | Type II diabetes | Is administered orally | 5 to 40mg, preferably 5 to 20mg |
| Amisulbutamide | Type II diabetes | Is administered orally | Up to 17 mg/. mu.g |
| INN or research code | Preferred treatment | Preferred routes of administration | Typical daily dose (dose range) for a single treatment |
| Azasulam urea | Type II diabetes | Is administered orally | 2 to 16mg |
| Glibenclamide | Type II diabetes | Is administered orally | |
| Tribenuron-methyl | Type II diabetes | Is administered orally | 12.5 to 75mg |
| Glibenclamide | Type II diabetes | Is administered orally | 1.75 to 10.5mg |
| Gliquidone | Type II diabetes | Is administered orally | 15 to 120mg |
| Glimepiride | Type II diabetes | Is administered orally | 1 to 6mg |
| Gliclazide | Type II diabetes | Is administered orally | 30 to 120mg |
| Metformin | Type II diabetes | Is administered orally | 1000 to 3800mg |
| Acarbose | Type II diabetes | Is administered orally | 150 to 600mg, preferably 150 to 300mg |
| Miglitol | Type II diabetes | Is administered orally | 150 to 300mg |
| Voglibose | Type II diabetes | Is administered orally | 0.6 to 0.9mg |
| MURAGLTIAZAR | Type II diabetes | Is administered orally or by injection | 2.5 to 5mg |
| Rosiglitazone | Type II diabetes | Is administered orally | 4 to 8mg |
| Pioglitazone | Type II diabetes | Is administered orally | 15 to 45mg |
| RAGAGLITAZAR | Type II diabetes | Is administered orally | 0.1 to 10mg |
| Fagelitaza | Type II diabetes | Is administered orally | 0.5 to 10mg |
| TESAGLITAZAR | Type II diabetes | Is administered orally | 0.5 to 1mg |
| NAVEGLITAZAR | Type II diabetes | Is administered orally | 0.004 to 1.2mg |
| NETOGLITAZONE | Type II diabetes | Is administered orally | |
| RIVOGLITAZONE | Type II diabetes | Is administered orally | |
| K-111 | Type II diabetes | Is administered orally | 10 to 20mg |
| GW-677954 | Type II diabetes | Is administered orally | 2.5 to 20mg |
| FK-614 | Type II diabetes | Is administered orally | About 150 to 200mg |
| (mono) -lipid lowering amides | Type II diabetes | Is administered orally | ≈1000mg |
| Repaglinide | Type II diabetes | Is administered orally | 0.5 to 16mg |
| Nateglinide | Type II diabetes | Is administered orally | 180 to 540mg |
| Mitiglinide | Type II diabetes | Is administered orally | 40 mg/meal |
| SITAGLIPTIN | Type II diabetes | Is administered orally | ≈100mg |
| INN or research code | Preferred treatment | Preferred routes of administration | For a single treatmentTypical daily dose (dosage range) |
| SAXAGLIPTIN | Type II diabetes | Is administered orally | ≈10mg |
| VILDAGLIPTIN | Type II diabetes | Is administered orally | 25 to 100mg |
| DENAGLIPTIN | Type II diabetes | Is administered orally | |
| P32/98 | Type II diabetes | Is administered orally | |
| NVP-DPP-728 | Type II diabetes | Is administered orally | 300mg |
| Sildenafil | Type II diabetes mellitus type I diabetes mellitus | Is administered orally | 50 to 100mg |
| VARDENFIL | Type II diabetes mellitus type I diabetes mellitus | Is administered orally | 2.5 to 20mg |
| TADALAFIL | Type II diabetes mellitus type I diabetes mellitus | Is administered orally | 10 to 20mg |
