ITMI961116A1 - STABLE AND NON-HYGROSCOPIC SALTS OF L-CARNITINE AND ALCANOYL L-CARNI- TINE - Google Patents
STABLE AND NON-HYGROSCOPIC SALTS OF L-CARNITINE AND ALCANOYL L-CARNI- TINE Download PDFInfo
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- ITMI961116A1 ITMI961116A1 IT96MI001116A ITMI961116A ITMI961116A1 IT MI961116 A1 ITMI961116 A1 IT MI961116A1 IT 96MI001116 A IT96MI001116 A IT 96MI001116A IT MI961116 A ITMI961116 A IT MI961116A IT MI961116 A1 ITMI961116 A1 IT MI961116A1
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- salt
- alkanoyl
- cam
- itin
- acid
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- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical class C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title description 12
- 229960004203 carnitine Drugs 0.000 title description 7
- 150000003839 salts Chemical class 0.000 claims description 58
- 125000001589 carboacyl group Chemical group 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 239000003826 tablet Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 claims description 6
- 235000005911 diet Nutrition 0.000 claims description 6
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- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
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- 230000008569 process Effects 0.000 claims description 6
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
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- -1 isovaleryl Chemical group 0.000 claims description 3
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- 239000002904 solvent Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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- 230000001105 regulatory effect Effects 0.000 claims description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- 229940095064 tartrate Drugs 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
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- 230000002035 prolonged effect Effects 0.000 description 3
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 2
- 150000007513 acids Chemical group 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
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- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 description 1
- UFAHZIUFPNSHSL-MRVPVSSYSA-N O-propanoyl-L-carnitine Chemical compound CCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C UFAHZIUFPNSHSL-MRVPVSSYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 229940110767 coenzyme Q10 Drugs 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
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- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000020905 low-protein-diet Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
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- 235000016337 monopotassium tartrate Nutrition 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- 235000006408 oxalic acid Nutrition 0.000 description 1
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- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- KYKNRZGSIGMXFH-ZVGUSBNCSA-M potassium bitartrate Chemical compound [K+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O KYKNRZGSIGMXFH-ZVGUSBNCSA-M 0.000 description 1
- 229940081543 potassium bitartrate Drugs 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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Description
Descrizione dell'invenzione industriale avente per titolo: "SALI STABILI E NON IGROSCOPICI DI L-CARNITINA E DI ALCANOIL L-CARNITINE" Description of the industrial invention entitled: "STABLE AND NON-HYGROSCOPIC SALTS OF L-CARNITINE AND OF ALCANOYL L-CARNITINE"
La presente invenzione riguarda sali stabili e non igroscopici di L-cam itina e di alcanoil L-cam itine inferiori, un procedimento per la loro preparazione e composizioni solide contenenti tali sali particolarmente adatte alla somministrazione orale. The present invention relates to stable and non-hygroscopic salts of lower L-camitin and alkanoyl L-cam itins, a process for their preparation and solid compositions containing such salts particularly suitable for oral administration.
E' noto da tempo che la carnitina e i suoi alcanoil derivati si prestano a varie utilizzazioni terapeutiche. Ad esempio la L-cam itina è utilizzata in campo cardiovascolare quale farmaco di supporto nel trattamento dell'ischemia miocardica acuta e cronica, angina pectoris, insufficienza ed aritmie cardiache. In nefrologia è somministrata ad uremici cronici sottopósti a regolare trattamento emodialitico per contrastare l'astenia muscolare e l'insorgenza di crampi. La acetil L-cam itina trova applicazione in canpo neurologico nel trattamento sia di patologie del sistema nervoso centrale che delle neuropatie periferiche, in particolare della neuropatia periferica diabetica. La propionil L-cam itina viene impiegata per il trattamento della arteriopatia obliterante cronica particolarmente in pazienti presentanti in forma gravemente invalidante il sintomo della claudicatio intermittens . It has long been known that carnitine and its alkanoyl derivatives lend themselves to various therapeutic uses. For example, L-cam itina is used in the cardiovascular field as a support drug in the treatment of acute and chronic myocardial ischemia, angina pectoris, cardiac insufficiency and arrhythmias. In nephrology it is administered to chronic uremics undergoing regular hemodialysis treatment to counteract muscle asthenia and the onset of cramps. Acetyl L-cam itin finds application in the neurological field in the treatment of both central nervous system pathologies and peripheral neuropathies, in particular diabetic peripheral neuropathy. Propionyl L-cam itin is used for the treatment of chronic obliterating arteriopathy particularly in patients presenting the symptom of intermittent claudication in a severely disabling form.
Si sta d'altronde rapidamente diffondendo l'uso della cam itina e derivati per applicazioni diverse da tali utilizzazioni prettamente terapeutiche (o "etiche") sia pure tuttavia ad esse affini. On the other hand, the use of the path and derivatives for applications other than these purely therapeutic (or "ethical") uses, albeit however similar to them, is rapidly spreading.
