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EP1289493A1 - Compositions pharmaceutiques comprenant du desglymidodrine en tant que substance medicamenteuse active - Google Patents

Compositions pharmaceutiques comprenant du desglymidodrine en tant que substance medicamenteuse active

Info

Publication number
EP1289493A1
EP1289493A1 EP01933651A EP01933651A EP1289493A1 EP 1289493 A1 EP1289493 A1 EP 1289493A1 EP 01933651 A EP01933651 A EP 01933651A EP 01933651 A EP01933651 A EP 01933651A EP 1289493 A1 EP1289493 A1 EP 1289493A1
Authority
EP
European Patent Office
Prior art keywords
composition
hours
desglymidodrine
composition according
release
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01933651A
Other languages
German (de)
English (en)
Inventor
Claus Sundgreen
Ann Christina Schultz
Jimmy Hirschsprung Schlyter
Peder Mohr Olsen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Austria GmbH
Original Assignee
Nycomed Austria GmbH
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
Priority claimed from US09/823,093 external-priority patent/US6761904B2/en
Priority claimed from PCT/DK2001/000214 external-priority patent/WO2001074335A1/fr
Application filed by Nycomed Austria GmbH filed Critical Nycomed Austria GmbH
Publication of EP1289493A1 publication Critical patent/EP1289493A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
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    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • compositions comprising desglymidodrine as an active drug substance
  • the present invention relates to novel pharmaceutical compositions comprising desglymidodrine or a pharmaceutically acceptable salt thereof as an active drug substance.
  • Desglymidodrine is the active metabolite of the prodrug midodrine.
  • the pharmaceutical composition may be presented in a suitable dosage form for oral, parenteral, mucosal, nasal, sublingual, buccal, topical, vaginal, rectalor ocular etc. administration.
  • a pharmaceutical composition of the invention may be in the form of an immediate and/or modified release composition or it may be designed to release the active drug substance, desglymidodrine, in a relatively fast manner in order to enable a relatively fast onset of the therapeutic effect.
  • a pharmaceutical composition according to the invention has a suitable shelf-life, i.e. the desglymidodrine contained in the composition is not subject to a significant degradation under storage conditions normally acceptable for pharmaceuticals.
  • the invention also relates to a method for treating animals such as, e.g. mammals and humans with a novel pharmaceutical composition comprising desglymidodrine.
  • the invention relates to a novel use of desglymidodrine in the treatment of septic shock and to a method for treating mammals (e.g. humans) suffering from septic shock with a sufficient amount of desglymidodrine.
  • Desglymidodrine is the active metabolite of midodrine, i.e upon administration of midodrine to a patient, midodrine is (enzymatically) metabolised to desglymidodrine.
  • the indications of desglymidodrine are therefore similar to the indications of midodrine, but as will be explained below desglymidodrine may also be used for novel indications.
  • the indications of desglymidodrine include symptomatic orthostatic hypotension, syncope, orthostatic intolerance, symptomatic hypotension (e.g. hypotension associated with infections, the convalescent period, surgical operations, delivery, changes in the weather as well as what is called “difficulties in getting started in the mornings"), as well as in the control of hypotensive side effects of hypnotics and psychotropics.
  • symptomatic hypotension e.g. hypotension associated with infections, the convalescent period, surgical operations, delivery, changes in the weather as well as what is called “difficulties in getting started in the mornings”
  • desglymidodrine is expected to be effective in the treatment of urinary incontinence. Many of these indications call for a very individual treatment regimen where a basic "all day" treatment supplied with one or more fast onset formulations are very beneficial.
  • the invention in another aspect, relates to a method for treating hypotension and/or urinary incontinence, the method comprising administration to a patient in need thereof of an effective amount of desglymidodrine in a pharmaceutical composition according to the invention.
  • An interesting pharmaceutical composition according to the invention for this use is a controlled release composition, optionally together with one or more fast onset compositions comprising an effective amount of desglymidodrine.
  • Desglymidodrine is the active form of the prodrug midodrine.
  • Desglymidodrine is a potent adrenergic agonist at the alpha-1 receptors that are mainly localised in resistance and capacitance vessels and in the bladder neck.
  • the effect when given to patients suffering from orthostatic hypotension is an increase in blood pressure and when given to patients suffering from stress incontinence and improvement of continence. Clinical trials of the latter effect have up till now yielded conflicting results.
  • desglymidodrine As the active metabolite of midodrine, desglymidodrine is a potent drug substance.
  • focus has been directed to the development of suitable midodrine compositions most likely due to the detailed knowledge of the behaviour of midodrine in clinical studies.
  • the need for optimising the treatment of conditions responsive to midodrine has turned the inventors' focus on desglymidodrine.
  • the conversion step in vivo from the inactive form, midodrine, to the active form, desglymidodrine is omitted and, thus, it is anticipated that treatment with desglymidodrine can lead to a fast onset of the therapeutic effect.
  • compositions of desglymidodrine for use in the treatment of conditions for which midodrine is indicated.
  • Such compositions provide attractive alternatives or supplements to the treatment of diseases or conditions with a drug substance that acts by stimulating OH receptors.
  • Midodrine is a prodrug, which is activated within the human body by an enzymatic hydrolysis to release the therapeutically active metabolite desglymidodrine. Only very little information is available from the literature concerning desglymidodrine.
  • desglymidodrine acts by a stimulation of ⁇ -i receptors.
  • the prodrug of desglymidodrine, midodrine is used in the treatment of symptomatic orthostatic hypotension. Disorders causing orthostatic hypotension are e.g.,
  • Tumors hypothalamic, parasellar, posterior fossa
  • Multiple cerebral infarcts Wernicke's encephalopathy
  • Tabes dorsalis Traumatic and inflammatory myelopathies ⁇ Parkinson's disease ⁇
  • Hereditary system degenerations ⁇ Syringomyelia ⁇ Dysautonomia of advanced age ⁇ Multiple sclerosis Systemic diseases with autonomic neuropathy ⁇ Botulism ⁇
  • Diabetic neuropathy Primary systemic amyloidosis ⁇ Guillain-Barre syndrome ⁇ Porphyria ⁇ Lambert-Eaton myasthenic syndrome ⁇ Paraneoplastic autonomic neuropathy ⁇ Uremic neuropathy ⁇ Connective tissue disease ⁇ Tangier and Fabry's diseases ⁇ Vincristine and heavy metal neuropathies ⁇ Leprosy ⁇ Bi 2 deficiency ⁇ Chronic Chagas' disease ⁇ Propafenone neuropathy
  • midodrine may be used in disorders retrograde ejaculation; disorder of semen ejaculation, or to attenuate symptoms of chronic orthostatic hypotension due to autonomic failure in patients with Bradbury-Eggleston, Shy-Drager syndromes, diabetes mellitus disease and Parkinson's disease.
  • the prodrug of desglymidodrine, midodrine is approved in a variety of European and overseas countries including the U.S.A. mainly for the treatment of symptomatic orthostatic hypotension.
  • FDA has recommended a dosing of midodrine of up to 10 mg 3 times daily for the treatment of hypotension. According to FDA, the latest dose must not be given later than 6 pm for safety reasons in order to avoid or reduce the risk of supine hypertension. Other countries recommend that the latest dose must not be given later than 4 hours before bedtime.
  • Midodrine for use in stress urinary incontinence is a very promising use with a tremendous market potential also due to the ageing population.
  • Current conservative therapeutic approaches are ⁇ -sympathomimetics, pelvic floor exercises and estrogens, or surgery, which are rather complementary than competitive.
  • desglymidodrine is effective as a drug substance in the treatment of the above-metioned conditions. Furthermore, a completely novel indication for desglymidodrine is described in the following.
  • Septic shock is a condition in which bacteremia produces changes in the circulation resulting in critically reduced tissue perfusion.
  • Acute circulatory failure, hypotension and multiorgan failure are characteristic.
  • the pathogenesis is not fully understood but bacterial infection with release of toxins initiate a vicious circle of reactions resulting in vasodilatation and organ hypoperfusion.
  • the cornerstone of the treatment is antibiotics and circulatory support is mandatory to secure organ perfusion.
  • the circulatory disorders are treated with vasopressors initially dopamine followed by addition of norephinephrine and eventually epinephrine.
  • Norephinephrine has alfa adrenergic and slight beta adrenergic action whereas desglymidodrine only has alpha adrenergic action. Furthermore desglymidodrine does not cross the blood brain barrier in contrast to norepinephrine.
  • a pharmaceutical composition according to the invention contains desglymidodrine or a pharmaceutically acceptable salt thereof. From a clinical point of view it may in some cases be advantageous to include midodrine or a pharmaceutically acceptable salt thereof in the composition in order to take advantage of the different pharmacokinetic of the two different substances.
  • the invention also relates to a kit comprising two different compositions, one of the compositions being a composition as described above.
  • desglymidodrine or its prodrug midodrine are drugs of choice.
  • Desglymidodrine as well as midodrine exist in racemic form and in the form of the two enantiomeric species.
  • Desglymidodrine is also known as ST 1059, alpha-(aminomethyl)-2,5-dimethoxy- benzenemethanol. It may be present in racemic form, i.e. as ( ⁇ )-desglymidodrine, ( ⁇ )- ST1059 or ( ⁇ )-alpha-(aminomethyl)-2,5-dimethoxy-benzenemethanol, or in its enantiomeric form as (-)-desglymidodrine, (R)-desglymidodrine, (-)-ST1059, (R)-ST1059, (-)-alpha-(aminomethyl)-2,5-dimethoxy-benzenemethanol or (R)-alpha-(aminomethyl)-2,5- dimethoxy-benzenemethanol, or in its other enatiomeric form (+)-desglymidodrine, (S)- desglymidodrine, (+)-ST1059, (S)-ST1059, (+
  • a composition according to the invention may therefore include desglymidodrine in the racemic form (RS), in the enantiomeric form (R), in the enantiomeric form (S) or in mixtures thereof.
  • a composition contains the active metabolite desglymidodrine (ST 1059), and desglymidodrine is present in the form of ( ⁇ )- ⁇ -(aminomethyl)-2,5-dimethoxy-benzenemethanol ( ⁇ ST 1059), (+)- ⁇ -(aminomethyl)-2,5- dimethoxy-benzenemethanol (+ ST 1059), (-)- ⁇ -(aminomethyl)-2,5-dimethoxy- benzenemethanol (- ST 1059) or mixtures thereof.
  • a composition according to the invention contains desglymidodrine in the racemic form (RS), in the enantiomeric form (R), in the enantiomeric form (S) or in mixtures thereof, or it contains at least 90% w/w such as, e.g., at least 95% w/w, at least 97% w/w, at least 98% w/w, at least 99% w/w of desglymidodrine is present in the therapeutically active enantiomeric form.
  • the therapeutically active enantiomeric form of desglymidodrine is contemplated to be (-)- ⁇ - (aminomethyl)-2,5-dimethoxy-benzenemethanoI (- ST 1059) or the (R) form of desglymidodrine ((R) ST 1059).
  • Midodrine is also known as ST 1085, or 2-amino-N-[2-(2,5-dimethoxyphenyl)-2- hydroxyethylj-acetamide. It may be in present in racemic form, i.e. as ( ⁇ )-midodrine, ( ⁇ )- ST 1085, or ( ⁇ )-2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide, ( ⁇ )-2- amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyI]-acetamide, or in its enatiomeric form as (-)-midodrine, (R)-midodrine, (-)-ST 1085, (R)-ST 1085, (-)- 2-amino-N-[2-(2,5- dimethoxyphenyl)-2-hydroxyethyl]-acetamide or (R)- 2-amino-N-[2-(2,5
  • the invention relates to a pharmaceutical kit comprising two different pharmaceutical compositions and one of the compositions is a controlled release composition.
  • one of the compositions may contain midodrine as the active substance and the other may contain desglymidodrine.
  • desglymidodrine (and whenever relevant midodrine) is present in the form of a pharmaceutically acceptable salt such as a salt formed between desglymidodrine (and whenever relevant midodrine) and an inorganic acid such as e.g., a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a nitrite, a H 3 PO 3 salt, a H 3 PO 4 salt, a H 2 SO 3 salt, a sulfate, a H 2 SO 5 salt, or a salt formed between desglymidodrine (and whenever relevant midodrine) and an organic acid such as organic acids like e.g.
  • a pharmaceutically acceptable salt such as a salt formed between desglymidodrine (and whenever relevant midodrine) and an inorganic acid such as e.g., a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a
  • a composition according to the invention may comprise a further active drug substance, i.e. the composition may be in the form of a so-called combination composition comprising at least two different active drug substances.
  • the further active drug substance may be any active drug substance, which beneficially is used in combination with desglymidodrine.
  • interesting examples of further active drug substances are midodrine, steroids like e.g. hydrocortisone or fludrocortisone or somatostin analogoues like e.g. octreotide.
  • the dosage of the active drug substance present in a composition according to the invention depends inter alia on the specific drug substance, the age and condition of the patient and of the disease to be treated.
  • a composition according to the invention is designed for administration 1-6 times daily.
  • the dosage frequency depends on the specific condition to be treated and on the specific composition used.
  • a nasal composition may be administered only once daily e.g. in order to achieve a relatively fast onset of the therapeutic effect or it may be administered more often in order to treat break-through symptoms.
  • a controlled release composition according to the present invention aims at a dosage once, twice or three times daily, preferably once or twice daily.
  • the term "once daiIy"/"once-a-day” is intended to mean that it is only necessary to administer the pharmaceutical composition once a day in order to obtain a suitable therapeutic and/or prophylactic response; however, any administration may comprise co- administration of more than one dosage unit, such as, e.g. 2-4 dosage units.
  • a dosage unit which is constructed to deliver the active ingredient after only one daily administration is often preferred by the patient.
  • some patients may need a new dosage after e.g. 7-18 hours such as, e.g. about 7-8 hours or about 12 or about 18 hours if the patient e.g. has abnormal absorption or bowel transit time. If the individual has a relatively fast bowel transit time, some of the active drug substance may be excreted before the full dosage is released.
  • Controlled release compositions designed for topical (e.g. transdermal delivery systems), ocular (e.g. ocular delivery systems) or parenteral (e.g. parenteral delivery systems like implants) delivery of desglymidodrine generally aim at less frequent dosage.
  • a dosage frequency corresponding to 1-2 times a week or 1-2 times a month is often considered appropriate for such delivery systems.
  • the normal daily dose is from 2.5 to 10 mg three or up to four times daily (calculated as desglymidodrine hydrochloride), i.e. a daily dose of from about 7.5 mg to about 40 mg in the treatment of orthostatic hypertension.
  • a composition according to the present invention typically contains from about 2.5mg to about 50 mg desglymidodrine such as, e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg.
  • the treatment of septic shock is adjusted according to individual susceptibility to desglymidodrine with respect to blood pressure.
  • desglymidodrine is employed in another form, e.g. in another salt form than desglymidodrine hydrochloride
  • the above-mentioned dosage ranges are of course to be recalculated so that the same dosage is employed on a molar basis.
  • the total daily doses of desglymidodrine will depend on the indication for the treatment and the individually tolerated doses.
  • the composition or the kit of the present invention provides a possibility of a treatment regimen adapted for the specific patient.
  • the individual fast onset doses of a composition of the invention may be from 0.2 mg to 10 mg, preferreably from 0.5 mg to 7.5 mg such as of 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, or 5 mg.
  • desglymidodrine may be present as the racemic form or in one of its enantiomeric forms, preferably the therapeutically active enantiomeric form. In those cases where desglymidodrine is present in its therapeutically active enantiomeric form a reduction in the above-mentioned dosage ranges may be relevant.
  • a pharmaceutical composition of the invention comprises desglymidodrine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients.
  • a composition according to the invention may be in the form of a solid, semi-solid or fluid composition.
  • solid compositions are e.g. tablets such as, e.g, conventional tablets, effervescent tablets, melt tablets, coated tablets (e.g. film coated, enteric coated, controlled release coated), sublingual tablets, buccal tablets, capsules, sachets, powders, granules, pellets, microcapsules, microspheres, nanoparticles etc.
  • semi-solid compositions are e.g. ointments, creams, liniments, chewing gums, hydrogels, pastes, suppositories, enemas, etc.
  • fluid and/or liquid compositions are e.g.
  • a composition according to the invention may be suitable for administration via the oral, peroral, buccal, sublingual, rectal, vaginal, nasal, ocular, topical and parenteral route.
  • suitable compositions are also e.g. nasal compositions such as, e.g. nasal spray or nasal powder compositions, compositions for pulmonary administration such as, e.g. inhalators, chewing compositions such as, e.g., chewing gum, etc.
