MXPA00009396A

MXPA00009396A - Fizzy formulations

Info

Publication number: MXPA00009396A
Application number: MXPA/A/2000/009396A
Authority: MX
Inventors: Tritthart Wolfram; Andre Piskernig Maria; Kolbl Gottfried
Original assignee: Asta Medica Ag
Priority date: 1998-03-31
Filing date: 2000-09-26
Publication date: 2001-07-09

Abstract

The invention relates to rapidly decomposing forms of administering alkali-sensitive active agents, more particularly selegiline, for oral applications in the form of fizzy formulations, containing an alkali-sensitive active agent and a fizzy base consisting of one or several alkaline earth carbonates, an organically edible acid and/or alkali salt of a citric acid and optionally pharmaceutically usable additives.

Description

EFFERVESCENT FORMULATIONS Description of the invention The invention relates to fast-disintegrating solid administration forms in the form of effervescent formulations for alkaline-sensitive active substances, in particular selegiline, and to methods for their preparation. Selegiline (= L-N- (l-phenyl-isopropyl) N-methyl-2-propylamine) or its pharmaceutically usable salts are applied in the form of tablets in the therapy of Parkinson's disease. A multitude of administration forms for selegiline are described in the patent literature. In EP 404 807, EP 406 488, EP 509 761, EP 591 432, EP 593 807, EP 617 515, WO 94/23707, EP 647 137, EP 683 668, WO 95/18603, EP 655 900 and WO 96/02239 transdermal application forms are claimed, for example also in the form of plasters. In EP 582 186, WO 96/01612 and US ,484,608 pharmacological preparations for the controlled release of selegiline are listed, for example in the form of tablets, in US 5,128,145 osmotically active delivery systems and in WO 96/22435 oral formulations of normal release.

The subject of the patent application WO 96/12472 is a liposomal composition containing the active substance selegiline. The oral and sublingual application forms are claimed in WO 97/17067. In WO 95/07070, effervescent formulations containing at least two edible acids are described to avoid the insoluble residues of tricalcium citrate which may be produced during the dissolution of the effervescent formulations. In WO 93/00886 effervescent tablets with good storage stability are described, for example for the alkaline-sensitive active substances such as acetylcysteine, captopril and minoxidil, which contain an effervescent base constituted by a solid, combusible organic acid as carrier crystals, a carbonate or alkaline bicarbonate and an alkaline acid salt. Two layers are applied to the carrier crystals. The first layer is constituted by an acid different from that of the carrier crystals themselves and the second layer by an alkaline salt of one of the two acids. Selegiline is not stable in alkaline effervescent formulations. Nor is a multilayer structure sufficient to achieve stabilization. Alkaline carbonates and bicarbonates are more basic than alkaline earth carbonates, such as calcium carbonate.

