HRP20040575A2 - Pharmaceutical compositions based on azetidine derivatives - Google Patents

Pharmaceutical compositions based on azetidine derivatives Download PDF

Info

Publication number
HRP20040575A2
HRP20040575A2 HR20040575A HRP20040575A HRP20040575A2 HR P20040575 A2 HRP20040575 A2 HR P20040575A2 HR 20040575 A HR20040575 A HR 20040575A HR P20040575 A HRP20040575 A HR P20040575A HR P20040575 A2 HRP20040575 A2 HR P20040575A2
Authority
HR
Croatia
Prior art keywords
composition according
azetidine
general formula
pharmaceutical composition
azetidine derivative
Prior art date
Application number
HR20040575A
Other languages
Croatian (hr)
Inventor
Sophie Cote
Valurie Bobineau
Maria Teresa Peracchia
Klaus Wirth
Original Assignee
Aventis Pharma 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 Aventis Pharma Sa filed Critical Aventis Pharma Sa
Publication of HRP20040575A2 publication Critical patent/HRP20040575A2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Psychiatry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

Predloženi izum odnosi se na stabilne formulacije derivata azetidina. The proposed invention relates to stable formulations of azetidine derivatives.

Derivati azetidina koji se upotrebljavaju u farmaceutskim sastavima prema izumu mogu se prikazati s donjim općim formulama (Ia) ili (Ib): The azetidine derivatives used in the pharmaceutical compositions according to the invention can be represented by the following general formulas (Ia) or (Ib):

[image] [image]

u kojima in which

Ar je aromatska ili heteroaromatska skupina prema potrebi supstitirana s jednim ili više (C1-C4) alkila, halogenih, NO2, CN, (C1-C4)) alkoksi ili OH skupina. Ar is an aromatic or heteroaromatic group optionally substituted with one or more (C1-C4) alkyl, halogen, NO2, CN, (C1-C4)) alkoxy or OH groups.

U definiciji gornjih azetidinskih derivata, podrazumijeva se da aromatska skupina znači posebno fenilnu ili naftilnu skupinu, heteroaromatska skupina je piridil, furil, tienil, tiazolil/ imidazolil ili oksazolilna skupina, i halogen je fluor, klor, brom ili jod, In the definition of the above azetidine derivatives, it is understood that the aromatic group means especially a phenyl or naphthyl group, a heteroaromatic group is a pyridyl, furyl, thienyl, thiazolyl/imidazolyl or oxazolyl group, and a halogen is fluorine, chlorine, bromine or iodine,

U patentnim prijavama WO 00/15609, WO 01/64633, WO 01/64634 i WO 99/01451 opisani su derivati azetidinai opće formule (Ia) ili (Ib) i njihove primjene. Posebno, ti derivati azetidina su posebno povoljni zbog njihovog visokog afiniteta prema kanabinoid receptorima, a posebno tipu CB1 receptora. Patent applications WO 00/15609, WO 01/64633, WO 01/64634 and WO 99/01451 describe azetidine derivatives of the general formula (Ia) or (Ib) and their applications. In particular, these azetidine derivatives are particularly advantageous due to their high affinity for cannabinoid receptors, especially the CB1 receptor type.

Nažalost, derivati azetinidina su proizvodi koji su vrlo slabo topivi u vodi. Do sada se je predviđalo davanje derivata azetinidina opće formule (Ia) ili (Ib), posebno oralnim putem, u obliku tableta u formulacijama koje sadrže, između ostalog, celulozu, laktozu i druge pomoćne tvari. Međutim, takove formulacije nisu uvijek dovoljno prikladne za te proizvode koji se slabo tope u vodi zbog premale biološke raspoloživosti. Unfortunately, azetinidine derivatives are products that are very poorly soluble in water. Until now, it has been envisaged to administer azetinidine derivatives of the general formula (Ia) or (Ib), especially orally, in the form of tablets in formulations containing, inter alia, cellulose, lactose and other excipients. However, such formulations are not always suitable enough for those products that are poorly soluble in water due to insufficient bioavailability.

Brojni dokumenti opisuju sisteme koji su prikladni za solubilizaciju i/ili za poboljšavanje biološke raspoloživosti hidrofobnih aktivnih sastojaka. Međutim, ispitani sistemi su se za sada pokazali neučinkoviti za pripravu farmaceutskih sastava koji sadrže gore definirane azetidinske derivate koji su postojani i biološki raspoloživi i u kojima je derivat azetidina solubiliziran pri učinkovitoj koncentraciji. Numerous documents describe systems that are suitable for solubilizing and/or improving the bioavailability of hydrophobic active ingredients. However, the tested systems have so far proved to be ineffective for the preparation of pharmaceutical compositions containing the above-defined azetidine derivatives which are stable and biologically available and in which the azetidine derivative is solubilized at an effective concentration.

Posebno, J. Pharm Sciences, 89(8), 967 (2000) i Pharmaceutical Technologγ Europe, str. 20, septembar 2000, spominje formulaciju aktivnih sastojaka koji su slabo topivi u vodi, u trigliceridima srednjeg lanca. Međutim, pokusi provedeni s formulacijama na osnovi Miglyol® dali su nedovoljne rezultate sa stajališta njihove biološke raspoloživosti. In particular, J. Pharm Sciences, 89(8), 967 (2000) and Pharmaceutical Technologγ Europe, p. 20, September 2000, mentions the formulation of active ingredients that are poorly soluble in water, in medium chain triglycerides. However, experiments conducted with formulations based on Miglyol® gave insufficient results from the point of view of their bioavailability.

Osim toga, međunarodna patentna prijava W0 95/24893 opisuje sastave koji sadrže jestivo ulje, lipofilni tenzid i hidrofilni tenzid koji su predviđeni za formulaciju hidrofobnih aktivnih sastojaka i za pojačavanje njihove biološke raspoloživosti. Nažalost, gornji derivati azetinidina su pokazali preslabu biološku raspoloživost u toj vrsti formulacije. Posebno, formulacija takovih derivata azetinidina u sistemu Miglyol®/Capryol®/Cremophor® se je također pokazala nedovoljnom in vivo s farmako-kinetičkog stajališta. In addition, international patent application WO 95/24893 describes compositions containing an edible oil, a lipophilic surfactant and a hydrophilic surfactant which are intended for the formulation of hydrophobic active ingredients and for enhancing their bioavailability. Unfortunately, the above azetinidine derivatives showed too poor bioavailability in that type of formulation. In particular, the formulation of such azetinidine derivatives in the Miglyol®/Capryol®/Cremophor® system also proved insufficient in vivo from a pharmaco-kinetic point of view.

Sada je pronađeno, i to je predstavlja predmet predloženog izuma, da se mogu proizvesti kemijski i fizički postojani farmaceutski sastavi koji sadrže derivate opće formule (Ia) ili (Ib), prema potrebi u kombinaciji s drugim aktivnim sastojkom koji može pojačati učinke azetidinskih derivata opće formule (Ia) ili (Ib), u sistemu koji sadrži najviše 2 osnovne pomoćne tvari odabrane između neionskiskog tenzida hidrofilnog karaktera koji može solubilizirati derivat azetidina opće formule (Ia) ili (Ib) i, tamo gdje je to prikladno, aktivnog sastojka koji može pojačati učinke derivata azetidina, i uzrokovati stvaranje koloidnog sistema, prema potrebi s dodatkom druge pomoćne tvari lipofilne naravi, koja stabilizira formulaciju. It has now been found, and this represents the subject of the proposed invention, that it is possible to produce chemically and physically stable pharmaceutical compositions containing derivatives of the general formula (Ia) or (Ib), as necessary in combination with another active ingredient that can enhance the effects of the azetidine derivatives of the general of formula (Ia) or (Ib), in a system containing at most 2 basic excipients selected from a nonionic surfactant of a hydrophilic character that can solubilize an azetidine derivative of the general formula (Ia) or (Ib) and, where appropriate, an active ingredient that can enhance the effects of azetidine derivatives, and cause the formation of a colloidal system, if necessary with the addition of another auxiliary substance of a lipophilic nature, which stabilizes the formulation.

Prema izum, sastavi povoljno obuhvaćaju: According to the invention, the compositions advantageously include:

• najmanje jedan derivat azetidina opće formule (Ia) ili (Ib), • at least one azetidine derivative of the general formula (Ia) or (Ib),

• prema potrebi aktivan sastojak koji može pojačati učinke azetidinskog derivata opće formule (Ia) ili (Ib), • if necessary, an active ingredient that can enhance the effects of the azetidine derivative of the general formula (Ia) or (Ib),

• neionski tenzid hidrofilne naravi koji može solubilizirati derivat azetidina opće formule (Ia) ili (Ib) i, tamo gdje je to prikladno, aktivan sastojak koji može pojačati učinke azetidinskog derivata, i koji može uzrokovati stvaranje koloidnog sistema, • a nonionic surfactant of a hydrophilic nature that can solubilize an azetidine derivative of the general formula (Ia) or (Ib) and, where appropriate, an active ingredient that can enhance the effects of the azetidine derivative, and that can cause the formation of a colloidal system,

• prema potrebi tenzid lipofilne naravi koji ima HLB ispod 10 i koji stabilizira sastav, • if necessary, a lipophilic surfactant that has an HLB below 10 and that stabilizes the composition,

• prema potrebi s dodatkom odabranim iz skupine koju čine stabilizatori, konzervansi, sredstva koja omogućuju podešavanje viskoznosti, ili sredstva koja mogu modificirati, na primjer, organoleptička svojstva. • as necessary with an additive selected from the group consisting of stabilizers, preservatives, agents that enable viscosity adjustment, or agents that can modify, for example, organoleptic properties.

