TABLETS WHICH DO NOT DAMAGE THE OESOPHAGUS

Abstract: Tablets containing sodium carbonate or sodium bicarbonate were prepared from acidic drugs. When comparing with conventional commercially available capsules or tablets the adherence and locally damaging effect of doxycycline hydrochloride tablets prepared by this method were remarkably reduced.

Description: TABLETS WHICH DO NOT DAMAGE THE OESOPHAGUS The present invention is concerned with new table--: formulations prepared from acidic drugs such as doxycycline hydrochloride . When drugs are administered orally in capsule or tablet 5 form they can adhere to the oesophagus and damage it locally. Lately this problem has beer- studied with respect to τetra- cyclines such as doxycycline (see Med. J. Aust. 1975 1:236-7; JAMA 235 (1975) 2347-8; Lakarτidningen 75 (1978) *3 : 4509-13 ) . Doxycycline hydrochloride is cor.mercially available for 10 oral use primarily as hard gelatin capsules. ..her_ moistened in the mouth and throat the surface cf τhe hard gelatin cap¬ sule becomes slimy and sticky if large amount of liquid is not swallowed at the same time. If a capsule gets stuck in the oesophagus, swallowing large quantities of liquid will 15 not loosen ii. Thus τhe casing of the capsule and its contents dissolve in the oesophagus and may damage it locally. The dam¬ age caused by doxycycline hy rcchloride arises primarily from its acidity . Tablets do not tend tc adhere tc the oesophagus as 20 easily as hard gelatin capsules. Doxycycline hydrcchlcr de has thus also become commercially available in various tablet formulations. However tablets do not solve the pr hlem completely, since various drugs have also caused damage by ■ A adhering in tablet form. The risk is especially great with 25 slowly disintegrating tablets or non-disintegrating, long- acting matrix tablets. I t is c cat e; :ablε τs t US U - V s - . cx. ( s e e * - ;= -r* — tidningen 75 (1978) 49:4513). The sticking mechanist, is prob¬ ably the same as in the case cf hard gelatin capsules; 30 i.e. the polymer of the film coating becomes slimy and sticky due to the action of fluids in the mouth and threat. OMPI Surprisingly it has now beet- fcur-d that adherence tc the oesophagus of tablets containing drugs can be reduced ccncider- ably by adding a carbonate to the tablet which when moistened releases carbon dioxide ue to the presence of the acidic drug. 5 Alkaline earth metal carbonates and bicarbonates are suitable though alkali metal carbonates and bicarbonates are preferred, sodium bicarbonate being the most preferred. The amount of carbonate can vary over a fairly wide range depending upon the drug, the tablet formulation and the desired neutralizing 10 effect. A suitable amount would be from 0.01 to 3.0 equivalents of carbonate per equivalent of drug. The tablets can be prepared by granulating the active agent with the usual auxiliary agents using a conventional wet or dry granulation method, then adding the carbonate to 15 the dry granules and then tabletting the mixture. It is also possible to add the carbonate at the granu¬ lation stage, but in that case the granulation must be carried out under completely dry conditions . Drugs which are not acidic enough to release carbon * 0 dioxide from carbonates can be made more acidic by adding a small amount of organic acid. The acid can be added by mixing the drug with the powdered acid or ~ ~ - moistening the drug with a solution of the acid followed cf drying. Preparation is otherwise the same as for formulations containing acidic drugs. 25 The organic acid can be selected from pharmaceutically accept¬ able acids, such as citric acid, tartaric acid and ascorbin acid. Suitable amounts are from C.ll tc- 3.0 equivalents of acid pe equivalent cf carbonate. The tablets can also be coated with a layer containing 30 a carbonate which releases carbcn dioxide slowly when moistened. " Sodium bicarbonate is used with an organic acid in effer¬ vescence tablets. I ' .e tablets disintegrate rapidly in water producing carbon dioxide and the solid tablet is thus trans¬ formed into a solution which can be taken as an effervescent 35 drink. Ef ervescence tablets contain a substantially larger amount of carbonate a d organic acid than the tablets described here . It is believed that the reduced adherence of the new tablets described here tc the oesophagus is due to small carbon ■ -Od oxide bubbles formed on the surface cf the tablet when it is moistened. The carbonate also neutralizes the surface cf the tablet and its surroundings and thus reduces the local damaging effect of the. acidic drug. The amounts of carbonate are so small that they have no effect en the pH of the stomach or on 5 the absorption of the drug. The acidic drug can also be made into a slowly disinte¬ grating tablet or even into a non-disintegrating, long-acting matrix tablet without the danger of the tablet causing pro¬ longed local stress by adhering to the oesophagus. 10 Doxycycline hydrochloride tablets prepared according to the formulations given here were compared with some commercially available preparations . Adherence was examined using a special device for measuring the force required to release a capsule which had adhered to τhe oesophagus Of a pig. To compare the 15 local stress caused by the acidity of τhe preparations one capsule or tableτ was slurriec in 10 ml of water and the pH of the slurry was measured. The results of the comparison tests are presented in the following table. 20 Table: Comparison between some commercially available doxycycline hydrochloride preparations and preparations according to the formulations given here. 'j- - Adherence to the oesophagus car- be almost eliminated using the method presented here as the fricticr-al force between the preparation and the oesophagus without real adherence is from 0.01 to 0.15 . Additionally the pH values of the aqueous slurries of the preparations presented here are so nigh that adherence would probably not cause damage. No differences in absorption were noticed between the preparations given here and ccmmerciaiiy available preparations Among drugs to which this invention can be applied are tetracycline antibiotics such as doxycycline hydrochloride and tetracycline hydrochloride . Other agents belonging to the tetracycline group, such as cxytetracycline , chlortetracycline , dimethyl chlortetracycline and etacycline can also be prepared according to the formulations given here. Emeprone bromide is one drug "which damages the oesophagus, but is not sufficiently acidic τo cause release of carbon dioxide from carbonates. Additionally the method presented here can be used with irritative anti-inflammatory agents, such as incomethacine and acetylsalicylic acid. The following examples will further illustrate the inven ¬ tion . Examnle 1 cxycyclin. h drochloric, respond. Dcxycyclin Lactose (excipient) Corn starch (excipient and disintegrant ) P lyvinyl pyrrolidcne (bindi Magnesium εtearate (lub ioan Sodium bicarbonate (adjuvant according to the invention) The active agent and exoi -nuiated with the binding agent using a ccnvεntic Iry granulation method. The lubricant and a jn- .dec with the dry Ξranules and the mixture is co: > tablettes . Example 2 Doxycyclin. hydrochlorid . respond doxycyclin. 150 mg Lactose (excipient) 50 mg Acrylic resin (binding agent) 15 mg Magnesium stearate (lubricant) 3 mg Sodium bicarbonate (adjuvant 35 mg according to the invention) Tablets are prepared- as in example 1 Example 3 Tetracyclin. hydrochlorid. respond, tetracyclin. 500 mg Microcrystalline cellulose 70 mg (excipient, .binding agent Polyvinyl pyrrolidone (binding agent) 15 mg Silicon dioxide (glidant) 2 mg Magnesium stearate (lubricant) 4 mg Sodium bicarbonate (adjuvant 70 mg according to the invention) Tablets are -orenared as xamt>_s Example 4 Emepron. bromid. 100 mg Citric acid (acidifying agent) 6 mg Lactose (excipient) 100 mg Hydrogenated castor oil (rir.cir.; 20 mg agent which removes th< .--.-. J_ ;; e * phenomeno ) Magnesium stearate mg Calcium carbonate 18 mg 'ablets are prepared a: examn--e

