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Home , Crystal violet, Econazole

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(11) EP 2 385 821 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/02 (2006.01) A61K 47/10 (2006.01) 31.08.2016 Bulletin 2016/35 A61K 31/4174 (2006.01)

(21) Application number: 10703346.6 (86) International application number: PCT/HU2010/000003 (22) Date of filing: 08.01.2010 (87) International publication number: WO 2010/079373 (15.07.2010 Gazette 2010/28)

(54) IMPROVED PHARMACEUTICAL FORMULATION VERBESSERTE PHARMAZEUTISCHE FORMULIERUNG FORMULATION PHARMACEUTIQUE AMÉLIORÉE

(84) Designated Contracting States: (74) Representative: Stolmár & Partner AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Patentanwälte PartG mbB et al HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL Blumenstraße 17 PT RO SE SI SK SM TR 80331 München (DE) Designated Extension States: AL BA RS (56) References cited: EP-A1- 0 271 882 EP-A1- 0 770 384 (30) Priority: 09.01.2009 HU 0900010 EP-A2- 0 404 376 WO-A1-97/00670 07.01.2010 HU 1000006 WO-A2-2007/079389 US-A- 4 853 211 US-A1- 2005 276 836 (43) Date of publication of application: 16.11.2011 Bulletin 2011/46 • PHILLIPS A J: "Treatment of non-albicans Candida vaginitis with vaginal (73) Proprietor: Egis Gyógyszergyár Zrt. suppositories" AMERICAN JOURNAL OF 1106 Budapest (HU) OBSTETRICS & GYNECOLOGY, MOSBY, ST LOUIS, MO, US LNKD- (72) Inventors: DOI:10.1016/J.AJOG.2005.03.034, vol. 192, no. 6, • MIKULASIK, Endre 1 June 2005 (2005-06-01), pages 2009-2012, H-9783 Egyházasrádóc (HU) XP004937211 ISSN: 0002-9378 • SZAKALY, Péter H-9900 Körmend (HU)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 385 821 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 385 821 B1 2

