EP2227224A2 - Composition pharmaceutique améliorée contenant un agoniste dopaminergique non ergoté et procédé de préparation de celle-ci - Google Patents

Composition pharmaceutique améliorée contenant un agoniste dopaminergique non ergoté et procédé de préparation de celle-ci

Info

Publication number
EP2227224A2
EP2227224A2 EP07856784A EP07856784A EP2227224A2 EP 2227224 A2 EP2227224 A2 EP 2227224A2 EP 07856784 A EP07856784 A EP 07856784A EP 07856784 A EP07856784 A EP 07856784A EP 2227224 A2 EP2227224 A2 EP 2227224A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
ropinirole
active ingredient
dopamine agonist
composition according
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Withdrawn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
EP07856784A
Other languages
German (de)
English (en)
Inventor
Evangelos Karavas
Efthimios Koutris
Eleni Stathaki
Vicky Samara
Anastasia Kalaskani
Dimitrios Bikiaris
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.)
Pharmathen SA
Original Assignee
Pharmathen SA
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 Pharmathen SA filed Critical Pharmathen SA
Publication of EP2227224A2 publication Critical patent/EP2227224A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to improved pharmaceutical compositions and in particular to a formulation for oral administration comprising a therapeutically effective quantity of a non- ergoline dopamine agonist, such as Ropinirole or pharmaceutical acceptable salt thereof, in combination with amino acids, such as Methionine, as an antioxidant and a process for the preparation thereof for the treatment of Parkinson's disease and Restless Legs Syndrome (RLS).
  • a non- ergoline dopamine agonist such as Ropinirole or pharmaceutical acceptable salt thereof
  • amino acids such as Methionine
  • Ropinirole is a known non-ergoline dopamine agonist, a selective D2-agonist, employed for the treatment of Parkinson's disease with much less undesirable side effects than other dopaminergic agents.
  • Ropinirole is a potent CNS active non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D 2 and D 3 dopamine receptor subtypes, binding with a higher affinity to D 3 than to D 2 receptor subtypes. Additionally, Ropinirole presents a moderate affinity for opioid receptors and a negligible in vitro affinity for 5-HT 1 , 5-HT 2 , Dopamine D 1 , benzodiazepine, GABA, muscarinic, alpha ! , alpha 2 and beta adrenoceptors.
  • Ropinirole used in the dosage form is in the form of the crystalline hydrochloride salt (4- (2-di-n- propylaminoethyl)-2 (3H)-indolone hydrochloride), which has been pharmaceutically approved for human use.
  • Ropinirole hydrochloride is a white to pale greenish-yellow powder with a melting range of 243° to 250° and a solubility of 133mg/ml in water. It is also soluble in methanol, slightly soluble in ethanol and very slightly soluble in acetonitrile.
  • Ropinirole is known to be susceptible to degradation upon exposure to moisture and elevated temperatures. Additionally, it tends to interact with other tablet ingredients when exposed to stress conditions and decomposes. The degradation of the active ingredient results in reduced drug effectiveness and treatment failure.
  • the susceptibility to decomposition can be controlled by handling the compound and storing the final dosage form in a controlled environment, so as to preserve the therapeutic potency of the active pharmaceutical ingredient.
  • the stability of pharmaceutical compositions containing a non-ergoline dopamine agonist and in particular, Ropinirole or pharmaceutical acceptable salt thereof can also be influenced by the selection of the excipients.
  • the bioavailability and the release rate of the pharmaceutical dosage can also be enhanced by the selection of the excipients.
  • certain stabilizing agents have been incorporated into pharmaceutical compositions containing Ropinirole.
  • the amount of the stabilizing agent to be used in a particular formulation depends upon the dosage form itself, the size of the dosage form and the amount of active ingredient (strength) present in the dosage form.
  • the pharmaceutical formulations of Ropinirole or salt thereof stabilized to oxidation are preferably formulations for oral administration. Such formulations include solid or liquid dosage forms such as for example tablets, capsules, powders and suspensions, including any sustained release preparations thereof.
  • EP 0 314 387 discloses a pharmaceutical composition which comprises a dopamine agonist, such as pergolide, which is susceptible to decomposition by light, and an amount of a stabilizing agent, such as PVP, a-tocopherol succinate and propyl gallate.
