Patent Application: US-92858104-A

Abstract:
the present invention relates to a controlled - release pharmaceutical composition comprising at least one active agent and an inactive matrix , said matrix comprising chitosan and derivatives thereof , and further comprising a hydrophilic polysaccharide polymer selected from the group of carbohydrate gums , specifically xanthan gum , and to the preparation and use of said composition .

Description:
the invention shall now be further described and illustrated by the following examples with respect to the attached fig1 - 9 and tables 1 - 3 . all examples are provided by way of example only , without any intended limitation to the scope of the invention . fig1 shows a schematic depiction of an oral dosage unit , e . g . a tablet , composed of a controlled - release pharmaceutical composition of the present invention . passing the highly acidic stomach ( ph & lt ; 3 ), certain amounts of the pharmacologically active ingredient are released from the tablet . upon reaching the small intestine and thus a more neutral , slightly alkaline medium ( ph & lt ; 7 . 5 ), an insoluble complex is formed in situ at the surface of the tablet followed by an extensive drug release . fig2 shows the dissolution profiles of ambroxol - hcl ( 75 mg ) from directly compressed matrix tablets . each formulation was subjected to 0 . 1 m hcl for 2 hrs , then to phosphate buffer , ph 6 . 8 . dissolution conditions : rpm , 75 ; apparatus , usp basket ; volume , 500 ml ; temperature , 37 ° c . ch refers to chitosan , and xg refers to xanthan gum . fig3 shows the dissolution profiles of metoclopramide - hcl from matrix systems comprising xanthan gum and / or chitosan . each formulation was subjected to 0 . 1 m hcl for 1 hr , then to phosphate buffer , ph 6 . 8 . dissolution conditions : rpm , 500 ; apparatus , usp paddle ; volume , 600 ml ; temperature , 37 ° c . fig4 shows the dsc thermograms of chitosan ( a ), xanthan gum ( b ), chitosan / xanthan gum ( 1 : 1 ) core material ( c ), and chitosan / xanthan gum ( 1 : 1 ) gel layer ( d ) obtained after an in vitro dissolution study , which includes the exposure of the matrices to 0 . 1 hcl for two hrs , and then the medium was replaced by phosphate buffer , ph 6 . 8 , for the rest of 24 hrs . thus , fig4 demonstrates that xanthan gum may bind to chitosan through ion pair interaction to form an insoluble complex ( co - acervate ). fig5 shows the kinetic parameters of ambroxol - hcl released from the binary mixture of chitosan and xanthan gum . the drug to polymer ratio was 1 : 3 . the continuous line represents the release parameters in acidic medium , and the dashed line represents the release parameters in neutral medium . fig6 shows the dissolution profile of salbutamol sulfate in different polysaccharide mixtures . each formulation was subjected to 0 . 1 m hcl for 1 hr , then to phosphate buffer , ph 6 . 8 . dissolution conditions : rpm , 50 ; apparatus , usp paddle ; volume , 500 ml ; temperature , 37 ° c . fig7 shows the dissolution profile of ketotifen fumarate from different systems . each formulation was subjected to 0 . 1 m hcl for 1 hr , then to phosphate buffer , ph 6 . 8 . dissolution conditions : rpm , 50 ; apparatus , usp paddle ; volume , 500 ml ; temperature , 37 ° c . fig8 shows the decrease in tablet dry weight ( erosion ) ( a ) and the water uptake ( swelling ) ( b ) during the dissolution process of chitosan / xanthan gum ( 1 : 1 ) matrices with ambroxol - hcl ( drug loaded ) and without ambroxol - hcl ( drug unloaded ). fig9 shows an in vivo experiment comparing the kinetics of ambroxol - hcl serum concentrations after a single oral administration of 75 mg ambroxol - hcl via a controlled - release tablet of the present invention ( referred to as t1 ) and mucosolvan 75la ( referred to as r ). drug to polymer ratio of t1 was 1 : 3 . the average of 6 subjects is shown in normal scale ( a ), and in semilog scale ( b ). in order to assess the controlled - release properties and the matrix - forming ability of the hydrophilic polysaccharides which combination is object of the present invention , overall compaction studies , in vitro drug releasing assays and in vivo studies were conducted . pharmacologically active agents which were used as model basic agents in the present invention were ambroxol - hcl , metoclopramide - hcl , propranolol - hcl , salbutamol sulfate , ketotifen fumarate . polymers finally used were cationic chitosan and anionic xanthan gum ( in a first approach , also anionic sodium alginate was tested ). drug to polymer ratio was set constant at 1 : 3 by weight ( cf table 1 below ), irrespective of whether the polysaccharides were individually used or a binary polymer mixture was used instead . in the latter case , the ratios of chitosan to xanthan gum tested were 1 : 4 , 1 : 