WO2008008024A9 - Formes polymorphes de chlorhydrate de spirapril - Google Patents

Formes polymorphes de chlorhydrate de spirapril

Info

Publication number
WO2008008024A9
WO2008008024A9 PCT/GB2007/002653 GB2007002653W WO2008008024A9 WO 2008008024 A9 WO2008008024 A9 WO 2008008024A9 GB 2007002653 W GB2007002653 W GB 2007002653W WO 2008008024 A9 WO2008008024 A9 WO 2008008024A9
Authority
WO
WIPO (PCT)
Prior art keywords
ray powder
powder diffractogram
spirapril hydrochloride
polymorph
spirapril
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.)
Ceased
Application number
PCT/GB2007/002653
Other languages
English (en)
Other versions
WO2008008024A2 (fr
WO2008008024A3 (fr
Inventor
Aleksandar Danilovski
Maja Devcic
Marina Marinkovic
Ernest Mestrovic
Tina Mundofer
Petar Tudja
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.)
Pliva Hrvatska doo
Pliva Istrazivanje i Razvoj doo
Original Assignee
Pliva Hrvatska doo
Pliva Istrazivanje i Razvoj doo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pliva Hrvatska doo, Pliva Istrazivanje i Razvoj doo filed Critical Pliva Hrvatska doo
Priority to EP07848377A priority Critical patent/EP2069360A2/fr
Publication of WO2008008024A2 publication Critical patent/WO2008008024A2/fr
Publication of WO2008008024A9 publication Critical patent/WO2008008024A9/fr
Publication of WO2008008024A3 publication Critical patent/WO2008008024A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention is concerned with new polymorphic forms of spirapril hydrochloride, processes for preparing the new polymorphic forms, pharmaceutical compositions containing them, therapeutic uses thereof and methods of treatment employing them.
  • Spirapril hydrochloride is chemically designated [8S-[7[R*(R*)],8R*]]-7-[2-[[l-[ethoxycarbonyl]-3- phenylpropyl]ammo]-l-oxo ⁇ ropyl]-l,4-dithia-7-azaspiro[4,4]nonane-8-carboxylate hydrochloride and can be represented by the following structural formula:
  • Spirapril hydrochloride is a non-sulphydryl angiotensin converting enzyme (ACE) inhibitor prodrug which is converted to the active diacid metabolite, spiraprilat, following administration. It may be used in the treatment and prevention of cardiovascular disorders including hypertension, congestive heart failure and left ventricular dysfunction. It may also be used in the treatment and prevention of nephropathy in diabetes mellitus.
  • ACE angiotensin converting enzyme
  • Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapour pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture a drug substance and a drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of a drug product.
  • Polymorphic forms as referred to herein can include crystalline and amorphous forms as well as solvate and hydrate forms, which can be further characterised as follows:
  • Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice.
  • Solvates are crystal forms containing either stoichiometric or non-stoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate.
  • Drug substance polymorphic forms can exhibit different chemical, physical and mechanical properties as referred to above, including aqueous solubility and dissolution rate, hygroscopicity, particle shape, density, flowability, and cornpactibility, which in turn may affect processing of the drug substance and/or manufacturing of the drug product.
  • Polymorphs can also exhibit different stabilities. The most stable polymorphic form of a drug substance is often chosen during drug development based on the minimal potential for conversion to another polymorphic form and on its greater chemical stability. However, a meta-stable form can alternatively be chosen for various reasons, including better bioavailability.
  • polymorphic forms of the pharmaceutically acceptable salt of spirapril, spirapril hydrochloride with advantageous properties.
  • the advantages are selected from, depending upon the form selected, increased physical stability, improved dissolution, improved morphology, improved properties when formulated and improved properties during storage.
  • anhydrous spirapril hydrochloride and polymorphic forms I, II, III, IV and V of spirapril hydrochloride are provided by the present invention.
  • the crystalline structure of anhydrous spirapril hydrochloride according to the present invention is characterised as having an X-ray powder diffractogram, or substantially the same X-ray powder diffractogram, as is shown in Figure 1.
  • Anhydrous spirapril hydrochloride according to the present invention is further characterised as having characteristic peaks (2 ⁇ ) selected from one or more of the following: 8.1+0.2°, 9.7+0.2°, 14.2 ⁇ 0.2°, 16.3 ⁇ 0.2°, 18.4+0.2° and 19.3 ⁇ 0.2°. Further peaks (2 ⁇ ) associated with anhydrous spirapril hydrochloride according to the present invention are selected from one or more of the following: 15.4 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.4 ⁇ 0.2°, 23.0 ⁇ 0.2° and 26.9+0.2°.
  • the properties of the crystalline structure of anhydrous spirapril hydrochloride, according to the present invention may be summarised as follows:
  • the crystalline structure of polymorph I of spirapril hydrochloride according to the present invention is characterised as having an X-ray powder diffractogram, or substantially the same X-ray powder diffractogram, as is shown in Figure 2.
  • Polymorph I of spirapril hydrochloride according to the present invention is further characterised as having characteristic X-ray powder diffractogram peaks (2 ⁇ ) selected from one or more of the following: 6.5+0.2°, 8.1 ⁇ 0.2°, 16.2+0.2°, 20.4 ⁇ 0.2°, 24.3 ⁇ 0.2°. Further characterising X-ray powder diffractogram peaks (2 ⁇ ) associated with polymorph I of spirapril hydrochloride according to the present invention are selected from one or more of the following: 9.3+0.2°, 13.2+0.2°, 17.4+0.2°, 19.3+0.2° and 26.5 ⁇ 0.2°.
