PROCEDURE FOR THE PRODUCTION OF A POWDER WITH A CONTENT OF MIKROVERKAPSELTEM AMPICILLIN ESTER ACID ADDITION SALT

D (-) - A-Aminobenzylpenicillin (ampicillin) was used due to its broad action spectrum and its suitability for oral administration widespread as antibacterial means, in particular with pädiatrischen applications. The administration l' thoxycarbonyloxyäthylesters mentioned by ampicillin, in the following with the international Kurzbezeiohnung “Bacampicillin”, leads to higher blood values at ampicillin than this with oral administration (see the US-PS Nr.3, 873.521 and Bodin et al., Antimiorobial Agents and Chemotherapy, 8 (5), P. 518-525). The free Eacampicillin base is with difficulty to manufacture, unstably and water-insolubly, which makes the oral administration practically impossible. The pharmaceutical acceptable acid addition salts of Bacampicillin, e.g. the hydrochloride, are generally wasseri0 solubly. Unfortunately such water-soluble acid addition salts possess a widerwärtigen taste, which makes the product for the pädiatrische use unacceptable. Conventional taste masking techniques, like the addition of Süßstoffen or aromatizing means, are able to not accordingly mask the strong taste of Bacampicillin Säureadditionssalzen. In accordance with one vorbekanntGn method did not become Baoampicillinhydrochlorid with a coat from ÄthylzelIulose microencapsulates, and the micro caps were combined with firm girder elements in a Sachet. Contents of the Sachets are mixed with water, in order to receive a diluted single dosage suspension with a pH value from approximately 5 to. Even with immediate sips after the Rekonstituieren a strong Bacampicillinhydrochlorid taste is to be determined, which can be extremely widerwärtig for a child. The use of these after the state of the art did not rekonstituierten suspension for multiple dosage administration is possible due to the Gesvhmacksproblems. As well known drugs for reasons of the taste masking with a coat from a mixture of Athylzellulose and Hydroxypropylzellulose can microencapsulate to become, whereby the micro caps are then rekonstituiert to a suspension. The state of the art however does not point a successful application out to this or another coat method on the problem of the production of a stable suspension of a Bacampivillin Säureadditionssalzes with benefitable taste and good bio-availability. A goal of the invention is thus the production of an aqueous formulation of an acid addition salt of Baaampioillin for the oral Verabreiohung with 1st intensified bio-availability, i.e. rapid and effective absorption of the active component from the digestive tract, 2. a taste, which make it suitable for the pädiatrische use, and 3rd satisfactory stability, so that the aqueous formulation can be given nae.h to the Rekonstituieren a patient several days long under practical maintenance of the strength, the acceptable taste and the bio-availability. o the procedure according to invention for the production of a powder with a content of mikroverkapseltem ampicillin ester, which leads by addition from water to a pharmaceutical aqueous suspension of the micro caps, is characterized by that one a) particle of a pharmaceutical acceptable, water-soluble acid addition salt of Bacampicillin with a particle size of less than 0.25 mm with a coat, that essentially from a mixture of ethyl cellulose and Hydroxypropylzellulose in a mass relationship of 1,5: 1 to 2: 1 exists, covers, whereby micro caps are formed and b} these micro caps with pharmaceutical acceptable suspension girder elements mix, whereby the girder elements sports club are selected that the pH value after suspension of the powder obtained, rekonstituierten pharmaceutical aqueous suspension at least 6.9 amount to. The mass relationship from ethyl cellulose to the Hydroxypropylzellulose in the coat is stopped in such a way that the pharmaceutical suspension has a stability from at least 8ü% retention strength after 14 days with for instance 3°C and an average maximum blood serum ampicillin content of at least 6 pg/ml after oral administration to adults supplies. Rekonstituierten pharmaceutical suspension, D, h obtained the highly desired combination of characteristics under employment available of the according to invention powder. the bio-availability, Gesvhmaeksmaskierung, stability, enters only if the critical delimitation of the PH is kept - value of the suspension medium. Besides must fall the relationship of thylzellulose to filler material in the coat into a special range, which depends on the particularly used filler material. In accordance with the invention a powder is manufactured, which is rekonstituierbar by water additive to a pharmaceutical suspension of Bacampioillin Säureadditionssalz Mikrokapseln in an aqueous