| Pramlintide | Type II diabetes mellitus type I diabetes mellitus | Subcutaneous injection | 20 to 120. mu.g |
| Emoke house | Type II diabetes | Is administered orally | 10 to 50mg |
| HMR-1426 | Type II diabetes | Is administered orally | |
| CETILISTAT | Type II diabetes | Is administered orally | 120 to 920mg |
| Sibutramine | Type II diabetes | Is administered orally | 10 to 150mg |
Examples
Table 3: preferred combinations
| Example numbering | Combination of | |
| 1 | Roflumilast | Human insulin |
| 2 | roflumilast-N-oxide | Human insulin |
| 3 | Roflumilast | Insulin analogues |
| 4 | roflumilast-N-oxide | Insulin analogues |
| 5 | Roflumilast | BIM-51077 |
| 6 | roflumilast-N-oxide | BIM-51077 |
| 7 | Roflumilast | EXENATIDE |
| 8 | roflumilast-N-oxide | EXENATIDE |
| Example number | Combination of | |
| 9 | Roflumilast | CJC-1131 |
| 10 | roflumilast-N-oxide | CJC-1131 |
| 11 | Roflumilast | ZP-10 |
| 12 | roflumilast-N-oxide | ZP-10 |
| 13 | Roflumilast | Tolbutamide |
| 14 | roflumilast-N-oxide | Tolbutamide |
| 15 | Roflumilast | Tolbutamide sodium salt |
| 16 | roflumilast-N-oxide | Tolbutamide sodium salt |
| 17 | Roflumilast | Methanesulfonamidothion |
| 18 | roflumilast-N-oxide | First of allAzolourides |
| 19 | Roflumilast | Glipizide |
| 20 | roflumilast-N-oxide | Glipizide |
| 21 | Roflumilast | Amisulbutamide |
| 22 | roflumilast-N-oxide | Amisulbutamide |
| 23 | Roflumilast | Azasulam urea |
| 24 | roflumilast-N-oxide | Azasulam urea |
| 25 | Roflumilast | Glibenclamide |
| 26 | roflumilast-N-oxide | Glibenclamide |
| 27 | Roflumilast | Tribenuron-methyl |
| 28 | roflumilast-N-oxide | Tribenuron-methyl |
| 29 | Roflumilast | Glibenclamide |
| 30 | roflumilast-N-oxide | Glibenclamide |
| 31 | Roflumilast | Gliquidone |
| 32 | roflumilast-N-oxide | Gliquidone |
| 33 | Roflumilast | Gliquidone sodium salt |
| 34 | roflumilast-N-oxide | Gliquidone sodium salt |
| 35 | Roflumilast | Glimepiride |
| 36 | roflumilast-N-oxide | Glimepiride |
| 37 | Roflumilast | Gliclazide |
| 38 | roflumilast-N-oxide | Gliclazide |
| Example numbering | Combination of | |
| 39 | Roflumilast | Metformin |
| 40 | roflumilast-N-oxide | Metformin |
| 41 | Roflumilast | Metformin hydrochloride |
| 42 | roflumilast-N-oxide | Metformin hydrochloride |
| 43 | Roflumilast | Acarbose |
| 44 | roflumilast-N-oxide | Acarbose |
| 45 | Roflumilast | Miglitol |
| 46 | roflumilast-N-oxide | Miglitol |
| 47 | Roflumilast | Voglibose |
| 48 | roflumilast-N-oxide | Voglibose |
| 49 | Roflumilast | MURAGLTIAZAR |
| 50 | roflumilast-N-oxide | MURAGLTIAZAR |
| 51 | Roflumilast | Rosiglitazone |
| 52 | roflumilast-N-oxide | Rosiglitazone |
| 53 | Roflumilast | Rosiglitazone maleate |
| 54 | roflumilast-N-oxide | Rosiglitazone maleate |
| 55 | Roflumilast | Pioglitazone |
| 56 | roflumilast-N-oxide | Pioglitazone |
| 57 | Roflumilast | Pioglitazone dihydrochloride |
| 58 | roflumilast-N-oxide | Pioglitazone dihydrochloride |
| 59 | Roflumilast | RAGAGLITAZAR |
| 60 | roflumilast-N-oxide | RAGAGLITAZAR |
| 61 | Roflumilast | Fagelitaza |
| 62 | roflumilast-N-oxide | Fagelitaza |
| 63 | Roflumilast | TESAGLITAZAR |
| 64 | roflumilast-N-oxide | TESAGLITAZAR |