Prema izumu, nonionski tenzid hidrofilne naravi, koji može solubilizirati derivat azetidina opće formule (Ia) ili (Ib) i, tamo gdje je to prikladno, aktivni sastojak koji može pojačati učinke derivata azetidina, i koji može uzrokovati stvaranje koloidnog sistema, može se odabrati između krutih i polukrutih sredstava koja se tale pri niskoj temperaturi (T°C <60°C), ili između tekućih sredstava čiji HLB je između 10 i 20, kao što su gliceridi polietilen glikola i zasićenih masnih kiselina. According to the invention, a nonionic surfactant of a hydrophilic nature, which can solubilize an azetidine derivative of the general formula (Ia) or (Ib) and, where appropriate, an active ingredient which can enhance the effects of the azetidine derivative, and which can cause the formation of a colloidal system, can be selected between solid and semi-solid agents that melt at a low temperature (T°C <60°C), or between liquid agents whose HLB is between 10 and 20, such as glycerides of polyethylene glycol and saturated fatty acids.

Podrazumijeva se da u gornjoj definiciji zasićena masna kiselina može imati od 6 do 18 ugljikovih atoma, i da spomenuti gliceridi polietilen glikola (PEG) i zasićenih masnih kiselina mogu biti prirodnog ili sintetičkog porijekla. It is understood that in the above definition a saturated fatty acid can have from 6 to 18 carbon atoms, and that the mentioned glycerides of polyethylene glycol (PEG) and saturated fatty acids can be of natural or synthetic origin.

Na primjer, neionski tenzid s hidrofilnim karakterom može se odabrati između sredstava kao što je Labrasol® [kaprilkaproil makrogol-8 glicerid] i Gelucire® proizvoda: Gelucire 44/14, Gelucire 50/13, [lauroil (ili stearoil, palmitoil) makrogol-32 glicerid]. For example, a nonionic surfactant with a hydrophilic character can be selected from agents such as Labrasol® [caprylcaproyl macrogol-8 glyceride] and Gelucire® products: Gelucire 44/14, Gelucire 50/13, [lauroyl (or stearoyl, palmitoyl) macrogol- 32 glyceride].

Prema izvedbi izuma kojoj se daje prednost, sastav također može uključiti i površinski aktivno sredstvo lipofilnog karaktera koje ima HLB ispod 10, i koje stabilizira sastav. To se sredstvo može odabrati između sredstava koja mogu pojačati solubilizaciju derivata azetidina opće formule (Ia) ili (Ib) i, prema potrebi, dodanog aktivnog sastojka. Prema izumu, to sredstvo se može odabrati između glicerida polietilen glikola i masnih kiselina, posebno nezasićen masnih kiselina, estera polietilen glikola i masnih kiselina ili estera masnih kiselina i sorbitola. Podrazumijeva se da gornje masne kiseline mogu imati od 6 do 18 ugljikovih atoma. According to a preferred embodiment of the invention, the composition may also include a lipophilic surfactant having an HLB below 10, which stabilizes the composition. This agent can be chosen from agents that can enhance the solubilization of azetidine derivatives of the general formula (Ia) or (Ib) and, if necessary, the added active ingredient. According to the invention, this agent can be chosen from glycerides of polyethylene glycol and fatty acids, especially unsaturated fatty acids, esters of polyethylene glycol and fatty acids or esters of fatty acids and sorbitol. It is understood that the above fatty acids can have from 6 to 18 carbon atoms.

Na primjer, to sredstvo se može odabrati između oleinske kiseline, Labrafil® proizvoda [oleoil (ili lineoil) makrogol-8 glicerida], na primjer Labrafil M1944CS, Capryol-a 90® (polietilen glikol monokaprilat) ili Span-a 20 (sorbitol monolaurat) . Ovaj popis je dat bez namjere ograničavanja. For example, this agent can be selected from oleic acid, Labrafil® products [oleoyl (or lineoyl) macrogol-8 glyceride], for example Labrafil M1944CS, Capryol-a 90® (polyethylene glycol monocaprylate) or Span-a 20 (sorbitol monolaurate ). This list is not intended to be limiting.

Među gore navedenim pomoćnim tvarima posebnu i naročitu prednost imaju Labrasol, Gelucire® ili par Labrafil®/Labrasol®. Among the auxiliaries mentioned above, Labrasol, Gelucire® or the pair Labrafil®/Labrasol® have a special and special advantage.

Također se je pokazalo (ali nije objavljeno do datuma podnošenja predložene prijave) da za određena liječenja kao što je, na primjer, debljina, može biti korisno dati derivate azetinidina opće formule (Ia) ili (Ib) istovremeno sa sibutrarainom koji uzrokuje sinergistički učinak u smanjenju uzimanja hrane. It has also been shown (but not published by the filing date of the proposed application) that for certain treatments such as, for example, obesity, it may be beneficial to administer azetinidine derivatives of the general formula (Ia) or (Ib) simultaneously with sibutraine which causes a synergistic effect in reducing food intake.

Sibutramin i njegovi učinci su opisani u donjoj literaturi: W0 90/061110; D.H. RYAN et al., ObesityResearch, 3 (4), 553 (1995); H.C. JACKSON et al., British Journal of Pharmacologγ, 121, 1758 (1997); G. FANGHANEL et al., Inter. J. Obes., 24 (2), 144 (2000); G.A. BRAY et al., Obes. Res., 7(2), 189 (1999). Sibutramine and its effects are described in the following literature: WO 90/061110; D. H. RYAN et al., Obesity Research, 3 (4), 553 (1995); H.C. JACKSON et al., British Journal of Pharmacology, 121, 1758 (1997); G. FANGHANEL et al., Inter. J. Obes., 24 (2), 144 (2000); HIM. BRAY et al., Obes. Res., 7(2), 189 (1999).

Osim toga, za druga liječenja kao što je šizofrenija ili liječenje neuroloških poremećaja kao što je Parkinsonova bolest, može biti korisno dati derivate azetinidina opće formule (Ia) ili (Ib) istovremeno s jednim ili više sredstava koja aktiviraju dopaminergnu neuro-transmisiju u mozgu. Te kombinacije omogućuju pojačavanje učinka dopaminergne monoterapije (levodopa, dopaminergni agonisti, i inhibitori enzima), i oni omogućuju smanjenje sporednih učinaka, posebno diskinezije. In addition, for other treatments such as schizophrenia or the treatment of neurological disorders such as Parkinson's disease, it may be useful to administer azetinidine derivatives of general formula (Ia) or (Ib) simultaneously with one or more agents that activate dopaminergic neurotransmission in the brain. These combinations make it possible to enhance the effect of dopaminergic monotherapy (levodopa, dopaminergic agonists, and enzyme inhibitors), and they make it possible to reduce side effects, especially dyskinesia.

Među dopaminergnim agonistima mogu se posebno spomenuti slijedeći proizvod: bromokriptin (Novartis), kabergolin (Pharmacia Corp.), adrogolid (Abbott Laboratories), BAM-1110 (Maruko Seivaku Co Ltd), Duodopa® (Neopharma), L-dopa, dopados (Neopharma), CHP1512 (Chiesi), NeuroCell-PD (Diacrin Ine), PNU-95666 (Pharmacia & Upjohn), ropinirol (GlaxoSmithKline Beecham), pramipeksol (Boehringer Ingelheim), rotigotin (Discovery Therapeutics/ Lohmann Therapie System), spheramin (Titan Pharmaceuticals), TV1203 (Teva pharmaceutical), uridin (Polifarma). Among the dopaminergic agonists, the following product can be specially mentioned: bromocriptine (Novartis), cabergoline (Pharmacia Corp.), adrogolide (Abbott Laboratories), BAM-1110 (Maruko Seivaku Co Ltd), Duodopa® (Neopharma), L-dopa, dopados ( Neopharma), CHP1512 (Chiesi), NeuroCell-PD (Diacrin Ine), PNU-95666 (Pharmacia & Upjohn), ropinirole (GlaxoSmithKline Beecham), pramipexole (Boehringer Ingelheim), rotigotine (Discovery Therapeutics/ Lohmann Therapie System), spheramine (Titan Pharmaceuticals), TV1203 (Teva pharmaceutical), uridine (Polifarma).

Podrazumijeva se da sastavi koji sadrže dodatni aktivan sastojak različit od derivata azetidina opće formule (Ia) ili (Ib) i koji može pojačati njegove učinke može sadržavati proizvod kako je definiran u gornjem odlomku i da spomenuti sastavi spadaju u opseg predloženog izuma. It is understood that compositions containing an additional active ingredient different from the azetidine derivative of the general formula (Ia) or (Ib) and which can enhance its effects may contain the product as defined in the above paragraph and that said compositions fall within the scope of the proposed invention.

Prema izumu, aktivan sastojak opće formule (Ia) ili (Ib) predstavlja od 0,01 do 70 mas. % od ukupnog sastava. Ponajprije, on predstavlja od 0,05 do 50 mas. % i još bolje od 0,1 do 20 mas. % od ukupnog sastava. According to the invention, the active ingredient of the general formula (Ia) or (Ib) represents from 0.01 to 70 wt. % of the total composition. First of all, it represents from 0.05 to 50 wt. % and even better from 0.1 to 20 wt. % of the total composition.

