WO1992006704A1 - Method of treating or preventing type 1 diabetes by oral administration of insulin - Google Patents

Method of treating or preventing type 1 diabetes by oral administration of insulin Download PDF

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Publication number
WO1992006704A1
WO1992006704A1 PCT/US1991/007475 US9107475W WO9206704A1 WO 1992006704 A1 WO1992006704 A1 WO 1992006704A1 US 9107475 W US9107475 W US 9107475W WO 9206704 A1 WO9206704 A1 WO 9206704A1
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Prior art keywords
insulin
disease
diabetes
type
mammal
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PCT/US1991/007475
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English (en)
French (fr)
Inventor
Howard L. Weiner
George Eisenbarth
David Allen Hafler
Zhengri Zhang
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Autoimmune, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Autoimmune, Inc. filed Critical Autoimmune, Inc.
Priority to KR1019930701008A priority Critical patent/KR100239743B1/ko
Priority to DK91918981T priority patent/DK0552256T3/da
Priority to BR919106977A priority patent/BR9106977A/pt
Priority to EP91918981A priority patent/EP0552256B1/en
Priority to DE69132688T priority patent/DE69132688T2/de
Priority to CA002093806A priority patent/CA2093806C/en
Priority to HU9301050A priority patent/HU225054B1/hu
Priority to AU87679/91A priority patent/AU659419B2/en
Priority to AT91918981T priority patent/ATE204178T1/de
Publication of WO1992006704A1 publication Critical patent/WO1992006704A1/en
Priority to NO19931267A priority patent/NO319370B1/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/542—Mucosal route oral/gastrointestinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/543—Mucosal route intranasal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to methods and compositions for treating or preventing Type 1 diabetes mellitus.
  • the methods of the invention do not require parenteral administra ⁇ tion of therapeutic agents. More particulary, but not by way of limitation, the present invention is directed to agents and methods for treating or preventing autoimmune diseases having the characteristics of Type 1 diabetes mellitus.
  • Diabetes mellitus is characterized in two broad groups based on clinical manifestations, namely, the non- insulin-dependent or maturity onset form, also known as Type 2; and the insulin-dependent or juvenile onset form, also known as Type 1.
  • Type 2 non- insulin-dependent or maturity onset form
  • Type 1 insulin-dependent or juvenile onset form
  • SUBSTITUTE SHEET relative to their age and height, with rapid onset of the disease at an early age, often before 30, although Type 1 diabetes can occur at any age.
  • Diabetes mellitus is a metabolic disorder in humans with a prevalence of approximately one percent in the general population, with one-fourth of these being the Type 1, insulin- dependant category (Foster, D. ., Harrison's Principles of Internal Medicine, Chap. 114, pp. 661-678, 10th Ed., McGraw- Hill, New York).
  • the disease manifests itself as a series of hormone- nduced metabolic abnormalities which eventually lead to serious, long-term and debilitating complications involving several organ systems including the eyes, kidneys, nerves, and blood vessels.
  • Pathologically, the disease is characterized by lesions of the basement membranes, demonstrable under electron microscopy.
  • Type 1 diabetics characteristically show very low or immeasurable plasma insulin with elevated glucagon. Regardless of what the exact etiology is, most Type 1 patients have cir ⁇ culating antibodies directed against their own pancreatic cells including antibodies to insulin, to islet of Langerhans cell cytoplasm and to the enzyme glutamic acid decarboxylase. An immune response specifically directed against beta cells (insulin producing cells) leads to Type 1 diabetes. This specificity is supported by the above clinical picture, since beta cells secrete insulin while alpha cells secrete glucagon. Current therapeutic regimens for Type 1 diabetes include modifications to the diet in order to minimize hyper-
  • Type 1 diabetes usually manifests itself in adolescents and because the subcutaneous delivery of insulin requires strict, self-regimentation, compliance is often a serious problem.
  • the act of the parenteral ad ⁇ ministration itself can be very traumatic to juveniles. For the clinician, it is difficult to precisely regulate the amounts of insulin needed at any given time of the patient's day. Furthermore, it is all but impossible to regulate blood glucose levels in diabetic patients with parenteral insulin to
  • the art has long sought a method for preventing and/or treating Type 1 diabetes which does not involve paren ⁇ teral administration of insulin.