Description adhesive oleaginous base. [0007] The publication of Dellenbach et al. describes Field of the invention studies with oleaginous suppositories used for the treat- ment of Vulvovaginal , wherein the effective- [0001] The invention relates to a vaginal suppository 5 ness of sertarconazole containing suppository is com- with improved efficacy containing an active in- pared with containing suppositories (Dellen- gredient, wherein said active ingredient is present simul- bach P, Thomas JL, Guerin V, et al: Topical treatment of taneously in dissolved and suspended form in a suppos- vaginal candidosis with and econazole itory base containing polyethylene-glycol and polysorb- sustained-release suppositories. Int J Gynecol Obstet ate. The ratio of the suspended and dissolved active in- 10 2000; 71:S47-S52). 310 women with symptoms and gredient in the suppository is reproducible and said ratio signs of vulvovaginitis were enrolled in this randomized does not change during the storage. A further object of study. There was a trend towards a better efficacy of the present invention is a process for manufacturing said sertaconazole because the mycological recurrence rate pharmaceutical formulations. was lower than when using econazole. The patients were 15 treated with a 300-mg sertaconazole suppository and a Technical background of the invention 150-mg econazole sustained release suppository. The results were evaluated 1 week after treatment and pa- [0002] The most widespread vaginal diseases are sev- tients whose treatment was unsuccessfull received a eral kinds of fungal . In the treatment of these second suppository. 96 per cent of the patients were in- infections are generally used. Sev- 20 fected by Candida albicans. 105 women were not clini- eral pharmaceutical active ingredients are known for use cally cured after 1 week (49 in the sertaconazole group in this therapy. and 56 in the econazole group) and received a second [0003] There are some disadvantages when using tab- treatment lets for oral administration containing imidazole-type ac- [0008] The second administration was necessary be- tive ingredients. Absorption and distribution of the active 25 cause the recurrence of symptoms occured in high rate ingredient takes a long time until the area of the after the single dose application independently from the by the systemic circulation is reached. In order to achieve active ingredient used or its efficacy. The main reason sufficient blood concentration for treating said infections, of this problem is mostly the suppository base, which can high doses are necessary. The high amount of the active not penetrate into the narrow folds of the mucosal mem- ingredient causes difficulties during formulation and ad- 30 brane at themargin of uterusand vagina. Thereforesome ditionally it is inconvenient for the patient to take large active pathogens can remain on this surface and are able tablets. Because of the fast decomposition of the active to cause a high percentage of mycological recurrence. ingredient the treatment is to be carried out several times [0009] Polyethylene-glycols have been used as sup- a day or it may last several days. The poor solubility of pository base for a long time. As it is known the advan- the active ingredient and the large dose may cause sev- 35 tages of polyethylene glycol base suppositories over oil eral undesired side effects. base suppositories are the more favourable adhesion [0004] Several creams, ointments, solutions and emul- and extension properties. These facts are presented in sions used for local administration are known. In case of Example 2 (Comparative mold experience 2.1, 2.2). these formulations the active ingredient gets through di- [0010] A further important requirement towards intra- rectly to the area of infection, but the formulations are 40 vaginal suppositories is that they should reach all parts soon liquified thus the required amount of the active in- of the wall of vagina, including the narrow folds of the gredient is not present at the area of the infection and mucosal membrane. This can provide the development does not exhibit its effect through the desired period, and of the effect on the entire surface of the vagina. this can be inconvenient for the patient. [0011] Suppositories are known, in which the active [0005] Other therapeutic options for treating fungal in- 45 ingredient is dissolved or suspended, depending on the fections are vaginal suppositories containing an imida- character of the active ingredient. zole derivative. The vaginal suppositories should meet [0012] The dissolved active ingredient promptly exhib- some general requirements such as that the active in- its its effect but due to the poor adhesion capacity and gredient must be present at the infected area in suitable viscosity of the solution it only can difficultly adhere on form, in an appropriate amount and concentration for a 50 the wall of vagina and leaves the infected area soon, sufficient period in order to exhibit the required effect. therefore the period of the drug is shortened and the prob- The large number of publications in this field of therapy ability of the recurrence increased. A further disadvan- and the high variety of the marketed antifungal suppos- tage of the dissolved active ingredient containing sup- itories prove that the actually applied suppositories are pository is that the administration is to be repeated many able to satisfy only some of the above mentioned require- 55 times during the therapy. ments. [0013] Econazol (as the antifungal imidazol derivatives [0006] The known suppositories contain the active in- generally) is poorly soluble in water and oil or in the pol- gredient in suspended form formulated in a high mucosa- yethylene-glycol suppository base. Therefore such ac-

