Mais la polymyxine n'est pas du tout absorbée dans le sang du système gastro-intestinal et n'a d'effet que dans l'intestin et est utile pour le traitement des infections intestinales azithromycine prix Internet en y faisant des achats permettant d’économiser jusqu'à soixante-dix pour cent, tout en étant sûr de la qualité des produits pharmaceutiques.

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EP2 338 477A1
EUROPEAN PATENT APPLICATION
29.06.2011 Bulletin2011/26
A61K9/02 (2006.01)
A61K31/4439 (2006.01)
(21) Application number: 09015508.6
(22) Date of filing: 15.12.2009
(72) Inventor: Metz, Christian
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
82065 Baierbrunn (DE)
HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL
PT RO SE SI SK SM TR

(74) Representative: Peters, Hajo et al
ZACCO GmbH
Bayerstrasse 83
80335 München (DE)

(71) Applicant: bene-Arzneimittel GmbH
81479 München (DE)
Suppository comprising pantoprazole
The present invention concerns the field of phar- pantoprazole. In addition, the present invention concerns maceutical technology and relates to a suppository for a process for preparing such a suppository.
rectal administration comprising at least one pellet, inparticular, a pellet comprising the proton pump inhibitor 38 477
2 3
P
E

EP2 338 477A1
Description
name is 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyrid-inyl)methyl] sulfinyl]-1 H -benzimidazole, is a well-known The present invention concerns the field of proton pump inhibitor used for the treatment of acid-re- pharmaceutical technology and relates to a suppository lated diseases, including gastroesophageal reflux dis- for rectal administration comprising at least one pellet, in 5 ease (GERD), Barrett’s esophagus, peptic ulcer disease particular, a pellet comprising the proton pump inhibitor (PUD), Zollinger-Ellison syndrome, gastri-nomas, and pantoprazole. In addition, the present invention concerns esophagitis/gastritis (inflammation of the esophagus, a process for preparing such a suppository.
stomach) (Robinson, M. (2005) Proton pump inhibitors: Proton pump inhibitors, such as, for example, update on their role in acid-related gastrointestinal dis- omeprazole, pantoprazole, lasoprazole etc., inhibit the eases. Int. J. Clin. Pract. 59, 709-715).
gastric proton pump, i.e. the gastric H +, K+-adenosine However, due to its molecular structure, panto- triphosphatase (ATPase), by covalent binding to cysteine prazole exhibit a strong tendency to decompose in neu- residues of the ATPase in the parietal cell (Sachs, G. et tral and, in particular, acidic environment, to strongly al. (2006) Review article: the clinical pharmacology of colored decomposition products. Therefore, stability of proton pump inhibitors. Curr. Gastroenterol. Rep. 10, the administration form depends on the interaction of the used pharmaceutical excipients and pantoprazole.
However, oral administered proton pump inhib- Typically used suppository bases are neutral to itors are metabolized through the liver via the cytochrome slightly acid. For instance, the commonly used hard fats P450 (CYP) pathway. Therefore, plasma concentrations are mixtures of mono-, di- and triglycerides which are of co-administered drugs that are also metabolized by obtained by esterification of fatty acids. Therefore, hy- the CYP system, such as for example anticonvulsant, drolysis of these glycerides results in free fatty acids. The phenytoin, warfarin, might be altered (Chong, E. and En- socalled acid number of a suppository base declares the som, M.H. (2003) Pharmacogenetics of proton pump in- amount of potassium hydroxide in milligram necessary hibitors: a systematic review. Pharmacotherapy 23, to neutralize the free fatty acids present in one gram fat.
460-471). In addition, genetic polymorphisms of the spe- 25 The acids number of commonly used hard fat lies beyond cific CYP2C19 might cause unpredictable variations in 0.3. However, this number also indicates that there are the clearance of the inhibitors and thereby result in in- enough free acids present to promote the decomposition creased plasma levels (Robinson, M. and Horn, J. (2003) of pantoprazole, and thereby to results in unattractive Clinical pharmacology of proton pump inhibitors: what the practising physician need to know. Drugs 63, Therefore, in order to provide stable supposito- ries comprising pantoprazole, it is necessary to protect In contrast to most proton inhibitors (such as the acid-labile active drug from the action of the present omeprazole and lasoprazole), the specific proton pump acids within the base. Additionally, a considerable effort inhibitor pantoprazole exhibits the lowest interaction with has to be made during preparation to avoid traces of the CYP system, and therefore, the lowest risk of side moisture, which would promote hydrolysis of glycerides, effects induced by metabolization via the CYP system.
