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WO2003026653A1 - Composition pharmaceutique comprenant une metformine et un chlorure de n-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxyde-3-carboxymidoyle - Google Patents

Composition pharmaceutique comprenant une metformine et un chlorure de n-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxyde-3-carboxymidoyle Download PDF

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Publication number
WO2003026653A1
WO2003026653A1 PCT/HU2002/000098 HU0200098W WO03026653A1 WO 2003026653 A1 WO2003026653 A1 WO 2003026653A1 HU 0200098 W HU0200098 W HU 0200098W WO 03026653 A1 WO03026653 A1 WO 03026653A1
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WO
WIPO (PCT)
Prior art keywords
metformin
propoxy
pyridine
piperidinyl
hydroxy
Prior art date
Application number
PCT/HU2002/000098
Other languages
English (en)
Inventor
Katalin BÍRÓ
Mária KÜRTHY
Andrea JEDNÁKOVITS
Tamás MOGYORÓSI
István MÁTYÁS
László ÜRÖGDI
Zita JEGESNÉ CSÁKAI
Tímea RÁCZ
Original Assignee
Biorex Kutató És Fejlesztö Rt.
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 Biorex Kutató És Fejlesztö Rt. filed Critical Biorex Kutató És Fejlesztö Rt.
Publication of WO2003026653A1 publication Critical patent/WO2003026653A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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