  • the active ingredient and the stabilizing agent are comprised in an amount sufficient to achieve stabilization against degradation by light.
  • an object of the present invention to provide an improved solid dosage formulation for oral administration containing a non-ergoline dopamine agonist, and in particular, Ropinirole, or pharmaceutical acceptable salt thereof as an active ingredient, which overcomes the deficiencies of the prior art and avoids the degradation of the active ingredient.
  • Another aspect of the present invention is to provide a solid dosage formulation for oral administration containing a non-ergoline dopamine agonist and in particular, Ropinirole or pharmaceutically acceptable salt thereof as an active ingredient, with low concentration of the active ingredient, which is bioavailable and effective with sufficient self-life and good pharmacotechnical properties.
  • another aspect of the present invention is to provide a solid dosage formulation for oral administration containing a non-ergoline dopamine agonist, and in particular, Ropinirole or pharmaceutically acceptable salt thereof as an active ingredient, which can be prepared in dosage forms of different strength by proportionally adjusting the quantities of the excipients and the active ingredient, thereby providing a pharmacotechnical linearity, without affecting the dissolution profile and bioavailability of the active ingredient.
  • a further aspect of the present invention is to provide a method for the preparation of a stable solid dosage formulation for oral administration containing a non-ergoline dopamine agonist, and in particular, Ropinirole or pharmaceutically acceptable salt thereof as an active ingredient, thereby avoiding the decomposition of said active ingredient and improving the pharmacotechnical characteristics of said composition.
  • a pharmaceutical composition for oral administration comprising a non-ergoline dopamine agonist, such a Ropinirole or pharmaceutical acceptable salt thereof as an active ingredient, and an effective amount of an amino acid such as Methionine as an antioxidant to inhibit oxidation and/or degradation.
  • a non-ergoline dopamine agonist such as Ropinirole or pharmaceutical acceptable salt thereof as an active ingredient
  • an amino acid such as Methionine
  • the sieved mixture Adding to the sieved mixture the total quantities of at least one optional excipient of the internal phase such as a binder, a diluent, a disintegrant and mixing until uniform,
  • At least one optional excipient of the external phase such as glidant, a lubricant and mixing
  • a pharmaceutical composition comprising a non- ergoline dopamine agonist (e.g. Ropinirole or pharmaceutical acceptable salt thereof) is considered to be “stable” if said ingredient degradates less or more slowly than it does on its own and/or in known pharmaceutical compositions.
  • a non- ergoline dopamine agonist e.g. Ropinirole or pharmaceutical acceptable salt thereof
  • excipient is considered to be "incompatible" with an active ingredient (non-ergoline dopamine agonist e.g. Ropinirole or salt thereof) if it promotes the degradation of said active ingredient, that is to say, if said active ingredient degrades more or faster in the presence of said excipient when compared with the degradation of said active ingredient on its own.
  • active ingredient non-ergoline dopamine agonist e.g. Ropinirole or salt thereof
  • pharmaceutically acceptable refers to a form that is acceptable to the patient from a pharmacological or toxicological point of view, including acceptable composition, formulation, stability, bioavailability and acceptance by the patient.
  • the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, capsules and caplets.
  • the improved solid pharmaceutical composition of the present invention is characterized by physicochemical properties suitable for the tablet formulation by direct compression, the adequate release rate of the active ingredient (non-ergoline dopamine agonist e.g. Ropinirole or salt thereof) and the storage stability, by employing excipients practically devoiding the tendency to interact with the active ingredient, and possessing good compressibility properties.
  • the active ingredient non-ergoline dopamine agonist e.g. Ropinirole or salt thereof
  • the storage stability by employing excipients practically devoiding the tendency to interact with the active ingredient, and possessing good compressibility properties.
  • non-ergoline dopamine agonist such as Ropinirole is susceptible to degradation / oxidation upon exposure to moisture and heat and its tendency gets stronger when formulated and mixed with excipients or other active substances