Claims: Claim 1. Tablets containing acidic ■rug powders and a carbonate which releases carbon dioxide v.he: the tablet is moistened in the mouth and " throat. 2. Tablets according to claim 1, wherein tetracycline anti¬ biotics are used as the drug powders . 3. Tablets according to claim 2, wherein doxycycline hydrochloride is used as the drug powder. 4. Tablets according to any one of the preceding claims, wherein alkali metal carbonate or- bicarbonate is used as the carbonate. 5. Tablets according to claim 4, wherein sodium bicarbo¬ nate is used as the carbonate. 6. Tablets according to C-i . —i. e of the preceding claims, wherein 0.03 - 3.0 equivalents o :he carbonate is used per equivalent of the drug. 7. Method for preparing tab- :s accordng to any one c: the preceding claims , wherein th. :arbcnate is added tc the tablet compcsiticn at the grar-ul. L cr letting stage or where the tablets are coated - a laver ccntaininΞ sue: a carbonate . 8. Method according to •eir- tr-e car onate is added at the granulation or ting sta-se. -•-eτr-cc accorcmg to ; , wnerε n tr-e camonate is blended with the drv εranul a. . .xture b efore tab lettins .

Inventors: MARTTILA ESKO VEIKKO, MARVOLA MARTTI LAURI ANTERO, SOTHMANN GUNNAR ASLAK
Applicants: MARTTILA ESKO VEIKKO, MARVOLA MARTTI LAURI ANTERO, ORION YHTYMAE OY, SOTHMANN GUNNAR ASLAK
Application year: 1982
Main classification: A61K9
IPC codes: A61K9, A61K31