ITRM20090299A1 - THERAPEUTIC ASSOCIATION FOR THE TREATMENT OF PARKINSON'S DISEASE. - Google Patents
THERAPEUTIC ASSOCIATION FOR THE TREATMENT OF PARKINSON'S DISEASE. Download PDFInfo
- Publication number
- ITRM20090299A1 ITRM20090299A1 IT000299A ITRM20090299A ITRM20090299A1 IT RM20090299 A1 ITRM20090299 A1 IT RM20090299A1 IT 000299 A IT000299 A IT 000299A IT RM20090299 A ITRM20090299 A IT RM20090299A IT RM20090299 A1 ITRM20090299 A1 IT RM20090299A1
- Authority
- IT
- Italy
- Prior art keywords
- caffeine
- disease
- parkinson
- hydroxytryptophan
- htp
- Prior art date
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- A—HUMAN NECESSITIES
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Description
Descrizione dell’invenzione industriale dal titolo: “ASSOCIAZIONE TERAPEUTICA PER IL TRATTAMENTO DELLA MALATTIA DI PARKINSON”; Description of the industrial invention entitled: "THERAPEUTIC ASSOCIATION FOR THE TREATMENT OF PARKINSON'S DISEASE";
Descrizione Description
Campo della invenzione Field of the invention
La presente invenzione riguarda un’associazione farmacologica per migliorare la terapia nella malattia di Parkinson. In particolare, l’invenzione prevede l’utilizzo di caffeina (o altre metilxantine come la teobromina e la teofillina) in combinazione con il 5-idrossitriptofano (5-HTP; in forma racemica, levogira e destrogira, o il precursore triptofano) per la preparazione di un medicamento per il trattamento della malattia di Parkinson in grado di migliorare la terapia attuale. The present invention relates to a pharmacological association to improve therapy in Parkinson's disease. In particular, the invention provides for the use of caffeine (or other methylxanthines such as theobromine and theophylline) in combination with 5-hydroxytryptophan (5-HTP; in racemic, left-handed and right-handed form, or the tryptophan precursor) for the preparation of a medicament for the treatment of Parkinson's disease capable of improving current therapy.
L’invenzione si estende anche ad una formulazione farmaceutica sotto forma di una gomma da masticare. The invention also extends to a pharmaceutical formulation in the form of a chewing gum.
Background della invenzione Background of the invention
La Malattia di Parkinson affligge circa l’1% della popolazione sopra i 60 anni. Parkinson's disease affects about 1% of the population over 60.
Allo stato attuale i principali fattori critici/needs della patologia sono i seguenti: At present, the main critical factors / needs of the disease are the following:
Sintomi primari e sintomi ‘secondari’ Primary symptoms and 'secondary' symptoms
La Malattia di Parkinson si caratterizza con sintomi primari che colpiscono il movimento e altre funzioni. Per quanto riguarda le complicazioni motorie della malattia, i sintomi cardine sono tremore a riposo, rigidita’, rallentamento nei movimenti e instabilita’ posturale. Parkinson's disease is characterized by primary symptoms affecting movement and other functions. As for the motor complications of the disease, the key symptoms are tremor at rest, rigidity, slowing of movement and postural instability.
A questo quadro, si associano altri sintomi, definiti secondari; in particolare i disturbi cognitivi (per esempio demenzia) e i disturbi dell’umore (per esempio depressione). Sono inoltre generalmente presenti affaticamento, sonnolenza diurna, etc. Other symptoms, defined as secondary, are associated with this picture; in particular cognitive disorders (for example dementia) and mood disorders (for example depression). Fatigue, daytime sleepiness, etc. are also generally present.
Terapia Therapy
Non esiste un trattamento specifico che rallenti il decorso della malattia. There is no specific treatment that slows the course of the disease.
La terapia piu’ frequentemente usata e’ di tipo farmacologico che non cura il morbo ma porta ad un miglioramento sintomatologico significativo (1-3). Comunque, il trattamento farmacologico non sempre e’ efficace e comporta notevoli effetti collaterali. In particolare, il trattamento con L-dopa puo’ portare a complicazioni motorie a lungo termine (come discinesie), mentre i dopamino-agonisti possono indurre sonnolenza e allucinazioni. The most frequently used therapy is a pharmacological type that does not cure the disease but leads to a significant symptomatic improvement (1-3). However, drug treatment is not always effective and has significant side effects. In particular, treatment with L-dopa can lead to long-term motor complications (such as dyskinesias), while dopamine agonists can induce drowsiness and hallucinations.
Seppur il morbo di Parkinson non sia considerato fatale, la sua progressione procede inesorabilmente con peggioramenti significativi e con un accorciamento delle aspettative di vita rispetto alla popolazione generale. Detto questo appare evidente come allo stato attuale non sia presente sul mercato una formulazione che possa rallentare il decorso della patologia. Inoltre gli effetti collaterali della terapia esistente sono significativi e vanno spesso a sommarsi al quadro sintomatologico della patologia (si pensi ad esempio alla sonnolenza che oltre a far parte del quadro sintomatologico è spesso un effetto collaterale della terapia con dopamino-agonisti). Although Parkinson's disease is not considered fatal, its progression proceeds inexorably with significant worsening and a shortening of life expectancy compared to the general population. Having said this, it appears evident that at present there is no formulation on the market that can slow down the course of the disease. Furthermore, the side effects of existing therapy are significant and often add up to the symptomatological picture of the pathology (think for example of drowsiness which, in addition to being part of the symptomatological picture, is often a side effect of dopamine agonist therapy).
