WO1997002818A1 - Composition et procede pour traiter le diabete - Google Patents

Composition et procede pour traiter le diabete Download PDF

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Publication number
WO1997002818A1
WO1997002818A1 PCT/US1996/011462 US9611462W WO9702818A1 WO 1997002818 A1 WO1997002818 A1 WO 1997002818A1 US 9611462 W US9611462 W US 9611462W WO 9702818 A1 WO9702818 A1 WO 9702818A1
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WIPO (PCT)
Prior art keywords
insulin
vanadyl sulfate
per day
effective amount
composition
Prior art date
Application number
PCT/US1996/011462
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English (en)
Inventor
Enrique G. Gutierrez
Reynold Leboeuf
Original Assignee
Gutierrez Enrique G
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 Gutierrez Enrique G filed Critical Gutierrez Enrique G
Priority to AU64599/96A priority Critical patent/AU6459996A/en
Publication of WO1997002818A1 publication Critical patent/WO1997002818A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof

Definitions

  • the present invention is directed to compositions and methods of using the same for the treatment of diabetes.
  • the composition includes a combination of the oral hypoglycemic agent micronized glyburide and a trace rare metal supplement, such as the combination of micronized glyburide and vanadyl- containing compounds.
  • Vanadyl sulfate (V0S0 4 ) , which is readily available over the counter in the United States at local health food stores, is marketed as a nutritional supplement. Although it is used for other purposes as well, vanadyl sulfate has been taken to improve glycemic control. Vanadyl sulfate generates the vanadyl radical (VO 3 ) which has been shown to reverse diabetes in pancreatectomized rats.
  • the radical (V0 3 " ) is the predominate radical form in extracellular fluid. It is reduced intracellularly into the radical (V0 +2 ) which is the active form.
  • Vanadyl radical generating compounds have exceptional antidiabetic effects in animals. Vanadyl sulfate orally administered to animals has been shown to produce normoglicemia which can persist even after discontinuation of the therapy.
  • vanadyl radical generating compounds exhibit limited cytoplasmic penetration.
  • the active component of vanadyl radical generating compounds (VO +2 ) is present in only very small concentrations in the intracellular compartment.
  • VOS0 4 vanadyl sulfate
  • V0 +2 is found in the intracellular compartment after reduction from (V0 3 ") commonly present in the extracellular compartment.
  • the V0 +2 radical binds to sites located in the intracellular membrane surface inhibiting (Na + +K + ) - ATPase enzyme and thereby inhibiting the (K + ) potassium pump. This occurs in all tissues of the body.
  • Sulfonylureas exert hypoglycemic action and inhibit potassium channel transport by binding to proteins at the potassium channel.
  • glyburide is considered the most potent because it binds most firmly and for a longer time to the 140 kda protein at the potassium channel of all tissues of the body.
  • Micronized glyburide or small particle glyburide is absorbed more rapidly from the gastrointestinal tract than non-micronized glyburide.
  • Oral hypoglycemic agents such as tolazamide, tolbutamide, chlorpropamide, micronized and non-micronized glyburide, glimepiride, glypizide, metformin, and phenformin have been available as oral treatments for diabetes, typically non-insulin dependent (Type II) diabetes.
  • Oral hypoglycemic agents in general are disadvantageous because the extent , predictability and duration of the antidiabetic effect is unpredictable and these agents are often characterized by primary or secondary failure. Because oral hypoglycemic agents exhibit inconsistent hypoglycemic benefit, insulin therapy is preferred.
  • the present invention is also directed to a method of treating diabetes comprising administering to a warm blooded animal, including humans, a therapeutically effective amount of the composition of the present invention.
  • Figure 1 is a graph showing glucose levels for the treatment of a Type II adult onset diabetic patient using Glynase (micronized glyburide) alone, vanadyl sulfate alone and the composition of the present invention;
  • Figure 2 is a graph showing glucose levels for the treatment of a Type II insulin dependent diabetic in poor control using insulin alone and a composition of the present invention
  • Figure 3 is a graph showing glucose levels for the treatment of a Type I juvenile diabetic in poor control with insulin alone and with a composition of the present invention
  • Figure 4 is a graph showing glucose levels for the treatment of a Type II difficult to control diabetic with a history of unusual high frequency of hypoglycemic events with insulin and the composition of the present invention.
  • Figure 5 is a graph showing glucose levels for the treatment of a Type I diabetic with acanthosis nigricans and severe insulin resistance with no glycemic control and who is unresponsive to insulin therapy, with insulin alone and in combination with the present invention.
  • the present invention is directed to a composition and method of treating warm blooded animals, including humans suffering from diabetes with a pharmaceutical composition comprising a V0 +2 generating compound together with micronized glyburide as the active agents.
