IT201900019775A1 - LIPOSOMIAL NUTRACEUTICAL COMPOSITION - Google Patents
LIPOSOMIAL NUTRACEUTICAL COMPOSITION Download PDFInfo
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- IT201900019775A1 IT201900019775A1 IT102019000019775A IT201900019775A IT201900019775A1 IT 201900019775 A1 IT201900019775 A1 IT 201900019775A1 IT 102019000019775 A IT102019000019775 A IT 102019000019775A IT 201900019775 A IT201900019775 A IT 201900019775A IT 201900019775 A1 IT201900019775 A1 IT 201900019775A1
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Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/16—Inorganic salts, minerals or trace elements
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
- A23L29/294—Inorganic additives, e.g. silica
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/15—Vitamins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Mycology (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Inorganic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Descrizione dell’invenzione avente per titolo: Description of the invention entitled:
“COMPOSIZIONE NUTRACEUTICA LIPOSOMIALE” "LIPOSOMIAL NUTRACEUTICAL COMPOSITION"
Descrizione Description
Campo della tecnica Field of technique
La presente descrizione si riferisce al settore nutraceutico. Più in dettaglio la presente invenzione si riferisce si riferisce ad una peculiare formulazione liposomiale che consiste in una formulazione liquida oleosa e non acquosa che presenta il vantaggio di risultare particolarmente stabile anche dopo intervalli di tempo relativamente lunghi. Il tutto offrendo la possibilità di somministrare la detta composizione a tutti quei soggetti per i quali l’assunzione di formulazioni solide risulta inadeguata. The present description refers to the nutraceutical sector. More in detail, the present invention refers to a particular liposomal formulation which consists of an oily and non-aqueous liquid formulation which has the advantage of being particularly stable even after relatively long time intervals. All this by offering the possibility of administering the said composition to all those subjects for whom the intake of solid formulations is inadequate.
Arte nota Known art
I liposomi sono strutture vescicolari chiuse con dimensioni che variano dai 20 nm ai 25 nm fino ad arrivare ai 25µm. Presentano una struttura molto simile a quella delle membrane cellulari e si caratterizzano per il fatto che tale membrana presenta uno o più strati di lipidi anfifilici che delimitano un core idrofilo in cui si trova materiale in fase acquosa. La fase acquosa, inoltre, è presente anche all’esterno dei liposomi. Liposomes are closed vesicular structures with dimensions ranging from 20 nm to 25 nm up to 25µm. They have a structure very similar to that of cell membranes and are characterized by the fact that this membrane has one or more layers of amphiphilic lipids that delimit a hydrophilic core containing material in the aqueous phase. Furthermore, the aqueous phase is also present outside the liposomes.
La loro scoperta risale ai primi anni ‘60 da parte dell’ematologo inglese Alec Bangham durante la sperimentazione di un microscopio elettronico eseguita assieme al collega R.W. Horne. Questa scoperta ha suscitato sin da subito un interesse elevato, soprattutto in campo medico-farmaceutico. Difatti fin dagli anni ‘70 i liposomi sono stati utilizzati, in forma sperimentale, come veicoli dei farmaci. Successivamente la loro struttura è stata perfezionata al fine di aumentare la loro performance come agenti veicolanti di principi farmaceutici. Da un punto di vista strutturale gli strati anfifilici sono formati perlopiù da molecole fosfolipidiche: quelle dello strato più esterno sono regolarmente affiancate tra loro ed espongono la propria testa polare (porzione idrofila della molecola) verso l’ambiente acquoso che le circonda; la coda apolare (porzione idrofobica della molecola) è invece rivolta verso l’interno, dove si intreccia con quella del secondo strato lipidico, che ha un’organizzazione speculare alla precedente. Nello strato fosfolipidico interno, infatti, le teste polari sono rivolte verso l’ambiente acquoso contenuto nella cavità del liposoma. Their discovery dates back to the early 1960s by the English hematologist Alec Bangham during the experimentation of an electron microscope performed together with his colleague R.W. Horne. This discovery immediately aroused high interest, especially in the medical-pharmaceutical field. In fact, since the 1970s, liposomes have been used, in an experimental form, as vehicles for drugs. Subsequently their structure was perfected in order to increase their performance as carriers of pharmaceutical principles. From a structural point of view, the amphiphilic layers are mostly made up of phospholipid molecules: those of the outermost layer are regularly placed side by side and expose their polar head (hydrophilic portion of the molecule) to the aqueous environment that surrounds them; the apolar tail (hydrophobic portion of the molecule) is instead facing inwards, where it intertwines with that of the second lipid layer, which has a mirror organization to the previous one. In the internal phospholipid layer, in fact, the polar heads are turned towards the aqueous environment contained in the liposome cavity.