Tale risultato deriva da un riconoscimento sempre più ampio e supportato scientificamente che negli atleti o comunque in soggetti che praticano anche a livello non professionistico delle attività sportive, la L-cam itina contribuisce marcatamente a fornire energia alla muscolatura scheletrica ed ad aumentare la resistenza a sforzi prolungati ed intensi migliorando le prestazioni di tali soggetti. This result derives from an ever wider and scientifically supported recognition that in athletes or in any case in subjects who practice sporting activities even at a non-professional level, the L-cam itina contributes markedly to supplying energy to the skeletal muscles and to increasing resistance to efforts. prolonged and intense improving the performance of these subjects.
Inoltre, la L-caritina o i suoi alcanoil derivati inferiori costituiscono integratori nutrizionali indispensabili per i vegetariani la cui dieta è a basso tenore in carnitina e nei due amminoacidi naturali lisina e metionina che sono i precursori della biosintesi della L-cam itina nei reni e nel fegato. Le stesse considerazioni valgono per quei soggetti che si trovano costretti per periodi di tempo più o meno lunghi ad adottare delle diete povere di proteine. Furthermore, L-caritine or its lower alkanoyl derivatives are essential nutritional supplements for vegetarians whose diet is low in carnitine and in the two natural amino acids lysine and methionine which are the precursors of the biosynthesis of L-camitin in the kidneys and in the liver. The same considerations apply to those subjects who are forced to adopt low-protein diets for shorter or longer periods of time.
Varie conposizioni contenenti carnitina o derivati, da soli o in associazione ad altri principi attivi (si veda ad esempio l'associazione L-cam itina/coenzima Q10) hanno così ultimamente raggiunto il mercato degli integratori alimentari, dei prodotti dietetici, degli alimenti per sportivi e simili, cioè di quelle conposizioni che vendute come prodotti da banco non sono destinati a fini prettamente terapeutici ma si indirizzano al benessere ed a un generale miglioramento delle prestazioni dell'utilizzatore e per i quali è stato recentemente coniato il termine di "nutriceuticals". Various compositions containing carnitine or derivatives, alone or in association with other active ingredients (see for example the association L-cam itin / coenzyme Q10) have thus recently reached the market of food supplements, dietary products, foods for sports and the like, that is to say those conpositions which, sold as over-the-counter products, are not intended for purely therapeutic purposes but are aimed at the well-being and general improvement of the user's performance and for which the term "nutriceuticals" has recently been coined.
Di crescente interesse è inoltre l'uso della cam itina e derivati in campo veterinario e quali integratori di mangimi nell'allevamento di animali pregiati. The use of the cam itin and derivatives in the veterinary field and as feed supplements in the breeding of valuable animals is also of growing interest.
Ε' da tempo noto che la carnitina e i suoi alcanoil derivati sono estremamente igroscopici e poco stabili quando si presentano come sali interni (o "betaine") rappresentati dalla formula It has long been known that carnitine and its alkanoyl derivatives are extremely hygroscopic and not very stable when they occur as internal salts (or "betaines") represented by the formula
(R=H oppure alcanoile inferiore C1-C5). (R = H or lower alkanoyl C1-C5).
Ciò comporta complessi problemi di lavorabilità, stabilità e conservabilità sia delle materie prime che dei prodotti finiti. Ad esempio, le compresse di L-cam itina devono essere confezionate in "blister" per mantenerle fuori dal contatto con l'aria poiché altrimenti, anche in presenza di normali condizioni di umidità, si aiterebbero in breve tempo rigonfiandosi, diventando pastose ed appiccicose. Inoltre, a causa della insufficiente stabilità si liberano delle tracce di trimetilaranina che impartisce ai prodotti uno sgradevole odore di pesce. This involves complex problems of workability, stability and shelf life of both raw materials and finished products. For example, L-cam itina tablets must be packaged in "blisters" to keep them out of contact with the air because otherwise, even in the presence of normal humidity conditions, they would quickly start swelling, becoming pasty and sticky. Furthermore, due to insufficient stability, traces of trimethylaranine are released, which gives the products an unpleasant fishy smell.
E' altresì noto che i sali della cam itina e dei suoi alcanoil derivati presentano le stesse attività terapeutiche, rispettivamente nutrizionali o dietetiche, dei cosi detti "sali interni" (o "betaine") e possono venir pertanto utilizzati in loro vece, purché tali sali siano "farmacologicamente accettabili", non presentino cioè indesiderati effetti tossici o collaterali. In pratica quindi la scelta tra il "sale interno" e un sale vero e proprio della cam itina o alcanoil cam itina dipende sostanzialmente da considerazioni di tecnologia farmaceutica più che da considerazioni di attività terapeutica, nutrizionale o dietetica. It is also known that the salts of cam itin and its alkanoyl derivatives have the same therapeutic activities, respectively nutritional or dietary, of the so-called "internal salts" (or "betaines") and can therefore be used in their stead, provided that these salts are "pharmacologically acceptable", ie do not have unwanted toxic or side effects. In practice, therefore, the choice between the "internal salt" and a real salt of the cam itin or alkanoyl cam itin depends substantially on considerations of pharmaceutical technology rather than on considerations of therapeutic, nutritional or dietary activity.