1 and 4 : 1 . polysaccharide mixtures comprising the model basic agents were prepared in form of powders and granules ( cf . below ), and the mechanical properties were evaluated . the strength of tablets prepared from powder formulations was higher than that prepared from granules . however , no differences in drug release were observed . the difference in tablet strength became obvious during compaction . generally , granules possess better flow properties ( are more flowable ) than powder formulations but show larger elastic recovery stress upon compression . in the present invention , it was found that the ordinary granulation method resulted in the formation of porous granules . such pores will contract air pockets upon compaction . these air pockets resulted in a decrease of tablet strength and in an increase in elastic recovery . formation of small beads ( granules ) through modem technology may be the most appropriate solution . this would bring non - porous particles resulting in compaction with less elastic recovery and allowing easier handling by reducing the pressure applied in the tablet machine . a model basic agent ( cf . table 1 ) was mixed with a single polysaccharide ( xanthan gum or chitosan ) and with a binary polysaccharide mixture of chitosan / xanthan gum , respectively . prior to mixing , powders were deagglomerated by sieving . the components of each preparation were geometrically mixed by porcelain mortar and pestle for about 10 minutes before compression . biplanar , cylindrical tablets were manufactured by compressing the powder mixtures applying a pressure of about 443 mpa for 15 seconds by a low speed compaction machine ( hydraulic kbr press or instron instrument ). tablets were sealed properly with aluminium foil and placed in amber glass bottles for 24 hours . since low strength drugs are water - soluble basic drugs as well , the optimal formula developed for those drugs was also applied to low strength drugs . however , a filler was added in order to increase the tablet size up to 20 mg . different fillers ( cahpo 4 , mannitol , avicel ph101 , and nahco 3 ) were tried by mixing a filler with an active agent at first , followed by the addition of a binary polysaccharide mixture . similar to the high strength drugs , the ratio of low strengh drug / filler to polysaccharides was 1 : 3 ( cf table 1 ). the weight of the compressed mixture was the determinant in the die diameter : 13 mm for all formulations of high strength drugs to compress weights of 300 - 400 mg , and 6 mm for formulations of low strength drugs to compress weights of 80 - 120 mg . the optimal formulation obtained with tablets prepared from powder components , namely chitosan / xanthan gum at a ratio of 1 : 1 and a drug to polymer ratio of 1 : 3 , was used to prepare tablet starting material in granule form comprising ambroxol - hcl . 100 g powder mixture as described above ( cf . 1 . 1 .) was granulated with a 1 : 1 mixture of ethanol and water until a granulation wet mass was obtained (˜ 45 ml ). the wet mass was forced through a sieve , mesh no . 20 , and then dried at 65 ° c . until a moisture content was detected similar to the corresponding powder formula using a karl fisher titrator . the dried granules were passed through a sieve , aperture size 500 μm . samples were stored in well - closed bottles at room temperature . these granular mixtures were characterised before and after compression into tablet dosage forms . biplanar , cylindrical tablets were manufactured by compressing the granules applying a pressure of about 443 mpa for - 15 seconds by a hydraulic kbr press . the die diameter used was optimised to 13 mm to compress weights of 300 - 400 mg . in vitro assays with basic drugs ( and also with basic drugs of low strength , see below ) were carried out by applying an acidic medium in the first two hours followed by a neutral medium for the rest of the experimental period ( 13 ). in the development of controlled release formulations for basic drugs , ambroxol - hcl was chosen as a model for basic water - soluble molecules . in a first approach , ambroxol - hcl was added to xanthan gum and sodium alginate with a d : p ratio of 1 : 3 . ratios of xanthan gum and sodium alginate tested were 1 : 1 , 1 : 4 and 4 : 1 . there was no promising formulation that yielded a similar drug release pattern as mucosolvan 75la ® capsules , an ambroxol hydrochloride formulation commercially available from boehringer ingelheim ( germany ). in addition to ambroxol hydrochloride , mucosolvan 75la capsules further comprise stearyl alcohol , carnauba wax , polyvinyl pyrrolidone , and magnesium stearate as excipients , and gelatin , titanium dioxide , yellow iron oxide , red iron oxide , erythrosin ( e127 ), and indigotin ( e132 ) as components of the capsule shell . alternatively , chitosan was tested in a basic drug controlled - release composition . the suitable polymer mixture that results in a nearly similar drug release pattern as mucosolvan 75la was a mixture of chitosan and xanthan gum with a ratio of 1 : 1 ( fig2 ). this ratio showed the lowest drug release in both the acidic phase and the neutral phase among all combinations tested . similar findings were also found with propranolol - hcl ( cf . table 3 below ) and metoclopramide ( fig3 ). data in brackets represent s . d . each formulation was subjected to ph 1 . 