SWALLOWABLE TABLETS WITH HIGH CONTENT OF N-ACETYLCYSTEINE

Abstract: A swallowable tablet containing 80-95 % N-acetylcysteine by weight, 0.5-4 % by weight with respect to N-acetylcysteine of a binder and further pharmaceutically acceptable excipients, such as diluents, disintegrants, lubricants, optionally in the presence of a flowing agent and of a film-coating layer, is described.

Description: Swallowable tablets with high content of N-acetylcysteme The present invention relates to swallowable tablets with high content of N-acetylcysteine N-acetylcysteine (NAC) is a compound known for time and mainly used in therapy as mucolytic and expectorant (The Merck Index, XII ed , page 16, no 89) Usually NAC is administered by topical route or by oral route in the form of a granulate or tablet For the oral solid administration, presently NAC is formulated only at the maximum dose of 200 mg in chewable tablets to be dissolved in the mouth This implies the need to mask the taste as well as the smell of this active ingredient, known to be not very pleasant because of the presence of a sulphur group in the molecule Just for the need to use a high number and amount of excipients to mask the taste and the smell, there are on the market neither oral NAC formulations containing more than 65% by weight of active ingredient nor NAC formulations as swallowable tablets with a dose higher than 200 mg/tablet The formulation of tablets for the oral administration containing a high percentage of active ingredient is generally difficult US patent 4,908.210 (Eastman Kodak Company) claims a compressible powder containing 0 5-5% by weight of a specific mixture of lubricants (monoglycendes, propylene-glycol monoesters, a salt of a fatty acid ester of lactic acid) so to give finished tablets containing a percentage of active ingredient higher than 80% Such a powder shows economic drawbacks since some excipients of the lubncant mixture are particularly expensive US patent 5,501,861 (Takeda Chemical Industry Ltd) illustrates fast dissolving tablets containing the active ingredient in the percentage of 0 05-90% by weight of the semifinished product and a hydrosoluble carbohydrate in a percentage of 30-80% by weight However. this document underlines that the use of 30-70% by weight of active ingredient is preferred to obtain a tablet with a high dosage In fact, the examples of final formulation never contain percentages of active ingredient higher than 50% US patent 5,401,514 (Spiπg AG) claims an oral solid formulation of at least 50% NAC or carboxy-methyl-cysteine by weight in admixture with at least a cellulose, a soluble sugar, a sweetener and a flavour The same formulation is claimed with a NAC content of 100 mg and 200 mg The content of active mgredient in the exemplified formulations reaches 65% by weight at the maximum A swallowable tablet with a high content of NAC has been now found Therefore, the present invention relates to a swallowable tablet containing 80-95% NAC by weight, 0 5-4% by weight with respect to NAC of a binder and further pharmaceutically acceptable excipients Preferably, the swallowable tablet object of the present invention contains 80-95% NAC by weight, 1-3% bmder by weight, 2 5-14% diluent by weight, 1-4 5% dismtegrant by weight. 