Riassunto della invenzione Summary of the Invention
Compito della presente invenzione e’ di migliorare la terapia attuale utilizzata nel morbo di Parkinson, con particolare attenzione alla ricerca di nuove associazioni in grado di rallentare il decorso della malattia, migliorare l’efficacia della cura e diminuire gli effetti collaterali. The task of the present invention is to improve the current therapy used in Parkinson's disease, with particular attention to the search for new associations capable of slowing the course of the disease, improving the effectiveness of the treatment and reducing side effects.
A tale scopo la presente invenzione prevede di utilizzare un’associazione che comprende caffeina (o altre metilxantine) e 5-idrossitriptofano. For this purpose, the present invention provides for the use of an association that includes caffeine (or other methylxanthines) and 5-hydroxytryptophan.
La caffeina è la sostanza alcaloide contenuta nei chicchi del caffè. E’ molto simile alla teobromina, la sostanza alcaloide contenuta nel cacao e alla teofillina, l’alcaloide delle foglie di tè. Questi tre alcaloidi, molto diffusi nel mondo vegetale, vengono chiamati xantine perché hanno una struttura molecolare che si può pensare derivata dalla xantina. La caffeina, la teobromina e la teofillina sono xantine legate a gruppi metilici e quindi vengono denominate metil-xantine. La caffeina è 1,3,7-trimetilxantina, la teobromina è 3,7-dimeti-xantina e la teofillina è 1,3-dimeti-xantina. Caffeine is the alkaloid substance contained in coffee beans. It is very similar to theobromine, the alkaloid substance contained in cocoa and to theophylline, the alkaloid of tea leaves. These three alkaloids, very common in the plant world, are called xanthines because they have a molecular structure that can be thought to be derived from xanthine. Caffeine, theobromine and theophylline are xanthines linked to methyl groups and therefore are called methyl-xanthines. Caffeine is 1,3,7-trimethylxanthine, theobromine is 3,7-dimethylxanthine and theophylline is 1,3-dimethylxanthine.
L-5-idrossitriptofano o acido L-a-amino-b-(5-idrossiindolil) propionico, brevemente 5-HTP, deriva dal triptofano, aminoacido essenziale, noto per essere il precursore dell’idrossitriptamina, o serotonina (5-HT); più precisamente il 5-HTP rappresenta lo step intermedio di trasformazione del triptofano in serotonina, trasformazione che avviene a livello intracellulare. L-5-hydroxytryptophan or L-a-amino-b- (5-hydroxyindolyl) propionic acid, briefly 5-HTP, derives from tryptophan, an essential amino acid, known to be the precursor of hydroxytryptamine, or serotonin (5-HT); more precisely, 5-HTP represents the intermediate step of transformation of tryptophan into serotonin, a transformation that occurs at an intracellular level.
Recentemente, la comunita’ scientifica ha mostrato notevole attenzione alla caffeina. L’interesse verso questa sostanza psicotropa dal blando effetto psicostimolante e’ derivato da evidenze scientifiche epidemiologiche che hanno dimostrato una correlazione inversa tra l’uso di caffeina e l’incidenza del morbo di Parkinson (4). Questi dati statistici indicherebbero un potenziale effetto neuroprotettivo della caffeina nei confronti di patologie neurodegenerative come la malattia di Parkinson. Recently, the scientific community has shown considerable attention to caffeine. The interest in this psychotropic substance with a mild psychostimulating effect is derived from epidemiological scientific evidence that has shown an inverse correlation between the use of caffeine and the incidence of Parkinson's disease (4). These statistical data would indicate a potential neuroprotective effect of caffeine against neurodegenerative diseases such as Parkinson's disease.
L’effetto protettivo della caffeina e’ stato evidenziato anche su modelli animali della malattia (5). The protective effect of caffeine has also been highlighted on animal models of the disease (5).
Inoltre, la caffeina esercita un effetto stimolante sull’attivita’ motoria, ed in modelli animali di morbo di Parkinson, essa ha indotto un miglioramento significativo delle funzioni motorie in tale modello. Se inoltre consideriamo l’effetto collaterale della sonnolenza indotto dai farmaci anti-Parkinson, la caffeina potrebbe controbilanciare questo effetto indesiderato. Furthermore, caffeine exerts a stimulating effect on motor activity, and in animal models of Parkinson's disease, it has induced a significant improvement in motor functions in this model. If we also consider the side effect of sleepiness induced by anti-Parkinson drugs, caffeine could counterbalance this undesirable effect.
Invece, il 5-idrossitriptofano e’ stato utilizzato all’inizio nella terapia anti-Parkinson in combinazione con la L-Dopa perche’ aumentava la biodisponibilita’ di quest’ultima inibendo il catabolismo a livello epatico. Successivamente e’ stato evidenziato in modelli animali un aumento dell’attivita’ motoria a seguito di somministrazione di 5-idrossitriptofano (6). Inoltre, tale composto e’ dotato di proprieta’ antidepressive e pertanto potrebbe risultare utile nelle forme di Parkinson dove e’ associata anche la depressione. Instead, 5-hydroxytryptophan was initially used in anti-Parkinson therapy in combination with L-DOPA because it increased the bioavailability of the latter by inhibiting hepatic catabolism. Subsequently, an increase in motor activity was shown in animal models following the administration of 5-hydroxytryptophan (6). Furthermore, this compound has antidepressant properties and therefore could be useful in forms of Parkinson's where depression is also associated.
Alla luce di tali conoscenze, l’interesse degli inventori si è focalizzato sul possibile utilizzo di una associazione caffeina/5-idrossitriptofano, per la preparazione di farmaci da impiegare nel trattamento farmacologico del morbo di Parkinson, con l’obiettivo di migliorare, su diversi aspetti critici, l’attuale terapia anti-Parkinson. In light of this knowledge, the interest of the inventors focused on the possible use of a caffeine / 5-hydroxytryptophan combination, for the preparation of drugs to be used in the pharmacological treatment of Parkinson's disease, with the aim of improving, on different critical aspects, the current anti-Parkinson therapy.
