RU2351317C2 - System of separate medication delivery - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medications and concerns method of introduction of two therapeutically active anti-diabetes medications for treatment of sugar diabetes, including oral introduction to patient of system of delivery of anti-diabetes medications with different time of effect, where first therapeutically active anti-diabetes medication is selected from sulphonylurea and metglitinide analogue, which is discharged immediately after oral introduction of system of delivery of medication with different time of effect, and second therapeutically active anti-diabetes medication is selected from biguanidine anti-diabetes agent and thiazolidindione anti-diabetes agent, which is discharged during time period from 1 to 4 hours in such way that not more than 10% of active component is discharged during 45 minutes, and at least 70% of active component during 2 hours. Also described are system of separate delivery of medication with different time of effect and method of treating sugar diabetes or conditions associated with human sugar diabetes.

EFFECT: invention ensures coat rupture in definite time period.

13 cl, 17 tbl, 6 ex

Description

The present invention relates to a method for administering two or more therapeutically active drugs, including orally administering a separate drug delivery system to a patient, wherein the release time of two or more therapeutically active drugs is designed to provide the required disease control.

The present invention also relates to a method for administering two or more therapeutically active drugs, including orally administering to a patient a separate drug delivery system at a predetermined time before a patient takes a meal.

The present invention also relates to a separate drug delivery system that releases two or more antidiabetic drugs at different times after oral administration for the treatment of diabetes mellitus or conditions associated with diabetes mellitus.

In particular, the present invention relates to a separate drug delivery system that instantly releases one or more antidiabetic drugs after the oral administration of the system and, after a predetermined time after the oral administration of the system, reliably pulsates one or more antidiabetic drugs.

BACKGROUND OF THE INVENTION

It is often required that patients take medication multiple times to prevent and treat disease. Often patients are required to take different medications at different times. This gives patients inconvenience and, as a result, leads to non-compliance by patients with the prescribed dosages.

In order to obtain the required control over the symptoms of the disease or a measurable indicator of the condition, a combination of two different treatment methods could be undertaken at various given time points. For example, a first defined antidiabetic drug may be orally administered at a specific time before a meal to control post-meal glucose, and a second antidiabetic drug may be more useful in controlling glucose levels when taken with food. However, there are no prototypes of separate drug delivery systems that allow convenient administration of drugs. Thus, a method of administering two or more therapeutically active drugs, including an orally administered patient delivery system, is provided, wherein at least one first therapeutically active drug is released immediately after oral administration of the separate drug delivery system, and, at least one second therapeutically active drug is pulsed a certain time after the pen oral administration, with two or more therapeutically active drugs affect the disease in the same way or differently, but the mechanisms of influence are complementary, which provides control over the symptoms of the disease or a measurable indicator of the state of the disease, and besides the release time of two or more therapeutically active drugs is calculated in such a way that the necessary control of the disease is ensured.

At predetermined different points in time, two different drugs can also be taken, with one drug taken on an empty stomach and the other with food. The reasons why certain drugs are taken on an empty stomach or with food are known and include, for example, the rate or extent of absorption of the drug when taken on an empty stomach, other than the rate or degree of absorption of the drug in the presence of food, the degree of cleavage of the drug in gastric juice when taken with food, other than the degree of splitting of the drug when taken on an empty stomach, irritation of the stomach due to the use of the drug and, thus There is, therefore, a need for a method of administering two or more therapeutically active drugs, including a system for administering the drug separately to the patient at a predetermined time before the patient takes food, with at least one therapeutically active drug being released instantly after oral administration separate drug delivery systems and at least one therapeutically active drug is pulsed with torym break after a meal, that is, either immediately before a meal or during a meal or after a meal.

The administration of antidiabetic drugs such as glipizide approximately 30 minutes before a meal can lead to a maximum reduction in blood glucose after a meal, and therefore, the immediate release of such antidiabetic drugs is very important. On the other hand, an antidiabetic drug such as metformin is taken with food. A separate drug delivery system that instantly releases an antidiabetic drug, such as glipizide, after an oral administration of the system before meals, and which, with a delay, releases antidiabetic drugs like metformin in a pulsed mode, would allow it to withstand the regimen of drugs patients in compliance with the dosage and would provide optimal treatment for the disease.

Non-insulin-dependent diabetes mellitus (NIDDM), also known as diabetes in adulthood or type II diabetes mellitus, often leads to metabolic disorders and become the main cause of hyperglycemia. This is a heterogenetic disease with complex, obscure metabolic aspects. Insulin secretion may seem normal or even excessive, but not enough to compensate for insulin resistance. The disease is characterized by three main metabolic abnormalities that contribute to hyperglycemia. These include a partial or complete reduction in insulin secretion, peripheral tissue resistance to insulin, and an increase in the production of glucose by the liver on an empty stomach. Insulin resistance may also be responsible for obesity associated with NIDDM, although obesity itself is associated with insulin resistance: overweight worsens insulin resistance, while weight loss decreases blood glucose levels. Diet and exercise cause a decrease in insulin resistance and lead to a decrease in pancreatic insufficiency over time.

The goal of treatment for NIDDM is to normalize blood glucose while trying to prevent or reduce complications that may result from chronic hyperglycemia. A proper diet, backed up by exercise, causes a decrease in insulin resistance in patients with NIDDM and leads to the elimination of pancreatic insufficiency over time. If these measures are not enough, medications must be taken to control hyperglycemia. With oral medication, either the body's resistance to its own insulin decreases, or the secretion of insulin increases to the required level. Sulfonylureas and biguanides have been used in oral antidiabetic therapy. Other classes of oral antidiabetic drugs include alpha-glucosidase-based inhibitors, aldose reductase-based inhibitors, thiazolidinediones, insulin secretion enhancing agents, and others. These classes of formulations have been used effectively in monotherapy to achieve control of carbohydrate metabolism in patients with diabetes.

In the treatment of non-insulin-dependent diabetes mellitus, biguanide derivatives such as metformin, phenformin and buformin, usually in the form of their hydrochloride salt, were used as antihyperglycemic drugs. The mechanism of action of drugs belonging to this class includes a decrease in the production of glucose by the liver, a decrease in the absorption of glucose in the intestine, and an increase in the level of absorption and use of glucose. Biguanides improve glucose tolerance in patients with type II diabetes, while lowering both basal plasma glucose and plasma glucose after meals. With biguanide therapy, insulin secretion remains unchanged, while insulin levels on an empty stomach and plasma response to insulin can actually decrease throughout the day. Phenformin is still widely used as an antihyperglycemic drug, and of the other drugs, metformin is preferable to biguanide, since the normoglycemic effect it has is less likely to cause milk acidosis, which is a common side effect with phenformin therapy. Metformin is known to lower blood triglyceride levels and helps reduce body weight.

Sulfonylureas used in the treatment of type II diabetes mellitus include acetohexamide, carbamide, chlorpropamide, glipizide, glyburide (glibenclamide), glimepiride, glyclazide, glibornuride, glycuidone, glisoxepide, glyhexamide, fenbutamide, tolamide, tolamide, tolamide, tolamide, tolamide, tolamide These sulfonylureas are used as bases, but not as salts. The mechanism of action of these drugs includes lowering the concentration of glucose in the blood mainly by stimulating the release of endogenous insulin from the beta cells of the pancreas, and thus they act as agents that lower blood sugar. Sulfonylureas are used as dietary supplements to control non-insulin-dependent diabetes mellitus in patients whose hyperglycemia cannot be controlled by just one diet. To maximize blood glucose concentration after a meal, sulfonylurea is used 30 minutes before a meal.

As noted in the 55th edition of the Physicians' Desk Reference, published in 2001, metformin hydrochloride monotherapy, commercially available under the brand name Glucophage® from Bristol-Myers Squibb Co .) may be effective for patients who have no reaction to sulfonylurea, or who have only a partial reaction to sulfonylurea, or who have stopped responding to sulfonylurea. If in the case of such patients the use of Glucophage® monotherapy does not provide adequate glycemic control, then the combination of Glucophage® monotherapy and sulfonylurea can give a synergistic effect. In addition, it was found that monotherapy with sulfonylurea gives a positive reaction that lasts for 4-5 years, but in most patients the effectiveness of such therapy decreases over time. This is called a "secondary pathology" associated with oral therapy with drugs that lower blood sugar. In these cases, a combination of biguanides and sulfonylureas is used. Biguanides can affect insulin resistance, but cannot stimulate insulin secretion, while sulfonylureas can stimulate insulin secretion, but they cannot affect insulin resistance. Therapy, which combines the use of biguanide and sulfonylurea, has a synergistic effect on glucose control, since both drugs act differently, but they use complementary mechanisms.

Diabetes mellitus is a chronic disease with a variety of pathological manifestations and is accompanied by impaired lipid metabolism and blood circulation, as well as impaired carbohydrate metabolism. As a result, the disease tends to progress, causing in many cases complications. Therefore, in each case, it is necessary to choose one drug for the prevailing state of the disease. However, in clinical practice it is often difficult to make such a choice, because the use of each individual drug for one purpose is not sufficient for some conditions of the disease, and then various problems arise, such as side effects caused by an increased dose or long-term exposure to a single drug or drug. Therefore, for the treatment of NIDDM, there is a need to use combination therapy.

Alpha glucosidases are important for the breakdown of starches, dextrins, maltose and sucrose. Alpha glucosidase inhibitors inhibit glucose uptake from a carbohydrate load, while delaying the formation of glucosidase. Compounds of this class have the ability to prevent or reduce nephropathic lesions in diabetes. Common drugs in this class include acarbose, miglitol, emiglitate and voglibosis. Delayed alpha glucosidase delays the digestion of sucrose and other polysaccharides, thereby slowing down the rate of absorption of glucose and fructose. Acarbose is a complex oligosaccharide that competitively inhibits the formation of alpha-glucosidases in the interstitial brush region, including glucoamylase, sucrose, maltase and isomaltase. It is desirable that an alpha-glucosidase inhibitor be used as an antihyperglycemic agent because it does not cause hypoglycemia. This drug also has the ability to reduce body weight. Alpha-glucosidase-based inhibitors can be used along with other oral antidiabetic drugs to improve blood glucose control. The 55th edition of the Physician's Table Recommendations, 2001, states that acarbose reduces insulinotropic and weight-increasing effects caused by sulfonylurea when used together.