2 3 EP 2 385 821 B1 4 tive ingredients are used in the form of a suspension. taneously in suspended and dissolved form, wherein the Said suspension meets the therapeutic requirements be- ratio of the suspended and dissolved active ingredient is cause the particles adhere on the mucosal membrane of reproducible and does not change during the storage. the vagina and provide the therapeutically effective The ratio of the suspended and dissolved active ingredi- amount (i.e. microgram) of the active ingredient in an 5 ent can vary depending on the character of the active autoretard manner. The effect of the suppositories, which ingredient. consits only of the suspended active ingredient is long- [0020] A further aspect of the invention is a process lasting, but the effect develops slowly and there is a lower for the preparation of suppositories wherein a pre-deter- probability for the active ingredient to reach the infected mined portion of the active ingredient is dissolved in a area in the suitable concentration. 10 mixture containingpolyethylene-glycol and other excipi- [0014] Pharmaceutical compositions, which show the ents, thereafter the mixture is cooled and the remaining advantageous properties of the two dosage forms and portion of the active ingredient is suspended in the mix- are used simultaneously, are not known in prior art. ture in solid form [0015] It is known that some compositions containing polyethylene-glycol as vehicle, contain the active ingre- 15 Detailed description of the invention dient partially in dissolved and partially in precipitated form. But in case of these compositions the active ingre- [0021] The present invention relates to a vaginal sup- dient precipitates during the cooling of the composition pository containing an antifungal active ingredient simul- in a random manner and therefore the amount, particle taneously in suspended and dissolved form, wherein the size and dispersion of the precipitated active ingredient 20 ratio of the suspended and dissolved active ingredient is are occasional. Such composition are described in Ex- reproducible and does not change during the storage. ample 3 of US2005/276836 A1, in Example 4 of[0022] The ratio of the suspended and dissolved active US4853211A1, Example 7 of WO97/00670A1 and in ingredient can vary depending on the character of the page 2010, column 2, paragraph 3 of Phillips A. J., Am. active ingredient. J. Obst. & Gynec. (2005) vol. 192, no.6, p. 200p-2012. 25 [0023] Another aspect of the present invention is a sup- The ratio of the precipitated and dissolved active ingre- pository wherein a pre-determined portion of the active dient is random and not-reproducible; moreover the ratio ingredient is dissolved in a mixture containing polyethyl- can alter during storage ene-glycoland other excipients andthe remainingportion [0016] The object of the present invention is to provide of the active ingredient is suspended in the mixture in a pharmaceutical formulation which can ensure that the 30 solid form. The ratio of the suspended and dissolved ac- active ingredient is present at the inflected area in suit- tive ingredient can vary depending on the properties of able form, appropriate amount and concentration for a the active ingredient. sufficient period in order to exhibit the desired effect and [0024] Another aspect of the present invention is a the active ingredient is able to reach all parts of the wall process for the preparation of a polyethylene-glycol base of vagina, including the narrow folds of the mucosal mem- 35 suppository, which contains an antifungal active ingredi- brane. ent in dissolved and suspended form. The suppository of the present invention is prepared by dissolving a pre- Summary of the invention determined portion of the active ingredient in a polyeth- ylene component containing suppository base, cooling [0017] The present invention is based on the recogni- 40 the mixture, thereafter suspending the remaining portion tion that the advantageous properties of the two dosage of the active ingredient in the mixture. forms can be combined in one composition [0025] The melting point of the suppository base of the [0018] It has been surprisingly found that the compo- present invention is approximately 48-52 °C therefore it sition of the present invention can be formulated repro- doesnot dissolve at body temperature. However it is mild- ducibly in such way that a pre-determined portion of the 45 ly hygroscopic and soluble in water therefore it liquifies, active ingredient is dissolved and the remaining portion forms a viscous blend and is dissolved already under the is in suspended form. The dosage form of the present effect of minimal vaginal fluid.. invention has more favourable properties regarding the [0026] After liquefying and during dissolution the sus- development of the therapeutic effect than the composi- pended portion of the active ingredient is set free and the tions which contain the active ingredient solely in sus- 50 active ingredient particles disperse on the wall of the va- pended or in dissolved form. This observation can be gina thus developing the first effective front.. The sup- explained by the fact that the dissolved active ingredient pository of the present invention contains a second ef- exhibits its effect rapidly and can penetrate much deeper fective front, too. This front is developed by dissolving and the suspended part of active ingredient can maintain the suppository base in the body fluids, which penetrates this effect fora long period of time.This effect is enhanced 55 into the closed spaces and between the narrow folds of by the viscosity and adhesion of the vehicle. the mucosal membrane. During dissolution the polyeth- [0019] The present invention relates to a vaginal sup- ylene-glycol is diluted by water, therefore due to the sol- pository containing an antifungal active ingredient simul- ubility decrease the active ingredient precipitates in form