In particolare l’obiettivo primario che gli inventori si sono prefissi è stato quello di supportare la terapia attuale sul problema piu’ grave, cioè il miglioramento delle funzioni motorie che sono quelle maggiormente affette nella malattia di Parkinson (vedi più avanti i risultati sperimentali) In particular, the primary goal that the inventors set for themselves was to support current therapy on the most serious problem, that is, the improvement of motor functions which are those most affected in Parkinson's disease (see the experimental results below)
Secondariamente, e in modo sinergico all’obiettivo primario, con questa associazione si fornisce una risposta agli altri fattori critici (sintomi della patologia ed effetti collaterali delle terapie utilizzate). In particolare ci si pone gli obiettivi secondari di: Secondly, and synergistically with the primary objective, this association provides an answer to the other critical factors (symptoms of the disease and side effects of the therapies used). In particular, the secondary objectives are:
i) migliorare la terapia attuale per quanto riguarda gli effetti collaterali della terapia stessa e i sintomi secondari generalmente associati alla patologia. In particolare: i) improve the current therapy with regard to the side effects of the therapy itself and the secondary symptoms generally associated with the disease. In particular:
controbilanciare la sonnolenza diurna indotta dai dopamino-agonisti, counterbalance the daytime sleepiness induced by dopamine agonists,
migliorare i sintomi depressivi che sono spesso associati nella malattia di Parkinson; e improve the depressive symptoms that are often associated in Parkinson's disease; And
combattere le discinesie da L-Dopa, che è il farmaco maggiormente usato nel Parkinson. Infatti dopo alcuni anni di trattamento con L-Dopa, i pazienti Parkinsoniani sviluppano movimenti involontari incontrollati (le discinesie). Recentemente , un importante gruppo di ricerca svedese (Carta M. et al,2007) ha dimostrato in modelli animali che la causa delle discinesie potrebbe essere la dopamina (che si forma dalla L-Dopa somministrata) che viene rilasciata da cellule nervose serotoninergiche (cellule che normalmente rilasciano serotonina). In questo caso la somministrazione di 5-idrossitriptofano (precursore della serotonina) potrebbe impedire l’accumulo di L-Dopa nelle cellule serotoninergiche, prevenendo l’insorgenza delle discinesie. Questo perché il 5-HTP, (precursore della serotonina) viene normalmente preso dalle cellule serotoninergiche e quindi impedirebbe la captazione di L-dopa, competendo con essa. fight L-Dopa dyskinesias, which is the drug most used in Parkinson's. In fact, after a few years of treatment with L-Dopa, Parkinsonian patients develop uncontrolled involuntary movements (dyskinesias). Recently, an important Swedish research group (Carta M. et al, 2007) demonstrated in animal models that the cause of dyskinesias could be dopamine (which is formed from the administered L-dopa) which is released by serotonergic nerve cells (cells which normally release serotonin). In this case, the administration of 5-hydroxytryptophan (precursor of serotonin) could prevent the accumulation of L-Dopa in serotonergic cells, preventing the onset of dyskinesias. This is because 5-HTP, (precursor of serotonin) is normally taken up by serotonergic cells and therefore would prevent the uptake of L-dopa, competing with it.
ii) influenzare positivamente il decorso della malattia rallentando la neurodegenerazione e il peggioramento del quadro clinico che avviene negli anni susseguenti dalla scoperta del morbo. ii) positively influence the course of the disease by slowing down the neurodegeneration and worsening of the clinical picture that occurs in the years following the discovery of the disease.
Descrizione dettagliata dell’invenzione Detailed description of the invention
Una volta individuata l’associazione, gli inventori hanno proceduto a dimostrare sperimentalmente che tale formulazione caffeina/5HTP ha un effetto addittivo/sinergico sul miglioramento delle funzioni motorie in pazienti affetti dal Morbo di Parkinson. Once the association was identified, the inventors proceeded to experimentally demonstrate that this caffeine / 5HTP formulation has an additive / synergistic effect on improving motor functions in patients with Parkinson's disease.
I risultati di tali esperimenti sono evidenziati dai grafici della figura allegata dove: The results of these experiments are highlighted by the graphs of the attached figure where:
la Fig.1 mostra l’effetto dell’associazione caffeina (15mg/kg)/5-HTP (25mg/kg) sul turning controlaterale (numero di giri) nel modello di ratto trattato con la tossina 6-idrossidopamina (modello animale di morbo di Parkinson). I dati sono indicati come media ± errore standard. Fig. 1 shows the effect of the caffeine (15mg / kg) / 5-HTP (25mg / kg) association on the contralateral turning (number of turns) in the rat model treated with the 6-hydroxydopamine toxin (animal model of disease Parkinson's). Data are shown as mean ± standard error.
E’ stato utilizzato un modello animale di malattia di Parkinson che riproponesse alcuni dei sintomi motori presenti nel morbo (7). In particolare, in tale modello gli animali (ratti) vengono lesionati solo su di un lato del cervello (nell’area cerebrale nigro-striatale) utilizzando la tossina 6-idrossidopamina che distrugge inesorabilmente i neuroni nigro-striatali. Nel modello della 6-idrossidopamina vengono testate sostanze o associazioni per vedere se hanno un effetto anti-Parkinson. In particolare, le sostanze dotate di potenziale attivita’ antiparkinsoniana sono in grado di indurre il cosidetto fenomeno del “turning controlaterale” in questo modello animale. Se la sostanza ha un effetto sulle funzioni motorie, l’animale e’ in grado di fare un movimento girando su se stesso dalla parte opposta rispetto al lato della lesione. An animal model of Parkinson's disease was used that reproduced some of the motor symptoms present in the disease (7). In particular, in this model the animals (rats) are injured only on one side of the brain (in the nigro-striatal cerebral area) using the 6-hydroxydopamine toxin which inexorably destroys the nigro-striatal neurons. In the 6-hydroxydopamine model, substances or combinations are tested to see if they have an anti-Parkinson effect. In particular, substances with potential antiparkinsonian activity are able to induce the so-called phenomenon of "contralateral turning" in this animal model. If the substance has an effect on motor functions, the animal is able to make a movement by turning on itself on the opposite side with respect to the side of the lesion.
