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    • 专利摘要:
    PURPOSE: Provided is a method of reducing the rate of weight gain and/or of lowering fasting blood sugars in a diabetic patient who is using exogenous insulin to control blood sugars, and who is taking the insulin by other than a pulmonary route of administration. It comprises administering the insulin to the patient by the pulmonary route, as inhaled insulin. CONSTITUTION: A method of reducing the rate of weight gain in a diabetic patient who is using exogenous insulin to control blood sugars and who is taking the insulin by the subcutaneous and/or transdermal route of administration, is characterized by comprising administering the insulin to the patient by the pulmonary route, wherein the pulmonary insulin is delivered in the form of aerosolized insulin wherein the aerosol is atomized from a solution; the pulmonary insulin is administered as a dry powder; and the patient has been using exogenous insulin by a subcutaneous route, and is to be newly initiated on insulin.
    公开号:KR20020097033A
    申请号:KR1020020034812
    申请日:2002-06-21
    公开日:2002-12-31
    发明作者:윌리엄해라스 랜드슐쯔
    申请人:화이자 프로덕츠 인크.；
    IPC主号:
    专利说明:

    How to reduce fasting sugar and weight gain in diabetics {METHOD OF DECREASING FASTING SUGARS AND WEIGHT GAINS IN DIABETIC PATIENTS}
    [1] The present invention uses an exogenous insulin to control blood glucose and the weight of the diabetic patient comprising administering the insulin to the pulmonary route, i. A method of reducing growth and / or lowering fasting sugars. The present invention also relates to starting inhaled insulin in patients at risk of gaining weight or expressing high fasting blood glucose.
    [2] Background of the Invention
    [3] Diabetes is a serious metabolic disease defined by the presence of chronically elevated blood sugar levels. Traditional symptoms of diabetes in adults are polyuria and thirst with elevated levels of plasma glucose. Normal fasting plasma glucose concentration is less than 110 mg, per milliliter. Fasting concentrations in diabetic patients were found to be 126 mg or more per kilogram. In general, diabetes is expressed in response to damage to or beta cells in the pancreas.
    [4] Primary diabetes is classified as type 1 diabetes (also called insulin-dependent diabetes or IDDM) and type 2 diabetes (also called non-insulin dependent diabetes or NIDDM). Type 1 (combustible onset or insulin-dependent) diabetes is a well known hormone deficiency state, in which pancreatic beta cells appear to have been destroyed by the body's own immune defense mechanisms. Patients with type 1 diabetes have little or no endogenous insulin sequestration. These patients show extreme hyperglycemia. Type 1 diabetes was fatal until about 70 years ago, when insulin replacement therapy was first introduced with insulin derived from animal sources, and more recently with human insulin produced by recombinant DNA technology.
    [5] Type 2 diabetes is characterized by combined insulin resistance combined with relative insulin deficiency, ie insufficiency of the normal metabolic response of peripheral tissues to the action of insulin. In other words, insulin resistance is a condition in which circulating insulin causes subnormal biological responses. From a clinical point of view, insulin resistance exists when normal or elevated blood glucose levels persist despite normal or elevated levels of insulin. Hyperglycemia associated with type 2 diabetes can sometimes be reversed or ameliorated by diet or weight loss sufficient to restore peripheral tissue susceptibility to insulin. The progression of type 2 diabetes is associated with increasing blood glucose levels and is thought to be associated with a relative decrease in glucose-induced insulin secretion. Thus, for example, there may be insulin deficiency in terminal type 2 diabetes.
    [6] The progress over time of Type 1 vs. Type 2 diabetes can be (typically) significantly different. Childhood patients with type 1 diabetes (eg, pediatrics) may not be diagnosed until their bulk of pancreatic beta cells is destroyed and chronic insulin therapy is needed. Typically, Type 1 progresses for about two years until the pancreas is no longer producing enough insulin to meet the metabolic needs of the patient. Unlike type 1 diabetes, treatment of type 2 diabetes often does not require the use of insulin, and the condition itself can progress over decades. The practice of treatment in type 2 diabetes usually involves first attempting diet and lifestyle changes first and typically for 6-12 weeks. Features of the diabetic diet include adequate but not excessive total calorie intake by regular meals, limitations in the content of saturated fats, concomitant increases in polyunsaturated fatty acid content, and increased intake of dietary fiber. Lifestyle changes include the maintenance of regular exercise as a supplement to both weight control and also a decrease in insulin resistance. As mentioned above, in terminal type 2 diabetes, there may be an obvious insulin deficiency that ultimately requires administration of exogenous insulin to help type 2 patients regulate their glucose metabolism.