Definitions

  • the invention relates to pharmaceutical compositions containing a combination of metformin and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1- oxide-3-carboximidoyl chloride as active agent.
  • the composition of the invention can be used in the therapy of the diabetes mellitus, especially in the therapy of type II (non-insulin dependent, NIDD ) diabetes mellitus and its complications, especially in the therapy of diabetic neuropathy.
  • NIDD non-insulin dependent
  • Metformin i.e. 1,1-dimethyl-biguanidin (N,N-dimethylimido-dicarbonimidic diamide) is long since known and widely used biguanidin type antihyperglyce- mic agent.
  • compositions containing metformin alone are known from WO 97/02843, a combination of metformin and glibenclamide, a sulfonylurea type antihyperglycemic agent is known from WO 97/17975 and WO 00/03742, combinations of metformin and thiazolidine-dione derivatives are known from WO 98/57634.
  • the sulfonylurea derivatives stimulate the insulin secretion and thus complete the effect of metformin
  • the thiazolidine-dione derivatives which are insulin sensitizers strengthen the effect of metformin.
  • Metformin and nateglinide a phenylalanine derivative /N- ⁇ [trans-4-(1- methylethyl)-cyclohexyl]-carbonyl ⁇ -D-phenylalanine) are applied simultaneously in order to hinder the postprandial increase of blood glucose level by nateglinide and thereby reduce the mealtime glucose excursion (Diabetes Care Vol. 23, No 3, March 2000 and Diabetes Care Vol. 23, No 11 , November 2000).
  • compositions of combined active agents mentioned above are insufficient to reduce the blood glucose level at a substantial extent, which results in need of regular administration of insulin after a period of transition as the ill- ness progresses.
  • An other disadvantage of combined compositions containing metformin and a sulfonylurea type active agent is that they are not safe as to the exclusion of occurence of hypoglycemia.
  • compositions containing combinations of metformin with a fibrate, especially fenofibrate or bezafibrate are known from WO 99/40904. Due to the combination of the active ingredients the cholesterol level and the trigliceride level can also be reduced by the treatment besides the reduction of blood glucose, the reduction of the blood glucose, however, does not attain the desired extent.
  • metformin should be administered in controlled quantities due to risk factors (lactic acidosis) and unfavorable side effects, mainly certain gastrointestinal problems.
  • risk factors lactic acidosis
  • unfavorable side effects mainly certain gastrointestinal problems.
  • decreasing the relative amount of metformin is desirable in pharmaceutical compositions containing metformin in combinations.
  • Such an endavour appears from WO 97/17975 mentioned above.
  • a combination of active agents which provides a stronger reduction of blood glucose level, makes possible the decrease of the amount of metformin administered and has the slightest possible side effect. Disclosure of the invention
  • the invention provides a new pharmaceutical composition which is orally applicable in the treatment of diabetes mellitus which comprises a combination of metformin (N,N-dimethylimido-dicarbonimidic diamide) or an acid addition salt thereof and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3- carboximidoyl chloride or a stereoisomer thereof or an acid addition salt of the racemic or the optically active form thereof as active ingredient, if necessary, together with pharmaceutically acceptable carriers and optionally auxiliary materials.
  • metformin N,N-dimethylimido-dicarbonimidic diamide
  • the invention provides an orally applicable pharmaceutical composition for the treatment of diabetic neuropathy which comprises as active principle a combination of metformin (N,N-dimethylimido- dicarbonimidic diamide) or an acid addition salt thereof and N-[2-hydroxy-3-(1- piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride or a stereoisomer thereof or an acid addition salt of the racemic or the optically active form thereof.
  • metformin N,N-dimethylimido- dicarbonimidic diamide
  • metformin is preferably present in the composition as an acid addition salt formed with a mineral or organic acid such as hydrochloric, hydrobromic, acetic, lactic, oxalic, maleic, malonic, succinic, fumaric, citric, methanesulfonic and p-toluenesulfonic acid, where the hydro- chloride and the fumarate are preferred.
  • a mineral or organic acid such as hydrochloric, hydrobromic, acetic, lactic, oxalic, maleic, malonic, succinic, fumaric, citric, methanesulfonic and p-toluenesulfonic acid, where the hydro- chloride and the fumarate are preferred.
  • the N-[2-hydroxy-3-(1- piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride is preferably present in the composition of the invention in the form of an acid addition salt formed with a mineral or organic acid, such as hydrochloric, hydrobromic, maleic, fumaric, p-toluenesulfonic, methanesulfonic, citric and tartaric acid, preferably in the form of hydrochloride, citrate or maleate.
  • a mineral or organic acid such as hydrochloric, hydrobromic, maleic, fumaric, p-toluenesulfonic, methanesulfonic, citric and tartaric acid, preferably in the form of hydrochloride, citrate or maleate.
  • an optically active enantiomer of the N-[2-hydroxy-3-(1- piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride is present in the composition of the invention.
  • the most preferred composition contains an acid addition salt of metformin and (+)-R-N-[2-hydroxy- 3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate as active ingredients.
  • the weight ratio of metformin to the N-[2-hydroxy-3-(1-piperidinyl)- propoxy]-pyridine-1-oxide-3-carboximidoyl chloride varies preferably between 5:1 and 100:1.
  • the preferable weight ratio of metformin to N-[2-hydroxy-3-(1-piperidinyl)-propoxy]- pyridine-1-oxide-3-carboximidoyl chloride ranges from 10:1 to 50:1.
  • compositions for use in the treatment of diabetic neuropathy a weight ratio of metformin to N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride ranging from 25:1 to 75:1 is preferable.
  • the pharmaceutical composition of the invention is prepared by mixing the two active principles and vehicles and optionally auxiliary materials usually applied in the pharmaceutical industry in a conventional way.
  • the compositions of the invention are formulated for oral application into tablets, coated tablets, dragees, granulates, capsules, solutions or syrups.
  • the solid forms of the composition can contain fillers, such as microcrystalline cellulose, starch and lactose, lubricants, such as stearic acid and magnesium stearate, coating materi- als, such as sugar, film forming materials, such as hydroxymethyl cellulose or hydroxypropyl methyl cellulose as well as conventional flavours and colors.
  • the capsule formulations can be prepared with use of hard or soft gelatin capsules.
  • the pharmaceutical compositions of the invention are prepared in unit dosage forms for administering two or three times per day.
  • the daily dose of metformin is preferably 1000-2000 mg, that of N-[2-hydroxy-3-(1- piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride is preferably 2- 100 mg, the exact dose depending on the weight and age and the condition of the patient. These amounts are calculated for the base form of the active principles.