Grazie a questa loro particolare struttura, i liposomi possono rimanere immersi in una fase acquosa ospitando contemporaneamente al loro interno un contenuto acquoso nel quale possono essere dispersi principi attivi o altre molecole. Thanks to this particular structure, the liposomes can remain immersed in an aqueous phase, simultaneously hosting an aqueous content in which active ingredients or other molecules can be dispersed.
Nel contempo ‒ proprio grazie al doppio strato fosfolipidico ‒ viene impedita l’entrata e l’uscita di molecole d’acqua o comunque di molecole polari, isolando di fatto il contenuto del liposoma (che non può essere modificato dall’entrata o dall’uscita di acqua o soluti polari). At the same time - thanks to the phospholipid double layer - the entry and exit of water molecules or in any case of polar molecules is prevented, effectively isolating the content of the liposome (which cannot be modified by the entry or exit of water or polar solutes).
Come sopra accennato sono vettori che possono essere utilizzati per il rilascio controllato di differenti tipi di molecole attive e, grazie alle loro peculiari caratteristiche, trovano largo impiego in diversi campi di applicazione come quello farmaceutico, medico, nutraceutico, cosmeceutico. In campo medico, i liposomi sono utilizzati per il rilascio controllato di farmaci in modo da garantire una corretta perfomance dei principi attivi in essi accolti e opportunamente rilasciati in prossimità di tessuti e cellule bersaglio. Nel settore alimentare i liposomi hanno un grande potenziale come materiali “contenitori” per preservare molti ingredienti bioattivi, inclusi i composti che sono poco solubili in acqua, vitamine, proteine, peptidi, etc. Lo sviluppo di liposomi intelligenti con specifiche caratteristiche (in termini di dimensione, carica, capacità di carico, capacità di rispondere agli stimoli) per la biodisponibilità di farmaci e prodotti nutraceutici è essenziale per lo sviluppo di nuove strategie terapeutiche, come l’utilizzo di farmaci a base di acidi nucleici (NABDs) nella terapia genica, nonché per la produzione di nuove formulazioni per la sicurezza alimentare. Possono essere classificati sulla base della loro composizione e dimensione. As mentioned above, they are vectors that can be used for the controlled release of different types of active molecules and, thanks to their peculiar characteristics, they are widely used in various fields of application such as pharmaceutical, medical, nutraceutical, cosmeceutical. In the medical field, liposomes are used for the controlled release of drugs in order to guarantee a correct performance of the active ingredients they contain and appropriately released in the vicinity of target tissues and cells. In the food sector, liposomes have great potential as "container" materials to preserve many bioactive ingredients, including compounds that are poorly soluble in water, vitamins, proteins, peptides, etc. The development of intelligent liposomes with specific characteristics (in terms of size, charge, carrying capacity, ability to respond to stimuli) for the bioavailability of drugs and nutraceuticals is essential for the development of new therapeutic strategies, such as the use of drugs based on nucleic acids (NABDs) in gene therapy, as well as for the production of new formulations for food safety. They can be classified on the basis of their composition and size.