and, which would, therefore, increase the acid number Thus, pantoprazole is one of the preferred proton pump EP0645150 is related to compositions for rectal Remaining metabolization of pantoprazole via administration comprising a proton pump inhibitor, such the CYP systems can be reduced by rectal administra- as a benzimidazole, and a salt of fatty acids having 6 to tion. This non-invasive route delivers drugs via vena rec- 20 C atoms as a stabilizer, both of which are intermingled talis cranialis and vena cava inferior into the circulation.
with each other in a base for rectal administration.
While vena rectalis craniales firstly guides the blood via EP1037607 describes suppositories compris- vena porta to the liver and then to the circulation vena ing a plurality of individual active compound units, the cava inferior directly guides the blood to the circulation acid-labile active compound in the individual active com- avoiding any hepatic metabolization. Thus, rectal admin- pound units being surrounded by a mixture or at least istration of pantoprazole offers the possibility to limit the one sterol and at least one polymer, wherein the particle risk of metabolization via the CYP systems and thereby size of the individual units is less than 200 P m.
results in less side effects than the above mentioned oral EP1187601 concerns administrations forms for acid-labile active compounds, such as, for example sup- The rectal route has the additional advantages positories, comprising pharmaceutical excipients and that proton pump inhibitors, such as pantor-prazole, can multiple individual active compound units, wherein an ac- be also administered to patients in intensive care units id-labile active compound, such as pantoprazole, is or to patients in which oral administration is either difficult, present in the individual active compound units in a matrix for example in the case of hypersensitivity to taste im- made of a mixture comprising at least one solid paraffin pulse or difficulty in swallowing, or contraindicated due and at least one fatty alokohol or triglyceride or fatty acid to vomiting or after stomach operations.
ester. The multiple individual active compound units of EP1187601 are microspheres having a particle size in EP2 338 477A1
er might comprise hydroxpropylmethylcellulose and/or In W097/34580 a suppository for acid-labile ac- polyvinylpyrrolidone, optionally plasticizers, such as pro- tive compounds is described which, in addition to the pylene glycol, and/or other auxiliaries such as commonly active compound, contains poloxamer and hydrophilic known buffers, bases or pigments. An inert slightly water- soluble film layer might comprise, for example, ethylcel- lulose, polyvinyl acetate, and/or inorganic pr organic ma- tions for rectal administration, which contain omeprazole terials, such as, magnesium oxide, silicon oxide or su- as an active compound, a mixture of polyethylene glycols or a mixture or hard fat and sodium lauryl sulfate as well The main advantage of using such pellets is that pellets comprising pantoprazole and an inert layer In EP0619365 an orally administerable pellet is are already commercially available. Thus, preparation of described, which is resistant to gastric juice, wherein the the suppository according to the present invention can pellet consists of a core in which pantoprazole is in ad- be performed without any great technical effort and there- mixture with binder filler and optionally other auxiliary compounds, an inert water-soluble intermediate layer The number of pellets within the suppository surrounding the core, and an outer layer which is resistant depends on the amount of pantoprazole which should be administered and the used suppository base. Preferably, It is an object of the present invention to provide one pellet comprises 5 to 30 % (w/w) pantoprazole. More novel suppositories comprising the acid-labile active preferably, one pellet comprises 5, 7.5, 10, 12.5, 15, 17.5, compound pantoprazole, which can be prepared without 20 20, 22.5 or 25 % (w/w) pantoprazole.
great technical effort and exhibit both good storage sta- Preferably, the suppository according to the bility and controllability of the release of pantoprazole.
present invention contains between 1 and 400 mg pan- It has now been found, surprisingly, that orally toprazole, preferably between 5 and 80 mg of pantopra- administerable pellets comprising pantoprazole are suit- zole, more preferably between 5 and 70 mg, 5 and 60 able to be suspended in suppository base without de- mg, 5 and 50 mg, 5 and 40 mg. For instance, one sup- composing pantoprazole, and, in addition, that a suppos- pository might contain 5, 10, 15, 20, 25, 30, 35, 40, 45, itory comprising such pellets exhibit good stability during 50, 55, or 60 mg pantoprazole. The daily dose can be storage and controllability of the release of pantoprazole.