  • the object of the present invention is achieved by employing a an effective amount of an amino acid, such Methionine as an antioxidant.
  • Methionine is a sulphur-containing proteinogenic amino acid ( ⁇ -amino acid). It is classified as non-polar, it is hydrophobic, practically insoluble in water, resistant to heat and stable during storage. Methionine has been used in the present invention as a racemate or pure D- or L- form.
  • the antioxidant agent used herein is DL-Methionine.
  • the active ingredient non-ergoline dopamine agonist such as Ropinirole or salt thereof
  • a suitable amount of amino acid such as Methionine
  • any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with the unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability of the drug and the self-life of the pharmaceutical product, and provide a product exhibiting excellent bioavailability.
  • the present invention can be applied in the formulation of tablets, capsules, caplets, sachets or other solid dosage forms for oral administration of an active ingredient having stability problems especially related with heat and/or humidity of the atmosphere.
  • the manufacturing process for the preparation of the composition according to the present invention is simpler and inexpensive in comparison to any other conventional method.
  • direct compression was the chosen manufacturing method because it is faster, easier, adds fewer steps to the process, more economical, and considering the fact that the active ingredient employed in the present invention is susceptible to degradation upon exposure to moisture and heat.
  • the present invention provides a pharmaceutical composition comprising from about 0.05% to 50% by weight of Ropinirole or salt thereof and from about 0.05% to 5% by weight of Methionine.
  • the weight ratio of the Ropinirole or salt thereof to Methionine is preferably 1000:1 to 1 :100.
  • Preferred pharmaceutical compositions according to the present invention comprise Ropinirole or salt thereof in an amount approximately 0.05% to 40%, more preferably 0.05% to 25% and most preferably 0.05% to 15%. More preferred pharmaceutical compositions according to the present invention comprise Methionine in an amount approximately 0.05% to 2%, and most preferably 0.05% to 1.5%.
  • compositions are in the form of solid dosage forms for oral or sublingual administration such as tablets, capsules, caplets, troches, pastilles, pills, lozenges and the like, in all shapes and sizes, coated or uncoated. All percentages stated herein are weight percentages based on total composition weight, unless otherwise stated.
  • Another embodiment of the present invention is the use of the direct compression process for the preparation of solid dosage forms such as tablets containing Ropinirole or salt thereof.
  • Said direct compression process comprises:
  • compositions of the present invention are characterized by excellent pharmacotechnical properties, such as homogeneity, flowability and compressibility. Thanks to these properties, the solid dosage forms prepared by the above process exhibit excellent technical characteristics including disintegration time, dissolution rate, hardness, resistance to crashing, friability and stability, as better illustrated by the measurements during the stage of the development of the products.
  • compositions of the present invention may contain one or more formulation ingredients selected from a wide variety of excipients. According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form compositions.
  • Such ingredients include, but are not limited to, diluents, binders, compression aids, disintegrants, glidants, lubricants, flavours, water scavengers, colorants, sweetener, coating agents and preservatives.
  • Diluents may be, for example, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin, maltitol.
  • Binders may be, for example, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch and sucrose.
  • Disintegrants may be, for example, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, sodium docusate, guar gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch, pregelatinized starch.
  • Glidants may be, for example, calcium silicate, powdered cellulose, starch, talc, lubricants e.g. polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, starch, talc.
  • Example 1 Tablet of 0.25 mg Ropinirole (Comp. 1)