Sulla base della loro composizione vengono distinti in convenzionali, invisibili, cationici, mirati e liposomi che rispondo agli stimoli. Sulla base della dimensione possono essere classificati in vescicole multi lamellari (MLVs), Vescicole grandi Unilamellari (LUVs) e Vescicole Piccole Unilamellari (SUVs). Micro e nano liposomi sono sistemi altamente biocompatibili e biodegradabili che, grazie alla loro bassa tossicità e immunogenicità e alla loro capacità di incorporare farmaci idrofilici e idrofobici, sono candidati ideali per il rilascio controllato di diversi tipi di molecole attive per applicazioni farmaceutiche e nutraceutiche. Inoltre, la loro somiglianza con le membrane biologiche e la possibilità di funzionalizzazione mediante legame a specifici ligandi, che permettono il direzionamento del vettore verso tessuti target, li rendono sempre più importanti nel campo della terapia genica come sistemi per il trasporto di farmaci a base di acidi nucleici (NABDs). Based on their composition they are divided into conventional, invisible, cationic, targeted and liposomes that respond to stimuli. On the basis of the size they can be classified into multi-lamellar vesicles (MLVs), large unilamellar vesicles (LUVs) and small unilamellar vesicles (SUVs). Micro and nano liposomes are highly biocompatible and biodegradable systems which, thanks to their low toxicity and immunogenicity and their ability to incorporate hydrophilic and hydrophobic drugs, are ideal candidates for the controlled release of different types of active molecules for pharmaceutical and nutraceutical applications. Furthermore, their similarity with biological membranes and the possibility of functionalization by binding to specific ligands, which allow the vector to be directed towards target tissues, make them increasingly important in the field of gene therapy as systems for the transport of drugs based on nucleic acids (NABDs).
I liposomi, come sistemi per il rilascio controllato di farmaci, sono in grado di minimizzare la degradazione e la perdita dei farmaci, riducendo e prevedendo, allo steso tempo, effetti collaterali tossici; possono aumentare l’assorbimento e la biodisponibilità dei farmaci migliorandone la distribuzione e la penetrazione nei compartimenti cellulari. In generale, i due principali meccanismi che regolano il rilascio degli ingredienti attivi dai liposomi sono la diffusione e l’erosione. In particolare, in campo medico, per superare i limiti dovuti alla specificità dei comuni agenti terapeutici, i liposomi incapsulanti gli ingredienti attivi devono aumentare il loro accumulo vicino alle cellule bersaglio e facilitarne il rilascio al loro interno. Questo è possibile mediante due passaggi chiave: l’endocitosi e la fuoriuscita del principio attivo dall’endosoma. Il percorso endofitico è il maggiore meccanismo di inglobamento cellulare e rappresenta la modalità di internalizzazione dei liposomi nella cellula: i doppi strati fosfolipidici rispettivamente del liposoma e della membrana cellulare interagiscono tra loro portando ad una fusione tra le due membrane. Il processo è facilitato per liposomi cationici grazie all’interazione tra la loro carica positiva e quella negativa della membrana plasmatica. Successivamente all’internalizzazione, i liposomi contenenti le molecole attive vengono inglobati all’interno degli endosomi, organi interni alla cellula che prendono parte ai percorsi di smistamento e di secrezione cellulare. Qui i liposomi destabilizzano la membrana endosomiale evengono degradati ad opera di specifici enzimi assicurando il rilascio degli agenti terapeutici nell’ambiente citosolico; il meccanismo è chiamato “escape endosomiale”. In questo modo i liposomi evitano la degradazione delle molecole attive all’interno dei lisosomi, compartimenti cellulari preposti alla degradazione degli elementi di scarto o estranei alla cellula, e portano all’espressione di agenti terapeutici come i NABDs, all’interno del nucleo. Liposomes, as systems for the controlled delivery of drugs, are able to minimize the degradation and loss of drugs, reducing and foreseeing, at the same time, toxic side effects; they can increase the absorption and bioavailability of drugs by improving their distribution and penetration into cellular compartments. In general, the two main mechanisms that regulate the release of active ingredients from liposomes are diffusion and erosion. In particular, in the medical field, to overcome the limits due to the specificity of common therapeutic agents, the liposomes encapsulating the active ingredients must increase their accumulation near the target cells and facilitate their release within them. This is possible through two key steps: endocytosis and the release of the active ingredient from the endosome. The endophytic pathway is the major mechanism of cellular incorporation and represents the mode of internalization of the liposomes in the cell: the phospholipid double layers of the liposome and the cell membrane respectively interact with each other leading to a fusion between the two membranes. The process is facilitated for cationic liposomes thanks to the interaction between their positive and negative charge of the plasma membrane. After internalization, the liposomes containing the active molecules are incorporated within the endosomes, internal organs of the cell that take part in the sorting and cell secretion pathways. Here the liposomes destabilize the endosomal membrane and are degraded by specific enzymes ensuring the release of therapeutic agents into the cytosolic environment; the mechanism is called "endosomal escape". In this way, the liposomes avoid the degradation of the active molecules within the lysosomes, cellular compartments responsible for the degradation of waste elements or extraneous to the cell, and lead to the expression of therapeutic agents such as NABDs, within the nucleus.