2 for the initial 1 . 5 hrs , followed by ph 6 . 8 for the rest of the dissolution process . ch , chitosan ; xg , xanthan gum . the finding that xanthan gum , an anionic polymer , has the highest drug retardation power when mixed with chitosan in a ratio of 1 : 1 can be explained on the basis of complex formation . xanthan gum may bind to chitosan to form an insoluble complex ( co - acervate ) through ion pair interaction ( fig4 ). the complexation ratio was found to be 1 : 1 as proved by the dsc results ( cf . table 3 below ). the reaction between chitosan and xanthan gum might control drug permeation through the gel layer . the higher the degree of reaction between chitosan and xanthan gum , the more the retardation of the drug release would be . the reason might be that the two polymers develop a more restrict net work which renders drug diffusion . consequently , the complexation ratio between chitosan and xanthan gum may occur at 1 : 1 ratio . this could be confirmed by the maximal decrease in drug diffusion through the matrix ( lower drug release ) among all combinations tested . the reaction between chitosan and xanthan gum in the gel layer might be completed in the neutral medium . the presence of an insoluble coat around the tablet and the absence of any dimensional increase in size were important signs for the completion of the reaction . then , the drug release will be controlled by diffusion through this insoluble coat . the releasing profiles of ambroxol - hcl (& lt ; 60 %) from different chitosan and xanthan gum ratios in acidic medium was fitted to peppas equation ( power equation ) ( 14 ) using a non - linear least square method . the rate of drug release was expressed in terms of k value , and the mechanism of release in terms of release exponent ( n ). in the acidic phase , the lowest k was obtained for a mixture of chitosan and xanthan gum with 1 : 1 ratio indicating the lowest rate of drug release . also n indicates anomalous release but its value was almost the smallest and the closest one to 0 . 5 . it is known that the reason for the deviations of the release profiles from square root of time kinetics ( n = 0 . 5 ) is the phenomenon of polymer relaxation ( 15 ). this 1 : 1 ratio of chitosan / xanthan gum mixture involves the maximal contribution of drug with diffusion and the least polymer relaxation ( least deviation from n = 0 . 5 ) ( fig5 ). once the tablet comes into contact with neutral ph , e . g . reaching the small intestine , then the reaction between the positively charged chitosan and the negatively charged xanthan gum molecules is completed at the surface of the tablet . this leads to the formation of an insoluble porous coat from which the drug diffuses out to the dissolution medium . the use of 10 - 20 % nahco 3 as an excipient in the formulation leads to the following consequences : after placing the tablet in 0 . 1 m hcl , the tablet forms co 2 bubbles around within 10 minutes . this gas will stick in at the surface because of the high viscosity of the gel layer formed . this will rise the tablet up to the surface of the dissolution medium . the presence of 10 - 20 % nahco 3 has two functions . first , it will decrease the passage of the hcl molecules into the drug delivery system by making a gas ( co 2 ) around the tablet . this increases the tendency of drug release retardation . second , a floating tablet will be formed . this leads to the delay in the gastric emptying rate of the tablet . in addition , this will decrease drug release since only the down face of the tablet is now facing the dissolution medium . the release of ambroxol - hcl from chitosan / xanthan gum ( 1 : 1 ) matrix was found to occur largely due to swelling mechanism than to erosion mechanism . this was confirmed by conduction a swelling / erosion study with drug - unloaded polymer matrix ( chitosan / xanthan gum , 1 : 1 ), i . e . a placebo tablet , and with ambroxol - hcl - loaded matrix , i . e . a real tablet of the same polymer mixture with a drug to polymer ratio of 1 : 3 ( fig8 ). the drug - unloaded matrix showed nearly no decrease in tablet weight during the in vitro dissolution experiment indicating insignificant erosion mechanisms in the polymer matrix compared to the swelling mechanism . while the drug - loaded