  • Various attempts at alternate delivery methods for insulin have failed or have not progressed to a practical level.
  • oral insulin, transcutane- ous insulin delivery, and nasal insulin have not become clini ⁇ cally utilized.
  • Oral insulin does not affect blood glucose levels. Because it has been necessary to inject lipids into mammals receiving nasal insulin in order to get the insulin across the nasal mucosa, this route of insulin administration has been limited.
  • Type 2 diabetes SUBSTITUTE SHEET Oral dosage forms for treatment of Type 2 diabetes are available, (e.g. oral sulfonylureas). These orally admin ⁇ istered agents do not comprise insulin but rather stimulate the pancreas to produce insulin, and are only effective for treat- ent of certain forms of Type 2 diabetes.
  • oral agents such as sulfonylureas are ineffective due to markedly diminished or damaged beta-cell mass (Foster, D.W., Harrison's Principles of Internal Medicine, Chap. 114, p. 668, 10th Ed., McGraw-Hill, New York).
  • Type 1 diabetes is considered to be a disease of autoimmune etiology (Eisenbarth, G.S., New Engl.
  • Type 1 diabetes As an autoimmune disorder. These include the BB mouse (Nakbookda, A.F., et al., Diabetolo ⁇ ic 14; 199-207, 1978) and the NOD (non-obese diabetic) mouse in which diabetes develops spontaneously (Prochazka et al. Science 237;286, 1987). Islet-cell specific, CD4 and CD8 T-lymphocytes have been implicated as causative agents for damage to beta cells, demonstrated by decreased incidence of Type 1 diabetes in NOD mice (J ⁇ Exp. Med. 161:823, 1987).
  • SUBSTITUTE SHEET It is, therefore, an object of the present invention to provide agents and methods for treating and preventing autoimmune diseases in mammals having the characteristics of Type 1 diabetes. Prevention of Type 1 diabetes preferably involves treatment prior to hyperglycemia.
  • Another object of the present invention is to provide compositions and pharmaceutical formulations useful for treating mammals suffering from autoimmune diseases having the characteristics of Type 1 diabetes.
  • a still further object of the invention is to provide compositions and pharmaceutical formulations useful for oral administration to mammals for the purpose of preventing or attenuating the manifestations (i.e. clinical symptoms) of autoimmune diseases having the characteristics of Type 1 diabetes.
  • Prevention of Type 1 diabetes includes treatment prior to hyperglycemia.
  • oral ad ⁇ ministration of insulin is an effective treatment for eliminat ⁇ ing or reducing the need for insulin in Type 1 diabetics.
  • Oral insulin can prevent or ameliorate beta cell distruction and thereby decrease or eliminate traditional parenteral insulin therapy.
  • S UBSTITUTE SHEET Orally administerable pharmaceutical formulations containing insulin are prepared and administered to mammals who have manifested symptoms of Type 1 diabetes and/or diagnosed as having Type 1 diabetes. Additionally, subjects who are at risk for developing Type 1 diabetes (i.e. have demonstrated a predisposition to developing Type 1 diabetes through suitable means, such as genetic studies and analysis) are treated with similar oral preparations of insulin.
  • compositions for oral or enteral adminis- tration to treat Type 1 diabetes are prepared from commercially available insulin and a pharmaceutically acceptable carrier suitable for oral ingestion.
  • the quantity of insulin in each dose may be between 1 mg and 1000 mg. However the total dose required for treatment varies according to the individual. Generally, the total quantity of insulin required in practicing the present invention is a much larger dose than is the dosage that is administered parenterally to protect an individual afflicted with Type 1 diabetes against ketoacidosis.
  • an aerosol delivery system can be made with similar dosages of insulin as above with a pharmaceutical ⁇ ly suitable carrier or diluent.
  • Figure 1 is a graph showing the effects of orally administered porcine insulin on diabetes in NOD mice.
  • SUBSTITUTE SHEET Figure 2 is a graph showing the effects of oral porcine insulin on serum glucose concentrations post-adminis ⁇ tration of oral insulin in NOD mice.
  • Figure 3 is a graph showing the effect of oral ad- ministration of pancreatic extracts given at weekly intervals on the development of diabetes in NOD mice.