Razumljivo je da se doziranje može mijenjati prema stupnju ili naravi stanja koje se liječi. Tako se, dakle, količinu aktivnog proizvoda u sastavu prema izumu određuje tako da se može propisati prikladno doziranje. Rezultat toga je da se količinu derivata azetidina opće formule (Ia) ili (Ib) mijenja kao funkciju njegove topivosti u smjesi i također kao funkciju prikladnog doziranja za liječenje pacijenta. It is understood that the dosage may vary according to the degree or nature of the condition being treated. Thus, the amount of active product in the composition according to the invention is determined so that a suitable dosage can be prescribed. The result is that the amount of the azetidine derivative of general formula (Ia) or (Ib) varies as a function of its solubility in the mixture and also as a function of the appropriate dosage for the treatment of the patient.

Za ljude, dnevna doza data oralnim putem je općenito između 0,1 i 100 mg derivata azetidina opće formule (Ia) ili (Ib). Podrazumijeva se da za izbor najprikladnijeg doziranja treba uzeti u obzir težinu pacijenta, njegovo opće zdravstveno stanje, starost i sve faktore koji mogu utjecati na učinkovitost liječenja. Pripravljaju se ponajprije takovi sastavi da jedinična doza sadrži od 0,1 do 50 mg aktivnog proizvoda. For humans, the daily dose administered orally is generally between 0.1 and 100 mg of an azetidine derivative of general formula (Ia) or (Ib). It goes without saying that in order to choose the most suitable dosage, the weight of the patient, his general state of health, age and all factors that can affect the effectiveness of the treatment should be taken into account. Compositions are primarily prepared such that the unit dose contains from 0.1 to 50 mg of the active product.

Među derivatima azetinidina opće formule (Ia) ili (Ib), proizvodi kojima se daje veću i posebnu prednost jesu slijedeći: Among the azetinidine derivatives of the general formula (Ia) or (Ib), the products that are given greater and particular preference are the following:

• 1-[bis(4-klorfenil)metil]-3-[(3,5-difluor-fenil)-(metil-sulfonil)metilen]azetidin}; • 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro-phenyl)-(methyl-sulfonyl)methylene]azetidine};

• N-{1-[bis(4-klorfenil)metil]azetidin-3-il)-N-pirid-3-ilmetilsulfonamid; • N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl)-N-pyrid-3-ylmethylsulfonamide;

• N-{1-[bis(4-klorfenil)metil]azetidin-3-il}-N-(3,5-di-fluorfenil)metilsulfonamid; • N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide;

• N-{1-[bis-(4-klorfenil)metil]-azetidin-3-il}-N-(6-klor-pirid-2-il)metilsulfonamid; • N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(6-chloro-pyrid-2-yl)methylsulfonamide;

• N-{1-[bis-(4-klorfenil(metil]azetidin-3-il}-N-kvinol-6-il-metilsulfonamid. • N-{1-[bis-(4-chlorophenyl(methyl]azetidin-3-yl)}-N-quinol-6-yl-methylsulfonamide.

Podrazumijeva se da sastavi prema izumu koji sadrže ove proizvode imaju posebnu prednost. It goes without saying that compositions according to the invention containing these products have a particular advantage.

Alternativno, tamo gdje se uvodi i drugi aktivan sastojak, i u slučaju da je dodatni proizvod sibutramin, sastavi mogu sadržavati 0,2 do 15 mg. Međutim, ta količina prema potrebi može biti niža i ona se može mijenjati od 0,2 do 10 mg. Alternatively, where a second active ingredient is also introduced, and in case the additional product is sibutramine, the compositions may contain 0.2 to 15 mg. However, this amount can be lower as needed and can vary from 0.2 to 10 mg.

U slučaju da je dodatni proizvod L-dopa, sastavi mogu sadržavati 100 do 300 mg tog drugog aktivnog sastojka, ponajprije 250 mg. In case the additional product is L-dopa, the compositions may contain 100 to 300 mg of said second active ingredient, preferably 250 mg.

Neionski tenzid hidrofilne naravi, koji može uzrokovati stvaranje koloidnog sistema, može biti prisutan količinom od 20 do 100% u odnosu na ukupnu masu pomoćne tvari prisutne u sastavu, ponajprije od 40 do 100%, i još bolje od 60 do 100%. A nonionic surfactant of a hydrophilic nature, which can cause the formation of a colloidal system, can be present in an amount of 20 to 100% in relation to the total mass of auxiliary substances present in the composition, preferably from 40 to 100%, and even better from 60 to 100%.

Tamo gdje je to prikladno i ako sastav također sadrži i sredstvo lipofilne naravi koje ima HLB ispod 10, količina tog sredstva s niskom HLB vrijednošću može iznositi od 0,1 do 60% u odnosu na ukupnu masu pomoćne tvari prisutne u sastavu, i još bolje od 1 do 40%. Where appropriate and if the composition also contains an agent of a lipophilic nature that has an HLB below 10, the amount of this agent with a low HLB value can be from 0.1 to 60% relative to the total weight of the excipient present in the composition, and even better from 1 to 40%.

Ako sastav, nadalje, sadrži određene dodatke, to mogu biti stabilizatori, konzervansi, sredstva koja omogućuju podešavanje viskoznosti, ili sredstva koja mogu modificirati, na primjer, organoleptička svojstva. If the composition, furthermore, contains certain additives, these can be stabilizers, preservatives, agents that enable the adjustment of viscosity, or agents that can modify, for example, organoleptic properties.

Stabilizatori mogu biti, na primjer, antioksidanti odabrani posebno između α-tokoferola, askorbil palmitata, BHT (butil hidroksitoluen), BHA (butil hidroksianisol), propil galata ili jabučne kiseline. The stabilizers can be, for example, antioxidants selected in particular from α-tocopherol, ascorbyl palmitate, BHT (butyl hydroxytoluene), BHA (butyl hydroxyanisole), propyl gallate or malic acid.

Konzervansi se mogu odabrati, na primjer, između natrijevog metabisulfita, propilen glikola, etanola ili glicerina. Preservatives can be selected, for example, from sodium metabisulfite, propylene glycol, ethanol or glycerin.

Među sredstvima koja mogu poslužiti za podešavanje viskoznosti, ovdje se mogu spomenuti, na primjer, lecitini, fosfolipidi, propilen glikol alginat, natrijev alginat ili glicerin. Among the agents that can be used to adjust the viscosity, we can mention here, for example, lecithins, phospholipids, propylene glycol alginate, sodium alginate or glycerin.

Sredstva koja mogu modicirati organoleptička svojstva sastava jesu, na primjer, jabučna kiselina, fumarna kiselina, glicerin, vanilin ili mentol. Agents that can modify the organoleptic properties of the composition are, for example, malic acid, fumaric acid, glycerin, vanillin or menthol.

Kad se upotrijebe takovi dodaci, oni mogu predstavljati od 0,001% do 5 mas. % od ukupnog sastava. When such additives are used, they can represent from 0.001% to 5 wt. % of the total composition.

Prema izumu, farmaceutski sastav se može dobiti miješanjem, tamo gdje je to prikladno, osnovne pomoćne tvari {u slučaju krutih ili polukrutih pomoćnih tvari i prema potrebi nakon grijanja), i zatim, prema potrebi, miješanjem s dodacima, i zatim dodatkom derivata azetidina opće formule (Ia) ili (Ib) i, tamo gdje je to prikladno, aktivnog sastojka koji može pojačati učinke derivata azetidina opće formule (Ia) ili (Ib), i održavanjem miješanja tako da se dobije homogenu smjesu. According to the invention, the pharmaceutical composition can be obtained by mixing, where appropriate, the basic excipient (in the case of solid or semi-solid excipients and if necessary after heating), and then, if necessary, mixing with additives, and then adding azetidine derivatives in general of formula (Ia) or (Ib) and, where appropriate, an active ingredient capable of enhancing the effects of azetidine derivatives of general formula (Ia) or (Ib), and by maintaining mixing so as to obtain a homogeneous mixture.

Primjena ovog postupka opisana je s više pojedinosti dolje u primjerima. The application of this procedure is described in more detail below in the examples.

Sastavi prema izumu mogu se dobiti u tekućem, krutom ili u obliku paste. Compositions according to the invention can be obtained in liquid, solid or paste form.

Oni su posebno prikladni za primjenu u obliku tvrdih želatinskih kapsula ili mekih želatinskih kapsula, ili u obliku oralne otopine. They are particularly suitable for administration in the form of hard gelatin capsules or soft gelatin capsules, or in the form of an oral solution.

Sastavi prema izumu imaju posebnu prednost zbog njihove dobre postojanosti/ kako fizičke, tako i kemijske, i povećane biološke raspoloživosti koju oni nude nakon oralnog davanja derivata azetinidina opće formule (Ia) ili (Ib). The compositions according to the invention have a particular advantage due to their good stability/both physical and chemical, and the increased bioavailability they offer after oral administration of azetinidine derivatives of the general formula (Ia) or (Ib).

Posebnu prednost imaju sastavi koji sadrže: Compositions containing:

• najmanje jedan aktivan sastojak opće formule (Ia) ili (Ib), • at least one active ingredient of the general formula (Ia) or (Ib),

• neionski tenzid hidrofilne naravi koji može solubilizirati derivat azetidina opće formule (Ia) ili (Ib), i koji može uzrokovati stvaranje koloidnog sistema, • nonionic surfactant of a hydrophilic nature that can solubilize the azetidine derivative of the general formula (Ia) or (Ib), and that can cause the formation of a colloidal system,

• prema potrebi tenzid lipofiIne naravi koji ima HLB ispod 10, i koji stabilizira sastav, • if necessary, a lipophilic surfactant that has an HLB below 10 and that stabilizes the composition,

• prema potrebi dodatak odabran iz skupine koju čine stabilizatori, konzervansi, sredstva koja omogućuju podešavanje viskoznosti, ili sredstva koja mogu modificirati, na primjer, organoleptička svojstva. • if necessary, an additive selected from the group consisting of stabilizers, preservatives, agents that enable viscosity adjustment, or agents that can modify, for example, organoleptic properties.