3 5 EP 2 385 821 B1 6 of microparticles at the place of the dissolution (i.e. be- Example 1. : Investigation of the active ingredient tween the narrow folds of the mucosal membrane), thus dispersion developing the second effective front. [0027] The polyethylene-glycol and polysorbate based [0034] The mechanism of the active ingredient distri- suppository composition of the present invention con- 5 bution is shown on Figure 1 and 2. A slice of the suppos- tains preferably an active ingredient selected from eco- itory prepared according to Example 3 was placed into nazole, econazole-nitrate, , , body-temperature water in a Petri dish and the segment , , , , was allowed to stand for 5 minutes. In Figure 1 the non- , , , melted segment can be seen. Around the non-melted and/or , more preferably econazole and/or 10 segment there is a white ring which is the suspended econazole-nitrate or pharmaceutical acceptable salt active ingredient set free. Around the white ring there can thereof as antifungal active ingredient. The pharmaceu- be seen the radial band of the micro crystals which pre- tical composition of the present invention contains pref- cipitated from the solution along the decrease of concen- erably 150 to 300 mg econazole and/or econazole-ni- tration due to dilution. trate. 15 [0035] The microscopic structure of the micro crystal [0028] The pharmaceutical composition of the present band can be seen more closely in Figure 2. Said Figure invention may contain a polysorbate as excipient. The 2. shows the matrix, the suspended active ingredient par- polysorbate ingredient of the suppository may be Polys- ticles, which were suspended in the matrix and fell out orbate 20, Polysorbate 60 and/or Polysorbate 80, pref- from the matrix after melting and also the micro crystals erably Polysorbate 60. The polysorbate ingredient of the 20 which precipitated from the solution along the decrease suppository is present preferably in 1.5 per cent amount of concentration. by weight. [0029] Polyethylene-glycol polymer ingredient of the Example 2.: Comparative example suppository may be any of the known polyethylene-gly- cols with molecular weight of 100 to 4000, preferably25 [0036] In order to demonstrate, that the polyethylene- Macrogol 1500, Macrogol 1000 and/or Macrogol stear- glycol base suppository has more favourable adhesion ate. The known polyethylene-glycols with molecular and extension properties a comparison with oleaginous weight of 100 to 4000 can be the for example the follows: base suppositories some model-experiments were per- PEG 100, PEG 200, PEG 400, PEG 540, PEG 600, PEG formed. The results of said experiments are summarised 900, PEG 1000, PEG 1450, PEG 1540, PEG 2000, PEG 30 below. 3000, PEG 3350, PEG 4000. Commercially available pol- yethylene-glycol containing suppository bases can also 2.1. Slide-down test be used as a suppository base of the present invention. [0030] The amount of the suppository base is prefer- [0037] Comparative experiments were preformed to ably a ten-fold amount of the active ingredient. 35 study the adhesion properties of the mucosa membrane [0031] A further aspect of the present invention is a with a commercially available oleaginous-base suppos- process for the preparation of suppository, wherein the itory and with the suppository of Example 3. The aim of suppository mixture is poured; preferably the melted mix- the experiment was to establish whether the oleaginous ture is poured into a pre-covered suppository mold cavity. or the polyethylene-glycol base suppository has better This shell can be used as the final package of the sup- 40 mucosa-adhesive properties in vitro. pository. The suppository of the present invention is de [0038] 3,3 g average-weight suppositories were preferably prepared by dissolving a pre-determined por- poured from both mixtures and the mixture were marked tion of the active ingredient, preferably 20 per cent in a by in order to facilitate observation. polyethylene glycol containing suppository base. The [0039] A gelatine layer of 1 mm thickness poured into polysorbate is already dissolved in the polyethylene gly- 45 a 19 mm Petri dish served as mucosa model. The surface col. After dissolving the active ingredient the mixture is of the gelatine was spread over 20 ml of 0.5 per cent cooled. The next step is suspending the remaining por- methocell mucosa directly before the experiment. The tion of the active ingredient in the mixture. experiments were performed at body temperature, 37 °C. [0032] The main advantage of the present invention is [0040] At 37 °C the oleaginous suppository was melt that the composition of the suppository makes possible 50 and the suppository of the present invention was liquefied for the active ingredient not only to possess the antifungal by addition of 1,5 ml water. The mixtures were smoothly or anti-inflammatory effect but also to penetrate and be- spread over the models horizontally so that the entire ing absorbed between the narrow folds of the mucosal surface of the model was covered. After 5 minutes the membrane at the margin of uterus and vagina, thus ef- models were positioned vertically and the results were fectively decreasing the development of the recurrence. 55 evaluated after 1 minute. Figure 3. shows the results: the [0033] The invention is further elucidated by means of oleaginous base suppository can be seen in the left side following Examples without restricting the scope of the andthe suppositoryof the present invention can bee seen present invention to the Examples. in the right side of the Figure 3.