suspension medium, whereby the powder consists of a mixture of Bacampicillin10-Säureadditionssalz-Mikrokapseln and a row pharmaceutical acceptable Suspensicnsträgerbestandteile, whereby the micro caps a core from a pharmaceutical acceptable, water-soluble acid addition salt of Bacampicillin and whereupon a coat essentially from a mixture of thylzellulose and Hydroxypropylzellulose in a mass relationship of 1,5; 1 to 2: I exhibit, whereby the girder elements are selected in such a way that the pH value after suspension of the powder obtained rekonstituierten pharmaceutical aqueous suspension at least 6.9 amounts to; the new powder supplies an aqueous, pharmaceutical suspension by mixing with water. Available the according to invention formulation can be gebraaht in drying powder form into the trade, i.e. to the Rekonstituieren by a pharmacist by addition from water to the education of the new suspension for the oral multiple dose administration. The micro caps are easily moistened and suspended. The new suspension can then with the patient at home in a usual household refrigerator (i.e. with approximately 5°C) to be kept and for oral administration in time intervals over up to approximately 2 weeks, like by the physician be indicated, taken. The suspension should be naturally vibrated before the delivery of individual oral doses well. The rekonstituierte aqueous suspension contains typically for instance i00 to approximately 200 mg Bacampicillin - of Säureadditionssalz/5 ml suspension. The above-mentioned Trockenpulver knows also, if gewfinsGht, to which patients e.g. in the form of Sachets to the Rekonstituieren with water for oral single dose administration is distributed. Rekonstituierte suspensions for Einzeldosisverabreiehung are typically more diluted than such for multiple dose administration. Preferred the formulation of multiple dose from reasons of the Einfaahheit will naturally, the Trockenpulver to the rekonstituieren can by mixing the Bacampicillin Säureadditfonssalz Mikrokapseln with the other components existing in the rekonstituierten suspension after the specialist in the area of the pharmaceutical production well-known techniques be manufactured. The powder to the Rekonstituieren possesses good stability, in particular, at ambient temperature if the Bacampicillin Säureadditionssalz Mikrokapseln and remaining components of the powder were carefully gstrooknet, in order to remove Feuahtigkeit. By “pharmaceutical acceptable” acid addition salts such salts are understood, which are not toxic in the given doses. The pharmaceutical acceptable water-soluble acid addition salts ven Bacamplcillin, which can be used according to invention, e.g. cover such salts, like the I ydrocblorid, hydraulic bromide, sulfate, CIT advice, Tartrat and Maleat. According to invention the Bacampieillin manufactured in accordance with the first stage of the procedure - acid addition salt micro caps are manufactured preferentially after an air suspension coat technology, z, B. sausage he air suspension over course-proceed EN of the US-PS No. 3.117.027, Nr.3, 196.827, Nr.3, 241.520 and Nr.3, 253,944. With this procedure a Bacampicillin Säureadditienspulver in a bed is fluidisiert and a solution or a suspension by ethyl cellulose and a filler material in a volatile organic solvent, acetone, into the bed are e.g. sprayed. If droplets of this spray on the Bacampicillin Säureadditionssalzpulver separate and evaporates the solvent, a coat on the Bacampicillin Säureadditienssalzpulverkern forms. The final size of the micro caps becomes by the rough one the fluidisierten Bacampicillin Säureadditionssalzpulver and the mass relationship from coat to the Bacampici! Lin Säureadditionssalzpulver determines. The Bacampicillin Säureadditionssalz is brought before the covering on a size of less than 0.25 mm. If acetone is used as volatile organic solvent, the Bacampicfllin Säureadditionssalzpulver is preferably fluidisiert with damp air from 30 to 50°O. A preferential coat portion is 25 to 100%-Masse, related to the mass of the Säureaddidonssalzkerns. A coat, which constitutes less than for instance 25%-Masse, requires Rekonstitution to high dilution, around an acceptable taste aufrechtzuerha! ten. Upper courses, which constitute more than for instance 100%-Masse, are not preferential for economic reasons due to the costs of the 0berzugsbestandteile. A preferential size for the micro caps is under approximately 420 pm (i.e. the micro caps pass through by a filter with a mesh size of 0.42 mm). A particularly preferential portion of polymer coat 43 to 67%-Masse, in particular for instance 54%-Masse, related to the mass of the Bacampicillin Säureadditionssalzkerns is. The I0 preferential quality of the ethyl cellulose for the use the according to invention is that one with