PROCESS FOR REGULATING THE ABSORPTION RATE OF DRUGS AND A PHARMACEUTICAL FORMULATION

Abstract: The invention concerns a process for regulating the absorption rate of drugs comprising a carboxylic acid derivative selected from an anthranilic acid derivative, propionic acid derivative, acetic acid derivative, salicyclic acid derivative and a salt of these acids or a pyrazolole or benzothiazine derivative and the salts thereof. The agent regulating the absorption rate is an alkaline compound selected from Mg(OH)2, MgO, NaHCO3 and a mixture of these compounds. The invention also concerns pharmaceutical formulation with regulated absorption rate. The formulation comprises in addition to a pharmaceutically active agent which is a carboxylic acid derivative component and conventional formulation components, an absorption rate regulating agent which is an alkaline compound, such as an Mg-compound, Al-compound and/or Na-compound, or a mixture of two or more compounds.

Description: Process for regulating the absorption rate of drugs and a pharmaceutical formulation The present invention relates to a process and its application for preparing pharmaceutical formulations having an appropriate, i.e. accelerated or retarded rate of absorption. In oral administration of medicines, a slow absorption rate of the drug is frequently a problem when a rapid and anticipated medical effect is required. If absorption is too slow, the elimination of a drug occurring simultaneously with the absorption period may prevent the concentrations from rising t a required therapeutic level even if the total absorption of a drug were complete (fig. 1). This problem is particularly pronounced when using drugs with a short half-life e.g. for sudden attacks of pain. For example, a budding pain of migraine or gout may have time to develop as a result of slow drug absorption to the extent that an orally administered usual dosage of medicine takes a poor effect or no effect at all. This is why drugs must often be administered intramuscularly or even intravenously for assuring a rapid absorption rate. This way of administering is not only inconvenient and requires medical expertise but also there are no such injectable forms available of nearly all drugs. The absorption of tolfenamic acid from alimentary canal is relatively slow (PJ Pentikainen, PJ Neuvonen & C Backman: European Journal of Clinical Pharmacology 1984:17:67-75) and, thus, a therapeutical concentration and desired medical effect cannot often be attained. In fact, intense pain generally slows down emptying of the stomach and, thus, slows down also the absorption of medicines. By means of a rapidly absorbing formulation it would also be possible to reduce the need and use of injection-administered medicines (painkillers). On the other hand, a slower-than-normal absorption of medicines (e.g. fenamates) would be necessary a.o. in the treatment of chronic inflammatory conditions, e.g. rheumatic diseases. A slow rate of absorption would prolong the duration of medical effect and facilitate fewer dosages. This would be significant especially with medicines having a short half-life, since a slow absorption rate would then serve as a factor limiting the reduction of medicine concentrations in plasma (so-called flip- flop phenomenon). At the same time, a slow absorption rate would restrain the development of too high medicine concentrations causing side effects and, thus, it would be possible to increase single dosages. A slow absorption rate is a problem when using fenamate class medicines e.g. for migraine patients but the same problem applies to many other drugs as well. In case of fenamates, attempts have been made to solve this problem e.g. by using a micronized raw material, by administering methoclopramide along with fenamates for quicker emptying of the stomach, by taking caffeine along with fenamates or by making medical formulations in the form of suppositories, but the results have been poor. The inadequate effect of a medicine is often a result of the fact that the absorption rate is too slow even if the total absorption were complete. By means of this invention it is possible to regulate, to accelerate or retard the absorption of drugs from alimentary canal into blood circulation. The most important advantage is that the top concentration of medicine in blood can be attained at any given instant by accelerating or retarding the absorption as necessary. On the basis of the invention it is possible to optimize an absorption profile which is significant as a safety-improving factor e.g. by eliminating the administration of unnecessarily large doses of medicine. By virtue of accelerated absorption it is possible to attain a temporarily high medicine concentration even with a regular dose of medicine, which is desirable and appropriate in certain clinical situations. On the other hand, a retarded absorption can be used for avoiding too high peaks in medicine concentration while equalizing and prolonging the medical effect. This allows the administration of larger single doses of medicine. A process of the invention is characterized in that the agent for regulating the rate of absorption comprises an Mg-compound, Al-compound or Na-σompound or a mixture thereof. The drug is an orally administered medicine having an absorption profile which is too slow or too rapid in view of its intended application, such as a carboxylic acid derivative, such