  • Especially suited compositions for a fast onset are compositions in fluid form and in the form of nasal compositions as well as quick release tablets.
  • compositions for controlled or modified release of desglymidodrine are controlled release pellets, controlled release tablets, controlled release granules, controlled release capsules, transdermal delivery systems (e.g. patches, plasters), ocular delivery systems (e.g. lenses), parenteral delivery systems (e.g. implants, oil-based compositions) and bioadhesive delivery systems (e.g. for oral, buccal or topical use).
  • the controlled release of desglymidodrine may be obtained by employment of various controlled release techniques such as, e.g. matrix tablets, application of controlled release coating(s) etc.
  • the composition is in the form of tablets having a disintegration time of at the most about 2.5 min such as, e.g at the most about 30 sec, at the most about 45 sec, at the most about 1 min, at the most about 1.5 min or at the most about 2 min.
  • a composition of the invention has a shelf-life at room temperature of at least 6 months such as, e.g. at least 1 year, at least 1.5 years, at least 2 years, at least 2, 5 years, 3 years, 4 years or 5 years. Shelf-life is defined as the time period in which a change in the content of desglymidodrine in the composition is at the most ⁇ 10% w/w such as, e.g., at the most ⁇ 7.5% w/w or ⁇ 5% w/w; in the present context the shelf-life is determined under conditions of room temperature, 25 °C and a relative humidity of 60%.
  • the compositions of the invention are thus stable, i.e. no significant degradation of desglymidodrine is observed during normal storage conditions.
  • the release kinetics of desglymidodrine from the composition corresponds to that of a plain release tablet.
  • the release kinetic of desglymidodrine from such compositions corresponding to a zero or a first order release, a mixture of zero and first order release, or any other order of release such as, e.g. 1 1 / , second, third or fourth order release (the same applies also to controlled release compositions of the invention).
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising desglymidodrine (ST 1059) or a pharmaceutically acceptable salt thereof, the composition being adapted to provide desglymidodrine in such a manner that a relatively fast therapeutically effective concentration of desglymidodrine is obtained after administration of the composition.
  • a composition of the invention may be adapted to release desglymidodrine in such a manner that a relatively fast therapeutic effective concentration of desglymidodrine is obtained after administration of the composition e.g. to obtain an onset of action at the most 15 min after administration such as, e.g. at the most about 1 min, at the most about 2 min, at the most about 3 min, at the most about 4 min, at the most about 5 min, at the most about 7.5 min, at the most about 10 min or at the most about 12.5 min after administration.
  • a composition of the invention may be designed in such a manner that a therapeutically effective concentration is obtained within 90 min such as, e.g. within 60 min, within 45 min, within 30 min, within 20 min, within 15 min, within 10 min, within 5 min from administration of the composition.
  • a relatively fast peak plasma concentration of desglymidodrine is obtained about 1 min - 6 hours such as, e.g. about 5 min - 6 hours, about 10 min - 5 hours, about 15 min - 5 hours, about 0.5-6 hours, about 1-6 hours, about 2-5.5 hours, or about 2.5-5.2 hours after administration.
  • the invention relates to a controlled release pharmaceutical composition comprising desglymidodrine.
  • the controlled composition may be designed for administration via the oral, parenteral, topical, buccal, vaginal, ocular etc. route.
  • a controlled release pharmaceutical composition of desglymidodrine according to the invention may also be designed for administration once, twice or three times daily, preferably once or twice daily, i.e. a therapeutically effective concentration of desglymidodrine is maintained for a period of at least 6 hours such as, e.g. at least 7 hours, at least 8 hours, at least 9 hours or at least about 10-16 hours followed by a wash out period of about 8-12 hours in order to avoid side effect with respect to supine hypertension.
  • Such side effects are well known after administration of midodrine.
  • a controlled release composition provides a base line plasma concentration, which during most of the day is therapeutically effective. When a higher concentration is needed, only a minor supply of active drug substance is necessary to obtain a very fast relief from symptoms. If the base line plasma concentration is absent, it would be necessary to use a relative higher fast onset dose to reach the high therapeutically effective level.
  • the high therapeutically effective level may be due to individual circumstances in the patient or may be a consequence of physical routines and/or the nature of the underlying disease. The situations and symptoms are often well recognized and experienced by the patient himself.
  • the composition according to the present invention is a superior tool for obtaining an optimal treatment with a minimum of active drug substance.
  • a therapeutically effective concentration of desglymidodrine is defined as a plasma concentration of desglymidodrine of at least about 3 ng/ml such as, e.g. at least about 3.2 ng/ml, at least about 3.5 ng/ml, at least about 3.7 ng/ml, at least about 4.0 ng/ml, at least about 4.2 ng/ml, at least about 4.5 ng/ml, at least about 4.7 ng/ml or at least about 5 ng/ml.
  • the controlled release pharmaceutical composition may be designed to release desglymidodrine in such a manner that a relatively fast peak plasma concentration of desglymidodrine is obtained followed by a prolonged and relatively constant plasma concentration of desglymidodrine.
  • the patient may due to individual needs or because of activities during the day experience situations where an increase in the plasma concentration is needed for an optimal treatment regimen. Therefore, the patient may on an individual basis supply the controlled release composition with one or more administrations of a quick release composition or another composition providing a relatively fast onset.
  • composition according to the invention may comprise one or more further active drug substances.
  • Pharmaceutical kit may comprise one or more further active drug substances.
  • the invention relates to a pharmaceutical kit comprising a plain composition and a controlled release composition.
  • a pharmaceutical kit of the invention comprises
  • a relatively fast onset pharmaceutical composition wherein the composition is adapted to provide desglymidodrine in such a manner that a relatively fast therapeutically effective concentration of desglymidodrine is obtained after administration
  • a controlled release pharmaceutical composition wherein the composition is adapted to release desglymidodrine in such a manner that a therapeutically effective plasma concentration of desglymidodrine is maintained for at least about 2 hours, such as, e.g. at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours or at least about 9 hours.
  • the invention relates to a pharmaceutical kit comprising
  • a relatively fast onset pharmaceutical composition comprising midodrine, wherein the composition is adapted to provide midodrine in such a manner that a relatively fast therapeutically effective concentration of midodrine is obtained after administration, and ii) a controlled release pharmaceutical composition of desglymidodrine, wherein the composition is adapted to release desglymidodrine in such a manner that a therapeutically effective plasma concentration of desglymidodrine is maintained for at least about 2 hours, such as, e.g. at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours or at least about 9 hours.
  • a pharmaceutical kit comprising
  • a relatively fast onset pharmaceutical composition of desglymidodrine wherein the composition is adapted to provide desglymidodrine in such a manner that a relatively fast therapeutically effective concentration of desglymidodrine is obtained after administration
  • a controlled release pharmaceutical composition comprising midodrine, wherein the composition is adapted to release midodrine in such a manner that a therapeutically effective plasma concentration of midodrine is maintained for at least about 2 hours, such as, e.g. at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours or at least about 9 hours.
  • compositions may be prepared by a person skilled in the art optionally with guidance from Remington's Pharmaceutical Sciences and with guidance from the disclosure and examples of international patent application No. PCT/DK01/00213 and PCT/DK01/00214.
  • Any relevant formulation technique for preparing pharmaceutical compositions may be applied when formulating a composition according to the invention.
  • a person skilled in the art of pharmaceutical formulation techniques can find guidance in the handbook Remington's Pharmaceutical Sciences and in the non-limiting Examples herein.
  • any relevant non-controlled or controlled formulation technique for preparing an oral non-controlled or controlled release composition may be applied.
  • the dosage form may be in the form of a liquid having e.g. particles dispersed in a dispersion medium or it may be in the form of a single or a multiple unit dosage form intended for use as such as for dispersing in a dispersion medium before use.
  • controlled release formulation techniques Examples of different controlled release technologies especially for the preparation of compositions for oral use are:
  • Coated single units e.g. enteric coating and employment of amylose e.g. as a colon degradable excipient.
  • compositions are e.g. patches, plasters (for e.g. transdermal use), emulsions, imlants, dispersions (for e.g. parenteral, topical, vaginal or ocular use), or incorporation of desglymidodrine into a suitable delivery system (for e.g. vaginal, parenteral, ocular, buccal use).
  • the units comprise pellets, granules, crystals, mini tablets or mixtures thereof.
  • a relatively fast relase can be obtained by use of an uncoated unit.
  • a controlled release can be obtained by the application of a controlled release coating or by formulating the unit as a matrix or a coated matrix.
  • a delayed release can be obtained by the use of an enteric polymer or amylose, or by having units compressed as described in the triple compression technology, cf. the examples herein.
  • a composition according to the invention is in the form of a solid dosage form. such as, e.g., tablets, capsules, sachets, solid dispersion, crystals, granules and the like.
  • a controlled release composition according to the invention can also comprise at least two parts such as at least a first and a second part, each part contains desglymidodrine, and the first part being adapted to release desglymidodrine in a controlled manner during the first 0-14 such as, e.g.
  • At least one of the at least two parts is present in the composition in the form of a multiplicity of individual units such as, e.g. pellets or minitablets.
  • the individual pellets or minitablets may be the same or different, i.e. they may have the same or different dissolution characteristics.
  • a composition according to the invention may also as individual units contain minitablets, i.e. be in the form of a multiple unit dosage form comprising at least two different types of minitablets, the first type of minitablets corresponding to the first part and the second type of minitablets corresponding to the second part.
  • a minitablet is a tablet having a size in a range corresponding to from about 0.7 mm to about 7 mm in diameter such as, e.g., in a range corresponding to from about 1 to about 7 mm, from about 1.5 to about 6 mm, from about 2 mm to about 5 mm, from about 2 mm to about 4 mm such as in a range corresponding to from about 2 to about 3 mm in diameter.
  • a controlled release composition according to the invention may also as individual units contain relatively large crystals of the active drug substance.
  • the size of the unit is at the most about 1 mm such as, e.g., in a range corresponding to from about 0.1 to about 1 mm, from about 0.2 mm to about 0.8 mm, from about 0.2 mm to about 0.7 mm or from about 0.3 mm to about 0.7 mm.
  • a composition or a controlled release composition according to the invention may be in the form of a multiple unit dosage form, wherein the first or the second part is in the form of minitablets, in the form of pellets or in the form of large crystals of the active drug substance.
  • a composition according to the invention may comprise a third part adapted to release desglymidodrine relatively fast from the composition and/or a fourth part adapted to release desglymidodrine from the composiiton 6-10 hours after oral intake.
  • the third and/or, if present, the fourth part comprise pellets or minitablets or are a layer in a tablet.
  • a composition according to the invention may have a first part, a second part, a third part and/or a fourth part which have a release kinetic corresponding to a zero or a first order release or a mixture of zero and first order release.
  • Other orders of release may be 1.5, 2, 3 or 4.
  • compositions according to the invention may further comprise pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipient is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect perse.
  • a pharmaceutically acceptable excipient may be added to the active drug substance with the purpose of making it possible to obtain a pharmaceutical composition, which has acceptable technical properties.
  • compositions containing a specific desglymidodrine and a specific solvent e.g. the labelled desglymidodrine in the specific concentration used and in the specific solvent used (which in this case may be water).
  • Fillers/diluents/binders may be incorporated such as sucrose, sorbitol, mannitol, lactose (e.g., spray-dried lactose, ⁇ -lactose, ⁇ -lactose, Tabletose®, various grades of Pharma- tose®, Microtose or Fast-Floe®), microcrystalline cellulose (e.g., various grades of Avicel®, such as Avicel® PH101 , Avicel® PH102 or Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tai® and Solka-Floc®), hydroxypropylcellulose, L- hydroxypropylcellulose (low-substituted) (e.g.
  • maltodextrins e.g. Lodex® 5 and Lodex® 10
  • starches or modified starches including potato starch, maize starch and rice starch
  • sodium chloride sodium phosphate
  • calcium phosphate e.g. basic calcium phosphate, calcium hydrogen phosphate
  • calcium sulfate calcium carbonate
  • Disintegrants may be used such as cellulose derivatives, including microcrystalline cellulose, low-substituted hydroxypropyl cellulose (e.g. LH 11 , LH 22, LH 21 , LH 20, LH 32, LH 31, LH30); starches, including potato starch; croscarmellose sodium (i.e. cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®); alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Polyvidon® CL, Polyvidon® CL-M, Kollidon® CL,
  • cellulose derivatives including microcrystalline cellulose, low-substituted hydroxypropyl cellulose (e.g. LH 11 , LH 22, LH 21 , LH 20, LH 32, LH 31, LH30); starches, including potato starch; croscarmellose sodium (i.e. cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-So
  • Glidants and lubricants may be incorporated such as stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, colloidal silica, sodium stearyl fumarate, polyethylenglycols and alkyl sulphates.
  • Surfactants may be employed such as non-ionic (e.g., polysorbate 20, polysorbate 21 , polysorbate 40, polysorbate 60, polysorbate 61 , polysorbate 65, polysorbate 80, polysorbate 81 , polysorbate 85, polysorbate 120, sorbitane monoisostearate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate and polyvinylalkohol), anionic (e.g., docusate sodium and sodium lauryl sulphate) and cationic (e.g., benzalkonium chloride, benzethonium chloride and cetrimide) or mixtures thereof.
  • non-ionic e.g., polysorbate 20, polysorbate 21 , polysorbate 40, polysorbate 60, polysorbate 61
  • amphoteric surfactants are 1,2-diacyl-L-phosphatidylcholine, N-lauryl-N,N- dimethylglycine, alkylaminopropionic acid, alkyliminodipropionic acid, and dimethyl-(3- palmitamidopropyl)-aminoacetate.
  • compositions may include colorants, organoleptic improving agents, taste-improving agents, flavouring agents, antioxidants, vitamins, pH adjusting agents, solubilizing agents, wetting agents and buffering agents.
  • suitable compositions according to the invention include suppositories (emulsion or suspension type), solutions, enemas and rectal gelatin capsules (solutions or suspensions) as well as the compositions mentioned in the Examples herein.
  • Appropriate suppository bases include cocoa butter, esterified fatty acids, glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters.
  • Various additives like e.g. enhancers may be added.
  • nasal sprays and aerosols for inhalation are suitable compositions according to the invention.
  • the active drug substance is dissolved or dispersed in a suitable vehicle.
  • suitable vehicles and excipients present in the composition are all selected in accordance with conventional pharmaceutical practice in a manner understood by a person skilled in the art of formulating pharmaceutics (for specific examples, see the examples herein).
  • compositions according to the invention may contain conventionally non-toxic pharmaceutically acceptable carriers and excipients including microspheres and liposomes.
  • the compositions include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, dressings, bandages, plasters, and the like.
  • the pharmaceutical acceptable carriers or excipients may include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gelforming agents, ointment bases, perfumes and skin protective agents.
  • emulsifying agents are naturally occurring gums, e.g. gum acacia or gum 5 tragacanth, naturally occurring phosphatide, e.g soybean lecithin and sorbitan monooleate derivatives.
  • enhancers are alcohols (such as, e.g., ethanol, lauryl alcohol), esters (e.g. glycerol monolaurate), salicylic acid, anionic surfactant, (e.g. sodium dodecyl sulfate), 10 cationic surfactant (e.g. cetyltrimethyl ammonium bromide), non-ionic surfactants (e.g. polysorbates), phosporlipids (e.g.
  • phosphtidyl choline urea
  • propylene glycol DMSO