  • the crystalline structure of polymorph II of spirapril hydrochloride according to the present invention is characterised as having an X-ray powder diffractogram, or substantially the same X-ray powder diffractogram, as is shown in Figure 3.
  • Polymorph II of spirapril hydrochloride according to the present invention is further characterised as having characteristic X-ray powder diffractogram peaks (2 ⁇ ) selected from one or more of the following: 7.6 ⁇ 0.2°, 8.6 ⁇ 0.2°, 9.4 ⁇ 0.2°, 14.1 ⁇ 0.2°, 16.4 ⁇ 0.2° and 17.3 ⁇ 0.2°. Further characterizing X-ray powder diffractogram peaks (2 ⁇ ) associated with polymorph II of spirapril hydrochloride according to the present invention are selected from one or more of the following: 12.5+0.2°, 19.2+0.2°, 20.2 ⁇ 0.2°, 23.8 ⁇ 0.2° and 29.7 ⁇ 0.2°.
  • polymorph III of spirapril hydrochloride according to the present invention is characterised as having an X-ray powder diffractogram, or substantially the same X-ray powder diffractogram, as is shown in Figure 4.
  • Polymorph III of spirapril hydrochloride according to the present invention is further characterised as having characteristic X-ray powder diffractogram peaks (2 ⁇ ) selected from one or more of the following: 6.2 ⁇ 0.2°, 7.6+0.2°, 14.1 ⁇ 0.2°, 16.4 ⁇ 0.2° and 17.3 ⁇ 0.2°.
  • X-ray powder diffractogram peaks (2 ⁇ ) associated with polymorph III of spirapril hydrochloride according to the present invention are selected from one or more of the following: 10.2+0.2°, 12.5+0.2°, 19.2+0.2°, 20.3+0.2°, 23.8 ⁇ 0.2° and 24.2+0.2°.
  • the crystalline structure of polymorph IV of spirapril hydrochloride according to the present invention is characterised as having an X-ray powder diffractogram, or substantially the same X-ray powder diffractogram, as is shown in Figure 5.
  • Polymorph IV of spirapril hydrochloride according to the present invention is further characterised as having characteristic X-ray powder diffractogram peaks (2 ⁇ ): 7.6 ⁇ 0.2°, 8.1 ⁇ 0.2°, 14.1+0.2°, 16.4+0.2° and 17.4+0.2°. Further characterising X-ray powder diffractogram peaks (2 ⁇ ) associated with polymorph IV of spirapril hydrochloride according to the present invention are selected from one or more of the following: 5.7 ⁇ 0.2°, 12.5 ⁇ 0.2°, 13.3 ⁇ 0.2°, 19.3 ⁇ 0.2° and 20.4+0.2°.
  • the crystalline structure of polymorph V of spirapril hydrochloride according to the present invention is characterised as having an X-ray powder diffractogram, or substantially the same X-ray powder diffractogram, as is shown in Figure 6.
  • Polymorph V of spirapril hydrochloride according to the present invention is further characterised as having characteristic X-ray powder diffractogram peaks (2 ⁇ ) selected from one or more of the following: 7.1 ⁇ 0.2°, 10.2 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.8+0.2° and 22.3 ⁇ 0.2°. Further characterising X-ray powder diffractogram peaks (2 ⁇ ) associated with polymorph V of spirapril hydrochloride according to the present invention are selected from one or more of the following: 7.6+0.2°, 8.6+0.2°, 9.3+0.2°, 13.6+0.2° and 17.2 ⁇ 0.2°.
  • a polymorphic form of spirapril hydrochloride substantially as hereinbefore described is formed by solvent crystallisation.
  • the process can comprise dissolving spirapril hydrochloride in a suitable solvent, such as for example dioxane, anhydrous dioxane, acetonitrile, 1,2-propylene carbonate or the like, or mixtures thereof, and allowing crystals of the polymorphic form to form.
  • a suitable solvent such as for example dioxane, anhydrous dioxane, acetonitrile, 1,2-propylene carbonate or the like, or mixtures thereof, and allowing crystals of the polymorphic form to form.
  • an anti-solvent is added to a solution to decrease its solubility for a particular compound, thus resulting in precipitation.
  • Anti-solvents may include, for example, n-amyl acetate, anhydrous octane, anhydrous benzene, anhydrous tert-butylmethyl ether or anhydrous tetrachloromethane or mixtures thereof.
  • a polymorphic form of spirapril hydrochloride substantially as hereinbefore described is prepared by the following steps:
  • Polymorphic forms of spirapril hydrochloride are angiotensin converting enzyme (ACE) inhibitor prodrugs. They are thus useful in the treatment and prevention of cardiovascular disorders including hypertension, congestive heart failure and left ventricular dysfunction. They may also be used in the treatment and prevention of nephropathy in diabetes mellitus.
  • ACE angiotensin converting enzyme
  • the present invention further provides, therefore, pharmaceutical compositions comprising a therapeutically effective dose of a polymorphic form of spirapril hydrochloride according to the invention, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
  • Excipients are chosen according to the pharmaceutical form and the desired mode of administration.
  • terapéuticaally effective amount means an amount of a polymorphic form of spirapril hydrochloride according to the invention, which is capable of preventing, ameliorating or eliminating a disease state for which administration of an angiotensin converting enzyme (ACE) inhibitor is indicated.
  • ACE angiotensin converting enzyme
  • pharmaceutically acceptable it is meant that the carrier, diluent or excipient is compatible with a polymorphic form of spirapril hydrochloride according to the invention, and not deleterious to a recipient thereof.
  • a polymorphic form of spirapril hydrochloride according to the present invention is administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
  • the appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
  • a polymorphic form of spirapril hydrochloride according to the present invention can be used in creams, ointments or lotions. Oral administration is preferred.
  • the dose of a polymorphic form of spirapril hydrochloride according to the present invention can vary between 0.01 and 50 mg per kg of body weight per day.
  • Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of a polymorphic form of spirapril hydrochloride according to the present invention in combination with a pharmaceutical carrier.