Tuttavia molto spesso i liposomi presentano problemi di stabilità, soprattutto in ambiente acquoso, caratteristica che ne limita l’utilizzo esclusivamente in formulazioni solide predosate (capsule, compresse, granulati orosolubili, bustine). Tale limitazione impedisce di fatto la somministrazione di liposomi in pediatria ed in tutti i soggetti che hanno difficoltà nella deglutizione. Inoltre una formulazione predosata non permette di adattare la posologia di un prodotto alle reali necessità del paziente, ad esempio alcuni oligoelementi sono consigliati in base ai kg di peso o all’età. However, liposomes very often have stability problems, especially in an aqueous environment, a feature that limits their use exclusively in pre-dosed solid formulations (capsules, tablets, buccal granules, sachets). This limitation effectively prevents the administration of liposomes in pediatrics and in all subjects who have difficulty in swallowing. Furthermore, a pre-dosed formulation does not allow the dosage of a product to be adapted to the real needs of the patient, for example some trace elements are recommended based on the kg of weight or age.
A tal proposito scopo della presente domanda di brevetto per invenzione industriale è quello di proporre una nuova formulazione di liposomi che ne permetta la loro somministrazione in forma liquida offrendo tutti i vantaggi legati a tali formulazioni e superando le suddette criticità. In this regard, the purpose of the present patent application for industrial invention is to propose a new formulation of liposomes which allows their administration in liquid form, offering all the advantages linked to these formulations and overcoming the aforementioned criticalities.
Descrizione dell’invenzione Description of the invention
La presente descrizione si riferisce ad una peculiare composizione nutraceutica comprendente liposomi e caratterizzata dal fatto di risultare, grazie alla peculiare combinazione dei suoi ingredienti, in una formulazione liquida che permette alla stessa di essere somministrata più agevolmente rispetto alle note formulazioni solide liposomiali, offrendo così tutti quei vantaggi che rispondono alle esigenze della popolazione pediatrica e geriatrica per le quali la somministrazione di un componente per usi nutraceutici o farmaceutici risulta intuitivamente più agevole se il componente è in forma liquida. The present description refers to a peculiar nutraceutical composition comprising liposomes and characterized by the fact of resulting, thanks to the peculiar combination of its ingredients, in a liquid formulation which allows it to be administered more easily than the known solid liposomal formulations, thus offering all those advantages that meet the needs of the pediatric and geriatric population for which the administration of a component for nutraceutical or pharmaceutical uses is intuitively easier if the component is in liquid form.
Vantaggiosamente la composizione peculiarmente formulata in sospensione liquida secondo la presente invenzione offre anche la possibilità di essere somministrata secondo dosaggi arbitrari e più precisamente secondo specifiche esigenze del soggetto utilizzatore per il quale la formulazione solida non risponde alle sue esigenze. Advantageously, the composition specially formulated in liquid suspension according to the present invention also offers the possibility of being administered according to arbitrary dosages and more precisely according to specific needs of the user for whom the solid formulation does not meet his needs.
Vantaggiosamente la detta formulazione offre in primis il beneficio di risultare particolarmente stabile rispetto a formulazioni note che prevedono la sussistenza dei liposomi in forma liquida solo mediante la loro dispersione in un mezzo acquoso che notoriamente ne compromette la stabilità. Advantageously, said formulation offers first of all the benefit of being particularly stable with respect to known formulations which provide for the existence of liposomes in liquid form only through their dispersion in an aqueous medium which notoriously compromises their stability.
Più in dettaglio, la composizione opportunamente formulata secondo la presente invenzione si presenta come una sospensione oleosa e si basa oltre che sulla presenza di liposomi in forma essiccata, su altri ingredienti tre dei quali essenziali e due opzionali. More in detail, the composition suitably formulated according to the present invention is presented as an oily suspension and is based not only on the presence of liposomes in dried form, but on other ingredients, three of which are essential and two are optional.