Tali considerazioni di tecnologia farmaceutica vertono principalmente, se non addirittura esclusivamente, sulla possibilità di disporre di sali di L-cam itina e derivati che, a differenza dei sali interni, siano solidi, stabili, particolarmente all'immagazzinamento anche prolungato, non siano igroscopici e siano pertanto facilmente lavorabili e formulabili con gli usuali eccipienti utilizzando dispositivi di mescolamento, etc di tipo tradizionale e non pongano inoltre problemi di confezionamento quando trasformati in prodotti finiti. These pharmaceutical technology considerations mainly, if not exclusively, relate to the possibility of having L-camitin salts and derivatives which, unlike internal salts, are solid, stable, particularly for even prolonged storage, are not hygroscopic and they are therefore easy to work and formulate with the usual excipients using traditional mixing devices, etc and also do not pose packaging problems when transformed into finished products.
Tali sali, sia sotto forma di materia prima che quando formulati in prodotti finiti, non dovrebbero liberare, nemmeno in condizioni non ideali di conservazione, tracce di trimetilammina che avrebbe un effetto repellente sull'utilizzatore. These salts, both in the form of raw materials and when formulated in finished products, should not release traces of trimethylamine, which would have a repellent effect on the user, even in less than ideal storage conditions.
Infine, nel sale il rapporto molare fra caritina (o suo derivato) e acidi polibasici dovrebbe essere il più elevato possibile (ad es. 2:1 piuttosto che 1:1) per conseguire un elevato tenore in cam itina. Finally, in the salt the molar ratio between caritine (or its derivative) and polybasic acids should be as high as possible (eg 2: 1 rather than 1: 1) to achieve a high content in cam itin.
Il problema di reperire e fornire siffatti sali è stato già da tempo affrontato. The problem of finding and supplying such salts has already been addressed for some time.
Il brevetto giapponese 303067 (Tanabe Seiyaku) depositato il 28.12.1959 e pubblicato il 19.6.1962, n° di pubblicazione 5199/1962 descrive un procedimento per la preparazione dell'orotato di cam itina insegnando che esso è "vantaggiosamente meno igroscopico della cam itina e del suo tipico sale, cioè il cloruro di cam itina, e può venir pertanto facilmente lavorato". The Japanese patent 303067 (Tanabe Seiyaku) filed on 28.12.1959 and published on 19.6.1962, publication n ° 5199/1962 describes a process for the preparation of the orotate of cam itin teaching that it is advantageously less hygroscopic than the cam itin and its typical salt, that is cam itin chloride, and can therefore be easily worked ".
Il brevetto giapponese 419486 (Takeda), depositato l'8.4.1961 e pubblicato il 30.9.1963, n° di pubblicazione 19995/1963, descrive quali sali non igroscopici il fumarato acido e il maleato acido di carnitina. Japanese patent 419486 (Takeda), filed on April 8, 1961 and published on September 30, 1963, publication number 19995/1963, describes the acid fumarate and the acid maleate of carnitine as non-hygroscopic salts.
La domanda di brevetto francese 82 11626 (Sanofi) (n° di pubblicazione 2529 545) depositata il 2.7.1982 e pubblicata il 6.1.1984 descrìve, quali sali non igroscopici, il solfato acido e 1'ossalato acido della L-cam itina. French patent application 82 11626 (Sanofi) (publication n ° 2529 545) filed on 2.7.1982 and published on 6.1.1984 describes, as non-hygroscopic salts, the acid sulphate and acid oxalate of L-camitin.
Infine, il brevetto europeo 0 434 088 (Lonza), depositato il 21.12.1990, pubblicato il 26.6.1991, priorità CH del 22.12.1989 descrive l'uso del tartrato di L-cam itina non igroscopico (la cui preparazione e caratterizzazione chimico-fisica è peraltro già descritta da D. Miiller ed E. Strade in Hoppe Seyler's Z. Physiol. Chem. 353/ 618-622, aprile 1972) per la preparazione di forme solide atte alla somministrazione orale quali conpresse, capsule, polveri o granulati. Finally, the European patent 0 434 088 (Lonza), filed on 21.12.1990, published on 26.6.1991, priority CH of 22.12.1989 describes the use of the non-hygroscopic L-camitina tartrate (whose preparation and chemical characterization -physics is also already described by D. Miiller and E. Strade in Hoppe Seyler's Z. Physiol. Chem. 353 / 618-622, April 1972) for the preparation of solid forms suitable for oral administration such as tablets, capsules, powders or granulates .
Tutti tali sali della carnitina, pur essendo sostanzialmente meno igroscopici e offrendo dei vantaggi più o meno rilevanti rispetto ai sali interni, presentano tuttavia degli inconvenienti. All these carnitine salts, although substantially less hygroscopic and offering more or less significant advantages with respect to the internal salts, nevertheless have drawbacks.