  • This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.
  • a polymorphic form of spirapril hydrochloride according to the present invention is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
  • a preparation in the form of gelatin capsules can be obtained by mixing a polymorphic form of spirapril hydrochloride according to the present invention with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
  • a preparation in the form of a syrup or elixir or for administration in the form of drops can contain a polymorphic form of spirapril hydrochloride according to the present invention typically in conjunction with a sweetener, which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate color.
  • a sweetener which is preferably calorie-free
  • optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate color.
  • Water-dispersible granules or powders can contain a polymorphic form of spirapril hydrochloride according to the present invention mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
  • Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example polyethylene glycols.
  • Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
  • pharmacologically compatible dispersants and/or wetting agents for example propylene glycol or butylene glycol.
  • a polymorphic form of spirapril hydrochloride according to the present invention can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
  • the present invention further provides a polymorphic form of spirapril hydrochloride substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of an angiotensin converting enzyme (ACE) inhibitor. More specifically, the present invention provides a polymorphic form of spirapril hydrochloride, substantially as hereinbefore described, for use in the manufacture of a medicament for treating and preventing a number of disorders including cardiovascular disorders, such as hypertension, congestive heart failure and left ventricular dysfunction, and nephropathy in diabetes mellitus.
  • cardiovascular disorders such as hypertension, congestive heart failure and left ventricular dysfunction, and nephropathy in diabetes mellitus.
  • the present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of an angiotensin converting enzyme (ACE) inhibitor to a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a polymorphic form of spirapril hydrochloride, substantially as hereinbefore described. More specifically, the present invention provides a method of treating a number of disorders, including cardiovascular disorders, including hypertension, congestive heart failure and left ventricular dysfunction, and nephropathy in diabetes mellitus in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a polymorphic form of spirapril hydrochloride, substantially as hereinbefore described.
  • ACE angiotensin converting enzyme
  • the present invention also provides a corresponding method of treatment, which comprises administering to a patient a therapeutically effective amount of a polymorphic form of spirapril hydrochloride, substantially as hereinbefore described, so that the administered polymorphic form of spirapril hydrochloride according to the present invention, provides an enhanced therapeutic effect to the patient, compared to the therapeutic effect provided by corresponding administration of the existing forms of spirapril hydrochloride.
  • the present invention can be further illustrated by the following Figures and non-limiting Examples.
  • Figure 2 X-ray powder diffractogram of spirapril hydrochloride polymorph I according to the present invention obtained by using a Philips X'Pert PRO with CuKa radiation in 2 ⁇ - 3-40 ° range.
  • Figure 3 X-ray powder diffractogram of spirapril hydrochloride polymorph II according to the present invention obtained by using a Philips X'Pert PRO with CuKa radiation in 2 ⁇ — 3-40 ° range.
  • Figure 4 X-ray powder diffractogram of spirapril hydrochloride polymorph III according to the present invention obtained by using a Philips X'Pert PRO with CuKa radiation in 2 ⁇ - 3-40 ° range.
  • the single crystal study was performed using a Bruker Nonius FR591 /Kappa CCD diffractometer with CuKa radiation at temperature of 293(3 )K.
  • spirapril hydrochloride monohydrate 50 mg was dissolved in 3 mL of acetonitrile whilst heating. Molecular sieves were added in order to remove excess water and these were then removed by filtration. The solution was refrigerated allowing crystallisation to occur. Crystals suitable for single X-ray diffraction were obtained. These were filtered and washed with acetonitrile.
  • spirapril hydrochloride monohydrate 50 mg was dissolved in 3 mL of 1,2-propylene carbonate. Molecular sieves were added in order to remove excess water and these were then removed by filtration. Crystallisation occurred at room temperature. The product was filtered and washed with 1,2-propylene carbonate yielding 11 mg of white crystalline product.
  • spirapril hydrochloride form III 50 mg of spirapril hydrochloride monohydrate was dissolved in 3 mL of anhydrous dioxane whilst heating. 5 mL of anhydrous benzene was added dropwise resulting in the precipitation of a product, which was collected by filtration yielding 44 mg of a white crystalline product.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouvelles formes polymorphes de chlorhydrate de spirapril, des procédés de préparation de ces nouvelles formes polymorphes, des compositions pharmaceutiques contenant ces nouvelles formes polymorphes, l'utilisation thérapeutique de celles-ci ainsi que des méthodes de traitement les faisant intervenir.
PCT/GB2007/002653 2006-07-13 2007-07-13 Formes polymorphes de chlorhydrate de spirapril Ceased WO2008008024A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07848377A EP2069360A2 (fr) 2006-07-13 2007-07-13 Formes polymorphes de chlorhydrate de spirapril