Prema drugoj alternativi izuma, prednost imaju sastavi definirani kao gore koji sadrže najmanje jedan aktivan sastojak opće formule (Ia) ili (Ib), koji se može dati prije, istovremeno ili nakon davanja aktivnog sastojka koji može pojačati učinke derivata azetidina opće formule (Ia) ili (Ib). According to another alternative of the invention, compositions defined as above are preferred which contain at least one active ingredient of the general formula (Ia) or (Ib), which can be given before, simultaneously or after the administration of an active ingredient that can enhance the effects of azetidine derivatives of the general formula (Ia) or (Ib).

Podrazumijeva se da predložena garnitura koja sadrži, s jedne strane, sastav prema izumu definiran kao gore, kojem se daje prednost, i s druge strane, sastav koji sadrži aktivan sastojak koji može pojačati učinke derivata azetidina opće formule (Ia) ili (Ib), također spada u opseg predloženog izuma. Također se podrazumijeva da predložena garnitura može sadržavati, kao sastav koji može pojačati učinke derivata azetidina opće formule (Ia) ili (Ib), sastave koji sadrže sibutramin, ili koji sadrže sredstvo koje aktivira dopaminergnu neurotransmisiju u mozgu. It is understood that the proposed kit containing, on the one hand, the composition according to the invention defined as above, which is preferred, and on the other hand, a composition containing an active ingredient capable of enhancing the effects of azetidine derivatives of the general formula (Ia) or (Ib), also falls within the scope of the proposed invention. It is also understood that the proposed set can contain, as a composition that can enhance the effects of azetidine derivatives of the general formula (Ia) or (Ib), compositions that contain sibutramine, or that contain an agent that activates dopaminergic neurotransmission in the brain.

Slijedeći primjeri, koji su dati bez namjere ograničenja, prikazuju sastave prema predloženom izumu. The following examples, which are given without the intention of limitation, illustrate compositions according to the proposed invention.

Primjer 1 Example 1

Mješavina Labrasol/Labrafil M1944CS, omjera 60/40 (m/m) pripravljena je pri sobnoj temperaturi (20°C) miješanjem u čaši s magnetskom miješalicom 15 minuta 14,4 g Labrasola i 9,6 g Labrafila M1944CS. Opažena je vrlo dobra sposobnost miješanja. The Labrasol/Labrafil M1944CS mixture, ratio 60/40 (m/m) was prepared at room temperature (20°C) by mixing 14.4 g of Labrasol and 9.6 g of Labrafil M1944CS in a glass with a magnetic stirrer for 15 minutes. A very good mixing ability was observed.

200 mg 1-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil) (metilsulfonil)-metilen] azetidina se stavi u drugu čašu i nadopuni se na 20 g s mješavinom Labrasol/Labrafila M1944CS 60/40 tako da se dobije krajnju koncentraciju od 10 mg/g l-[bis (4-klorfenil)metil]-3-[(3,5-difluorfenil)-(metil-sulfonil)metilen]azetidina. Mješavinu od 3 sastojka se miješa mehanički (300 okr/min) 2 sata pri sobnoj temperaturi tako da se l-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil)(metilsulfonil)metilen]azetidin potpuno otopi. Dobivenu otopinu se podijeli po l g u začepijene staklene bočice i pohrani se pri 5°C. 200 mg of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)-methylene] azetidine is placed in another beaker and made up to 20 g with Labrasol/Labrafila M1944CS 60/40 mixture. so as to obtain a final concentration of 10 mg/g of 1-[bis (4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methyl-sulfonyl)methylene]azetidine. The mixture of 3 ingredients is stirred mechanically (300 rpm) for 2 hours at room temperature so that l-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is completely dissolve. The resulting solution is divided into 1 g portions in sealed glass vials and stored at 5°C.

Zadovoljavajuća kemijska i fizička postojanost dokazana je nakon l mjeseca pri 5°C. Satisfactory chemical and physical stability has been demonstrated after 1 month at 5°C.

U usporedbi sa sastavom l-[bis(4-klor-fenil)metil]-3-[(3,5-difluorfenil) (metil-sulfonilmetilen]azetidina u Miglyol-u 812®, opaženi su pojačani farmakokinetički parametri za faktor od najmanje 2,5. Compared to the composition of l-[bis(4-chloro-phenyl)methyl]-3-[(3,5-difluorophenyl) (methyl-sulfonylmethylene]azetidine in Miglyol 812®, enhanced pharmacokinetic parameters by a factor of at least 2.5.

Primjer 2 Example 2

Provedbom postupka kao gore u primjeru 1, ali počevši sa 16,8 g Labrasola i 7,2 g Labrafila M1944CS za pripravu mješavine Labrasol/Labrafila M1944CS s omjerom 70/30 (m/m), pripravljen je sastav koji je sadržavao 200 mg 1-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil)-(metil-sulfonil)-metilen]azetidina namještenog na 20 g s mješavinom Labrasol/Labrafila M1944CS 70/30 tako da je dobivena krajnja koncentracija od 10 mg/g l-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil)-(metil-sulfonil)-metilen]azetidina. By carrying out the procedure as above in example 1, but starting with 16.8 g of Labrasol and 7.2 g of Labrafil M1944CS to prepare a mixture of Labrasol/Labrafil M1944CS with a ratio of 70/30 (m/m), a composition containing 200 mg of 1 -[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methyl-sulfonyl)-methylene]azetidine adjusted to 20 g with a mixture of Labrasol/Labrafil M1944CS 70/30 so that a final concentration of 10 mg/g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methyl-sulfonyl)-methylene]azetidine.

Zadovoljavajuća kemijska i fizička postojanost dokazana je nakon 1 mjeseca pri 5°C. Satisfactory chemical and physical stability has been demonstrated after 1 month at 5°C.

Ovaj sastav je ispitan pokusom in vitro u usporedbi sa sastavom iz primjera 1. 400 mg sastava inkubirano je u 20 ml medija koji simulira želučanu tekućinu (literatura USP). Nakon inkubacije 2 sata pri 37°C, proveden je HPLC pokus nakon filtracije na filteru 2 m da se utvrdi postojanost koloidne formulacije. Postojanost ovog sastava ekvivalentna je ponašanju sastava iz primjera 1. This composition was tested in an in vitro experiment in comparison with the composition from Example 1. 400 mg of the composition was incubated in 20 ml of medium simulating gastric fluid (USP literature). After incubation for 2 hours at 37°C, an HPLC experiment was performed after filtration on a 2 m filter to determine the stability of the colloidal formulation. The stability of this composition is equivalent to the behavior of the composition from example 1.

Primjer 3 Example 3

Provedbom postupka kao gore u primjeru l, ali počevši sa 19,2 g Labrasola i 4,8 g Labrafila M1944CS za pripravu mješavine Labrasol/Labrafila M1944CS s omjerom 80/20 (m/m), pripravljen je sastav koji je sadržavao 200 mg l-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil)(metilsulfonil)-metilen]azetidina i koji je namješten na 20 g s mješavinom Labrasol/Labrafila M1944CS 80/20 tako da je dobivena krajnja koncentracija od 10 mg/g l-[bis(4-klorfenil(metil]-3-[(3,5-difluorfenil)-(metil-sulfonil)metilen]azetidina. By carrying out the procedure as above in example 1, but starting with 19.2 g of Labrasol and 4.8 g of Labrafil M1944CS to prepare a mixture of Labrasol/Labrafil M1944CS with a ratio of 80/20 (m/m), a composition was prepared that contained 200 mg l -[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine and which was adjusted to 20 g with a mixture of Labrasol/Labrafila M1944CS 80/20 so that a final concentration of 10 mg/g of 1-[bis(4-chlorophenyl(methyl)-3-[(3,5-difluorophenyl)-(methyl-sulfonyl)methylene]azetidine.

Zadovoljavajuća kemijska i fizička postojanost dokazana je nakon 1 mjeseca pri 5°C. Satisfactory chemical and physical stability has been demonstrated after 1 month at 5°C.

Ovaj sastav je ispitan pokusom in vitro u usporedbi sa sastavom iz primjera 1. 400 mg sastava inkubirano je u 20 ml medija koji simulira želučanu tekućinu (literatura USP). Nakon inkubacije 2 sata pri 37°C, proveden je HPLC pokus nakon filtracije na filteru 2 μm da se utvrdi postojanost koloidne formulacije. Postojanost ovog sastava ekvivalentna je ponašanju sastava iz primjera 1. This composition was tested in an in vitro experiment in comparison with the composition from Example 1. 400 mg of the composition was incubated in 20 ml of medium simulating gastric fluid (USP literature). After incubation for 2 hours at 37°C, an HPLC experiment was performed after filtration on a 2 μm filter to determine the stability of the colloidal formulation. The stability of this composition is equivalent to the behavior of the composition from example 1.