In un primo luogo, gli acidi fumarico, maleico e orotico formano con la L-cam itina e suoi alcanoil derivati dei sali in cui la carnitina o il derivato di questa e l'acido sono in rapporto equimolare, cioè 1:1 e non 2:1. Ciò costituisce uno svantaggio in quanto la percentuale della porzione a base di car itina, che è quella che esercita l'effetto terapeutico, dietetico o nutrizionale, è insoddisfacentemente bassa rispetto a quella che non svolge alcuna di queste funzioni, ed è tanto più bassa quanto maggiore è il peso molecolare dell'acido salificante impiegato. Così ad esempio, nell'orotato di L-cam itina, la L-cam itina ammonta solo al 51% circa. In the first place, fumaric, maleic and orotic acids form with L-cam itin and its alkanoyl derivatives of salts in which carnitine or its derivative and the acid are in an equimolar ratio, i.e. 1: 1 and not 2 : 1. This constitutes a disadvantage since the percentage of the carbohydrate-based portion, which is that which exerts the therapeutic, dietary or nutritional effect, is unsatisfactorily low compared to that which does not perform any of these functions, and is as low as the greater the molecular weight of the salifying acid used. Thus, for example, in L-camitin orotate, L-camitin amounts to only about 51%.
La L-caritina ossalato (anch'essa un sale 1:1) non viene utilizzata a causa della preoccupante tossicità dell'acido ossalico. L-caritine oxalate (also a 1: 1 salt) is not used due to the worrying toxicity of oxalic acid.
La L-cam itina tartrato che presenta il vantaggio di essere un sale 2:1 {percentuale di L-cam itina:68) non è suificlentamente stabile ad immagazzinamenti prolungati, liberando tracce di trirretìlamnina che provocano il precedente menzionato sgradevolissimo effetto olfattivo. The L-cam itin tartrate which has the advantage of being a 2: 1 salt (percentage of L-cam itin: 68) is not sufficiently stable to prolonged storage, releasing traces of trirretilamnine which cause the previously mentioned very unpleasant olfactory effect.
Inoltre, nessuno degli acidi precedentemente menzionati è in grado di formare sali solidi stabili e non igroscopici sia con la L-cam itina che con le alcanoil L-cam itine inferiori, in particolare con l'acetil L-cam itina. Cosi ad esempio, mentre la L-cam itina fumarato acido e la L-cam itina tartrato sono conposti ben cristallizzabili e non igroscopici (si vedano JP 419486, MUller e Strade, loc. cit. e EP 0434 088), la acetil L-cam itina fumarato acido, rispettivamente tartrato, sono conposti fortemente igroscopici, che presentano gli stessi inconvenienti del corrispondente sale interno. Furthermore, none of the above mentioned acids is capable of forming stable and non-hygroscopic solid salts with both L-cam itin and lower alkanoyl L-cam itins, in particular with acetyl L-cam itin. Thus, for example, while L-cam itin acid fumarate and L-cam itin tartrate are well crystallizable and non-hygroscopic compounds (see JP 419486, MUller and Strade, loc. Cit. And EP 0434 088), acetyl L- cam itin acid fumarate, respectively tartrate, are strongly hygroscopic compounds, which have the same drawbacks as the corresponding internal salt.
Costituisce lo scopo della presente invenzione fornire sali farmacologicamente accettabili della L-cam itina e delle alcanoil L-cam itine inferiori che non presentino né gli inconvenienti di igroscopicità, scarsa stabilità all 'immagazzinamento, difficoltà di lavorazione e problemi di confezionamento dei corrispondenti sali interni né gli inconvenienti sopramenzionati dei sali non igroscopici già noti. It is the object of the present invention to provide pharmacologically acceptable salts of L-camitin and lower alkanoyl L-cam itins that do not have the drawbacks of hygroscopicity, poor storage stability, processing difficulties and packaging problems of the corresponding internal salts or the aforementioned drawbacks of already known non-hygroscopic salts.
In particolare, è scopo della presente invenzione fornire sali solidi, e non igroscopici che siano stabili e non liberino tracce di trimetilammina neppure in condizioni di immagazzinamento ben più estreme (per durata, temperatura e percentuale di umidità relativa) di quelle sopportate dai sali noti. Inoltre, i sali non igroscopici secondo l'invenzione presentano lo stesso anione sia nel sale della L-carnitina che nei sedi delle alcanoil L-cam itine. In particular, it is an object of the present invention to provide solid and non-hygroscopic salts that are stable and do not release traces of trimethylamine even in storage conditions much more extreme (in terms of duration, temperature and percentage of relative humidity) than those supported by known salts. Furthermore, the non-hygroscopic salts according to the invention have the same anion both in the salt of the L-carnitine and in the sites of the alkanoyl L-cam itins.
I sali della presente invenzione sono sali della L-cam itina e di alcanoil L-cam itina con un tetraidrossiacido bicarbossilioo, di formula (I): The salts of the present invention are salts of L-camitin and alkanoyl L-camitin with a dicarboxylic tetrahydroxy acid, of formula (I):
(I) (THE)
in cui R è idrogeno o alcannile inferiore, lineare o ramificato, a 2-5 atomi di carbonio. wherein R is hydrogen or lower alkannyl, linear or branched, with 2-5 carbon atoms.