a Viskesität of 0,01 Pa.s (10 cP), which is soluble in high concentration in the acetone solution, which is preferably used with the air suspension coat technology. The preferential quality of the Hydroxypropylzellulose is with a molecular weight of approximately 60000. (Suitable ones thylzellulosen are such with the trade name “Ethocel” of the company Dew Chemical CO., Midland, Michigan, and suitable Hydroxypropylzellulssen is such with the trade name “Klucel” of the company Hsrcules Chemical CO., Wilmington, Delaware). A critical parameter for the success of the invention is the mass relationship from ethyl cellulose to the Hydroxypropylzellulose in the micro cap coat, it was found that the i thylzellulose/Hydroxypropylzellulose Masseverhältnis in the coat between 1,5: i and 2: 1 to be held must, in order to receive the desired characteristics of the rekonstituierten oral suspension. A lowering of this relationship under 1,5: I leads to that the taste masking receives only wing tip edge interpretation, which increases the possibility of a refusal by the patient, while a raising of the relationship over 2: I the bio-availability of the active substance after oral administration lowers. In order to suspend the Bacampicillin SRureadditionssalz Mikrokapseln in course of the Rekonstituiereus with water, an appropriate Trägervlskosltät is received usually by bringing hearts into the carrier, e.g. Xanthanharz. A pH value of at least 6.9 is critical in the Suspensionsmsdlum after the Rekonstitution. If the suspension medium has a lower pH value, the taste masking proves as insufficient. The desired pH value of the rekonstituierten suspension can by the use of buffering components, e.g. Natriumbicarbonat, in accordance with stage b) of the procedure according to invention to be reached. A particularly surprising characteristic of the invention is appropriate in it that the rekonstituierte suspension shows good stability, what their use for oral Mehrfaehdoslsverabreichung permits, even if the pH value of the aqueous suspension medium lies clearly over, beJ that stability problems for Baeampicillin as well known in aqueous media begins. By the term “pharmaceutical acceptable” aqueous suspension medium is understood a medium, which is not toxic in the given doses. Generally such a medium has a pH value under approximately 9 and exhibits substances, from which it admits is that they are safe for the intended use. Except the components, which are added for the controlling of the viscousty and the pH value, the suspension medium further, which well well-known components contain specialist in the area of the pharmaceutical production, can e.g. Suspension stabilizers, sugar, artificial Süßstoffe, aromatizing components. Konserviernngsstoffe and teilehenförmiges material, like titanium dioxide, in order to mask the visual feature of the micro caps. Preferential pH range for the Suspenslonsmedium is 7.9 to 8,2. Although the range of the invention is to be eingeschrankt by the following discussion of the mechanism in no way, the invention seems to work as follows: If the micro caps in aqueous medium are suspended, the water-soluble Hydroxypropylzellulose from the coat is leached out and leaves a multiplicity of pores, which connect the core of the active Bsstandteils with the aqueous medium. If however the Bacampicillin Säureadditlonssalz from these pores begins to out-diffuse, its foremost front meets to the pH value of the Suspensiensmediums (at least 6.9) and into the water-insoluble free base is converted. It is supposed this active Bestandtei! , that, into which pores converted into the free Nr.370994 base, that prevents pores clogged and substantial leaching out of the active component by the pores. Like that the taste of the rekonstituierten suspension is acceptable and the active component not a pH value suspended, with which stability problems can occur. Also no substantial leaching out of the active component enters the mouth of the patient during the temporary suspension unity the neutral or weak-drunk pH values in it. If the suspension is swallowed and achieves the sourer ranges of the gastro-intestinal tract, the micro caps are exposed however to pH values, at which the free Bacampicillin base is reconverted in the pores of the coat of the micro caps again into a water-soluble acid addition salt. The water-soluble Säureaddidonssalz of Bacampicillin flows then from the core i0 by the pores in the coat of the micro cap and unfolds a high bio-availability for the patient. The pharmaceutical suspensions obtained after suspension according to invention received of the powder on bio-availability, GeschmacksmaskJerung and stability were tested. The bio-availability can be determined by fairs of the middle blood serum AmpJcillJngehalte with a set of