0 1-1 5% lubricant by weight, optionally in the presence of a flowing agent and of a film- coating layer Still more preferably, the swallowable tablet object of the present invention contains 80-90% NAC by weight, 2-3% binder by weight, 3-14% diluent by weight, 1-4 5% dismtegrant by weight, 0 1-1% lubricant by weight, 0 1-1% flowing agent and optionally a film-coating layer equal to or lower than 4% by weight Examples of binders according to the present invention are linear polyvmylpyrrolidone, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, liquid glucose, gelatine and hydroxypropylcellulose Preferably linear polyvinylpirrohdone is used Examples of lubncants according to the present invention are magnesium stearate. sodium stearyl fumarate, sodium benzoate and polyethylene glycol Magnesium stearate is preferably used Examples of diluents according to the present invention are carbohydrates, such as lactose and saccharose, microcrystalhne cellulose and derivatives thereof, inorganic salts, such as dibasic calcium phosphate and sodium bicarbonate, polyalcohols, such as sorbitol, mannitol and xylitol, and mixtures thereof Microcrystalhne cellulose and its derivatives or mixtures thereof are preferably used Examples of disintegrants according to the present invention are cross-linked polyvmylpyrrolidone, sodium croscarmellosc. sodium carboxymethvl starch, starch. pregelatimzed starch and microcrystalhne cellulose Cross-linked polyvmylpyrrolidone and sodium croscarmellose are preferably used When present, the preferably used flowing agent is colloidal silica The tablet object of the invention is prepared by wet granulation of the active ingredient with a binder and optionally all or part of the estimated amount of diluent and/or of the lubricant The granulate is then mixed and compressed with the other excipients and the resultant tablet optionally undergoes a film-coating procedure This optional film-coatmg is carried out according to conventional techniques by preferably using cellulose acetate phthalate, ethylcellulose, hydroxypropylcellulose. hydroxypropylmethylcellulose and metacryhc acid co-polymers, as coating agents, m admixture with opacifiers, plasticizers and, optionalh . dyes and sweetening agents Preferably the preparation of the swallowable tablet object of the present invention is carried out by wet granulation of NAC with a binder The resultant granulate is then mixed with the remaining excipients and compressed The use of such a low amount of excipients makes possible the preparation of swallowable tablets containing a high dose of NAC, while keeping the final size of the tablet within acceptable values, that is suitable for the swallowing A particularly preferred feature of the present invention is therefore represented by the preparation of tablets containing a dose of NAC equal to or higher than 400 mg, more preferably equal to 600 mg The tablets containing 600 mg NAC, according to the present invention, have a weight from 630 mg to 750 mg For the preparation of tablets having this weight, conventional moulds such as, for example, convex tablets with 12-mm diameter or capsule-shaped tablets with sizes 18 16 x 7 41 mm, commonly used for swallowable tablets, can be used Furthermore, the tablets object of the present invention show physical characteπstics which fulfil the requirements imposed by the Official Pharmacopoeias For example, the hardness of the tablets will be generally from 6 to 14 Kp. the friability from 0 05 to 0 7% and the disintegration time lower than 15 minutes for the non-film coated tablets 0/59500 In order to better illustrate the present invention the following examples are now given. Example 1 Preparation of the granulates By using a wet granulation procedure in a rotogranulator, the following granulates were prepared (% by weight): The granulates (2 Kg each batch) were dried, screened and used for the preparation of the tablets according to what reported in the following examples. Example 2 Granulate A (2 Kg) was mixed with microcrystalline cellulose, sodium bicarbonate, PVP CL and magnesium stearate. The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight): NAC 