Sono preferiti i sali in cui il tetraidrossiacido bicarbossilico è scelto nel gruppo consistente di acido D-glucarico e acido galattarico e in cui R è scelto nel gruppo consistente di acetile, propionile, butirrile, valerile ed isovalerile. Salts in which the dicarboxylic tetrahydroxy acid is selected from the group consisting of D-glucaric acid and galactaric acid and in which R is selected from the group consisting of acetyl, propionyl, butyryl, valeryl and isovaleryl are preferred.
Sia l'acido D-glucarico che l'acido galattarico (più comunemente noto come acido mucico) e i relativi sali sono composti atossici. Infatti, è stato ad esempio proposto l'uso del mucato ammonico in luogo del bitartrato potassico quale lievito minerale nella preparazione di prodotti commestibili e nella produzione di sali granulari effervescenti. Inoltre, l'anione mucato è compreso nella lista degli "FDA-approved corranercially marketed salts" (si veda Journal of Pharmaceutical Sciences, voi. 66 n. 1, gennaio 1977, pag. 3). Both D-glucaric acid and galactaric acid (more commonly known as mucic acid) and their salts are non-toxic compounds. In fact, for example, the use of ammonium mucate in place of potassium bitartrate as mineral yeast in the preparation of edible products and in the production of effervescent granular salts has been proposed. Furthermore, the mucated anion is included in the list of "FDA-approved corranercially marketed salts" (see Journal of Pharmaceutical Sciences, vol. 66 no. 1, January 1977, p. 3).
Sono particolarmente preferiti quali sali secondo l'invenzione la L-cam itina mucato e la acetil L-cam itina raucato. I sali di questa invenzione, lasciati all'aria con umidità relativa del 60%, sono rimasti non igroscopici, solidi e scorrevoli. Particularly preferred as salts according to the invention are L-cam itin mucate and acetyl L-cam itin raucate. The salts of this invention, left in the air with relative humidity of 60%, remained non-hygroscopic, solid and free-flowing.
Un procedimento per la produzione dei sali della L-cam itina o di alcanoil L-cam itina con un tetraidrossiacido bicarbossilico di formula (I) comprende gli stadi consistenti nel: A process for the production of L-camitin or alkanoyl L-camitin salts with a dicarboxylic tetrahydroxy acid of formula (I) comprises the steps consisting of:
(a) sciogliere la L-cam itina sale interno o la alcanoil C2-C5 L-cam itina sale interno e l'acido tetraidrossibicarbossilico in acqua distillata ad una temperatura compresa fra la temperatura ambiente e 100‘C; (a) dissolve the L-cam itin internal salt or the alkanoyl C2-C5 L-cam itin internal salt and the tetrahydroxybicarboxylic acid in distilled water at a temperature between room temperature and 100'C;
(b) tirare a secco sotto vuoto con un bagno riscaldante esterno la cui temperatura è compresa fra 20 e 40°C la soluzione risultante ottenendo un residuo oleoso e riprendere il residuo oleoso con un solvente organico preferibilmente scelto fra acetone, metiletilchetone, diossano ed etere etilico, ottenendo un precipitato solido; e (b) drying the resulting solution under vacuum with an external heating bath whose temperature is between 20 and 40 ° C, obtaining an oily residue and taking up the oily residue with an organic solvent preferably selected from acetone, methylethylketone, dioxane and ether ethyl, obtaining a solid precipitate; And
(c) separare per filtrazione il precipitato solido ed eliminare da questo eventuali tracce di solvente e/o acqua, eventualmente in presenza di un disidratante, con ottenimento del sede di formula (I). (c) separating the solid precipitate by filtration and eliminating any traces of solvent and / or water from it, possibly in the presence of a dehydrating agent, obtaining the seat of formula (I).
Conducendo il procedimento su scala industriale, gli stadi (b) e (c) possono venir sostituiti da uno stadio di liofilizzazione. By conducting the process on an industrial scale, steps (b) and (c) can be replaced by a freeze-drying step.
Secondo l’invenzione, le composizioni solide, particolarmente adatte alla somministrazione orale, conprendono: According to the invention, the solid compositions, particularly suitable for oral administration, include:
(a) un sale della L-cam itina o di alcanoil L-cam itina con un tetraidrossiacido bicarbossilico di formula (I): (a) a salt of L-camitin or alkanoyl L-camitin with a dicarboxylic tetrahydroxy acid of formula (I):
(I) (THE)
in cui R è idrogeno o alcanoile inferiore, lineare o ramificato, a 2-5 atomi di carbonio, e wherein R is hydrogen or lower, linear or branched alkanoyl, with 2-5 carbon atoms, e
(b)un eccipiente farmacologicamente accettabile. (b) a pharmacologically acceptable excipient.