No effervescent formulations suitable for selegiline, an alkaline-sensitive active substance, are available to date. The reason for this may be that to date these formulations were unsuccessful due to the instability of selegiline, as shown in Figure 1. The therapeutic treatment of various diseases requires a very frequent ingestion of drugs and occasionally for life , particularly in the case of older people. A Parkinson's patient usually has problems ingesting tablets that require the subsequent intake of water. They also find it very difficult to take tablets for patients who have difficulty swallowing. Accordingly, there is a need for new solid forms of rapid disintegration administration, in particular effervescent formulations in the form of soluble tablets, buccal tablets or soluble granules guaranteeing simple swallowing, even for elderly people. The present invention is based on the problem of providing novel and therapeutically suitable effervescent formulations for selegiline and other alkaline-sensitive active substances. In particular, the soluble tablet formulations are also suitable for combined application with other soluble tablets such as L-dopa and benserazide according to EP 521 388. This problem is solved by the present invention which aims at fast administration forms. Disintegration for oral application with or without water, in the form of effervescent formulations containing an alkaline-sensitive active substance and an effervescent base consisting of one or more alkaline earth carbonates, an edible organic acid and / or an alkali salt of citric acid and optionally pharmaceutically usable auxiliaries. The subject of the invention are effervescent formulations in the form of granules, tablets or sachets. In the case of tablets, it can also be oral tablets. A particular embodiment of the invention relates to effervescent formulations containing selegiline or its pharmaceutically acceptable salts. The addition of water or the access of saliva to this type of effervescent preparations produces a suspension or solution with the development of CO2 gas, which has a good taste for ingestion. In this, a rapid release of the active substance is particularly important to ensure that the effect occurs rapidly. This is valid in particular for oral tablets. In the state of the art, effervescent formulations for various active substances and vitamins are known. In general, these effervescent formulations contain a medium capable of releasing C02, as well as a medium that induces the release of C02. As the medium capable of releasing C02, alkali metal carbonates or alkaline bicarbonates are preferably used, such as sodium carbonate or sodium bicarbonate. The formulations of alkaline earth metal carbonates are mainly related to preparations of mineral substances. As means for inducing the release of C02, edible organic acids or their salts which exist in solid form and which can be formulated with the active substance and the other auxiliary substances are used to obtain granules or tablets that do not develop C02 prematurely. The edible organic acids are, for example, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, ascorbic acid, maleic acid or citric acid. The pharmaceutically acceptable acid salts are for example the salts of polybasic acids which exist in solid form, in which there is at least one other acid function such as sodium hydrophosphate or disodium hydrophosphate or the corresponding citrates. The active substances are either in the effervescent formulation as readily soluble compounds, or are dissolved during the dissolution process with salt formation. However, it is also possible to disperse the hardly soluble active substances. Selegiline hydrochloride is extremely sensitive against the usual effervescent bases such as sodium bicarbonate, sodium carbonate or sodium hydrocitrate in combination with edible organic acids, such as citric acid or tartaric acid. In the usual effervescent formulations the disintegration of the active substance selegiline in amphetamine, methamphetamine and desmethylselegiline, and sublimation of the active substance occurs. The remarkable thing is that the disintegration in the mentioned metabolites is only partially produced. The main proportion of selegiline is sublimed in the presence of alkaline compounds, in particular alkaline carbonates, so that surprisingly already with a slight metabolization a loss of active substance occurs. Accordingly, after storage there is no longer the required purity and quantity of these selegiline effervescent formulations, which can be seen in Figure 2. Surprisingly the effervescent formulations on the alkaline-base basis according to the present invention are very stable. In this, a preferred embodiment resides in the use of calcium carbonate and citric acid as an effervescent base. It could be convenient if a partial reaction reaction of calcium carbonate to calcium citrate is generated by the citric acid. The proportions Small amounts of sodium citrate do not produce instabilities. In this this proportion should not exceed 15% of the total weight of the effervescent formulation. The selegiline effervescent formulations according to the invention show no significant loss of quality (Figure 3) even in the stress test at 40 ° C and 75% relative humidity as well as at room temperature. This has special significance because it is necessary to protect effervescent formulations well against air humidity during preparation., filling and storage, for which the processing is usually only carried out in rooms with low air humidity (Ritschel, Bio Tablette, Echtio Cauher KG 1966, pages 115 et seq.). As discussed in Wells's "Pharmaceutical Preformulation (John Wiley 1988), basic catalysis represents a critical mechanism for instability for many drug substances.Calcium carbonate is usually only used in effervescent tablets for the therapy of calcium, and not as a carrier of pharmacological substances for groups of active substances in which calcium does not contribute to therapy.Effervescent tablets containing calcium are generally used for the treatment of mineral metabolism. an effervescent granulate is disclosed to make a pharmaceutical preparation based on calcium carbonate and citric acid wherein 5-20 parts by weight of the citric acid are replaced by at least one other edible acid such as malic acid. as an additional auxiliary substance in pharmaceutical technology, for example as an auxiliary substance for dragee or as a diluent / solvent (Fiedler, Lexíkon der Hilfsstoffe, 3rd edition, 1989). The present effervescent formulations according to the invention allow the elaboration of a solution or suspension of pleasant taste ready to be drunk, preferably in a volume of 40 to 80 ml of water, which is easy to drink by drinking with tremor. This is also true in the case of geriatric patients. The buccal or sublingual effervescent preparations are applied directly to the buccal mucosa. The initabletas effervescent contain, for example, 5 to 10 mg of selegiline hydrochloride and approximately 1200 mg of an effervescent base, the "normal" effervescent tablets contain 2000 mg to 700Ó mg and the oral preparations 50 to 500 mg of an effervescent base . The dosage of the oral preparations can be clearly lower, for example 1-5 mg selegiline. In the effervescent formulations according to the invention, up to 90% of an effervescent base can be contained in the case of the low-dose active substances, and from 30% to 70% in the case of the active substances of higher dosage. The effervescent formulations also allow ingestion combined with other active substances, as is frequently required in the case of selegiline for the treatment of Parkinson's disease. Thus, effervescent selegiline formulations could be administered in combination with other soluble tablets, in particular combinations of L-dopa-benzerazide or soluble antadine tablets. A cocktail-type treatment is also possible, as described in EP 521 388. In this case, at least two different active substances are dissolved or suspended in one and the same amount of water, and thus are administered together. Selegiline can also be administered in combination with vitamin E in the form of effervescent formulations. According to the invention, these effervescent preparations can also be applied to other alkaline-sensitive active substances, such as erythromycin, clarithromycin, diazepa, ampicillin or phenobarbital. The preparation of the effervescent formulations according to the invention can be carried out according to usual processes known from the state of the art. For example, the acids and carbonates are granulated independently (wet granulation), with the active substances being preferably added to the acid granules. After mixing the perfectly dry granulates, soluble lubricants such as sodium benzoate or polyethylene glycols are added and compressed. According to the other method all the acids, carbonates and active substances are mixed together and heated in the reactor until, for example,, the citric acid releases its water of crystallization, thereby producing a granulate (WO 95/13130). Repeated agitation is required to obtain a uniform mass. This is then sieved quickly and dried perfectly. A good drying is definitely required to avoid a gradual disintegration of the tablets by the reaction of the acids with the carbonates. In order to achieve rapid drying, for example, vacuum drying chambers are used. In another variant of the preparation, the partial start of the acid reaction is carried out with basic components, with subsequent vacuum drying. To the dry granulate is mixed a lubricant soluble prior to compression. However, it is also possible to work with external lubrication. The effervescent granulate obtained according to the invention is compressed to obtain tablets or filled in sachets.