600.0 mg (84.4%) PVP K30 18.0 mg (2.5%) microcrystalline cellulose 50.8 mg (7.1%) sodium bicarbonate 20.0 mg (2.8%) PVP CL 16.0 mg (2.3%) magnesium stearate 6.2 mg (0.9%) total weight 71 1.0 rag Example 3 Granulate A (2 Kg) was mixed with microcrystalline cellulose, PVP CL and magnesium stearate. The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight): NAC 600.0 mg (83.8%) PVP K30 18 0 mg (2 5%) microcrystalline cellulose 75 8 mg (10 6%) PVP CL 16 0 mg (2 2%) magnesium stearate 6 2 mg (0 9%) total weight 716 0 mg Example 4 Granulate A (2 Kg) was mixed with microcrystalline cellulose, PVP CL, magnesium stearate and colloidal silica The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (83 9%) PVP K30 18 0 mg (2 5%) microcrystalhne cellulose 60 0 mg (8 4%) PVP CL 30 0 mg (4 2%) magnesium stearate 3 5 mg (0 5%) colloidal silica 3 5 mg (0 5%) total weight 715 0 mg Example 5 Granulate A (2 Kg) was mixed with dibasic calcium phosphate, PVP CL. magnesium stearate and colloidal silica The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% b\ weight) NAC 600 0 mg (83 8%) PVP K30 18 0 mg (2 5%) dibasic calcium phosphate 60 8 mg (8 5%) PVP CL 30 0 mg (4 2%) magnesium stearate 3 6 mg (0 5%) colloidal silica 3 6 mg (0 5%) total weight 716 0 mg Example 6 Granulate A (2 Kg) was mixed with lactose. PVP CL. magnesium stearate and colloidal silica The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (83 33%) PVP K30 18 0 mg (2 50%) lactose 75 0 mg (10 42%) PVP CL 16 0 mg (2 22%) magnesium stearate 6 4 mg (0 89%) colloidal silica 4 6 mg (0 64%) total weight 720 0 mg Example 7 Granulate A (2 Kg) was mixed with microcrystalhne cellulose, sodium croscarmellose and magnesium stearate The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (85 7%) PVP K30 18 0 mg (2 6%) microcrystalline cellulose 45 8 mg (6 5%) sodium croscarmellose 30 0 mg (4 3%) magnesium stearate 6 2 mg (0 9%) total weight 700 0 mg Example 8 Granulate A (2 Kg) was mixed with microcrystalhne cellulose, PVP CL and magnesium stearate The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (85 7%) PVP K30 18 0 mg (2 6%) microcrystalhne cellulose 45 8 mg (6 5%) PVP CL 30 0 mg (4 3%) magnesium stearate 6 2 mg (0 9%) total weight 700 0 mg Example 9 Granulate C (2 Kg) was mixed with PVP CL. magnesium stearate and colloidal silica The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (%> by weight) NAC 600 0 mg (84 4%) PVP K30 20 0 mg (2 8%) lactose 54 0 mg (7 6%) PVP CL 30 0 mg (4 2%) magnesium stearate 4 0 mg (0 6%) colloidal silica 3 0 mg (0 4%) total weight 711 0 mg Example 10 Granulate D (2 Kg) was mixed with microcrystalhne cellulose, PVP CL, magnesium stearate and colloidal silica The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (82 6%) PVP K30 15 0 mg (2 1%) lactose 54 0 mg (7 4%) microcrystalline cellulose 30 0 mg (4 1%) PVP CL 20 0 mg (2 8%) magnesium stearate 4 0 mg (0 6%) colloidal silica 3 0 mg (0 4%) total weight 726 0 mg Example 11 Granulate E (2 Kg) was mixed with microcrystalhne cellulose. PVP CL, magnesium stearate and colloidal silica The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 600 O mg (81 52%) PVP K30 20 O mg (2 72%) mannitol 54 0 mg (7 34%) microcrystalhne cellulose 30 0 mg (4 08%) PVP CL 25 0 mg (3 40%) magnesium stearate 4 0 mg (0 54%) colloidal silica 3 0 mg (0 40%) total weight 736 0 mg Example 12 Granulate F (2 Kg) was mixed with dibasic calcium phosphate, PVP CL, magnesium stearate and colloidal silica The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% weight) NAC 600 O mg (81 52%) PVP K30 15 O mg (2 04%) mannitol 54 0 mg (7 34%) dibasic calcium phosphate 40 0 mg (5 44%) PVP CL 20 0 mg (2 72%) magnesium stearate 4 0 mg (0 54%) colloidal silica 