Preferibilmente, le composizioni secondo l'invenzione si presentano sotto forma di preparati farmaceutici o preparati da banco, integratori alimentari o prodotti dietetici, oppure quali prodotti veterinari o mangimi. Preferably, the compositions according to the invention are presented in the form of pharmaceutical preparations or over-the-counter preparations, food supplements or dietetic products, or as veterinary or feed products.
Le composizioni secondo l'invenzione possono comprendere oltre agli usuali eccipienti anche sostanze riempitive, agenti leganti, lubrificanti, agenti distaccanti, agenti regolatori di flusso, agenti disperdenti, coloranti ed aromatizzanti. Tutti tali eccipienti e additivi sono ben noti ed evidenti agli esperti di tecnologia farmaceutica e alimentare. In addition to the usual excipients, the compositions according to the invention can also comprise filling substances, binding agents, lubricants, release agents, flow regulating agents, dispersing agents, coloring and flavoring agents. All such excipients and additives are well known and evident to those skilled in pharmaceutical and food technology.
In forma di dosaggio unitario le composizioni si possono presentare come pastiglie, compresse, compresse masticabili, o capsule, comprendenti una quantità di' sale di L-cam itina o di alcanoil Lcam itina di formula (I) corrispondente a 50-1000 mg, preferibilmente 100-500 mg, di L-cam itina, rispettivamente di alcanoil L-cam itina, sale interno. In unit dosage form the compositions can be presented as tablets, tablets, chewable tablets, or capsules, comprising an amount of L-camitin or alkanoyl Lcamitin salt of formula (I) corresponding to 50-1000 mg, preferably 100-500 mg, of L-camitin, respectively of alkanoyl L-camitin, internal salt.
Per l’uso veterinario sono preferite le polveri o i granulati. For veterinary use, powders or granulates are preferred.
Vengono di seguito forniti esempi di preparazione di sedi secondo l’invenzione e di conposizioni atte a varie utilizzazioni. Examples of preparation of seats according to the invention and of arrangements suitable for various uses are given below.
L-CAKNITINA MUCATO (2:11 L-CAKNITINA MUCATO (2:11
Una miscela di 12,90 g (0,08 moli) di L-cam itina sale interno e 8,41 g (0,04 moli) di acido mucico vennero sciolti sotto agitazione in 720 mL di acqua distillata a 70°C fino a completa dissoluzione. Si lasciò raffreddare spontaneamente a 30°C e quindi si fece evaporare il solvente sotto vuoto tenendo la temperatura del bagno esterno fra 30 e 40'C. A mixture of 12.90 g (0.08 mol) of L-cam itin internal salt and 8.41 g (0.04 mol) of mucic acid were dissolved under stirring in 720 mL of distilled water at 70 ° C up to complete dissolution. It was allowed to spontaneously cool to 30 ° C and then the solvent was evaporated under vacuum keeping the temperature of the external bath between 30 and 40 ° C.
Al residuo oleoso denso vennero aggiunti 250 mL di acetone e si tenne sotto forte agitazione fino a completa solidificazione del prodotto. Si sospese l'agitazione, si lasciò stare la miscela per pochi minuti, si decantò l'acetone, si aggiunsero altri 150 mL di acetone fresco e si tenne sotto forte agitazione per altri 10-15 minuti. Si decantò nuovamente l’acetone e si fece seccare sotto vuoto a 30-35’C in presenza di setacci molecolari. 250 mL of acetone were added to the thick oily residue and kept under strong stirring until the product was completely solidified. The stirring was stopped, the mixture was left to stand for a few minutes, the acetone was decanted, another 150 mL of fresh acetone was added and the mixture was kept under strong stirring for another 10-15 minutes. The acetone was decanted again and dried under vacuum at 30-35'C in the presence of molecular sieves.
Si ottennero 21,1 g (99%) di L-cam itina mucato come solido bianco. 21.1 g (99%) of mucated L-camitin were obtained as a white solid.
ESEMPIO 2 EXAMPLE 2
ACETIL L-CARNITINA MUCATO (2:1) ACETYL L-CARNITINE MUCATO (2: 1)
8,41 g (0,04 moli) di acido mucico vennero sciolti sotto agitazione in 750 mL di acqua distillata a 95°C, quindi si portò la temperatura a 70*C e si aggiunsero 16,26 g (0,08 moli) di acetil L-cam itina Scile interno. La risultante soluzione limpida venne raffreddata rapidamente a 30°C e l'acqua evaporata sotto vuoto tenendo la temperatura del bagno esterno fra 25 e 30°C. 8.41 g (0.04 moles) of mucic acid was dissolved under stirring in 750 mL of distilled water at 95 ° C, then the temperature was brought to 70 ° C and 16.26 g (0.08 moles) were added. of acetyl L-cam itina internal Scile. The resulting clear solution was rapidly cooled to 30 ° C and the water evaporated under vacuum keeping the temperature of the external bath between 25 and 30 ° C.