    [7] Whether classified as Type 1 or Type 2, diabetics suffer from special medical problems that are not characteristic of most non-diabetic disorders. The most serious of these are (1) weight gain, which can induce obesity and also insulin resistance, and (2) chronic high levels of fasting glucose. This is particularly true for diabetic patients who administer insulin themselves by the subcutaneous route, the most common route of administration used by diabetics, but these conditions can also be expressed by diabetic patients who administer insulin by the percutaneous route. . Patients who gain weight ultimately become obese and have a special set of problems associated with becoming obese, including heart attacks and increased risk of obesity and / or other heart conditions associated with significant weight gain Experience the risk of experiencing a general burden on blood vessels. In addition, the lower the fasting glucose in the normal range of diabetic patients, the more likely patients are attributable to retinopathy, neuropathy, stroke, heart attack, kidney disease and / or failure, erectile dysfunction, and amputation (ie, insufficient blood flow and sensory loss). It is well known that it is less likely to suffer from complications of diabetes such as amputation of one limb.
    [8] The present invention encompasses administering the insulin in the pulmonary route, ie inhaled insulin, to diabetic patients who use exogenous insulin to control blood glucose and who are taking (or taking) the insulin by subcutaneous and / or transdermal routes of administration. To provide a method for reducing the weight gain rate in the diabetic patients. Insulin delivered by the pulmonary pathway is sometimes referred to herein as "pulmonary insulin", which is synonymous with "inhaled insulin" in the present specification (including claims).
    [9] The present invention further comprises administering the insulin by the pulmonary route to a diabetic patient using exogenous insulin to control blood glucose and taking the insulin by a subcutaneous and / or transdermal route of administration. Provided are methods for lowering glucose levels.
    [10] Accordingly, the present invention provides a method of reducing weight gain or lowering fasting glucose in diabetic patients who are taking exogenous insulin subcutaneously and / or transdermally. In the main embodiment, the patient is simply converted to a new dosage form that requires the patient to take all or part of the insulin they are taking via the pulmonary route. Accordingly, the present invention particularly provides for (1) conversion to pulmonary insulin completely or partially in diabetic patients who are already adopting a mode of administration of subcutaneous and / or transdermal insulin and actually suffering from the conditions described above; (2) In new diabetic patients who are considered at risk of developing these conditions, dosing regimens that require pulmonary insulin in whole or in part, never attempting to administer it subcutaneously and / or transdermally, i. I think it can be applied to get started. In particular, the present invention is preferably carried out by switching the administration of subcutaneously administered insulin to a dosage regimen that requires all or part of insulin administration to inhaled insulin in patients suffering from either or both of the above conditions. .
    [11] The conditions of weight gain and fasting glucose mentioned above are generally separate conditions that must be treated or treated separately. For example, a drug or treatment that improves (ie, lowers) the rate of weight gain does not necessarily lead to reduced fasting glucose, and vice versa. Indeed, improved or stable best glycemic control often leads to increased weight gain in diabetics. For this reason, the present invention is very surprising in that it provides a method for reducing weight gain as well as lowering fasting glucose.
    [12] "Patients taking insulin" include patients newly diagnosed with diabetes and are about to begin their insulin regimen to help control blood sugar. Therefore, the present invention can be applied not only to type 1 diabetes but also to type 2 diabetes.
    [13] As used above and in the claims, the phrase "comprising the administration of insulin to the patient by the pulmonary route" applies in most cases to switch the patient from the transdermal route of insulin administration to administration of the inhalation / pulmonary route. do. As noted above, the claims also indicate that patients taking subcutaneous or percutaneously exogenous insulin are only partially converted to inhaled insulin as part of their new dosage form, and therefore still subcutaneous insulin as part of the new dosage form. And / or conditions when percutaneously administered. Thus, for example, patients who administer insulin only by subcutaneous injection may involve taking insulin within the scope of the present invention, for example, by combining a single injection of subcutaneous long-acting insulin with inhaled insulin before meals. It may also be converted to a dosage form.
    [14] "Insulin" means a polypeptide recognized in the art for use in the treatment of diabetes in substantially purified form, and also in various commercially available forms, including excipients. The term includes naturally extracted human insulin, recombinantly produced human insulin, insulin extracted from bovine and / or swine sources, recombinantly produced pig and bovine insulin, and mixtures thereof. The term “insulin” also refers to an insulin homologue in which one or more of the amino acids in the polypeptide chain are replaced with a replacement amino acid and / or one or more amino acids are deleted, or one or more additional amino acids are added to the polypeptide chain. It means to include. In general, such insulin homologues of the present invention are "super" in which the ability of insulin homologues to affect serum glucose levels is substantially increased compared to hepatoselective insulin homologues that are more active in the liver than in conventional insulin and adipose tissue. ) Insulin homologues ". The present invention may also use monomeric aerosolized inhaled insulin, such as insulin lispro.
    [15] "Fasting glucose" is the value of glucose in the blood measured under a specific set of prescribed conditions, e.g., in the morning before bedtime breakfast and in the morning before the patient eats. Means level. This can typically be measured by a number of methods well known in the art, most of which can utilize commercially available products, for example in the form of a kit. The “normal” values for fasting glucose measured ranged from 80 mg / dL to 126 mg / dL. The lower the fasting glucose value within this range, the better for the patient. Accordingly, the present invention provides a method of lowering fasting glucose within this range, in particular when the fasting glucose falls within this normal range and also when the patient's fasting glucose first starts at a value of 126 mg / dl or more.