Sono stati eseguiti esperimenti iniziali a diverso dosaggio di caffeina e 5-HTP per trovare le condizioni da utilizzare nell’esperimento dell’associazione. La caffeina ha iniziato ad essere efficace in questo modello animale di Parkinson alla dose di 15mg/kg e questa e’ stata la dose utilizzata nell’esperimento di associazione. Invece il 5-HTP non ha indotto nessun effetto fino alla dose di 100mg/kg. L’esperimento di associazione caffeina/5-HTP e’ stato fatto alle dosi di caffeina di 15mg/kg e di 5-HTP di 25mg/kg Come controllo sono state utilizzate le due sostanze da sole allo stesso dosaggio. In questo esperimento sono stati impiegati circa 30 animali, 10 per esperimento. L’associazione caffeina/5HTP ha evidenziato un potenziamento sugli effetti motori rispetto a caffeina e 5-HTP da soli. In particolare, come si puo’ notare dalla figura 1, la caffeina ha prodotto 4 giri controlaterali, il 5HTP non ha prodotto alcun effetto, mentre l’associazione ha prodotto 6 giri controlaterali inducendo un potenziamento del 50%. Tale indicazione scientifica sull’associazione caffeina/5HTP suggerisce che tale combinazione puo’ portare ad un miglioramento nella terapia farmacologica della malattia di Parkinson. Initial experiments were performed at different dosages of caffeine and 5-HTP to find the conditions to be used in the association experiment. Caffeine began to be effective in this animal model of Parkinson's at a dose of 15mg / kg and this was the dose used in the association experiment. On the other hand, 5-HTP did not induce any effect up to the dose of 100mg / kg. The caffeine / 5-HTP association experiment was carried out at caffeine doses of 15mg / kg and 5-HTP of 25mg / kg As a control, the two substances were used alone at the same dosage. About 30 animals were used in this experiment, 10 per experiment. The caffeine / 5HTP association has shown an enhancement on motor effects compared to caffeine and 5-HTP alone. In particular, as can be seen from figure 1, caffeine produced 4 contralateral turns, 5HTP did not produce any effect, while the association produced 6 contralateral turns inducing a 50% enhancement. This scientific indication on the caffeine / 5HTP association suggests that this combination can lead to an improvement in the drug therapy of Parkinson's disease.
Secondo la presente invenzione, si rivendica pertanto l’utilizzo in combinazione dei due principi attivi caffeina e 5 idrossitriptofano per la preparazione di un medicamento per la cura e prevenzione della Malattia di Parkinson, dove detti principi attivi caffeina e 5 idrossitriptofano sono presenti in un rapporto in peso fra loro compreso tra 1:1,5 e 1:3. Vantaggiosamente, le quantità della caffeina sono comprese nel range da 15mg a 165 mg e quelle del 5 idrossitriptofano nel range da 15 mg a 300mg. According to the present invention, the use in combination of the two active ingredients caffeine and 5 hydroxytryptophan is therefore claimed for the preparation of a medicament for the treatment and prevention of Parkinson's disease, where said active ingredients caffeine and 5 hydroxytryptophan are present in a ratio by weight between them between 1: 1.5 and 1: 3. Advantageously, the quantities of caffeine are included in the range from 15mg to 165 mg and those of 5 hydroxytryptophan in the range from 15mg to 300mg.
Di preferenza il dosaggio ottimale dell’associazione nella forma tecnica di una compressa, prevede caffeina in misura di 16 mg e 5 idrossitriptofano in misura di 50 mg per compressa. Vengono illustrate qui di seguito anche compresse dove il rapporto caffeina/triptofano è raddoppiato arrivando a 32 mg di caffeina e 100 mg di 5 idrossitriptofano per compressa. Preferably, the optimal dosage of the combination in the technical form of a tablet, provides caffeine in the measure of 16 mg and 5 hydroxytryptophan in the measure of 50 mg per tablet. Also illustrated below are tablets where the caffeine / tryptophan ratio has doubled to 32 mg of caffeine and 100 mg of 5 hydroxytryptophan per tablet.
Altre formulazioni per somministrazioni in gomme da masticare, in sciroppo, in gel e spray con rapporti caffeina/triptofano di 16/50 e 32/100, verranno più avanti indicate a titolo illustrativo. Other formulations for administration in chewing gum, in syrup, in gel and spray with caffeine / tryptophan ratios of 16/50 and 32/100, will be indicated below by way of illustration.
Forme farmaceutiche e dosaggi dell’associazione in oggetto Di seguito si riporta il razionale della forma farmaceutica che si ritiene di particolare valore aggiunto nel paziente con malattia di Parkinson: Pharmaceutical forms and dosages of the association in question Below is the rationale for the pharmaceutical form which is considered to be of particular added value in patients with Parkinson's disease:
-Chewing gums: formulazione particolarmente indicata nella Malattia di Parkinson, in quanto oltre a garantire il raggiungimento dell’obiettivo primario (miglioramento funzioni motorie) permette, sinergizzando con la masticazione, di innalzare la soglia dell’attenzione, fornendo una risposta mirata alla problematica frequente della sonnolenza diurna (sintomo secondario della malattia ed effetto collaterale della terapia con dopaminoagonisti). - Chewing gums: formulation particularly indicated in Parkinson's disease, as in addition to guaranteeing the achievement of the primary objective (improvement of motor functions), it allows, by synergizing with chewing, to raise the attention threshold, providing a targeted response to frequent problems daytime sleepiness (secondary symptom of the disease and side effect of dopamine agonist therapy).