Si elaborò come descritto nell'esempio precedente, ottenendo la acetil L-cam itina mucato come solido bianco, con resa pressoché quantitativa. It was processed as described in the previous example, obtaining the acetyl L-cam itin mucate as a white solid, with an almost quantitative yield.
ESEMPIO 3 EXAMPLE 3
PROPIONIL L-CARNITINA MUCATO (2:11 PROPIONYL L-CARNITINE MUCATO (2:11
Partendo dalla propionil L-caritina sale interno e operando in modo del tutto analogo a quello descritto per la preparazione della Starting from propionyl L-caritine it rises internally and operating in a completely similar way to that described for the preparation of
acetil L-car itina mucato sostituendo l'evaporazione sotto vuoto con la liofilizzazione si ottenne con resa quantitativa la propionil L-cam ìtina mucato. acetyl L-caritin mucate by substituting evaporation under vacuum with lyophilization, propionyl L-campin mucate was obtained with a quantitative yield.
Form iazione per compresse masticabili di L-carnitina mucato Form iation for chewable L-carnitine mucate tablets
Una compressa masticabile contiene: One chewable tablet contains:
Pricipio attivo: Active principle:
L-cam itina mucato 9 1,650 L-cam itina mucato 9 1,650
(pari a g 1 di L-cam itina, sale interno) (equal to 1 g of L-cam itina, internal salt)
Form iazione per compresse di ace til L-car itina mucato Form iation for ace til L-car itin mucate tablets
Una compressa contiene: One tablet contains:
Eccipienti: Excipients:
cellulosa microcristallina, polivinilpirrolidone magnesio stearato, cellulosa acetoftalato, dietilftalato, dimeticone. microcrystalline cellulose, polyvinylpyrrolidone magnesium stearate, cellulose acetophthalate, diethylphthalate, dimethicone.
Form iazione per compresse di propionil L-car itina mucato Form iation for propionyl L-caritin mucate tablets
Una compressa contiene: One tablet contains:
Claims (12)
Priority Applications (26)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT96MI001116 IT1283086B1 (en) | 1996-05-31 | 1996-05-31 | New stable and non-hygroscopic mucate(s) of L(-)carnitine and alkanoyl L(-)carnitine(s) - useful for making oral compositions for use as e.g. pharmaceutical compositions, food supplements, health foods, veterinary products and fodders |
| US09/194,608 US5952379A (en) | 1996-05-31 | 1997-05-26 | Stable, non-hygroscopic salts of L(-)carnitine and alkanoyl L(-)carnitines, a process for their preparation and solid, orally administrable compositions containing such salts |
| NZ333061A NZ333061A (en) | 1996-05-31 | 1997-05-26 | Stable, non-hygroscopic salts of l(-)carnitine and alkanoyl l(-)carnitines with mucic acid, a process for their preparation and solid, orally administrable compositions containing such salts |
| JP50017398A JP4160634B2 (en) | 1996-05-31 | 1997-05-26 | Stable non-hygroscopic salts of L (-) carnitine and alkanoyl L (-) carnitines, processes for their preparation and solid orally administrable compositions containing said salts |
| CNB971951454A CN1177807C (en) | 1996-05-31 | 1997-05-26 | Stable, non-hygroscopic salts of L(-) carnitine and alkanoyl L(-) carnitinges, process for their preparation and solid, orally administrable compositions containing such salts |
| IL12726697A IL127266A (en) | 1996-05-31 | 1997-05-26 | Stable, non-hygroscopic mucate salts of l(-) carnitine and alkanoyl l(-) carnitines, a process for their preparation and solid, orally administrable compositions containing such salts |
| HU9903455A HU228008B1 (en) | 1996-05-31 | 1997-05-26 | Stable,non-hygroscopic salts of l(-)carnitine and alkanoyl l(-) carnitines,a process for their preparation and solid,orally administrable compositions containing such salts |
| AU29612/97A AU718308B2 (en) | 1996-05-31 | 1997-05-26 | Stable, non-hygroscopic salts of L(-)carnitine and alkanoyl L(-)carnitines, a process for their preparation and solid, orally administrable compositions containing such salts |
| ES97924007T ES2156381T3 (en) | 1996-05-31 | 1997-05-26 | STABLE NON-HYGROSCOPIC SALTS OF L (-) CARNITINE AND ALCANOIL-L (-) CARNITINS, A PROCEDURE FOR THE PREPARATION AND SOLID COMPOSITIONS, ADMINISTRABLE BY ORAL, CONTAINING SALES. |
| EP97924007A EP0914315B1 (en) | 1996-05-31 | 1997-05-26 | Stable, non-hygroscopic salts of l(-)carnitine and alkanoyl l(-)carnitines, a process for their preparation and solid, orally administrable compositions containing such salts |
| CZ19983915A CZ290902B6 (en) | 1996-05-31 | 1997-05-26 | Salts of carnitine derivatives |