  • the present invention addresses the need for an alternate to existing methods for the treatment of Type 1 diabetes from an autoimmune model and in particular at treat- ment for the prevention of diabetes. Because Type 1 patients are predominantly adolescents, it is believed that long term insulin therapy will no longer be required due to preservation of undamaged beta cell function if treatment is initiated at the onset of the disorder using the compositions and methods of the present invention. In addition, if the methods of the present invention are initiated at a time when some beta cell function still exists, parenteral insulin therapy can be reduced. Thus, the present invention provides means whereby long term insulin therapy would be reduced or no longer be required.
  • SUBSTITUTE SHEET sive fragments of insulin or analogs thereof is effective for the treatment and prevention of Type 1 diabetes.
  • This is a radical departure from traditional (parenteral) insulin therapy in that insulin is adminstered in order to damp down or shut off the hosts autoimmune response and not for its en- docrinologic (metabolic) effect.
  • Oral administration of insulin has not proved to be effective in treating any form of diabetes because proteolytic enzymes present in the stomach and digestive system degrade the polypeptide before it can reach the bloodstream.
  • intranasal administration of insulin has also not previously been shown to be effective in treating any form of diabetes.
  • Treatment shall mean the treatment of active disease in patients with some level of undamaged, insulin- producing beta cells as well as prophylactic administration for use in patients having a high risk for developing the disease.
  • Oral administration shall mean both oral adminis- tration and enteral administration (direct incubation into the stomach) .
  • Type 1 diabetes shall mean a) individuals having a blood relative with Type 1 diabetes; b) autoantibody-positive individuals without overt Type 1 diabet ⁇ es. These auto antibodies include cytoplasmic islet cell autoantibodies, insulin antibodies and glutamic acid decar- boxylase autoantibodies; c) individuals with Histocompatibility (HLA) type DR3 or DR4DQW8; d) individuals with glucose abnor ⁇ malities such as a loss of first phase insulin secretion on glucose tolerance tests.
  • HLA Histocompatibility
  • DR3 or DR4DQW8 individuals with glucose abnor ⁇ malities such as a loss of first phase insulin secretion on glucose tolerance tests.
  • “Mammal” shall mean any organism having an immune system and therefore susceptible to Type 1 diabetes.
  • Active disease shall mean autoimmune destruction of islet beta cells.
  • “Aerosol” refers to finely divided solid or liquid particles that may be created using a pressurized system such as a nebulizer.
  • the liquid or solid source material contains insulin and/or disease suppressive fragments of insulin and analogs thereof as defined herein.
  • Disease suppressive fragments of insulin includes any peptide or polypeptide containing partial amino acid sequences or moieties of insulin and possessing the ability to treat or prevent a disease having the characteristics of Type 1 diabetes. Such fragments need not possess the autoantigenic or endocrinolocic (metabolic) properties of the entire insulin molecule.
  • SUBSTITUTE SHEET insulin or disease suppressive fragments thereof which possess the same biologic activity, i.e., the ability to suppress or prevent disease symptoms of Type 1 diabetes, upon oral or aerosol administration.
  • the term includes peptides having amino acid sequences which differ from the amino acid sequence of insulin or disease suppressive fragments thereof by one or more amino acid residues while still retaining the disease suppressive activity of insulin or its ability to prevent or alleviate the symptoms of Type 1 diabetes. These analogs do not necessarily need to possess the endocrinologic effects of insulin.
  • NOD non-obese diabetic mice
  • the present invention provides a method for treating or preventing a disease having the characteristics of Type 1 diabetes in a mammal comprising administering to a mammal, suffering from or at risk for Type 1 diabetes, an effective
  • JUBST1TUTE SHEET amount of an oral insulin dosage form to treat or prevent the symptoms of diabetes is not limited
  • the methods of the present invention will not eliminate the need for parenteral insulin therapy in patients with damaged beta cells who do not produce enough insulin to regulate their blood sugar.
  • newly diagnosed Type 1 diabetic patients or those at risk for the disease (as defined above), who have substantially intact (undamaged) beta cells will not go on to develop Type 1 diabetes and parenteral insulin administration may be elimina ⁇ ted.