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Evaluation: Composition of the base: Polysorbate 60 1,5% [0041] It can be concluded that the oleaginous base Macrogol 1500 98,5% suppository slid down from the surface and flow back on the top of the model, the adhesion of the suppository was 5 not satisfactory. The mixture of the present invention was Formulation of the suppository (~1 kg/300 pieces): adhered at the whole surface of the model and no flow- back was observed. This mixture had more favourable [0048] 985 g Macrogol 1500 is melted and 15 g Polys- adhesion properties. orbate 60 is dissolved in the molten mass. Subsequently 10 the temperature is adjusted to 60 degree Celsius and 2. 2. Vaginal-model experiment 900 g from the mixture is weighted. 18 g of econazole are dissolved in the mixture under continuously stirring [0042] To demonstrate the behaviour of the supposi- (this is the 20 per cent of the total econazole content). tories in the vagina the dialysis-membrane experiment After total dissolution the mixture is adjusted to 55 °C and was except that said model was used for direct observa- 15 the the remaining 72 g econazol is suspended in the mix- tion instead of measuring the active ingredient liberation ture. The mixture is continuously stirred until pouring. (Yamazaki M, Itoh S, Sasaki N, Tanabe K, Uchiyama M. [0049] The suppository mass is poured into Erweka Modification of the dialysis membrane method for drug mold type pre-covered PE cased PVC mold cavity and release from suppositories. Pharm Res 1993; 10: after congealing the mold is heat sealed 927-929). 20 [0043] The oleaginous base suppository and the sup- Example 4.: Econazole nitrate containing vaginal pository of the present invention were placed into the suppository membrane according to Figure 4. [0044] The membranes were studied in a 37 °Cwater [0050] The composition of the suppository and the bath. After 10 minutes the oleaginous suppository melt- 25 process for manufacturing the suppository are the same ed, while the polyethylene base suppository started to as described in Example 3. In case of using econazole dissolve due to the low humidity, which could penetrate nitrate 85 per cent (85 g) of the active ingredient are dis- through to the membrane, as it can be seen in Figure 5. solved and 15 per cent (15 g) of the active ingredient is [0045] Figure 6 shows the condition of the supposito- suspended in the base. ries after 1 hour. It can be seen that the oleaginous sup- 30 pository completely melted and the mass of the suppos- Example 5.: Miconazole containing vaginal suppos- itory was pressed up to the opening along the folds of itory the membrane due to the pressure of the water (tissue pressure in the organisms). The suppository of the [0051] The composition of the suppository and the present invention did not completely melt, but the sus- 35 process for manufacturing the suppository are the same pension penetrated into the narrow folds of the mem- as it is decribed in Example 3. In case of using mikonazole brane despite of the pressure of the water and filled in 66 per cent (66,7 g) of the active ingredient is dissolved the available place. and 33 per cent (33,3 g) of the active ingredient are sus- pended in the base. Conclusions: 40 Example 6.: Miconazole nitrate containing vaginal [0046] Our experiments support the previous findings suppository that the polyethylene-glycol base suppositories have much more favourable adhesion and expansion proper- [0052] The composition of the suppository and the ties in comparisone with oleaginous base suppositories. 45 process for manufacturing the suppository are the same as described in Example 3. In case of using miconazole Example 3.: Econazole containing vaginal supposi- nitrate 70 per cent (70 g) of the active ingredient are dis- tory solved and 30 per cent (30 g) of the active ingredient are suspended in the base. [0047] The following composition were used for pre- 50 pare one suppository with 3300 g. : Example 7.: Ketoconazole containing vaginal sup- pository Econazole 300 mg Base: 3000 mg [0053] The composition of the suppository and the 55 process for manufacturing the suppository are the same as described in Example 3. In case of using ketoconazole 80 per cent (80 g) of the active ingredient are dissolved and 20 per cent (20 g) of the active ingredient are sus-

