DE1792283A1 - Pharmaceutical preparation for oral administration - Google Patents

Description

Pharaaeeu-tischee preparation for oral administration

Pharmaceutical tablets for oral administration have heretofore been provided with various coatings to suit their taste zu vuräec & en, sine linger sustained release of the active ingredient to achieve or use the active ingredient just for absorption to release the small intestine at certain points. Pure iesie Purposes, as is well known, various Earze weröonj used but in all known cases, oil ranks an increase in that drugs absorb and enter the bloodstream let take in. One of the preferred methods, among others Medicines in the form of such preparations are also available is the keratinizing of the preparation "

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It is also known that gastric Dara juices have different pH values, which change from an acidic pH in the stomach to a weakly alkaline pH in the small intestine. With knowledge of this fact it is relatively easy to produce preparations from which the active ingredient is absorbed into a certain part of the gastric-Dara canal. Ee are but today many drugs that are based on the fact, especially au act in the colon, ms bacteria or parasites fight su.! Times the previously known methods, drugs of this type in? Oria suppositories or particularly coated tablets proffered However give tablets or Suppositories, even with the best methods known today, do not release sufficiently large amounts of active substance to the large intestine, because the active substance in these preparations is released prematurely through leaching or echaniiohe energy and, as a result, is absorbed into the blood vessels to an undesirably high level and is distributed in the body. For this reason, much larger doses have hitherto been necessary in order to provide effective arsenic consumption in the large intestine, since the losses are reduced.

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The invention is based on the task of developing a pha "as" utiaohee preparation for oral administration * ur disposal "and the like put, desee »active ingredient in dia juices in Hag« n and ia thin

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2535 ■ -: ■■■■■. , is practically not released in the intestine, but in the large intestine is practically completely released, as a result of which it is practically not absorbed in the Hagen intestinal canal, but practically TollstSadig is set free in the large artery for dissolution.

This is achieved, according to the invention, by a pharmaceutical preparation for oral administration, which is characterized in that the active ingredient in the form of brush particles is embedded in a "hair" in such a way that it remains essentially protected by the resin, while the particles are protected by the stomach and pass through the patient's small intestine, but are released practically completely when the particles reach the large intestine, the hars and slopes of the same being selected so that the active ingredient in an accelerated dissolution process in a certain artificial liquid in an hour to 2 to 12 # and in 3 hours su 18 to 88 i * goes into solution. This preparation can take the form of a pill, a tablet, a suspension, or a. Capsule, because the active ingredient particles are from the protective substance, in order to get the result: The I * a% aret give * i & i ^ i ^^ im '·;

Bar area of the Dieläarms free, νό is known to be the least Absorption of the drug takes place «As a result, it forms in the patient to whom the drug is given

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does not reveal a notable concentration of active substances in the blood. Analysis of the stool, however, shows that practically all of the active ingredient goes into solution and is available for local treatment of the large intestine. Such preparations are therefore particularly suitable for the local treatment of infections and parasites in the large intestine, which require a relatively high concentration of active ingredients, and for the use of medicaments which should preferably not be distributed in the body by the bloodstream.

The preparation according to the invention is produced by coating fine particles of the drug in question with a relatively insoluble, pharmaceutically acceptable resin or being embedded in the same, the range of the resin being measured in relation to the desired amount of the active ingredient so that in the following accelerated solution test described in an hour from 2 to 12 # and 3 hours from 18 to 88 fi of the active ingredient in an artificial intestinal fluid go into solution "the thus-coated particles can then be compressed into tablets, processed into pills, in a form suitable for oral administration liquid Carrier suspended or placed in a capsule, which consists of substances that dissolve in the gastric-Dario canal. Tablets produced in this way can be coated in order to give them a better appearance, a pleasant feel

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to give sohmaok or an IMrsere shelf life · a However, such a coating of the tablets is not necessary if the Hars is combined with the active ingredient in the manner specified above.