as an anthranil acid derivative, a propionic acid deriva¬ tive, an acetic acid derivative, a salicylic acid derivative or a salt of these acids or a pyrazolone or benzothiazine derivative. Examples of the above carboxylic acids include: - anthranilic acid: tolfenamic acid, mefenamic acid, flufenamic acid, meclofenamic acid, ethofenamic acid and/or equivalent - propionic acid: fenbufen, fenoprofen, flurbiprofen, indoprofen, ibuprofen, ketoprofen, naproxen, pirprofen or thiaprofen, - acetic acid: dichlofenac, indomethaσin, sulindac, tolmetin or zomepirac. - salicylic acid: acetyl salicylic acid, benorilate or diflunisal, Pyrazolone is preferably azapropazone and benzothiazine is piroxicam. A drug of the invention having a regulated absorption rate contains, in addition to conventional formulation components, as an absorption rate regulating agent some alkaline compound, such as Mg-compound, Al-compound, Na-compound, or a mixture of two or more compounds. Preferred compounds in a process of the invention comprise acidic antiinflammatory painkillers and particulary prefered are anthranilic acids, such as tolfenamic acid or mefenamic acid or the salts thereof or propionic acids, such as ibuprofen or its salts. The absorption rate regulating agent comprises the use of alkaline compounds. Those can be used either individually or in mixtures. For example, use of sodium carbonate together with other agents improves the decomposition of a pharmaceutical formulation or e.g. the draining of a capsule. The invention will now be described in more detail with reference made to the accompanying drawings and the following examples. Six test persons were subjected to a cross-over study and orally given magnesium hydroxide (within the range of 85 mg - 1700 mg) and fenamate (tolfenamic acid, 400 mg, 2 tablets "Clotam"(reg.trade mark, AS Gea Farmaceutisk Fabrik, Denmark) 200 mg; or mefenamic acid, 500 mg, 1 tablet "Ponstan Forte"(reg.trade mark, Parke-Davies comp., Michigan,USA) 500 mg). The absorption of fenamates occurred rapidly compared with absorption taking place in identical control conditions (= without magnesium hydroxide). The peak concentrations of tolfenamic acid and mefenamic acid in blood rise in average 2 -3 times higher and are attained appr. 1 hour earlier than in control conditions (fig. 2 and 3). In persons having a poor absorption of fenamates the increase of peak concentrations of e.g. tolfenamic acid can be up to 10- fold through the action of magnesium hydroxide (fig. 4). The rate of absorption of ibuprofen (400 mg; tabl. "BURANA"; reg.trade mark, Farmos-Yhtyma Oy, Finland) was also accelerated significantly by the concomitant ingestion of Mg-hydroxide. Since medicines are generally taken with water, the administration of pharmaceutical tablets in the above tests was immediately followed by 150 ml of water with magnesium hydroxide blended therein. With the above dosages, magnesium hydroxide did not cause any side effects. Thus, magnesium hydroxide is capable of providing an increase in the absorption rate of e.g. tolfenamic acid, mefenamic acid and ibuprofen. As indicated by the test results shown in figs. 4 and 5, the absorption rate can also be adjusted in the opposite direction, i.e. it can be retarded by using aluminium hydroxide (1000 mg) instead of magnesium hydroxide. In a cross¬ over study performed with six persons, aluminium hydroxide retarded the absorption of tolfenamic acid (2 tablets "Clotam" 200 mg; ) compared with control conditions. Figure 6 presents the mean results of tests with a pharmaceutical formulation according to the invention containing tolfenamic acid. Said formulation is disclosed in example 11. The results of these tests conducted on twelve volunteeres show the same tendency than those of figures 1 to 5. Figures 7-10 reveal the change in plasma concentration after the administration of a formulation according to the invention containing ibuprofen and magnesium oxide (example 12). The figures show the results obtained in four patients. The formulation "Burana", (reg. trade mark, Farmos-Yhtyma Oy, Finland) a conventional ibuprofen formulation, but not containing the alkaline components of this invention, is used as comparison. The results revealed in figures 7 to 10 clearly show that a very rapid and strong rise in the plasma concentration is obtained by the inventive formulation. 735 mg The amounts of components 1. - 5. required by a desired production batch are mixed in a suitable dry blender as well as moisturized and granulated with an aqueous or water-in-ethanol solution of component 6. The dried granules are sieved, component 7. added with short mixing and compressing into tablets having a weight of circa 735 mg. Some of component 3, e.g. 75 mg/tablet, can be added in granules together with component 7. If desired, the tablets can be coated with a coating film that is rapidly decomposable in stomach. Example 2 Tablet formulation The components and preparation process as in example 1 but wit the amount of magnesium hydroxide per tablet being 400 mg. The total mass of a tablet will thus be 935 mg and tablets are preferably compressed in the form of capsules. Example 3 Tablet formulation The components and preparation process as in example 2 but with the amount of tolfenamic acid per tablet being 100 mg. The total mass of a tablet will thus be 835 mg. This composition makes it possible to employ a relatively high dosage