5 9 EP 2 385 821 B1 10 pended in the base. 7. Vaginal suppository base according to claim 4, which contains 1.5 per cent of polysorbate, preferably Example 8.: containing vaginal sup- Polysorbate 60. pository 5 8. Process for preparing vaginal suppository according [0054] The composition of the suppository and the to claim 1, which comprises pouring the suppository process for manufacturing the suppository are the same mass, preferably pouring the melted mixture into a as described in Example 3. In case of using metronida- pre-covered suppository mold cavity. zole 90 per cent (90 g) of the active ingredient are dis- solved and 10 per cent (10 g) of the active ingredient are 10 9. Process for manufacturing vaginal suppository con- suspended in the base. taining an antifugal or anti-inflammatory active ingre- dient simultaneously in suspended and dissolved form thereof which comprises dissolving a pre-de- Claims terminated portion of the active ingredient in a mix- 15 ture of polyethylene-glycol and other excipients dis- 1. Vaginal suppository containing an antifungal or anti- solved therein, cooling the mixture and suspending inflammatory active ingredient simultaneously in the remaining portion of active ingredient therein. suspended and dissolved form, wherein the ratio of the suspended and dissolved active ingredient is re- producible and does not change during the storage, 20 Patentansprüche wherein the composition can be formulated repro- ducibly in such a way that a pre-determined portion 1. Vaginalzäpfchen, enthaltend einen antimykotischen of the active ingredient is dissolved and the remain- oder antiinflammatorischen Wirkstoff gleichzeitig in ing portion is in suspended form, the vaginal sup- suspendierter und gelöster Form, wobei das Verhält- pository obtainable by dissolving a predetermined 25 nis zwischen sich in Suspension befindlichem und portion of the active ingredient in a mixture of poly- gelöstem Wirkstoff reproduzierbar ist und sich wäh- ethylene-glycoland otherexcipients dissolved there- rend der Lagerung nicht ändert, wobei die Zusam- in, cooling the mixture and suspending the remaining mensetzung reproduzierbar so formuliert werden portion of active ingredient therein. kann, dass ein vordefinierter Anteil des Wirkstoffs 30 gelöst ist und der übrige Anteil in suspendierter Form 2. Vaginal suppository according to claim 1, wherein ist, das Vaginalzäpfchen erhältlich durch Lösen ei- the antifungal active ingredient is econazole, econa- nes vordefinierten Anteils an Wirkstoff in einer Mi- zole-nitrate, bifonazole, butoconazole, clotrimazole, schung aus Polyethylen-Glykol und anderen darin croconazole, fenticonazole, ketoconazole, metroni- gelösten Arzneiträgern, Abkühlen der Mischung und dazole, miconazole, miconazole nitrate, omocona- 35 In-Suspension-Bringen des übrigen Anteils an Wirk- zole, oxiconazole, sulconazole and/or tioconazole, stoff darin. preferably econazole and/or econazole-nitrate or pharmaceutical acceptable salt thereof. 2. Vaginalzäpfchen gemäß Anspruch 1, wobei der an- timykotische Wirkstoff Econazol, Econazolnitrat, Bi- 3. Vaginal suppository according to claim 1, wherein 40 fonazol,Butoconazol, Clotrimazol, Croconazol, Fen- the suppository contains 150 to 300 mg econazole ticonazol, Ketoconazol, Metronidazol, Miconazol, and/or econazole nitrate. Miconazolnitrat, Omoconazol, Oxiconazol, Sulcona- zol und/oder Tioconazol ist, bevorzugt Econazol 4. Vaginal suppository according to claim 1, which con- und/oder Econazolnitrat oder ein pharmazeutisch tains polysorbate in the suppository mass as excip- 45 verträgliches Salz davon. ient, and the polysorbate ingredient is Polysorbate 20, Polysorbate 60 and/or Polysorbate 80, prefera- 3. Vaginalzäpfchen gemäß Anspruch 1, wobei das bly Polysorbate 60. Zäpfchen 150-300 mg Econazol und/oder Econa- zolnitrat enthält. 5. Vaginal suppository according to claim 1, wherein 50 the polyethylene-glycol polymer ingredient of the 4. Vaginalzäpfchen gemäß Anspruch 1, welches Poly- suppository is a polyethylene-glycol with molecular sorbat in der Zäpfchenmasse als Arzneiträger ent- weight of 100 to 4000, preferably Macrogol 1500, hält, und der Polysorbat-Bestandteil Polysorbat 20, Macrogol 1000 and/or Macrogol stearate. Polysorbat 60 und/oder Polysorbat 80 ist, bevorzugt 55 Polysorbat 60. 6. Vaginal suppository according to claim 1, which con- tains ten-fold amount of the active ingredient as sup- 5. Vaginalzäpfchen gemäß Anspruch 1, wobei der Po- pository base. lyethylen-Glykol-Polymerbestandteil des Zäpfchens

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ein Polyethylen-Glykol mit einem Molekulargewicht nazole et/ou de nitrate d’éconazole. von 100-4000 ist, bevorzugt Macrogol 1500, Ma- crogol 1000 und/oder Macrogolstereat. 4. Suppositoire vaginal selon la revendication 1, qui contient du polysorbate dans la masse de supposi- 6. Vaginalzäpfchen gemäß Anspruch 1, welches die 5 toire comme excipient, et l’ingrédient de polysorbate zehnfache Menge an Wirkstoff als Zäpfchenbasis est le Polysorbate 20, le Polysorbate 60 et/ou le Po- enthält. lysorbate 80, de préférence le Polysorbate 60.