To achieve a complete or almost complete coating on the individual active ingredient particles, various resins can be used, with some particles forming larger agglomerates * during the coating process, but the individual active ingredient particles are still essentially covered isomerically by the resin, depending on the solubility of the resin in question Resin can be combined with a smaller or larger amount of the same with the active ingredient. The amount of resin also depends, to a lesser extent, on the solubility of the drug to be administered. If the drug is very soluble, a somewhat larger amount of resin is used so that as little as possible of the drug goes into solution prematurely as a result of the possible unrolling of the coating on the rope. In the case of highly soluble drugs, a coating on the pills, capsules or pressed data sheets may therefore be advisable.

The preparation vegetable of the invention migrates through unchanged the stomach and at least through the upper part of the small intestine. In the case of tablets, these gradually disintegrate into

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smaller particles, which inaer are still practically entirely of the resin are covered so that the active ingredient contained in the particles does not come into contact with the intestinal fluids comes. In the case of suspensions or capsules, the coated particles are released as such (as the coated particles pass through the small intestine) the agglomerates become alimodal by physical and chemical forces broken, and the resin surrounding the drug particles is gradually worn away, so at that time, too which the particles reach the large intestine, practically the whole active ingredient is set free. The professional is readily able to use the preparation according to the invention with suitable selection of the amount and type of resin Manufactured in such a way that only the lowest possible release of the active ingredient occurs in the stomach and small intestine, whereas the largest possible release of the active ingredient occurs in the large intestine. For easy Determination of the amount of the resin in question, which is necessary for the active ingredient in the Diekdara to have an effect the following test procedure is used:

One or more tablets which contain a known active ingredient and which are invented by a combination of Active ingredient and resin have been made into one Crushing device naob. Stoli-Gerehberg brought in, the sioh in a known amount of artificial gut string »loading

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finds, as it is in the U.S. Pharmacopoeia XVII (1965 »page 919), which however does not contain pancreatin. The device is used in which the artificial intestinal fluid containing Beeherglas with, .ner constant frequency of 28 to 32 strokes per minute over a distance of 5 to 6 cm moved up and down »The artificial juice is kept at a temperature of 38 ° C; however, in deviation from the disintegration test described in the TJ.S ° Pharmacopoeia no plastic washers used. Every half an hour, small samples are taken from the disintegrating beaker with a pipette taken. The pipette is through one piece at the receiving end Extended plastic tube containing a cotton ball, so that no particles enter the pipette when the sample is taken can. Me analysis of these samples, which are only dissolved Containing active ingredient, is carried out according to the method most suitable for the respective active ingredient in the tablet. on In this way, the active substance in the sample is determined only to the extent to which it has gone into solution «, suspended free active substance particles and those particles which are responsible for the Are still coated with the resin at the time of sampling in the results not »This accelerated dissolution test provides a fast method that can be carried out in vitro to determine the behavior of the new preparation in vivo »If the result obtained in vitro has a dissolution rate shows within the ranges given above

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(or in the graph between the following described curves), the preparation has the desired Properties in vivo.

Pills, capsules or suspensions can also be put in analyze the manner described above for tablets.

The figure shows a diagram in which the concentration of the dissolved active ingredient of certain and different, according to the invention of the tablets produced as a function of the time applied, as in the above-described solution test is determined. The concentrations of the active ingredient at different time intervals are as percentages of the total The amount of active ingredient in the tablets below is indicated » Curve A is the curve for. a tablet with a ratio of " massively high dissolution speed} a tablet that solves faster than gs corresponds to curve A, dissolves too quickly to settle for the Goidinschen local Be ~ action, and would lead to an increasing consensus

tration of the active ingredient in the blood, so that accordingly lower active ingredient & tight in the large intestine for reduction The curve B represents the rate of dissolution of a very slowly dissolving.sn tablet according to the invention represents ι if the speed of dissolution of the tablet is due to the fact that the tablet has an older resinous iron or a more insoluble one

Hara contains, aooh is further reduced, the tablet can migrate through the entire derm canal without the active ingredient being completely released. In other words: the preparation produced according to the invention, which after the above-described touch in vitro results in a solution curve which lies in the area between curves A and B, leads to the desired release of the active ingredient in the large intestine of the human body, without any appreciable concentration of active ingredients ia'Blut 2SU produce, and without excessive T © rlust-s with m & chair excreted, not freigeeetz ~ tesi agent. In particular seigeii the curves that a tray © whose active ingredient is in © isier hours to 2 to 12 ^ and in 3 hours to 18-88 i> in solution, for the delivery of Wirkstoffs- is well suited practically only at the Diekdarm. DIqb means that in patients with such a tablet, there is no significant concentration of active ingredient in the blood, as the analysis of the merely dissolved material in the stool shows that practically all of the active ingredient goes into solution and is used for the local treatment of the colon Available.