Più in dettaglio, la composizione nutraceutica in oggetto comprende, oltre ai liposomi, dall’85% al 95% in peso di acidi grassi derivati da cocco e palma con catene che possono essere a diversa lunghezza (ovvero selezionate in base alla densità finale desiderata secondo il tipo di liposoma e di sostanza attiva contenuta nella struttura liposomiale) in modo da ottenere una sospensione efficace per i suoi scopi. I detti acidi grassi conferiscono, vantaggiosamente, un sapore gradevole ed un’eccellente tollerabilità da parte dell’organismo umano. La detta composizione prevede altresì dallo 0,55% allo 0,85% in peso di biossido di silicio (agente anti cacking) necesario per evitare l’aggregazione e la precipitazione dei liposomi; dallo 0,3% in peso allo 0,5% in peso di Vitamina E, antiossidante necessario per prevenire l’ossidazione degli acidi grassi e dei fosfo lipidi; dallo 0,2% in peso allo 0,5% in peso di aroma liposolubile che può opzionalmente migliorarne il gusto ed infine dallo 0,1% allo 0,15% in peso di un edulcorante, tipicamente a base di glicosidi steviolici e/o sucralosio, che può, anch’esso se opzionalmente presente, conferire una nota di dolcezza alla composizione. More in detail, the nutraceutical composition in question includes, in addition to liposomes, from 85% to 95% by weight of fatty acids derived from coconut and palm with chains that can be of different length (i.e. selected on the basis of the desired final density according to the type of liposome and active substance contained in the liposomal structure) in order to obtain an effective suspension for its purposes. These fatty acids advantageously confer a pleasant taste and excellent tolerability by the human body. The said composition also provides from 0.55% to 0.85% by weight of silicon dioxide (anti-cacking agent) necessary to avoid the aggregation and precipitation of liposomes; from 0.3% by weight to 0.5% by weight of Vitamin E, an antioxidant necessary to prevent the oxidation of fatty acids and phospho-lipids; from 0.2% by weight to 0.5% by weight of fat-soluble flavor which can optionally improve the taste and finally from 0.1% to 0.15% by weight of a sweetener, typically based on steviol glycosides and / or sucralose, which can, also if optionally present, give a note of sweetness to the composition.
Quest’ultima viene preparata secondo la presente invenzione mediante apposito procedimento che prevede la miscelazione dei suddetti ingredienti, e specificatamente almeno di quelli indicati come essenziali, vale a dire i liposomi; gli acidi grassi derivati da cocco e palma; il biossido di silicio e la vitamina E. Tale miscelazione avviene a freddo e con una velocità di agitazione di almeno 10000 rpm per un intervallo di tempo che varia da 3 a 7 minuti e preferibilmente per 5 minuti. The latter is prepared according to the present invention by means of a special process which provides for the mixing of the aforementioned ingredients, and specifically at least those indicated as essential, namely liposomes; fatty acids derived from coconut and palm; silicon dioxide and vitamin E. This mixing takes place cold and with a stirring speed of at least 10000 rpm for a time interval ranging from 3 to 7 minutes and preferably for 5 minutes.
Vantaggiosamente tale formulazione non prevede l’impiego di conservanti, come risulterà deducibile dalla consultazione dei dati ottenuti dai test sperimentali inerenti alle prove di stabilità eseguite su campioni della formulazione secondo l’invenzione, e che verranno qui di seguito presentanti in associazione ad una delle forme di realizzazione preferite dell’invenzione. Advantageously, this formulation does not provide for the use of preservatives, as will be deduced from the consultation of the data obtained from the experimental tests inherent to the stability tests carried out on samples of the formulation according to the invention, and which will be presented hereinafter in association with one of the forms preferred embodiments of the invention.