  • One unit dosage form contains the corresponding amounts of active agents, the metformin preferably as an acid addition salt thereof and the N-[2- hydroxy-3-(1 -piperidinyl)-propoxy]-pyridine-1 -oxide-3-carboximidoyl chloride preferably in the form of an acid addition salt of an optically active enantiomer thereof.
  • the invention also relates to a method of treatment of diabetes mellitus comprising the administration of a combination of metformin (N,N- dimethylimido-dicarbonimidic diamide) or an acid addition salt thereof and N-[2- hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride or a stereoisomer thereof or an acid addition salt of the racemic or the optically active form thereof to the patient.
  • metformin N,N- dimethylimido-dicarbonimidic diamide
  • the invention provides a method of treatment of diabetic neuropathy comprising the administration of a combination of metformin (N,N- dimethylimido-dicarbonimidic diamide) or an acid addition salt thereof and N-[2- hydroxy-3-(1 -piperidinyl)-propoxy]-pyridine-1 -oxide-3-carboximidoyl chloride or a stereoisomer thereof or an acid addition salt of the racemic or the optically active form thereof to the patient.
  • metformin N,N- dimethylimido-dicarbonimidic diamide
  • mice Groups of male Wistar rats of 300-350 g body weight, at least 6 animals in each group were used in the experiments. The animals fasting at least 14 hours were treated intravenously with 40 mg/kg streptozotocin (STZ) freshly dissolved in physiological saline in order to induce diabetes. The concentration of the stock solution was 40 mg/ml and the applied amount was 0,1 ml/100g.
  • STZ streptozotocin
  • the animals were placed in rat stocks after a period of 24 hours following the STZ treatment. 1-1,5 mm of tips of tails were cut by scissors and at least 200 ⁇ l blood samples were taken into Eppendorf tubes. The blood samples were centrifuged at 2500 rpm while cooling (4 °C). In the obtained sera the blood glucose levels were measured by Vitros 250 automatic analyzer. Animals having a nonfasted serum glucose level over 15 mmol/liter were considered diabetic.
  • N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride (referred to as compound A in the followings) was applied orally in 12 mg/kg doses (calculated for the base).
  • Metformin was applied in 250 mg/kg p. o. doses.
  • One group of animals was treated with compound A alone, other groups were treated with metformin and a combination of metformin and compound A, respectively, for 1 month after the time of demonstrating that diabetes had been developed.
  • At the end of period of treatment 0,5 ml blood was taken gently from the conscious animals fasting at least 14 hours, sera were obtained in the way described above and blood glucose levels were measured with automatic analyzer. The results of the determination are shown in Table 1.
  • the obtained data are expressed in mean ⁇ SE form.
  • the table contains the values of Student's impaired batht" test obtained when comparing the individual groups.
  • Goto Kakizaki (GK) inbred rat strain is selectively bred from normal out- bred Wistar rats for high glucose levels. It is a widely accepted animal model for research in type II diabetes mellitus. (Motoy Koyama et al: American Journal of Pathology 153 (2) 537-545, 1988; Metabolism 49 (3) 347-352, 2000).
  • MNCV muscle motor
  • SNCV sensory nerve conduction velocities
  • FR polysynaptic nociceptive flexor reflex
  • Evoked electromyograms are amplified (Iso-Dam Isolated Biological Amplifier, WPI, World Precision Instruments, Inc. U.S.A.), averaged and stored (IBM compatible PC) to analyse the curves by experimentor blind to the treatment identity.
  • ER extensor reflex
  • the sciatic and tibial nerves of the left hind limb are electrically stimulated (square wave impulses of supramaximal intensity and 0.03 ms width) at sciatic notch or ankle, respectively (SOP No: PRE NP 022, 2002). After recording of responses the distance between the two stimulation points are measured.
  • Each EMG consists of two components: 1/ the short-latency direct motor response (M) evoked by stimulation of A- ⁇ motor fibres and 2/ the mono- synaptically elicited Hoffmann reflex response (H) due to activation of propriocep- tive afferents. Latency of both the M- and H- components of EMG, taken from plantar muscles, are measured for calculation of MNCV and SNCV.
  • EMG responses are analysed by means of Matlab software (The MathWorks, Inc., Natick, Mass., USA).
  • NCVs and FR-EMG areas are expressed as means ⁇ SE, with significance set at p ⁇ 0.05.
  • One way ANOVA (with Tukey- Kramer multiple comparisons test) is used for parametric values, and Kruskal- Wallis nonparametric ANOVA test (with Dunn's multiple comparisons test) is carried out for comparison of nonparametric values.
  • Reduction (deficit) in NCVs, due to neuropathy, and their recovery (improvement) caused by treatments, are presented in percentage. At least 7 animals were in each group.
  • Metformin hydrochloride (+)-R-N-[2-hydroxy-3-(1 -piperidinyl)-propoxy]- pyridine-1-oxide-3-carboximidoyl chloride citrate, around a half of microcrystal- line cellulose and croscarmellose sodium are blended in a planetary mixer.
  • An aqueous solution of polyvinyl pyrrolidone is added and the mixture is wet granulated.
  • the granules are dried at 60 °C, sieved and introduceed into a cone blender.
  • Magnesium stearate and the remaining portion of microcrystalline cellulose are added and the mixture is homogenized.
  • the mix is filled in a tablet press and formed into tablets.
  • Capsulated medicine is prepared with the following composition: metformin hydrochloride 250 mg
  • the active principles, the fillers and the auxiliaries are blended in a planetary mixer and the mixture is wet granulated with water.
  • the granules are dried at 60 °C and sieved.
  • the granules are filled into hard gelatine capsules.
  • Coated tablets are prepared with the following composition: metformin hydrochloride 800 mg
  • the tablets are prepared as described in Example 1.
  • Granules are prepared by wet granulating from the active principles and the required auxiliary materials. The granules are mixed with the tabletting materials and pressed into tablets. The tablets are coated with hydroxypropyl methylcellulose film.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur une composition pharmaceutique s'administrant par voie orale et destinée au traitement du diabète et de ses complications, cette composition comprenant comme principe actif une combinaison de metformine (diamide N,N-diméthylimido-dicarbonimidique), ou d'un sel d'addition acide de celle-ci, et de chlorure de N-[2-hydroxy-3-(1-pipéridinyl)-propoxy]-pyridine-1-oxyde-3-carboxymidoyle ou d'un stéréoisomère de celui-ci ou d'un sel d'addition acide de la forme racémique ou optiquement active de celui-ci. L'invention porte également sur un procédé de traitement du diabète et sur un procédé de traitement de la neuropathie diabétique.
PCT/HU2002/000098 2001-09-27 2002-09-26 Composition pharmaceutique comprenant une metformine et un chlorure de n-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxyde-3-carboxymidoyle WO2003026653A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP0103939 2001-09-27
HU0103939A HU0103939D0 (en) 2001-09-27 2001-09-27 Pharmaceutical composition containing methformin and n-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride

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WO2003026653A1 true WO2003026653A1 (fr) 2003-04-03

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005041965A1 (fr) * 2003-10-30 2005-05-12 Cytrx Corporation Utilisation d'un derive d'un halogenure d'acide hydroximique pour traiter des maladies neurodegeneratives
EP1752147A4 (fr) * 2004-06-04 2007-10-31 Kowa Co Médicament pour la prévention ou le traitement du diabète
WO2008039514A1 (fr) * 2006-09-26 2008-04-03 Cytrx Corporation Compositions pharmaceutiques et procédés destinés à traiter des maladies associées à une neurodégénérecence
WO2008137149A1 (fr) * 2007-05-04 2008-11-13 Cytrx Corporation Guérison des plaies diabétiques
WO2016041561A1 (fr) * 2014-09-15 2016-03-24 Orphazyme Aps Formulation arimoclomol
US10532085B2 (en) 2010-11-30 2020-01-14 Orphazyme A/S Methods for increasing intracellular activity of Hsp70
US10543204B2 (en) 2008-06-26 2020-01-28 Orphazyme A/S Use of Hsp70 as a regulator of enzymatic activity
US10898476B2 (en) 2016-04-13 2021-01-26 Orphazyme A/S Heat shock proteins and cholesterol homeostasis
US11253505B2 (en) 2016-04-29 2022-02-22 Orphazyme A/S Arimoclomol for treating glucocerebrosidase associated disorders
US11707456B2 (en) 2020-11-19 2023-07-25 Kempharm Denmark A/S Processes for preparing arimoclomol citrate and intermediates thereof
KR102804202B1 (ko) * 2014-09-15 2025-05-12 제브라 덴마크 에이/에스 아리모클로몰 제제

Citations (2)

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WO2000050403A1 (fr) * 1999-02-26 2000-08-31 BIOREX Kutató és Fejlesztő Rt. Chlorure de n-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxyde-3-carboximidoyl et ses utilisations dans le traitement de la resistance a l'insuline
WO2001079174A1 (fr) * 2000-04-18 2001-10-25 BIOREX Kutató és Fejlesztő Rt. Derive de pyridine-1-oxyde, et processus de transformation de ce derive en composes pharmaceutiquement efficace

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WO2000050403A1 (fr) * 1999-02-26 2000-08-31 BIOREX Kutató és Fejlesztő Rt. Chlorure de n-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxyde-3-carboximidoyl et ses utilisations dans le traitement de la resistance a l'insuline
WO2001079174A1 (fr) * 2000-04-18 2001-10-25 BIOREX Kutató és Fejlesztő Rt. Derive de pyridine-1-oxyde, et processus de transformation de ce derive en composes pharmaceutiquement efficace

Non-Patent Citations (1)

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Title
ZIMMET P ET AL: "CLINICAL EFFICACY OF METFORMIN AGAINST INSULIN RESISTANCE PARAMETERS SINKING THE ICEBERG", DRUGS, ADIS INTERNATIONAL LTD, AT, vol. 58, no. SUPPL 1, 1999, pages 21 - 28, XP000913604, ISSN: 0012-6667 *