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example 1

A solution of 5 g of polyvinyl acetate of high viscosity ("Gelva C3-V3O", horgöstollt from Shawinigan Besin Corporation) in 50 ml of methyl chloride is placed in a mixing bowl added to 250 g of erythroynycinate arate and thus ver ~ mixes. If necessary, methylene chloride is also added

^w and the Miech process continued until the mass is partially dry. The mixture is granulated, poured through a sieve of 0.833 mm hash width onto 2ablatta slipped with paper and dried for 16 hours at 49.degree. The dry Ifrythromyoinstaaratkurner are transferred back to a mixing tray and there is a 5rBa2.uS.at made of 132 g Hatriufflcitratpulver and 21 g Polyvinylpyrrolidon ysrsetat, which has been sifted through a sieve with 0.37 ®m mesh size Ha »se granu-

P lated and by a 4.7 im. Maschenwoite poured onto a paper-lined tablet. The grains are as described above, dried, poured through a sieve to a size of 1.168 mm, and put into a mixer with 7.5 g of a disintegrant with a size of up to 0.37 mm. The ice cream is thoroughly cleaned and then tablets are prepared in the usual way

Each 4 ^ 5jiag apply and every 150 as erythroeycin activity . keep. ^v

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1000 of these tablets are soaked in a coating pan in the usual way with 150 ml of a normal coating solution containing cellulose acetate E.t-pb.thalate, propylene glycol, a wetting or dispersing agent, yellow colorants, titanium dioxide, talc powder, alcohol isxä acetone. after 3edea behalf of Beschicktunc ^ löeung the Sablatten with Talkiuapulver vorden eingeotäu'ct, biu about dis Hälftö the loading φ is woi'cLen eohichtungelösung applied. Dar rest is loading

The layering solution is put in place without talcum powder. The layered Tablets are then placed on a tray for 12 hours at 57.8 ° C, S4 hours at 43 ° C and 4-8 hours at 49 ° Ο dried up.

Two of these tablets are subjected to the above-mentioned dissolution test using 650 ml of icodified artificial intestinal juice as the meat liquid. The artificial juice is prepared by dissolving 6.8 g of Konokaliuiaphosphat in W 900 Bl water, whereupon 38 ral 1η sodium hydroxide solution is added, if necessary then the pH value is adjusted to 7.4 with further sodium hydroxide solution and the solution is diluted to 1000 ml.

This solution is used every 30 minutes during the test Samples of 2 ml taken. The samples are bit 7 ml of water diluted, shaken, and 2 ml of this diluted solution

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siiiig are acidified with 2 al 12η sulfuric acid. then 2 ml of an arsenic molybdate test solution are added, the The mixture is kept in boiling water for 10 to 12 minutes and then cooled while shaking. The absorption of light at 730 Εμ is determined with the spectrophotometer and with that of test rods compared to a well-known one Have erythroniycin content and treated in the same tfeia © been aind. Mo arsenonolybdate solution is produced, by 50 δ Amiftoniusiuolybaat in 900 sil water Löot, slowly with cooling and cooling 42 al 96 #ige sulfuric acid «? and this solution with 6 g of disodium rsenate in 50 ml Water added. The test reagent is kept at 37 ° G for 24 hours and then held against the action until sur use protected from light. The analysis results of the samples are shown in the figure as a curve €.

In the example above, if the compressed tablet was before the Coating is investigated according to the solution test described, practically the same solution curve is obtained.

Using the ingredients and procedures described above tablets are made with 50 mg erythromycin stearate and before and after dome coating according to the above, accelerated dissolution test investigated. The results can also be found in the illustration. The curve D

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is obtained with the coated tablets, curve E with the uncoated tablets. The result is that the coating on the tablets is not necessary and, if it is present, does not change the quality of the tablets considerably. The curves show fav ner that sswiachsyi doa tablets xait 50 mg tind with 150 mg active ingredient no> 3 indicate & there is a difference in the speed.