La formulazione in chewing gums è caratterizzata dall’aggiunta di eccipienti caratterizzati da un’azione di enhancer (es. vitamina E) e da una tecnica di ‘mascheramento’ del gusto amaro della caffeina. The chewing gums formulation is characterized by the addition of excipients characterized by an enhancer action (eg vitamin E) and a 'masking' technique of the bitter taste of caffeine.
Una preferita formulazione di chewing gum sostanzialmente consiste di: A preferred chewing gum formulation basically consists of:
- una base di gomma insolubile all’acqua; - a water insoluble rubber base;
- una porzione solubile all’acqua - a water-soluble portion
- aromi. - aromas.
La porzione solubile all’acqua si scioglie con una parte dell’aroma della gomma in un periodo di tempo durante la masticazione. The water-soluble portion dissolves with part of the aroma of the gum over a period of time during chewing.
Per lavorare con la base di gomma e miscelare in essa altri ingredienti, il materiale deve essere prima ammorbidito. To work with the rubber base and mix other ingredients in it, the material must first be softened.
Una volta che la base di gomma è resa pieghevole, gli altri ingredienti: Once the gum base is made pliable, the other ingredients:
- 5 idrossitriptofano - 5 hydroxytryptophan
- caffeina, - caffeine,
- trealosio, - trehalose,
- xilitolo (altri zuccheri come saccarosio, destrosio, maltosio, destrina, zucchero invertito essiccato, fruttosio, levulosio, galattosio, sciroppo di frumento, corn syrup or alcooli di zucchero come sorbitolo, mannitolo), - xylitol (other sugars such as sucrose, dextrose, maltose, dextrin, dried invert sugar, fructose, levulose, galactose, wheat syrup, corn syrup or sugar alcohols such as sorbitol, mannitol),
- aromi, - aromas,
- Estratti di Stevia e/o dolcificanti molto intensi (taumatina, diidrocalconi, acesulfame potassico, aspartame, sucralosio, alitame, saccarina, ciclamati e altri additivi, per esempio polioli e glicerina, enhancers buccali) vengono addizionati in essa e miscelati. - Stevia extracts and / or very intense sweeteners (thaumatin, dihydrocalcones, acesulfame potassium, aspartame, sucralose, halitame, saccharin, cyclamates and other additives, for example polyols and glycerin, buccal enhancers) are added to it and mixed.
Dopo miscelazione, la gomma si raffredda leggermente prima dell’estrusione in diverse forme. Poi la gomma viene condizionata e stagionata sotto temperatura e umidità controllate. After mixing, the rubber cools slightly before extrusion in different shapes. Then the rubber is conditioned and cured under controlled temperature and humidity.
La base di gomma insolubile generalmente comprende: elastomeri, resine, grassi ed olii, cere, ammorbidenti e riempitivi inorganici. The insoluble rubber base generally includes: elastomers, resins, greases and oils, waxes, softeners and inorganic fillers.
Gli elastomeri possono comprendere poliisobutilene, isobutilene-isoprene copolimero e gomma stirene butadiene, come pure lattici naturali come il chicle. Le resine includono resine polivinil-acetato e terpene. Grassi e olii possono anche essere inclusi nella base di gomma, compresi sego, oli vegetali idrogenati e parzialmente idrogenati e burro di cacao. The elastomers may include polyisobutylene, isobutylene-isoprene copolymer and styrene butadiene rubber, as well as natural latexes such as chicle. Resins include polyvinyl acetate and terpene resins. Fats and oils can also be included in the gum base, including tallow, hydrogenated and partially hydrogenated vegetable oils, and cocoa butter.
Cere comunemente impiegate comprendono paraffina, e cere micro-crystalline e naturali come cera d’api e cera carnauba. Commonly used waxes include paraffin, and micro-crystalline and natural waxes such as beeswax and carnauba wax.
La base di gomma insolubile costituisce da circa il 5% a circa il 95% in peso della gomma. The insoluble rubber base constitutes about 5% to about 95% by weight of the rubber.
La base di gomma comprende anche un componente di riempimento. Il componente di riempimento può essere: carbonato di calcio, carbonato di magnesio, talco, dicalcio fosfato o pirofosfato di sodio(SPP),e pirofosfato acido di sodio (SAPP). The rubber base also includes a filler component. The filling component can be: calcium carbonate, magnesium carbonate, talc, dicalcium phosphate or sodium pyrophosphate (SPP), and sodium acid pyrophosphate (SAPP).
Il riempitivo può costituire fra circa il 5% e circa il 60% in peso della base di gomma. The filler may comprise between about 5% and about 60% by weight of the rubber base.
Le basi di gomma contengono anche ammorbidenti compresi glicerol monostearato e triacetina. Rubber bases also contain softeners including glycerol monostearate and triacetin.
Inoltre, basi di gomma possono anche contenere ingredienti opzionali come antiossidanti, ascorbil palmitato, etc., colori, ed emulsificanti (polisorbato 60, polisorbato 80). Furthermore, rubber bases may also contain optional ingredients such as antioxidants, ascorbyl palmitate, etc., colors, and emulsifiers (polysorbate 60, polysorbate 80).
La presente invenzione prevede comunque l’impiego di ogni base di gomma commercialmente accettabile. However, the present invention provides for the use of any commercially acceptable rubber base.