  • the methods and composi ⁇ tions of the present invention will reduce the amount of insulin needed by those individuals having some beta cell
  • Insulin for use in the present invention can be obtained from numerous commercial sources such as Novo
  • Porcine-derived insulin, human semi-synthetic insulin (Nordisk-USA) and cloned recom- binant insulin (Eli Lilly) can be used when practicing the method of the present invention.
  • Disease suppressive fragments and analogs of insulin for use in the present invention can be synthesized using well known solid phase synthesis techniques (Merrifield, R.B. Fed.
  • Analogs can be provided using the known amino acid sequence of insulin as disclosed in Atlas of Protein Sequence and Structure, Natl. Biochem. Res. Foundation, vol. 5, pgs. 209-211.
  • Disease-suppressive analogs and fragments can also be obtained using recombinant DNA techniques well-known in the art.
  • insulin or disease suppressive fragments or analogs thereof are introduced into a mammal suffering from or at risk for a disease having the characteristics of Type 1 diabetes, orally or enterally, in an amount of between about 2 mg per kg body weight of said mammal and about 10 mg per kg body weight of said mammal per day, and may be administered in a single dose form or multiple dose forms.
  • the insulin is administered in an amount between about 2.5 mg and about 5.0 mg per kg body weight of said mammal per day.
  • the exact amount to be administered will vary depending on the severity and stage of a patient's disease and the physical condition of the patient.
  • SUBSTITUTE SHEET The present invention also is directed to oral dosage forms and pharmaceutical formulations for administration to mammals suffering from or at risk for diseases having the characteristics of Type 1 diabetes. It will be understood that any statistically significant attenuation in the disease symptoms of Type 1 diabetes pursuant to the treatment of the present invention is within the scope of the invention.
  • Each oral formulation according to the present inven ⁇ tion may additionally comprise inert constituents including pharmaceutically acceptable carriers, diluents, fillers, solubilizing or emulsifying agents and salts as is well-known in the art.
  • tablets may be formulated in accor ⁇ dance with conventional procedures employing solid carriers well-known in the art.
  • Capsules employed in the present invention may be made from any pharmaceutically acceptable material such as gelatin or cellulose derivatives.
  • Sustained release oral delivery systems and/or enteric coatings for orally administered dosage forms are also contemplated such as those described in U.S. Patent No. 4,704,295 issued November 3, 1987, U.S. Patent No. 4,556,552 issued December 3, 1985, U.S. Patent No.' 4,309,404 issued January 5, 1982 and U.S. Patent No. 4,309,406 issued January 5, 1982.
  • solid carriers examples include bentonite, silica and other commonly used carriers.
  • Further non-limiting exam- pies of carriers and diluents which may be used in the formula ⁇ tions of the present invention include saline and any physio-
  • SUBSTITUTE SHEET logically buffered saline solution such as phosphate buffered saline (PBS) and water.
  • PBS phosphate buffered saline
  • unit content of active ingredient or ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.
  • the preferred route of administration of the dosage forms of the present invention is orally or enterally.
  • Pre- ferred oral or enteral pharmaceutical formulations or dosage forms may comprise for example, between about 1 mg and about 1000 mg of insulin.
  • the pharmaceutical formulations or dosage forms of the present invention can also be administered to mammals suffering from diseases having the characteristics of Type 1 diabetes in aerosol form. It is expected that lower amounts of insulin, disease suppressive fragments or analogs thereof will be required using aerosol administration for treating or preventing Type 1 diabetes as has been found when treating experimental allergic encephalomyelitis (EAE) with myelin basic protein (MBP) and adjuvant arthritis with collagen as disclosed in co-pending U.S. Patent Application Ser. No. 454,486 filed December 20, 1989.
  • EAE experimental allergic encephalomyelitis
  • MBP myelin basic protein
  • the amounts of insulin or disease suppres- sive fragments or analogs thereof which may be administered in an aerosol dosage form would be between about 0.1 mg and 10 mg per kg body weight of a mammal per day and may be administered
  • the aerosol pharmaceutical formulations of the present invention may include, as optional ingredients, pharma ⁇ ceutically acceptable carriers, diluents, solubil zing or emulsifying agents, and salts of the type that are well-known in the art. Examples of such substances include normal saline solutions, such as physiologically buffered saline solutions, and water.
  • the route of administration of insulin or disease suppressive fragments or analogs thereof is in an aerosol or inhaled form.