Preferably the alkaline-sensitive active substance such as selegiline is linked to neutral carrier substances to achieve good homogeneity. Neutral carrier substances for the effervescent formulations according to the invention are lactose, sucrose, sorbitol, mannitol, starch, pectins or celluloses. Other auxiliary substances, such as colorants, sugar or sweeteners can improve the appearance and / or taste characteristics of aqueous solutions or suspensions that are obtained by the disintegration of the effervescent tablet. The use of dyes can serve both to improve the appearance and also to identify the preparation. Suitable dyes permitted to be used in pharmacology are for example carotenes or chlorophylls. Sugar or sweeteners may be sucrose, xylitol, D-glucose, sorbitol, mannitol, lactose, aspartases as well as a-saccharin, acesulfam or sodium cyclamate. The following examples should explain the invention in more detail, without limiting it: Example 1 mg SOLUBLE TABLET Selegiline Hydrochloride 10 MgC03 96 CaC03 248 Citric Acid 522 Aspartase 4 Lactose 100 Aroma 15 995 Example 2 g SOLUBLE TABLET Selegi .lina hydrochloride 10 Calcium carbonate 310 Citric acid 620 Aspartase 7 Aroma 10 Sodium citrate 53 1,010 Example 3 mg SOLUBLE TABLET Selegi .lina Hydrochloride 10 CaCO3 380 Citric acid 500 Sodium cyclamate 7 Saccharin sodium 1 Aroma 15 Yellow 6 1 Example 4 mg SOLUBLE TABLET Selegiline 5 Calcium carbonate 331 Citric acid 625 Aspartase 10 Aroma 10 Sodium citrate 19 1,000 Example 5 mg GRANULATED Selegi .lina Hydrochloride 5 EFFERVESCENT CaC03 410 Citric acid 600 Sodium cyclamate 5 Saccharin sodium 1 Aroma 20 Mannitol 152 Aerosil 2 Colidin 3 Aspartase 2 1,200 Example 6 mg GRANULATED Selegi .lina Hydrochloride 10 EFFERVESCENT CaCO3 357 Citric acid 522 Sodium cyclamate 5.7 Saccharin sodium 0.9 Aroma 15 Mannitol 187 Aerosil 2 Colidin 2 Aspartase 2 Yellow 6 1 Sodium citrate 100 1,204.6 Example 7 mg SOLUBLE TABLET Selegiline 5 MgC03 100 CaC03 320 Citric acid 450 Aspartase 3 Lactose 50 Aroma 15 943 Example 8 mg MOUTH TABLET Selegiline hydrochloride 5 Calcium carbonate 250 Citric acid 112 Aspartase 4 Aroma 10 Sodium citrate 30 411 Example 9 mg MOUTH TABLET Selegiline hydrochloride 5 Calcium carbonate 205 Citric acid 200 Sodium cyclamate 2 Sodium saccharin 0.5 Aroma 7 Mannitol 71 Aerosil 1 Colidin 1.3 Aspartase 1 493.8 Example 10 mg GRANULATED Erythromycin 500 EFFERVESCENT CaC03 520 Citric acid 720 Sodium cyclamate 7 Saccharin sodium 1 Flavor 15 Corn starch 60 Yellow 6 1 1,824 Example 11 mg GRANULATE Diazepa 5 EFFERVESCENT MgC03 100 CaC03 320 Citric acid 450 Aspartase 3 Lactose 50 Aroma 15 943

