HK1036010B - Fizzy formulations - Google Patents

Description

Effervescent formulations

The invention relates to solid, rapidly disintegrating dosage forms for the administration of alkali-sensitive active ingredients, in particular selegiline, in the form of effervescent preparations, and to a method for the production thereof.

Selegiline (═ L-N- (1-phenylisopropyl) -N-methyl-2-propynyl-amine) or a pharmaceutically acceptable salt thereof is used in the form of a tablet in the treatment of parkinson's disease.

A number of dosage forms for selegiline have been described in the patent literature. EP404807, EP 406488, EP 509761, EP 591432, EP 593807, EP 617515, WO 94/23707, EP 647137, EP 683668, WO 95/18603, EP 655900 and WO 96/02239 claim transdermal administration forms, for example comprising patches.

EP 582186, WO 96/01612 and US 5484608 describe pharmaceutical dosage forms for controlled release of selegiline, for example in the form of tablets, US 5128145 describes osmotic delivery systems and WO 96/22435 describes normal release oral formulations. The subject of the invention of patent application WO96/12472 is a liposome composition comprising the active ingredient selegiline. The buccal and sublingual administration forms are claimed in WO 97/17067.

WO 95/07070 describes effervescent formulations comprising at least two different edible acids in order to avoid the possibility of generating insoluble residues of tricalcium citrate when the effervescent formulation is dissolved. WO 93/00886 describes effervescent tablets with good storage stability for active ingredients sensitive to alkalis, such as acetylcysteine, captopril and minoxidil, said tablets comprising an effervescent matrix 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 were coated on the support crystals. The first layer consists of an acid different from the carrier crystal and the second layer consists of an alkali metal salt of one of the two acids.

Selegiline is unstable in base-containing effervescent formulations. Even a multilayer construction is not sufficiently stabilized. Alkali metal carbonates and bicarbonates are more basic than alkaline earth metal carbonates, the latter being, for example, calcium carbonate. To date, there is no effervescent formulation suitable for selegiline, which is an active ingredient sensitive to alkalinity. This is partly due to the possible instability of selegiline, and such formulations have not been successful to date, as shown in figure 1.

In particular for the elderly, the treatment of different conditions requires very frequent dosing, in some cases even long-term dosing. Parkinson's patients often face problems in taking tablets (and subsequently drinking fluids) due to intense tremor. Also, the administration of tablets is very difficult for dysphagic patients.

There is therefore a need for novel solid rapidly disintegrating dosage forms for administration, in particular effervescent formulations in the form of soluble tablets, buccal tablets or soluble granules, which are easy to administer even to the elderly.

It is an object of the present invention to provide novel and therapeutically advantageous effervescent formulations for selegiline and other active ingredients that are sensitive to alkalinity.

According to EP 521388, the soluble tablets are also particularly suitable for use in combination with other soluble tablets, such as L-dopa and benserazide.

This object is achieved by the present invention which provides a rapidly disintegrating dosage form for administration with or without aqueous intake in the form of an effervescent preparation, which comprises an alkali-sensitive active ingredient and an effervescent base consisting of one or more alkaline earth metal carbonates, organic food acids and/or alkali metal salts of citric acid, and, where appropriate, pharmaceutically acceptable auxiliaries.

The present invention provides effervescent formulations in the form of granules, tablets or Sachets (Sachets). The tablet may also be buccal.

A particular embodiment of the present invention relates to an effervescent formulation comprising selegiline or a pharmaceutically acceptable salt thereof.

By addition of water or contact of saliva with the effervescent preparation, with CO₂The evolution of gas produces a suspension or solution which has a good taste during administration. Here, a rapid release of the active ingredient is of particular importance to ensure a rapid onset of action. This applies in particular to buccal tablets.