Thiazolidinediones are another class of antidiabetic drugs that are thought to enhance the effects of insulin, thus stimulating the use of glucose in peripheral tissues, possibly stimulating non-oxidative glucose metabolism in the muscle and suppressing gluconeogenesis in the liver. Drugs belonging to this class stimulate fat formation and reduce plasma triglyceride and free fatty acids. Examples of thiazolidinediones that are commonly used in diabetes are troglitazone, pioglitazone, rosiglitazone, ciglitazone, darglitazone and englitazone. Although thiazolidinediones enhance the action of insulin at the cellular level, they do not stimulate the release of insulin and do not mimic its action. The therapeutic effect in the treatment of thiazolidinedione depends on the availability of adequate amounts of insulin. The use of an antidiabetic drug based on thiazolidinedione simultaneously with sulfonylurea provides a balance of stimulated insulin secretion with increased insulin resistance.

Now, when controlling NIDDM, a new class of insulinotropic drugs (secretion enhancing drugs), called metglitinide analogues, or regulators of glucose supplied with food, are used. Compounds of this class have a speed, short-term effect, are not sulfonylurea, are oral agents that lower blood sugar, which act by regulating the content of glucose from food. The regulation of glucose supplied with food is aimed at restoring the reaction to insulin in the first stage as a result of eating, which is absent in patients with NIDDM. Repaglinide, the most commonly used drug of this class, provides more stringent glycemic control while reducing the risk of hypoglycemic events. This drug lowers blood glucose levels while stimulating pancreatic secretion of insulin. This action depends on the functioning beta cells in pancreatic islets. Repaglinide blocks ATP-dependent potassium channels in the beta-cell membrane by forming bonds in the characterized regions. This blockage of the potassium channel depolarizes the beta cell, which leads to the opening of calcium channels. The resulting increased influx of calcium causes insulin secretion. The mechanism of the ion channel is selective for tissue with low affinity for the cardiac and skeletal muscle. Repaglinide is rapidly absorbed and rapidly removed, providing a quick recovery of insulin levels that occur after a meal to an afternoon level. The release of insulin depends on the glucose content and decreases at low glucose concentrations. Repaglinide also provides a flexible meal schedule and safety. As a result of a short half-life of plasma and the lack of accumulation of repaglinide with repeated administration, the risk of hypoglycemia between meals and at night is significantly reduced. The drug acts synergistically with biguanides and thiazolidinediones, especially metformin and troglitazone. The dose of repaglinide administered before each meal is from 0.5 to 4 mg.

Prototypes provide systems in which a combination of antidiabetic drugs is used to treat non-insulin-dependent diabetes mellitus. US patent No. RE 37330 (to replace US patent No. 5922769) proposes a method for treating non-insulin-dependent diabetes mellitus in cases of secondary failure caused by treatment using a composition based on a combination of glibenclamide and metformin hydrochlorides with a mass ratio of more than 1: 100, including, if necessary, the introduction to the subject of the same composition based on a combination of glibenclamide and metformin in the form of hydrochlorides with a mass ratio of 1: 100. The patent also describes the results of a clinical study, which shows that the maximum dose of glibenclamide, which does not cause any side effects, is 15 mg per day, while the same dose of metformin is 1500 mg per day, and that the use of such a composition on based combination with a ratio less than stated in the patent would lead to formulations that do not give the optimal therapeutic effect. The patent also describes the combination of glibenclamide and metformin in tablet form. The composition is not disclosed in the patent, while sulfonylureas are released instantly, and biguanide is released with a delay, in particular, with a given delay.

US Pat. No. 6,031,004 (hereinafter '004) discloses the use of a composition based on a combination of new salts of metformin and glyburide in the treatment of type II diabetes mellitus. In this invention, both the salt of metformin and glyburide is released instantly. The composition is not disclosed in the patent, while sulfonylurea is released instantly, and biguanide is released with a delay, in particular, with a given delay.

U.S. Patent No. 6,099,862 (hereinafter '862) describes a controlled release pharmaceutical tablet which consists essentially of (a) a core consisting essentially of (i) metformin or a pharmaceutically acceptable salt thereof, (ii) glipizide, ( iii) polyvinylpyrrolidone and (iv) sodium lauryl sulfates, (b) optionally from an airtight membrane around the core, (c) a semipermeable membrane membrane covering said core, including - (i) cellulose acetates, (ii) polyethylene glycol with an average molecular weight of 380o 420, and (iii) a plasticizer, and (d) at least one passage in a semipermeable membrane to allow the release of metformin and glipizide from the core into the environment of use, providing therapeutic levels of metformin and glipizide from twelve to twenty-four hours . In this invention, both the salt of metformin and glipizide are released slowly after oral administration. The composition is not disclosed in the patent, while sulfonylurea is released instantly, and biguanide is released with a delay, in particular, with a given delay.

PCT applications WO 98/57649 and WO 99/03476 describe a composition based on a combination of an insulin-sensitive drug such as thiazolidinedione and an agent that enhances the secretion of insulin such as sulfonylurea. The PCT application WO 99/03477 describes a method for treating diabetes mellitus and related conditions using a composition based on a combination of an insulin-sensitive drug, an agent that enhances insulin secretion, and an antihyperglycemic drug based on biguanide. A thiazolidinedione like troglitazone, ciglitazone, rosiglitazone, pioglitazone or englitazone is used as an insulin-sensitive drug used in this combination, and sulfonylurea or repaglinide is used as an agent that enhances insulin secretion. Thus, the application describes a combination of thiazolidinedione, sulfonylurea or repaglinide and biguanide. The application says that the claimed combination has a synergistic effect when taken in the form of a single dosage, and therefore the amount of each drug required is reduced. However, all drugs are excreted in the usual way, which reduces flexibility when administering the drug.

PCT application WO 99/03478 describes a method for treating diabetes mellitus and related conditions using a composition based on a combination of an insulin-sensitive drug, an insulin secretion enhancing agent, and an alpha glucosidase inhibitor. Thiazolidinedione is used as an insulin-sensitive drug, sulfonylurea or repaglinide is used as an insulin secretion enhancing agent, while an alpha-glucosidase-based inhibitor is selected from acarbose, emulsate and miglitol. The application states that such a combination has a beneficial effect on glycemic control as a result of a synergistic effect and also has minimal side effects. However, the invention does not provide separate delivery of drugs based on a combination of two or more antidiabetic drugs, while one antidiabetic drug is released instantly, and another antidiabetic drug (a) is allocated with a given delay.

US Pat. No. 6,011,049 discloses a composition comprising a combination of synergistic amounts of sulfonylurea, thiazolidinedione (glitazone) antidiabetic drug, and biguanide. The patent says that since the non-stimulated insulin secretory ability of beta cells is very low with NIDDM, changing only insulin resistance gives only partial advantages. Therefore, the system maintains the level of stimulated insulin secretion using sulfonylurea with the addition of glitazone to improve insulin sensitivity, thus ensuring a level of glycemic control that cannot be obtained using only one of the drugs. However, the invention does not propose a separate drug delivery system based on a combination of two or more antidiabetic drugs.

PCT patent WO 98/56378 for the manufacture of a preparation ready to stimulate food-related insulin secretion in order to treat postprandial hyperglycemia in NIDDM patients, provides a short-acting drug that lowers blood sugar, which can stimulate insulin secretion from beta cells. This system uses repaglinide or a combination of repaglinide with long-acting drugs that lower blood sugar, such as metformin, sulfonylurea or troglitazone. The patent says that repaglinide stimulates endogenous insulin secretion associated with food intake, while metformin increases tissue sensitivity to insulin, this combination significantly increases glycemic control. This combination is used during meals. However, this invention does not provide separate drug delivery in the form of a composition based on a combination of two or more antidiabetic drugs so that one antidiabetic drug is released instantly and another antidiabetic drug (other antidiabetic drugs) is released with a given delay.

US Pat. No. 6,166,043 (hereinafter '043) proposes a method for reducing the amount of active ingredients administered to a patient diagnosed with diabetes, which comprises using a therapeutically effective amount of an insulin sensitivity enhancing agent in combination with biguanide. A thiazolidinedione selected from the group consisting of pioglitazone and troglitazone is used as an agent that enhances insulin sensitivity in the system, and the biguanide is selected from the group consisting of metformin, phenformin, and buformin. This combination is administered to the patient in the form of a mixture, or the drugs are administered independently of each other, while both drugs are released instantly.

US Pat. No. 6,172,090 (hereinafter '090) describes a method for reducing side effects from administering active ingredients to a patient with a diabetic diagnosis, which comprises administering to said patient a therapeutically effective amount of an agent that enhances insulin sensitivity in combination with biguanide. As in the '043 patent, a combination of a thiazolidinedione such as pioglitazone or troglitazone and a biguanide such as metformin, phenformin or buformin, which are administered independently of each other or in a mixture, is described.

In this invention, thiazolidinedione and biguanide are released instantly after oral administration of the drug.

US Pat. No. 6,153,632 (hereinafter '632) describes a composition for treating diabetes mellitus comprising a therapeutically effective amount of an insulin-sensitive drug and a therapeutically effective amount of an antidiabetic drug, the latter being selected from a group of drugs that includes orally administered insulin injectable insulin, sulfonylurea, biguanide and an alpha glucosidase inhibitor. Thiazolidinedione is used as an insulin-sensitive drug. Both one and the other antidiabetic drug are released instantly after oral administration of the composition.

PCT application WO 98/57634 (hereinafter '634) describes a method for treating diabetes mellitus and an associated condition comprising the use of an effective non-toxic and pharmaceutically acceptable amount of an insulin-sensitive preparation and a biguanide-based antihyperglycemic drug. Thiazolidinedione is used as an insulin-sensitive drug. In this invention, both one and the other antidiabetic drug are released instantly.

PCT application WO 00/28989 discloses a pharmaceutical composition comprising an insulin-sensitive drug and another antidiabetic drug and a pharmaceutically acceptable carrier thereof, the composition providing a modified release of at least an insulin-sensitive drug and other antidiabetic drug. The modified release may be delayed release using a composition resistant to gastric juice, or extended release using a cleavable, non-splittable or eroding matrix, or a controlled release composition. Thiazolidinedione is used as an insulin-sensitive drug, while another antidiabetic drug is selected from the group of drugs, which includes an alpha glucosidase inhibitor, biguanide and an insulin secretion enhancing agent, while an insulin secretion enhancing agent, sulfonylurea, repaglinide or nateglinide is used. The patent says that this combination provides an effective delivery of antidiabetic drugs, while providing effective glycemic control, and has no adverse effects. However, the invention does not provide separate drug delivery based on a combination of two or more antidiabetic drugs so that one antidiabetic drug is released instantly and another antidiabetic drug (other antidiabetic drugs) is released with a given delay.

