Effervescent formulations

[0002] The invention relates to solid, rapidly disintegrating oral dosage forms for pharmaceutical administration as effervescent formulations for alkali-sensitive active ingredients, such as selegiline, and to a process for their preparation.

[0003] The (−) form of deprenyl, also known as selegiline (phenylisopropyl-methylpropynylamine) or its pharmaceutically acceptable salts, are used in the form of tablets as an antiparkinsonian drug.

[0004] A large number of forms for administration of selegiline have been described in the patent literature. Transdermal administration forms including, for example, patches, are disclosed in European patents Nos. 404 807; 406 488; 509 761; 591 432; 593 807; 617 515; 647 137; 683 668; 655 900; WO 96/02239; WO 95/18603; and WO 94/23707.

[0005] Drug forms for the controlled release of selegiline, for example in the form of tablets, are described in European patent No. 582 186; in WO 96/01612; and in U.S. Pat. No. 5,484,608, and osmotically acting release systems are described in U.S. Pat. No. 5,128,145; and normal-release oral formulations are described in WO 96/22435.

[0006] Patent application WO 96/12472 discloses a liposomal composition which comprises the active ingredient selegiline.

[0007] Buccal and sublingual forms of administration are disclosed in WO 97/-17067. WO 95/07070 describes effervescent formulations which, to avoid the insoluble residues of tricalcium citrate which can be formed when effervescent formulations are dissolved, comprise at least two different edible acids.

[0008] WO 93/00886 describes effervescent tablets having good storage stability, for example alkali-sensitive active ingredients such as acetylcysteine, captopril and minoxidil. The tablets comprise an effervescent base containing a solid edible organic acid as carrier crystals, an alkali metal carbonate or bicarbonate and an alkali metal salt of the acid. Two layers are applied onto the carrier crystals. The first layer contains a different acid than the carrier crystals, and the second layer contains the alkali metal salt of one of the two acids.

[0009] Selegiline is unstable in alkali-containing effervescent formulations. Even a multilayer construction is not sufficient for stabilization. Alkali carbonates and bicarbonates are more basic than alkaline earth carbonates, such as calcium carbonate. There are no suitable effervescent formulations known for selegiline, which is an alkali-sensitive active ingredient. This may partly be due to the fact that such formulations were so far not successful due to the instability of selegiline, as also shown in FIG. 1.

[0010] The therapeutic treatment of various disorders requires, in particular in elderly people, a very frequent and in many cases even the permanent taking of pharmaceuticals.

[0011] Parkinson patients usually have problems due to strong tremor when swallowing tablets with liquids. Likewise, taking of tablets is very difficult for patients that have difficulties swallowing.

[0012] Therefore there is a need for novel solid, rapidly disintegrating oral dosage forms of administration, particularly effervescent formulations in the form of soluble tablets, buccal tablets or soluble granules which ensure easy administration, even for example, for elderly patients.

[0013] It is an object of the present invention to provide novel and therapeutically advantageous effervescent formulations for selegiline as well as for other alkali-sensitive active ingredients.

[0014] The soluble-tablet-formulations of the present invention are also suitable in the combined use with other soluble tablets, such as with L-dopa, and benzerazide as described in European patent No. 521 388.

[0015] This object is achieved by the present invention which provides rapidly disintegrating oral dosage forms with or without water as an effervescent formulation comprising an alkali-sensitive active ingredient and an effervescent base of at least one of (i) an alkaline earth metal carbonate, (ii) an organic edible acid, and (iii) an alkali metal salt of citric acid and, optionally, pharmaceutically acceptable auxiliary ingredient.

[0016] The present invention provides effervescent formulations in the form of granules, tablets or sachets. The tablets can also be buccal tablets.

[0017] A suitable embodiment of the invention involves effervescent formulations of selegiline or its pharmaceutically acceptable salts.