Effervescent formulations suitable for use with various active ingredients and vitamins are known in the art. These effervescent formulations generally comprise a substance capable of releasing CO₂And an agent for inducing CO₂The released agent. Preference is given to using a catalyst which releases CO₂The reagent (b) is an alkali metal carbonate or alkali metal bicarbonate, such as sodium carbonate or sodium bicarbonate. The alkaline earth metal carbonate formulations relate primarily to inorganic formulations. For inducing CO₂The releasing agent is edible organic acid or its salt, which exists in solid form and can be formulated into granule or tablet with active ingredient and other adjuvants without releasing CO prematurely₂. Suitable edible organic acids are, for example, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, ascorbic acid, maleic acid or citric acid. Pharmaceutically acceptable acid salts are, for example, salts of polyacids which are present in solid form, wherein also at least one acid function is present, for example sodium dihydrogen phosphate or disodium hydrogen phosphate, or the corresponding citrate salts. The active ingredients can be present in the effervescent preparation both as readily soluble compounds and can be dissolved by salt formation during the dissolution process. However, it is also possible to disperse sparingly soluble active ingredients.

Selegiline hydrochloride is extremely sensitive to conventional effervescent bases such as sodium bicarbonate, sodium carbonate or sodium citrate in combination with organic food acids such as citric acid or tartaric acid. In these conventional effervescent formulations, the active ingredient selegiline is decomposed into amphetamine, methamphetamine (methamphetamine) and desmethylselegiline, and the active ingredient sublimes. It should be noted that the decomposition to the above-mentioned metabolites occurs only partially. In the presence of alkali metal compounds, in particular alkali metal carbonates, the major part of selegiline is sublimed, so that surprisingly, even with only a slight metabolic effect, a loss of active ingredient occurs. As can be seen from figure 2, these selegiline effervescent formulations no longer reached the desired purity and amount after storage.

Surprisingly, the effervescent alkaline earth metal-based formulations according to the invention are very stable.

Here, a preferred embodiment is the use of calcium carbonate and citric acid as effervescent base. It may be advantageous if a portion of the calcium carbonate reacts with citric acid to give calcium citrate. Small amounts of sodium citrate do not lead to instability. However, the amount may not exceed 15% of the total weight of the effervescent formulation.

The selegiline effervescent formulation according to the invention shows no loss of the relevant amount at room temperature, even in the stress test (Stresstest) at 40 ℃ and 75% relative atmospheric humidity (figure 3).

This is particularly important since effervescent preparations have to be sufficiently protected from atmospheric moisture during production, canning and storage, and therefore the preparation process is generally carried out only at room temperature and relatively low atmospheric moisture (Ritschel, Bio tablet, Echtio Cauher KG 1966, p.115f). As disclosed by Wells in Pharmaceutical preparation (John Wiley 1988), basic catalysis is the determining mechanism responsible for instability in a large number of drugs.

In effervescent tablets, calcium carbonate is generally used only for calcium therapy, and not as a pharmaceutical excipient as an active ingredient, in which case calcium does not contribute to the treatment. Calcium-containing effervescent tablets are generally used for the treatment of mineral metabolism. WO 95/07070 describes effervescent granules based on calcium carbonate and citric acid for the preparation of pharmaceutical preparations, wherein 5 to 20 parts by weight of citric acid are replaced by at least one other edible acid, for example malic acid.

Calcium carbonate is also used as an additional auxiliary in pharmaceutical technology, for example as an auxiliary or extender for sugar coatings (Fiedler, dictionary of auxiliaries (Lexikon der Hilfsstoffe), 3rd edition, 1989).

The effervescent preparation according to the invention can be prepared as a ready-to-drink solution or suspension with good taste in 40 to 80ml of water, also drinkable in the case of tremors. This is also suitable for the elderly patients. Buccal or sublingual effervescent formulations are administered directly on the oral mucosa.

Micro effervescent tablets for example contain 5 to 10mg selegiline HCl and approximately 1200mg effervescent base, "standard" effervescent tablets contain 2000mg to 7000mg effervescent base, and buccal formulations contain 50 to 500mg effervescent base. The dosage of the buccal formulation may be quite low, for example 1-5mg selegiline. The effervescent formulations according to the invention may comprise up to 90% of effervescent base in the case of low dose active ingredients and 30% to 70% of effervescent base in the case of high dose active ingredients.