  • triethanolamine N.Ndimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone and derivatives thereof, tetragydrofuryl alcohol, Azone.
  • a unit comprised in a composition according to the invention or the composition itself may be coated with a modified release coating.
  • the modified release coating is a substantially water-insoluble but water-diffusible coating.
  • the modified release coating may be applied on the multiple units or on the single units from a solution and/or suspension preferably in an aqueous solvent, but an organic 25 coating composition may also be applied.
  • the modified release coating may also be applied as a compression coating comprising a dry mixture of polymer(s) and the e.g. the active drug substance.
  • matrix-forming agents are hydroxypropylmethylcellulose such as, e.g., 1828, 30 2208, 2906 or 2910 according to USP, hydroxypropylcellulose, micronised ethylcellulose, low-substituted hydroxypropylcellulose (LH 20, 21 , 31).
  • film-forming agents which are suitable for use in accordance with the present invention are agents selected from the group consisting of cellulose derivatives such as, 35 e.g., ethylcellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose valerate, cellulose acetate propionate; acrylic polymers such as, e.g., polymethyl methacrylate; vinyl polymers such as, e.g., polyvinyl acetate, polyvinyl formal, polyvinyl butyryl, vinyl chloride-vinyl acetate copolymer, ethylene-vinyl acetate copolymer, vinyl chloride-propylene-vinyl acetate copolymer; silicon polymers such as, e.g., ladder polymer of sesquiphenyl siloxane, and colloidal silica; polycarbonate; polystyrene; polyester; coumarone-indene polymer; polybutadiene; and other high molecular synthetic polymers.
  • the acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the acrylic coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as that which is commercially available from Rohm Pharma under the tradename Eudragit®.
  • the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the tradenames Eudragit® RL 30 D and Eudragit® RS 30 D, respectively.
  • Eudragit® RL 30 D and Eudragit® RS 30 D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1 :20 in Eudragit® RL 30 D and 1 :40 in Eudragit® RS 30 D.
  • Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the Eudragit® RL/RS dispersions may be mixed together in any desired ratio in order to ultimately obtain a modified release formulation having a desirable dissolution profile.
  • the most desirable modified release formulations may be obtained from a retardant coating based on Eudragit® NE 30D, which is a neutral resin having a molecular weight of 800,000.
  • enteric polymers examples include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxy propyl methyl cellulose acetate phthalate, hydroxy propyl methyl cellulose acetate succinate, carboxy methyl ethyl cellulose, polyvinyl acetate phthalate, copolymer of vinyl acetate and crotonic acid and poly(methacrylic acid, ethacrylate), and Eudragit® S 12.5, Eudragit® S 100, Eudragit® FS 30D (all from Rohm), Sureteric® (from Colorcom), Aquateric® (from FMC) or HPMCP (from Shin-Etsu).
  • the amount of coating applied is adapted so as to obtain a predetermined dissolution characteristic of the composition.
  • the amount of coating applied should also be adapted so that there will be no rupturing problems.
  • the coating may be admixed with various excipients such as plasticizers, anti-adhesives such as, e.g., colloidal silicium dioxide, inert fillers, lipophilic agents such as, e.g, stearic acid, capric acid or hydrogenated castor oil, colon targeting excipients such as, e.g. amylose, ethylcellulose, Eudragit S 12.5 etc., and pigments in a manner known perse.
  • excipients such as plasticizers, anti-adhesives such as, e.g., colloidal silicium dioxide, inert fillers, lipophilic agents such as, e.g, stearic acid, capric acid or hydrogenated castor oil, colon targeting excipients such as, e.g. amylose, ethylcellulose, Eudragit S 12.5 etc., and pigments in a manner known perse.
  • Tackiness of the water-dispersible film-forming substances may be overcome by simply incorporating an anti-adhesive in the coating.
  • the anti-adhesive is preferably a finely divided, substantially insoluble, pharmaceutically acceptable non-wetting powder having anti-adhesive properties in the coating.
  • anti-adhesives are metallic stearates such as magnesium stearate or calcium stearate, microcrystalline cellulose, or mineral substances such as calcite, substantially water-insoluble calcium phosphates or substantially water-insoluble calcium sulphates, colloidal silica, titanium dioxide, barium sulphates, hydrogenated aluminium silicates, hydrous aluminium potassium silicates and talc.
  • the preferred anti-adhesive is talc.
  • the anti-adhesive or mixture of anti-adhesives is preferably incorporated in the coating in an amount of about 0.1-70% by weight, in particular about 1-60% by weight, and preferably about 8-50% by weight of the film layer.
  • the units or the composition may further comprise an outer film layer.
  • the outer second layer comprises a water-based film-forming agent which prevents adhesion between the units at elevated temperatures and imparts flowability to the units, the water-based film-forming agent being anti-adhesive at temperatures above about 40 °C, especially temperatures above about 50 °C, such as a temperature between about 60 °C and about 120 °C, and being selected from diffusion coating materials such as ethylcellulose or enteric coating materials such as anionic poly(meth)acrylic acid esters, hydroxypropylmethylcellulosephthalate, celluloseacetatephthalate, polyvinyl- acetatephthalate, polyvinylacetatephthalate-crotonic acid copolymerisates, or mixtures thereof, or water-soluble coating materials such as water-soluble cellulose derivatives, e.g.
  • hydroxypropylcellulose carboxymethylcellulose, methylcellulose, propylcellulose, hydroxyethylcellulose, carboxyethylcellulose, carboxymethylhydroxyethylcellulose, hydroxymethylcellulose, carboxymethylethylcellulose, methylhydroxypropylcellulose or hydroxypropylmethylcellulose.
  • the plasticizer is normally incorporated in an amount of less than 20% by weight, calculated on the dry matter content of the coating composition.
  • a relatively fast onset composition according to the invention may be any composition well known in the art to provide a relative fast release.
  • polyethyleneglycols is especially preferred such as more n-ethylene glycols represented by the following formula
  • n-ethylene glycols are monoethylene glycol (1 EG), di ethylene glycol (2EG), triethylene glycol (3EG), tetraethylene glycol (4EG), penta ethylene glycol (5EG), hexaethylene glycol (6EG), heptaethylene glycol (7EG), octaethylene glycol (8EG), nonaethylene glycol (9EG), decaethylene glycol (10EG), undecaethylene glycol (11 EG), dodecaethylene glycol (12EG), tridecaethylene glycol (13EG), and tetradecaethylene glycol (14EG).
  • the ethylene glycols may be used in the form of the single compounds or as a mixture of two or more n-ethylene glycols, e.g. commercial products such as polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300) or polyethylene glycol 400 (PEG 400).
  • the polyethyleneglycols may be used in combination with glycofurols ( ⁇ -[(tetrahydro-2- furany)methyl]- ⁇ -hydroxy-poly(oxy-1 ,2-ethanediyl)). The latter may also be used separately.
  • the volume of a nasal dosage is preferably within 500 ⁇ l such as within 300 ⁇ l such as in 5 a range of 10-250 ⁇ l.
  • the prodrug midodrine is not measured in plasma at least not at a therapeutic level while the extent of absorption of the active metabolite is identical to that of a solution.
  • the prodrug midodrine is not measured in plasma at least not at a therapeutic level while the extent of absorption of the active metabolite is identical to that of a solution.
  • T ma ⁇ corresponds to approx. 3 hours.
  • a t max of about 1-2 hour for desglymidodrine is observed after oral intake of midodrine and the corresponding value for midodrine itself is a T max of about
  • a composition containing desglymidodrine may be suitable for use as the sole medicament or it may be suitable for use in combination with another drug substance such as, e.g., midodrine.
  • the invention provides a kit containing at least two different parts at least one of which contains desglymidodrine.
  • compositions for normal or relatively quick release of desglymidodrine a composition for normal or relatively quick release of desglymidodrine and a composition for controlled release of desglymidodrine.
  • the invention relates to a kit comprising two compositions, the one being a normal or relatively quick release composition and the other being a controlled release composition.
  • the compositions of the kit generally contains desglymidodrine, but there may be situations where it is advantategous to have the normal/quick release composition having a content of midodrine or, alternatively, to have the controlled release composition being a midodrine controlled release compositon.
  • kit is intended to include i) a package comprising at least a first and a second pharmaceutical composition, wherein the first composition is designed to release the desglymidodrine relatively fast in order to obtain a relatively fast onset of the therapeutic effect and the second composition is in the form of a controlled release composition (cf. a co-pending patent application by the same Applicant) which is designed to give a release pattern as described below in order to utilize the possibility of having the active drug substance absorbed not only in the upper part of the gastrointestinal tract but also during its passage through colon, the first and the second composition may be of the same kind, e.g. in the form of tablets or capsules or they may be in the form of two different types of pharmaceutical compositions e.g.
  • the first composition may be in the form of plain tablets or a nasal spray and the second composition may be in the form of controlled release tablets or capsules, and ii) a pharmaceutical composition which include a first and a second part, wherein the first part is designed to release desglymidodrine relatively fast in order to obtain a relatively fast onset of the therapeutic effect and the second part is a controlled release part (cf. a co-pending patent application by the same Applicant) which is designed to give a release pattern as described below in order to utilize the possibility of having the active drug substance absorbed not only in the upper part of the gastrointestinal tract but also during its passage through colon, and the first and the second part are presented in the form of a single composition such as, e.g. in the form of a tablet, a capsule (e.g. containing pellets which may be the same or different), sachets, powders etc
  • the composition (or part) intended for relatively fast release contains desglymidodrine as the active substance and the composition (or part) intended for controlled release contains desglymidodrine or midodrine or a combination thereof.
  • compositions of the invention are those, which are designed to release desglymidodrine relatively fast in order to obtain a relatively fast onset of action, i.e an action within 1-2 min after administration such as, e.g. within about 3 min. within about 4 min, within about 5 min, within about 7.5 min, within about 10 min within about 12.5 min or within about 15 min after administration.
  • Tablets (plain): disintegration time less than 15 min and often less than 5 min such as, e.g. 1-3 min.
  • Sublingual, buccal and melt tablets by mould technique: disintegration time less than about 30 sec such as, e.g. about 2-10 sec; by compression or compacting: disintegration time less than about 4 min such as, e.g.. about 2-3 min.
  • compositions normally contain desglymidodrine in dissolved form. Thus, no retardation of the release of the active drug substance from such compositions is expected.
  • the active substance generally is desglymidodrine, but in the case of a kit midodrine may be included as well.
  • the initial relase described for the controlled release composition also applies for the desglymidodrine composition intended for a relatively fast release of the active substance.
  • the present inventors have developed a pharmaceutical controlled release composition for oral use containing midrodrine and/or desglymidodrine and the composition is designed to the release of desglymidodrine in at least the following consecutive steps:
  • Step 1 an initial relatively fast release of desglymidodrine (in order to obtain a relatively fast onset of action)
  • Step 2 a steady release or a slower release than in step 1 of desglymidodrine (in order to maintain a plasma concentration of desglymidodrine which is prolonged and relatively constant)
  • Step 3 a second rise in release of desglymidodrine (in order to take advantage of absorption from the colon, i.e. such a second rise release is designed to take place when the composition (or the disintegrated parts of the composition) reaches the colon; normally this is regarded to take about 8 hours after oral intake
  • Step 4 a decline in release rate corresponding to that essentially all desglymidodrine have been released from the composition.
  • the first part or first composition of the kit according to the invention i.e. the part or composition giving rise to a relatively fast onset of desglymidodrine
  • the first part or first composition of the kit according to the invention releases the active drug substance as described in step 1 above.
  • details relating to such a first step including the relevant formulation techniques as well as the relevant pharmacokinetic parameters (absorption, metabolism and elimination) also apply to the non-controlled desglymidodrine composition of the invention.
  • the above release pattern is contemplated in order to obtain the desired plasma concentration of desglymidodrine during day and night after administration orally once or twice daily.
  • the release pattern above is based on the following requirements with respect to the plasma concentration of desglymidodrine:
  • a peak concentration is intended to mean a peak value, a shoulder value or a plateau value in the concentration
  • a relatively constant plasma concentration of desglymidodrine for approximately about 4.5-14 hours such as, e.g., about 5-14 hours, about 6-14 hours, about 7-14 hours, about 8-13 hours, about 9-13 hours, about 10-14 hours, about 10-13 hours, or such as, e.g. for at least about 4.5 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, or at least about 11 hours.
  • the constant plasma concentration of desglymidodrine may last for at least about 12 hours, at least about 13 hours or at least about 14 hours, 3. a decline in plasma concentration with a half-life of e.g. about 3-4 hours to avoid supine hypertension but other half-lives may also be acceptable e.g. reflecting a continous release of midodrine and/or desglymidodrine from the composition.
  • compositions according to the invention are therefore designed based on the following principle; the term "part” is intended to include a separate part within the composition (the composition may contain pellets of e.g. two different types, or an integrated element of the composition, e.g. a multilayer tablet):
  • the composition contains a part intended for relatively fast release of desglymidodrine 2.
  • the composition contains a part intended for prolonged release of desglymidodrine (or wherever relevant midodrine), and the prolonged release is intended to last for at least about 7-8 hours.
  • the composition contains a part intended to release desglymidodrine (or wherever relevant midodrine) relatively fast when the composition (or the disintegrated parts of the composition) reaches the colon, i.e. about 6-10 hours such as, e.g., about 8 hours after oral administration.
  • kits according to the invention comprises a controlled release pharmaceutical composition for oral use comprising midodrine (ST 1085) or a pharmaceutically acceptable salt thereof and/or its active metabolite desglymidodrine (ST 1059) or a pharmaceutically acceptable salt thereof, the composition being adapted to release desglymidodrine in such a manner that a relatively fast peak plasma concentration of desglymidodrine is obtained and that a therapeutically effective plasma concentration of desglymidodrine is maintained for at least about 9 hours such as, e.g. at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, or at least about 14 hours.
  • a relatively fast peak (or shoulder or plateau) plasma concentration of desglymidodrine is obtained about 15 min - 6 hours such as, e.g. about 0.5-6 hours, about 1-6 hours, about 2-5.5 hours, or about 2.5-5.2 hours after oral administration of a composition according to the invention.
  • the plasma concentration of desglymidodrine after administration of midodrine and/or desglymidodrine is preferably maintained at a therapeutically active level for about 5-16 hours, such as, e.g., about 6-16 hours, about 7- 16, about 8-15, about 9-15, about 10-15, about 11-14, about 12-14 or about 13, or for at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours or at least about 16 hours.
  • 5-16 hours such as, e.g., about 6-16 hours, about 7- 16, about 8-15, about 9-15, about 10-15, about 11-14, about 12-14 or about 13, or for at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least
  • n is n ⁇ 60%, such as, e.g., n ⁇ 50% or n ⁇ 40% and wherein n is the plasma concentration in ng/ml and monitored in a healthy person.
  • the determination of the "relatively constant level” is perfomed as described in Example 28 herein.
  • the initial fast release from the controlled release composition may be supplemented with or replaced by a separate fast onset composition (e.g. another composition or another part or composition of the kit) resulting in a peak plasma concentration within the period stated for the initial rise in plasma concentration.
  • a separate fast onset composition gives a flexibility with respect to the dose administered, i.e. if needed a relatively low or a relatively high dose of the active drug substance may be administered dependent on the patient's needs.
  • the invention relates to such relatively fast onset compositions.
  • relevant active drug substances for use in a composition according to the invention are any drug substance for which a dissolution pattern as described below is of relevance.