| CA002256712A CA2256712C (en) | 1996-05-31 | 1997-05-26 | Stable, non-hygroscopic salts of l(-)carnitine and alkanoyl l(-)carnitines, a process for their preparation and solid, orally administrable compositions containing such salts |
| BR9709627A BR9709627A (en) | 1996-05-31 | 1997-05-26 | Stable non-hygroscopic salts of L (-) carnitine and alkanoyl (-) carnitines a process for their preparation and orally administrable solid compositions containing such salts |
| PL97330189A PL188558B1 (en) | 1996-05-31 | 1997-05-26 | Stable non-hygroscopic salts of l(-)carniotin and alkanoyl l(-)carnitins, method of obtaining them and soil compositions for oral administration containing such salts |
| SK1649-98A SK283105B6 (en) | 1996-05-31 | 1997-05-26 | Stable, non-hygroscopic salts of L(-)carnitine and alkanoyl L(-)carnitines, a process for their preparation and solid orally administrable compositions containing such salts |
| PCT/EP1997/002693 WO1997046512A1 (en) | 1996-05-31 | 1997-05-26 | Stable, non-hygroscopic salts of l(-)carnitine and alkanoyl l(-)carnitines, a process for their preparation and solid, orally administrable compositions containing such salts |
| PT97924007T PT914315E (en) | 1996-05-31 | 1997-05-26 | (-) CARNITINE AND ALCANOYL (-) CARNITINES PROCESS FOR THEIR PREPARATION AND SOLID ADMINISTRABLE COMPOSITIONS ORALLY CONTAINING SUCH SAIs |
| DK97924007T DK0914315T3 (en) | 1996-05-31 | 1997-05-26 | Stable, non-hygroscopic salts of L (-) - carnitine and alkanoyl-L (-) - carnitines, process for preparing such salts and solid compositions containing such salts for oral administration |
| TR1998/02492T TR199802492T2 (en) | 1996-05-31 | 1997-05-26 | Stable non-hygroscopic salts of L(-) carnitine and the alkanol L(-) carnitine, a process for their preparation and solid, oral intake containing such salts possible compounds. |
| EE9800422A EE03604B1 (en) | 1996-05-31 | 1997-05-26 | Stable non-hygroscopic salts of L (-) - carnitine and alkanoyl L (-) - carnitine, process for their preparation and solid oral compositions containing these salts |
| AT97924007T ATE200479T1 (en) | 1996-05-31 | 1997-05-26 | STABLE NON-HYGROSCOPIC SALTS OF L(- )CARNITINE AND ALKANOYL-L(-)CARNITINES, METHOD FOR THE PRODUCTION THEREOF AND SOLID, ORALLY ADMINISTERED COMPOSITIONS CONTAINING THEM |
| DE69704561T DE69704561T2 (en) | 1996-05-31 | 1997-05-26 | STABLE NON-HYGROSCOPIC SALTS OF L (-) CARNITIN AND ALKANOYL-L (-) CARNITINES, A METHOD FOR THE PRODUCTION THEREOF AND SOLID, ORAL-ADDIBLE COMPOSITIONS CONTAINING SUCH SALTS |
| NO19985562A NO323593B1 (en) | 1996-05-31 | 1998-11-27 | Stable, non-hydroscopic salts of L (-) carnitine and alkanoyl-L - (-) carnitines, a process for their preparation, and solid, orally administrable compositions containing such salts |
| IS4914A IS2085B (en) | 1996-05-31 | 1998-11-30 | Continuous, non-persistent salts of L (-) carnitine and alkanoyl L (-) carnitine, a process for preparing them and compositions of solids containing such salts which can be administered orally |
| HK00103735A HK1024463A1 (en) | 1996-05-31 | 2000-06-21 | Stable, non-hygroscopic salts of l(.)carnitine andalkanoyl l(-)carnitines, a process for their prep aration and solid, orally administrable compositions containing such salts. |
| GR20010400820T GR3035969T3 (en) | 1996-05-31 | 2001-05-31 | Stable, non-hygroscopic salts of l(-)carnitine and alkanoyl l(-)carnitines, a process for their preparation and solid, orally administrable compositions containing such salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT96MI001116 IT1283086B1 (en) | 1996-05-31 | 1996-05-31 | New stable and non-hygroscopic mucate(s) of L(-)carnitine and alkanoyl L(-)carnitine(s) - useful for making oral compositions for use as e.g. pharmaceutical compositions, food supplements, health foods, veterinary products and fodders |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| ITMI961116A0 ITMI961116A0 (en) | 1996-05-31 |
| ITMI961116A1 true ITMI961116A1 (en) | 1997-12-01 |
| IT1283086B1 IT1283086B1 (en) | 1998-04-07 |
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| IT96MI001116 IT1283086B1 (en) | 1996-05-31 | 1996-05-31 | New stable and non-hygroscopic mucate(s) of L(-)carnitine and alkanoyl L(-)carnitine(s) - useful for making oral compositions for use as e.g. pharmaceutical compositions, food supplements, health foods, veterinary products and fodders |
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| Country | Link |
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| ITMI961116A0 (en) | 1996-05-31 |
| IT1283086B1 (en) | 1998-04-07 |
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