Effervescent formulations may also be administered in combination with other active ingredients, which is often required in the case of treatment of parkinson's disease with selegiline. Thus, the selegiline effervescent formulation can be administered in combination with other soluble tablets, in particular L-dopa/benserazide combinations or soluble amantadine tablets. Cocktail therapy as described in EP 521388 is also possible. Here, at least two different active ingredients are dissolved or suspended together in a certain amount of water and then administered together. Selegiline can also be administered in an effervescent formulation with vitamin E. According to the invention, these effervescent preparations can also be used for other active ingredients which are sensitive to alkalis, such as erythromycin, clarithromycin, diazepam, ampicillin or phenobarbital.

The effervescent formulations according to the invention can be prepared according to conventional methods known in the art. For example, the acid and carbonate are granulated separately (wet granulation), wherein the active ingredient is preferably incorporated into the acidic particles. After mixing the carefully dried granules, a soluble lubricant, such as sodium benzoate or polyethylene glycol, is added and the mixture is tableted.

According to another method, all the acid, carbonate and active ingredient are mixed together and heated in a reactor until, for example, citric acid liberates its water of crystallization and forms granules (WO 95/13130). Repeated stirring is required to obtain a homogeneous mass. Then screened rapidly and dried carefully. Effective drying is absolutely necessary to avoid progressive disintegration of the tablet due to the reaction of the acid with the carbonate. To achieve rapid drying, for example, a vacuum drying cabinet may be used. In another preparation, the acid is partially reacted with the basic component and then dried under reduced pressure. A soluble lubricant is mixed into the dry granules prior to tableting. However, tablets may be prepared by an external lubrication method. The resulting effervescent granules according to the invention are then compressed into tablets or filled into sachets.

In one embodiment of the invention, some of the calcium carbonate has been partially reacted with citric acid to provide calcium citrate.

The alkali-sensitive active ingredients of selegiline and the like are preferably bound to a neutral carrier substance to obtain good homogeneity. Suitable neutral carrier substances for the effervescent preparations according to the invention are lactose, sucrose, sorbitol, mannitol, starch, pectin or cellulose. Other adjuvants, such as colorants, sugars or sweeteners, may improve the appearance and/or taste of the aqueous solution or suspension obtainable by disintegration of the effervescent tablet. The use of a colorant serves to both improve appearance and identify the formulation. Colorants approved for use in pharmacy are, for example, carotenoids or chlorophyll.

Suitable sugars or sweeteners are sucrose, xylitol, D-glucose, sorbitol, mannitol, lactose, aspartame and sodium saccharin, acesulfame or sodium cyclamate.

The following examples are intended to illustrate the invention in more detail, but without limiting it.Example 1mg soluble tablet selegiline HCl 10MgCO₃ 96CaCO₃248 citric acid 522 aspartame 4 lactose 100 flavor15

995 Example 2mg soluble tablet selegiline HCl 10 calcium carbonate 310 citric acid 620 aspartame 7 spice 10 sodium citrate53

1010Example 3 mg soluble tablet selegiline HCl 10CaCO₃380 citric acid 500 sodium cyclamate 7 sodium saccharin 1 perfume 15 pigment yellow 61

914 Example 4mg soluble tablet selegiline 5 calcium carbonate 331 citric acid 625 aspartame 10 spice 10 sodium citrate19

1000 Example 5mg effervescent granule selegiline HCl 5CaCO₃410 citric acid600 sodium cyclamate 5 sodium saccharin 1 flavor 20 mannitol 152A highly dispersed silica gel (Aerosil) 2Kollidon 3 aspartame2

1200 Example 6mg effervescent granule selegiline HCl 10CaCO₃357 citric acid 522 sodium cyclamate 5.7 saccharin sodium 0.9 perfume 15 mannitol 187A highly dispersed silica gel (Aerosil) 2Kollidon 2 aspartame 2 pigment yellow 61 sodium citrate100