Many prototypes relate to pharmaceutical formulations from which a drug is released after a delay. Some prototypes with the release of drugs after a given time are described in US patent No. 3247066; in Irish application IE 902533; US Pat. No. 4,871,549; U.S. Patent No. 5,229,131; in PCT publication WO 99/18938 and in PCT publication WO 00/74655. All of them relate to systems consisting of a core that swells after absorption of the surrounding fluid, and from a shell that breaks under pressure from the swollen core. However, none of these prototypes describes a separate drug delivery system designed to provide the necessary disease control, including:

but. a first composition comprising one first therapeutically active drug or more thereof, and

b. a second composition comprising one second or more therapeutically active drug, wherein at least one first therapeutically active drug is released instantly after oral administration of the separate drug delivery system and at least one second therapeutically active drug the drug is pulsed a certain time after oral administration, with two or more therapeutically active drugs A number of drugs affect the disease in the same way or in different ways, while the mechanisms of influence complement each other, which provides control over the symptoms of the disease or a measurable indicator of the state of the disease, and also the time it takes to release two or more therapeutically active drugs designed in such a way that the necessary disease control is ensured. In particular, none of the prototypes says that it would be beneficial for the treatment of diabetes mellitus by oral administration of a separate drug delivery system comprising one therapeutically active antidiabetic drug or a greater number of such drugs, while at least one first therapeutically active antidiabetic drug is released instantly after oral administration of the separate drug delivery system and at least one second erapevticheski active antidiabetic drug is released in a pulsed mode after a certain time after the oral administration. In addition, a separate drug delivery system is not considered, which provides instant release of at least one first therapeutically active drug after oral administration of the separate drug delivery system at a predetermined time before a meal, and allocates at least one second a therapeutically active antidiabetic drug during a meal. In the prototypes discussed in US patent No. 3247066, in European application 1123700, in US patent No. 5260069 and in US patent No. 4871549, systems are considered that are different from the system of the present invention in that they relate to dosage forms with controlled release. In this case, the dose of the drug is divided into many units and there is no guarantee that this unit will burst at a given time in a reliable manner. According to statistics, different units are broken at different times and, thus, on average after a while, a controlled release of the active component is ensured. In accordance with the present invention in a single unit contains the total amount of active component, which is intended to be released at a given time. An important requirement for the use of such systems in relation to a large number of patients is that the system must deliver the drug at a certain time in a reliable manner to a large number of patients using this system. Thus, the shell must be torn securely, the core must be immediately destroyed, after which the drug must be reliably released in a pulsed mode. For example, if in five to ten cases out of a hundred shells do not open or break at a certain time, but the gap takes a much longer time when tested by mixing in various mixing modes and in different water compositions, then there is no certainty that this gap will occur at a given time. In addition, if the change in pH can affect the release before rupture, then there is no certainty that the release will occur at a given time. In addition, if a rupture of the membrane occurs, but the therapeutically active drug does not stand out from all or some units in the pulsed mode, then there is no certainty that there will be a pulsed release at a given time. Prototypes of the type WO 99/18938, WO 00/74655 and IE 902533 do not mention the reliability of the gap or separation from a large number of tablets or the optimization process of the compositions in order to ensure a reliable gap or reliable separation with a large number of tablets. US Pat. No. 5,229,131 discloses a large amount of data on the proportion of tablets breaking up after 30 minutes and 60 minutes, and the proportion of tablets releasing their contents after 60 minutes and 120 minutes (Tables 12-18). Tablets do not provide reliable tearing, as provided by the composition of the present invention, while 36 of 36 tablets are torn within ± 50% of the time of rupture of the shell. Although there are many prototypes, however, there are no commercially successful systems that provide separate delivery of drugs in a reliable manner.

The prototypes do not mention compositions or systems containing a composition based on a combination of two or more therapeutically active antidiabetic drugs, with at least one therapeutically active antidiabetic drug being released instantly and at least one therapeutically active drug being released with a delay or at a specified interval.

OBJECT OF THE INVENTION

An object of the present invention is to provide a method for administering two or more therapeutically active drugs, including an oral drug delivery system orally administered to a patient, wherein at least one first therapeutically active drug is released instantly after oral administration of the separate drug delivery system and, at least one second therapeutically active drug is pulsed after a predetermined time after oral administration, in this case two or more therapeutic active drugs affect the disease in the same way or differently, but the mechanisms of influence complement each other, which provides control over the symptoms of the disease or for a measurable indicator of the state of the disease, and also with this time, the allocation of two or more therapeutically active drugs is calculated in such a way that provides the necessary control over the disease.

Another objective of the present invention is a method of administering two or more therapeutically active drugs, including a system for separately administering a drug separately to a patient at a predetermined time before a patient takes food, wherein at least one therapeutically active drug is released instantly after oral administration separate drug delivery systems and at least one therapeutically active drug is excreted in impa in ice mode some time after eating.

A particular objective of the present invention are the above methods of administering two or more therapeutically active antidiabetic drugs.

The aim of the present invention is a system for the separate delivery of drugs designed to provide the necessary control over the disease, including:

but. a first composition comprising one first therapeutically active drug or more thereof, and

b. a second composition comprising one second or more therapeutically active drug, wherein at least one first therapeutically active drug is released instantly after oral administration of the separate drug delivery system and at least one second therapeutically active drug the drug is pulsed a certain time after oral administration, with two or more therapeutically active drugs A number of drugs affect the disease in the same way or in different ways, while the mechanisms of influence complement each other, which provides control over the symptoms of the disease or a measurable indicator of the state of the disease, and also the time it takes to release two or more therapeutically active drugs designed in such a way that the necessary disease control is ensured.

Another objective of the present invention is a system for the separate delivery of drugs for the treatment of diabetes mellitus or conditions associated with diabetes mellitus, including:

but. a first composition comprising one therapeutically active antidiabetic drug or a greater number of such drugs excreted in a pulsed mode after a certain delay;

b. a second composition comprising one second therapeutically active antidiabetic drug or a greater number of such drugs released instantly after oral administration of the separate drug delivery system.

Another objective of the present invention is a system for separate delivery of drugs, as mentioned above, while the first composition is allocated in a pulsed mode at a specified time, while in the form of a pulse after a predetermined time interval following the oral administration of a system of separate delivery of drugs, an antidiabetic medicine.

Another objective of the present invention is a system for the separate delivery of drugs, including a composition that is emitted in a pulsed mode at a given time, consisting of a core, including one therapeutically active antidiabetic drug or more, a swelling agent and, possibly, a water-soluble composition (compositions ) to initiate osmosis, and the composition of the shell, including one film-forming polymer or a greater number of them, and after swelling of the core, the shell it breaks down and in a pulsed manner in a reliable manner after a predetermined time after oral administration of the separate drug delivery system, therapeutically active drug is released.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a method for administering two or more therapeutically active drugs, including an oral drug delivery system orally administered to a patient, wherein at least one first therapeutically active drug is released instantly after oral administration of the separate drug delivery system and at least one second therapeutically active drug is pulsed out ty for a certain time after oral administration, with two or more therapeutically active drugs affect the disease in the same way or differently, and the mechanisms of influence are complementary, which provides control over the symptoms of the disease or for a measurable indicator of the state of the disease, and in addition, the release time of two or more therapeutically active drugs is calculated in such a way that the necessary control of the disease is ensured.

The present invention also contemplates a method of administering two or more therapeutically active drugs, including a system for separately administering a separate drug delivery to a patient at a predetermined time prior to the patient taking a meal, wherein at least one therapeutically active drug is released instantly after oral administration of a separate drug delivery system and at least one therapeutically active drug stands out in a pulsed mode some time after eating.

In particular, in accordance with the present invention, methods of administration for two or more therapeutically active antidiabetic drugs are contemplated.

Further, in accordance with the present invention, there is considered a separate drug delivery system designed to provide the necessary disease control, including:

but. a first composition comprising one first therapeutically active drug or more thereof, and

b. a second composition comprising one second or more therapeutically active drug, wherein at least one first therapeutically active drug is released instantly after oral administration of the separate drug delivery system and at least one second therapeutically active drug the drug is pulsed a certain time after oral administration, with two or more therapeutically active drugs A number of drugs affect the disease in the same way or in different ways, while the mechanisms of influence complement each other, which provides control over the symptoms of the disease or a measurable indicator of the state of the disease, and also the time it takes to release two or more therapeutically active drugs designed in such a way that the necessary disease control is ensured.

In accordance with the present invention, in particular, a separate drug delivery system for treating diabetes mellitus or conditions associated with diabetes mellitus is considered, including:

but. a first composition comprising one therapeutically active antidiabetic drug or a greater number of such drugs excreted in a pulsed mode after a certain delay;

b. a second composition comprising one second therapeutically active antidiabetic drug or a greater number of such drugs released instantly after oral administration of the separate drug delivery system.

It is desirable that in the separate drug delivery system discussed above, the first composition would be a composition that releases the antidiabetic drug in a pulsed manner after a predetermined time interval or after the time interval following oral administration of the separate drug delivery system.

Another objective of the present invention is a system for the separate delivery of drugs, including a composition that is emitted in a pulsed mode at a given time, consisting of a core, including one therapeutically active antidiabetic drug or more, a swelling agent and, possibly, a water-soluble composition (compositions ) to initiate osmosis, and the composition of the shell, including one film-forming polymer or a greater number of them, and after swelling of the core, the shell it breaks down and in a pulsed manner in a reliable manner after a predetermined time after oral administration of the composition, a therapeutically active drug is released.