either administered as a single dose or in several doses Therefore, the invention relates in a first aspect using the suppositories of the present invention.
to a suppository comprising at least one pellet and sup- 30 In one preferred embodiment of the suppository pository base, wherein the pellet comprises a core and according to the present invention, the pellet further com- an inert layer surrounding the core, wherein the core com- prises a layer which is resistant to gastric juice surround- "Pellets" according to the invention are individ- Suitable layers resistant to gastric juice are ual active compound units comprising the active com- known in art. For instance, a methacrylic acid/methyl pound pantoprazole within the core of the pellet. Thereby, methacrylate copolymer might be used, optionally, with pantoprazole can be admixed with fillers, binders and/or an additionally plasticizer. Preferably, the layer resistant other pharmaceutical auxiliaries within the core. Such to gastric juice is applied on the inert water-soluble layer.
pellets can be easily obtained by providing commercial In one embodiment of the suppository of the available sucrose starter pellets followed by applying present invention the pellet comprises pantoprazole free pantoprazole. Preferably, a solution of pantoprazole is acid, pantoprazole salt(s), pantoprazole hydrate(s), pan- sprayed on the sucrose starter pellets. The solution of toprazole cyclodextrin inclusion complex(es), amino acid pantoprazole might also contain any pharmaceutical salt(s) of pantoprazole with cyclodextrin, pantoprazole auxiliary, such as, for example, a binder. Additionally, a sodium aqua complex(es), and metal (II) complex(es) of solution of pharmaceutical auxiliaries might be also ap- pantoprazole, optionally in form of one of its stereoi- plied on the sucrose starter pellets, either before applying somers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its Fillers, binders and pharmaceutical auxiliaries stereoisomers, preferably enantiomers or diastereom- used for the preparation of pellets are known in the art.
ers, or in any mixing ratio, optionally in crystalline or amor- For instance, lactose, mannitol, polyvinylpyrrolidone, mi- 50 crocrystalline cellulose and hydroxymethylpropylcellu- For instance, pantoprazole free acid might be lose are suitable fillers, binders and pharmaceutical aux- present as crystalline form III or as amorphous form.
Pantoprazole salts, such as anhydrous salts of "Inert layers" surrounding the core of the pellets pantoprazole, hydrate salts of pantoprazole, and hydrate are commonly known layers usually applied before ap- solvate salts of pantoprazole are known in the art. Ex- plication of layers which are resistant to gastric juice.
amples of pantopazole salts are pantoprazole sodium, These inert layers might be either water-soluble or slight- pantoprazole potassium, pantoprazole zinc (II), panto- ly water-soluble. For instance, an inert water-soluble lay- prazole magnesium, pantoprazole calcium, pantopra- EP2 338 477A1
zole copper (II), pantoprazole mangan (II), pantoprazole is in the range of 0.1 to 1.0 mm, of 0.1 to 0.9 mm, of 0.1 cobalt (II), pantoprazole choline salt, pantoprazole to 0.8 mm, of 0.1 to 0.7 mm, of 0.1 to 0.6 mm, of 0.1 to tetraalkyl ammonium salt, pantoprazole sodium sesqui- 0.5 mm. Preferably, the size of the pellet is in the range hydrate, for example, pantoprazole sodium sesquihy- of 0.2 to 1.0 mm, of 0.2 to 0.9 mm, of 0.2 to 0.8 mm, of drate (2:2:3) (form I), pantoprazole sodium monohydrate, 5 0.2 to 0.7 mm, of 0.2 to 0.6 mm, of 0.2 to 0.5 mm. More for example, sodium monohydrate (form A and form B, preferably, the size of the pellet is in the range of 0.25 to form B is the more stable one), pantoprazole magnesium 1.0 mm, of 0.25 to 0.9 mm, of 0.25 to 0.8 mm, of 0.25 to hydroxy salts having the general formula (PPI) 0.7 mm, of 0.25 to 0.6 mm, of 0.25 to 0.5 mm, or, alter- (OH-)2x (H20)z, pantoprazole magnesium monohydrate natively, of 0.3 to 1.0 mm, of 0.3 to 0.9 mm, of 0.3 to 0.8 monosolvate, wherein for instance the solvate is methyl 10 mm, of 0.3 to 0.7 mm, of 0.3 to 0.6 mm, of 0.3 to 0.5 mm.