La composizione peculiarmente formulata ed oggetto della presente invenzione risulta tale da rendere i nutrienti selezionati e incapsulati all’interno dei liposomi, ovvero quelli da “condurre” nell’organismo del soggetto utilizzatore della detta composizione, in uno stato decisamente più stabile rispetto a quello ottenibile con formulazioni liquide di liposomi che utilizzano acqua come agente disperdente e rispetto alle formulazioni solide che risultano ad oggi le uniche utilizzabili se si utilizzano nutrienti in forma liposomiale stando alla riconosciuta labilità della durevolezza delle formulazioni liquide acquose. The peculiarly formulated composition and object of the present invention is such as to make the selected and encapsulated nutrients within the liposomes, or those to be "conducted" in the organism of the user of the said composition, in a decidedly more stable state than the one obtainable with liquid formulations of liposomes that use water as a dispersing agent and with respect to solid formulations which are currently the only ones that can be used if nutrients in liposomal form are used according to the recognized lability of the durability of aqueous liquid formulations.
Descrizione delle figure Description of the figures
L’invenzione verrà qui di seguito dettagliatamente descritta anche con riferimento alle figure annesse in cui: The invention will be described in detail below also with reference to the attached figures in which:
FIGURA 1 mostra le immagini di un campione, secondo la presente invenzione, di composizione nutraceutica a base di pirofosfato ferrico come ingrediente, ottenute mediante microscopia a scansione elettronica SEM. Le immagini mostrano chiaramente che il Ferro liposomiale ha una distribuzione mono dispersa e confermano la presenza di aggregati con dimensioni intorno ai 100 mcm e di particelle più piccole intorno ai 40-50 mcm. Con ingrandimenti maggiori si apprezza la struttura sub-micrometrica del materiale. FIGURE 1 shows the images of a sample, according to the present invention, of a nutraceutical composition based on ferric pyrophosphate as an ingredient, obtained by SEM scanning electron microscopy. The images clearly show that liposomal iron has a mono dispersed distribution and confirm the presence of aggregates with dimensions around 100 mcm and of smaller particles around 40-50 mcm. With higher magnifications you can appreciate the sub-micrometric structure of the material.
FIGURA 2 mostra un grafico relativo alla distribuzione della dimensione delle particelle di composizione liposomiale di pirofosfato ferrico valutate dopo differenti tempi di invecchiamento della detta composizione. Più in dettaglio la figura in questione mostra che dall’analisi granulometrica realizzata si evince che il campione analizzato al t=0 (curva 1) presenta un diametro medio di 42,3 cm, in particolare il 10% del campione ha un diametro fino a 10,2 mcm mentre il 90% fino a 77,72 mcm. Il campione analizzato al t=1 (curva 2), presenta una distribuzione granulometrica con diametro medio di 55,2 mcm, il 10% del campione ha diametro fino a 10,8 mcm mentre il 90% fino a 116 mcm. Da questo primo confronto si evince che, a causa di fenomeni di aggregazione lipidica, le dimensioni medie sono in leggero aumento, specialmente per quanto riguarda le particelle di dimensioni maggiori che allungano la coda della distribuzione. Il campione osservato al t=2 (curva 3) invece presenta una distribuzione granulometrica più confortabile con quella iniziale. Ciò è spiegabile per via di fenomeni di aggregazione/disgregazione, comportamento tipico dei complessi lipidici in soluzione. FIGURE 2 shows a graph relating to the size distribution of the particles of liposomal composition of ferric pyrophosphate evaluated after different aging times of said composition. More in detail, the figure in question shows that from the particle size analysis carried out it can be seen that the sample analyzed at t = 0 (curve 1) has an average diameter of 42.3 cm, in particular 10% of the sample has a diameter up to 10.2 mcm while 90% up to 77.72 mcm. The sample analyzed at t = 1 (curve 2), has a particle size distribution with an average diameter of 55.2 mcm, 10% of the sample has a diameter up to 10.8 mcm while 90% up to 116 mcm. From this first comparison it is clear that, due to lipid aggregation phenomena, the average size is slightly increasing, especially as regards the larger particles that lengthen the tail of the distribution. The sample observed at t = 2 (curve 3), on the other hand, has a more comfortable particle size distribution than the initial one. This can be explained by the phenomena of aggregation / disintegration, typical behavior of lipid complexes in solution.
FIGURA 3 mostra le immagini ottenute mediante analisi al microscopio ottico del campione liquido della composizione nutraceutica a base di pirofosfato ferrico. Alcuni liposomi sono evidenziati con un cerchio. Da queste osservazioni si evince che il campione è stabile e non subisce alterazioni nel tempo. FIGURE 3 shows the images obtained by optical microscope analysis of the liquid sample of the nutraceutical composition based on ferric pyrophosphate. Some liposomes are highlighted with a circle. From these observations it is clear that the sample is stable and does not undergo alterations over time.