In this context, the term “conditions associated with diabetes mellitus” means conditions associated with a prediabetic state, conditions associated directly with diabetes mellitus and complications associated with diabetes mellitus. In this context, the term "conditions associated with a prediabetic state" refers to conditions such as insulin resistance, including hereditary insulin resistance, decreased glucose tolerance, obesity, and increased blood insulin levels. Diabetes-related conditions themselves include hyperglycemia, insulin resistance, including acquired insulin resistance and obesity. In addition, conditions associated with diabetes mellitus itself include arterial hypertension and cardiovascular disease, in particular atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome, and steroid-induced insulin resistance, and gestational diabetes. "Complications associated with diabetes" include kidney disease, especially kidney disease associated with type II diabetes, neuropathy and retinopathy. Kidney diseases associated with type II diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, nephritis syndrome, hypertensive nephrosclerosis, and advanced kidney disease.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a method for administering two or more therapeutically active drugs, including an oral drug delivery system orally administered to a patient, wherein at least one first therapeutically active drug is released instantly after oral administration of the separate drug delivery system and at least one second therapeutically active drug is pulsed out taking a certain amount of time after oral administration, with two or more therapeutically active drugs affect the disease in the same way or differently, but the mechanisms of influence are complementary, which provides control over the symptoms of the disease or for a measurable indicator of the state of the disease, and in addition, the release time of two or more therapeutically active drugs is calculated in such a way that the necessary control of the disease is ensured. The separate drug delivery system can be appropriately optimized to provide improved disease control when there is a measurable indicator of the condition of the disease such as blood pressure, pulse, blood glucose, urination frequency, eye pressure, etc. However, system optimization can be appropriately performed based on clinical observation of disease symptoms associated with a blood glucose profile that is affected by a therapeutically active drug.

A therapeutically active drug can be selected from the class of therapeutic agents, i.e., from alcoholic drugs, drugs used in Alzheimer's disease, anesthetics, acromegaly drugs, painkillers, anti-asthma drugs, anti-cancer drugs, anticoagulants, antithrombotic drugs, anticonvulsants drugs, antidiabetic drugs, antiemetics, glaucoma medicines, an tigistamines, antibacterial drugs, drugs for Parkinson's disease, drugs for platelets, antirheumatic drugs, antispasmodics, anticholinergics, antitussive drugs, carbonic anhydrase inhibitors, cardiovascular drugs, cholinesterase inhibitors, drugs for the treatment of central disorders nervous system, central nervous system stimulants, drugs tv for the treatment of cystic fibrosis, substances with an affinity for the dopamine receptor, drugs for the treatment of endometritis, therapy for erectile dysfunction, drugs for infertility, drugs for the gastrointestinal tract, immunomodulators, immunosuppressive drugs, drugs for improving memory, drugs for migraine, muscle relaxants, nucleoside analogues, drugs for the treatment of osteoporosis, parasympathomimetics, prostaglandins, psychotherapeutically active drugs, with remedies, sleeping pills, tranquilizers, drugs used for skin diseases, steroids and hormones.

The term "pulsed release" should be understood as the characteristic of the release of the drug from conventional tablets and capsules, which does not provide a slow, prolonged, controlled or late release of a therapeutically active drug. For example, in accordance with one embodiment of the present invention, where the predetermined pulsed release time is approximately 70 minutes, “therapeutically active drug release in pulsed mode” comprises the release of not more than 10% of the active component in 45 minutes and at least , 70% of the active component in 2 hours when tested according to the US Pharmacopoeia method for solubility in a buffer with a pH level of 6.8 at 37 ± 0.5 ° C in the apparatus of the United States Pharmacopeia type II with a speed of 75 revolutions per minute.

The present invention also contemplates a method of administering two or more therapeutically active drugs, including a system for separately administering a separate drug delivery to a patient at a predetermined time prior to the patient taking a meal, wherein at least one therapeutically active drug is released instantly after oral administration of a separate drug delivery system and at least one therapeutically active drug it is released in a pulsed mode after a delay approximately at the time of eating, that is, either immediately before eating, or during eating, or after eating.

In particular, in accordance with the present invention, methods for administering to a patient two or more therapeutically active antidiabetic drugs are contemplated.

Further, in accordance with the present invention, there is considered a separate drug delivery system designed to provide the necessary disease control, including:

but. a first composition comprising one first therapeutically active drug or more thereof, and

b. a second composition comprising one second or more therapeutically active drug, wherein at least one first therapeutically active drug is released instantly after oral administration of the separate drug delivery system and at least one second therapeutically active drug the drug is pulsed a certain time after oral administration, with two or more therapeutically active drugs A number of drugs affect the disease in the same way or in different ways, while the mechanisms of influence complement each other, which provides control over the symptoms of the disease or a measurable indicator of the state of the disease, and also the time it takes to release two or more therapeutically active drugs designed in such a way that the necessary disease control is ensured. None of the prototypes describe such systems for the separate delivery of drugs.

In accordance with the present invention, in particular, a separate drug delivery system for treating diabetes mellitus or conditions associated with diabetes mellitus is considered, including:

but. a first composition comprising one therapeutically active antidiabetic drug or a greater number of such drugs excreted in a pulsed mode after a certain delay;

b. a second composition comprising one second therapeutically active antidiabetic drug or a greater number of such drugs released instantly after oral administration of the separate drug delivery system.

It is desirable that in the separate drug delivery system discussed above, the first composition would be a composition that releases the antidiabetic drug in a pulsed manner after a predetermined time interval or after the time interval following oral administration of the separate drug delivery system.

In particular, in accordance with the present invention, there is considered a separate drug delivery system comprising a composition which is pulsed at a predetermined time, consisting of a core comprising one or more therapeutically active antidiabetic drugs, a swelling agent, and possibly a water-soluble the composition (compositions) for initiating osmosis, and the composition of the shell, including one film-forming polymer or more of them, while after swelling with rdtseviny shell is broken and the therapeutically active agent is released in a pulsed mode.

The total amount of the active component of the present invention is contained in a single unit composition, emitted in a pulsed mode at a given time. An important requirement for the use of such systems in relation to a large number of patients is that the system must deliver the drug at a certain time in a reliable manner to a large number of patients using this system. Thus, the shell must be torn securely, the core must be immediately destroyed, after which the drug must be reliably released in a pulsed mode. For example, if in five to ten cases out of a hundred shells do not open or break at a certain time, but the gap takes a much longer time when tested by mixing in various mixing modes and in different water compositions, then there is no certainty that this gap will occur at a given time. In addition, if the change in pH can affect the release before rupture, then there is no certainty that the release will occur at a given time. In addition, if a rupture of the membrane occurs, but the therapeutically active drug is not excreted in a pulsed mode from all or some units, then there is no certainty that a pulsed release will occur at a given time.

The composition of the separate drug delivery system of the present invention, emitted in a pulsed manner at a predetermined time, has these desirable features so that ruptures of the membrane and the release of a therapeutically active drug from it occur in a reliable manner after a predetermined time after oral administration of the composition in pulsed mode.

In particular, in the separate drug delivery system of the present invention, the composition emitted in a pulsed mode at a given time is optimized as follows:

but. the core can swell at the required speed to the required size;

b. the sheath film has the necessary strength, ductility and water permeability; and

from. the amount of the applied composition of the shell is adjusted so that when the core swells, the shell breaks and in the pulse mode, the therapeutically active drug is released reliably after a specified time after oral administration of the composition, while a reliable break means that 36 tablets break apart after a specified time of 36, as evidenced by tests of tablets for solubility in an aqueous medium according to the method of the United States Pharmacopeia at 37 ± 0.5 ° C in the apparatus of the United States Pharmacopeia type I or II at a speed of 50 to 100 rpm. In addition, if the set time is in the range from 1 to 4 hours, then 36 of the 36 tablets are torn within ± 50% of the set time; and if the set time is from 4 to 12 hours, then 36 out of 36 tablets are torn within ± 25% of the set time.

In accordance with certain preferred options, the separate drug delivery system of the present invention includes:

1. a separate drug delivery system, wherein the antidiabetic drug of the first composition is a biguanide-based antidiabetic drug, and in the second composition, the sulfonylurea is the antidiabetic drug;

2. a separate drug delivery system, wherein the first-order antidiabetic drugs are selected from the group consisting of an alpha-glucosidase inhibitor, thiazolidinedione and an insulin secretion enhancing agent; and as an antidiabetic drug of the second composition, an agent is used that enhances the secretion of insulin; further, if the means enhancing the secretion of insulin are present in both the first and second formulations, then these are different means;

3. a separate drug delivery system, wherein the antidiabetic drug of the first composition is a biguanide-based antidiabetic drug, and as the antidiabetic drug of the second composition, an agent is selected that is selected from the group consisting of an agent that enhances insulin secretion, and thiazolidinedione is possible in combination with an alpha glucosidase inhibitor;

4. a separate drug delivery system, wherein the antidiabetic drug of the first composition is a biguanide-based antidiabetic drug, and an alpha-glucosidase inhibitor is used as the antidiabetic drug of the second composition.

In accordance with the present invention, the composition emitted in a pulsed mode at a predetermined time, absorbs liquid from the environment, which leads to swelling of the funds included in the core. Then, after rupture of the shell under the influence of mechanical pressure caused by the swelling of the agent that is part of the core, a therapeutically active antidiabetic drug is released at a predetermined time in a predetermined time. The time of rupture of the shell can be controlled by changing (a) the degree and speed of swelling of the core; (b) the composition of the shell, designed to be allocated in a pulsed mode at a given time by using various components and their ratios; and (c) shell thickness.

The swellable agent used in the composition emitted in a pulsed mode at a given time includes one or more swellable hydrophilic polymers. The amount or relative content of polymers varies. However, a sufficient amount of material is present in the core, which, when absorbed, provides a pressure caused by swelling in excess of the adhesive strength of the shell surrounding the tablet or core. It is desirable that the polymers be used in a dry state or in such a form that provides sufficient capacity to absorb water. Examples of the swellable hydrophilic polymers of the present invention, which can be used in a composition which is pulsed at a given time as swellable agents, can be polymers of the class of vinylpyrrolidone such as povidone, or crosslinked polyvinylpyrrolidone such as crospovidone; cellulose and cellulose derivatives such as microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxyalkyl cellulose or crosslinked carboxyalkyl celluloses and their alkali metal salts; starch-based sodium glycolate, starch and starch derivatives, ion exchange resins and mixtures thereof. It is desirable that such a swellable agent be used as a swellable agent, which would significantly swell, but do not form a strong gel, and which can be selected from the group of agents that include crosslinked sodium carboxymethyl cellulose, crosslinked polyvinylpyrrolidone and starch-based sodium glycolate . It is desirable that the swellable agent also has good capillary properties and is capable of swelling several times when absorbed from the environment compared to the original volume.