Primjer 4 Example 4

Provedbom postupka kao gore u primjeru 1, ali počevši s 21,6 g Labrasola i 2,4 g Labrafila M1944CS za pripravu mješavine Labrasol/Labrafila M1944CS s omjerom 90/10 (m/m) pripravljen je sastav koji je sadržavao 200 mg l-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil)-(metilsulfonil)-metilen]azetidina koji je namješten na 20 g s mješavinom Labrasol/Labrafila M1944CS 90/10 tako da je dobivena krajnja koncentracija od 10 mg/g l-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil)(metil-sulfonil)metilen]azetidina. By carrying out the procedure as above in example 1, but starting with 21.6 g of Labrasol and 2.4 g of Labrafil M1944CS to prepare a Labrasol/Labrafil M1944CS mixture with a ratio of 90/10 (m/m), a composition containing 200 mg l- [bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methylene]azetidine which was adjusted to 20 g with a mixture of Labrasol/Labrafila M1944CS 90/10 so that a final concentration of 10 mg/g 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine.

Zadovoljavajuća kemijska i fizička postojanost dokazana je nakon 1 mjeseca pri 5°C. Satisfactory chemical and physical stability has been demonstrated after 1 month at 5°C.

Ovaj sastav je ispitan pokusom in vitro u usporedbi sa sastavom iz primjera 1. 400 mg sastava inkubirano je u 20 ml medija koji simulira želučanu tekućinu (literatura USP). Nakon inkubacije 2 sata pri 37°C, proveden je HPLC pokus nakon filtracije na filteru 2 um da se utvrdi postojanost koloidne formulacije. This composition was tested in an in vitro experiment in comparison with the composition from Example 1. 400 mg of the composition was incubated in 20 ml of medium simulating gastric fluid (USP literature). After incubation for 2 hours at 37°C, an HPLC experiment was performed after filtration on a 2 µm filter to determine the stability of the colloidal formulation.

Postojanost ovog sastava ekvivalentna je ponašanju sastava iz primjera 1. The stability of this composition is equivalent to the behavior of the composition from example 1.

Primjer 5 Example 5

Provedbom postupka kao gore u primjeru l, ali počevši samo s 24 g Labrasola pripravljen je sastav koji je sadržavao 200 mg l-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil) (metil-sulfonil)metilen]azetidina koji je namješten na 20 g s Labrasolom tako da je dobivena krajnja koncentracija od 10 mg/g l-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil)(metil-sulfonil)metilen]azetidina. By carrying out the procedure as above in example 1, but starting only with 24 g of Labrasol, a composition containing 200 mg of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) (methyl-sulfonyl) was prepared. methylene]azetidine which was adjusted to 20 g with Labrasol so that a final concentration of 10 mg/g l-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene] was obtained azetidine.

Zadovoljavajuća kemijska i fizička postojanost dokazana je nakon l mjeseca pri 5°C. Satisfactory chemical and physical stability has been demonstrated after 1 month at 5°C.

Ovaj sastav je ispitan pokusom in vitro u usporedbi sa sastavom iz primjera 1. 400 mg sastava inkubirano je u 20 ml medija koji simulira želučanu tekućinu (literatura USP). Nakon inkubacije 2 sata pri 37°C, proveden je HPLC pokus nakon filtracije na filteru 2 μm da se utvrdi postojanost koloidne formulacije. This composition was tested in an in vitro experiment in comparison with the composition from Example 1. 400 mg of the composition was incubated in 20 ml of medium simulating gastric fluid (USP literature). After incubation for 2 hours at 37°C, an HPLC experiment was performed after filtration on a 2 μm filter to determine the stability of the colloidal formulation.

Postojanost ovog sastava ekvivalentna je ponašanju sastava iz primjera 1. The stability of this composition is equivalent to the behavior of the composition from example 1.

Primjer 6 Example 6

Provedbom postupka kao gore u primjeru 1, ali počevši s 24 g Gelucira 44/14 kao zamjene za mješavinu Labrasol/ Labrafila M1944CS. Gelucir 44/14 se najprije rastali pri temperaturi u području od 55°C. 200 mg l-[bis(4-klorfenil)-metil]-3-[(3,5-difluorfenil)(metilsulfonil)-metilen]-azetidina se stavi u čašu i namjesti se na 20 g s Gelucirom 44/14 tako da se dobije krajnju koncentraciju od 10 mg/g 1-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil)(metil-sulfonil)metilen]azetidina. Mješavinu od 2 sastojka se miješa s magnetskom miješalicom (300 okr/min) 1 sat pri 50-55°C da se 1-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil)-(metilsulfonil)-metilen]-azetidin potpuno otopi. Masu se podijeli u tvrde želatinske kapsule koje se pohrane preko noći u zaleđivač pri -20°C. Zatim se ljusku tvrdih želatinskih kapsula odvoji pomoću noža od krute mase iz kapsula. Uzorci se pohrane u začepljene bočice pri 5°C. By carrying out the procedure as above in example 1, but starting with 24 g of Gelucira 44/14 as a substitute for the mixture of Labrasol/ Labrafila M1944CS. Gelucir 44/14 first melted at a temperature in the range of 55°C. 200 mg of l-[bis(4-chlorophenyl)-methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]-azetidine is placed in a beaker and adjusted to 20 g with Gelucir 44/14 so that obtained a final concentration of 10 mg/g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine. The mixture of 2 ingredients was stirred with a magnetic stirrer (300 rpm) for 1 hour at 50-55°C to give 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl )-methylene]-azetidine dissolves completely. The mass is divided into hard gelatin capsules that are stored overnight in a freezer at -20°C. Then, the shell of the hard gelatin capsules is separated from the hard mass of the capsules using a knife. The samples are stored in stoppered vials at 5°C.

Zadovoljavajuća kemijska i fizička postojanost dokazana je nakon l mjeseca pri 5°C. Satisfactory chemical and physical stability has been demonstrated after 1 month at 5°C.

Ovaj sastav je ispitan pokusom in vitro u usporedbi sa sastavom iz primjera 1. 400 mg sastava inkubirano je u 20 ml medija koji simulira želučanu tekućinu (literatura USP). Nakon inkubacije 2 sata pri 37°C, proveden je HPLC pokus nakon filtracije na filteru 2 μm da se utvrdi postojanost koloidne formulacije. This composition was tested in an in vitro experiment in comparison with the composition from Example 1. 400 mg of the composition was incubated in 20 ml of medium simulating gastric fluid (USP literature). After incubation for 2 hours at 37°C, an HPLC experiment was performed after filtration on a 2 μm filter to determine the stability of the colloidal formulation.

Postojanost ovog sastava ekvivalentna je ponašanju sastava iz primjera 1. The stability of this composition is equivalent to the behavior of the composition from example 1.

Primjer 7 Example 7

Mješavina Labrasol/Labrafila M1944CS s omjerom 60/40 (m/m) pripravljena je pri sobnoj temperaturi (20°C) miješanjem u čaši s magnetskom mješalicom 15 minuta 30 g Labrasola i 20 g Labrafila M1944CS. Opažena je vrlo dobra sposobnost miješanja. 20 mg l-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil) (metilsulfonil)-metilen]azetidina se stavi u menzuru od 10 ml. Kad se namjesti na 10 ml s potrebnom količinom mješavine Labrasol/Labrafila M1944CS 60/40, smjesu od 3 sastojka se miješa s magnetskom miješalicom (500 okr/min) 2 sata pri sobnoj temperaturi da se 1-[bis(4-klorfenil)metil]-3-[(3,5-difluorfenil)(metilsulfonil) -metilen]-azetidin potpuno otopi. Dobivenu otopinu se podijeli u začepijene staklene bočice po 2,5 ml i pohrani se pri 5°C. The Labrasol/Labrafila M1944CS mixture with a ratio of 60/40 (m/m) was prepared at room temperature (20°C) by mixing 30 g of Labrasol and 20 g of Labrafil M1944CS in a beaker with a magnetic stirrer for 15 minutes. A very good mixing ability was observed. 20 mg of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)-methylene]azetidine is placed in a 10 ml beaker. When adjusted to 10 ml with the required amount of Labrasol/Labrafil M1944CS 60/40 mixture, the 3-ingredient mixture was stirred with a magnetic stirrer (500 rpm) for 2 hours at room temperature to give 1-[bis(4-chlorophenyl)methyl ]-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]-azetidine dissolves completely. The resulting solution is divided into 2.5 ml stoppered glass vials and stored at 5°C.

Ova formulacija koncentracije od 2 mg/ml 1-[bis(4-klorfenil)metil]-3-[(3,5-difluor-fenil)-(metilsulfonil)-metilen]-azetidina je upotrijebljena za provedbu farmako-kinetičkih studija na majmunima nakon oralnog davanja doze od 1 mg/kg. U tu svrhu ta je otopina razrijeđena na jednu desetinu s jabučnim sokom da se olakša davanje životinji. Emulzija dobivena nakon razrjeđivanja bila je fizički i kemijski postojana najmanje jedan sat. This formulation with a concentration of 2 mg/ml of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro-phenyl)-(methylsulfonyl)-methylene]-azetidine was used to perform pharmacokinetic studies on monkeys after oral administration of a dose of 1 mg/kg. For this purpose, this solution is diluted to one tenth with apple juice to facilitate administration to the animal. The emulsion obtained after dilution was physically and chemically stable for at least one hour.