Descrizione dettagliata dell’invenzione Detailed description of the invention
In una delle sue forme di realizzazione preferite, la composizione nutraceutica liposomiale risultante in una formulazione liquida consistente in una sospensione oleosa, comprende pirofosfato ferrico liposomiale come principio attivo. Preferibilmente la detta composizione comprende per 5 ml di prodotto 334 mg di pirofosato ferrico liposomiale conferente un apporto in Ferro come Fe<3+ >di 5 mg. Oltre ai suddetti ingredienti sono compresi: acidi grassi a catena media; silice colloidale anidra come anti-agglomerante; Stevia Rebaudiana e/o Rebaudioside; vitamina E come antiossidante ed un aroma al gusto di biscotto-vaniglia. Il tutto senza zuccheri e senza conservanti aggiunti. In one of its preferred embodiments, the liposomal nutraceutical composition resulting in a liquid formulation consisting of an oily suspension comprises liposomal ferric pyrophosphate as the active ingredient. Preferably, the said composition comprises for 5 ml of product 334 mg of liposomal ferric pyrophosate giving a contribution of 5 mg in Iron as Fe <3+>. In addition to the above ingredients are included: medium chain fatty acids; anhydrous colloidal silica as anti-caking agent; Stevia Rebaudiana and / or Rebaudioside; vitamin E as an antioxidant and a biscuit-vanilla flavored aroma. All without sugar and without added preservatives.
È di interesse per la Richiedente sottolineare ancora che ad oggi il prodotto sopra indicato presenta diverse criticità formulative legate alla labilità strutturale dei liposomi, tipicamente instabili in ambiente liquido acquoso. Come più volte ripetuto nel corso della presente descrizione, ad oggi l’unica possibilità formulativa è rappresentata da formulazioni solide contenenti liposomi essiccati. L’obiettivo è quello di realizzare un prodotto liquido a base di liposomi che permetterebbe di avere numerosi vantaggi in termini di dosabilità e praticità del prodotto. La formulazione liquida permette difatti di somministrare il prodotto agevolmente anche in campo geriatrico e pediatrico dove la somministrazione liquida rappresenta molto spesso l’unica via di somministrazione. It is of interest to the Applicant to point out again that to date the above indicated product has various formulation criticalities linked to the structural lability of the liposomes, typically unstable in aqueous liquid environment. As repeated several times in the course of this description, to date the only formulation possibility is represented by solid formulations containing dried liposomes. The goal is to create a liquid product based on liposomes that would allow for numerous advantages in terms of dosability and practicality of the product. The liquid formulation allows the product to be administered easily even in the geriatric and pediatric field where liquid administration is very often the only route of administration.
Campioni della detta composizione sono stati preparati miscelando tra loro i vari componenti e dosando la miscela ottenuta in flaconi, tipicamente ma non limitatamente in PET ambra, da 20 mL a 200 mL, preferibilmente da 50 mL. I detti flaconi possono presentare diverse tipologie di dosaggio tra cui: misurino dosatore, pipetta contagocce, siringa dosatrice, contagocce a capovolgimento. I campioni così preparati sono stati conservati a temperatura ambiente fino al loro impiego per i test di stabilità. Samples of said composition were prepared by mixing the various components together and dosing the mixture obtained in bottles, typically but not limited to amber PET, from 20 mL to 200 mL, preferably of 50 mL. These bottles can have different types of dosage including: measuring cup, dropper pipette, dosing syringe, overturning dropper. The samples thus prepared were stored at room temperature until they were used for stability tests.
Le seguenti analisi sono state effettuate in differenti laboratori al fine di valutare i seguenti parametri legati alla stabilità del prodotto: The following analyzes were carried out in different laboratories in order to evaluate the following parameters related to the stability of the product:
Stabilità chimico fisica e microbiologica (Test eseguiti presso LM Laboratorio Merceologico Srl Parma, Italia). Chemical, physical and microbiological stability (Tests performed at LM Laboratorio Merceologico Srl Parma, Italy).