    [16] Administering insulin by the "pulmonary route" or as "pulmonary insulin" means administering insulin to inhaled insulin. In addition, “inhaled insulin” is generally an aerosolized wet or dry particulate or droplet insulin-containing administered by directing the aerosol through the mouth to the deep lungs, thereby allowing the patient to “breathe” the insulin-containing aerosol into the lungs. Means formulation. The formulation may contain dry particles inhaled from a dry powdered inhaler, such as, for example, available from Inhale Therapeutics Systems, San Carlos, Calif. Inhaled insulin preparations may also be particulate insulin-containing preparations suspended in propellants. Alternatively, the formulation may be a wet aerosol, ie a liquid aerosol of the type produced from an aqueous solution of insulin by a liquid nebulizer system (see Laube, Journal of Aerosol Medicine, Vol. 4, No. 3, 1991 and United States of America). Patent No. 5,320,094, which is incorporated herein by reference in its entirety). Precise aerosol formulations are not believed to be particularly important, so powders, whether liquid or dried, are easy to penetrate into the deep lungs, where the alveoli are believed to act as a portal from the lungs to blood. One size may be in the form of a dry insulin or a type of wet insulin-containing aerosol produced from a nebulizer. Generally, this particle size is less than about 10 μm. "Inhaled insulin" is in contrast to "nasal administered insulin" where insulin is administered in the nasal passages and poorly absorbed from the nasal mucosa into the bloodstream.
    [17] In the present invention, inhaled insulin is used to lower weight gain and fasting glucose levels in diabetic patients, meaning that inhaled insulin can be administered to patients at risk for either (or both) of these (s) conditions. do. “At risk” patients who have experienced weight gain and / or high fasting glucose levels in the past and are therefore considered to have risk factors simply because of their medical history of already having experienced one or both of these conditions. It may mean. “At risk” may also not suffer from high weight gain or high fasting glucose, but in other ways is not sufficient for other factors such as insufficient glycemic control, ie high glucose levels above the normal range or excessive weight gain that is believed to be above normal. By patient it is believed to be at risk for these conditions. Such a patient may be considered to start with a dosage form of inhaled insulin from the start, ie never initiate subcutaneous or transdermal administration of insulin. When initiating inhaled insulin in a patient, the patient generally experiences a lower rate of weight gain and / or ultimately lower absolute weight once the patient's weight gain is stable. Patients will additionally and / or optionally experience a lower mean level of fasting glucose as compared to patients self-administering insulin only by subcutaneous and / or transdermal administration. For example, when a patient switches from subcutaneous self-administration of insulin to inhaled insulin treatment form, the patient generally seeks to reduce weight gain, stop weight gain, or in some cases even lose weight. And the phrase "decrease in weight gain" means to include all of these conditions. Thus, inhaled insulin can lower the level of fasting glucose in diabetic patients, reduce the rate of weight gain in these patients, or induce both compared to subcutaneous and / or percutaneously administered insulin patients.
    [18] From a time when a patient is diagnosed with a risk of weight gain and / or high fasting glucose, or actually diagnosed with weight gain or with a high fasting glucose level, the fasting glucose level certainly exceeds 126 mg / dL Administration of inhaled insulin to is preferred. Inhaled insulin treatment should last forever until body weight and / or fasting glucose returns to an acceptable level determined by the attending physician, or if such return to the level deemed satisfactory by the physician fails.
    [19] details
    [20] A. Inhaler / Administration
    [21] Any inhaler known in the art can be used in the present invention so long as it can deliver a therapeutically effective dose of insulin to the deep lungs. This includes all devices such as those classified as dry powder inhalers, nebulizers and metered dose inhalers. Potentially useful are the trade names Turbohaler (Astra), Rotahaler ™ (Glaxo), Diskus ™ (Glaxo), Ultravent nebulizer (Mallinckrodt), Acorn II nebulizer (Marquest medical Products, Bentolin ™ Quantitative Inhaler (Glaxo), Spinhaler ™ Powder Inhalers (Fisons) and the like are known in the art.
    [22] In a preferred embodiment, the insulins are those described in US Pat. Nos. 6,089,228, 5,458,135, 5,775,320, 5,785,049, 5,740,794 and WO 93/00951, all of which are incorporated herein by reference. Aspirated as dry powder using the same hand-held device. Such a device can be obtained from Inhale Therapeutics Systems, San Carlos, CA.
    [23] B. Formulation
    [24] Any agent capable of producing an aerosolized form of insulin that can be inhaled and delivered to a patient via the intrapulmonary route can be used in connection with the present invention. Specific information regarding formulations that can be used in connection with an aerosolized delivery device is described in Remingtons' Pharmaceutical Sciences, AR Gennaro editor (final edition), Mack Publishing Company. Regarding insulin preparations, see also Sciarra et al., Journal of Pharmaceutical Sciences , Vol. 65, No. 4, 1976, which is useful.