Primjer 8 Example 8

Mješavina Labrasol/Labrafila M1944CS s omjerom 60/40 (m/m) pripravljena je pri sobnoj temperaturi (20°C) miješanjem u čaši s magnetskom miješalicom 15 minuta 30 g Labrasola i 20 g Labrafila M1944CS. Opažena je vrlo dobra sposobnost miješanja. 20 mg N-{1-[bis(4-klorfenil)metil]-azetidin-3-il}-N-(3,5-difluorfenil)-metilsulfonamida se stavi u menzuru od 10 ml. Kad se nadopuni na 10 ml s potrebnom količinom mješavine Labrasol/Labrafila M1944CS 60/40, mješavinu od 3 sastojka se miješa s magnetskom miješalicom (500 okr/min) 2 sata pri sobnoj temperaturi da se N-{1-[bis(4-klorfenil)metil]-azetidin-3-il}-N-(3,5-difluor-fenil)-metilsulfonamida potpuno otopi. Dobivenu otopinu se podijeli po 2,5 ml u začepijene bočice i pohrani se pri 5°C. The Labrasol/Labrafila M1944CS mixture with a ratio of 60/40 (m/m) was prepared at room temperature (20°C) by mixing 30 g of Labrasol and 20 g of Labrafil M1944CS in a beaker with a magnetic stirrer for 15 minutes. A very good mixing ability was observed. 20 mg of N-{1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide is placed in a 10 ml beaker. When made up to 10 ml with the required amount of Labrasol/Labrafila M1944CS 60/40 mixture, the 3-ingredient mixture was stirred with a magnetic stirrer (500 rpm) for 2 hours at room temperature to give N-{1-[bis(4- chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluoro-phenyl)-methylsulfonamide completely dissolves. The obtained solution is divided into 2.5 ml bottles and stored at 5°C.

Ova formulacije koncentracije od 2 mg/ml N-{1-[bis(4-klorfenil)metil]azetidin-3-il}-N-(3,5-difluorfenil)metilsulfonamida je upotrijebljena za provedbu farmakokinetičkih studija na majmunima nakon oralnog davanja doze od 1 mg/kg. This formulation at a concentration of 2 mg/ml of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide was used to conduct pharmacokinetic studies in monkeys after oral administration. doses of 1 mg/kg.

U tu svrhu ta je otopina razrijeđena na jednu desetinu s jabučnim sokom da se olakša davanje životinji. Emulzija dobivena nakon razrjeđivanja bila je fizički i kemijski postojana najmanje jedan sat. For this purpose, this solution is diluted to one tenth with apple juice to facilitate administration to the animal. The emulsion obtained after dilution was physically and chemically stable for at least one hour.

Primjer 9 Example 9

Mješavina Labrasol/Labrafila M1944CS s omjerom 60/40 (m/m) pripravljena je pri sobnoj temperaturi (20°C) miješanjem u čaši s magnetskom mješalicom 15 minuta 30 g Labrasola i 20 g Labrafila M1944CS. Opažena je vrlo dobra sposobnost miješanja. 10 mg N-{1-[bis(4-klor-fenil)-metil]azetidin-3-il}-N-pirid-3-ilmetil-sulfonamida se stavi u menzuru od 10 ml. Kad se nadopuni na 10 ml s potrebnom količinom mješavine Labrasol/Labrafila M1944CS 60/40, mješavinu od 3 sastojka se miješa s magnetskom mješalicom (500 okr/min) 2 sata pri sobnoj temperaturi da se N-{1-[bis(4-klor-fenil)metil]azetidin-3-il}-N-pirid-3-ilmetil-sulfonamid potpuno otopi. Dobivenu otopinu se podijeli po 2,5 ml u začepljene bočice i pohrani se pri 5°C. The Labrasol/Labrafila M1944CS mixture with a ratio of 60/40 (m/m) was prepared at room temperature (20°C) by mixing 30 g of Labrasol and 20 g of Labrafil M1944CS in a beaker with a magnetic stirrer for 15 minutes. A very good mixing ability was observed. 10 mg of N-{1-[bis(4-chloro-phenyl)-methyl]azetidin-3-yl}-N-pyrid-3-ylmethyl-sulfonamide is placed in a 10 ml beaker. When made up to 10 ml with the required amount of Labrasol/Labrafila M1944CS 60/40 mixture, the 3-ingredient mixture was stirred with a magnetic stirrer (500 rpm) for 2 hours at room temperature to give N-{1-[bis(4- chloro-phenyl)methyl]azetidin-3-yl}-N-pyrid-3-ylmethyl-sulfonamide dissolves completely. The resulting solution is divided into 2.5 ml vials and stored at 5°C.

Ova formulacije koncentracije od 1 mg/ml N-{1-[bis(4-klorfenil)metil]azetidin-3-il}-N-pirid-3-ilmetilsulfonamida je upotrijebljena za provedbu farmakokinetičkih studija na štakorima nakon oralnog davanja doze od 1 mg/kg. This formulation at a concentration of 1 mg/ml of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-pyrid-3-ylmethylsulfonamide was used to conduct pharmacokinetic studies in rats after oral administration of a dose of 1 mg/kg.

Primjer 10 Example 10

Provedbom postupka kao gore u primjeru 9, ali počevši s 30 mg N-{1-[bis(4-klorfenil)metil]azetidin-3-il}-N-pirid-3-ilmetil-sulfonamida namještenog na 10 ml s mješavinom Labrasol/Labrafila M1944CS 60/40, pripravljena je otopina koja je sadržavala 3 mg/ml N-{1-[bis(4-klor-fenil)metilj-azetidin-3-il}-N-pirid-3-ilmetilsulfonarnida. By carrying out the procedure as above in Example 9, but starting with 30 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-pyrid-3-ylmethyl-sulfonamide adjusted to 10 ml with the Labrasol mixture /Labrafila M1944CS 60/40, a solution containing 3 mg/ml of N-{1-[bis(4-chloro-phenyl)methyl-azetidin-3-yl}-N-pyrid-3-ylmethylsulfonamide was prepared.

Ova formulacija koncentracije od 3 mg/ml N-{1-[bis(4-klorfenil)metil]azetidin-3-il}-N-pirid-3-ilmetilsulfonamida je upotrijebljena za provedbu farmakoloških studija na štakorima nakon oralnog davanja doze od 3 mg/kg. This formulation at a concentration of 3 mg/ml of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-pyrid-3-ylmethylsulfonamide was used to conduct pharmacological studies in rats after oral administration of a dose of 3 mg/kg.

Primjer 11 Example 11

Provedbom postupka kao gore u primjeru 9, ali počevši s 50 mg N-{1-[bis(4-klorfenil)metil]azetidin-3-il}-N-pirid-3-ilmetil-sulfonamida namještenog na 5 ml s mješavinom Labrasol/Labrafila M1944CS 60/40, pripravljena je otopina koja je sadržavala 10 mg/ml N-{1-[bis{4-klorfenil)-metil]azetidin-3-il}-N-pirid-3-ilmetilsulfonamida. By carrying out the procedure as above in Example 9, but starting with 50 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-pyrid-3-ylmethyl-sulfonamide adjusted to 5 ml with the Labrasol mixture /Labrafila M1944CS 60/40, a solution containing 10 mg/ml of N-{1-[bis{4-chlorophenyl)-methyl]azetidin-3-yl}-N-pyrid-3-ylmethylsulfonamide was prepared.

Ova formulacija je pri koncentraciji od 10 mg/ml N-{1-[bis(4-klorfenil)metil]azetidin-3-il}-N-pirid-3-ilmetil-sulfonamida upotrijebljena za provedbu farmakoloških studija na štakorima nakon oralnog davanja doze od 10 mg/kg. This formulation at a concentration of 10 mg/ml of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-pyrid-3-ylmethyl-sulfonamide was used to conduct pharmacological studies on rats after oral administration doses of 10 mg/kg.

Claims (17)