The alkali metal salt of crosslinked carboxyalkyl cellulose, i.e. crosslinked sodium carboxymethyl cellulose, also known as croscarmellose sodium or Ac-Di-Sol, is commercially available under the name Nymcel® ZSX, Pharmacel® XL, Primellose® or Solutab®. The amount of swellable agent that can be used depends on the required time to rupture the shell, torn in a pulsed mode at a given time, the properties and quantities of other core components, as well as on the composition and thickness of the shell. In general, croscarmellose sodium can be used as a polymer swellable agent, the mass fraction of which is in the range of about 0.5% to 50% of the core, it is desirable that its mass fraction is in the range of about 2% to 40% of the core, even better so its mass fraction was approximately in the range from 5% to 20% of the core. In accordance with certain preferred embodiments of the present invention, the mass fraction of croscarmellose sodium is in the range of about 6% to 10% of the core, it is even better that its mass fraction is in the range of about 7% to 9% of the core.

Polymers of vinylpyrrolidone or polyvinylpyrrolidone (PVP), also known as povidone, are synthetic polymers consisting essentially of linear groups of 1-vinyl-2-pyrrolidinone, the polymerization of which produces polymers of different molecular weights ranging from 2,500 to 3,000,000 daltons. PVP is commercially available under the name Kollidon® (BASF), Plasdone® and Peristone®. Depending on the viscosity in an aqueous solution, PVP is divided into different grades, for example, PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-60, PVP K-90 and PVP K-120. The value K corresponds to the calculated value of the viscosity of PVP in an aqueous solution relative to water. Crospovidone or a cross-PVP synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidinone can also be used as a swelling hydrophilic polymer. In the commercial network, it is known as Kollidon CL and Polyplasdone XL, and its molecular weight exceeds 1,000,000 daltons. In accordance with the present invention, the mass content of crospovidone is in the range from about 2% to 5% of the core. According to a preferred embodiment of the present invention, PVP K-30 is used as the swelling hydrophilic polyvinylpyrrolidone, the molecular weight of which is approximately 50,000 daltons. Its mass fraction can be approximately in the range of 0.5% to 5% of the core, it is desirable that its mass fraction is approximately in the range of 1% to 2% of the core.

Starch-based sodium glycolate, the sodium salt of starch carboxymethyl ether, can also be used as a polymer swellable agent. Its molecular weight ranges from 500,000 to 1,000,000 daltons, and in the commercial network it is known as Explotab and Primojel. In accordance with the present invention, the mass fraction of starch-based sodium glycolate can be in the range of about 0.5% to 40% of the core, it is desirable that its mass fraction is in the range of about 2% to 40% of the core, even better mass fraction was approximately in the range from 2% to 10% of the core.

It is desirable that the composition of the separate drug delivery system of the present invention, emitted in a pulsed mode at a given time, contain a capillary agent. In this context, the term “capillary agent” should be understood more broadly than a conventional capillary agent, and it refers to any pharmaceutical excipient that provides water to the core through any suitable mechanism, preferably using capillaries, which is typical for conventional capillary agents. Materials suitable for use as capillary agents in a pulsed composition at a predetermined time include colloidal silicon dioxide, kaolin, titanium dioxide, finely divided silica, alumina, sodium lauryl sulfate, microcrystalline cellulose, low molecular weight polyvinylpyrrolidone, tentonite and. P.

According to a preferred embodiment of the present invention, microcrystalline cellulose (MCC) is used as the capillary. Its chain consists of approximately 250 glucose molecules and has the form of a microcrystal, consisting primarily of crystalline clusters obtained by removing amorphous regions of pure cellulose by hydrolytic degradation using mineral acid. The average molecular weight of the MCC is approximately 36,000 Daltons and there are several varieties of MCC that differ in bulk density, particle size and moisture content. In the commercial network, MCC is known as Vivapur®, Avicel®, Vivacel®, Emcocel®, Fibrocel® and Tabulose®. According to a preferred embodiment of the present invention, Avicel® PH 102 particles, on average 100 microns in size (i.e. 8% or less, are held on a No. 60 sieve (as defined by the American Society for Testing Materials) and 45% or more held on a sieve No. 200 (as defined by the American Society for Testing Materials) at a moisture content of 5%) are used as a composition emitted in a pulsed mode at a given time, with a mass fraction of approximately 2% to 5% s core, it is desirable that this value is approximately in the range from 2% to 3% of the core.

When the drug itself does not provide sufficient osmotic pressure to allow absorption of fluid from the environment in the core of the composition pulsed at a given time, water-soluble formulations suitable for causing osmosis, i.e. osmotic agents, are used. Osmotic agents that may be present in the core of a pulsed formulation at a given time include all pharmaceutically acceptable and pharmacologically inert water-soluble formulations referred to in the US Pharmacopoeia, as in Remington: Science and Practice Pharmacies, 20th Edition , authors Lippincott, Williams and Wilkins (Lippincott Williams and Wilkins), pcs. Philadelphia, USA, 2000. Generally, pharmaceutically acceptable water-soluble salts of inorganic or organic acids or non-ionic organic compounds with high water solubility, for example, carbohydrates such as sugar, or amino acids are preferred. Examples of agents used to induce osmosis include inorganic salts such as magnesium chloride or magnesium sulfate, lithium, sodium or potassium chloride, lithium, sodium or potassium hydrogen phosphate, lithium, sodium or potassium secondary phosphate, organic acid salts such as acetate sodium or potassium, magnesium succinate, sodium benzoate, sodium citrate or sodium ascorbate; carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, raffinose; water soluble amino acids such as glycine, leucine, alanine or methionine; urea and the like, and mixtures thereof. The mass fraction of osmotic agents that can be used depends on the specific osmotic agent used and can range from about 1% to 60% of the core.

In addition to the ingredients described above, the core of a pulsed formulation at a predetermined time may contain pharmaceutically acceptable excipients such as binders, disintegrants for dosage forms, lubricants, and the like. Examples of commonly used binders include starch, gelatin, sugars such as sucrose, glucose, dextrose, molasses and lactose; acacia, sodium alginate, cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethyl cellulose and the like; polymers such as polyvinylpyrrolidone, Veegum, polyethylene glycol, waxes, and the like. The composition emitted in a pulsed mode at a predetermined time according to the present invention can be optimized in order to ensure reliable rupture without the use of capillary means. However, it was found that when using a capillary means the problem of optimizing the reliability of the gap is solved more easily.

Examples of lubricants that can be used in a pulsed composition at a given time include talc, magnesium stearate, calcium stearate, aluminum stearate, stearic acid, hydrogenated vegetable oils, colloidal silicon dioxide, polyethylene glycol, cellulose derivatives such as carboxyalkyl cellulose and its alkali metal salts, or mixtures thereof. Hydrophobic or water-insoluble lubricants can impair water absorption properties of the core, while hydrophilic or water-soluble lubricants do not and are preferred. Colloidal silica is a more preferred lubricant. A mixture of colloidal silicon dioxide and magnesium stearate can be used as the preferred lubricant. In more preferred embodiments, a combination of microcrystalline cellulose and colloidal silicon dioxide is used as the capillary, and silicon dioxide is used as the lubricant. In the commercial network, colloidal silicon dioxide is known as Aerosil® from Degussa-Huls, Nippon and Fischer GmbH. As a preferred embodiment, colloidal silica-based lubricant Aerosil® 200 is used with a specific outer surface area of approximately 200 m ² / g. The mass fraction of colloidal quartz can be approximately in the range from 0.5% to 5% of the core.

According to a preferred embodiment of the present invention, the core of a pulsed formulation at a predetermined time is obtained by mixing a therapeutically active drug with a swelling agent and a binder in a rapidly rotating granulator mixer and granulating the mixture. According to a preferred embodiment of the present invention, only part of the total swellable agent is included in the composition, and the rest is mixed in the lubrication step with the dried granules. The granules obtained using a suitable granulating solvent are sieved wet through a sieve and then dried in a fluidized bed dryer at 40-50 ° C. to a moisture content of 2-3%. Then the dried granules are sieved through a sieve with a mesh size of 2 mm and mixed with one lubricant or a large amount of lubricants and capillary. As described above, in accordance with a preferred embodiment of the present invention, the remainder of the swellable agent is admixed at this stage. Lubricant granules may be incorporated into hard gelatin capsules or may be compressed to form compressed tablets or cores.

The therapeutically active drug, including compressed cores / capsules, is coated with a coating composition comprising one or more film-forming polymer in order to obtain a composition released in a pulsed fashion at a predetermined time. Film-forming polymers that can be used to form this composition, which is pulsed at a given time, are selected from the group consisting of water-insoluble polymers, pH-dependent polymers and a mixture of water-soluble and water-insoluble polymers or mixtures thereof. As examples of suitable film-forming polymers, cellulose ester derivatives such as methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, cellulose acetate phthalate, pH independent methacrylic acid copolymers and methacrylic esters are available which are available on a commercial network called Eud mixtures of them. The release time of a therapeutically active drug of the first composition can be changed by selecting the constituent membranes and / or by changing the ratio of these components. By selecting the appropriate components and the appropriate ratios, it is possible to ensure the allocation after a given time after oral administration of the separate drug delivery system. According to a preferred embodiment of the present invention, a mixture of a water-insoluble polymer with a water-soluble polymer is used to obtain a delayed release coating. In accordance with preferred embodiments of the present invention, ethyl cellulose is used as the water-insoluble polymer, and hydroxypropyl methyl cellulose is used as the water-soluble polymer. Preferably, this mixture is used with a mass ratio of ethyl cellulose to hydroxypropyl methyl cellulose from 0:20 to 20: 0, it is desirable that this ratio be in the range from 6: 3 to 9: 3.