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AU2004285343B2 (en) * 2003-10-30 2010-05-13 Orphazyme A/S Use of a hydroximic acid halide derivative in the treatment of neurodegenerative diseases
JP2007509920A (ja) * 2003-10-30 2007-04-19 シトルックス コーポレイション 神経変性疾患の治療におけるヒドロキシム酸クロライドの使用
WO2005041965A1 (fr) * 2003-10-30 2005-05-12 Cytrx Corporation Utilisation d'un derive d'un halogenure d'acide hydroximique pour traiter des maladies neurodegeneratives
US8962604B2 (en) 2003-10-30 2015-02-24 Orphazyme Aps Use of a hydroximic acid halide derivative in the treatment of neurodegenerative diseases
EP2020233A2 (fr) 2003-10-30 2009-02-04 CytRx Corporation Utilisation d'un dérivé d'un halogénure de l'acide hydroximique pour traiter des maladies neurodégénératives
EA011301B1 (ru) * 2003-10-30 2009-02-27 СиУайТиАрЭкс КОРПОРЕЙШН Применение галоидного производного гидроксимовой кислоты для лечения нейродегенеративных заболеваний
EP1752147A4 (fr) * 2004-06-04 2007-10-31 Kowa Co Médicament pour la prévention ou le traitement du diabète
WO2008039514A1 (fr) * 2006-09-26 2008-04-03 Cytrx Corporation Compositions pharmaceutiques et procédés destinés à traiter des maladies associées à une neurodégénérecence
WO2008137149A1 (fr) * 2007-05-04 2008-11-13 Cytrx Corporation Guérison des plaies diabétiques
US11938125B2 (en) 2008-06-26 2024-03-26 Zevra Denmark A/S Use of Hsp70 as a regulator of enzymatic activity
US10543204B2 (en) 2008-06-26 2020-01-28 Orphazyme A/S Use of Hsp70 as a regulator of enzymatic activity
US11304941B2 (en) 2008-06-26 2022-04-19 Orphazyme A/S Use of HSP70 as a regulator of enzymatic activity
US11045460B2 (en) 2008-06-26 2021-06-29 Orphazyme A/S Use of Hsp70 as a regulator of enzymatic activity
US10532085B2 (en) 2010-11-30 2020-01-14 Orphazyme A/S Methods for increasing intracellular activity of Hsp70
KR102487452B1 (ko) * 2014-09-15 2023-01-10 오르파짐 에이/에스 아리모클로몰 제제
CN107106494A (zh) * 2014-09-15 2017-08-29 奥菲泽米有限公司 阿瑞洛莫制剂
KR102804202B1 (ko) * 2014-09-15 2025-05-12 제브라 덴마크 에이/에스 아리모클로몰 제제
AU2015317447B2 (en) * 2014-09-15 2021-02-25 Zevra Denmark A/S Arimoclomol formulation
RU2745292C2 (ru) * 2014-09-15 2021-03-23 Орпхазиме А/C Состав с аримокломолом
JP2017528521A (ja) * 2014-09-15 2017-09-28 オーファザイム エーピーエス アリモクロモル製剤
EP3922242A1 (fr) * 2014-09-15 2021-12-15 Orphazyme A/S Formulation arimoclomol
US11229633B2 (en) 2014-09-15 2022-01-25 Orphazyme A/S Arimoclomol formulation
WO2016041561A1 (fr) * 2014-09-15 2016-03-24 Orphazyme Aps Formulation arimoclomol
US10709700B2 (en) 2014-09-15 2020-07-14 Orphazyme A/S Arimoclomol formulation
KR20170062470A (ko) * 2014-09-15 2017-06-07 오르파짐 에이피에스 아리모클로몰 제제
KR20230019974A (ko) * 2014-09-15 2023-02-09 오르파짐 에이/에스 아리모클로몰 제제
KR102638203B1 (ko) * 2014-09-15 2024-02-19 제브라 덴마크 에이/에스 아리모클로몰 제제
KR102582559B1 (ko) * 2014-09-15 2023-09-26 제브라 덴마크 에이/에스 아리모클로몰 제제
KR20230148350A (ko) * 2014-09-15 2023-10-24 제브라 덴마크 에이/에스 아리모클로몰 제제
US10898476B2 (en) 2016-04-13 2021-01-26 Orphazyme A/S Heat shock proteins and cholesterol homeostasis
US11253505B2 (en) 2016-04-29 2022-02-22 Orphazyme A/S Arimoclomol for treating glucocerebrosidase associated disorders
US11707456B2 (en) 2020-11-19 2023-07-25 Kempharm Denmark A/S Processes for preparing arimoclomol citrate and intermediates thereof

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