3 0 mg (0 40%) total weight 736 0 mg Example 13 Granulate G (2 Kg) was mixed with microcrystalhne cellulose, sodium bicarbonate, PVP CL and magnesium stearate The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (84 39%) PV K30 18 O mg (2 53%) PEG 6000 6 0 mg (0 84%) microcrystalhne cellulose 50 8 mg (7 15%) sodium bicarbonate 14 O mg (1 97%) PVP CL 16 O mg (2 25%) magnesium stearate 6 2 mg (0 87%) total weight 711 0 mg Example 14 Granulate G (2 Kg) was mixed with microcrystalhne cellulose, colloidal silica. PVP CL and magnesium stearate The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (83 22%) PVP K30 18 O mg (2 49%) PEG 6000 6 0 mg (0 83%) PVP CL 30 O mg (4 16%) microcrystalhne cellulose 60 0 mg (8 32%) colloidal silica 3 5 mg (0 49%) magnesium stearate 3 5 mg (0 49%) total weight 721 0 mg Example 15 Granulate G (2 Kg) was mixed with microcrystalhne cellulose, colloidal silica, PVP CL and magnesium stearate The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 400 0 mg (83 22%) PVP K30 12 O mg (2 49%) PEG 6000 4 0 mg (0 83%) PVP CL 20 O mg (4 16%) microcrystalline cellulose 40 0 mg (8 32%) colloidal silica 2 33 mg (0 49%) magnesium stearate 2 33 mg (0 49%) total weight 480 66 mg Example 16 Granulate G (2 Kg) was mixed with microcrvstalline cellulose, colloidal silica. PVP CL and magnesium stearate The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 200 0 mg (83 22%) PVP K30 6 0 mg (2 49%) PEG 6000 2 0 mg (0 83%) PVP CL 10 O mg (4 16%) microcrystalhne cellulose 20 0 mg (8 32%) colloidal silica 1 16 mg (0 49%) magnesium stearate 1 16 mg (0 49%) total weight 240 32 mg Example 17 Granulate A (2 Kg) was mixed with PVP CL. microcrystal ne cellulose, colloidal silica and magnesium stearate The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 400 0 mg (83 92%) PVP K30 12 O mg (2 52%) PVP CL 20 O mg (4 19%) microcrystalhne cellulose 40 0 mg (8 39%) colloidal silica 2 33 mg (0 49%) magnesium stearate 2 33 mg (0 49%) total weight 476 66 mg Example 18 Granulate A (2 Kg) was mixed with PVP CL, microcrystalhne cellulose, colloidal silica and magnesium stearate The mixture was compressed to obtain tablets having the following composition expressed as mg/tablet (% by weight) NAC 200 0 mg (83 92%) PVP K30 6 0 mg (2 52%) PVP CL 10 O mg (4 19%) microcrystalhne cellulose 20 O mg (8 39%) colloidal silica 1 16 mg (0 49%) magnesium stearate 1 16 mg (0 49%) total weight 238 32 mg Example 19 The tablets prepared as described in example 4 were coated with a mixture of hydroxypropylmethylcellulose, titanium dioxide and PEG 6000 The mixture was suspended in water (suspension at 10-15%) and sprayed into a coating pan The resultant film-coated tablets have the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (82 4%) PVP K30 18 O mg (2 5%) microcrystalhne cellulose 60 0 mg (8 2%) PVP CL 30 O mg (4 1%) magnesium stearate 3 5 mg (0 5%) colloidal silica 3 5 mg (0 5%) HPMC 5 O mg (0 7%) titanium dioxide 5 0 mg (0 7%) PEG 6000 3 0 mg (0 4%) total weight 728 0 mg Example 20 The tablets prepared as described in example 4 were coated with a mixture of metacryhc acid copolymer, titanium dioxide and polysorbate 80 The mixture was suspended in water (suspension at 10-15%) and sprayed into a coating ban The resultant film-coated tablets have the following composition expressed as mg/tablet (% by weight) NAC 600 O mg (82 27%) PVP K30 18 O mg (2 47%) microcrystalhne cellulose 60 0 mg (8 23%) PVP CL 30 O mg (4 11%) magnesium stearate 3 5 mg (0 48%) colloidal silica 3 5 mg (0 48%) metacryhc acid copolymer 9 2 mg ( 1 26%) titanium dioxide 3 3 mg (0 45%) polysorbate 80 1 8 mg (0 25%) total weight 729 3 mg Example 21 The tablets prepared as described in example 4 were coated with a