Example 2

In a clinical test tablets of 50 jag Erythromycinstöar t administered, which have been prepared in the above manner on 5 people, but 6.5 mg per tablet contain Haisstärke * Each person be administered tablets _7? one saber every 8 hours. Sound the individual persons are taken one hour _r 2 hours, 4 hours and 30 hours after administration is first tablet blood samples. After 1 hour, 2 hours and 4 hours, the blood samples show a mean value of less than 0.02 μ & / ml erythromycin Ie blood serum and after 30 hours a mean value of a little over 0.02 μβ / πΐ; so no appreciable amount of erythromycin has been absorbed and taken up by the blood stream. At the same time, all stool excretions from the persons, starting with the first day of treatment, are analyzed over a total of 4 days

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The mean amount of craving erythromycin found in the stool in the 5 people on the first day is 26 pg / g, on the second day 188 μg / g, on the third day 210 μg / g and on the fourth day 171 ig / & *

In a parallel experiment, seven normal film-coated tablets each containing 100 mg srythromyoinstearate are administered to 5 people at intervals of 8 hours. The mean concentration of the active ingredient in the blood serum reaches 0.09 μ & / ιη1 after 1 hour, 0.12 μg / ml _r after 4 hours 0.10 μβ / πΐ and after 30 hours 0.06 μβ / ΐηΐ, while the Stool analysis shows a mean value of 16 μg / g on the first day, a mean value of 28 μg / g on the second day, a mean value of 115 μβ / g on the third day and a mean value of 67 μβ / g on the fourth day.

From the above numbers it can be seen that the normal Erythrosiyoin stearate tablets lead to the formation of a considerable concentration of erythromycin in the blood while with the patients who took the tablets according to the invention found practically no erythromycin in the bloodstream will. On the other hand, the active ingredient in the new tablets does not go through without being released by the body results from the stool analyzes: In the case of the persons »who were given the normal 100 mg tablets, is

the middle amount of crythroayoin found in stool altogether 226 μ ^ £, whirling the 50 ag-T * tablets (i.e. dit half dose) devices of the invention in four fagon iu one Gesemtauesoheierung on dissolved erythromycin τοη 595 μβ / β to lead.

Example 3 φ

A group of 50 patients suffering from dysentery Take 2 tablets of 150 ng erythromycinetearteart each day Example 1 presented * Each patient is treated in this manner for seven consecutive positions 15 days after the treatment »that 44 batients have been whitened *

Another group Sound 30 patients suffering from uloerativer _m Ämöbenkrankheit, in two groups like that. divided into 15 patients each. One group was given tablets containing 300 ag of erythromycin produced for seven days according to Example 1, and tablets containing 150 mg of erythro-ejycin twice a day were given to the other group for seven days. Observation of the large intestine through rectosigmoidoscopy shows that the ulcers have healed and no srophozoites can be found in the debrideal skin of 24 patients after the end of treatment. Both

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another six patients have actually shrunk the ulcers and generally improved; in the mucous membrane clay animal trophozoites are found in these patients; they cannot be detected in the sole skin of the other two patients.

In dan above examples, the individual Arßneimittel are ^w particles coated with a special resin, but can also .hierfür similar polymers are used s.Bo carbozylgruppenhaltige polyvinyl ©, copolymers of polyvinyl and Haieinsäureanhydrid, PoIymethacrylsäure, copolymers "us ethylene and Haleinsäureanhydrid, copolymers of KethaoryXetare and methacrylic acid methyl ester, Ethyloelluloee, wax ·, mixtures of these compounds as well as mixtures of the same old shellac. In general, any polyamide can be used as well as embedding the Sinsel-P te Hohen dee active substances, since our solubility in the Kagen dam juices is poor.