  • the most interesting drug substances in this respect and with respect to treatment of orthostatic hypotension and urinary incontinence are the prodrug midodrine and its active metabolite desglymidodrine.
  • a composition according to the invention includes desglymidodrine, or a combination of midodrine and desglymidodrine. Of course such compositions may also contain other active drug substances, if relevant.
  • a peak plasma concentration of desglymidodrine is obtained abot 1-2 min after administration such as, eg. about 2-5 min, about 5-10 min or about 15-30 min after administration or 15-90 min after oral administration.
  • the plasma concentration of desglymidodrine after oral administration is maintained at a relatively constant level for about 0.7-4 hours such as, e.g. at least about 0.7 hours, at least about 1 hour, at least about 2 hours, at least about 3 hours, or at least about 4 hours.
  • the term "relatively constant” is intended to mean m is m ⁇ 60%, such as, e.g., m ⁇ 50% or m ⁇ 40% and wherein m is the plasma concentration in ng/ml and monitored in a healthy person.
  • the determination of the "relatively constant level” is perfomed as described in Example 28 herein.
  • compositions (inter alia relatively fast onset compositions and controlled release compositions, respectively) are illustrated in the Examples.
  • a target plasma profile and release profile can be designed for the controlled release composition or the controlled release part of the kit comprising desglymidodrine.
  • Fig. 2 is given a target dissolution profile and a target release rate curve. Suitable dissolution methods are found in the Examples herein.
  • ⁇ 30% such as, e.g. ⁇ 25%, ⁇ 20%, + 15%, ⁇ 10% or ⁇ 0%
  • ⁇ 30% w/w ⁇ 20% w/w, ⁇ 10%w/w, ⁇ 7.5% w/w, ⁇ 5% w/w, ⁇ 0% w/w
  • the controlled release composition of a kit according to the invention contains midodrine or a pharmaceutically acceptable salt thereof then the release pattern of midodrine generally follows the patterns given above for desglymidodrine.
  • the controlled release composition of a kit according to the invention contains midodrine or a pharmaceutically acceptable salt thereof and desglymidodrine or a pharmaceutically acceptable salt thereof, then the release pattern of the sum of midodrine and desglymidodrine is calculated on a molar basis follows the patterns given above for midodrine.
  • a controlled release composition according to the present invention normally has a release rate of desglymidodrine (or whenever relevant midodrine) - when tested in vitro employing any of Dissolution Method I, II, III or IV - that corresponds to a curve that has a shape corresponding to i) a relatively fast first initial release followed by ii) a steady release or a slower release than in step i) above, which is followed by iii) a second rise in release rate and, finally, iv) a decline in release rate.
  • the second rise in release rate takes place 5-10 hours such as, e.g., about 5-9 hours, about 6-8 hours after start of the dissolution test, or 6.5-9 hours after start of the dissolution test simulating the time it takes to reach the colon after oral administration.
  • the steady release period it normally starts about 1-3 hours after the start of the dissolution test, and the steady release is maintained for at least 2 hours such as, e.g. at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours such as about 6-8 hours.
  • the release rate of desglymidodrine (or midodrine or the sum of midodrine and desglymidodrine on a molar basis) from a controlled release composition of a kit according to the invention - when tested in vitro employing dissolution apparatus 2 (paddle) according to USP and Ph.
  • dissolution apparatus 2 praddle
  • 100 rpm, 0.1 N hydrochloric acid as dissolution medium or any of Dissolution Method I, II, III or IV as described herein and a temperature of 37 °C - in %/hour is as follows ( ⁇ 10-40%such as, e.g. ⁇ 10-30% or ⁇ 10%, ⁇ 15% or ⁇ 20% of the values stated below):
  • 2-30% such as, e.g., 2- 10 %/hour), about 10 %/hour about 8 hours after start of the test (range e.g. 2-15 %/hour), about 2 %/hour about 10 hours after start of the test (range e.g. 0-10 %/hour), about 1 %/hour about 12 hours after start of the test (range e.g. 0-10 %/hour).
  • a controlled release composition according to the invention is normally suitable for administration once or twice daily, and it differs from a plain tablet composition, e.g. Gutron® tablets, in many ways.
  • a plain tablet composition e.g. Gutron® tablets
  • pharmacokinetic values of importance for achievement of a prolonged therapeutic effect of a composition according to the invention are given in Example 28 herein.
  • W 50 of desglymidodrine (defined as corresponding to the time the plasma concentration curve is or is above 50% of the C max value) is from about 5 to about 12 hours such as, e.g. from about 6 to about 11 hours such as, e.g. at least about 7 hours.
  • T max is increased with a factor of at least 2 when compared with a plain Gutron® tablet administered in the same dose.
  • T max is determined from a plasma concentration versus time curve and the plasma concentration reflects the sum concentration in nmol/l of midodrine and desglymidodrine.
  • MRT mean residence time
  • a factor of at least 1.5 such as, e.g., at least 2, at least 2.5 or at least 3 when compared with a plain Gutron® tablet administered in the same dose.
  • MRT is determined from a plasma concentration versus time curve and the plasma concentration reflects the sum concentration in nmol/l of midodrine and desglymidodrine.
  • MRT for midodrine is at least about 1.5 hours such as, e.g., at least about 2 hours, at least about 2.5 hours or at least about 3 hours
  • MRT for desglymidodrine is at least about 6 hours such as, e.g., at least about 7 hours, at least about 7.5 hours, at least about 8 hours, at least about 8.5 hours, at least about 9 hours, or at least about 9.5 hours.
  • fig. 1 shows the estimated plasma concentration of desglymidodrine
  • fig. 2 shows the estimated in vitro target for dissolution of desglymidodrine and the estimated release rate,and figs. 3-4 illustrate the results of Example 28.
  • 0.1 HCl is prepared by dilution of concentrated HCl (37%) with purified water.
  • the dissolution parameters are described in Method I.
  • the measurement is performed by
  • Buffer solution pH 3 is prepared by dissolving 23.6 g potassium dihydrogen phosphate in
  • the dissolution is performed as described in Method I.
  • the sample is withdrawn with a pipette and transferred to a syringe.
  • the sample is filtered through a 0.7 ⁇ m filter.
  • the first ml is returned to the vessel in order to reduce deviation from the desired volume.
  • a sample of approximately 1.5 - 2 ml is transferred to the vial, the rest is returned to the vessel.
  • the absorbances of the filtered samples are measured as described.
  • a standard curve is calculated by linear regression, using the standard solutions.
  • the peak area of the sample is the sum of the peak area of Midodrine Hydrochloride and the peak area of Desglymidodrine hydrochloride, where the latter is divided by the relative response factor 1.25.
  • results are calculated as % released at any time and presented as a mean value of the six samples together with min and max.
  • Dissolution media at change to pH 6.0 Addition of 130 ml 0.23 M Na 3 P0 4 solution Dissolution media at change to pH 7.5 Addition of further 70 ml 0.23 M Na 3 P0 solution Time for change to pH 6.0 2 hours (120 min) Time for change to pH 7.5 7.5 hours (450 min) Rotation speed 100 rpm
  • Vessel no 7 is added Na 3 P0 4 solution in parallel with the six sample vessels
  • 0.1 N HCl is prepared by dilution of concentrated HCl (37%) with purified water.
  • Na 3 PO 4 solution Dissolve an amount of Na 3 PO 4 -12H 2 O in a bit of 1M HCI-R and add water to a concentration of 0.23 M. (Strong alkaline).
  • Buffer solution pH 6.0 600 ml 0.1 N HCl is added 130 ml 0.23 M Na 3 PO solution.
  • Buffer solution pH 7.5 Buffer solution pH 6.0 is added further 70 ml 0.23 M Na 3 PO solution.
  • Two solutions are prepared with a concentration of 10 ⁇ g/ml midodrine hydrochloride in 0.1 N HCl. 0.1 N HCl is used as blind. The absorbances of the solutions are measured on the spectrophotometer.
  • the dissolution parameters are described in Method III.
  • the measurement is performed 0 by HPLC.
  • Buffer solution pH 3 is prepared by dissolving 23.6 g potassium dihydrogen phosphate in
  • HCl HCl are prepared.
  • the solutions should be stored in refrigerator.
  • the dissolution is performed as described in Method III.
  • the sample is withdrawn with a pipette, transferred to a syringe.
  • the sample is filtered through a 0.7 ⁇ m filter.
  • the first ml is returned to the vessel in order to reduce deviation from the desired volume.
  • a sample of approximately 1.5 - 2 ml is transferred to the vial, the rest is returned to the vessel.
  • the absorbances of the filtered samples are measured as described.
  • a standard curve is calculated by linear regression, using the standard solutions.
  • the peak area of the sample is the sum of the peak area of midodrine hydrochloride and the peak area of desglymidodrine hydrochloride, where the latter is divided by the relative response factor 1.25.
  • results are calculated as % released at any time and presented as a mean value of the six samples together with min and max.
  • Dissolution medium isotonic buffer pH 6.8 or purified water Volumen: 600 ml Sample time: 5 min RP-HPLC: Phosphate buffer pH 3 : methanol 77:23 (v/v) Detection at 290 nm.
  • Dissolution apparatus 2 according to USP and Ph. Eur.
  • Dissolution medium isotonic buffer pH 6.8 or purified water Volume: 600 ml
  • desglymidodrine refers to desglymidodrine-HCI, if nothing else is mentioned.
  • a core weighing 100 mg is compressed using a punch 6 mm in diameter.
  • the core is compression coated using 165 mg of the 1 st compression layer composition and a punch of 9 mm in diameter.
  • the thus compression coated core is compression coated again using 250 mg of the 2 nd compression layer composition and a punch of 11 mm in diameter.
  • a composition comprising desglymidodrine 0.96 mg, Methocel E5 9.7 mg and talc 8.7 mg is applied to the tablet by spray coating.
  • Composition Core: Desglymidodrine 1.33 mg
  • a core weighing 60 mg is compressed using a punch of 6 mm in diameter.
  • the core is compression coated using 135 mg of the 1 st compression layer composition and a punch of 9 mm in diameter.
  • the thus compression coated core is compression coated again using 145 mg of the 2 nd compression layer composition and a punch of 11 mm in diameter.
  • a composition comprising desglymidodrine 0.59 mg, hydroxypropylmethyl cellulose E 5 3.58 mg, talc 2.65 mg and propylene glycol 0.71 mg is applied to the tablet by spray coating.
  • top coat comprising hydroxypropylmethyl cellulose E 5 1.79 mg, talc 1.25 mg and propylene glycol 0.36 mg is applied to the tablet by spray coating.
  • Desglymidodrine composition made as a coated matrix
  • compositions are prepared:
  • Composition 1 Core: Desglymidodrine 8.0 mg Klucel LF 342.0 mg
  • Composition 2 Core: Desglymidodrine 8.0 mg
  • Cores of both composition 1 and composition 2 are compressed using a punch 10 mm in diameter. Core weighing 350 mg.
  • Both types of cores are coated with an insoluble inner coat and a soluble outercoat.
  • the release profile can be shifted up or down by changing the amount of weight increase of cores when applying the inner coat. If suitable, the release profile can be changed by coating with other acrylic resins such as Eudragit RL 30 D, Eudragit RS 30 D or combinations thereof, or using other types of film forming agents such as ethylcellulose or silicone polymers.
  • the release profile can be changed by using other types of matrix former such as acrylic resins, other types of cellulose ethers such as L-HPC (low-substituted hydroxypropylcellulose), HPC (hydroxypropylcellulose), HPMC (hydroxypropylmethylcellulose), HEC (hydroxyethylcellulose), MC (methylcellulose), HEMC (hydroxyethylmethylcellulose), EC (ethylcellulose) or other viscosity grades of HPC (hydroxypropylcellulose).
  • matrix former such as acrylic resins
  • other types of cellulose ethers such as L-HPC (low-substituted hydroxypropylcellulose), HPC (hydroxypropylcellulose), HPMC (hydroxypropylmethylcellulose), HEC (hydroxyethylcellulose), MC (methylcellulose), HEMC (hydroxyethylmethylcellulose), EC (ethylcellulose) or other viscosity grades of HPC (hydroxypropylcellulose).
  • Composition 1 Core (Non pareil) 200 mg
  • Non-pareil beads are coated in four steps with four different films in a fluid bed coater.
  • a final layer of coating comprising the outer coat is applied and the films are cured at 70°C
  • Composition 2 Core (Non pareil) 200 mg Non-pareil beads are coated in seven steps with four different films alternating with a blank film in a fluid bed coater.
  • the four different film formulations are similar to the four different film formulations in composition 1 , the alternating coats are as follows:
  • film comprising 3. coat 6. film comprising Alternating coat 7. film comprising 4. coat
  • a final layer of coating comprising outer coat in composition 1 is applied and the films are cured at 70°C.
  • Composition 3 Core (Non pareil) 200 mg
  • Non-pareil beads are coated in four steps with four different films in a fluid bed coater:
  • a final layer of coating comprising outer coat is applied.
  • the release profile can be changed by coating with other acrylic resins such as Eudragit RL 30 D, Eudragit RS 30 D or combinations thereof, or using other types of film forming agents such as ethylcellulose or silicone polymers, or incorporating lipophilic compounds such as, e.g., stearic acid, capric acid or hydrogenated castor oil in the film.
  • acrylic resins such as Eudragit RL 30 D, Eudragit RS 30 D or combinations thereof
  • film forming agents such as ethylcellulose or silicone polymers
  • lipophilic compounds such as, e.g., stearic acid, capric acid or hydrogenated castor oil in the film.
  • the present example illustrates the preparation of a coated pellet composition.
  • the aim is to prepare pellets having a release kinetic different from zero order release.
  • Pellets are prepared from the following ingredients:
  • I + II + III + IV are admixed in a Fielder intensive mixer at an appropriate time and mixing intensity.
  • V is applied to the mixture (l-IV) while mixing. When V is applied the mixing is continued at an appropriate time with an appropriate mixing intensity.
  • the wetted mass is extruded through a screen with apertures between 0.4 -1.0 mm.
  • the extrudate is spheronised until the surface of the resulting pellets is smooth.
  • An inner and an outer coating are applied:
  • the weight of the pellets is increased with 8.5% w/w.
  • the pellets are coated in a fluid bed with appropriate process parameters.
  • an outer coat is applied Immediately after the inner coat has been applied an outer coat is applied.
  • the weight of the pellets is increased with 1 % w/w.
  • the pellets are coated in a fluid bed with appropriate process parameters.
  • the weight of 1 unit dose containing 30 mg desglymidodrine is 272.7 mg.
  • the release profile can be shifted up or down by changing the amount of weight increase of pellets when applying the inner coat.
  • the release profile may be changed using different mixtures of pellet fractions having different amounts of inner coating applied.
  • the release profile may also be changed by coating with other acrylic resins such as Eudragit RL 30 D, Eudragit RS 30 D or combinations thereof, or using other types of film forming agents such as ethylcellulose or silicone polymers.
  • the release profile can be changed by applying a fraction of non-coated pellets or by applying an enteric coating to a fraction of pellets.
  • the present example illustrates the preparation of a coated pellet composition.
  • the aim is to prepare pellets having a release kinetic different from zero order release.
  • Coated pellets are prepared from the following ingredients:
  • composition and manufacturing process of pellets are similar to Example 5.
  • a paraffin-containing coating are applied; the weight of the pellets is increased with 6% w/w.
  • the pellets are coated in a fluid bed with appropriate process parameters.
  • the weight of 1 unit dose containing 30 mg desglymidodrine is 263.7 mg.
  • Preparation of a controlled release composition having a zero order release The present example illustrates the preparation of a coated bead composition. The aim is to prepare beads having a zero order release kinetic.
  • Coated beads are prepared as follows: 5
  • Non dissolvable non-pareil beads of equal size are coated with a suspension of desglymidodrine.
  • a diffusion barrier is coated on top of the desglymidodrine layer, and thereby controlling the release of desglymidodrine.
  • the beads are coated with coating suspension 1 (containing desglymidodrine)
  • the weight of the beads is increased with 9% w/w.
  • the beads are coated employing appropriate process parameters. 5
  • the beads are coated with coating suspension 2:
  • V Purified water 979.6 g 5 The weight of the coated beads is increased with 6% w/w.
  • the pellets are coated employing appropriate process parameters.
  • the beads are coated with coating suspension 3:
  • the weight of the coated beads is increased with1% w/w.
  • the beads are coated in a fluid bed employing appropriate process parameters.
  • the weight of 1 unit dose containing 20 mg desglymidodrine is 587.5 mg.
  • the release profile can be shifted up or down.
  • the release profile may be changed using different mixtures of bead fractions having different amounts of second coating suspension applied.
  • the release profile may also be changed by coating with other acrylic resins such as Eudragit RL 30 D, Eudragit RS 30 D or combinations thereof, or using other types of film forming agents such as ethylcellulose or silicone polymers.
  • the above-mentioned filmforming agents can also be combined with pore forming agents such as cellulose ethers, polyoles, PEG'S.
  • the release profile can be changed by applying an enteric coating to a fraction of the coated beads.
  • the present example illustrates the preparation of a coated minitablet composition.
  • the aim is to prepare coated minitablets of equal size in order to obtain a zero order release kinetic.
  • I + II are transferred to a Fielder intensive mixer and admixed at an appropriate time and mixing intensity.