isobutyl ketone, pantoprazole magnesium dihydrate, In one embodiment of the suppository accord- pantoprazole magnesium hydrate, optionally in form of ing to the present invention, the suppository base is se- one of its stereoisomers, preferably enantiomers or di- lected from the group consisting of water-soluble bases, astereomers, its racemate or on form of a mixture of at oleaginous bases, emulsion bases and ointment bases.
least two of its stereoisomers, preferably enantiomers or 15 These bases are commonly employed in the manufac- diastereomers, or in any mixing ratio, optionally in crys- ture of suppositories. Water-soluble bases are, for in- stance, polyethylene glycol (e.g.PEG-400, 1000, 1540, Crystalline forms of pantoprazole sodium salts 4000 and 6000, inclusive of their mixtures), glycerin, glyc- are, for instance, II, IV, V, VI, VIII, IX, X, XI, XII, XIII, XIV, ero-gelatin, propylene glycol, sorbitol, mannitol, aqueous XV, XVII, XVIII, XIX, XX. Pantoprazole sodium solvates gel bases such as natural gums (e.g. gum tragacanth, are commonly known, wherein the solvate might be ac- gum acasia, karaya gum, Irish moss, guar gum, xanthan etone, butanol, methyl ethyl ketone, dimetzhylcarbonate, gum, locust bean gum, etc.), cellulose derivatives (e.g.
propanol, or 2-methylpropanol. Metal (II) complex(es) of methylcellulose, carboxymethylcellulose, etc.), acrylic pantoprazole are also known in the art, wherein the metal polymers (e.g. polyacrylic acid, polymethacrylic acid, etc.), vinyl polymers (e.g. polyvinylpyrrolidone, polyvinyl Preferred enantiomers of pantoprazole are, for methyl ether, carboxypolymethylene, etc.), synthetic instance, (-)-(S)-pantoprazole and (+)- (R)-pantoprazole, polysaccharides (e.g. poly-sucrose, polyglucose, poly- (-)-(S)-pantoprazole sodium, (-)-(S)-pantoprazole potas- lactose, etc.), starch, dextrin, pectin, sodium alginate etc.
sium, (-)-(S)-pantoprazole calcium, (-)-(S)-pantoprazole Oleaginous bases are, for instance, cacao butter, laurin magnesium, (-)-(S)-pantoprazole zinc, (-)-(S)-pantopra- fat, isocacao, fatty acid glycerides such as Suppocire zole magnesium dehydrate, (-)-(S)-pantoprazole sodium (Gatefosse, France), Witepsol (Dynamit Nobel, Germa- solvate hydrate, (-)-(S)-pantoprazole sodium sesquihy- ny)(e.g. Witepsol W-35, H-5, etc.), Migriol (Dynamit No- drate, or as (-)-(S)-pantoprazole sodium monohydrate, bel, Germany), etc., and vegetal oils such as sesame oil, (+)-(R)-pantoprazole sodium, (+)-(R)-pantoprazole po- soybean oil, corn oil, cottonseed oil, olive oil etc. Emul- tassium, (+)-(R)-pantoprazole calcium, (+)-(R)-panto- sion bases are, for instance, systems based on, for ex- prazole magnesium, or (+)-(R)-pantoprazole zinc, ample, a) cacao buffer formulated with cholesterol and glycerin, with lecithin and water, with Lanette Wax SX (based on cetyl alcohol-stearyl alcohol sulfate ester and (+)-(R)-pantoprazole sodium sesquihydrate, or as containing about 10% of phosphate ester), with cetyl al- (+)-(R)-pantoprazole sodium monohydrate. One pre- cohol and sodium lauryl sulfate, or with glycerin monos- ferred enantiomer is ()-(S)-pantoprazole, preferably as tearate, and b) systems prepared by ading sodium lauryl (-)-(S)-pantoprazole sodium, (-)-(S)-pantoprazole mag- sulfate, Tween, or the like to fatty acid monglycerides, nesium dehydrate, (-)-(S)-pantoprazole sodium solvate monolene (propylene glycol- alpha - monostearate), hydrate, (-)-(S)-pantoprazole sodium sesquihydrate, or wood wax, white Japan wax, stearyl alcohol, cetyl alcohol as (-)-(S)-pantoprazole sodium monohydrate, optionally 45 or the like. Ointment bases are, for instance, purified lan- olin, sodium lauryl sulfate etc. Among others, the pre- In one particular preferred embodiment of the ferred water-soluble bases are polyethylene glycols, the suppository of the present invention the pellet comprises preferred oleaginous bases are fatty acid mono-, di- or pantoprazole as its free base, as pantoprazole sodium, tri-glycerides such as Witepsols and Migriols (Dynamit as pantoprazole sodium sesquihydrate, or as pantopra- 50 Nobel, Germany), the preferred emulsion base are cacao zole sodium monohydrate, optionally in form of one of its butter-Lanette Wax SX etc., and the preferred ointment stereoisomers, preferably enantiomers or diastereom- bases are purified lanolin and others. These bases are ers, its racemate or on form of a mixture of at least two used either singly or in combination.