  • the active agents may be administered together or separately so long as the active agents can coact in the body to achieve the desired effect. It is preferred that the active agents be administered together, and most preferably in a single formulation. If administered separately, administration is preferably conducted at or about the same time.
  • V0 +2 generating compound or vanadyl compound shall mean any compound which forms the radical (VO +2 ) in the body (e.g. which releases the same when intracellularly administered to a warm blooded animal) .
  • vanadyl compounds examples include sodium orthovanadate, sodium metavanadate, bis oxovanadium, sodium metavanadate (NaV0 3 ) , vanadyl sulfate (V0S0 4 ) , sodium orthovanadate (Na 3 V0 4 ) , ammonium metavanadate (NH 4 V0 3 ") , aluminum orthophosphate vanadia ( V 2 0 5 - A 1 P 0 4 ) , d i p e r o x o v a n a d a t e , bis(maltolato)oxovanadiu (IV) (BMOV) , V0C1 3 , V0C1 2 , VC1 3 , peroxovanadium(pv) compounds, K 2 [VO(0 2 ) 2 (picolinato) ] 2H 2 0) [bpv(pic) ] VO(0 2 ) (picolin
  • the VO "3 radical is reduced after entry into the cells into the radical V0 +2 .
  • the element vanadium readily changes oxidation state, it is preferred to describe the therapeutic amounts of V0 +2 generating compounds on the basis of the weight of the element vanadium.
  • the preferred VO +2 generating compound is vanadyl sulfate in part because it is considered least toxic.
  • the amount of the V0 +2 radical necessary to obtain the desired results in accordance with the present invention is generally in the range of from about 5 to 60 mg/day for humans, preferably from about 20 to 35 mg/day.
  • the amount of the compound necessary to obtain the desired amount of the V0 +2 radical can be readily calculated.
  • vanadyl sulfate (VOS0 4 ) can generally be administered in an amount of from about 10 to 120 mg/day, preferably from about 30 to 90 mg/day, most preferably from about 60 to 90 mg/day.
  • Vanadyl sulfate is commercially available as a nutritional supplement from several sources including GNC health food stores.
  • micronized glyburide is representative of members of the sulfonylurea family which comprise the second active agent of the present invention. These compounds lower blood glucose by stimulating the release of insulin from the pancreas initially when therapy is begun then later normalize glucose via unknown extrapancreatic or peripheral effects.
  • Micronized glyburide or small particle glyburide is administered in accordance with the present invention in an amount of from about 0.75 to 12 mg/day, preferably from about
  • Micronized glyburide is currently available from UpJohn under the name GlynaseTM PresTabsTM and as a generic product by Coply.
  • Micronized glyburide may be administered in accordance with the present invention as a single dose or up to four times daily, preferably in one dose with the vanadyl radical generating compound as previously described.
  • the active ingredients of the present invention are administered orally in the form of tablets, capsules, caplets, soft gel capsules and the like.
  • the amount of each active ingredient which is administered per day will depend on the extent of the patient's condition as determined by the extent of the loss of glycemic control.
  • Assessment of insulin resistance can be achieved by clinical observation of its manifestations such as hirsutism, hyperpigmentation, and acne in women. It can also be measured by performing a glucose tolerance test with concomitant measurements of serum glucose and insulin concentrations.
  • glycemic control can be achieved through monitoring serum glucose concentrations, fasting and postprandial as well as measuring glycohemoglobin and fructosamine and through the use of a glucose tolerance test.
  • a typical daily dosage of vanadyl sulfate and micronized glyburide based on the extent of loss of glycemic control or for insulin resistance for a typical patient is set forth in Table 1.
  • the combination of the V0 +2 generating compound and micronized glyburide is generally administered over a period of from about 2 weeks to 6 months, preferably from about 3 to 14 weeks, most preferably from about 4 to 12 weeks.
  • the total amount of the VO +2 generating compound (e.g. vanadyl sulfate) administered is generally from about 1000 to 3000 mg. Shorter or longer durations of treatment can be employed depending on patient response. Once response is achieved it can be administered indefinitely without any significant adverse or side effects.
  • a dosage of 60-90 mg of vanadyl sulfate and 6-l2mg of micronized glyburide are administered once daily, preferably in the morning for at least 8 weeks and up to 20 weeks until a response is noted with stabilization of serum glucose concentrations at the normal or near normal ranges. Thereafter, the dosage regimen is reduced to 6 mg of glyburide/60 mg of vanadyl sulfate administration. Glycemic control is achieved independently of insulin production.
  • the active components are commercially available and can be utilized as such in the present invention. However, if fixed combination dosages forms are desired, they may be formulated by grinding each of the commercially available components together and placing the appropriate amount of the combination in an appropriate dosage delivery form (e.g. capsule or tablet) by known techniques. Alternatively, the active components may be optionally mixed along with pharmaceutically acceptable carriers (e.g. cornstarch, lactose, lecithin, soybean oil, glycerine and the like) as desired, and the mixture put up into an appropriate dosage form according to known techniques in the art. Ideally a tablet containing 3 mg glyburide and 30 mg vanadyl sulfate would be most practical for this purpose.