  • Granulation is performed at an appropriate time and mixing intensity.
  • the drying of the wet granulate is carried out in an Aeromatic fluid bed.
  • the dried granulate is passed through a suitable sieve.
  • IV + V are sieved through a 0.3 mm sieve and admixed to the sieved particulate mixture in a cube mixer for 10 min.
  • the thus obtained particulate mixture is compressed into tablets weighing 15 mg.
  • a dose of 30 mg desglymidodrine corresponds to 10 minitablets.
  • the minitablets are coated with inner and outer coatings corresponding to the description of coating suspension 2 and 3 in Example 7.
  • the release profile can be shifted up or down
  • the release profile may be changed using mixtures of mintablet fractions having different amounts of inner coating applied.
  • the release profile may also be changed by coating with other acrylic resin such as Eudragit RL 30 D, Eudragit RS 30 D or combinations thereof, or using other types of film forming agents such as ethylcellulose or silicone polymers.
  • filmforming agents can also be combined with pore forming agents such as, e.g., cellulose ethers, polyoles, PEG's, etc.
  • the release profile may be changed applying an enteric coating to a fraction of coated minitablets.
  • I + II are admixed in a Fielder intensive mixer at an appropriate time and mixing intensity.
  • the mixture is wetted with V while mixing at an appropriate mixing intensity.
  • the wetted mixture is granulated at an appropriate time and mixing intensity.
  • the drying of the wet granulate is carried out in an Aeromatic fluid bed.
  • the dried granulate is passed through a suitable sieve.
  • Ill + IV are sieved through a 0.3 mm sieve and admixed to the sieved particulate mixture in a cube mixer for 10 min.
  • the thus obtained particulate mixture is compressed into tablets weighing 15 mg.
  • a dose of 30 mg desglymidodrine is contained in 10 minitablets.
  • the release profile can be changed by using other cellulose ethers such as HPC, L-HPC, HPMC or combinations of thereof.
  • the principle of a matrix composition may also be used for a single unit tablet containing the total amount of desglymidodrine in one unit.
  • the minitablets may be coated with inner and outer coatings corresponding to the description of coating suspension 2 and 3 in Example 7.
  • the amount of coating applied may be varied to shift the dissolution profile up or down.
  • V Isopropyl alcohol 800.0 g
  • I + II are admixed in a Fielder intensive mixer at an appropriate time and mixing intensity.
  • the mixture is wetted with V while mixing at an appropriate mixing intensity.
  • the wetted mixture is granulated for an appropriate time and mixing intensity.
  • the drying of the wet granulate is carried out in an Aeromatic fluid bed.
  • the dried granulate is passed through a suitable sieve.
  • Ill + IV are sieved through a 0.3 mm sieve and admixed to the sieved particulate mixture in a cube mixer for 10 min.
  • the thus obtained particulate mixture is compressed into tablets weighing 15 mg.
  • a dose of 30 mg of desglymidodrine is contained in 10 minitablets.
  • the minitablets may be coated according to Example 7.
  • the amount of coating applied may be varied to shift the dissolution profile up or down.
  • a tablet was prepared from the following ingredients:
  • Lactose monohydrate 180.00 g
  • Hydroxypropylmethyl49.6 g cellulose E 50 The granulate for 1 st compression layer is prepared in the following way: Desglymidodrine and Starch 1500 was mixed by hand. This mixture and lactose monohydrate is mixed in a Moulinex food processor for 30 sec.
  • the granulating fluid comprising Eudragit RS 30 D and acetyl tributylcitrate is mixed by stirring for 5 min.
  • the granulating fluid was applied to the powder mixture while mixing in the Moulinex food processor.
  • the time for applying the granulating fluid is 45 sec.
  • Wet massing time for the moist powder mixture is 30 sec.
  • the moist granulate is tray dried and the dried granulate is passed through a 1000 ⁇ m screen.
  • the granulate for 2 nd compression layer is prepared in the following way: Desglymidodrine and hydroxypropylmethyl cellulose E 50 are mixed by hand and passed through a 500 ⁇ m screen.
  • a double compression tablet is prepared in the following way:
  • a shallow concave round punch of 11 mm in diameter is used to compress the tablet.
  • 250 mg granulate for 1 st compression layer is weighed into the die and compressed gently to a loose compact.
  • 200 mg granulate for 2 nd compression layer is weighed on top the loose compact.
  • the loose compact and the granulate for 2 nd compression layer is compressed with a force of approx. 17 kN to form a coherent tablet.
  • a film containing desglymidodrine and a blank film is applied to the tablets.
  • a desglymidodrine controlled release product is prepared by manufacturing one type of pellet, which afterwards is coated with different types of film coatings.
  • the capsule ends up with 3 different types of pellets (one non-coated pellet, one controlled release (CR)- coated pellet and one enteric coated (EC)-pellet).
  • the pellet is prepared by the use of an extrusion/spheronization technique.
  • the ingredients are listed in Scheme 12-1.
  • the ingredients are mixed and wetted in a Fielder high shear mixer in which the water is applied by a nozzle.
  • the wetted mass is extruded in a Nica E 140 extruder with a screen size of 600 ⁇ m (those pellets which are being used for non coated pellets and for CR-coating) or 800 ⁇ m (those pellets used for EC-coating).
  • the extrudate is spheronized in a laboratory unit for 5 min.
  • the pellets are dried in a laboratory scale fluid bed for approx. 75 min at 50°C.
  • the dried pellets used for non coated pellets and for CR-coating are passed through a screen of 700 ⁇ m and the dried pellets used for EC-coating are fractionated with a lower screen of 500 ⁇ m and a upper screen of 1000 ⁇ m.
  • Step 1 pellets (non coated pellets)
  • pellets are not coated, as it is used as an immediate release unit.
  • the pellets are a part of the content in the capsule.
  • Inner coat 1788.1 g per 3000.0 g pellets (dry matter: 9% of the core weight)
  • Outer coat 375.0 g per 3000.0 g pellets (dry matter: 1% of the core weight)
  • the bed temperature is maintained substantially in the interval from 20-25°C by adjustment of the liquid flow rate or the inlet temperature.
  • the inlet air temperature is kept at approximately 32°C.
  • the coated pellets are cured at a bed temperature of approximately 70°C for 30 min. Then the pellets are passed through a screen 1.0 mm. Oversized material is discarded.
  • the bed temperature is maintained substantially in the interval from 30-38°C by adjustment of the liquid flow rate or the inlet temperature.
  • the inlet air temperature is kept at approximately 49°C.
  • step 1 The 3 different pellets (steps 1, 2 and 3) are filled into capsules by hand.
  • the amount of pellets per capsule is shown in Scheme 12-4.
  • composition made by employment of mixing a matrix granulate and a slow release granulate
  • composition of the granulates are equal to the granulates described in Example 11. 250 mg of granulate called 1 st compression layer (slow release granulate) is mixed with 200 mg of granulate called 2 nd compression layer (matrix granulate).
  • a shallow concave round punch 11 mm in diameter is used to compress the tablet.
  • the granulate mixture is placed in the die and the granulate is compressed with a compression force of approx. 17 kN to form a coherent tablet.
  • a release controlling film After compression a release controlling film, a film containing desglymidodrine and a blank film were applied to the tablets.
  • the film compositions and the applied amounts are equal to the compositions and amounts applied in Example 11.
  • the present example illustrates the preparation of plain tablets containing desglymidodrine as the active drug substance.
  • the moist granulate was passed through a 1000 ⁇ m sieve and tray dried at 52 °C for 3 hours.
  • the dried granulate was passed through a 1000 ⁇ m sieve.
  • VI + VII was passed through a 300 ⁇ m sieve and mixed by hand with equal parts of the granulate. This mixture was admixed in a cube mixer for 5 min.
  • the obtained particulate mixture was compressed into tablets weighting 130 mg using a punch of 6 mm in diameter.
  • Powder preparation e.g for use in a needle-free device
  • the particle size distributions for the ingredients should be appropriate for deposition of the composition in an appropriate layer of the skin e.g. 0.5 ⁇ m to 10 ⁇ m.
  • the powder is filled into a drug casette, each containing 4 mg desglymidodrine.
  • Suspending agents such as glucose, lactose, celluloses, starches (maize-, rice-, potato-), calcium phosphate or mixtures of these may be used.
  • Liquid composition for use in a needle-free device
  • I is dissolved in III upon continuous stirring.
  • the remaining solid ingredients (II) are added to the solution one by one during continuous stirring.
  • purified water is added to a total weight of 1000.0 g.
  • the formulation is filtrated (0,22 ⁇ m) and is filled into glass devices with a piston (e.g. teflon) and a stopper (e.g. rubber (natural or synthetic substances)). '
  • Tonicity agents may be dextrose, glycerol, sorbitol, mannitol, potassium nitrate and sodium sulphate decahydrate or mixtures thereof.
  • pH may be adjusted to the appropriate value by use of additional buffer salts such as citric acid, sodium citrate, and potassium dihydrogen phosphate or mixtures of these.
  • additional buffer salts such as citric acid, sodium citrate, and potassium dihydrogen phosphate or mixtures of these.
  • Liquid compositions for pulmonal delivery Liquid compositions for pulmonal delivery
  • the particle size distribution should be appropriate for deposition of the composition in the lung, e.g. 0.5 ⁇ m to 10 ⁇ m.
  • the product is filled into suitable pressurised multi-dose containers delivering e.g.100 ⁇ l pr. dose.
  • propellants such as dichlorodifluoromethane, dichlorotetrafluoroethane and trichlorofluoromethane or mixtures of these may be used.
  • Glidants such as oleic acid and derivatives and isopropyl myristate or mixtures of these may be used to reduce friction during administration.
  • Example 17.2 Glidants such as oleic acid and derivatives and isopropyl myristate or mixtures of these may be used to reduce friction during administration.
  • I is dissolved in III upon continuous stirring.
  • the remaining solid ingredients (II) are added to the solution one by one during continuous stirring.
  • purified water is added to a total weight of 1000.0 g.
  • the composition is filled into 2 ml ampoules or other suitable unit-dose containers.
  • excipients may also be added such as polyethylene glycol, alcohol, glycofurol, phospholipids, poloxamer, polyoxyethylene castor oil derivatives, polysorbates, propylene glycol and cyclodextrins or combinations of these.
  • Tonicity agents may be e.g dextrose, glycerol, sorbitol, mannitol, sodium chloride, potassium nitrate and sodium sulphate decahydrate or mixtures thereof.
  • pH may be adjusted to the appropriate value by use of additional buffer salts such as citric acid, sodium citrate, and potassium dihydrogen phosphate or mixtures of these.
  • additional buffer salts such as citric acid, sodium citrate, and potassium dihydrogen phosphate or mixtures of these.
  • Sufficient microbiological preservation may be achieved by addition of benzalconium chloride or parabenes.
  • Suitable flavours can be added to the composition and use of sweeteners such as saccharin, acesulfame, aspartame, cyclamate salts or mixtures of these can further adjust the taste.
  • Powder composition for pulmonal delivery Composition
  • the particle size distributions for the ingredients should be appropriate for deposition of the composition in the lung, e.g. 0.5 ⁇ m to 10 ⁇ m. I and II are carefully mixed and sieved. The powder is filled into capsules or other suitable unit-dose containers, each containing 10 mg of the composition.
  • suspending agents such as lactose, celluloses, starches (maize-, rice-, potato-) calcium phosphate or mixtures of these may be used.
  • a nasal composition of desglymidodrine is buffered, and tonicity adjusted and it can be delivered from a device, which may or may not require the presence of antimicrobial agents in the composition.
  • the amount of desglymidodrine reaching the systemic circulation may be increased by addition of absorption enhancer(s) to the composition.
  • the total amount of absorption enhancers included in the composition will, typically, vary between 0.01 % and 10%. However, some absorption enhancers may also serve as vehicles and thereby totally replace the content of water in the composition.
  • the final nasal composition may be a homogenous liquid, a suspension, an emulsion, a gel or a powder.
  • the dose administered intranasally may be adjusted by choice of the volume of the formulation, ranging from 10 ⁇ l to 250 ⁇ l per nostril or of the mass of the composition, ranging from 5 mg to 50 mg. Specific examples of nasal compositions
  • Composition Function of ingr.
  • I is dissolved in III upon continuos stirring.
  • the remaining solid ingredients (II) are added to the solution one by one during continuos stirring.
  • purified water is added to a total weight of 1000.0 g.
  • composition is filled into appropriate nasal spray devices delivering e.g. 100 ⁇ l pr.dose.
  • pH may be adjusted to the appropriate value by use of additional buffer salts such as citric acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
  • additional buffer salts such as citric acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
  • Sufficient microbiological preservation may be achieved by addition of benzalconium chloride, sorbic acid or parabenes such as methylparaben, ethylparaben, propylparaben and butylparaben or mixtures of these.
  • Composition Function of ingr.
  • composition is filled into appropriate nasal spray devices delivering e.g. 100 ⁇ l pr.dose.
  • pH may be adjusted to the appropriate value by use of additional buffer salts such as citric acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
  • additional buffer salts such as citric acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
  • Sufficient microbiological preservation may be achieved by addition of benzalconium chloride, sorbic acid or parabenes such as methylparaben, ethylparaben, propylparaben and butylparaben or mixtures of these.
  • Liposomes are spherical self-closed structures composed of concentric bilayers that entrap part of the solvent or active drug substance in the central core or in the bilayer depending on the hydrophilicity of the active drug substance. Liposomes are predominantly made of natural amphiphilic lipids, e.g. phospolipids. Liposomes are likely to enhance the penetration of the active ingredient into the mucosa such as, e.g. the nasal, buccal, oral, rectal or vaginal mucosa.
  • the liposomes can be based on liposome forming lipids and liposome stabilising or destabilising lipids.
  • the total amount of lipids in the composition can vary between 20- 80% w/w.
  • the ratio between liposome forming lipids and stabilising/destabilising lipids can be between 1 :1 to 40:1 (on a molar basis) or the composition can contain liposome forming lipids alone.
  • I is dissolved in II upon continuos stirring. Following complete dissolution of the solids, purified water is added to a total weight of 1000.0 g.
  • the dry mix of DSPC:CH (7 mol DSPC :2 mol CH) (IV) is dispersed in water, and dehydrated.
  • the liquid composition containing desglymidodrine is poured into the dehydrated DSPC:CH during vigorous stirring to rehydrate the mixture of DSPC:CH.
  • pH may be adjusted to the appropriate value by use of additional buffer salts such as citric acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
  • Sodium edetate may be added to the composition as stabiliser.
  • Sufficient microbiological preservation may be achieved by addition of sorbic acid or parabenes such as methylparaben, ethylparaben, propylparaben and butylparaben.
  • Propylene glycol (10%) can be added to potentiate the antimicrobial activty of the parabens in the presence of some amphiphilics.
  • the composition is filled into appropriate nasal spray devices delivering the desired dose.
  • the volume of the dose can be between 10-250 ⁇ l, preferably 100 ⁇ l.
  • the dose can also be administrered by application of two puffs, one in each nostril.
  • vesicle forming lipids can also be used instead of DSPC in the lipid bilayer.
  • amphiphilic lipids may be cationic, anionic or neutral, such as DPPC, DLPC, DOPC, DSEPC, dialkyl (C 8 -C 20 ) sulfosuccinate or fatty alcohol ethoxylate (with alkyl chain length of C 8 -C 20 and 4 to 6 ethoxy groups).
  • the molecular amount of lipids compared to active compound can be optimised with different liposome building lipids.
  • CH can be replaced by cholesterol derivatives or any other stabiliser/destabiliser such as alkyl (C 8 -C 20 ) phosphate, alkyl (C 8 -C 20 ) sulfate, alkyl (C 8 -C 20 ) ethersulfate, alkyl (C 8 -C 20 ) ether carboxylate.
  • stabiliser/destabilisers can be employed such as stearoyl lysophosphatidyl choline, lysophosphatidylcholine, palmitoyl lysophosphatidyl choline and didecanoyl phosphatidyl choline.
  • a buccal composition of desglymidodrine is buffered and tonicity adjusted. It can be delivered from a device, which may or may not require the presence of antimicrobial agents in the formulation. The amount of desglymidodrine reaching the systemic circulation may be increased by addition of absorption enhancer(s) to the composition.
  • the total amount of absorption enhancers included in the composition will, typically, vary between 0.01% and 10%. However, some absorption enhancers may also serve as vehicles and thereby totally replace the content of water in the formulation.
  • the final buccal formulation may be a homogenous liquid, a suspension, an emulsion, a gel or a powder.
  • the dose administered buccally may be adjusted by choice of the volume of the formulation, ranging from 10 ⁇ l to 500 ⁇ l or the mass of the composition, ranging from 5 mg to lOO mg.
  • Composition Function of ingr.
  • I is dissolved in II upon continuos stirring. Following complete dissolution of the solids, purified water is added to a total weight of 1000.0 g.
  • the dry mix of DSPC.CH (7 mol DSPC:2 mol CH) (IV) is dispersed in water, and dehydrated.