1204.6 Example 7mg soluble tablet selegiline HCl 5MgCO₃ 100CaCO₃320 citric acid 450 aspartame 3 lactose 50 flavor15

943 Example 8Buccal tablet selegiline HCl 5 calcium carbonate 250 citric acid 112 aspartame 4 flavor 10 sodium citrate30

411 Example 9mg buccal tablet selegiline HCl 5 calcium carbonate 205 citric acid 200 sodium cyclamate 2 sodium saccharin 0.5 perfume 7 mannitol 71A highly dispersed silica gel (Aerosil) 1Kollidon 1.3 aspartame1

493.8 Example 10mg effervescent granule erythromycin 500CaCO₃520 citric acid 720 sodium cyclamate 7 saccharin sodium 1 perfume 15 corn starch 60 pigment yellow 61

1824 Example 11Effervescent granule diazepam 5MgCO₃ 100CaCO₃320 citric acid 450 aspartame 3 lactose 50 flavor15

943

Claims (17)

1. Solid, rapidly disintegrating dosage form for oral administration in the form of an effervescent preparation, comprising selegiline or a pharmaceutically acceptable salt thereof as active ingredient and an effervescent base consisting of one or more alkaline earth metal carbonates, organic food acids and/or alkali metal salts of citric acid and optionally pharmaceutically acceptable auxiliaries.

2. The effervescent formulation of claim 1 in the form of soluble tablets, granules and cachets which are dissolved in an appropriate amount of water prior to administration.

3. An effervescent formulation according to claim 1 in the form of a buccal or sublingual tablet for direct administration to the oral cavity.

4. Effervescent preparation according to claim 1, characterized in that the effervescent base used is calcium carbonate and/or magnesium carbonate and citric acid.

5. An effervescent formulation according to claim 1 or 4, characterised in that the effervescent base used is calcium carbonate and citric acid.

6. An effervescent formulation according to claim 1 or 4 characterised in that the effervescent base may contain up to 15% sodium citrate.

7. Effervescent preparation according to claim 1, characterized in that it may comprise vitamin E.

8. Effervescent formulation according to claim 1, characterized in that the mini effervescent tablets comprise 5mg to 10mg selegiline HCl and 1200mg effervescent base.

9. Effervescent formulation according to claim 1, characterized in that the buccal formulation comprises 1-10mg selegiline HCl and 50 to 500mg effervescent base.

10. Effervescent formulation according to claim 9, characterized in that the buccal formulation comprises 5-10mg selegiline HCl and 50-500mg effervescent base.

11. Effervescent preparation according to claim 1, characterized in that it can contain colorants, sugars and sweeteners as additional auxiliaries.

12. An effervescent formulation according to claim 11 characterised in that the additional adjuvant is sucrose, xylitol, D-glucose, sorbitol, mannitol, lactose, aspartame, sodium saccharin, acesulfame or sodium cyclamate.

13. Process for the preparation of an effervescent formulation according to claim 1, characterized in that the calcium and/or magnesium carbonate and the organic food acid are granulated separately, wherein selegiline or a pharmaceutically acceptable salt thereof is added to one granulate, and the dried granulate is subsequently mixed, or all the components of the effervescent formulation are mixed together.

14. Process for the preparation of an effervescent formulation according to claim 13, characterized in that the calcium and/or magnesium carbonate and the organic food acid are granulated separately, wherein selegiline or a pharmaceutically acceptable salt thereof is added to the acidic granules.

15. Process for the preparation of an effervescent formulation according to claim 13 or 14, characterized in that to obtain good homogeneity, selegiline or a pharmaceutically acceptable salt thereof is bound to a neutral carrier substance.

16. Process for the preparation of effervescent formulations according to claim 15, characterized in that the carrier substance used is lactose, sucrose, sorbitol, mannitol, starch, pectin or cellulose.

17. A process for the preparation of an effervescent formulation according to claim 13 or 14, characterized in that some of the calcium carbonate has been partially reacted with citric acid to obtain calcium citrate.