Pressed cores / capsules containing a therapeutically active drug are coated with a coating solution, which includes film-forming polymers included in a suitable solvent system, and this solution is applied until a certain increase in weight, shell thickness, depending on a given release time is obtained active drug. The sheath material can be applied using any technology that provides a continuous film of substantially equal thickness. One way to obtain a shell involves rotating a layer of uncoated cores in a conventional tub to coat the tablets and apply a solution or dispersion of the coating agent in a suitable solvent by pouring or spraying the solution onto the cores in motion. Other fluidized bed technologies such as fluidized bed, vertical spray and the like can also be applied. The coated cores are dried by heat, dry air and, if necessary, can be cured by dry air, annealing or forced moisture separation. In accordance with one embodiment of the present invention, the pressed core is coated with a solution of ethyl cellulose and hydroxypropyl methyl cellulose to obtain a mass of about 2% to 20% by weight of the pressed core, it is desirable that the mass fraction of the shell is in the range of about 5% to 10% of the core; it is better that its mass fraction is approximately in the range from 9% to 10% of the pressed core. For coating the cores, an automated, perforated tub is used, then the cores with the casing are dried and cured in a longline dryer for 24 hours at 40-50 ° C.

The present invention relates to any separate drug delivery system in which a first composition comprising a therapeutically active antidiabetic drug and a second composition comprising a therapeutically active antidiabetic drug are physically separated from each other, which provides different rates of release of two active drugs funds. Such separation, or separation, can be performed on a macro scale, for example, with means included in separate units (such as tablets, powder, granules, balls, etc.) for simultaneous or sequential administration, or the separation of drugs can be performed on a micro scale , for example, with agents present within the same unit. Two separate units are introduced into one unit of the separate drug delivery system by filling capsules with them.

In the separate drug delivery system of the present invention, the first and second composition can be either in the form of a plurality of particles such as particles, balls or granules, or in the form of concentric or laminar layers on tablets, or in separate units such as a compressed tablet. Many particles can be obtained by any of the usual methods, including mixing, granulation, extrusion, spheronization, layering on various seeds, etc., as well as other known methods. A compressed tablet core can be obtained by compressing particulate in a tablet mold. When using conventional methods for producing a shell, the first composition is surrounded by a delayed-release preparation, which includes delayed-release material, which is selected from the group consisting of enteric polymers, water-insoluble polymers, hydrophobic compounds, hydrophilic non-polymer compositions, hydrophilic polymers and etc. and mixtures of them. Coated particulates or tablets of the first composition and uncoated particles or tablets of the second composition may be in capsules. Alternatively, tablets comprising the first composition may be pressed onto the second composition using a special die for coating the tablets, or a second layer consisting of the second composition may be pressed onto the pressed first composition to form bilayer tablets.

The second composition used in the separate drug delivery system is in the form of particulates or tablets that are loaded into capsules along with the first composition that is pulsed at a given time. In other cases, tablets of the first composition, pulsed at a predetermined time, can be surrounded by a second composition and compressed in a press to coat the tablets to obtain a unit dosage form with a core composition pulsed at a specified time, and with instant composition from a shell comprising a therapeutically active drug of the second composition. The second composition can be incorporated in various ways into the separate drug delivery system of the present invention. Particles of a therapeutically active drug of the second composition can be obtained by mixing the drug with pharmaceutically acceptable excipients, such as binders, excipients, disintegrants, and the like. or by further granulating the mixture. The granules obtained in this way are dried and a lubricant is obtained with the introduction of one or more lubricants.

An immediately release layer of the second composition can be administered by mixing the therapeutically active antidiabetic drug with pharmaceutical adjuvants such as film-forming agents, plasticizers, etc., in a suitable solvent or solvent system, and applying the composition released in a pulsed manner at a predetermined time, s using conventional known methods of coating. Examples of film forming agents that can be used in the present invention include cellulose derivatives such as cellulose acetate phthalate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxypropylethyl cellulose, ethyl cellulose, methyl cellulose, microcrystalline cellulose, methacrylic acid / esters of methacrylic acid, acetate or ethyl acetate, the like. mixtures of them. According to a preferred embodiment of the present invention, hydroxypropyl methylcellulose is used as a film-forming agent together with a therapeutically active agent, the mass fraction of which is in the range of about 2% to 20% of the composition emitted in a pulsed mode at a predetermined time, it is desirable that its mass fraction is approximately in the range from 2% to 5% of the composition. Examples of plasticizers, which, however, are not limited to the scope of the present invention, are glycerin, propylene glycol, polyethylene glycol, sorbitol, triacetin, diethyl phthalate, mineral oil, petroplatinum, lanolin and the like. In accordance with a preferred embodiment of the present invention, polyethylene glycol 4000 is used as a plasticizer, the mass fraction of which is from 0% to 5% of the core, it is desirable that its mass fraction is approximately in the range from 0.1% to 1% of the core. The therapeutically active drug, hydroxypropyl methyl cellulose and polyethylene glycol 4000 are mixed in a suitable solvent or solvent system. The solution obtained in this way is used for coating the core of the composition released in a pulsed mode at a predetermined time until the required mass is obtained in a conventional tub for coating the tablets. Then the tablets are dried in a longline dryer at a temperature of 40-50 ° C for 24 hours.

The separate drug delivery system is designed to provide instant release of at least one therapeutically active antidiabetic drug and delayed release of at least one therapeutically active antidiabetic drug.

The following is a description of the present invention with reference to a specific embodiment, wherein as one antidiabetic drug that is released immediately after oral administration, a biguanide-based antidiabetic drug is used, and as one antidiabetic drug that is pulsed after given time, sulfonylurea is used; however, this option is given for illustration only and in no way limits the scope and essence of the present invention.

Examples of biguanide-based antidiabetic drugs that can be used in accordance with the present invention include metformin, phenformin and buformin and their pharmaceutically acceptable salts.

Examples of sulfonylureas that can be used in accordance with the present invention include acetohexamide, carbutamide, chlorpropamide, glipizide, glyburide (glibenclamide), glimepiride, glyclazide, glibornuride, glycuidone, glyxoxepide, glyhexamide, fenbutamide, tolazamide, tolamide, tolamide, tolamide, tolamide, etc.

The amount of the biguanide and sulfonylurea antidiabetic drug is selected in such a way that this combination provides optimal benefits in cases of diabetes mellitus or conditions associated with diabetes mellitus, with a reduction in the number of adverse effects. The patent RE 37330 claims the use of a composition based on the combination of glibenclamide with metformin in a ratio of 1: 100 in the treatment of non-insulin-dependent diabetes mellitus. The results of the clinical study mentioned in patent RE 37330 indicate that the maximum daily dose of sulfonylurea, which is considered optimal for the most severe, difficult to treat cases, is 15 mg. However, this dose should be combined with a maximum daily dose of biguanide of 1500 mg, which provides the maximum therapeutic effect along with a reduction in the number of adverse effects. The patent claims the use of this composition based on a combination in other mass ratios from 1: 160 to 1: 200.

According to preferred embodiments of the present invention, glipizide is used as the sulfonylurea used in the second formulation. In accordance with another preferred embodiment of the present invention, glibenclamide is used as the sulfonylurea in the second composition. In accordance with the present invention, metformin, or a pharmaceutically acceptable salt thereof, preferably a hydrochloride salt, is used as the preferred biguanide-based antidiabetic drug. It is desirable that the mass ratio of metformin hydrochloride to glipizide is in the range from about 250: 1 to 50: 1. The mass of glipizide is in the range of about 2 mg to 15 mg, while the weight of metformin hydrochloride is in the range of about 200 mg to 1.5 g. For example, a single drug delivery system includes 250 mg of metformin hydrochloride and 2 5 mg of glipizide, or 850 mg of metformin hydrochloride and 5 mg of glipizide, or 1 g of metformin hydrochloride and 10 mg of glipizide. In preferred embodiments of the present invention, a single unit delivery system comprises 500 mg of metformin hydrochloride and 5 mg of glipizide.

The mass ratio of metformin hydrochloride to glibenclamide is in the range from about 250: 1 to 50: 1, it is desirable that this ratio is 100: 1. The weight of glibenclamide is in the range of about 1 mg to 10 mg, while the weight of metformin hydrochloride is in the range of about 200 mg to 1.5 g. In preferred embodiments of the present invention, a single drug delivery system comprises 250 mg of metformin hydrochloride and 1.25 mg of glibenclamide, or 5000 mg of metformin hydrochloride and 2.5 mg of glibenclamide, it is desirable that the mass of metformin hydrochloride is 250 mg and the mass of glibenclamide is 2.5 mg, it is even better that the mass of hydrochloride was 500 mg of metformin and glibenclamide weight was 5 mg.

The following examples do not limit the scope of the present invention and are provided by way of illustration.

Example 1

The separate drug delivery system of the present invention is obtained in accordance with the data shown in Table 1.

Table 1 Ingredients Amount mg Mass fraction,% A. Instant Sulfonylurea Granules Glipizide 5,0 6.67 Microcrystalline Cellulose (MCC) 13.0 17.33 Lactose Monohydrate 51,175 68,23 Polyvinylpyrrolidone (PVP K-30) 1,5 2.0 Starch-based sodium glycolate 3,5 4.67 Sodium Lauryl Sulfate 0,075 0.1 Magnesium stearate 0.75 1,0 Total 75 100.0 B. delayed-release biguanide core The core is Metformin hydrochloride 500,0 83.33 Croscarmellose sodium (Ac-Di-Sol) 50,0 8.33 Simple corn starch (as 10% starch paste) 17.0 2.83 Microcrystalline Cellulose (MCC) 13.5 2.25 Colloidal silicon dioxide 13.5 2.25 Magnesium stearate 6.0 1,0 Total 600,0 100.0 Shell Ethyl cellulose 40.7 The coating is applied until a coating mass of 9.5% of the core mass is obtained. Hydroxypropyl methylcellulose 16.3

Sulfonylurea granules of instant release were obtained by sieving glipizide, lactose monohydrate and microcrystalline cellulose (MCC) and starch-based sodium glycolate through a No. 40 sieve (in accordance with the requirements of the American Society for Testing of Materials) with further mixing of the powders. For granulation of the dry powder mixture, a solution of PVP K-30 in water was used. The granules thus obtained were dried to a moisture content of not more than 3%. Then these granules were passed through a No. 25 sieve (in accordance with the requirements of the American Society for Testing Materials). Finally, to obtain the finished granules, these granules were mixed with talc and magnesium stearate. A method of preparing a core containing delayed release biguanide included sieving metformin hydrochloride and croscarmellose sodium through a suitable sieve and mixing them in a high-speed granulator mixer. The dry powder mixture was then granulated using 10% starch paste, followed by wet milling in a Fitz grinder. The granules obtained in this way were dried to a moisture content of 3-4%. Then the dry granules were crushed in a Fitz crusher and passed through a sieve with a mesh size of 1.5 mm, after which they passed through a No. 16 sieve (in accordance with the requirements of the American Society for Testing of Materials). Then, the metformin hydrochloride granules were mixed with MCC, colloidal silicon dioxide and magnesium stearate, and the thus obtained mixture with lubricant was pressed on a rotary machine using elongated shaped dies. Then, tablets were coated onto tablets in a conventional coating vial using a solution of ethyl cellulose and hydroxypropyl methyl cellulose mixed with methanol and dichloromethane.