The above examples illustrate the production of tablets, which contain brythromyl stearate as an active ingredient for local application by oral administration, since it is supposed to exert its pharaohean effect on the large intestine * Solohe tablets are particularly suitable for combating amoebic disease and other parasitic infections of the lower ropes of the ter-

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The invention, however, is nodding! Tablets besehrankt, Ite ErythrciQ ^ oin entlialtsn as active ingredient. Other Medicines »which often 'against bacteria or parasites iia DiöMarm used are Cnloso ^ uin »Jodehlorhydröxyajuin, Mjodhydroxyquiii, leomycin, certain Setraoyeline and other medicines used to treat DariD infections and malfunctions.

The FachEarax temm easy to determine the quantities of the respective filigree resin which are required in order to cool a l'ahlette ilt of the stated loaujigsgesciiwindiglrait. If a particular insoluble han; used or Eit a particular resin one is made especially harW $ ablette, can aioh fallsgeschwindiglceit Zer-the Sablette by changing the tablet zuswe et send Zerfallsnittele stunning river en ₀ Sun's contains B · those OBEA bWchriebijne tablet 5 £ disintegration the " middle and shows in the Löaunig test an Ibsungsgesohwindig-: celt in 1 hour of 9 1> im4. in 3 hours from 47 years. "The same tablet can also be made with smaller or larger amounts of the same or some other disintegration agent. This changes the time until the ingested tablets disintegrate into smaller amounts, the speed of dissolution However, since the drug does not change> essential5 it only depends on the type and amount of the hardness in question.

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2535 'The invention differs from the previously known preparations in that each drug particle is coated with a slowly disintegrating or slowly dissolving resin or embedded in such a resin, the amount and type of resin being selected so that the drug particles are practically unchanged go through the gastrointestinal cavities until they reach the large intestine.

"The resin is selected so that its rate of dissolution is independent of the pH value. This is an essential one Difference from known preparations in which a resin only contains the medicinal substance at certain pH values protects. In other words: the preparation of the seed of the invention does not become dependent, as was previously the case depending on the pH value, but available for local application depending on the time.

Methods other than that of embedding the drug particles or covering them with the hair can also be used described above can be applied. The active ingredients can be made by air suspension coating or by other means Processes which lead to a practically complete coverage of the particular activity of the resin to lead. The drug particles thus coated can then in the known ^ way to preparations »such as tablets, pills, Capsules or suspensions, to be further processed.

The suspensions produced according to the invention} tablets or pills can also contain usual additives / such as fillers, Geeehiiaokastoffe, diluents, dyes, pigments UBV. * Included. Depending on the final fora desired can also use the coated particles described above Wetting agents, dispersants, plasticizers, disintegrating agents etc. can be added. The particle size of the active ingredients has no great significance, since larger particles more resin distributed over fewer particles than with smaller ones Particles coated with the same amount of resin. Therefore, you can use the active ingredient in practically any Use particle size range, as the dissolution in the, intestinal juices by appropriate choice of the resin and the amount the same can be controlled.

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Claims (1)

Abbott Laboratories _{14 August} 2535 Claims (ρ 1. Pharmaceutical preparation for oral administration, characterized in that that the active ingredient is in the form of single particles is embedded in a resin in such a way that it remains substantially protected by the resin when the particles pass through migrate through the patient's stomach and small intestine, but is practically completely set free when the Particles reach the colon, the resin and amount thereof being selected so that the active ingredient in one accelerated solution test in a certain artificial m - intestinal fluid dissolves 2 to 12 # in 1 hour and 18 to 88 # in 3 hours «, 2 »Pharmaceutical preparation according to claim 1 in? Ora a tablet . 3. A pharmaceutical preparation according to claim 1 in the form of a suspension. - 20 109847/1762 ■ - '■ ■ ^;:; · ^: * ■■■ *? ■■ BlarnazeUülechea preparation according to claim 1, characterized in that that the active ingredient is erythroinycin stearate. 5. Yerfahron for the production of pharmaceutical preparations according to claim 1, characterized in that the active ingredient present in the form of fine particles is coated with a resin, the near type and amount is selected so that the auo active ingredient and resin t> existing particles in artificial The liquid can go into solution in 1 hour from 2 to 12 56 and in 5 hours at 18 to 88 $>. • - ■ 6. The method according to claim 5, characterized in that as Active ingredient Erytiiroicyüinstsarat Terwendst is. 109847/17 62 Ζ2 Blank page