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0613927.3 2006-07-13
GBGB0613927.3A GB0613927D0 (en) 2006-07-13 2006-07-13 Pharmaceutically acceptable salt and polymorphic forms

Publications (3)

Publication Number Publication Date
WO2008008024A2 WO2008008024A2 (fr) 2008-01-17
WO2008008024A9 true WO2008008024A9 (fr) 2008-03-13
WO2008008024A3 WO2008008024A3 (fr) 2009-02-12

Family

ID=36955585

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2007/002653 Ceased WO2008008024A2 (fr) 2006-07-13 2007-07-13 Formes polymorphes de chlorhydrate de spirapril

Country Status (4)

Country Link
EP (1) EP2069360A2 (fr)
DE (2) DE202007019054U1 (fr)
GB (1) GB0613927D0 (fr)
WO (1) WO2008008024A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4470972A (en) 1981-04-28 1984-09-11 Schering Corporation 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids
US4847384A (en) * 1987-03-12 1989-07-11 Sandoz Pharm. Corp. Process for the preparation of certain nitrogen-containing mono- and bicyclic ace inhibitors, and novel intermediates useful therefor
US5403593A (en) 1991-03-04 1995-04-04 Sandoz Ltd. Melt granulated compositions for preparing sustained release dosage forms

Also Published As

Publication number Publication date
DE102007032613A1 (de) 2008-01-24
EP2069360A2 (fr) 2009-06-17
GB0613927D0 (en) 2006-08-23
WO2008008024A2 (fr) 2008-01-17
DE202007019054U1 (de) 2010-05-12
WO2008008024A3 (fr) 2009-02-12

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