Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide

Definitions

• This invention relates to improvements in pharmaceutical compounds and is particularly concerned with new formulations and uses for a cardiac drug.
• ISH isolated systolic 10 hypertension
• One of the objectives in the clinical trials with nitroglycerine has been selectively to be 25 able to reduce systolic blood pressure as it was believed that a reduction in systolic blood pressure would be beneficial in reducing stroke risk.
• isosorbide-5-mononitrate can be used to provide satisfactory therapy for the treatment of ISH.
• Isosorbide-5-mononitrate hereinafter designated 5- ISMN
• 5- ISMN is frequently used clinically for the treatment of angina pectoris but we have now found that once daily administration of 5-ISMN can provide selective lowering of the systolic blood pressure, particularly during the day, and so can reduce risk of stroke for those patients at risk.
• the present invention provides the use of isosorbide-5-mononitrate for the manufacture of a medicament for the treatment of isolated systolic hypertension in the human or animal body.
• the present invention also provides a method for reducing the risk of stroke in a patient having isolated systolic hypertension by administering to such a patient an amount of isosorbide-5-mononitrate sufficient to bring about a selective reduction in systolic blood pressure.
• Clinical studies on 5-ISMN in the treatment of angina have already established that administration of two or three daily doses of 5-ISMN, 20 or 30 mg per dosage, can lead, over a period of time, to the development of drug tolerance, in other words, that ever increasing dosage amounts become necessary to maintain the same therapeutic effect.
• This tolerance problem is avoided by administration of a once daily 60 mg extended release formulation and of course, results in improved patient compliance as well.
• a still further benefit arising from the use of a once daily dose of 5-ISMN from an extended release formulation is that the plasma concentration of 5-ISMN tends to be at its highest during the waking hours immediately following administration and at its lowest during the hours of sleep which is the final part of the 24 hour cycle. This fits in particularly well with the need, in the treatment of ISH, for there to be a high plasma concentration during the waking hours when selective lowering of SBP is required with a reduced concentration during the sleeping hours when SBP tends to be lower anyway, compared to the daytime level.
• Imdur extended release formulation a particularly convenient source of 5-ISMN for use in the treatment of ISH
• other formulations are also acceptable from the technical point of view.
• the active 5- ISMN ingredient contained within an inert insoluble porous matrix that is based upon paraffin wax and an alkali metal aluminium silicate.
• extended release formulations are very well-known in the pharmaceutical industry and other types of inert insoluble porous matrices can be used based on different proportions of paraffin wax and sodium aluminium silicate, different types of paraffin wax and sodium aluminium silicate or by the use of other inert insoluble porous matrixforming polymers.
• 5-ISMN for the treatment of ISH in an extended release formulation in which a core of active 5-ISMN is coated with a release rate controlling polymeric membrane.
• Such coated beads can be filled into gelatin capsules which will dissolve in the stomach to release the coated beads or can be compressed with other conventional excipients into fast disintegrating tablets which will release the coated beads.
• the coated beads can act as individual delivery units releasing 5-ISMN over a suitable time period.
• the release rate can be varied by varying the applied amount of the film-forming polymers and/or the ratio between the soluble and insoluble polymers and other ingredients in the film.
• the beads themselves can comprise 5-ISMN formulated with lactose or mannitol together with cellulose and starch and indeed, such a formulation can be used without coating as a normal release formulation.
• the normal release formulation can then be coated with a release rate controlling film that can be based upon a mixture of water-soluble and water-insoluble cellulose derivatives.
• these can be a mixture of the various grades of polymers sold under the name "Eudragit" in proportions that are selected to give the desired release rate of the active ingredient in vivo.
• 5-ISMN immediate release formulation
• Such immediate release tablets will normally release more than 80% of the formulated drug load within 30 minutes of testing in vitro and their in vivo behaviour will be similar.
• a daily dose of 60 mg of 5-ISMN made available on a once daily basis through an extended release formulation that will provide an in vivo release rate of not more than about 40% within the first hour, not more than about 55 % within the first 2 hours, not more than about 85% within the first 6 hours but substantially all of the active ingredient within 12 to 16 hours provides appropriate medication for the treatment of ISH.
• Formulations containing lower or higher amounts, e.g., 30 mg or 120 mg of 5-ISMN can also be used but here, consideration will need to be given to the achievement of appropriate plasma levels of 5- ISMN.
• This Example describes an immediate release tablet containing the following ingredients.
• This Example describes immediate release beads coated with a release rate controlling polymeric membrane.
• Lactose or mannitol (filler) 25 % w/w
• the ingredients for the tablet are formulated together with the assistance of the water which is then allowed to evaporate after tabletting of the ingredients.
• the resulting tablets are then coated by conventional methods with a film comprising a methylene chloride/isopropyl alcohol solution of 50% w/w ethyl cellulose and 50% w/w Eudragit RL.
• the film coating is applied at a thickness to provide a release rate of 5- ISMN in vitro of not more than 40% within the first hour, not more than 55% within the first 2 hours, not more than 85% within the first 6 hours but substantially 100% within 12 hours.
• This particular study was carried out on a group of 11 patients selected from a group of 70 angina patients.
• the group of 11 were selected as having a day-time systolic blood pressure in the sitting or standing position at the baseline that was 160 mm Hg or higher.
• the trial was carried out using 60 mg extended release 5-ISMN in the Imdur formulation.
• the trial was carried out in a double-blind cross-over study in which the patients took either Imdur or Placebo orally once a day shortly after waking. Each treatment period lasted for 2 weeks preceded by a 2- week placebo run-in period. All of these patients were angina patients who were also been treated by chronic ⁇ -andreno- receptor blocking therapy throughout the study. Blood pressure was measured for 3 hours after each administration of Imdur or Placebo.
• the systolic and diastolic blood pressure was measured in the usual way with a cuff. Systolic blood pressure was measured either standing or sitting.
• This Example describes a similar study carried out on a different group of angina patients, some of whom were also treated with a ⁇ -blocker throughout the study. It was found that there was no significant difference in the systolic blood pressure reduction observed as between those patients receiving ⁇ -blocker therapy at the same time and those who did not receive the ⁇ -blocker therapy.
• This trial was carried out on a group of 44 angina patients, almost all of whom had a baseline systolic blood pressure of at least 160 mm.
• the trial was carried out in a randomised double-blind, double-dummy cross-over regime using 60 mg of 5-ISMN in the Imdur formulation and Placebo. Medication was administered once a day shortly after awaking. There was a 2-week Placebo run-in period followed by two 4-week periods with active treatment. The age range of the patients was 50 to 83 years old.
• Systolic blood pressure was measured in the supine position 5 minutes after administration of medication and standing systolic blood pressure was measured 6 minutes after administration of medication. Blood pressure was measured by the usual arm cuff. The results are set out in mm of mercury in Table 3 below.
• Results were also analysed from a similar clinical trial carried out on a group of 109 patients including the 44 patients mentioned above. Blood pressure was again measured in supine position 5 minutes after medication and in the standing position 1 and 6 minutes after medication. The results obtained, in mm of mercury, are set out in Table 4 below.
• DPB diastolic blood pressure

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• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Polyesters Or Polycarbonates (AREA)

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• 1995
  • 1995-02-28 WO PCT/SE1995/000206 patent/WO1996026722A1/en not_active Application Discontinuation
  • 1995-02-28 AU AU22694/95A patent/AU2269495A/en not_active Abandoned
  • 1995-02-28 KR KR1019970705960A patent/KR19980702554A/ko not_active Application Discontinuation
  • 1995-02-28 JP JP8526186A patent/JPH11501026A/ja active Pending

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