mixture of polyvinylalcohol, titanium dioxide, talc. so a lecithin and xanthan gum, commercialh available as Opadry OY-B-28920 The mixture was suspended in water and spra\ed into a coating pan The resultant film- coated tablets (12 mm diameter) have the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (80 7%) PVP K30 18 O mg (2 42%) PVP CL 30 O mg (4 03%) microcrystalhne cellulose 60 0 mg (8 06%) colloidal silica 3 5 mg (0 47%) magnesium stearate 3 5 mg (0 47%) Opadry OY-B-28920 28 6 mg (3 85%) total weight 743 6 mg Example 22 The tablets prepared as descnbed in example 14 were coated with a mixture of polyvinylalcohol, titanium dioxide, talc, soya lecithin and xanthan gum, commerciall } available as Opadry OY-B-28920 The mixture was suspended in water and sprayed into a coatmg pan The resultant film- coated tablets (12 mm diameter) have the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (80 0%) PV K30 18 O mg (2 4%) PEG 6000 6 O mg (0 8%) PVP CL 30 0 mg (4 0%) microcrystalhne cellulose 60 0 mg (8 0%) colloidal silica 3 5 mg (0 47%) magnesium stearate 3 5 mg (0 47%) Opadry OY-B-28920 28 84 mg (3 86%) total weight 749 84 mg Example 23 The tablets prepared as descnbed in example 15 were coated with a mixture of polyvinylalcohol, titanium dioxide, talc, soya lecithin and xanthan gum, commercially available as Opadry OY-B-28920 The mixture was suspended in water and sprayed into a coatmg pan The resultant film- coated tablets (10 mm diameter) have the following composition expressed as mg/tablet (% by weight) NAC 400 O mg (80 0%) PVP K30 12 0 mg (2 4%) PEG 6000 4 0 mg (0 8%) PVP CL 20 0 mg (4 0%) microcrystalhne cellulose 40 0 mg (8 0%) colloidal silica 2 33 mg (0 47%) magnesium stearate 2 33 mg (0 47%) Opadry OY-B-28920 19 24 mg (3 86%) total weight 499 9 mg Example 24 The tablets prepared as described in example 16 were coated with a mixture of polyvinylalcohol, titanium dioxide, talc, soya lecithin and xanthan gum, commercially available as Opadry OY-B-28920 The mixture was suspended in water and spraved into a coatmg pan The resultant film- coated tablets (8 mm diameter) have the following composition expressed as mg/tablet (% by weight) NAC 200 0 mg (80 0%) PVP K30 6 0 mg (2 4%) PEG 6000 2 0 mg (0 8%) PVP CL 10 O mg (4 0%) microcrystalline cellulose 20 0 mg (8 0%) colloidal silica 1 16 mg (0 47%) magnesium stearate 1 16 mg (0 47%) Opadry OY-B-28920 9 58 mg (3 86%) total weight 249 9 mg Example 25 The tablets prepared as described in example 17 were coated with a mixture of polyvinylalcohol, titanium dioxide, talc, soya lecithin and xanthan gum, commercially available as Opadry OY-B-28920 The mixture was suspended in water and sprayed into a coatmg pan The resultant film- coated tablets (10 mm diameter) have the following composition expressed as mg/tablet (% by weight) NAC 400 0 mg (80 7%) PVP K30 12 0 mg (2 42%) PVP CL 20 O mg (4 03%) microcrystalhne cellulose 40 0 mg (8 06%) colloidal silica 2 33 mg (0 47%) magnesium stearate 2 33 mg (0 47%) Opadry OY-B-28920 19 04 mg (3 85%) total weight 495 7 mg Example 26 The tablets prepared as described in example 18 were coated with a mixture of polyvinylalcohol. titanium dioxide, talc, soya lecithin and xanthan gum, commercialh available as Opadry OY-B-28920 The mixture was suspended in water and sprayed into a coating pan The resultant film- coated tablets (8 mm diameter) have the following composition expressed as mg/tablet (% by weight) NAC 200 0 mg (80 7%) PVP K30 6 O mg (2 42%) PVP CL 10 0 mg (4 03%) microcrystalline cellulose 20 0 mg (8 06%) colloidal silica 1 16 mg (0 47%) magnesium stearate 1 16 mg (0 47%) Opadry OY-B-28920 9 53 mg (3 85%) total weight 247 85 mg Example 27 The tablets prepared as descnbed