1. Postojan farmaceutski sastav, naznačen time, da on sadrži najmanje jedan derivat azetidina opće formule: [image] u kojoj Ar je aromatska ili heteroaromatska skupina prema potrebi supstitirana s jednim ili više (C1-C4)alkila, halogenih, NO2, CN, (C1-C4) alkoksi ili OH skupina, prema potrebi u kombinaciji s drugim aktivnim sastojkom koji može pojačati učinke azetidinskog derivata opće formule (Ia) ili (Ib) , u sistem koji sadrži najviše 2 osnovne pomoćne tvari odabrane između nonionskih tenzida hidrofilne naravi koje mogu solubilizirati derivat azetidina opće formule (Ia) ili (Ib) i, tamo gdje je to prikladno, aktivni sastojak koji može pojačati učinke azetidinskog derivata, i koji može uzrokovati stvaranje koloidnog sistema, prema potrebi s dodatkom druge pomoćne tvari lipofilne naravi, koja stabilizira formulaciju.1. A stable pharmaceutical composition, characterized in that it contains at least one azetidine derivative of the general formula: [image] where Ar is an aromatic or heteroaromatic group optionally substituted with one or more (C1-C4) alkyl, halogen, NO2, CN, (C1-C4) alkoxy or OH groups, optionally in combination with another active ingredient that can enhance the effects of the azetidine derivative of the general formula (Ia) or (Ib), in a system containing at most 2 basic excipients selected from nonionic surfactants of a hydrophilic nature that can solubilize the azetidine derivative of the general formula (Ia) or (Ib) and, where appropriate, an active ingredient that can enhance the effects of the azetidine derivative, which can cause the formation of a colloidal system, if necessary with the addition of another auxiliary substance of a lipophilic nature, which stabilizes the formulation. 2. Farmaceutski sastav prema zahtjevu 1, naznačen time, da on sadrži: • najmanje jedan derivat azetidina opće formule (Ia) ili (Ib) prema zahtjevu 1, • prema potrebi drugi aktivan sastojak koji može pojačati učinke azetidinskog derivata opće formule (Ia) ili (Ib), • neionski tenzid hidrofilne naravi koji može solubilizirati derivat azetidina opće formule (Ia) ili (Ib) i, tamo gdje je to prikladno, aktivni sastojak koji može pojačati učinke azetidinskog derivata, i koji može uzrokovati stvaranje koloidnog sistema, • prema potrebi tenzid lipofilne naravi koji ima HLB ispod 10, i koji stabilizira sastav, • prema potrebi s dodatkom odabranim iz skupine koju čine stabilizatori, konzervansi, sredstva koja omogućuju podešavanje viskoznosti, ili sredstva koja mogu modificirati, na primjer, organoleptička svojstva.2. Pharmaceutical composition according to claim 1, characterized in that it contains: • at least one azetidine derivative of the general formula (Ia) or (Ib) according to claim 1, • if necessary, another active ingredient that can enhance the effects of the azetidine derivative of the general formula (Ia) or (Ib), • a nonionic surfactant of a hydrophilic nature that can solubilize an azetidine derivative of the general formula (Ia) or (Ib) and, where appropriate, an active ingredient that can enhance the effects of the azetidine derivative, and that can cause the formation of a colloidal system, • if necessary, a lipophilic surfactant that has an HLB below 10 and that stabilizes the composition, • as necessary with an additive selected from the group consisting of stabilizers, preservatives, agents that enable viscosity adjustment, or agents that can modify, for example, organoleptic properties. 3. Farmaceutski sastav prema zahtjevu 1 ili 2, naznačen time, da on sadrži: • najmanje jedan derivat azetidina opće formule (Ia) ili (Ib) prema zahtjevu 1, • neionski tenzid hidrofilne naravi koji može solubilizirati derivat azetidina prema zahtjevu 1, i koji može uzrokovati stvaranje koloidnog sistema, • prema potrebi tenzid lipofilne naravi koji ima HLB ispod 10, i koji stabilizira sastav, i • prema potrebi dodatak odabran iz skupine koju čine stabilizatori, konzervansi, sredstva koja omogućuju podešavanje viskoznosti, ili sredstva koja mogu modificirati, na primjer, organoleptička svojstva.3. Pharmaceutical composition according to claim 1 or 2, characterized in that it contains: • at least one azetidine derivative of the general formula (Ia) or (Ib) according to claim 1, • nonionic surfactant of a hydrophilic nature that can solubilize the azetidine derivative according to claim 1, and which can cause the formation of a colloidal system, • if necessary, a lipophilic surfactant that has an HLB below 10 and that stabilizes the composition, i • if necessary, an additive selected from the group consisting of stabilizers, preservatives, agents that enable viscosity adjustment, or agents that can modify, for example, organoleptic properties. 4. Farmaceutski sastav prema bilo kojem zahtjevu 1 do 3, naznačen time, da je aromatska skupina azetidinskog derivata opće formule (Ia) ili (Ib) odabrana između fenilne ili naftilne skupine.4. Pharmaceutical composition according to any of claims 1 to 3, characterized in that the aromatic group of the azetidine derivative of the general formula (Ia) or (Ib) is selected from a phenyl or naphthyl group. 5. Farmaceutski sastav prema bilo kojem zahtjevu 1 do 3, naznačen time, da je heteroaromatska skupina odabran iz niza koji čine piridil, furil, tienil, tiazolil, iraidazolil i oksazolilna skupina.5. Pharmaceutical composition according to any of claims 1 to 3, characterized in that the heteroaromatic group is selected from the group consisting of pyridyl, furyl, thienyl, thiazolyl, iridazolyl and oxazolyl group. 6. Farmaceutski sastav prema bilo kojem zahtjevu 1 do 5, naznačen time, da je neionski tenzid hidrofilne naravi koji može solubilizirati derivat azetidina opće formule (Ia) ili (Ib) i, tamo gdje je to prikladno, aktivni sastojak koji može pojačati učinke azetidinskog derivata, i koji može uzrokovati stvaranje koloidnog sistema, odabran između glicerida polietilen glikola i zasićenih masnih kiselina čiji HLB je između 10 i 20.6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it is a nonionic surfactant of a hydrophilic nature that can solubilize an azetidine derivative of the general formula (Ia) or (Ib) and, where appropriate, an active ingredient that can enhance the effects of azetidine derivatives, and which can cause the formation of a colloidal system, selected from glycerides of polyethylene glycol and saturated fatty acids whose HLB is between 10 and 20. 7. Farmaceutski sastav prema zahtjevu 6, naznačen time, da gliceridi polietilen glikola i zasićenih masnih kiselina su gliceridi polietilen glikola i zasićenih masnih kiselina koji sadrže od 6 do 18 ugljikovih atoma.7. Pharmaceutical composition according to claim 6, characterized in that the glycerides of polyethylene glycol and saturated fatty acids are glycerides of polyethylene glycol and saturated fatty acids containing from 6 to 18 carbon atoms. 8. Farmaceutski sastav prema zahtjevu 6 ili 7, naznačen time, da gliceridi mogu biti prirodnog ili sintetičkog porijekla.8. Pharmaceutical composition according to claim 6 or 7, characterized in that the glycerides can be of natural or synthetic origin. 9. Farmaceutski sastav prema bilo kojem zahtjevu 1 do 8, naznačen time, da je pomoćna tvar lipofilne naravi, koja stabilizira sastav, odabrana između glicerida polietilen glikola i nezasićenih masnih kiselina, estera polietilen glikola i masnih kiselina, ili estera masnih kiselina i sorbitola koji imaju HLB manji od 10.9. Pharmaceutical composition according to any claim 1 to 8, characterized in that the auxiliary substance of a lipophilic nature, which stabilizes the composition, is selected from glycerides of polyethylene glycol and unsaturated fatty acids, esters of polyethylene glycol and fatty acids, or esters of fatty acids and sorbitol which have an HLB less than 10. 10. Farmaceutski sastav prema bilo kojem zahtjevu 1 do 9, naznačen time, da se sistem koji sadrži najviše 2 pomoćne tvari sastoji od Labrasol®-a, Gelucire®-a ili para Labrafil®/Labrasol®-a.10. Pharmaceutical composition according to any claim 1 to 9, characterized in that the system containing at most 2 excipients consists of Labrasol®, Gelucire® or the Labrafil®/Labrasol® pair. 11. Farmaceutski sastav prema bilo kojem zahtjevu 1 do 10, naznačen time, da je aktivni sastojak dobiven od azetidina, definiranog u zahtjevu 1, prisutan količinom od 0,01 do 70 mas. % od ukupnog sastava.11. Pharmaceutical composition according to any claim 1 to 10, characterized in that the active ingredient obtained from azetidine, defined in claim 1, is present in an amount of 0.01 to 70 wt. % of the total composition. 12. Farmaceutski sastav prema bilo kojem zahtjevu 1 do 11, naznačen time, da neionski tenzid hidrofilne naravi koji može solubilizirati derivat azetidina prema zahtjevu 1, i koji može uzrokovati stvaranje koloidnog sistema, je prisutan količinom od 20 do 100% u odnosu na ukupnu masu pomoćne tvari u sastavu.12. Pharmaceutical composition according to any claim 1 to 11, characterized in that the nonionic surfactant of a hydrophilic nature, which can solubilize the azetidine derivative according to claim 1, and which can cause the formation of a colloidal system, is present in an amount of 20 to 100% in relation to the total mass auxiliary substances in the composition. 13. Farmaceutski sastav prema bilo kojem zahtjevu 1 do 12, naznačen time, da tamo gdje je to prikladno, sredstvo lipofilne naravi, koje stabilizira formulaciju, je prisutno količinom od 0,1 do 60% u odnosu na ukupnu masu pomoćne tvari u sastavu.13. Pharmaceutical composition according to any claim 1 to 12, characterized in that, where appropriate, an agent of a lipophilic nature, which stabilizes the formulation, is present in an amount of 0.1 to 60% in relation to the total weight of the excipient in the composition. 14. Postupak za pripravu sastava prema bilo kojem zahtjevu 1 do 13, naznačen time, da se u slučaju krute ili polukrute pomoćne tvari pripravi smjesu osnovne pomoćne tvari, tamo gdje je to prikladno, ako je potrebno grijanjem, i zatim se, prema potrebi, pripravi smjesu s dodacima, i zatim se doda derivat azetidina definiran kao u zahtjevu 1 i, tamo gdje je to prikladno, doda se aktivni sastojak koji može pojačati učinke azetidinskog derivata opće formule (Ia) ili (Ib), definiran kao u zahtjevu 1 i miješanje se održava tako da se dobije homogenu smjesu.14. The process for preparing the composition according to any of claims 1 to 13, characterized in that, in the case of a solid or semi-solid auxiliary substance, a mixture of the basic auxiliary substance is prepared, where appropriate, if necessary by heating, and then, if necessary, prepare a mixture with additives, and then add the azetidine derivative defined as in claim 1 and, where appropriate, add an active ingredient capable of enhancing the effects of the azetidine derivative of the general formula (Ia) or (Ib), defined as in claim 1 and mixing is maintained so that a homogeneous mixture is obtained. 15. Garnitura, naznačena time, da ona sadrži sastav prema zahtjevu 3 i sastav koji sadrži aktivni sastojak koji može pojačati učinke azetidinskog derivata definiranog u zahtjevu 1.15. Set, characterized in that it contains a composition according to claim 3 and a composition containing an active ingredient that can enhance the effects of the azetidine derivative defined in claim 1. 16. Garnitura prema zahtjevu 15, naznačena time, da ona sadrži sastav prema zahtjevu 3 i sastav koji sadrži sibutramin.16. The set according to claim 15, characterized in that it contains the composition according to claim 3 and the composition containing sibutramine. 17. Garnitura prema zahtjevu 15, naznačena time, da ona sadrži sastav prema zahtjevu 3 i sastav koji sadrži sredstvo koje aktivira dopaminergnu neurotransmisiju u mozgu.17. Set according to claim 15, characterized in that it contains a composition according to claim 3 and a composition containing an agent that activates dopaminergic neurotransmission in the brain.
HR20040575A 2001-12-21 2004-06-18 Pharmaceutical compositions based on azetidine derivatives HRP20040575A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0116638A FR2833842B1 (en) 2001-12-21 2001-12-21 PHARMACEUTICAL COMPOSITIONS BASED ON AZETIDINE DERIVATIVES
PCT/FR2002/004514 WO2003053431A2 (en) 2001-12-21 2002-12-20 Pharmaceutical compositions based on azetidine derivatives

