Patent Application: US-51755805-A

Abstract:
a formulation , especially a pharmaceutical formulation , comprises an active agent and a carrier for the active agent , wherein the carrier comprises a beta - limit dextrin . the formulation may be a bioadhesive pharmaceutical formulation in which the beta - limit dextrin acts as a mucoadhesive agent . the active agent is a pharmaceutically active agent or a flavour or fragrance which is intended for delivery into the buccal cavity . a use of beta - limit dextrin as a disintegrant , a dispersant , and a mucoadhesive agent is also described . also described is a nutritional product such as an energy drink which includes beta - limit dextrin as an energy source .

Description:
these dextrins may be produced from starches of different botanical origins and different genetic modifications , chemical , enzymatic or physical derivatives . since all the amylose is converted to maltose , it is much more cost effective to use high amylopectin (‘ waxy type ’) starches where there is a higher proportion of amylopectin — the origin of the β - limit dextrin . the dextrin may be produced by a number of routes and the following method does not exclude material produced by other routes nor using other sources of enzyme or processing conditions . the dextrin is produced in conjunction with maltose from the α - glucan hydrolysis . in the method descried below , the maltose is removed by dialysis leaving pure dextrin . however , the maltose could be left in the product as an option ( to impart sweetness and novel functionality ). waxy maize starches ( c . 25 g ) were dissolved in 500 ml acetate buffer ( 0 . 02m , ph 4 . 8 ) at 100 ° c . for at least 1 hour . after cooling to room temperature , crystalline sweet potato β - amylase ( 5 × 10 3 units , sigma a - 7005 ) was added and the mixture was thoroughly mixed . the mixture were then transferred into dialysis tubing ( visking code dtv 12000 . 13 . 000 ) and incubated for 36 hours at 37 ° c . under dialysis against the same buffer , which was renewed three times during the first 3 hours and twice afterwards . chromatography would be a preferred industrial separation method . after the reaction had been terminated by heating the mixture for 10 mins at 100 ° c ., the coagulated protein was removed by centrifugation , and then ethanol was added to the solution . the resulting precipitate was collected by centrifugation , dissolved in water ( 250 ml ) and then re - precipitated by the addition of ethanol . the precipitate recovered on centrifugation was finally dissolved in water and then dried ( below ). the dextrin was dried using freeze drying and spray drying ( including use of small pilot scale büchi mini spray dryer model b - 191 ). the spray dried material is a fine powder with good flow characteristics . the freeze dried material makes a fine lyophilised matrix . this may be milled to a powder which tends to be a little electrostatic in character . the material was also wet granulated from the dried materials which was , itself , readily tableted ( below ). solvent / temperature (° c .) solubility ( w / v , %) water 25 ° c . 31 water 50 ° c . 34 0 . 01m hcl ( ph2 ) 25 ° c . 33 0 . 01m hcl ( ph2 ) 50 ° c . 43 0 . 01m naoh ( ph12 ) 25 ° c . 34 0 . 01m naoh ( ph12 ) 50 ° c . 36 the stability was assessed where the time for the solution to become opaque then form precipitates at different ph &# 39 ; s was determined . ph storage stability ( days ) 3 94 7 9 11 17 the product of β - amylase hydrolysis was analysed by gel permeation chromatography ( gpc , using sepharose cl - 2b gels ) according to karkalas and tester ( 1992 ) before and after dialysis ( to remove maltose ). accordingly the retention time and molecular weight of the dextrin was smaller than the native amylopectin ( with maltose present prior to dialysis ). this confirms that the native amylopectin molecules were selectively hydrolyzed . to prove that the rheological properties of a drug in solution with a sugar ( glucose ) or the β - limit dextrin are different in terms of interactions the following experiment was conducted . samples of theophylline and either glucose or the β - limit dextrin were dispersed in water ( to give a concentration of 1 % theophylline , w / w and either 1 % with respect to glucose or beta - limit dextrin , w / w ) within sealed screw capped tubes . these were sealed and mixed and kept in a 25 ° c . water bath . the viscosity was immediately determined using a brookfield dv - iii viscometer ( brookfield engineering laboratories , inc ., usa ) fitted with a cone and spindle cp - 40 system ( 2 . 