| 65 | Roflumilast | NAVEGLITAZAR |
| 66 | roflumilast-N-oxide | NAVEGLITAZAR |
| 67 | Roflumilast | NETOGLITAZONE |
| 68 | roflumilast-N-oxide | NETOGLITAZONE |
| Example numbering | Combination of | |
| 69 | Roflumilast | RIVOGLITAZONE |
| 70 | roflumilast-N-oxide | RIVOGLITAZONE |
| 71 | Roflumilast | RIVOGLITAZONE hydrochloride |
| 72 | roflumilast-N-oxide | RIVOGLITAZONE hydrochloride |
| 73 | Roflumilast | K-111 |
| 74 | roflumilast-N-oxide | K-111 |
| 75 | Roflumilast | K-111 sodium salt |
| 76 | roflumilast-N-oxide | K-111 sodium salt |
| 77 | Roflumilast | GW-677954 |
| 78 | roflumilast-N-oxide | GW-677954 |
| 79 | Roflumilast | FK-614 |
| 80 | roflumilast-N-oxide | FK-614 |
| 81 | Roflumilast | (-) -antihyperglycemic amides |
| 82 | roflumilast-N-oxide | (-) -antihyperglycemic amides |
| 83 | Roflumilast | Repaglinide |
| 84 | roflumilast-N-oxide | Repaglinide |
| 85 | Roflumilast | Nateglinide |
| 86 | roflumilast-N-oxide | Nateglinide |
| 87 | Roflumilast | Mitiglinide |
| 88 | roflumilast-N-oxide | Mitiglinide |
| 89 | Roflumilast | Mitiglinide potassium |
| 90 | roflumilast-N-oxide | Mitiglinide potassium |
| 91 | Roflumilast | Mitiglinide calcium |
| 92 | roflumilast-N-oxide | Mitiglinide calcium |
| 93 | Roflumilast | SITAGLIPTIN |
| 94 | roflumilast-N-oxide | SITAGLIPTIN |
| 95 | Roflumilast | Phosphoric acid SITAGLIPTIN |
| 96 | roflumilast-N-oxide | Phosphoric acid SITAGLIPTIN |
| 97 | Roflumilast | SAXAGLIPTIN |
| 98 | roflumilast-N-oxide | SAXAGLIPTIN |
| Example numbering | Combination of | |
| 99 | Roflumilast | VILDAGLIPTIN |
| 100 | roflumilast-N-oxide | VILDAGLIPTIN |
| 101 | Roflumilast | DENAGLIPTIN |
| 102 | roflumilast-N-oxide | DENAGLIPTIN |
| 103 | Roflumilast | P32/98 |
| 104 | roflumilast-N-oxide | P32/98 |
| 105 | Roflumilast | Fumaric acid P32/98 |
| 106 | roflumilast-N-oxide | Fumaric acid P32/98 |
| 107 | Roflumilast | Hydrochloric acid P32/98 |
| 108 | roflumilast-N-oxide | Hydrochloric acid P32/98 |
| 109 | Roflumilast | NVP-DPP-728 |
| 110 | roflumilast-N-oxide | NVP-DPP-728 |
| 111 | Roflumilast | Sildenafil |
| 112 | roflumilast-N-oxide | Sildenafil |
| 113 | Roflumilast | Sildenafil citrate |
| 114 | roflumilast-N-oxide | Sildenafil citrate |
| 115 | Roflumilast | Sildenafil hemicitrate |
| 116 | roflumilast-N-oxide | Sildenafil hemicitrate |
| 117 | Roflumilast | Sildenafil mesylate |
| 118 | roflumilast-N-oxide | Sildenafil mesylate |
| 119 | Roflumilast | VARDENFIL |
| 120 | roflumilast-N-oxide | VARDENFIL |
| 121 | Roflumilast | Hydrochloric acid VARDENFIL |
| 122 | roflumilast-N-oxide | Hydrochloric acid VARDENFIL |
| 123 | Roflumilast | Dihydrochloride VARDENFIL |
| 124 | roflumilast-N-oxide | VARDENFLL dihydrochloride |
| 125 | Roflumilast | TADALAFIL |
| 126 | roflumilast-N-oxide | TADALAFIL |
| 127 | Roflumilast | Pramlintide |
| 128 | roflumilast-N-oxide | Pramlintide |
| Example numbering | Combination of | |
| 129 | Roflumilast | Pramlintide acetate |
| 130 | roflumilast-N-oxide | Pramlintide acetate |
| 131 | Roflumilast | Emoke house |
| 132 | roflumilast-N-oxide | Emoke house |
| 133 | Roflumilast | HMR-1426 |
| 134 | roflumilast-N-oxide | HMR-1426 |
| 135 | Roflumilast | CETILISTAT |