  • Tablets of the above formulation were prepared according to the following manufacturing process: Ropinirole HCL, Microcrystalline cellulose, Microcellac and Croscarmellose sodium were admixed to complete homogeneity. The above mixture was passed through a sieve. The sieved mixture was then mixed with colloidal silicon dioxide. Finally magnesium stearate was added and mixed until complete homogeneity. The resulting granule was compressed into tablets.
  • the produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications. However, the stability results were not satisfactory.
  • Tablets of the above composition 2 were prepared according to the following manufacturing process: Ropinirole HCL and DL-Methionine were mixed together for sufficient time and then Microcrystalline cellulose, Microcellac and Croscarmellose sodium were added and mixed. Subsequently, Colloid silicon dioxide was added and mixed. Finally magnesium stearate was added and mixed until complete homogeneity. The resulting granule was compressed into tablets.
  • composition 2 The stability results of composition 2 were acceptable and much more improved than of composition 1.
  • Example 3 Tablet of 0.25 mg Ropinirole (Comp. 3)
  • compositions of the above composition 3 were prepared according to the manufacturing process of composition 2.
  • compositions 3 comprising a ratio of Ropinirole hydrochloride to DL-methionine 2:5 and
  • Example 4 Tablet of 0.25 mg Ropinirole (Comp. 4 * )
  • Microcellac 100 is sieved.
  • step 6 The mixture of step 6 is added to the mixture of step 5 for adequate time till suitable content uniformity is achieved.
  • dissolution test One of the most critical pharmacotechnical tests is the dissolution test as it is strongly correlated with the bioavailability of the product.
  • a Paddle Apparatus 50rpm, 37 0 C, time 30min, while as a dissolution medium 900ml of H 2 O was used.
  • the dissolution profile of the composition 4 showed a faster release profile and disintegration time. Also, the release at 30 minutes is over 95% compared to 92% of composition 2, showing that better homogeneity of these tablets.
  • Composition 4 showed improved pharmacotechnical characteristics such as lower disintegration time, increased release of the active ingredient release in the dissolution test and improved uniformity of the low content of the active ingredient.
  • composition 4 was investigated for its scalability, while a process validation was performed in order to prove the repeatability and accuracy of the manufacturing process and the proposed formulations. All the above mentioned characteristics were also investigated for formulations of 0,25mg, 0,5mg, lmg, 2mg and 5mg strength equivalent weight of Ropinirole per tablet and 3 batches per strength were used.
  • composition 4 and the manufacturing process are suitable in order to provide a repeatable and high quality product.
  • Another object of the present invention was to prepare a pharmaceutical composition that is stable and the active ingredient does not degradates for a long period of storage time. Therefore, tablets of composition 4, three batches of each strength, were packed in blisters and exposed to normal (25°C ⁇ 2°C/60% ⁇ 5% RH), intermediate (30°C ⁇ 2°C/65% ⁇ 5% RH) and accelerated (40°C ⁇ 2°C/75% ⁇ 5% RH) stability studies according to the current ICH guidelines. The stability results under normal conditions for the five different strengths are shown in Table 2 below (one batch each strength).
  • the results show a good stability of the product and compatibility between the drug substance and the excipients proposed by the present invention.
  • the excellent results regarding the physicochemical characteristics, the excellent stability of the product as well as the simple and economic manufacturing process indicate the advantages of the present invention relative to the commonly used methods and excipients for the formulation of Ropinirole.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une préparation pharmaceutique de formes posologiques solides destinées à une administration par voie orale, laquelle préparation comprend une quantité thérapeutiquement efficace d'un agoniste dopaminergique non ergoté ou d'un sel pharmaceutiquement acceptable de celui-ci, notamment du ropinirole ou un sel pharmaceutiquement acceptable de celui-ci, combiné à un acide aminé, tel qu'un anti-oxydant, ainsi qu'un procédé de préparation de cette préparation.
EP07856784A 2007-12-17 2007-12-17 Composition pharmaceutique améliorée contenant un agoniste dopaminergique non ergoté et procédé de préparation de celle-ci Withdrawn EP2227224A2 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2007/011047 WO2009076983A2 (fr) 2007-12-17 2007-12-17 Composition pharmaceutique améliorée contenant un agoniste dopaminergique non ergoté et procédé de préparation de celle-ci