La parte solubile in acqua della gomma da masticare può ulteriormente comprendere: ammorbidenti come la lecitina, in particolare lisofosfatidilcoolina, lisofosfatidil etanolamina, glicerine dolcificanti, agenti aromatizzanti, e combinazioni di questi, enhancers buccali (vedi Tabella 1 sopra riportata). Ammorbidenti sono aggiunti alla gomma da masticare allo scopo di ottimizzare la capacità masticatoria e la sensazione in bocca della gomma. Gli ammorbidenti, anche conosciuti nel settore come plastificanti o agenti di plastificazione, generalmente costituiscono fra circa lo 0.5% e circa il 15% in peso della gomma da masticare. The water-soluble portion of chewing gum may further include: softeners such as lecithin, in particular lysophosphatidylcooline, lysophosphatidyl ethanolamine, sweetening glycerine, flavoring agents, and combinations thereof, buccal enhancers (see Table 1 above). Softeners are added to chewing gum in order to optimize the chewing ability and mouthfeel of the gum. Softeners, also known in the art as plasticizers or plasticizing agents, generally make up between about 0.5% and about 15% by weight of the chewing gum.
ESEMPI DI FORMULAZIONE EXAMPLES OF FORMULATION
SOMMINISTRAZIONE NASALE IN SPRAY NASAL ADMINISTRATION IN SPRAY
Presentiamo due formulazioni in polvere per la somministrazione nasale tramite un insufflatore meccanico Il preparato deve essere in forma amorfa particellare con un range da 2-20 micron e una distribuzione gaussiana molto ristretta. We present two powder formulations for nasal administration via a mechanical insufflator. The preparation must be in particle amorphous form with a range of 2-20 microns and a very narrow Gaussian distribution.
A) Rapporto caffeina/ triptofano 16/50 A) Caffeine / tryptophan ratio 16/50
Prima narice First nostril
Ingredienti %p/p Ingredients% w / w
Caffeina 8 8 mg per puff Caffeine 8 8 mg per puff
5 idrossitriptofano 25 25 mg per puff Idrossipropilcellulosa 0,5 0,5 mg per puff Mannitolo 66,5 66,5 mg per puff Seconda narice 5 hydroxytryptophan 25 25 mg per puff Hydroxypropylcellulose 0.5 0.5 mg per puff Mannitol 66.5 66.5 mg per puff Second nostril
Ingredienti %p/p Ingredients% w / w
Caffeina 8 8 mg per puff 5idrossitriptofano 25 25 mg per puff Idrossipropilcellulosa 0,5 0,5 mg per puff Mannitolo 66,5 66,5 mg per puff Totale somministrazione Caffeine 8 8 mg per puff 5 hydroxytryptophan 25 25 mg per puff Hydroxypropylcellulose 0.5 0.5 mg per puff Mannitol 66.5 66.5 mg per puff Total administration
Ingredienti Ingredients
Caffeina 16 mg Caffeine 16 mg
5 idrossitriptofano 50 mg 5 hydroxytryptophan 50 mg
Idrossipropilcellulosa 1 mg Hydroxypropylcellulose 1 mg
Mannitolo 133mg Mannitol 133mg
Insufflatore nasale: ogni puff da 100 mg Nasal insufflator: each 100 mg puff
B) Rapporto caffeina/ triptofano 32/100 B) Caffeine / tryptophan ratio 32/100
Una narice One nostril
Ingredienti %p/p Ingredients% w / w
Caffeina 16 16 mg per puff Caffeine 16 16 mg per puff
% idrossitriptofano 50 50 mg per puff Idrossipropilcellulosa 0,5 0,5 mg per puff Mannitolo 33,5 33,5 mg per puff % hydroxytryptophan 50 50 mg per puff Hydroxypropylcellulose 0.5 0.5 mg per puff Mannitol 33.5 33.5 mg per puff
Seconda narice Second nostril
Ingredienti %p/p Ingredients% w / w
Caffeina 16 16 mg per puff Caffeine 16 16 mg per puff
5 idrossitriptofano 50 50 mg per puff Idrossipropilcellulosa 0,5 0,5 mg per puff Mannitolo 33,5 33,5 mg per puff 5 hydroxytryptophan 50 50 mg per puff Hydroxypropylcellulose 0.5 0.5 mg per puff Mannitol 33.5 33.5 mg per puff
Totale somministrazione Total administration
Ingredienti Ingredients
Caffeina 32 mg Caffeine 32 mg
5 idrossitriptofano 100 mg Idrossipropilcellulosa 1 mg 5 hydroxytryptophan 100 mg Hydroxypropylcellulose 1 mg
Mannitolo 67mg Mannitol 67mg
Insufflatore nasale: ogni puff da 100 mg Nasal insufflator: each 100 mg puff
- -
SOMMINISTRAZIONE IN COMPRESSE DA 200 MG CIASCUNA ADMINISTRATION IN TABLETS OF 200 MG EACH
C) Rapporto caffeina/ triptofano 16/50 C) Caffeine / tryptophan ratio 16/50
Ingredienti per compressa %p/p mg per compressa Caffeina 8 16 5idrossitriptofano 25 50 Ingredients per tablet% w / w mg per tablet Caffeine 8 16 5 hydroxytryptophan 25 50
Cellulosa microgranulare 5 10 Polivinilpirrolidone 0,5 1 Microgranular cellulose 5 10 Polyvinylpyrrolidone 0.5 1
Amido 33,5 67 Starch 33.5 67
Magnesio stearato 0,5 1 Magnesium stearate 0.5 1
Talco 25 50 Talc 25 50
Silice precipitata 2,5 5 Precipitated silica 2.5 5
Peso totale 200 Total weight 200
SOMMINISTRAZIONE in compresse da 216 mg ciascuna ADMINISTRATION in tablets of 216 mg each
D) Rapporto caffeina/ triptofano 32/100 D) Caffeine / tryptophan ratio 32/100