  • the insulin and related compounds of the present invention can be administered as a dry powder or in an aqueous solution.
  • Preferred aerosol pharmaceutical formula ⁇ tions may comprise for example, a physiologically-acceptable buffered saline solution containing between about 1 mg and about 1000 mg of insulin, disease suppressive fragments or analogs thereof.
  • Dry aerosol in the form of finely divided solid particles of insulin, disease suppressive fragments or analogs thereof that are not dissolved or suspended in a liquid are also useful in the practice of the present invention.
  • the insulin may be in the form of dusting powders and comprise finely divided particles having an average particle size of
  • Finely divided particles may be prepared by pul ⁇ verization and screen filtration using techniques well known in the art. The particles may be administered by inhaling a predetermined quantity of the finely divided material, which can be in the form of a powder.
  • the carriers and/or diluents that are useful in the aerosol pharmaceutical formula ⁇ tions of the present invention include water and physiological- ly-acceptable buffered saline solutions such as phosphate buffered saline solutions pH 7.0-8.0.
  • the pharmaceutical formulations of the present inven ⁇ tion may be administered in the form of an aerosol spray using for example, a nebulizer such as those described in U.S. Patent Nos. 4,624,251 issued November 25, 1986; 3,703,173 issued November 21, 1972; 3,561,444 issued February 9, 1971 and 4,635,627 issued January 13, 1971.
  • the aerosol material is inhaled by the subject to be treated.
  • Aerosol delivery system of the type disclosed herein are available from numerous commercial sources including Fisons
  • the methods of the present inven ⁇ tion are particularly well-suited for use in pediatric or adolescent patients developing Type 1 diabetes or the first year of onset of hyperglycemia in whom the secondary effects of the disease (such as vascular damage, kidney damage and diabet ⁇ ic retinopathy) have not been totally manifested. These are also the patients in whom the traumatic effects of daily insulin injections are usually most severely felt.
  • EXAMPLE 1 EFFECT OF FEEDING PORCINE-INSULIN
  • Taconic Laboratories Germantown, MA
  • animals were orally administered Porcine insulin Novo Laboratories, Danbury, CT
  • Porcine insulin Novo Laboratories, Danbury, CT
  • the urine was tested weekly for the presence of glucose using Glucosuria test tape (Eli Lilly, Indianapolis, IN) . If an animal tested 3+ or higher on the glucose urine test, a serum sample was taken and blood glucose measured using a glucose analyzer (Beckman) . If the blood glucose was 220 or higher, the animals were classified as diabetic and then sacrificed.
  • Glucosuria test tape Eli Lilly, Indianapolis, IN
  • a serum sample was taken and blood glucose measured using a glucose analyzer (Beckman) . If the blood glucose was 220 or higher, the animals were classified as diabetic and then sacrificed.
  • the normal blood insulin level in an animal is between 120 to 170 mg/decaliter or mg/dl.
  • the blood sugars in the animals that were fed PBS that developed diabetes were: 575, 485, 459, 500, 375, 400, 362, 395, 480 mg/dl.
  • the blood sugar in the animals that were fed 10 micrograms of insulin which developed diabetes were: 330, 420, 315, 459, 520, 487 mg/dl.
  • Blood sugars in animals fed 100 micrograms of insulin that became diabetic were: 290, 600, 450, 500 mg/dl. Animals that were fed 1 mg of insulin were also tested in terms of blood sugar. None of the animals developed diabetes as mea ⁇ sured by urine testing but the blood sugar was tested as a confirmation. Blood sugar on 10 representative animals from the group fed 1 mg insulin were: 174, 128, 125, 125, 145, 123, 136, 155, 115, 130 mg/dl.
  • SUBSTITUTE SHEET protein obtained from Pel Freez, Rogers, AR
  • Blood glucose was then measured over the next 24 hour period.
  • a separate group of animals were injected subcutaneously with 20 micrograms of Porcine insulin. All animals were kept in the fasting state.
  • animals given subcutaneous insulin had an immediate drop in the glucose level with a decrease cf approximately 80 mg % that persisted over a 4 hour period and then slowly returned to normal.
  • Animals which received oral insulin or oral myelin basic protein had no drop in the blood glucose; in fact there was an increase in blood glucose most probably related to the protein load. Over the next 24 hours there was a gradual decrease in blood glucose in all groups of animals since the animals were in a fasting state. This was seen both in animals fed insulin and animals fed myelin basic protein.