  • the liquid composition containing desglymidodrine is poured into the dehydrated DSPC:CH during vigorous stirring to rehydrate the mixture of DSPC:CH.
  • pH may be adjusted to the appropriate value by use of additional buffer salts such as citric acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
  • Sodium edetate may be added to the composition as stabiliser.
  • Sufficient microbiological preservation may be achieved by addition of sorbic acid or parabenes such as methylparaben, ethylparaben, propylparaben and butylparaben.
  • Propylene glycol (10%) can be added to potentiate the antimicrobial activty of the parabens in the presence of some amphiphilics.
  • the composition is filled into appropriate buccal spray devices delivering the desired dose.
  • the volume of the dose can be between 10-500 ⁇ l or the dose can be administrered by application of multiple puffs.
  • vesicle forming lipids can also be used instead of DSPC in the lipid bilayer.
  • amphiphilic lipids may be cationic, anionic or neutral, such as DPPC, DLPC, DOPC, DSEPC, dialkyl (C 8 -C 2 o) sulfosuccinate or fatty alcohol ethoxylate (with alkyl chain length of C 8 -C 2 o and 4 to 6 ethoxy groups).
  • the molecular amount of lipids compared to active compound can be optimised with different liposome building lipids.
  • CH can be replaced by cholesterol derivatives or another stabiliser/destabiliser such as alkyl (C 8 -C 20 ) phosphate, alkyl (C 8 -C 2 o) sulfate, alkyl (C 8 -C 20 ) ethersulfate, alkyl (C 8 -C 20 ) ether carboxylate.
  • another stabiliser/destabiliser such as alkyl (C 8 -C 20 ) phosphate, alkyl (C 8 -C 2 o) sulfate, alkyl (C 8 -C 20 ) ethersulfate, alkyl (C 8 -C 20 ) ether carboxylate.
  • Composition Function of ingr. I Desglymidodrine 40.0 g Active ingr.
  • composition is filled into appropriate buccal spray devices delivering e.g. 100 ⁇ l pr.dose.
  • pH may be adjusted to the appropriate value by use of additional buffer salts such as citric acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
  • additional buffer salts such as citric acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
  • Sufficient microbiological preservation may be achieved by addition of benzalconium chloride, sorbic acid or parabenes such as methylparaben, ethylparaben, propylparaben and butylparaben or mixtures of these.
  • Composition Function of ingr.
  • composition is filled into appropriate buccal spray devices delivering e.g. 100 ⁇ l pr.dose.
  • pH may be adjusted to the appropriate value by use of additional buffer salts such as citric acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
  • additional buffer salts such as citric acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
  • Sufficient microbiological preservation may be achieved by addition of benzalconium chloride, sorbic acid or parabenes such as methylparaben, ethylparaben, propylparaben and butylparaben or mixtures of these.
  • Sublingual tablets are designed to give a fast disintegration in the mouth by the amount of salvia normally available in that region.
  • the disintegration time is therefore very short or short and there may be additives, which promote salvia secreting in the composition.
  • a fast disintegration together with a high solubility of the drug substance give the possibility of a fast absorption through the mucous membrane of the mouth, especially under the tongue where the blood vessels run close to the surface.
  • Sublingual absorbed drugs avoid more or less the first pass liver metabolism.
  • Sublingual tablets may be prepared by mould technique, by direct compression or by conventional wet granulation or dry granulation (e.g. roller compaction) of the ingredients.
  • taste improving substances may be added to promote salvia secretion.
  • This may include artificial sweeteners (cyclamate, saccharin sodium, aspartame, etc.), natural sweeteners (saccharose, sorbitol, xylitol, etc.), week organic acids (citric-, acetic-, ascorbic acid, etc.) natural or artificial flavours (strawberry, black currant, pineapple, apple, orange, lemon, etc.) in the below mentioned compositions.
  • Ethanol 96% equal parts q.s. q.s. Moist, agent ill Lactose 53 g 51 g Filler
  • lactose and mannitol may be varied from 25 to about 100 g. Dose 100 mg (50-200 mg) corresponds to 2.0 or 4.0 mg desglymidodrine of the two compositions, respectively.
  • II is prepared, and I is dissolved in II. The solution is incorporated in III to a homogeneous mixture is achieved. More II may be added.
  • the moistured mass is spread on a suitable plate equipped with wholes into which the mass is pressed and which have a depth that gives the wanted dose of drug substance.
  • the wet mass is pressed out of the wholes and allowed to dry before further handling. (Sublingual tablet preparation by mould-technique).
  • Ill may be replaced by mixtures of different volatile organic solvents and may have a water content of 0 - 90%.
  • Ill may be replaced by different mixtures of soluble pharmaceutically acceptable excipients as sorbitol, mannitol, xylitol, maltodextrin, lycasin, lactitol etc.
  • Composition Function I Desglymidodrine 2.0 g 4.0 g active ingr. II Tablettose 55.0 g 55.0 g filler III Cellulose, microcryst. Type 102 10.0 g 10.0 g filler/binder
  • I is mixed with II and further with III, IV and V and compressed into tablets.
  • the amount of the filler, tablettose, may vary from 25 to 75 g, the filler/binder (cellulose) may vary from 5 to 25 g, the disintegrant from 1 to 15 g, magnesium stearate from 0.1 to 2.5 g and talc from 1.0 to 10 g.
  • Mass weight of 77 mg corresponds to a dose of 2.0 mg or mass weight of 79 mg corresponds to a dose of 4.0 mg desglymidodrine in the two compositions, respectively.
  • Disintegration time is short (30 sec - 4 min).
  • Tablettose may be replaced by other qualities of lactose with good flowability.
  • Agar may be replaced by other disintergrants as croscarmellose sodium/calcium or the like, crosspovidone, starch glycolate, alginates or other disintegrants.
  • Magnesium stearate may be replaced by other glidants as different types of silica colloidal hydrous or anhydrous, Ca-stearate, stearic acid, sodium stearylfumarate, cotton-seed oil, hydrogenated vegetable oils or other suitable lipid substances as e.g. Myvatex.
  • the amount of maize starch may vary from 5 to 15 g, lactose from 30 to 100 g, mannitol from 10 to 80 g, and magnesium stearate from 0.5 to 5 g.
  • Disintegration time is about 5 min.
  • Maize starch may be replaced by other suitable starches such as rice- or potato starch. Lactose may be replaced by maltodextrine, dextrin etc.
  • Povidone 30 may be replaced by povidone VA 64 or 90 or gelatine or pregelatinized starch or different types of cellulose (methylcellulose, hydroxypropyl cellulose etc.).
  • Mannitol may be replaced by sorbitol, xylitol, maltitol, maltodextrin, lactitol, etc.
  • Magnesum stearate may be replaced by other glidants as different types of colloidal silica hydrous or anhydrous, Ca-stearate, stearic acid, sodium stearylfumarate, cotton-seed oil, hydrogenated vegetable oils or other suitable lipid substances as e.g. Myvatex.
  • Melt-tablets are also referred to as fast/rapidly- disintegrating tablets, dispersing tablets and dissolving tablets. In this example, the term “melt-tablet” is applied.
  • Melt-tablets are a tablet dosage form for oral administration, one that disintegrates instantaneously and releasing the drug, which dissolves or disperse rapidly in saliva and afterwards swallowed without the need for water.
  • the drug substance is absorbed via the gastrointestinal tract.
  • melt-tablets are designed in a way so the drug substance are to be absorbed through the buccal mucosa. In that case the bioavailability of the drug from the melt-tablet may be even greater than observed for standard dosage forms. Further more side-effects may be reduced if they are caused by first-pass metabolites. A description of the variability of the melt-tablets
  • melt-tablets are namely freeze-drying (lyophilisation), spray drying, tablet moulding and direct compression.
  • lyophilisation freeze-drying
  • spray drying spray drying
  • tablet moulding direct compression
  • the total amount of disintegrating agents and/or highly water-soluble excipients can vary between 5-80% (w/v) and the total amount of binding agents can vary between 0.05-5% (w/v).
  • Water is used to ensure the porous structure.
  • Sufficient microbiological preservatives (benzoic acid, methylparaben etc.) may be added to prevent microbiological growth of the aqueous solution during production. When the product has been dried, the preservative has no further function.
  • Taste improving agents may be added to promote salvia secretion. This may include artificial sweeteners (aspartame, cyclamate, saccharin etc.), natural sweeteners (sucrose, sorbitol, xylitol etc.) week organic acids (citric-, ascorbic acid etc.), natural or artificial flavours (strawberry, black currant, pineapple, apple, orange, lemon etc.). Colouring agents may also be added to give the melt-tablets elegance and identity.
  • Permeation enhancers sodium lauryl sulphate etc.
  • pH-adjusting excipients hydroochloride, sodium hydroxide etc.
  • Collapse protecting agents glycine etc.
  • composition Function of ingredient I Desglymidodrine 4.0 g Active
  • the solution is filled in PVC blister with a diameter of 15 mm and a depth of 6 mm, so the resulting dose of Desglymidodrine is 4.0 mg pr. tablet.
  • the blisters are placed on the shelves of the freeze-dryer. Samples are frozen to -45°C at a rate of 0.5°C/min and kept at this temperature for 1.5 hour. Primarily, drying is performed by keeping the blisters for 8 hour at a pressure of 1 mbar, a shelf temperature of -10°C, and a condensor temperature of -60°O
  • excipient II may be replaced by lactose, mannitol, dextrose, xylitol, fructose, sucrose, maltose, sorbitol etc. or mixtures of these.
  • disintegrating agent croscarmellose, crospovidone etc. may be added.
  • Other excipients may also be used instead of III. These excipients may be gelatine, tragacanth gum, agar, acacia, alginate, dextran, povidone, hydroxyethylcellulose etc. or mixtures of these.
  • Rectal solution is a way of drug administration, which can be used independently of the condition of the patient. Furthermore a quite quick onset of effect is seen for some compositions. A major part of the absorbed drug dose does not undergo first pass metabolism, which in some cases may be an advantage.
  • the amount of rectal solution to give one dose is kept on the small amount of 1-4 ml such as, e.g., 2.0 ml. This is to avoid any emptying reflex from the rectum mucosa after applying the solution in the rectum.
  • the solution will be dispensed in a suitable container as a single-dose syringe or sealed plastic tube. Both equipped with a suitable tip.
  • 24.1 A solution with high content of pharmaceutical acceptable organic solvent to promote absorption
  • 24.2 A simple aqueous isotonic solution
  • 24.3 A simple slightly viscous aqueous isotonic
  • 24.4 An aqueous pH-adjusted isotonic solution.
  • composition Function of ingredient
  • Glycerol may be exchanged with glycofurol, polythylene glycols 200 to 600, propylene glycol or similar non-irritant suitable solvent.
  • the amount of glycerol may vary from about 200 to 800 g.
  • composition Function of ingredient
  • the mixture of paraoxibenzoates may be exchanged with other suitable preservatives.
  • composition Function of ingredient
  • the mixture of paraoxibenzoates may be exchanged with other suitable preservatives.
  • the amount of viscosity increasing agent may vary from about 2 to about 8 g.
  • composition Function of ingredient
  • the mixture of parabenzoates may be exchanged by other suitable preservative.
  • Sodium acetate may be exchanged by other suitable pH regulating substance or a buffer mixture with pH in the interval of 7.0 - 8.0.
  • the amount of buffer agent may vary from about 0.5 to about 3.0 g.
  • Oral drops are a dosage form for peroral administration.
  • the formulation allows the patient to use a dose of 5 - 15 drops of the product and, optinally, dilute this dose in water or other better tasting liquids (e.g. orange juice) before ingestion.
  • the amount of oral drops containing one drug dose is kept at the small amount of 5 - 15 drops.
  • the standard volume of drops is normally 10 - 25 ml in a bottle equipped with a suitable tip. This tip is constructed to deliver the drops with a speed suitable for counting the drops as they leave the tip, when the bottle is turned around with the button up. This aggregate has to confirm with Ph. Eur demands.
  • composition Function of ingredient
  • composition Function of ingredient
  • the mixture of paraoxibenzoates may be exchanged with other suitable preservatives.
  • One dose of 2.0 mg is equivalent to approximately 4 drops (have to be measured exactly), this does is normally ingested in 20 - 200 ml water or other drinkable fluid.
  • Oral solution is for peroral administration.
  • the oral solution is in the form of a solution of the drug substance in a suitable and well tasting vehicle.
  • Oral solution is normally given in a volume of 2.0 - 15 ml measured with a suitable device, which is able to give the desired volume with the specified (Ph.Eur.) precision.
  • Oral solution may be taste masked and may be formulated with or without sugar, furthermore viscosity-increasing substance may be added to make to make the handling and administration of the solution easier.
  • Composition Function of ingredient Desglymidodrine 0.400 g 0.800 g Active ingr.
  • Preservative may be added.
  • 0.1 N HCl may be added to adjust pH in the interval 2.5 - 3.5.
  • Composition Function of ingredient Desglymidodrine 0.800 g Active ingr. Black currant juice 240 g Taste masking Sorbitiol 400 g Sweetener
  • 0.1N HCl may be added to adjust pH in the interval 2.5 - 3.5.
  • the concentration of the active ingredient may be changed in the interval of 0.1 to 10 g if needed.
  • Potassium sorbate may be exchanged with other suitable preservatives.
  • Black currant juice may be exchanged with other fruit juices or mixtures of these.
  • Sorbitol may be exchanged with other sweetener as mannitol, xylitol, maltodextrin, lycasin, lactitol etc. or mixtures of these.
  • Levomenthol may be exchanged with other taste masking ingredients: natural or artificial flavours (strawberry, black currant, pineapple, apple, orange, lemon etc. or mixtures of these). Artificial sweeteners (aspartame, cyclamate, saccharin etc) and/or week organic acids
  • Colours may also be added to improve the organoleptic properties.
  • composition Function of ingredient
  • 0.1 N HCl may be added to adjust pH in the interval 2.5 - 3.5.
  • Poloxamer 8000 may be exchanged with other GRAS accepted surfactants.
  • the composition of this example has a high content of taste masking ingredients, which explains the need for a surfactant. Dose 5.0 ml equivalents 4.0 mg desglymidodrine.
  • Solution for infusion is a ready for use solution aimed for infusion in one of the major veins.
  • Solutions for injection may be injected i.v., s.c, i.m. or by any other suitable route.
  • the solution is formulated as simple as possible.
  • the pH may be adjusted in acidic direction and this cause the infusion time have to run over a couple of minutes. In some cases this is done by injection of a desglymidodrine solution for infusion into an already established infusion of glucose or sodium chloride.
  • composition Function of ingredient
  • 0.1 N HCl at pH 2.5 - 3.5 may be added.
  • the solution may also be presented in vials or the form of a unit dose e.g. in ampoules.
  • Transdermal drug delivery systems are designed to deliver a drug substance through the skin for systemic circulation and effect.
  • a transdermal drug delivery system can be designed to deliver a drug substancento the skin at a given rate.
  • Transdermal drug delivery systems can be prepared in different ways; Drug substance in an adhesive type of delivery system, a drug substance in a matrix type of delivery system or in a reservoir type of delivery system, or by a combining the different types of preparation techniques.
  • the three types of delivery systems offer different ways in controlling the release of drug from the delivery system into the skin. The formulation principle of the three different systems are described in the following:
  • the backing is a filmforming polymer e.g. containing ethylcellulose, plastic and/or alufoil or other impermeable material.
  • Adhesive layer may contain an adhesive, pressure sensitive polymer layer, e.g. polyacrylate, ethylcellulose or silicone.
  • An enhancer like e.g. lauric acid, dioctylcyclohexane, glycerin, n- dodecanol, Eutanol G, isopropylmyristat, PEG 400, propandiol and/or Tween 80 may be added.
  • the drug substance can be dissolved or dispersed in the adhesive layer e.g. by a solvent casting or hot melt process.
  • the drug substance can be incorporated in the adhesive layer as microreservoirs.
  • a protective liner to be removed before use, is attached to the adhesive side.
  • the backing is a filmforming polymer e.g. containing ethylcellulose, plastic and/or alufoil or other impermeable material.
  • the matrix may contain a hydrophilic or lipophilic polymer matrix comprising e.g. polyisobutylene.
  • An enhancer like; lauric acid, dioctylcyclohexane, glycerin, n-dodecanol, Eutanol G, isopropylmeristat, PEG 400, propandiol or Tween 80 may be added.
  • Drug The drug substance is dispersed in the matrix layer or it may be incorporated in the matrix by a moulding process or be incorporated in the layer as microreservoirs.
  • Membrane A rate controlling membrane e.g. of polymeric material might be used to control the diffusion of the drug into the skin.
  • An adhesive layer might be applied on the membrane. The membrane might be omitted.
  • Adhesive layer may contain an adhesive, pressure sensitive polymer layer, e.g. polyacrylate, ethylcellulose or silicone.
  • the adhesive is applied on the rim of the patch, surrounding the matrix-containing drug.
  • a protective liner to be removed before use, is attached to the adhesive side.
  • the backing is a filmforming polymer e.g. containing ethylcellulose, plastic and/or alufoil or other impermeable material.
  • the reservoir may contain e.g. an unleachable, viscous liquid medium (e.g. silicone fluid) or a releasable solvent (e.g. alkyl alcohol or glycerol)
  • an unleachable, viscous liquid medium e.g. silicone fluid
  • a releasable solvent e.g. alkyl alcohol or glycerol