of its stereoisomers, preferably enantiomers or diaster- In one preferred embodiment of the suppository eomers, or in any mixing ratio, optionally in crystalline or 55 according to the present invention, the suppository base is an oleaginous base selected from the group consisting In one preferred embodiment of the suppository of cacao butter, laurin fat, isocacao, fatty acid glycerides according to the present invention, the size of the pellet EP2 338 477A1
In an even more preferred embodiment of the es, emulsion bases and ointment bases.
suppository according to the present invention, the sup-pository base is fatty acid glycerides. Preferably, such 6. Suppository according to claim 5, wherein the sup-
fatty acid glycerides are hard fats used for the production pository base is an oleaginous base selected from of rectal suppositories. Such hard fats are also known as 5 the group consisting of cacao butter, laurin fat, iso- Adeps solidus or Adeps neutralise. Hard fats are mixtures cacao, fatty acid glycerides and vegetable oils.
of mono-, di- and triglycerides which are obtained by es-terification of fatty acids. Such hard fats are commercially 7. Suppository according to claim 6, wherein the sup-
available, for instance, under the name Witepsol®. Fur- pository base are fatty acid glycerides.
ther pharmaceutically acceptable auxiliaries, such as, stabilizers, consistency-improving additives etc. might be 8. Process for preparing a suppository according to any
Another aspect of the present invention relates to a process for preparing a suppository according to the present invention comprising the steps of b) cooling the suppository base,c) suspending the at least one pellet into the suppository base while stirring constantly, d) cooling the suspension while stirring con- c) suspending the at least one pellet into the sup- e) transferring the suspension into suppository d) cooling the suspension while stirring constantly, e) transferring the suspension into suppository f) gradually cooling the filled suppository forms.
forms, andf) gradually cooling the filled suppository forms.
1. A suppository comprising at least one pellet and sup-
pository base, wherein the pellet comprises a core and an inert layer surrounding the core, wherein thecore comprises pantoprazole.
2. Suppository according to claim 1, wherein the pellet
further comprises a layer which is resistant to gastric 35juice surrounding the inert layer.
3. Suppository according to claim 1 or 2 comprising
pantoprazole free acid, pantoprazole salt(s), panto-prazole hydrate(s), pantoprazole cyclodextrin inclu- 40sion complex(es), amino acid salt(s) of pantoprazolewith cyclodextrin, pantoprazole sodium aqua com-plex(es), and metal (II) complex(es) of pantoprazole,optionally in form of one of its stereoisomers, pref-erably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoi-somers, preferably enantiomers or diastereomers,or in any mixing ratio, optionally in crystalline oramorphous form.
4. Suppository according to any of claims 1 to 3, where-
in the size of the pellet is in the range of 0.5 to 1.0mm, preferably in the range of 0.1 to 0.5 mm, morepreferably in the range of 0.25 to 0.5 mm.
5. Suppository according to any of claims 1 to 4, where-
in the suppository base is selected from the groupconsisting of water-soluble bases, oleaginous bas-

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