Publications (1)

Publication Number Publication Date
HRP20040575A2 true HRP20040575A2 (en) 2004-10-31

Family

ID=8870824

Family Applications (1)

Application Number Title Priority Date Filing Date
HR20040575A HRP20040575A2 (en) 2001-12-21 2004-06-18 Pharmaceutical compositions based on azetidine derivatives

Country Status (32)

Country Link
EP (1) EP1458413B1 (en)
JP (1) JP5021887B2 (en)
KR (1) KR20040068308A (en)
CN (1) CN100388918C (en)
AP (1) AP1754A (en)
AR (1) AR037687A1 (en)
AU (1) AU2002364866B2 (en)
BR (1) BR0215048A (en)
CA (1) CA2470443A1 (en)
CO (1) CO5590911A2 (en)
DE (1) DE60233071D1 (en)
DK (1) DK1458413T3 (en)
EA (1) EA006510B1 (en)
EC (1) ECSP045162A (en)
FR (1) FR2833842B1 (en)
HK (1) HK1070840A1 (en)
HR (1) HRP20040575A2 (en)
HU (1) HUP0402586A3 (en)
IL (1) IL162563A0 (en)
MA (1) MA27086A1 (en)
ME (1) MEP16608A (en)
MX (1) MXPA04005558A (en)
MY (1) MY138172A (en)
NO (1) NO20042781L (en)
NZ (1) NZ533225A (en)
OA (1) OA12750A (en)
PL (1) PL203248B1 (en)
RS (1) RS55504A (en)
TW (1) TWI256304B (en)
UA (1) UA77736C2 (en)
WO (1) WO2003053431A2 (en)
ZA (1) ZA200404338B (en)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1498122A1 (en) * 2003-07-18 2005-01-19 Aventis Pharma S.A. Semi-solid systems containing azetidine derivatives
EP1498123A1 (en) * 2003-07-18 2005-01-19 Aventis Pharma S.A. Emulsifying systems containing azetidine derivatives
KR20060124756A (en) 2004-02-17 2006-12-05 라보라토리오스 델 드라. 에스테브.에스.에이. Substituted azetidine compounds, their preparation and use as medicaments
FR2879932B1 (en) * 2004-12-27 2007-03-23 Aventis Pharma Sa FORMULATIONS INJECTABLE OR ORALLY ADMINISTRATIVE OF AZETIDINE DERIVATIVES
WO2007003962A2 (en) 2005-06-30 2007-01-11 Prosidion Limited Gpcr agonists
GB0700122D0 (en) 2007-01-04 2007-02-14 Prosidion Ltd GPCR agonists
RS52065B (en) 2007-01-04 2012-06-30 Prosidion Ltd Piperidine gpcr agonists
CA2674360A1 (en) 2007-01-04 2008-07-10 Prosidion Limited Piperidine gpcr agonists
AR064735A1 (en) 2007-01-04 2009-04-22 Prosidion Ltd GPCR AGONISTS AND PHARMACEUTICAL COMPOSITION BASED ON THE COMPOUND
PE20081849A1 (en) 2007-01-04 2009-01-26 Prosidion Ltd PIPERIDIN-4-IL-PROPOXY-BENZAMIDE DERIVATIVES AS GPCR AGONISTS
GB0720390D0 (en) 2007-10-18 2007-11-28 Prosidion Ltd G-Protein coupled receptor agonists
GB0720389D0 (en) 2007-10-18 2008-11-12 Prosidion Ltd G-Protein Coupled Receptor Agonists
FR2923719B1 (en) * 2007-11-15 2009-11-20 Sanofi Aventis PHARMACEUTICAL COMPOSITIONS BASED ON AZETIDINE DERIVATIVES
FR2928149B1 (en) 2008-02-29 2011-01-14 Sanofi Aventis AZETIDINE-DERIVED COMPOUNDS, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2946650B1 (en) * 2009-06-16 2011-08-19 Sanofi Aventis ESTERS DERIVED FROM AZETIDINES, THEIR PREPARATION AND THEIR USE IN THERAPEUTICS.
UA153183U (en) 2022-10-27 2023-05-31 Андрій Валерійович Максимов GLASS FOR DRINK PREPARATION

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR73668B (en) * 1978-11-21 1984-03-28 Hoffmann La Roche
US5631365A (en) * 1993-09-21 1997-05-20 Schering Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
HRP980026A2 (en) * 1998-01-20 1999-10-31 Pliva Pharm & Chem Works 1-izothiazolydinone derivatives of azetidine-2-ones, processes for the preparation and use thereof
DE1015046T1 (en) * 1998-07-14 2001-02-08 Em Ind Inc MICRODISPERSION ADMINISTRATION SYSTEM FOR MEDICINAL PRODUCTS
FR2783246B1 (en) * 1998-09-11 2000-11-17 Aventis Pharma Sa AZETIDINE DERIVATIVES, THEIR PREPARATION AND THE MEDICINES CONTAINING THEM
FR2805817B1 (en) * 2000-03-03 2002-04-26 Aventis Pharma Sa PHARMACEUTICAL COMPOSITIONS CONTAINING AZETIDINE DERIVATIVES, NOVEL AZETIDINE DERIVATIVES AND THEIR PREPARATION
FR2805818B1 (en) * 2000-03-03 2002-04-26 Aventis Pharma Sa AZETIDINE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FR2805810B1 (en) * 2000-03-03 2002-04-26 Aventis Pharma Sa PHARMACEUTICAL COMPOSITIONS CONTAINING 3- AMINO-AZETIDINE DERIVATIVES, THE NEW DERIVATIVES AND THEIR PREPARATION
FR2814678B1 (en) * 2000-10-04 2002-12-20 Aventis Pharma Sa COMBINATION OF AN ANTAGONIST OF THE CB1 RECEPTOR AND SIBUTRAMINE, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE FOR THE TREATMENT OF OBESITY

Also Published As

Publication number Publication date
FR2833842A1 (en) 2003-06-27
AP1754A (en) 2007-07-18
EA006510B1 (en) 2005-12-29
DE60233071D1 (en) 2009-09-03
NZ533225A (en) 2007-02-23
TW200301108A (en) 2003-07-01
AU2002364866B2 (en) 2006-11-30
CA2470443A1 (en) 2003-07-03
CN1602206A (en) 2005-03-30
HUP0402586A3 (en) 2011-05-30
HUP0402586A2 (en) 2005-03-29
BR0215048A (en) 2004-11-03
RS55504A (en) 2007-06-04
DK1458413T3 (en) 2009-11-23
ECSP045162A (en) 2004-08-27
TWI256304B (en) 2006-06-11
JP2005516945A (en) 2005-06-09
HK1070840A1 (en) 2005-06-30
FR2833842B1 (en) 2004-02-13
WO2003053431A3 (en) 2003-12-18
CN100388918C (en) 2008-05-21
UA77736C2 (en) 2007-01-15
EP1458413B1 (en) 2009-07-22
MEP16608A (en) 2010-06-10
EP1458413A2 (en) 2004-09-22
MY138172A (en) 2009-04-30
AP2004003066A0 (en) 2004-06-30
MXPA04005558A (en) 2004-12-06
PL372708A1 (en) 2005-07-25
IL162563A0 (en) 2005-11-20
WO2003053431A2 (en) 2003-07-03
MA27086A1 (en) 2004-12-20
EA200400843A1 (en) 2004-12-30
ZA200404338B (en) 2005-06-02
NO20042781L (en) 2004-09-20
AR037687A1 (en) 2004-12-01
OA12750A (en) 2006-07-03
KR20040068308A (en) 2004-07-30
PL203248B1 (en) 2009-09-30
CO5590911A2 (en) 2005-12-30
AU2002364866A1 (en) 2003-07-09
JP5021887B2 (en) 2012-09-12

Similar Documents

Publication Publication Date Title
US20060166959A1 (en) Pharmaceutical compositions based on azetidine derivatives
HRP20040575A2 (en) Pharmaceutical compositions based on azetidine derivatives
US20050037062A1 (en) Emulsifying systems containing azetidine derivatives
US20080293686A1 (en) Semi-solid systems containing azetidine derivatives
JP2008525390A (en) Injectable or orally deliverable formulations of azetidine derivatives

Legal Events

Date Code Title Description
A1OB Publication of a patent application
ARAI Request for the grant of a patent on the basis of the submitted results of a substantive examination of a patent application
ODRP Renewal fee for the maintenance of a patent

Payment date: 20091216

Year of fee payment: 8

OBST Application withdrawn