[0018] By addition of water to, or contacting such effervescent formulations with saliva, a suspension or solution is formed with CO₂evolution, and the suspension or solution develops a pleasant taste during taking. Here, a rapid release of the active ingredient is of particular importance to ensure a rapid onset of action. This applies particularly to buccal tablets.

[0019] The invention is described with reference being had to the accompanying drawing, wherein

[0020] FIG. 1 is a curve showing the alkali instability of selegiline;

[0021] FIG. 2 is a curve comparing the degradation characteristics of different effervescent selegiline compositions; and

[0022] FIG. 3 is a curve showing a stress stability test of selegiline compositions.

[0023] Effervescent formulations are known in the prior art for various active ingredients and vitamins. These effervescent formulations generally include an agent which is capable of releasing CO₂, and an agent which induces the release of CO₂. Suitable agents capable of releasing CO₂which are used include alkali metal carbonates or alkali metal bicarbonates, such as sodium carbonate and sodium bicarbonate. Alkaline earth metal carbonate formulations are mainly contained in mineral preparations. Suitable agents for inducing CO₂release include edible organic acids, or their acidic salts, which are present in solid form and which can be formulated with the active ingredient and the other auxiliaries to provide granules or tablets, without premature evolution of CO₂.

[0024] Suitable edible organic acids include, for example, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, ascorbic acid, maleic acid or citric acid. Pharmaceutically acceptable acidic salts include, for example, salts of polybasic acids which are present in solid form and in which at least one acid function is present, such as sodium dihydrogen or disodium hydrogen phosphate or the corresponding citrates.

[0025] The active ingredients are either present in the effervescent formulation as readily soluble compounds, or they are solubilized by salt formation during the dissolution process. However, it is also possible to disperse poorly soluble active ingredients.

[0026] Selegiline hydrochloride is extremely sensitive to the customary effervescent bases such as sodium bicarbonate, sodium carbonate or sodium hydrogen citrate in combination with organic edible acids, such as citric acid or tartaric acid.

[0027] In these customary effervescent formulations, the selegiline active ingredient is degraded to amphetamine, methamphetamine and demethylselegiline, and the active ingredient undergoes sublimation. It should be noted that degradation to the above mentioned metabolites occurs only partly. The main part of selegiline sublimes in the presence of alkali metal compounds, particularly alkali metal carbonates, so that surprisingly, loss of active ingredient occurs even in the case of only slight metabolization. As can be seen from FIG. 2, the required purity and quantity are no longer met after storage of these effervescent selegiline formulations.

[0028] Surprisingly, effervescent formulations based on alkaline earth metals in accordance with the present invention are very stable. Most suitably calcium carbonate and citric acid are used as the effervescent base.

[0029] It can be advantageous to have some of the calcium carbonate react with citric acid to give calcium citrate.

[0030] Small amounts of sodium citrate do not cause instabilities. However, these amounts may not be more than about 15% of the total weight of the effervescent formulation.

[0031] At room temperature and even in the stress test at 40° C. and 75% relative atmospheric humidity, the effervescent selegiline formulations according to the present invention show no relevant loss of quality (FIG. 3). This is of particular importance since effervescent formulations have to be well protected against atmospheric humidity during production, filling and storage. Therefore, their preparation is generally carried out only in areas having low atmospheric humidity (Ritschel, Bio Tablette, Echtio Cauher KG 1966, p. 115 f). As discussed by Wells in Pharmaceutical Preformulation (John Wiley publisher, 1988), basic catalysis is in a large number of medicaments a decisive reason for instability.

[0032] Although calcium carbonate is known to be used in effervescent tablets but only in cases where calcium therapy is required with calcium as an active ingredient, but not as medicinal excipient for other active ingredients where calcium does not contribute to the therapy. Calcium-containing effervescent tablets are generally employed for treating mineral metabolism problems. Thus, for example WO 95/07070 describes effervescent granules of calcium carbonate and citric acid for producing a pharmaceutical preparation, where 5-20 parts by weight of the citric acid are replaced by at least one other edible acid, such as malic acid.