    [25] Various different insulin-containing aerosol formulations can be used in connection with the present invention. The active ingredient in such formulations is insulin, which is preferably recombinantly produced human insulin, but may comprise insulin extracted from animal sources. Insulin may also be an insulin homologue which is a homologue of recombinantly produced human insulin. Insulin and / or homologues may exist only as their only active ingredient, but insulin may also be present with additional active ingredients such as sulfonylureas. However, these active ingredients are generally administered separately to more closely control the dosage and serum glucose levels.
    [26] Regardless of the active ingredient, there are several basic types of insulin preparations that can be used in connection with the present invention. All of these formulations preferably contain insulin with a pharmaceutically acceptable carrier suitable for intrapulmonary administration. According to the first formulation, a low boiling point high volatility propellant is combined with the active ingredient and a pharmaceutically acceptable excipient. The active ingredient may be provided, for example, as a suspension or dry powder in the propellant, or the active ingredient may be dissolved in solution in the propellant. All of these agents can be easily included in a container having a valve as its only opening. Because the propellant is very volatile, i.e. has a low boiling point, the contents of the container are under pressure. Thus, if a low boiling propellant is used, the propellant is retained in the pressurized canister of the device and remains in the liquid state. When the valve is actuated, the propellant is released to push the active ingredient together with the propellant from the canister. The propellant "flashes" when exposed to the surrounding atmosphere, ie the propellant evaporates immediately. Ignition occurs so quickly that actual delivery to the patient's lungs becomes an essentially pure active ingredient. The "ignition" phenomenon caused by the use of low boiling propellants can significantly increase the practicality of the present invention over nebulizers or formulations that do not use such propellants in that large amounts of drugs can be easily administered in a short time. In addition, because the substance delivered to the lung is essentially a pure drug, the dosage is easier and more closely controlled to monitor, which is an important feature of the method of the present invention. Thus, when using such a delivery device, it is preferable to use low boiling point chlorofluorocarbons or hydrocarbons such as low boiling point propellants such as trichlorofluoromethane and dichlorodifluoromethane. The development of non-chlorofluorocarbon containing propellants which are low boiling point propellants will make their use in connection with the present invention clear to those skilled in the art.
    [27] According to a second formulation, insulin is provided in solution. In this embodiment, the dry powder is preferably dissolved in an aqueous solvent to form a solution, which solution moves through the porous membrane to produce an aerosol for inhalation. Such solutions may be solutions of the type available commercially for injection and / or other solutions more suitable for intrapulmonary delivery. An example of a solution suitable for producing an aqueous aerosol from a nebulizer is 0.9% saline, described in US Pat. No. 5,320,094 (Laube).
    [28] A preferred form for inhaled administration of insulin is dry powder. Preferred insulin dry powders include those described in US Pat. No. 5,997,848 to Patton et al. These insulin powders have a diameter selected to allow penetration into the alveoli of the lungs, generally less than 10 μm in diameter, preferably less than 7.5 μm, most preferably less than 5 μm and generally in the range from 0.1 μm to 5 μm. It consists of free flowing fine particles having. Preferably, the insulin particle size ranges from 0.5 to 3.5 μm. The particle sizes described above generally apply to solid particles. In addition, larger size particles may be used which are aerodynamically light and much larger than 10 μm, ie having an average diameter of 5 to 30 μm. Such particles generally have a low tap density of less than 0.4 g / cm and an average diameter of 1 to 3 microns. Such particles are described in US Patent RE 37,053 E and PCT Publication Application WO 01/13891, both of which are incorporated herein by reference. In any case, the insulin powder used must have a size suitable to penetrate into the deep lungs where it can be absorbed through the alveoli.
    [29] Alternatively, amorphous insulin can be prepared by lyophilization (freeze-drying), vacuum drying or evaporation drying a suitable insulin solution under conditions that produce an amorphous structure. The amorphous insulin thus produced can then be ground or milled to produce particles in the desired size range. Crystalline dry powder insulin may be formed by grinding or jet milling of bulk crystalline insulin. A preferred method of forming insulin powders containing microparticles in the desired size range is spray drying, where pure bulk insulin (usually in crystalline form) is firstly physiologically acceptable aqueous buffer, typically pH approximately Dissolve in citrate buffer in the range 2-9. Insulin dissolves at a concentration of 0.01% to 1% by weight, generally 0.1% to 0.2%. This solution can then be spray dried in a conventional spray dryer obtained from commercial suppliers such as Buchi, Niro and the like to obtain a substantially amorphous particulate product.
