US 7,943,176 B2  7  8  geously this coating should retain the acid being present in the  core as long as the formation of the propiverine acid ionpair  has completely finished.  If  the coating prematurely solubi› lises or if it leaks too much, the gastric fluid always being  present in a large excess penetrates into the interior of the  particles and neutralises the acid being present there. Thus,  because of the low solubility of the propiverine in the pH  range of the gastric fluid practically no active agent can be  dissolved and diffuse from the particles. The acid being  present in the interior of the particles lowers the pH value of  the penetrating intestinal fluid, and then forms the corre› sponding ionpair. After that the solution of the propiverine  acid ionpair being formed in the interior diffuses through the  membrane into the intestine. Although unfavourable pH con› ditions are again dominating here, obviously over-saturation  phenomena occur, ensuring a sufficient resorption of the per  se hardly soluble active agent. Naturally the acid being  present in the particles is furthermore reduced during the  course of the release so that actually a strong decrease in the  diffusing amount or in the release of propiverine should  occur. In order to avoid the latter the retardation coating  controlling the release rate should preferably be "partially  soluble" in the gastric fluid. The term "partially soluble" has  to be understood in the meaning of a certain permeability or as  a diffusion resistance, respectively. Further, said retardation  coating should additionally guarantee that in the interior of  the particles acidic pH conditions are always predominating  and optionally occurring pH deviations caused by food influ› ences or by other influences are adjusted.  Even small  deviations  in the ratio  of Eudragitfi  RS/Eudragitfi RL/Eudragitfi S lead to drastic changes of the  release profiles.  If  the ratio of Eudragitfi RS/Eudragitfi  RL/Eudragitfi S of2:1:2 purely found by chance is slightly  changed to a ratio of 1.5:1:2.5 (Example 9) this reduction of  the intestinal fluid insoluble component with low permeabil- ity (Eudragitfi RS) and the increased portion of the intestinal  fluid soluble material (Eudragitfi S) leads to a faster release  of the active agent or to a heavy diffusion of the acidic com› ponent, respectively.  This effect may be explained as follows: Since the gastric  fluid insoluble, intestinal fluid soluble material of this coating  is dissolved in the intestinal fluid after a certain residence time  of the particles in the intestinal fluid, a too heavy release in the  upper intestinal tract is effectively suppressed with a ratio of  Eudragitfi RS/Eudragitfi L/Eudragitfi S of 2:1:2, and the  release of the active agent is completely shifted to the medium  and lower intestinal tracts. Thus, said retardation coating  reduces the particularly rapid resorption in the upper intesti› nal tract without reducing the total release of the active agent  from the particles. This leads indisputably to a prolongation  of the release of the active agent.  In order to obtain a gastric fluid resistance and not too high  initial release values in the following or to further modify the  release characteristics, respectively, it is common practice in  the art to apply further retardation coating with gastric fluid  insoluble and intestinal fluid soluble materials, for example  Eudragitfi L or Eudragitfi S, respectively.  Furthermore the retardation coatings used according to the  invention may contain typical adjuvants, like for example  plasticisers,  wetting agents  and anti-adhesive  agents.  Examples for suitable pharmacologically secure plasticisers  are glycerine triacetate, polyethyleneglycols and citric acid  esters, like triethylcitrate. The application of retardation coat› ings onto the active agent containing particles may be done  with methods known per se, for example in a rapidly rotating  vessel or by spraying the lacquers in fluidised bed processes.  Preferably, however, also in this embodiment one of the  already mentioned acidic substances is used and the acidic  substance as well as the active agent is embedded in the  In particular suitable release characteristics may be  achieved by matrix retardation, for example by means of a  matrix tablet.  In contrast to the so-called multiple-unit formulations  based on pellets or spheroid particles, retarded preparations  of propiverine may also be produced in any other way, for  example as single-unit formulation.  In the following the granular particles are coated with  generally known gastric fluid insoluble and intestinal fluid  soluble and/or gastric fluid insoluble and intestinal fluid  insoluble retarded agents, like for example Eudragitfi NE,  Eudragitfi L etc. Generally known tabletting adjuvants, like  microcrystalline cellulose, crospovidone, polyvinylpyrroli› done, magnesiumstearate etc., are added, the total blend is  thoroughly mixed and pressed into tablets. Furthermore the  thus produced tablets can be coated with suitable coatings,  which may be release modifying. Even in this case the retar› dation layers guarantee the formation of a propiverine acid  ionpair and its controlled diffusion. Since the inventive for› mulations decompose in less than 5 minutes and thereby  release hundreds of retarded propiverine acid particles the  decomposition time does not have any influence on the  release behaviour.  Such granular particles may, however, also be produced by  other methods, for example by extrusion/spheronisation,  apart from the compacting method described.  These so-called spheroid tablet formulations are produced  in that propiverine or one of the pharmaceutically acceptable  salts thereof in the inventive molar ratio with one or several  acidic substances is compacted under strong pressure  together with spheronising agents, like for example lactose,  microcrystalline cellulose, hydroxypropylcellulose, with  lubricating agents, like for example magnesiumstearate, and  with further adjuvants, like for example polyvinylpyrroli› done, in a microcrystalline form, for example with a particle  size ofless than 0.25 mm, and is then once again broken and  screened to a particle size of, for example, 0.5-1.5 mm, the  fine fraction is once again compacted and these technological  steps are repeated as long as the total mixture of the granular  particles have been transferred into the desired size.  A further preferred embodiment of so-called multiple-unit  formulations are granules and compact particles containing  one or more acidic substances apart from propiverine or one  salt thereof which are not embedded in a retarding matrix, but  which only include this mixture together with one or more  controlled release coatings, and which are subsequently com- pacted into tablets.  The retarded particles obtained which may be in the form  of retarded pellets, granules or compacted particles may be  filled into capsules or sachets, preferably hard gelatine cap› sules, as desired.  It is possible to blend particles having dif› ferent delay levels and to optionally also add non-delayed  particles of the active agent as a so-called starting dose. The  retarding particles may, however, be compacted together with  tabletting adjuvants, like cellulose, lactose, magnesiumstear› ate and the like, into tablets. This is in particular possible with  retarding particles having a diameter below 1 mm without  substantially damaging the retardation coatings. Such a table  decomposes in less than 1 minute and releases the propiverine  retarding particles in their inventive form-like the hard  gelatine capsule does.  The subsequent drying of the pellets in order to remove the  residual solvents originating from the suspension is known  from the prior art. 