Ingredienti per compressa %p/p mg per compressa Caffeina 14,8 32 5idrossitriptofano 46,29 100 Cellulosa microgranulare 4,6 10 Polivinilpirrolidone 0,46 1 Ingredients per tablet% w / w mg per tablet Caffeine 14.8 32 5hydroxytryptophan 46.29 100 Microgranular cellulose 4.6 10 Polyvinylpyrrolidone 0.46 1
Amido 31,0 67 Starch 31.0 67
Magnesio stearato 0,46 1 Magnesium stearate 0.46 1
Silice precipitata 2,3 5 Precipitated silica 2.3 5
Peso totale 216 Total weight 216
SOMMINISTRAZIONE in sciroppo – dose per 10 ml ADMINISTRATION in syrup - dose for 10 ml
E) Rapporto caffeina/ triptofano 16/50 Ingredienti %p/p mg per 10 ml Caffeina 0,16 16 E) Caffeine / tryptophan ratio 16/50 Ingredients% w / w mg per 10 ml Caffeine 0.16 16
5 idrossitriptofano 0,5 50 Idrossipropilcellulosa 0,5 5 5 hydroxytryptophan 0.5 50 Hydroxypropylcellulose 0.5 5
PVP K90 0,2 20 PVP K90 0.2 20
Aroma Aroma
Tampone fosfato pH 5,5-6,5 Phosphate buffer pH 5.5-6.5
Acqua depurata Qb a 100 gr - Purified water Qb 100 gr -
SOMMINISTRAZIONE in gel – dose per 10 ml ADMINISTRATION in gel - dose for 10 ml
F) Rapporto caffeina/ triptofano 16/50 Ingredienti %p/p mg per 10 ml Caffeina 0,16 16 F) Caffeine / tryptophan ratio 16/50 Ingredients% w / w mg per 10 ml Caffeine 0.16 16
5 idrossitriptofano 0,5 50 Alginato di sodio 1 100 Carbopol 0,2 20 Ipromellosa 0,5 50 5 hydroxytryptophan 0.5 50 Sodium alginate 1 100 Carbopol 0.2 20 Hypromellose 0.5 50
Aroma Qb Tampone fosfato pH 5,5-6,5 Aroma Qb Phosphate buffer pH 5.5-6.5
Acqua depurata Qb a 100 gr Purified water Qb 100 gr
G) Rapporto caffeina/ triptofano 32/100 Ingredienti %p/p mg per 10 ml Caffeina 0,32 32 G) Caffeine / tryptophan ratio 32/100 Ingredients% w / w mg per 10 ml Caffeine 0.32 32
5 idrossitriptofano 1 100 Alginato di sodio 1 100 Carbopol 0,2 20 Ipromellosa 0,5 50 5 hydroxytryptophan 1 100 Sodium alginate 1 100 Carbopol 0.2 20 Hypromellose 0.5 50
Aroma Qb Tampone fosfato pH 5,5-6,5 Aroma Qb Phosphate buffer pH 5.5-6.5
Acqua depurata Qb a 100 gr - Purified water Qb 100 gr -
SOMMINISTRAZIONE in gomme (ciascun pacchetto di gomme contiene 5 gomme) ADMINISTRATION in tires (each packet of tires contains 5 tires)
H) Rapporto caffeina/ triptofano 16/50 H) Caffeine / tryptophan ratio 16/50
Ogni gomma pesa 2 grammi Each tire weighs 2 grams
Ingredienti A Ingredients A
% mg/striscia “Caffeina ” 0,8 16 L5-idrossitriptofano 2,5 50 Xilitolo 6.25 125 % mg / strip "Caffeine" 0.8 16 L5-hydroxytryptophan 2.5 50 Xylitol 6.25 125
Altro zucchero alcool 48.37 967.5 Other sugar alcohol 48.37 967.5
di zucchero of sugar
Base di gomma 34 680 Glicerina 1.75 35 Lecitina liquida 0.15 3.75 Lisolecitina 0.187 1.25 Rubber base 34 680 Glycerin 1.75 35 Liquid lecithin 0.15 3.75 Lysolecithin 0.187 1.25
Menta 1.125 22.5 Mint 1.125 22.5
Peso totale mg 2000 Total weight 2000 mg
I) Rapporto caffeina/ triptofano 32/100 I) Caffeine / tryptophan ratio 32/100
Ingredienti A1 A1 ingredients
% mg/striscia “Caffeina ” 1,6 32 % mg / strip "Caffeine" 1.6 32
L5-idrossitriptofano 5,0 100 Xilitolo 6.25 125 L5-hydroxytryptophan 5.0 100 Xylitol 6.25 125
Altro zucchero alcool 48.37 901.5 Other sugar alcohol 48.37 901.5
di zucchero of sugar
Base di gomma 34 680 Glicerina 1.75 35 Lecitina liquida 0.15 3.75 Lisolecitina 0.187 1.25 Rubber base 34 680 Glycerin 1.75 35 Liquid lecithin 0.15 3.75 Lysolecithin 0.187 1.25
Menta 1.125 22.5 Mint 1.125 22.5
Peso totale mg 2000 Total weight 2000 mg
Somministrazione in gomme con aggiunta di vitamina E Administration in gums with the addition of vitamin E
L) Rapporto caffeina/ triptofano 16/50 L) Caffeine / tryptophan ratio 16/50
Ingredienti B Ingredients B
% mg/striscia “Massa fusa di Vitamina E 1,6 32 mg pari a 16 mg di TPGS e Caffeina” caffeina % mg / strip "Molten mass of Vitamin E 1.6 32 mg equal to 16 mg of TPGS and Caffeine" caffeine
L 5-idrossitriptofano 3.25 50 Xilitolo 6.25 125 Altro zucchero, zucchero 43.35 1050.5 di alcool L 5-hydroxytryptophan 3.25 50 Xylitol 6.25 125 Other sugar, sugar 43.35 1050.5 alcohol
Base di gomma 34 680 Glicerina 1.75 35 Lecitina liquida 0.15 3.75 Lisolecitina 0.187 1.25 Menta 1.125 22.5 Rubber base 34 680 Glycerin 1.75 35 Liquid lecithin 0.15 3.75 Lysolecithin 0.187 1.25 Mint 1.125 22.5
M) Rapporto caffeina/ triptofano 32/100 M) Caffeine / tryptophan ratio 32/100
Ingredienti B1 Ingredients B1
% mg/striscia “Massa fusa di Vitamina E 3,2 64 mg pari a 32 mg di TPGS e Caffeina ” caffeina % mg / strip "Molten mass of Vitamin E 3.2 64 mg equal to 32 mg of TPGS and Caffeine" caffeine
L 5-idrossitriptofano 6,5 100 L 5-hydroxytryptophan 6.5 100
Xilitolo 6.25 125 Xylitol 6.25 125
Altro zucchero, alcool di 43.35 968.5 Other sugar, alcohol of 43.35 968.5