  • pharmaceutically acceptable carriers e.g. cornstarch, lactose, lecithin, soybean oil, glycerine and the like
  • the active components are commercially available in bulk form or may also be prepared by known methods.
  • Glyburide can be prepared in accordance with published Netherland Patent Application 66/03,398; CA. 66/65, 289h (1967) ; Aumuller et al., Arzneimettel-Forsch. 16, 1640 (1966) ; and Belgian Patent 730,791 each of which is incorporated herein by reference. Additional details about micronized glyburide can be found in U.S. Patent Nos. 4,916,163 and 4,735,805, each of which is also incorporated herein by reference.
  • the subject received 60 mg of vanadyl sulfate and 6 mg of Glynase per day for a period of approximately one month. There was an immediate and significant reduction in both the level of serum glucose concentrations of the subject and the degree of serum glucose fluctuations. Thereafter for a period of approximately one week, the amount of vanadyl sulfate was increased to 70 mg per day and there was a further drop of glucose level to approximately 110 mg/dl. The subject discontinued the composition in accordance 5. with the present invention and was placed on Glynase 3mg for approximately six weeks. The level of glucose remained in the desirable range of from about 90 to 110 mg/dl.
  • Glynase therapy was discontinued and the subject was placed on 15 mg of vanadyl sulfate per day with glucose levels remaining below about 110 0 mg/dl. Thereafter all medication was discontinued and the patient maintained normal glucose levels (e.g. between 90 and 110 mg/dl) independently. 8 months after discontinuing the therapy the patient's glycohemoglobin or HgbAic was 5.5% (non- diabetic 3-6%; good control 6-9%. The patient was not following 5 a diet or exercise regimen during this time and his weight remained stable. This suggests the treatment may have arrested and reversed the illness.
  • Example 2 As shown with the subject discussed in Example 1, the combination of vanadyl sulfate and Glynase resulted in a 0 significant lowering of glucose levels and maintenance of glucose levels within a narrow, normal range. In this case this effect persisted indefinitely even after discontinuing the therapy.
  • Example 2 As shown with the subject discussed in Example 1, the combination of vanadyl sulfate and Glynase resulted in a 0 significant lowering of glucose levels and maintenance of glucose levels within a narrow, normal range. In this case this effect persisted indefinitely even after discontinuing the therapy.
  • glucose levels were high and sporadic in the range of 235 to 360 mg/dl.
  • glucose levels were reduced to as low as 200 but still remained unacceptably high.
  • the subject's glycohemoglobin level also rose to greater than 10%.
  • Glucose levels dropped from a high of about 215 mg/dl to a low of about
  • a 14 year old white female was diagnosed with Type I juvenile insulin dependent diabetes mellitus at the age of 11.
  • the subject was receiving 25 units of insulin in the morning and 20 units of insulin in the evening as per established therapy. Thereafter, insulin administration was continued and the combination of 60 mg vanadyl sulfate and 6 mg of Glynase was added to the insulin therapy administered daily over the course of approximately 6 weeks. Initially the subject's glucose levels were very erratic ranging from a low of 80 to a high of about 200 mg/dl. However, after about 4 weeks of therapy, glucose levels began to stabilize from a high of about 160 to a low of about 100 mg/dl.
  • vanadyl sulfate/Glynase therapy was continued and insulin therapy was reduced, first to 12 units per day, then to 10 units per day and finally to 5 units per day.
  • glucose levels became stabilized in or about the range of 110 mg/dl.
  • insulin therapy was discontinued and after an initial uptake in glucose levels, the glucose levels began to stabilize at about 110 mg/dl.
  • Example 3 The subject of Example 3 was able to come off insulin and maintain normal, consistent glucose levels without insulin administration after administration of the composition of the present invention.
  • a 77 year old white male was diagnosed with insulin dependent diabetes mellitus. He was considered to be a brittle diabetic. He had extreme difficulty with frequent hypoglycemic events where blood sugar levels would drop to below 20 mg/dl as often as two or three times weekly. This happened for approximately 10 years in spite of many different treatments employing insulin therapy.
  • the subject received 500 mg of glucophage, a known oral anti-diabetic drug as well as 6 mg of
  • the subject's glucose levels remained high and erratic over the course of the therapy but he stopped having hypoglycemic induced comas. After approximately two months glucophage was eliminated from the therapy. There was a noticeable further improvement in both the glucose level and the changes in glucose levels from day to day.
  • the subject also had several fructosamine tests over the two months of good control which were in the normal range confirming good control.
  • fructosamines glycohemoglobin
  • serum glucose measurements establish that the patient possessed glycemic control.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