| 136 | roflumilast-N-oxide | CETILISTAT |
| 137 | Roflumilast | Sibutramine |
| 138 | roflumilast-N-oxide | Sibutramine |
| 139 | Roflumilast | Sibutramine hydrochloride |
| 140 | roflumilast-N-oxide | Sibutramine hydrochloride |
Table 4: preferred triple combinations are:
| example numbering | Triple combination | ||
| 141 | Roflumilast | Metformin | Human insulin |
| 142 | roflumilast-N-oxide | Metformin | Human insulin |
| 143 | Roflumilast | Metformin hydrochloride | Human insulin |
| 144 | roflumilast-N-oxide | Metformin hydrochloride | Human insulin |
| 145 | Roflumilast | Rosiglitazone | Human insulin |
| 146 | roflumilast-N-oxide | Rosiglitazone | Human insulin |
| 147 | Roflumilast | Rogue maleate saltKetones | Human insulin |
| 148 | roflumilast-N-oxide | Rosiglitazone maleate | Human insulin |
| 149 | Roflumilast | Rosiglitazone | Metformin |
| 150 | roflumilast-N-oxide | Rosiglitazone | Metformin |
| 151 | Roflumilast | Rosiglitazone maleate | Metformin |
| 152 | roflumilast-N-oxide | Rosiglitazone maleate | Metformin |
| 153 | Roflumilast | Rosiglitazone maleate | Metformin hydrochloride |
| 154 | roflumilast-N-oxide | Rosiglitazone maleate | Metformin hydrochloride |
| 155 | Roflumilast | Pioglitazone | Insulin |
| Example numbering | Triple combination | ||
| 156 | roflumilast-N-oxide | Pioglitazone | Insulin |
| 157 | Roflumilast | Pioglitazone dihydrochloride | Insulin |
| 158 | roflumilast-N-oxide | Pioglitazone dihydrochloride | Insulin |
| 159 | Roflumilast | Pioglitazone | Metformin |
| 160 | roflumilast-N-oxide | Pioglitazone | Metformin |
| 161 | Roflumilast | Pioglitazone | Metformin hydrochloride |
| 162 | roflumilast-N-oxide | Pioglitazone | Metformin hydrochloride |
| 163 | Roflumilast | Pioglitazone dihydrochloride | Metformin |
| 164 | roflumilast-N-Oxide compound | Pioglitazone dihydrochloride | Metformin |
| 165 | Roflumilast | Pioglitazone dihydrochloride | Metformin hydrochloride |
| 166 | roflumilast-N-oxide | Pioglitazone dihydrochloride | Metformin hydrochloride |
| 167 | Roflumilast | Glimepiride | Insulin |
| 168 | roflumilast-N-oxide | Glimepiride | Insulin |
| 169 | Roflumilast | Glimepiride | Metformin |
| 170 | roflumilast-N-oxide | Glimepiride | Metformin |
| 171 | Roflumilast | Glimepiride | Metformin hydrochloride |
| 172 | roflumilast-N-oxide | Glimepiride | Metformin hydrochloride |
| 173 | Roflumilast | Glimepiride | Rosiglitazone |
| 174 | roflumilast-N-oxide | Glimepiride | Rosiglitazone |
| 175 | Roflumilast | Glimepiride | Rosiglitazone maleate |
| 176 | roflumilast-N-oxide | Glimepiride | Rosiglitazone maleate |
| 177 | Roflumilast | Glimepiride | Pioglitazone |
| 178 | roflumilast-N-oxide | Glimepiride | Pioglitazone |
| 179 | Roflumilast | Glimepiride | Pioglitazone dihydrochloride |
| 180 | roflumilast-N-oxide | Glimepiride | Pioglitazone dihydrochloride |
Pharmacology (Single drug)
Model (model)
Female C57BLKs db/db mice of 10 to 11 weeks of age obtained from M & B NS (8680 Ry, Denmark) were used in the study. Ten mice were housed per cage, allowing them to freely access water and to follow a rodent standard laboratory diet (chow 3433, Provimi Kliba SA, 4303Kaiseraugst, Switzerland).