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Dispersion Chemistry (AREA)
  • Physiology (AREA)
  • Nutrition Science (AREA)
  • Zoology (AREA)
  • Emergency Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouvelles compositions pharmaceutiques comprenant du desglymidodrine ou un sel pharmaceutiquement acceptable de celui-ci en tant que substance médicamenteuse active. Le desglymidodrine est un métabolite actif du promédicament midodrine. La composition pharmaceutique peut se présenter selon une posologie acceptable pour l'administration orale, parentérale, mucosale, nasale, sublinguale, buccale, topique, vaginale, rectale, oculaire, etc. Une composition pharmaceutique de l'invention peut avoir la forme d'une composition à libération immédiate et/ou modifiée ou être destinée à libérer la substance médicamenteuse active, le desglymidodrine, de façon relativement rapide afin de permettre à l'effet thérapeutique de se manifester assez rapidement. Les compositions ont une durée de conservation appropriée, c'est-à-dire que le desglymidodrine contenu dans la composition n'est pas sujet à une dégradation sensible lors du stockage dans des conditions normalement acceptables pour les produits pharmaceutiques. L'invention concerne aussi un procédé pour traiter des animaux tels que les mammifères et les humains avec une nouvelle composition pharmaceutique comprenant du desglymidodrine. Elle concerne aussi un nouveau procédé d'utilisation du desglymidodrine dans le traitement du choc septique et un procédé pour traiter des mammifères (tels que les humains) souffrant du choc septique avec une quantité suffisante de desglymidodrine.
EP01933651A 2000-05-26 2001-05-23 Compositions pharmaceutiques comprenant du desglymidodrine en tant que substance medicamenteuse active Withdrawn EP1289493A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DKPA200000841 2000-05-26
DK200000841 2000-05-26
US09/823,093 US6761904B2 (en) 2000-03-31 2001-03-29 Pharmaceutical kit comprising midodrine as active drug substance
WOPCT/DK01/00214 2001-03-29
US823093 2001-03-29
PCT/DK2001/000214 WO2001074335A1 (fr) 2000-03-31 2001-03-29 Composition pharmaceutique contenant de la midodrine comme substance medicamenteuse active
PCT/DK2001/000362 WO2001089473A1 (fr) 2000-05-26 2001-05-23 Compositions pharmaceutiques comprenant du desglymidodrine en tant que substance medicamenteuse active