humans or depths periodically after oral administration. Maximum blood serum values at ampicillin with humans will usually receive min between 30 and 60 after oral administration of the suspension obtained under employment according to invention manufactured of the powder. With the determination of the influence of parameters of the Mikrokapse] of coat on the bio-availability in vivo was found that the results of the bio-availability correlate with humans well with one in vitro test, with which the percentage on after 15 to 60 min from a micro cap portion of set free Bacampicillin Säureadditionssalzen suspended in water in a rotary Standardflaschenvorri “htung with 370C is measured. The equilibrium pH value of the water, in which the micro caps are suspended, is about 5.5, which is for instance the pH value, which one finds within the duodenum range of the digestive tract, the range of the digestive tract directly beside the stomach. The Geschmaeksmaskierung can be determined with human taste test persons. The Stabilitä [t of the rekonstituierten formulation and the Trockenpulvers for the Bekonstituieren can probably be measured after standard techniques well-known on the field of activity. The following example are the invention more near to describe. Example 1: (A) Production of Bacampicillin hydrochloride Mikrokapseln a solution with a content of 48 g/l ethyl cellulose (N.F., 0.01 Pa.s and/or I0 cP], 32 g/l Hydroxypropylzellulose (F.C.C., mg = 60000, Klucel EF), remainder acetone was manufactured. The solution was then filtered by gauze. Bacampicillin more hydrochloridpulver (by a filter with 3 of a mesh size of approximately 0.30 mm gesiebt, 940 g) then in the GranuHerkammer of a Wurster Luftsuspensions Besahiahters with damp air by 2°C one suspended and one sprayed with the above filtered solution, until a coat had been applied by 35%-Masse, related to the mass of the Bacampicillin hydrochloride, on its particles. The coat contained Äthylzel] ulose and Hydroxypropylzellulese in a mass ratio of 1,5: i, anfa]] end ikrokapseln by e n filter with a mesh size by 0.42 mm were then led. Then the micro caps (663 g) became dried under vacuum 4 h with 35°G and then further 16 h under vacuum without warmth. (B) Production from Trockenpulver to the Rekonstituieren the following firm of components 30 min in a V-mixer (S. Perry, Chemical Engineers' Handbook ", 4th Aufl.) was mixed: Natriumbicarbonat ...................... 31.4 g Mannit ................................ 334.5 g Natriumcarboxymethylzellulose ......... 31.4 g Xanthanharz ........................... 62.7 g titanium dioxide ........................... 62.7 g of presscash sugars ...................... 2194.0 g WJldkirscharoma (artificially, food quality, spray-dried)…. 55.0 g Natriumbenzoat ....................... 31.4 g Nr.$70994 the received mixture was led by a filter with bottle wines by 0.42 mm, mixed again 15 min in a V-mixer and mixed then 10 a min in a V-mixer with 158,8 g of the Bacampicillin hydrochloride Mikrokapseln manufactured in accordance with (A). The stability of this according to invention manufactured Troakenpulvers corresponded to 85%-igem effectiveness receipt after 6 weeks with 500C. Production of a suspension for oral administration the Trockenpulver manufactured according to invention in accordance with example 1 was mixed with water and the mixture was by hand strongly vibrated, whereby an aqueous suspension for oral administration with a strength became to receive to added water from 200 mg Bacampicillin-hydrochlorid/10 ml. This suspension had a pH value of 7,6 and a stability ven 89% effect receipt after 14 days with 50C. Example 2: Production from Trockenpulver to the Rekonstituieren the following firm components were weighed and 30 min in a V-mixer were mixed, after they had been dried separately 16 h with 50°C in a Stokes Trogtrockner: Natriumbicarbonat .................... 77.5 g blannit ............................... 837.5 g Natriumcarboxymethylzellulose ....... 25.0 g Xanthanharz ......................... 5 0 g titanium dioxide .......................... 157.5 g of presscash sugars .................... 5480.0 g Saceharinnatrium ..................... 25.0 g the mixture was then led by a Fitzpatrick mill, in order to eliminate lumps. The resulting material became 30 min in a V-mixer with 199,0 g Wildkirscharoma (art product of food quality, spray-dried) and 872.0 g Bacampicillin hydrochloride Mikrokapseln - 35%-Masse coat from ethyl cellulose: Hydroxypropylzellulose (mass relationship 1,5: 1) mixed, whereby the micro caps, how in example l (a) was described, manufactured. The received mixture was dried 2 h with 50°C under vacuum. The stability of this Trockenpulvers to the Rekonstituieren corresponded to 97%igem effect receipt after 12 weeks with 50°C. Production of a suspension for oral administration as following example 1 descriptive, was prepared an aqueous suspension for oral administration made of the Trockenpulver to the Rekonstituieren, in accordance with example 2. This suspension had a strength of 200 mg Bacampicillin hydrochloride per 5 ml suspension, a pH value of 7,4 and a stability according to 95 per cent effect receipt after 14 days with 3 to 5,5°C. Example 3: Production ven Trockenpulver to the Bekonstituißren as in the Beispie! 