Claims

CLAIMS Solid forms of rapid disintegration for oral administration in the form of effervescent formulations containing an alkaline-sensitive active substance and an effervescent base consisting of one or more alkaline earth carbonates, an edible organic acid and / or an alkali salt of citric acid, and optionally pharmaceutically usable auxiliary substances. Effervescent formulations according to claim 1, in the form of soluble tablets, granules or sachets which, prior to ingestion, dissolve in suitable quantities of water. Effervescent formulations according to claim 1, in the form of buccal or sublingual tablets that are applied directly to the buccal cavity. Effervescent formulations according to claims 1-3, characterized in that selegiline, erythrocycline, clarithromycin, diazepam, ampicillin and phenobarbital, or the corresponding pharmaceutically usable salts, can be used as alkaline-sensitive active substances. Effervescent formulations according to claims 1-4, characterized in that selegiline or its pharmaceutically active salt is preferably used as the active substance. Effervescent formulations according to claim 1, characterized in that calcium carbonate and / or magnesium carbonate and citric acid are used as effervescent bases. Effervescent formulations according to claims 1 and 6, characterized in that calcium carbonate and citric acid are preferably used as the effervescent base. Effervescent formulations according to claims 1 and 6, characterized in that the effervescent base can contain up to 15% sodium citrate. The effervescent formulations according to claim 1, characterized in that they can contain effervescent vitamin E FForormmuullaacciiooness according to claim 1, characterized in that up to 90% of an effervescent base can be contained in the case of alkaline-sensitive active substances of low dosage. Effervescent formulations according to claim 1, characterized in that in the case of alkaline-sensitive active substances of higher dosage, 30% to 70% of an effervescent base can be contained. 12, Effervescent formulations according to claims 1 and 5, characterized in that the effervescent minitablets contain 5 mg to 10 mg of selegiline hydrochloride and 1200 g of an effervescent base. 13. Effervescent formulations according to claims 1 and 5, characterized in that the buccal preparations contain 1-10 mg, in particular 5 mg to 10 mg of selegiline hydrochloride and 50 to 500 mg of an effervescent base. 14, Effervescent formulations according to claim 1, characterized in that as additional auxiliary substances may contain dyes, sugar or sweeteners such as sucrose, xylitol, D-glucose, sorbitol, mannitol, lactose, aspartases, Na-saccharin, acesulfam or sodium cyclamate. 15, Method for the preparation of effervescent formulations according to claim 1, characterized in that either calcium carbonate and / or magnesium carbonate and the edible organic acid are separately granulated, with the alkaline-sensitive active substance being preferably added to the acid granulate and then the dry granules are mixed, or all the components of the effervescent formulation are intermixed together. Method for the preparation of effervescent formulations according to claim 15, characterized in that the alkaline-sensitive active substance is linked to a neutral carrier substance to obtain a good homogeneity. Method for the preparation of effervescent formulations according to claim 16, characterized in that lactose, sucrose, sorbitol, magnitol, starch, pectins or celluloses are used as carriers. Method for the preparation of effervescent formulations according to claim 15, characterized in that a part of the calcium carbonate initiates a reaction for by citric acid to form calcium citrate.