    [30] Dry insulin powders may consist essentially of insulin particles within the required size range and may be substantially free of other biologically active ingredients, pharmaceutical carriers, and the like. Such "neat" formulations may contain minor ingredients, such as preservatives, which are present in small amounts, typically less than 10% by weight, typically less than 5% by weight. By using such a pure formulation, the number of inhalations required for even higher dosages can often be substantially reduced to only one breath.
    [31] Insulin powders useful in the present invention may optionally be combined with pharmaceutical carriers or excipients suitable for respiratory and pulmonary administration. Such carriers may simply be used as bulking agents if desired to reduce the insulin concentration in the powder to be introduced to the patient, but may be used in a powder disperser to enhance the stability of the insulin composition and provide more efficient and reproducible delivery of insulin. It may be used to improve the dispersibility of the powder and to improve the handling properties of insulin, such as fluidity and consistency, to facilitate preparation and filling of the powder.
    [32] Suitable carrier materials may be in the form of amorphous powders, crystalline powders, or combinations of amorphous and crystalline powders. Suitable materials include (a) carbohydrates such as fructose, galactose, glucose, monosaccharides such as D-mannose, sorbose, and the like; Disaccharides such as lactose, trehalose, cellobiose and the like; Cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin; And polysaccharides such as raffinose, maltodextrin, dextran and the like; (b) amino acids such as glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine and the like; (c) organic salts prepared from organic acids and bases such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, and the like; (d) peptides and proteins such as aspartame, human serum albumin, gelatin and the like; (e) alditol, such as mannitol, xylitol, and the like. Preferred groups of carriers include lactose, trehalose, raffinose, maltodextrin, glycine, sodium citrate, tromethamine hydrochloride, human serum albumin and mannitol.
    [33] Such carrier material may be combined with insulin prior to spray drying, ie by adding the carrier material to a buffer prepared for spray drying. In this way, the carrier material can be formed simultaneously with the insulin particles and as part of the insulin particles. Typically, when the carrier is formed by spray drying with insulin, insulin is present in each individual particle in a weight percentage in the range of 5% to 95%, preferably 20% to 80%. The remainder of the particles may be primarily a carrier material (typically 5% to 95% by weight, generally 20% to 80%), but may also include buffer (s) and other components as described above. It may also include. The presence of carrier material in the particles delivered to the alveolar portion of the lung (ie, in the required size range up to 10 μm) was found not to significantly interfere with the systemic absorption of insulin.
    [34] Alternatively, the carrier can be prepared separately in dry powder form and combined with dry powder insulin by blending. Powder carriers prepared separately may generally be crystalline (to avoid moisture absorption), but in some cases may also be amorphous or mixtures of crystalline and amorphous forms. The size of the carrier particles can be selected to improve the flowability of the insulin powder and is typically in the range of 25 μm to 100 μm. Carrier particles within this size range generally do not penetrate into the alveolar portion of the lung and are primarily separated from insulin in the delivery device prior to inhalation. Thus, particles penetrating into the alveolar portion of the lung essentially consist of insulin and buffer. Preferred carrier materials are crystalline mannitol having a size in the above-mentioned range.
    [35] Dry insulin powders useful in the present invention may also be combined with other active ingredients. For example, it may be desirable to combine small amounts of amylin or active amyloid analogs in insulin powders to improve the treatment of diabetes. Amylin is a hormone secreted with insulin from pancreatic β-cells in normal (non-diabetic) individuals. Amylin is believed to modulate insulin activity in vivo, and it has been suggested that simultaneous administration of amylin and insulin could improve blood sugar control. A product that is particularly convenient for achieving this co-administration by combining insulin and dry powder amylin in the composition of the present invention is provided. Amylin can be combined with insulin at 0.1% to 10% by weight (based on the total weight of insulin in one dose), preferably 0.5% to 2.5% by weight. Amylin is available from commercial suppliers such as Amylin Corporation (San Diego, Calif.) And can be readily formulated in the compositions of the present invention. For example, amylin can be dissolved in an aqueous solution or other suitable solution with insulin and optionally a carrier, and the resulting solution can be spray dried to produce a powder product.
    [36] The dry powdered insulin composition of the present invention is preferably aerosolized by dispersing in flowing air or other physiologically acceptable gas streams in a conventional manner. One system suitable for such a dispersion is described in co-pending US patent application Ser. No. 07 / 910,048, published in WO 93/00951, the entire disclosure of which is incorporated herein by reference. The overall operation of such a device is described herein.
    [37] Preferred dry powder formulations used in the tests described below, particularly for use in the inhalers described above, are described in Example 98 in WO 98/16205, the entirety of which is incorporated herein by reference. This was achieved by spray drying a formulation at pH 7.3 containing 7.50 mg insulin, 1.27 mg mannitol, 3.38 mg sodium citrate, 0.026 mg sodium hydroxide and 0.32 mg glycine per ml of deionized water at a total solid concentration of 12.5 mg / ml. A dry powder is prepared, wherein the formulation is spray dried to produce a dry powder having an average particle size of less than 5 μm. The powder is delivered to the deep lungs through an inhaler. Preferred modes of treatment with dry powdered insulin are as described in US Pat. No. 5,997,848, above.