Publications (1)

Publication Number Publication Date
EP1289493A1 true EP1289493A1 (fr) 2003-03-12

Family

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Application Number Title Priority Date Filing Date
EP01933651A Withdrawn EP1289493A1 (fr) 2000-05-26 2001-05-23 Compositions pharmaceutiques comprenant du desglymidodrine en tant que substance medicamenteuse active

Country Status (4)

Country Link
EP (1) EP1289493A1 (fr)
AU (1) AU2001260089A1 (fr)
CA (1) CA2409950A1 (fr)
WO (1) WO2001089473A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1318674B1 (it) * 2000-08-08 2003-08-27 Nicox Sa Faramaci per l'incontinenza.
JP2003300873A (ja) * 2002-04-12 2003-10-21 Nitto Denko Corp 貼付剤およびその製造方法
US8157788B2 (en) * 2003-11-06 2012-04-17 Paolo L. Manfredi Multi-site drug delivery platform
CA2936748C (fr) 2014-10-31 2017-08-08 Purdue Pharma Methodes et compositions destinees au traitement du trouble de deficit d'attention
JP7364568B2 (ja) * 2017-12-22 2023-10-18 ゼナメッド コーポレーション 持続放出ミドドリン塩酸塩組成物及び使用方法
US10722473B2 (en) 2018-11-19 2020-07-28 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
WO2020176807A1 (fr) 2019-02-27 2020-09-03 Vanderbilt University Méthodes de traitement de la douleur du nerf trijumeau
WO2021198995A1 (fr) * 2020-04-02 2021-10-07 Cadila Healthcare Limited Solutions parentérales aqueuses stables de desglymidodrine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074334A1 (fr) * 2000-03-31 2001-10-11 Nycomed Austria Gmbh Composition pharmaceutique a liberation controlee a base de midodrine et/ou desglymidodrine

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
US5610174A (en) * 1995-06-02 1997-03-11 Synaptic Pharmaceutical Corporation Use of α1A -selective adrenoceptor agonists for the treatment of urinary incontinence

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074334A1 (fr) * 2000-03-31 2001-10-11 Nycomed Austria Gmbh Composition pharmaceutique a liberation controlee a base de midodrine et/ou desglymidodrine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0189473A1 *

Also Published As

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CA2409950A1 (fr) 2001-11-29
WO2001089473A1 (fr) 2001-11-29

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