  • Example 2 An identical experiment to Example 1 was performed in which NOD mice (14-17 per group) were fed one homogenized pancreas derived from Lewis rats in 0.5 mis PBS. As shown in
  • EXAMPLE 4 EFFECT OF AEROSOL ADMINISTRATION OF INSULIN ON DIABETES IN NOD MICE
  • Insulin (0 to 1 mg as in Examples 1 and 2) will be administered to NOD mice as described above in Examples 1 and 2 except in aerosol form by nebulizer. It is expected that aerosolized insulin will be effective in preventing the manifestation of symptoms (i.e. hyperglycemia) of Type 1 diabetes in the treated mice.
  • Insulin (0 to 1 mg as in Examples 1 and 2) will be administered to NOD mice which are suffering from hyperglycemia in an oral and aerosol form. The treatments will begin by weeks 12-20 of age, by which the serum glucose levels are at

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PCT/US1991/007475 1990-10-10 1991-10-10 Method of treating or preventing type 1 diabetes by oral administration of insulin WO1992006704A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
KR1019930701008A KR100239743B1 (ko) 1990-10-10 1991-10-10 인슐린을 함유하는 타입 1 당뇨병 치료용 경구투여, 장내투여 또는 흡입경구투여용 제제
DK91918981T DK0552256T3 (da) 1990-10-10 1991-10-10 Fremgangsmåde til at behandle eller forebygge type 1 diabetes ved peroral indgivelse af insulin
BR919106977A BR9106977A (pt) 1990-10-10 1991-10-10 Metodo para suprimir destruicao autoimune de celuias beta pancreaticas,formulacao farmaceutica,metodo de profilaxia,metodo para prevenir o surgimento de diabetes tipo 1 e metodo para tratar um mamifero
EP91918981A EP0552256B1 (en) 1990-10-10 1991-10-10 Method of treating or preventing type 1 diabetes by oral administration of insulin
DE69132688T DE69132688T2 (de) 1990-10-10 1991-10-10 Methode zur behandlung und vorbeugung von typ-1 diabetis durch orale verabreichung von insulin
CA002093806A CA2093806C (en) 1990-10-10 1991-10-10 Method of treating or preventing type 1 diabetes by oral administration of insulin
HU9301050A HU225054B1 (en) 1990-10-10 1991-10-10 Process for producing a pharmaceutical composition to protect working ability of pancreas
AU87679/91A AU659419B2 (en) 1990-10-10 1991-10-10 Method of treating or preventing type 1 diabetes by oral administration of insulin
AT91918981T ATE204178T1 (de) 1990-10-10 1991-10-10 Methode zur behandlung und vorbeugung von typ-1 diabetis durch orale verabreichung von insulin
NO19931267A NO319370B1 (no) 1990-10-10 1993-04-01 Fremgangsmate for fremstilling av formulering for behandling eller forebyggelse av type 1 diabetes ved oral administrering av insulin

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US20010056063A1 (en) 2001-12-27
IL99699A (en) 2002-04-21
US5843886A (en) 1998-12-01
KR930702022A (ko) 1993-09-08
ATE204178T1 (de) 2001-09-15
AU659419B2 (en) 1995-05-18
DK0552256T3 (da) 2001-12-10
JP2548056B2 (ja) 1996-10-30
CA2093806C (en) 2003-12-30
CA2093806A1 (en) 1992-04-11
KR100239743B1 (ko) 2000-02-01
DE69132688D1 (de) 2001-09-20
US5643868A (en) 1997-07-01
HU225054B1 (en) 2006-05-29
EP0552256A4 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1994-04-27
US5763396A (en) 1998-06-09
NO931267D0 (no) 1993-04-01
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US5858968A (en) 1999-01-12
EP0552256A1 (en) 1993-07-28
HUT64235A (en) 1993-12-28
NO931267L (no) 1993-05-05
US6703361B2 (en) 2004-03-09
BR9106977A (pt) 1993-08-31
JPH06504986A (ja) 1994-06-09
EP0552256B1 (en) 2001-08-16
DE69132688T2 (de) 2001-11-29
NO319370B1 (no) 2005-07-25

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