    [38] C. test
    [39] The tests used to assess the patient's condition and whether the dosage form of inhaled insulin is appropriate herein are fasting measurements and / or random serum, plasma or whole blood glucose measurements that are well known in the art. Using this method, glucose concentrations and plasma or serum insulin concentrations, the latter of which are typically measured by radioimmunoassay or related techniques, are examined with samples before and after orally or intravenously administering a known amount of glucose. . There is a known normal pattern of glucose / insulin response to glucose attempts. Normal fasting glucose levels typically fall within the range of 80-126 milligrams (mg / dl), per deciliter. Glucose levels above 126 mg / dL may be sufficient to initiate the patient with inhaled insulin or to convert the patient from a therapeutic dosage of subcutaneous insulin to inhaled insulin. Laboratory methods for measuring glucose and insulin levels are widely available commercially.
    [40] The amount of insulin administered via inhalation and the appropriate dosage form are generally determined by the attending physician. In general, when insulin is administered in the form of an aerosol in combination with recombinantly produced human insulin and excipients, patients typically have one to four individual dry powder dosages, from 0.5 to 50 mg per day, usually 1 An amount of inhaled insulin in the range of 0.5 to 25 mg is administered per day. Dosing itself generally involves administering the required dosage in one or more, usually one to four, inhalations from a suitable inhaler or nebulizer. Regardless of the form in which inhaled insulin is delivered, that is, whether the insulin is delivered as a dry powder, as an aqueous aerosol produced by the nebulizer, or as a suspension in a propeller delivered from a metered dose inhaler, systemically to the patient. Delivers 1.5 to 150 units of insulin delivered (1 mg of inhaled insulin generally corresponds to about 3 units (U) of recombinant human insulin delivered systemically). Highly active insulin homologues may be administered in substantially smaller amounts while obtaining substantially the same effect with respect to serum glucose levels.
    [41] The effectiveness of inhaled insulin over subcutaneous insulin in reducing weight gain and improving fasting plasma glucose is illustrated by the following clinical trials. This test demonstrates that "Efficacy and safety of inhaled insulin compared with subcutaneous human insulin therapy in subjects with type 2 diabetes: 6-month, outpatient, parallel comparison experiment. WITH TYPE 2 DIABETES MELLITUS: A SIX-MONTH, OUTPATIENT, PARALLEL COMPARATIVE TRIAL).
    [42] The main objectives of the study were as follows: in subjects with type 2 diabetes 1. whether blood glucose control could be achieved by inhaled insulin (INH) as effectively as at least by conventional subcutaneous (SC) insulin dosage regimens. To measure; 2. To evaluate the resistance and safety of inhaled insulin and its effect on measurements of lung function after 6 months of exposure. The trial was designed as a randomized 6-month (24-week) parallel outpatient trial with an open-label, 4-week introduction period in subjects with type 2 diabetes. After screening, the subject maintained a control SC insulin dosage regimen consisting of twice daily (BID) administration of mixed standard insulin and NPH insulin. After the introduction phase, subjects received either a randomized SC injection or dry powder inhaled insulin dosage form (Ultralente ™ injection at bedtime with pre-meal inhaled insulin (TID)) for the next 24 weeks. Applied. The inhaler used was a dry powder inhaler obtained from Inhale Therapeutics Systems Inc., San Carlos, CA.
    [43] Men and women aged 35-80 years with a stable SC insulin dosing schedule (BID for at least 2 months prior to screening) and having type 2 (insulin-independent) diabetes for over a year were included in this study. Subjects needed to have a screening of 6% to 11% and pre-randomized glycosylated hemoglobin (HbA1c). There are no specific fasting plasma glucose levels or body weight requirements, but participants with a Body Mass Index (BMI) of 35 or higher required consultation with the investigators. Table 1 shows the quality of the subject.
    [44] Evaluation group:Inhaled insulinSC insulin Randomize149150 cure149149 complete132140 stop179 Evaluation of efficacy: Full Analysis Set (ITT) Per Protocol Set (evaluable)146143149145 Assessment of safety: side effects laboratory test lung function test149135145149142145
    [45] The primary efficacy endpoint was the change in HbA1c from baseline to 24 weeks of treatment. HbA1c was collected at -4, -1, 0, 6, 12 and 24 weeks. Secondary efficacy endpoints include fasting plasma glucose and changes in body weight (-4 weeks and every 4 weeks thereafter) and the percentage of subjects who reached acceptable glycemic control (HbA1c <8% or <7% at 24 weeks), Glucose and insulin increments (baseline, 24 weeks), fasting lipids (weeks 0 and 24), and glucose monitoring at home, 2 hours post-meal, according to a standard diet. The incidence and severity of hypoglycemia was monitored. A survey of treatment satisfaction and preferences was also performed (-4, -1, 6, 12 and 24 weeks).