in example 4 were coated with a mixture of polyvinylalcohol, titanium dioxide, talc, soya lecithin and xanthan gum, commercially available as Opadry OY-B-28920, added with sodium saccharin The mixture was suspended in water and sprayed into a coatmg pan The resultant film- coated tablets have the following composition expressed as mg/tablet (% by weight) NAC 600 0 mg (80 6%) PVP K30 18 O mg (2 4%) PVP CL 30 O mg (4 0%) microcrystalhne cellulose 60 0 mg (8 0%) colloidal silica 3 5 mg (0 5%) magnesium stearate 3 5 mg (0 5%) Opadry OY-B-28920 28 6 mg (3 8%) sodium sacchaπn 1 4 mg (0 2%) total weight 745 mg By working in a similar way, tablets having a lower content of sodium saccharm in the film- coating mixture, 1 0 mg and 0 5 mg respectively, were prepared

Claims: Claims 1) A swallowable tablet containing 80-95% N-acetylcysteine by weight, 0 5-4% b\ weight with respect to N-acetylcysteine of a binder and further pharmaceutically acceptable excipients 2) A swallowable tablet according to claim 1 containing 80-95% N-acetylcysteine b\ weight, 1-3% binder by weight, 2 5-14% diluent by weight, 1-4 5% dismtegrant by weight 0 1-1 5% lubricant by weight optionally in the presence of a flowing agent and of a film- coating layer 3) A swallowable tablet according to claim 1 or 2 containing 80-90% N-acetylcysteine by weight, 2-3% binder by weight, 3-14% diluent weight, 1-4 5% dismtegrant by weight. 0 1-1% lubricant by weight. 0 1-1% flowing agent and optionally a film-coating layer equal to or lower than 4% by weight 4) A tablet according to one of the preceding claims wherein the binder is selected among linear polyvmylpyrrolidone, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, liquid glucose, gelatine and hydroxypropylcellulose 5) A tablet according to claim 4 wherein the binder is linear polyvinylpirrohdone 6) A tablet according to one of the preceding claims wherein the lubricant is selected among magnesium stearate, sodium stearyl fumarate. sodium benzoate and polvethvlene glycol 7) A tablet according to claim 6 wherein the lubricant is magnesium stearate 8) A tablet according to one of the preceding claims wherein the diluent is selected among carbohydrates, microcrystalhne cellulose and derivatives thereof, inorganic salts, polyalcohols, and mixtures thereof 9) A tablet according to claim 8 wherein the diluent is microcrystalhne cellulose its derivatives or mixtures thereof 10) A tablet according to one of the preceding claims wherein the dismtegrant is selected among cross-linked polyvmylpyrrolidone, sodium croscarmellose, sodium carboxymethvl starch, starch, pregelatimzed starch and microcrvstalline cellulose 11) A tablet according to claim 10 wherein the dismtegrant is cross-linked polyvinylpyrrohdone or sodium croscarmellose 12) A tablet according to one of the preceding claims containing colloidal silica as flowing agent 13) A process for the preparation of a swallowable tablet according to one of the preceding claims which compπses the wet granulation of N-acetylcysteine with a binder and optionally all or a part of the estimated amount of diluent, the mixing of the granulate with the remaining excipients, the compression and the optional film-coating of the tablet

Inventors: BARINA RICCARDO, CASTEGINI FRANCO, GRASSANO ALESSANDRO, GURRIERI GIOVANNI, ZULIANI ITALO, BARINA, RICCARDO, CASTEGINI, FRANCO, GRASSANO, ALESSANDRO, GURRIERI, GIOVANNI, ZULIANI, ITALO
Applicants: BARINA RICCARDO, CASTEGINI FRANCO, GRASSANO ALESSANDRO, GURRIERI GIOVANNI, ZAMBON SPA, ZULIANI ITALO, BARINA, RICCARDO, CASTEGINI, FRANCO, GRASSANO, ALESSANDRO, GURRIERI, GIOVANNI, ZAMBON GROUP S.P.A., ZULIANI, ITALO
Application year: 2000
Main classification: A61K31
IPC codes: A61K9, A61K31