matrix showed a decrease in tablet dry weight , of course , due to the release of the drug from the matrix ( fig8 a ), the rate of decrease in weight was almost equivalent to the rate of drug release from the dissolution profile . these findings indicated that the erosion mechanism has very little effect on the drug release from this matrix system . the study of water uptake is shown in fig8 b indicating the swelling kinetics of drug - loaded and drug - unloaded polymer matrices . the swelling effect is thought to be due to solvent penetration in the hydrophilic polymers within the matrix . at the beginning of the acidic phase , swelling occurred at a high rate , later , the rate was decreasing . this is due to the effect exerted by the swollen polymer layers at the surface that prevent solvent penetration to the inside of the gel layer . swelling increases polymeric chain movement and the opportunity for the reaction . in the neutral medium , the reaction is completed between chitosan and xanthan gum . this might result in squeezing of water outside the developed water - insoluble complex co - acervate and forming a polymer - rich gel layer . this was manifested by the decrease in water uptake in the neutral medium during the first hour . the developed hydrogel would be less porous in the drug - unloaded matrix than the drug - loaded matrix . the release of drug out of the gel layer would result in the development of a larger porous structures . the pores facilitated more water penetration into the drug - loaded matrix compared to the drug - unloaded matrix . this explains the increase in water uptake ability of the drug - loaded matrix after two hours in the neutral medium . salbutamol sulfate is a low strength water - soluble basic drug . the suggested formulation here would have a chitosan / xanthan gum ratio of 1 : 1 , which previously has been developed for basic drugs ( see above ). the addition of a chitosan - xanthan gum mixture having a ratio of 1 : 1 with a d : p ratio of 1 : 3 was not sufficient to increase the tablet size . low strength drugs always require the addition of a filler to increase the size of the tablet . different fillers were tried in the formulation , namely cahpo 4 , mannitol , avicel ph101 and nahco 3 ( fig6 ). the dissolution profile of the formulation containing nahco 3 was best among all formulations tested . when compared with a previous work , where chitosan and xanthan gum were used as drug - release retarding polymers ( 16 ). the formulation of chitosan and xanthan gum with 1 : 1 ratio containing nahco 3 had the advantage of decreasing drug release in acidic medium ( fig6 ). another advantage of the addition of nahco 3 would be the development of a floating controlled - release drug delivery system . a floating system will increase the overall retention time in the gut , which may be attributed to the buoyancy of the tablet in the stomach ( 17 ). similar findings were observed with ketotifen fumarate , another low strength water - soluble basic drug ( fig7 ). also tested with the same matrix , i . e . chitosan - xanthan gum ( 1 : 1 ) matrix , and the filler was nahco 3 . the release was compared to a previous work , where chitosan and sodium alginate were used as retarding polymers with a ratio of 1 : 1 . the release of the drug from chitosan - xanthan ( 1 : 1 ) matrix using nahco 3 was slightly more retarded in acidic medium and nearly similar in basic medium ( fig7 ). the feature disclosed in the foregoing description , in the claims and / or in the drawings may , both separately and in any combination thereof , be material for realising the invention in diverse forms thereof . a controlled - release tablet according to the present invention comprising 75 mg ambroxol - hcl and having a drug to polymer ratio of 1 : 3 was applied as an oral single dose to six healthy volunteers , and the serum concentrations were determined with time . mucosolvan 75la was used as a reference . as demonstrated in fig9 , the controlled - release composition of the present invention resulted in a more constant release of ambroxol - hcl into the serum . in particular , the abrupt increase in serum concentration during the initial ten minutes produced by mucosolvan 75la was absent . thus , the controlled - release composition of the present invention is superior to the reference formulation with regard to drug release retardation . the features disclosed in the foregoing description , in the claims and / or in the drawings may , both separately and in any combination thereof , be material for realising the invention in diverse forms thereof . 1 v . dhopeshwarkar and j . zataz . evaluation of xanthan gum in the preparation of sustained release matrix systems . drug dev . ind . pharm ., 19 , pp 999 - 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