    [46] Safety assessments included: a full physical examination at screening and a brief physical examination at weeks 0 and 4, 8, 16 and 24 (including throat, chest, blood pressure and heart rate); 12-lead ECG (screening and week 24); Chest X-ray (screening, 24 weeks); Clinical laboratory safety testing (screening and 24 weeks); Insulin antibodies (weeks 0 and 24); And pregnancy tests (screenings) for women with potential fertility. Comprehensive pulmonary function tests (spirametry, lung volume, diffusivity, and oxygen saturation) were performed at baseline (-3 weeks) and week 24 (spirametry was also performed at week 12). Observed and autogenous side effects were recorded. High resolution computerized tomography scans of the throat at selected sites were performed on a subset of subjects at baseline and week 24.
    [47] The following statistical methods were used: The primary efficacy endpoint was the change in HbA1c at 24 weeks from baseline, which was a full analysis set (ITT) and a per protocol set (evaluable: Primary analysis group) both. Analysis of the covariance (ANCOVA) model in terms of baseline HbA1c, center and treatment was appropriate for changes 24 weeks from baseline HbA1c values. If 24 weeks HbA1c was not available, transition was made to the final evaluable HbA1c value after baseline (LOCF). Non-inferiority of inhaled insulin relative to subcutaneous insulin was determined when the upper limit of the 95% confidence interval was less than 0.5%, the protocol-defined non-inferiority threshold.
    [48] The therapeutic effect on the continuous secondary efficacy parameter was assessed using an ANCOVA model similar to the primary model for HbA1c. The proportion of subjects who reached pre-defined glycemic control targets (HbA1c <8% and <7%) at Week 24 were analyzed using logistic regression. The risk ratio of hypoglycemic expression was estimated using survival analysis, which counts the process approach to recurrent expression, where the analytical model only included the duration for treatment.
    [49] Efficacy Results: In brief, the two regimens showed similar general glycemic control with respect to HbA1c levels despite slightly lower overall hypoglycemic risk (95 for adjusted risk ratios (RR) between groups not crossing 1). % Confidence interval (proven by 95% CI). However, fasting plasma glucose at the end of the trial was 16 mg / dL lower for INH dosing compared to SC dosing (as evidenced by the 95% confidence interval (95% CI) for the adjusted difference not crossing zero). . In addition, the INH group increased 0.1 kg on average, while the SC group increased 1.4 kg, and the adjusted difference between the groups -1.3 kg was significant (by 95% CI for the adjusted difference not crossing zero). Proven).
    [50] Except where noted, the results shown in Table 2 below for the evaluable analysis set.
    [51]
    [52] HbA1c at baseline and at the end of the test is shown in Table 3 below; Number of subjects (%).
    [53] HbA1c<7%7% to <8%8% to <9%≥9% Inhaled insulin (n = 143) at baseline test25 (17.5) 67 (46.9)45 (31.5) 42 (29.4)47 (32.9) 15 (10.5)26 (18.2) 19 (13.3) At the end of the SC insulin (n = 145) baseline test17 (11.7) 46 (31.7)51 (35.2) 54 (37.2)45 (31.0) 33 (22.8)32 (22.1) 12 (8.3)
    [54] Safety results are shown in Table 4 below:
    [55] Number of subjects evaluated (expression) [discontinuation due to expression] Inhaled insulinSC insulin All causal side effects a. 149 (141) [2]149 (143) [2] Per tester, T / R side effects manifested b 149 (126) [2]149 (118) [0] Severe adverse events in all causal relationships a 149 (13) [0]149 (12) [2] Laboratory Test Abnormal (Normal Baseline)135 (43) [0]142 (56) [0] Laboratory Test Abnormal (Abnormal Baseline)114 (17) [0]128 (13) [0] Note) T / R-treatment-related; Stop - Disc'd a drugs test during or 1-1 adverse events reported in the expression of any causal therapy delay period b-start or timing (timing) and is independent of the treatment of the test drug-related side effects expression
    [56] Two deaths occurred in this trial, none of which were treatment-related. There were 25 cases of severe adverse event (SAE). One of these (SC insulin group) was treatment-related. Two of the serious adverse event manifestations in the SC insulin group (and none in the inhaled insulin group) resulted in permanent discontinuation. Almost all subjects in both treatment groups experienced adverse events (all causal and treatment-related) during the trial. Most of the reported adverse events were mild or moderate symptomatic side effects. There were 23 (15%) subjects with 30 severe adverse events in the inhaled insulin group and 11 (7%) subjects with 16 severe adverse events in the subcutaneous insulin group.
    [57] The most commonly reported side effect was treatment-related hypoglycemia. In addition to the reported hypoglycemia, some of the other reported treatment-related side effects (eg, lethargy, tremor, dizziness, sweating, headache) may have mild or relative symptoms of hypoglycemia. In general, the number of subjects with adverse effects due to body system and treatment relevance was balanced between inhaled and subcutaneous insulin groups. There was a greater number of treatment-related respiratory adverse events in the inhaled insulin group than in the subcutaneous insulin group. The manifestation of these adverse events was almost all of the increased cough, and their incidence and prevalence were greater in the inhaled insulin group. The incidence of cough decreased significantly over the course of the trial.