Record of experiment
Mice were acclimated to the local animal device for a period of 1 week and retroorbital blood samples were taken 3 to 7 days before the start of the study.
Mice were given vehicle, roflumilast or roflumilast-N-oxide, respectively, every morning. Roflumilast or roflumilast-N-oxide was suspended in 4% methylcellulose and gavage was carried out orally using oral feeding & dosing syringes (external diameter: 1.5mm, TSE GmbH, 61350 BadHomburg, germany). The dose administered was 10ml/kg body weight in volume per administration.
Daily food (chow 3433) and water intake (total food intake per day divided by number of animals) was calculated for each animal before or during treatment with roflumilast or roflumilast-N-oxide.
Study for 10 days:mice were given vehicle, roflumilast or roflumilast-N-oxide, respectively, every morning. On day 9, the standard diet of laboratory animals was removed 1 hour after dosing, and mice were fasted for 24 hours. On day 10, after the mice were administered the vehicle, roflumilast or roflumilast-N-oxide for 1 hour, glucose tolerance was evaluated by orally administering 1g/kg/10ml glucose. Blood samples were taken before and 15 minutes after administration of glucose and glucose (accu-chek, Roche Diagnostics GmbH, 68298Mannheim, Germany) levels were measured.
Results
Table 5 shows the food intake of mice in one day (24 hour period) before or during the application of roflumilast-N-oxide:
table 5:
| daily (24 hour period) food intake [ g/mouse ] before the first separate administration of vehicle, roflumilast-N-oxide] | Daily (24 hour period) food intake of vehicle, roflumilast-N-oxide [ g/mouse ] were given separately] | |||||||||||||
| Number of days | -5 | -4 | -3 | -2 | -1 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | |
| Excipient (4% methyl cellulose) | 5.2 | 5.7 | 5.8 | 5.6 | 5.7 | 5.7 | 5.4 | 5.5 | 5.5 | 5.8 | 5.9 | 5.1 | 5.1 | |
| roflumilast-N-oxide-1 mg/kg | 6.0 | 5.9 | 6.4 | 6.4 | 6.4 | 5.7 | 5.4 | 5.8 | 5.5 | 5.6 | 5.8 | 5.4 | 5.5 | |
| roflumilast-N-oxide-3 mg/kg | 5.5 | 6.4 | 6.4 | 6.1 | 6.1 | 4.9 | 4.9 | 4.5 | 4.5 | 4.6 | 4.9 | 4.3 | 4.2 | |
| roflumilast-N-oxide-10 mg/kg | 6.0 | 6.2 | 6.4 | 6.4 | 6.5 | 2.9 | 3.3 | 3.5 | 2.9 | 3.0 | 3.1 | 2.6 | 3.8 | |
| roflumilast-N-oxide-30 mg/kg | 5.8 | 6.4 | 6.5 | 6.2 | 6.3 | 1.4 | 0.9 | 1.2 | 0.8 | 0.9 | 1.1 | 0.7 | 0.6 | |
[ days "-1" represents a 24 hour period prior to the first vehicle/roflumilast-N-oxide administration; day "1" represents a 24 hour period after the first vehicle/roflumilast-N-oxide administration; day "2" represents a 24 hour period after the second vehicle/roflumilast-N-oxide administration; etc. ]
Table 6 shows the water uptake in mice during one day (24 hours) before or during the application of roflumilast-N-oxide:
table 6:
| daily (24 hour period) water intake [ g/mouse ] before the first separate administration of vehicle, roflumilast-N-oxide] | The vehicle, roflumilast-N-oxide, were administered separately in daily (24 hour period) water intake [ g/mouse] | ||||||||||||||