The delayed release biguanide core was then mixed with 75 mg of instant release sulfonylurea granules and encapsulated in '0' size gelatin capsules. A delayed-release biguanide-based composition and 75 mg sulfonylurea granules were tested for dissolution in a buffer with a pH of 6.8 at 37 ± 0.5 ° C in a US Type II Pharmacopoeia apparatus (with a rotation speed of 75 revolutions per minute). Table 2 shows the excretion profile for metformin, and Table 3 shows the excretion profile for glipizide. The rupture time of the membrane deposited on a biguanide-based core with pulsed release at a given time was observed for 30 tablets which were tested for dissolution. The tablets were found to open reliably in the range of about 1 hour to 1, 3 hours after the start of the solubility test.

table 2 Time min The share of the excreted metformin,% (± tolerance) 45 1 ± 0.5 105 91 ± 6.89 120 98 ± 4.26

Table 3. Time min The proportion of secreted glipizide,% (± tolerance) 45 88 ± 2.19

The tablets were tested in different environments at different pH levels and using different devices, the opening time was recorded. Table 4 shows the test data.

Table 4 No. p / p Wednesday Conditions Opening time 6 tablets (hour, min) one. pH 6.8 United States Pharmacopeia Type I, 100 rpm 1.08; 1.25; 1.13; 1.16; 1.02; 1.12 2. pH 6.8 United States Pharmacopeia Type I, 100 rpm 1.04; 1.14; 1.18; 1.09; 1.09; 1.25 3. PH 6.8 United States Pharmacopeia Type I, 100 rpm 1.23; 1.05; 0.59; 1.12; 0.58; 1.25 four. pH 6.8 United States Pharmacopeia Type I, 100 rpm 1.18; 1.26; 1.24; 1.01; 1.12; 1.06 5. pH 6.8 US Pharmacopoeia Type II, 75 rpm 1.28; 1.30; 1.21; 1.17; 1.09; 1,03 6. 0.1 NHCl USP, Type II, 75 rpm, 1.07; 1.18; 1.21; 1.10; 1.03; 1.30 7. pH 6.8 US Pharmacopoeia apparatus, Type II, 50 rpm 1.02; 1.39; 1.28; 1.21; 1.03; 1.26 8. 0.1 NHCl US Pharmacopoeia apparatus, Type II, 50 rpm 1.24; 1.10; 1.05; 1.12; 1.29; 0.50

Example 2

The separate drug delivery system of the present invention is obtained in accordance with the data shown in Table 5.

Table 5 Ingredients Amount mg Mass fraction,% A. Sulfonylurea granules instant release - Glipizide 5,0 6.67 Lactose Monohydrate 64,175 85.56 Starch-based sodium glycolate 3,5 4.67 Polyvinylpyrrolidone (PVP K-30) 1,5 2.0 Sodium Lauryl Sulfate (SLN) 0,075 0.1 Magnesium stearate 0.75 1,0 Total 75 100.0 B. delayed-release biguanide core Core Metformin hydrochloride 500,0 83.33 Croscarmellose sodium (Ac-Di-Sol) 50,0 8.33 Simple corn starch (as 10% starch paste) 17.0 2.83 Microcrystalline Cellulose (MCC) 13.5 2.25 Colloidal silicon dioxide 13.5 2.25 Magnesium stearate 6.0 1,0 Total 600,0 100.0 Shell Ethyl cellulose 42.0 The coating is applied until a coating mass of 9.8% of the core mass is obtained. Hydroxypropyl methylcellulose 16.8

Instant sulfonylurea granules were obtained by sieving glipizide, lactose monohydrate and MCC through a No. 40 sieve (as required by the American Society for Testing Materials), followed by mixing of the powders. For granulation of the dry powder mixture, a solution of PVP K-30 and sodium lauryl sulfate in water was used. The rest of the technology remained the same as in Example 1. The delayed-release biguanide cores were also prepared according to the method described in Example 1.

Instant release sulfonylurea granules (75 mg) were mixed with delayed-release biguanide cores and the mixture was encapsulated. A composition based on delayed release biguanide and sulfonylurea granules was studied for dissolution in a buffer with a pH of 6.8 buffers at 37 ± 0.5 ° C in a US Type II Pharmacopoeia apparatus (with a rotation speed of 75 revolutions per minute). Table 6 shows the release profile for metformin, and Table 7 shows the release profile for glipizide. The rupture time of the membrane deposited on a biguanide-based core with pulsed release at a given time was observed for 30 tablets which were tested for dissolution. The tablets were found to open reliably in the range of about 1 hour to 1.3 hours after the start of the solubility test.

Table 6 Time min The proportion of released metformin,% 45 one 120 91 ± 5.33

Table 7 Time min The proportion of released glipizide,% 45 98 ± 1.55

The tablets of Example 2 of the present invention were tested in water at various pH levels and using different devices, the opening time was recorded. Table 8 shows the test data.

Table 8 No. p / p Wednesday Conditions Opening time 6 tablets (hour, min) one. pH 6.8 USP, Type I,
rotation speed 100 rpm 1.15; 1.04; 1.16; 1.13; 1.21; 1.16 2. pH 6.8 United States Pharmacopeia Type I, 100 rpm 1.37; 1.18; 1.20; 1.12; 1.00; 1.15 3. pH 6.8 USP, Type I, 100 rpm
min 1.02; 1.15; 1.07; 1.10; 1.15; 0.53 four. 0.1 NHCl US Pharmacopoeia Type II, 75 rpm 1.11; 1.10; 0.50; 0.58; 0.59; 0.45 5. pH 6.8 US Pharmacopoeia apparatus, Type II, 50 rpm 1.00; 1.09; 0.55; 1.09; 1.09; 1.22 6. 0.1 NHCl United States Pharmacopeia Type I, 100 rpm 1.02; 1.00; 1.23; 1.23; 1.26; 1.01

Example 3

The separate drug delivery system of the present invention is obtained in accordance with the data shown in Table 9.

Table 9 Ingredients Amount mg Mass fraction,% A. Instant Sulfonylurea Granules glibenclamide 5,0 6.67 Lactose Monohydrate 64,175 85.48 Starch-based sodium glycolate 3,5 4.67 Polyvinylpyrrolidone (PVP K-30) 1,5 2.0 Sodium Lauryl Sulfate (SLN) 0,075 0.1 Magnesium stearate 0.75 1,0 Total 75 100.0 B. delayed-release biguanide core Core Metformin hydrochloride 500,0 83.33 Croscarmellose sodium (Ac-Di-Sol) 50,0 8.33 Simple corn starch (as 10% starch paste) 17.0 2.83 Microcrystalline Cellulose (MCC) 13.5 2.25 Colloidal silicon dioxide 13.5 2.25 Magnesium stearate 6.0 1,0 Total 600,0 100.0 Shell Ethyl cellulose 42.0 The coating is applied until a coating mass of 9.8% of the core mass is obtained. Hydroxypropyl methylcellulose 16.8

A separate drug delivery system was prepared in accordance with a technology similar to that described in Example 2. The instant release sulfonylurea granules (75 mg) were mixed with delayed release biguanide cores and the mixture was encapsulated.

Delayed release biguanide formulations and sulfonylurea granules were tested for solubility. The isolation profile for metformin is similar to that obtained in Example 2. Solubility studies of glibenclamide were carried out using a Tris 0.025 M buffer with a pH level of 9.01 at 37 ± 0.5 ° C in a US Type II Pharmacopoeia apparatus (at a speed of 50 revolutions per second). minute); Table 10 shows the research data.

Table 10 Time min The relative proportion of released glibenclamide,% fifteen 93 ± 2.09 thirty 95 ± 1.72 45 96 ± 1,53

Example 4

The separate drug delivery system of the present invention is obtained in accordance with the data shown in Table 11.

Table 11 Ingredients Amount mg Mass fraction,% A. Instant Release Granules Rosiglitazone maleate (equivalent to 8 mg of rosiglitazone base) 10.6 11.04 Lactose Monohydrate 78.09 81.25 Starch-based sodium glycolate 4,5 4.69 PVP K-30 1.92 2.0 Magnesium stearate 0.96 1,0 Total 95.98 99.98 B. delayed-release biguanide core The core is Metformin hydrochloride 500,0 83.33 Croscarmellose sodium (Ac-Di-Sol) 50,0 8.33 Plain corn starch
(as 10% starch paste) 17.0 2.83 Microcrystalline Cellulose (MCC) 13.5 2.25 Colloidal silicon dioxide 13.5 2.25 Magnesium stearate 6.0 1,0 Total 600,0 100.0 Shell Ethyl cellulose 42.0 The coating is applied until a coating mass of 9.8% of the core mass is obtained. Hydroxypropyl methylcellulose 16.8

A separate drug delivery system was prepared in accordance with a technology similar to that described in Example 2. The instant release rosiglitazone maleate granules were mixed with delayed-release biguanide cores and the mixture was encapsulated.

The composition based on biguanide with delayed release and granules of rosiglitazone maleate were studied for solubility. The excretion profile for metformin is similar to the excretion profile obtained in Example 2. Rosiglitazone maleate solubility studies were performed using 0.1 N HCl at 37 ± 0.5 ° C in a USP type apparatus (at a speed of 50 revolutions per minute), the results studies are shown in Table 12.

Table 12 Time min Relative fraction of released rosiglitazone,% 10 97 ± 2.72 twenty 96 ± 3,00 thirty 96 ± 2,82

Example 5

In order to determine the rupture time of the shell in vivo, the delayed release biguanide core of the present invention was subjected to radiological examination. In radiological studies, the compositions of Example 2 were used with 25 mg of barium sulfate added to the core. Delayed-release metformin tablet cores containing barium sulfate were prepared according to the method described in Example 1, and barium sulfate was mixed with starch paste to ensure uniform core distribution.