zucchero sugar
Base di gomma 34 680 Rubber base 34 680
Glicerina 1.75 35 Glycerin 1.75 35
Lecitina liquida 0.15 3.75 Liquid lecithin 0.15 3.75
Lisolecitina 0.187 1.25 Lysolecithin 0.187 1.25
Menta 1.125 22.5 Mint 1.125 22.5
Peso totale mg 2000 Total weight 2000 mg
La massa fusa di Vitamina E TPGS/caffeina indicata fra gli ingredienti delle ultime due formulazioni viene ottenuta come segue: The melt of Vitamin E TPGS / caffeine indicated among the ingredients of the last two formulations is obtained as follows:
Massa fusa di Vitamina E TPGS/caffeina Melted mass of Vitamin E TPGS / caffeine
Vitamina E TPGS e caffeina (o i suoi sali) sono miscelate a caldo (40-45 °C) nel rapporto 1:1 fino a fondere completamente la vitamina E TPGS, formando una massa fusa di Vit.E TPGS/caffeina. La massa fusa è poi raffreddata sino alla formazione di una massa solida. Vitamin E TPGS and caffeine (or its salts) are mixed hot (40-45 ° C) in the ratio 1: 1 until the vitamin E TPGS is completely melted, forming a melt of Vit.E TPGS / caffeine. The melt is then cooled until a solid mass is formed.
In alternativa alle formulazioni sopra riportate, gli inventori hanno sperimentato anche la possibilità di utilizzare, invece dei due principi attivi puri, ottenuti per sintesi, due fitoterapici con titolo noto di caffeina e 5-HTP. A titolo esemplificativo e non già limitativo citiamo qui la Coffe Arabica, titolata in caffeina (la parte secca ne contiene mediamente il 12 per mille) e la Griffona Simplicifolia, titolata in L-5-idrossitriptofano (l’estratto secco si trova generalmente titolato al 20% di 5-HTP, ma esistono anche forme con maggiore concentrazione, sino al 97,98%). Questo consente di somministrare ai pazienti solo dei prodotti naturali di libero impiego, che vengono utilizzati comunemente nei prodotti erboristici disponibili oggi sul mercato. As an alternative to the formulations reported above, the inventors have also experimented with the possibility of using, instead of the two pure active ingredients, obtained by synthesis, two phytotherapics with a known title of caffeine and 5-HTP. By way of non-limiting example, we mention here Coffe Arabica, titrated in caffeine (the dry part contains on average 12 per thousand) and Griffona Simplicifolia, titrated in L-5-hydroxytryptophan (the dry extract is generally titrated to 20% of 5-HTP, but there are also forms with higher concentration, up to 97.98%). This allows patients to be administered only natural products for free use, which are commonly used in herbal products available on the market today.
Si sono qui descritte alcune forme realizzative della presente invenzione. E’ peraltro evidente che numerose altre formulazioni possono essere utilizzate senza uscire dall’ambito della presente invenzione come definito dalle rivendicazioni che seguono. Some embodiments of the present invention have been described here. It is also clear that numerous other formulations can be used without departing from the scope of the present invention as defined by the following claims.
Bibliografia Bibliography
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US20050249827A1 (en) * | 2004-04-30 | 2005-11-10 | Gardiner Paul T | Nutritional composition which promotes weight loss, burns calories, increases thermogenesis, supports energy metabolism and/or suppresses appetite |
US20060193795A1 (en) * | 2005-02-25 | 2006-08-31 | Arthur Zuckerman | Appetite suppressant mouth spray |
US20070116779A1 (en) * | 2005-11-23 | 2007-05-24 | Elizabeth Mazzio | Comprehensive nutraceutical agent for treatment/ prevention of Parkinson's disease |
WO2007065595A2 (en) * | 2005-12-07 | 2007-06-14 | Ucb Pharma, S.A. | Xanthine derivatives, processes for preparing them and their uses |
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US5698525A (en) * | 1989-04-03 | 1997-12-16 | Interneuron Pharmaceuticals, Inc. | Reducing post-prandial fluctuations in plasma concentrations of large neutral amino acids (LNAA) |
WO1999008681A1 (en) * | 1997-08-13 | 1999-02-25 | Nutracorp Scientific, Inc. | Inducing neurotransmitter and neuropeptide activity |
US20050249827A1 (en) * | 2004-04-30 | 2005-11-10 | Gardiner Paul T | Nutritional composition which promotes weight loss, burns calories, increases thermogenesis, supports energy metabolism and/or suppresses appetite |
WO2005107779A2 (en) * | 2004-04-30 | 2005-11-17 | New Hc Formulations Ltd. | Weight loss composition and method of inducing weight loss |
US20060193795A1 (en) * | 2005-02-25 | 2006-08-31 | Arthur Zuckerman | Appetite suppressant mouth spray |
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