7. Vaginalzäpfchen gemäß Anspruch 4, welches 1,5 % 5. Suppositoire vaginal selon la revendication 1, dans Polysorbat enthält, bevorzugt Polysorbat 60. 10 lequel l’ingrédient polymère de polyéthylène-glycol du suppositoire est un polyéthylène-glycol avec un 8. Verfahren zur Herstellung eines Vaginalzäpfchen poids moléculaire de 100 à 4000, de préférence le gemäß Anspruch 1, welches umfasst Eingießen der Macrogol 1500, le Macrogol 1000 et/ou le stéarate Zäpfchenmasse, bevorzugt Eingießen der ge- de Macrogol. schmolzenen Mischung in einen vorher abgedeck- 15 ten Hohlraum einer Zäpfchen-Form. 6. Suppositoire vaginal selon la revendication 1, qui contient une quantité décuple de l’ingrédient actif 9. Verfahren zur Herstellung von Vaginalzäpfchen ent- comme base de suppositoire. haltend einen antimykotischen oder antiinflammato- rischen Wirkstoff gleichzeitig in suspendierter und 20 7. Base de suppositoire vaginal selon la revendication gelöster Form davon, welches umfasst Lösen eines 4, qui contient 1,5 pour cent de polysorbate, de pré- vordefinierten Anteils an Wirkstoff in einer Mischung férence de Polysorbate 60. aus Polyethylen-Glykol und anderen darin gelösten Arzneiträgern, Abkühlen der Mischung und In-Sus- 8. Procédé de préparation d’un suppositoire vaginal pension-Bringen des übrigen Anteils des Wirkstoff 25 selon la revendication 1, qui comprend verser la darin. masse de suppositoire, de préférence verser le mé- lange fondu dans une cavité de moule de supposi- toire couverte au préalable. Revendications 30 9. Procédé de fabrication d’un suppositoire vaginal 1. Suppositoire vaginal contenant un ingrédient actif contenant un ingrédient actif antifongique ou anti- antifongique ou anti-inflammatoire simultanément inflammatoire simultanément sous forme suspen- sous forme suspendue et dissoute, dans lequel le due et dissoute de celui-ci qui comprend dissoudre rapport de l’ingrédient actif suspendu et dissous est une portion prédéterminée de l’ingrédient actif dans reproductible et ne change pas au cours du stocka- 35 un mélange de polyéthylène-glycol et d’autres exci- ge, dans lequel la composition peut être formulée de pients dissous en son sein, refroidir le mélange et manière reproductible de telle sorte qu’une portion mettre en suspension la portion restante d’ingrédient prédéterminée de l’ingrédient actif est dissoute et la actif en son sein. portion restante est sous forme suspendue, le sup- positoire vaginal pouvant être obtenu en dissolvant 40 une portion prédéterminée de l’ingrédient actif dans un mélange de polyéthylène-glycol et d’autres exci- pients dissous en son sein, refroidissant le mélange et mettant en suspension la portion restante d’ingré- dient actif en son sein. 45

2. Suppositoire vaginal selon la revendication 1, dans lequel l’ingrédient actif antifongique est l’éconazole, le nitrate d’éconazole, le bifonazole, le butoconazo- le, le clotrimazole, le croconazole, le fenticonazole, 50 le kétoconazole, le métronidazole, le miconazole, le nitrate de miconazole, l’omoconazole, l’oxiconazole, le sulconazole et/ou le tioconazole, de préférence l’éconazole et/ou le nitrate d’éconazole ou un sel pharmaceutique acceptable de celui-ci. 55

3. Suppositoire vaginal selon la revendication 1, dans lequel le suppositoire contient 150 à 300 mg d’éco-

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 2005276836 A1 [0015] • WO 9700670 A1 [0015] • US 4853211 A1 [0015]

Non-patent literature cited in the description

• DELLENBACH P ; THOMAS JL ; GUERIN V et al. • PHILLIPS A. J. Am. J. Obst. & Gynec., 2005, vol. Topical treatment of vaginal candidosis with sertaco- 192 (6), 200, , 2012 [0015] nazole and econazole sustained-release supposito- • YAMAZAKI M ; ITOH S ; SASAKI N ; TANABE K ; ries. Int J Gynecol Obstet, 2000, vol. 71, S47-S52 UCHIYAMA M. Modification of the dialysis mem- [0007] brane method for drug release from suppositories. Pharm Res, 1993, vol. 10, 927-929 [0042]

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