of magnesium hydroxide compared to the dosage of tolfenamic acid, 400 mg : 100 mg or 800 mg : 200 mg, should the dosage be 2 tablets. Exam le 4 Ca sule formulation Components 1 - 4 are mixed with each other in a suitable dry blender and the pulverized mixture is granulated 5. with an aqueous or water-in-ethanol solution. The dried granules are sieved, adding therein a mixture of components 6 and 7 with brief mixing. The finished mixture is metered in covellite capsules, appr. 520 mg in each. Example 5 Capsule formulation The components and preparation process as in example 4 but with the amount of tolfenamic acid being 100 mg and, respectively, the amount of magnesium hydroxide being 300 mg per tablet. The contents of a capsule have thus a mass of 520 mg. Example 6 Powdered composition 1. Tolfenamic acid 200 mg 2. Magnesium hydroxide 200 mg 3. Lactose 150 mg Components 1 - 3 are mixed with each other and metered e.g. in aluminium laminated dosage bags 550 mg. For improved handling of the powdered composition, the mixture of components 1 - 3 can be granulated e.g. with polyvidone (25 mg/dose), followed by packing the sieved granules in dosage bags a 575 mg. Example 7 Powdered composition 1. Tolfenamic acid 200 mg 2. Magnesium hydroxide 1700 mg 3. Lactose 300 mg 4. Polyvidone 80 mg Components 1 - 3 are mixed with each other and the powdered mixture is granulated 4. with an aqueous or water-in-ethanol solution. The dried and sieved granules are packed in dosage bags a 2280 mg. Within the described range of basic composition, the amount of magnesium hydroxide can be varied within the range of 85 - 1700 mg with no trouble. Example 8 Tablet formulation The components and preparation process as in example 1 but with lactose replaced by sodium bicarbonate. Example 9 Capsule formulation As in example 4 but containing only components 1 and 2. Example 10 Capsule formulation As in example 4 but containing only components 1 and 2 and, in addition to those, 100 mg of sodium bicarbonate. Example 11 Tablet formulation The tablets are formed following the conventional tablet forming technic of example 1 but using the following composition. Emcocel 90 M Talc. Calc. stear Spir.fort. Ag. purif. 700 mg Example 12 Tablet formulation The preparation process is a conventional one substantially according to example 1 but with the following components: Nucleus: Tolfenamic acid Magn.hydroxid*.pond. Cellulos.microcrist. Polyvidon. 25000 Natr.stearylfumar Core: Eudragit R E Talc. Volatile comp.: Spir.fort. q.s. Isopropanol q.s. Aceton q.s, In all the above examples, magnesium hydroxide can be replaced by an equivalent weight of magnesium oxide. The exact, stoichiometric equivalence is 40.30 parts of magnesium oxide corresponding to 58,32 mg of magnesium hydroxide. In the above examples 1 - 10, magnesium hydroxide has been used as an agent enhancing the absorption rate of an active agent. However, if the purpose is to prepare a formulation of the invention, wherein the absorption rate of an active agent is indeed retarded, the magnesium hydroxide employed in the above examples is replaced by an equivalent amount of aluminium hydroxide. The same way, the active agent, tolfenamic acid or ibuprofen, can be replaced by a pharmacologically equivalent amount of an appropriate drug mentioned in the specification.

Claims: Claims 1. A process for regulating the absorption rate of drugs comprising a carboxylic acid derivative selected from an anthranilic acid derivative, propionic acid derivative, acetic acid derivative, salicylic acid derivative and a salt of these acids or a pyrazolole or benzothiazine derivative and the salts, thereof, c h a r a c t e r i z e d in that the agent regu¬ lating the absorption rate comprises an alkaline compound selected from Mg(OH)2, MgO , NaHCθ3 and Al(0H)3 and a mixture of these compounds. 2. A pharmaceutical formulation with regulated absorption rate c h a r a c t e r i z e d .in that, in addition to the pharmaceutical component and conventional formulation components, it contains an absorption rate regulating agent which comprises an alkaline compound, such as a Mg-compound, Al-compound and/or Na-compound, or a mixture of two or more compounds. 3. A formulation as set forth in claim 2, c h a r a c t e ¬ r i z e d in that the pharmaceutical comprises a carboxylic acid derivative, such as an anthranilic acid derivative, propionic acid derivative, acetic acid derivative, salicylic acid derivative or a salt of these acids or a pyrazolone or benzothiazine derivative. 4. A formulation as set forth in claim 2, c h a r a c t e ¬ r i z e in that the anthranilic acid is tolfenamic acid, mefenamic acid, flufenamiσ acid, meclofenamiσ acid and/or an equivalent. 5. A formulation as set forth in any of the claims 2 to 4, c h a r a c t e r i z e d in that the Mg-compound is Mg(OH)2 or MgO. 6. A formulation as set forth in any of claims 2 to 4, c h a r a c t e r i z e d in that the Na-compound is NaHCθ3. 7. A formulation as set forth in any of claims 2 to 4, c h a r a c t e r i z e d in that the Al-compound is Al(OH)3» 8. A formulation as set forth in any of claims 2 to 7, c h a r a c t e r i z e d in that the formulation is in the form of a tablet, capsule, powder, suspension or mixture.

Inventors: NEUVONEN PERTTI J, NEUVONEN, PERTTI, J.
Applicants: NEUVONEN PERTTI J, NEUVONEN, PERTTI, J.
Application year: 1989
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K33, A61K47