Méthode de traitement du diabète chez un patient en souffrant, par l'administration audit patient d'une dose thérapeutiquement efficace d'un composé pharmaceutiquement acceptable générant du VO+2 et d'une dose thérapeutiquement efficace d'un glyburide micronisé.
PCT/US1996/011462 1995-07-10 1996-07-09 Composition et procede pour traiter le diabete WO1997002818A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64599/96A AU6459996A (en) 1995-07-10 1996-07-09 Composition and method for treating diabetes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US100495P 1995-07-10 1995-07-10
US60/001,004 1995-07-10

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454635A (en) * 1965-07-27 1969-07-08 Hoechst Ag Benzenesulfonyl-ureas and process for their manufacture
US4275069A (en) * 1979-01-22 1981-06-23 The Upjohn Company Anti-diabetic 1,2-dihydro-2-oxo-6-alkyl-nicotinic acids
US5023358A (en) * 1987-08-11 1991-06-11 Panmedica S.A. Vanadyl organo-mineral compound, method for obtaining such a compound, pharmaceutical composition containing this organo-mineral compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454635A (en) * 1965-07-27 1969-07-08 Hoechst Ag Benzenesulfonyl-ureas and process for their manufacture
US4275069A (en) * 1979-01-22 1981-06-23 The Upjohn Company Anti-diabetic 1,2-dihydro-2-oxo-6-alkyl-nicotinic acids
US5023358A (en) * 1987-08-11 1991-06-11 Panmedica S.A. Vanadyl organo-mineral compound, method for obtaining such a compound, pharmaceutical composition containing this organo-mineral compound

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