| Number of days | -5 | -4 | -3 | -2 | -1 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | ||
| Excipient (4% methyl cellulose) | 7.9 | 8.8 | 6.5 | 6.9 | 6.7 | 7.2 | 7.7 | * | 9.0 | 8.5 | 8.1 | 7.9 | 8.1 | ||
| roflumilast-N-oxide-1 mg/kg | 9.2 | 9.4 | 8.4 | 7.9 | 8.6 | 7.6 | 6.9 | * | 7.1 | 8.0 | 7.7 | 8.5 | 7.2 | ||
| roflumilast-N-oxide-3 mg/kg | 9.8 | 4.3 | 7.6 | 7.6 | 9.1 | 5.1 | 5.9 | * | 5.9 | 5.7 | 5.4 | 5.4 | 5.2 | ||
| roflumilast-N-oxide-10 mg/kg | 12.1 | 9.6 | 7.9 | 8.2 | 9.6 | 2.9 | 3.5 | * | 3.2 | 3.7 | 3.3 | 3.0 | 4.1 | ||
| roflumilast-N-oxide-30 mg/kg | 10.1 | 12.4 | 10.0 | 9.4 | 10.1 | 2.3 | 2.4 | * | 2.6 | 3.0 | 2.9 | 3.3 | 2.5 | ||
| *There are no numerical values due to technical artifacts | |||||||||||||||
[ days "-1" represents a 24 hour period prior to the first vehicle/roflumilast-N-oxide administration; day "1" represents a 24 hour period after the first vehicle/roflumilast-N-oxide administration; day "2" represents a 24 hour period after the second vehicle/roflumilast-N-oxide administration; etc. ]
Table 7 shows the blood glucose levels before and after 15 minutes of glucose application, mice were treated with roflumilast for 10 days.
TABLE 7
| Blood glucose [ mg/ml](before administration of glucose) | Blood glucose [ mg/ml](15 minutes after glucose administration) | |
| Excipient (4% methyl cellulose) | 360 | 574 |
| Roflumilast-1 mg/kg | 347 | 507 |
| Roflumilast-10 mg/kg | 191 | 412 |
Table 8 shows the blood glucose levels before and after 15 minutes of glucose application, mice were treated with roflumilast-N-Oxide (Rof-N-Oxide) for 10 days.
TABLE 8
| Blood glucose [ mg/ml](before administration of glucose) | Blood glucose [ mg/ml](15 minutes after glucose administration) | |
| Excipient (4% methyl cellulose) | 301 | 533 |
| Rof-N-Oxide-1mg/kg | 220 | 595 |
| Rof-N-Oxide-3mg/kg | 174 | 467 |
| Rof-N-Oxide-10mg/kg | 139 | 423 |
| Rof-N-Oxide-30mg/kg | 146 | 326 |
Summary of the invention
Treatment with roflumilast-N-oxide has been shown to reduce the dose dependence of daily food intake in db/db mice. In addition, the daily water intake of db/db mice is reduced during treatment with roflumilast-N-oxide due to increased diabetes, which leads to high blood glucose levels. Furthermore, treatment with roflumilast or roflumilast-N-oxide has been shown to reduce fasting and postprandial blood glucose levels in db/db mice according to the biochemical test procedure detailed above.
Claims (2)
1. Use of roflumilast or a pharmaceutically acceptable salt thereof as sole therapeutic substance for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
2. Use of roflumilast-N-oxide or a pharmaceutically acceptable salt thereof as sole therapeutic substance for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05101772.1 | 2005-03-08 | ||
| EP05101772 | 2005-03-08 | ||
| PCT/EP2006/060418 WO2006094933A1 (en) | 2005-03-08 | 2006-03-03 | Roflumilast for the treatment of diabetes mellitus |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1116077A1 HK1116077A1 (en) | 2008-12-19 |
| HK1116077B true HK1116077B (en) | 2012-10-26 |
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