    [58] The mean change from baseline in pulmonary function test data (FEV1, FVC, TLC and DLco) was small and similar for the two groups.
    [59] There were no significant findings on blood pressure, heart rate, physical examination, chest X-ray, or ECG. There was an average change of 12.2 mg / dL in triglycerides in both the inhaled insulin group and the SC insulin group, and the average change in total, HDL and LDL cholesterol was very small.
    [60] This study is merely an example of the results presented by the INH versus SC dosing regime. Although the weight and fasting plasma glucose results in other studies did not always reach statistically significant levels, they consistently showed a similar trend. For example, another very similar test in type 1 (insulin dependent) diabetic patients aged 12-65 was 0.2 kg less weight gain (not significant) in INH group than in SC group and INH group than in SC group. At 38 mg / dl lower fasting plasma glucose (significant). In addition, these results were associated with similar overall glycemic control (determined by the HbA1c value at the end of the test) and slightly lower hypoglycemic expression rates.
    [61] Inhaled insulin can be used in comparison to insulin administered subcutaneously and / or percutaneously in accordance with the present invention to prevent weight gain and lower fasting glucose levels in diabetic patients.
    权利要求:
    Claims (14)
    [1" claim-type="Currently amended] Insulin for reducing the weight gain of the patient, which uses exogenous insulin to control blood glucose and includes insulin administered by the pulmonary route to a diabetic patient receiving the insulin subcutaneously and / or transdermally and a pharmaceutically acceptable carrier. Formulation.
    [2" claim-type="Currently amended] The formulation of claim 1, wherein the pulmonary insulin is delivered in the form of aerosolized insulin nebulized from solution.
    [3" claim-type="Currently amended] The formulation according to claim 1, wherein the pulmonary insulin is administered as a dry powder.
    [4" claim-type="Currently amended] The formulation of claim 1, wherein the patient has been using exogenous insulin by the subcutaneous route.
    [5" claim-type="Currently amended] The formulation of claim 1, wherein the patient has been using exogenous insulin by the transdermal route.
    [6" claim-type="Currently amended] The formulation of claim 1, wherein the patient newly initiates insulin.
    [7" claim-type="Currently amended] The formulation of claim 1, wherein the effective amount of pulmonary insulin is delivered by a propellant from a metered dose inhaler to a solution or suspension of insulin.
    [8" claim-type="Currently amended] For lowering fasting glucose levels in the patient, which uses exogenous insulin to control blood glucose and includes insulin administered by the pulmonary route to diabetic patients receiving the insulin subcutaneously and / or transdermally and a pharmaceutically acceptable carrier. Insulin preparations.
    [9" claim-type="Currently amended] The formulation of claim 8, wherein the pulmonary insulin is delivered in the form of aerosolized insulin nebulized from solution.
    [10" claim-type="Currently amended] The formulation according to claim 8, wherein the pulmonary insulin is administered as a dry powder.
    [11" claim-type="Currently amended] The formulation of claim 8, wherein the patient has been using exogenous insulin by the subcutaneous route.
    [12" claim-type="Currently amended] The formulation of claim 8, wherein the patient has been using exogenous insulin by the transdermal route.
    [13" claim-type="Currently amended] The formulation of claim 8, wherein the patient newly initiates insulin.
    [14" claim-type="Currently amended] The formulation of claim 8, wherein the effective amount of pulmonary insulin is delivered from the metered dose inhaler to the solution or suspension of insulin by a propellant.
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    同族专利:
    公开号 | 公开日
    JP2003012543A|2003-01-15|
    CA2390757A1|2002-12-21|
    HK1049617B|2007-03-16|
    PL354641A1|2002-12-30|
    CZ20022151A3|2003-04-16|
    HK1049617A1|2007-03-16|
    HU0202042A2|2004-05-28|
    CN1393265A|2003-01-29|
    IL150209D0|2002-12-01|
    HU0202042A3|2004-06-28|
    US20050220722A1|2005-10-06|
    AU4884102A|2003-01-02|
    EP1270012A1|2003-01-02|
    SK9042002A3|2003-05-02|
    CN1289143C|2006-12-13|
    NZ519403A|2005-03-24|
    ZA200204859B|2004-01-28|
    US20030079747A1|2003-05-01|
    HU0202042D0|2002-08-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-06-21|Priority to US30004901P
    2001-06-21|Priority to US60/300,049
    2002-06-21|Application filed by 화이자 프로덕츠 인크.
    2002-12-31|Publication of KR20020097033A
    优先权:
    申请号 | 申请日 | 专利标题
    US30004901P| true| 2001-06-21|2001-06-21|
    US60/300,049|2001-06-21|
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