[0033] Calcium carbonate is also employed as additional auxiliary ingredients in pharmaceutical technology, for example as auxiliary ingredients for sugar coating or as extender (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, 1989).

[0034] A ready-to-drink solution or suspension with pleasant taste can be prepared with the effervescent formulations of the present invention, suitably in a volume of from 40 to 80 ml of water, which can be easily drunk even in cases of tremor. This also applies to geriatric patients. Buccal or sublingual effervescent preparations are administered directly at the mucosa of the mouth.

[0035] Effervescent minitablets can suitably contain from about 5 to about 10 mg of selegiline HCl or other alkali-sensitive active ingredient, and approximately 1200 mg of an effervescent base, while normal effervescent tablets contain from about 2000 mg to about 7000 mg, and buccal preparations suitably contain from about 50 to about 500 mg of an effervescent base. The dose in the buccal preparation can be considerably lower, for example 1-5 mg of e.g. selegiline. In the case of low-dosed active ingredients, the effervescent formulations according to the present invention can comprise up to about 90%, and in the case of high-dosed active ingredients, from about 30% to about 70% of an effervescent base.

[0036] The effervescent formulations also permit combined taking together with other active ingredients, as is frequently required in the case of selegiline in Parkinson treatment. Thus, effervescent selegiline formulations can be administered in combination with other soluble tablets, in particular L-dopa/benzerazide combinations or soluble amantadine tablets.

[0037] A cocktail treatment, as described in European patent No. 521 388 is also possible. Here, at least two different active ingredients are dissolved or suspended together in an amount of water and are then administered together. Selegiline can also be administered together with vitamin E in effervescent formulations.

[0038] As already mentioned, these effervescent preparations of the present invention can also be employed with other alkali-sensitive active ingredients, such as erythromycin, clarithromycin, diazepam, ampicillin, and phenobarbital.

[0039] The effervescent formulations according to the present invention can be prepared by conventional processes known in the art. The acids and carbonates are, for example, granulated separately (wet granulation), where the active ingredients are suitably added to the acidic granules. After mixing of the carefully dried granules, soluble lubricants, such as sodium benzoate or polyethylene glycols, are added, and the mixture is compressed.

[0040] According to another method, all acids, carbonates and active ingredients are mixed together and heated in a reactor until the citric acid, for example, releases its water of crystallization and granules are formed (see e.g. WO 95/13130). Repeated stirring is required to obtain a uniform material. This is then sieved rapidly and carefully dried. Efficient drying is absolutely necessary to avoid gradual disintegration of the tablets by reaction of the acids with the carbonates.

[0041] Vacuum drying cabinets can be used, for example, to achieve rapid drying. In another method of preparation the acid is partially reacted with the basic components, followed by drying under reduced pressure. A soluble lubricant is admixed to the dry granules before compression. However, tableting can also be carried out by using external lubrication.

[0042] The effervescent granules that are obtained according to the invention, are then compressed to tablets or filled into sachets.

[0043] The alkali-sensitive active ingredient, such as selegiline, is suitably bound to neutral auxiliary ingredients to obtain good homogeneity. Suitable neutral carrier substances for the effervescent formulations according to the invention include lactose, sucrose, sorbitol, mannitol, starch, pectins or cellulose. Other auxiliary ingredients, such as colorants, sugars or sweeteners, can improve the appearance and/or the taste of the aqueous solutions or suspensions obtainable by disintegration of the effervescent tablet.

[0044] The use of colorants can serve both for improving the appearance and for identifying the preparation. Suitable colorants which are approved for use in pharmaceuticals include carotenoids and chlorophyl.

[0045] Suitable sugars or sweeteners include sucrose, xylitol, D-glucose, sorbitol, mannitol, lactose, aspartame, sodium, saccharin, acelsulfam, and sodium cyclamate.

[0046] The following examples illustrate the invention in more detail.