4 cm dimension and 0 . 8 ° angle ) with a thermostatically controlled temperature of 25 ° c . a silicon viscosity standard ( 96 . 2 mpas at 25 ° c .) from brookfield was used for calibration . the results are shown in fig1 . the properties of formulations containing the dextrin which have none , some or all of the maltose removed ( howsoever ) differ in their properties . these are also considered below . the solubility of the dextrin and its high molecular weight make it very valuable as a component of drinks to provide a slow release of energy . β - limit dextrin was wet - granulated as described later in this application . two formulations were prepared where the carbopol formulation was used as a standard as it has well established mucoadhesive properties . tablets were made using a single - punch tablet press ( manesty f3 , liverpool , uk ) and 6 mm diameter flat punches . β - limit dextrin formulation produced thicker tablets due to the lower bulk density of the mixture . the tablet &# 39 ; s crushing strength was measured using a tablet hardness tester ( model tbh28 , erweka , heusenstamm , germany ). at compaction pressure of 35n , crushing strength of 45n was obtained for β - limit dextrin formulation whereas the value for carbopol formulation was 160n . mucoadhesion test was carried out in vitro using double strength nutrient agar coated with a 5 % solution of porcine mucin over the surface . measurements were made with a texture analyser ( ta - xt2i , stable micro systems , surrey , uk ) by applying a force of 0 . 15n and a contact time of 10 minutes . the adhesive forces obtained are shown in fig2 . as can be seen in fig2 , the mucoadhesive force of the carbopol formulation was about 0 . 40n on average , with the average value for the β - limit dextrin formulation about the same ( 0 . 38n ). under these conditions therefore the mucoadhesive force of β - limit dextrin was very similar to the carbopol . the contact force was then increased to 0 . 25n . the proportion of β - limit dextrin was increased to 30 % and this was found to be the optimal concentration . three formulations were prepared as follow : a ‘ placebo ’ tablet was also prepared that contained no known mucoadhesion . mucoadhesion force was measured as mentioned above with contact time of 10 minutes . the average mucoadhesive forces are 0 . 097n , 0 . 245n and 0 . 450n for tablets containing placebo , chitosan and carbopol respectively comparing to the value of 0 . 464n for β - limit dextrin . the results ( see fig3 ) demonstrate that the β - limit dextrin does have significant mucoadhesive properties . the mucoadhesive property of β - limit dextrin can be improved by addition of other polysaccharides ( e . g . sodium alginate ). two formulations were prepared as follow : the mucoadhesive forces measured as described above are 0 . 629n and 0 . 544n for formulation a and formulation b respectively , although 0 . 464n was obtained without addition of sodium alginate for the previous formulation ( page 24 ). the above results ( see also fig4 ) show that the addition of alginate does increase the mucoadhesive force of β - limit dextrin significantly . solutions / suspensions containing the dextrin and theophylline ( e . g . 10 % with respect to the dextrin and 0 . 1 % with respect to theophylline ) were freeze - dried where easily hydratable matrices were formed . these melt type formulations can also be milled to produce fine powders . the matrices ‘ melted ’ or rather dissolved and dispersed exceedingly easily when water came into contact with them . it is evident that freeze - dried products could be made from this material . it was found that the dextrin could be tableted directly to form products with different drugs . the following examples exemplify this . β - limit dextrin was prepared from waxy maize starch and was spray dried to form a fine powder . samples ( 15 g ) of the β - limit dextrin ( dried by freeze drying ) was wet massed with 5 ml water using an fp296 mixer ( kenwood ltd , uk ). granules were then spread evenly over a drying tray and dried overnight at 60 ° c . dried granules were passed through a 300 μm mesh to produce a free - flowing powder . two formulations were produced using the same water - soluble drug but different types of additional tabletting excipient since the tablet release matrix ( first ) formulation was not easily tabletable with drug alone ( as friable tablets were produced ). each formulation was then tested using a standard usp ii paddle dissolution apparatus ( st - 7 model , caleva ltd , uk ) at 37 ° c . in 1000 ml water ( λ max propranolol . hcl = 298 nm ). the formulation was mixed for 30 minutes using an orbital turbula ™ mixer ( glen - creston ltd , middlesex , uk ). the resultant mixture was then tableted with a 7 . 