2 a mixture was made of the following components: Nr.370994 l0 1S Bacampicillin hydrochloride Mikrokapseln - 35%-Masse coat from ethyl cellulose: Hydr oxyprcpylze! lulose (mass relationship 1,5: I) - Production such as n Beispie! l descriptive ............ 3ß64,0 g Natriumbicarbonat .................... 739.3 g Mannit ............................... 3580.0 g Natrlumcarboxymethylzellulose ........ 107.0 g Xanthanharz .......................... 214.0 g titanium dioxide .......................... 674.1 g of presscash sugars .................... 23460.0 g Saccharinnatrium ..................... 107.6 g Wildkirscharoma (food quality, artificially, sprühgetrooknet] ........................... 882.4 g production of a suspension for oral administration as following example I descriptive, was prepared an aqueous suspension for oral Ver2D abreiohung made of the Trockenpulver to the Rekonstituieren, in accordance with example 3. This Suspensien had a strength of 125 mg Bacampicillin-hydroehlorid/5 ml suspension, a pH value of 7,8 and a stability from 94% effect receipt after 14 days with 3 to 5,5°C. Gesehmacksermittlung with human subjects: Samples of the suspension which can be evaluated were given to each adult serving from ten as taste test persons. D e critic were asked to evaluate the taste of the suspension by assigning notes from I to 9 after the following scale: 9 - extremely likes; 8 - much likes; 7 - moderately likes; 6 - little likes: - neither likes nor to 5 unpopularly; 4 - easily unpopularly; 3 - moderately unpopularly; 2 - very unpopularly; 1 - extremely unpopularly, the total number of the notes assigned by the critics by the number judge divided, in order to receive the middle taste evaluation. A taste evaluation of 5,0 or more highly is regarded acceptably than. With application of above function for suspensions described following the examples 1, the 2 and/or 3 regarding their production the following results were received: Suspension under employment of the powder middle manufactured in accordance with example taste evaluation a) 5.4 b) 5.7 b) 6.1 a) = Geschmaoksauswertung within 5 min oral in each case bio-availability after oral administration A) of 21 healthy men, ekonstituieren after the Rekonstituieren b) = taste evaluation 30 min after the I, between 19 and 35 years and with a mass from 63 to 91 kg i0 kept ml to the suspension under employment of the powder in accordance with example 2, then about 1.7 1 water. Proportioning took place 30 min after the Rekonstituieren. Blood tests 0, 20, 40, 60, 80, 120, 240, 360 and 480 min were inferred from each person after proportioning. After coagulating blood serum was separated rapidly from each sample and stored up to the analysis on serum content of ampicillin with the help of an automated micro-biological agar diffusion test with -20°C. The central peak serum ampicillin content for the 21 persons amounted to 6.7 t, g/tal 40 min after proportioning. A comparison test with 400 mg Baeampieillin-HC1-Tabletten resulted in a central peak - serum ampicillin content from 5,8 llg/ml 40 min after proportioning. B) How following Beispie! I besehrieben, was prepared an aqueous suspension for oral Verabreiehung with a strength water added by 400 mg Baeampieillin-HCl/30 ml made of the Treekenpulver to the Rekonstituieren, in accordance with example 1. As in A) a test with two groups of eight adults men resulted in a middle peak serum AmpicillingehaIt of 6.9 t, g/tal 43 min after proportioning with a portion of the aqueous suspension (freshly rekonstituiert) with 400 ml Bacampicillin-HC1, compared to a middle peak serum ampicillin content of 6,4 IJg/ml 60 min after proportioning with 400 mg-Bacampicillin-HC1-Tablette. C) As in A) a test with seven small children resulted in a middle peak serum ampicillin content of 14,4 pg/ml 60 min after proportioning with a portion of the suspension, whose production was described following example 2, with 28 mg Bacampicillin-HC1/kg of Körpermasse of the Versuehsperson. This excellent result suggested the possibility of receiving high serum 20-ampicillin contents with pädiatrischen applications with more diluted suspensions e.g. with the suspension, whose production was described following example 3, in order to obtain so also an improved utilization of the active component.