Six healthy male volunteers were tested for single dose effects. Before administering the drug, subjects starved overnight and for 4 hours after drug administration. It was forbidden to drink 2 hours before the dose and within 2 hours after its introduction. Each test subject, along with 240 ml of drinking water, was injected with one core of delayed-release metformin tablets containing barium sulfate. 4 hours after the administration of the drug, ordinary food was served. The x-ray was carried out 30, 45, 60, 75 and 90 minutes after the dose of the drug. Table 13 shows the result of the radiological examination.

Table 13 Volunteer n / a The position of the tablet, min thirty 45 60 75 90 one Proximal small intestine (intact tablet) Proximal small intestine (intact tablet) Unclear (tablet intact) Subcostal region of the colon on the left side (tablet intact) Tablet completely disappeared 2 Tablet is not visible Tablet is not visible Tablet is not visible Tablet is not visible Tablet is not visible 3 Small intestine (tablet intact) Small intestine (tablet intact) Unclear Small intestine (tablet intact) Tablet completely disappeared four The bottom of the stomach (tablet intact) Pyloric stomach (intact tablet) Pyloric stomach (intact tablet) Pyloric stomach (intact tablet) Proximal jejunum loop (tablet disintegration) 5 Distal area of the jejunum loop (tablet intact) Proximal iliac loop (intact tablet) Iliac loop (tablet disintegration) Iliac loop (tablet disintegration) Tablet completely disappeared 6 Pyloric stomach (intact tablet) Pyloric stomach (intact tablet) Bend between the duodenum and jejunum (tablet intact) The distal area of the duodenum (tablet disintegration) Tablet completely disappeared

As can be seen from Table 13, the tablet was not observed in volunteer No. 2, which could happen due to the insufficient content of barium sulfate in the core. In four of the five remaining volunteers, the tablet completely disintegrated after 90 minutes, and in volunteer No. 4, the tablet after 90 minutes marked the beginning of tablet disintegration.

Example 6

Comparative Example 1

This example illustrates the process of optimizing composition to reliably rupture a shell at a specific time.

The tablet cores were prepared according to the composition shown in Table 14. The shell rupture time was set to 1 hour.

Table 14 Ingredients Amount mg Metformin hydrochloride 500,0 Croscarmellose sodium (Ac-Di-Sol) 34.5 PVP K-90F 10.0 Magnesium stearate 5,0 Total 550.0

The cores described above were coated with a composition of ethyl cellulose and hydroxypropyl methyl cellulose dissolved in a solvent system consisting of 4: 1 methylene chloride and methanol. The ratio of ethyl cellulose to hydroxypropyl methyl cellulose was varied in order to evaluate its effect on the shell rupture time. When the ratio was 9: 2 and the weight after coating was increased by 4% of the total mass of the core, the time to rupture the shell was approximately 2 hours. The time of rupture of the shell can be reduced by reducing the mass of the applied composition of the shell. However, with a ratio of ethyl cellulose to hydroxypropyl methyl cellulose equal to 9: 2, the shell rupture time was sensitive to this factor, and this could lead to a change in the shell rupture time as a result of a change in mass applied depending on the batch. It was found that with a minimum change in mass as a result of coating from 4% to 3%, the time of rupture of the shell was reduced to 45-60 minutes. With an increase in the relative content of hydroxypropylmethyl cellulose, the shell rupture time decreased. The ratios of ethyl cellulose to hydroxypropyl methyl cellulose were estimated to be in the range of 8: 3 to 7: 3, and unexpectedly concluded that at these ratios, the shell rupture time was approximately 1 hour and that the rupture time of the shell was independent of the weight of the coating applied. However, the shell did not break in a reliable manner, which is clear from the results of the estimates of the shell rupture time in the solubility tests given in Table 15. The test was carried out in the US Type II Pharmacopoeia apparatus at a pH of 6.8 and a rotation speed of 50 revolutions per second. a minute.

Table 15 Relative weight gain (%) when applying a shell of ethyl cellulose and hydroxypropyl methyl cellulose with a ratio of 7.5: 3 The number of test tablets Opening time, min 9% eighteen 60, 53, 60,> 135, 60, 58, 48, 50,> 135, 50, 75, 55, 65, 64, 55, 55, 55, 48 eleven% eighteen 90, 71, 78, 80,> 150, 79, 60, 66, 73, 60, 91.70, 76, 85, did not open, 76, 76, did not open 14.6% 6 66, 65, 78, 180, 86, 60

It can be seen that, on average, the shell rupture time satisfies the given rupture time, which is approximately 1 hour, however, the reliability of the rupture is low, therefore, in some tablets, the rupture of the shell is excessively long. To ensure reliability during rupture of the shell and the release of the drug, the composition of the shell remained unchanged, and the composition of the core was optimized, for example, in the image of the compositions described in Examples 1 and 2.

Reference Example 2

The following example is taken from Example 1 of European patent 408496, which is the equivalent of IE 902533. The tablets were made in accordance with the composition shown in Table 16.

Table 16 Ingredients Amount, mg / tablet Core Diclofenac Sodium 50 mg Polyvinylpyrrolidone (crosslinked) 100 mg Sodium chloride 50 mg Silica Airgel (Aerosil® 200) 7 mg Magnesium stearate 3 mg Shell Cellulose acetate (contains 32% acetyl) 31 mg Cellulose Acetate (Contains 32.9% Acetyl) 32.33 mg Hydroxypropyl methylcellulose 3.33 mg

The core components were mixed in a drum mixer and compressed in a tablet press using an 8 mm concave die. The constituent shells were dissolved in a mixture of methylene chloride and methanol. This solution was used to coat the cores in the fluidized bed. By coating the core, three different batches were obtained with an increase in mass (relative to the mass of the core) of 4% and 9.8%. Within 48 hours, the tablets were dried.

The tablets obtained in accordance with this composition were tested in 900 ml of water at 37 ° C, Table 17 shows the opening time.

Table 17 The mass of the shell relative to the mass of the core,% Observations The specified disclosure time in accordance with the data of table 1 of Example 1 of patent IE 902533 4% (before drying) One tablet opened after approximately 45 minutes. The remaining tablets did not open up to 3 hours 20 minutes 65 minutes 4% (after drying for 48 hours at 40 ° C) One tablet opened after about 30 minutes, and the other opened after about 50 minutes. The remaining tablets did not open up to 2 hours and 15 minutes 65 minutes 9.8% Not a single tablet was opened up to 2 hours 56 minutes 120 minutes

The observations described above indicate that tablets obtained in accordance with the composition described in patent IE 902533 do not meet the specified opening time and do not provide reliable disclosure, as described in the claims of the cited patent.

Embodiments of the invention that are referred to during the description are for illustrative purposes only and do not limit the scope of the invention.

Claims (13)

1. A method of administering two therapeutically active antidiabetic drugs for treating diabetes mellitus, comprising orally administering to a patient a time-dependent antidiabetic drug delivery system, wherein the first therapeutically active antidiabetic drug is selected from urea sulfonyl and a metglitinide analogue that is released immediately after oral administration introducing a time-dependent drug delivery system; and a second therapeutically active ant the diabetic drug is selected from a biguanidine antidiabetic agent and a thiazolidinedione antidiabetic agent, which is released in a period of 1 to 4 hours, so that no more than 10% of the active component is released in 45 minutes and at least 70% of the active component in 2 hours 2. The system of separate delivery of drugs with time-distributed action for the treatment of diabetes mellitus or conditions associated with diabetes mellitus, including
but. a first composition comprising a first therapeutically active antidiabetic drug selected from urea sulfonyl and a metglitinide analog, which is released immediately after oral administration of a drug delivery system with a time-spaced action, and
b. a second composition comprising a second therapeutically active antidiabetic drug selected from a biguanidine antidiabetic agent and a thiazolidinedione antidiabetic agent, which is released in a period of 1 to 4 hours, so that no more than 10% of the active component is released in 45 minutes and at least at least 70% of the active ingredient in 2 hours 3. The system of separate delivery of drugs with time-distributed action according to claim 2, including metformin hydrochloride and glipizide, the mass ratio of which is 100: 1. 4. The system of separate delivery of drugs with time-distributed action according to claim 3, including metformin hydrochloride in an amount of 500 mg and glipizide in an amount of 5 mg. 5. The system of separate delivery of drugs with time-distributed action according to claim 2, including metformin hydrochloride and glibenclamide, the mass ratio of which is 100: 1. 6. The system of separate delivery of drugs with time-distributed action according to claim 5, including metformin hydrochloride in an amount of 500 mg and glibenclamide in an amount of 5 mg. 7. The system of separate delivery of drugs with time-distributed action according to claim 2, comprising a second composition comprising a core composition comprising a therapeutically active antidiabetic drug, which is a biguanidine antidiabetic agent, a swelling agent and possibly a water-soluble composition (s) for initiation osmosis, and the composition of the shell, including ethyl cellulose and hydroxypropyl methyl cellulose, where the mass fraction of the core shell is in the range of approximately from 9 to 10% by weight of the core and the mass ratio of ethyl cellulose to hydroxypropyl methyl cellulose is 7.5: 3. 8. The system of separate delivery of drugs with time-distributed action according to claim 7, characterized in that the predetermined time is in the range from 1 to 4 hours, and 36 of the 36 tablets are torn within ± 50% of the specified time. 9. The system of separate drug delivery with time-spaced action according to claim 8, the predetermined release time is approximately 70 minutes 10. The system of separate delivery of drugs with time-distributed action according to claim 7, characterized in that the swelling agents are selected from the group consisting of croscarmellose sodium, crosslinked polyvinylpyrrolidone and starch-based sodium glycolate. 11. The system of separate delivery of drugs with time-spaced action of claim 10, characterized in that the composition of the core further includes a capillary agent, which is selected from microcrystalline cellulose and colloidal silicon dioxide. 12. The system of separate delivery of drugs with time-spaced action according to claim 11, characterized in that the composition of the core further includes starch. 13. A method for the treatment of diabetes mellitus or conditions associated with human diabetes mellitus, which includes the use of a separate drug delivery system with time-spaced action according to claim 2.