95 mm concave punch and die set using an e2 single punch tablet press ( bwi - manesty ltd , liverpool , uk ). the dissolution properties of the tablets are shown in fig5 . the components were mixed and compressed as with the previous formulation ( 1 ). the dissolution properties of the tablets are shown in fig6 . better weight uniformity is obtained indicative of improved powder flow . low hardness may be improved by adding a compression binding agent . these may be made from milling dried matrices ( e . g . ‘ 2 ’). however , powders can also be made directly by for example spray drying . solutions containing the dextrin and theophylline ( e . g . 10 % with respect to the dextrin and 0 . 1 % with respect to theophylline ) were spray dried where very fine powders were prepared that disperse very easily upon hydration . these may be tableted ( see above ) or utilised in sachet type formulations . it is anticipated that pulmonary type delivery products could be made from small particles comparable or smaller than dimensions present in these powders . the β - limit dextrin was dissolved in water ( for example a 10 % solution ) with theophylline ( for example 0 . 1 %). the solution was found to be very stable at room temperature and could be used as a liquid formulation for oral delivery of drugs and for parenteral administration . liquid formulations were also made with the dextrin alone . it is clear that the stability of the dextrin makes it valuable as a provider of energy in appropriate nutritional products . the material will have a slower hydrolysis profile with for example α - amylase compared to maltodextrin because of its higher molecular weight . spray mists were made with the solutions using a variety of devices and support the application in nasal / pulmonary applications . β - limit dextrin was dissolved in deionised water , to which vitamin a solution ( 1 mg / ml ) was added to give final concentration of 1 % for β - limit dextrin . film was obtained after convection - oven drying the mixture in a foil tray at 30 , 40 or 50 ° c . overnight . it was noted that rather surprisingly the β - limit dextrin could facilitate the dissolution of drugs . there are many potential applications with respect to dispersing and solubilising insoluble compounds . the following example indicates that this is so . β - limit β - limit dextrin drugs ( 1 %) water dextrin ( 5 %) ( 10 %) ascorbic acid dissolved dissolved dissolved glucose dissolved dissolved dissolved theophylline not suspended suspended suspended aspirin not suspended suspended suspended it is also apparent that the material could be potentially used for intra - peritoneal dialysis if a low osmotic α - glucan is required . the product would potentially fulfil the need in this area provided by oligosaccharide type products like ‘ icodextrin ’ produced by ml laboratories . the following example indicates that this is so . the osmolality of β - limit dextrin solution ( 5 %) was measured using an advanced 3300 crysocopic osmometer which was pre - calibrated with 0 . 9 % aqueous sodium chloride solution . maltodextrin ( maldex 150bb , amylum ) was used to act as a control . the results are presented as follow . the cop 10k ( the measured osmotic pressure of the solution across a membrane with a pore size of 10 , 000 daltons ) of the same sample solutions was also measured using an osmomat 030 colloid osmotic pressure osmometer . a 6 % haes solution was used to calibrate the pore size as it varies depending on the age of the membrane . the cop 10k results are given as follow . osmolality cop10k samples ( 5 %) ( milliosmol / kg ) ( mmhg ) β - limit dextrin 16 . 2 3 . 9 maltodextrin 43 . 7 20 . 9 similarly to the icodextrin product discussed above , it is anticipated that the material could function to prevent tissue adhesion . drinks were prepared from 0 - 20 % β - limit dextrin and flavourings (& lt ; 0 . 1 %). the product is not sweet . hence , sweetening was added in ( a ) the form of sugar ( sucrose , 5 - 10 %) or ( b ) aspartame (& lt ; 0 . 1 *) plus flavours . the products had a much better organoleptic property and could be used as the basis of formulated energy products . the invention is not limited to the embodiments hereinbefore described which may be varied in detail without departing from the spirit of the invention . ammeraal , r . and friedman , r . 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