Publications (1)

Publication Number Publication Date
EP2227224A2 true EP2227224A2 (fr) 2010-09-15

Family

ID=39099786

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07856784A Withdrawn EP2227224A2 (fr) 2007-12-17 2007-12-17 Composition pharmaceutique améliorée contenant un agoniste dopaminergique non ergoté et procédé de préparation de celle-ci

Country Status (2)

Country Link
EP (1) EP2227224A2 (fr)
WO (1) WO2009076983A2 (fr)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5114948A (en) * 1989-10-19 1992-05-19 Eli Lilly And Company Stabilized pergolide compositions
US7122203B2 (en) * 2000-05-08 2006-10-17 Eli Lilly And Company Stabilized formulations of 6-hydroxy-3-(-4-[2-(piperidin-1-yl) ethoxy]phenoxy)-2-(4-methoxyphenyl) benzo[b]thiophene and salts thereof
US20070243240A9 (en) * 2000-08-24 2007-10-18 Fred Windt-Hanke Transdermal therapeutic system
US20020123503A1 (en) * 2000-12-21 2002-09-05 Malcolm Ross Cabergoline pharmaceutical compositions and methods of use thereof
US20070275060A1 (en) * 2005-08-05 2007-11-29 Osmotica Costa Rica Sociedad Anonima Extended release solid pharmaceutical composition containing carbidopa and levodopa
US20070190130A1 (en) * 2006-02-16 2007-08-16 Mark William A Protein hydrolysate excipients

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009076983A3 *

Also Published As

Publication number Publication date
WO2009076983A3 (fr) 2009-11-12
WO2009076983A2 (fr) 2009-06-25

Similar Documents

Publication Publication Date Title
KR101733533B1 (ko) 울리프리스탈 아세테이트 정제
CA2691752C (fr) Composition pharmaceutique contenant un antagoniste des canaux calciques de type dihydropyridine et son procede de preparation
US8187635B2 (en) Pharmaceutical composition containing a pyrrolidone anticonvulsant agent and method for the preparation thereof
AU2003289320A1 (en) Solid drug for oral use
US20020123503A1 (en) Cabergoline pharmaceutical compositions and methods of use thereof
WO2020175897A1 (fr) Formulation à libération contrôlée contenant du mirabegron ou un sel pharmaceutiquement acceptable de ce dernier
WO2005020998A1 (fr) Compositions pharmaceutiques a base de moxifloxacine et leurs procedes de preparation
US7959948B2 (en) Pharmaceutical composition of quetiapine fumarate
KR20150003726A (ko) 프라수그렐을 함유하는 안정한 즉시방출형 경구 약제학적 조성물
WO2009049648A2 (fr) Composition pharmaceutique améliorée contenant un agent antiviral et procédé de préparation de celle-ci
US20070293479A1 (en) Olanzapine pharmaceutical composition
EP3539536A1 (fr) Composition pharmaceutique de sunitinib ou de son sel dans sa forme polymorphe i
EP2303233B1 (fr) Forme galénique orale solide contenant l agent anti-plaquettaire clopidogrel et son procédé de préparation
EP2227224A2 (fr) Composition pharmaceutique améliorée contenant un agoniste dopaminergique non ergoté et procédé de préparation de celle-ci
US20180235911A1 (en) Stable pharmaceutical composition of alogliptin and metformin fixed dose combination
JP2020183382A (ja) フィンゴリモド塩酸塩含有製剤及びフィンゴリモド塩酸塩含有製剤の製造方法
EP2197423B1 (fr) Composition pharmaceutique améliorée contenant un modulateur de récepteur strogène sélectif, et procédé de préparation de celui-ci
JP2014070061A (ja) シクロデキストリンとの混合体を含有する錠剤
JP7355846B2 (ja) 固形製剤
CA3234841A1 (fr) Compositions pharmaceutiques
WO2024126409A1 (fr) Composition pharmaceutique contenant du siponimod
TR2021017729A2 (tr) Mi̇kroni̇ze tofasi̇ti̇ni̇b i̇çeren bi̇r fi̇lm kapli tablet
WO2017114597A1 (fr) Formes pharmaceutiques comprenant du ((cis)-n-(4-(diméthylamino) -1,4-diphénylcyclohexyl)-n-méthylcinnamamide

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20100706

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

RAX Requested extension states of the european patent have changed

Extension state: RS

Payment date: 20100607

Extension state: BA

Payment date: 20100607

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20140701