- Titolo in Ferro; - Iron title;
- Ossidazione degli acidi grassi (perossidi, rancidità); - Oxidation of fatty acids (peroxides, rancidity);
- Titolo in vitamina E; - Vitamin E title;
- Carica Microbica, lieviti e muffe. - Microbial load, yeasts and molds.
Stabilità strutturale dei liposomi: (le seguenti analisi microscopiche e granulometriche sono state eseguite presso il dipartimento di Ingegneria Industriale dell’Università degli Studi di Salerno). Structural stability of liposomes: (the following microscopic and particle size analyzes were performed at the Department of Industrial Engineering of the University of Salerno).
- Analisi morfologiche - microscopia a scansione elettronica SEM del campione essiccato; - Morphological analysis - SEM scanning electron microscopy of the dried sample;
- Analisi granulometrica tramite tecnologia DLS; - Particle size analysis using DLS technology;
- Analisi al microscopio ottico del campione liquido. - Optical microscope analysis of the liquid sample.
I campioni preparati come suddetto, ovvero mediante miscelazione degli ingredienti e successivo stoccaggio in appositi flaconi, sono stati inviati nei sopra specificati laboratori per eseguire dei test di stabilità al t0, ovvero dopo una settimana dalla loro preparazione; al t1 ovvero dopo 90 giorni di invecchiamento accelerato; al t2 ovvero dopo 180 giorni di invecchiamento accelerato. The samples prepared as above, or by mixing the ingredients and subsequent storage in special bottles, were sent to the above specified laboratories to carry out stability tests at t0, that is, one week after their preparation; at t1 or after 90 days of accelerated aging; at t2 or after 180 days of accelerated aging.
L’invecchiamento accelerato è stato effettuato indipendentemente in entrambi i laboratori mediante termostatazione a 40°C ± 2°C e 75% RH ± 5% RH. A seguito dei risultati ottenuti interesse della Richiedente è anche procedere con test di invecchiamento naturale fino a 36 mesi eseguendo tutte le analisi sopra elencate ogni sei mesi. La seguente tabella mostra i risultati delle prove chimiche effettuate: Accelerated aging was carried out independently in both laboratories by thermostating at 40 ° C ± 2 ° C and 75% RH ± 5% RH. Following the results obtained, the Applicant is also interested in proceeding with natural aging tests up to 36 months by performing all the analyzes listed above every six months. The following table shows the results of the chemical tests carried out:
Tabella 1 Table 1
In aggiunta ai sopra indicati risultati presentati in tabella, test visivi eseguiti nel suddetto laboratorio LM hanno confermato che al termine delle prove di invecchiamento accelerato i campioni analizzati non presentavano alcun fenomeno di cambiamento della colorazione, precipitazione e/o affioramento. In addition to the above results presented in the table, visual tests performed in the aforementioned LM laboratory confirmed that at the end of the accelerated aging tests the analyzed samples did not show any phenomenon of color change, precipitation and / or surfacing.
Alla luce dei risultati ottenuti dalle prove eseguite in laboratorio si è evinto che la soluzione di ferro liposomiale in liposomi è da considerarsi stabile, con una shelf-life di diciotto mesi. In the light of the results obtained from the tests carried out in the laboratory, it was concluded that the solution of liposomal iron in liposomes is to be considered stable, with a shelf-life of eighteen months.
I campioni preparati sono stati anche sottoposti ad analisi morfologiche con Microscopia a scansione elettronica SEM utilizzando uno strumento FE-SEM. Il campione è stato deposto tramite un bi-adesivo di carbonio su uno stub di alluminio e per la visualizzazione al microscopio. Ha subito un processo di metallazione con oro usando uno sputter coater. The prepared samples were also subjected to morphological analyzes with SEM scanning electron microscopy using a FE-SEM instrument. The sample was deposited via a carbon double-sided adhesive on an aluminum stub and for viewing under the microscope. It underwent a gold metallation process using a sputter coater.
La seguente tabella mostra i risultati ottenuti dall’analisi granulometrica dei campioni tramite tecnologia DLS. The following table shows the results obtained from the particle size analysis of the samples using DLS technology.
Tabella 2. Table 2.
È stata altresì eseguita un’analisi al microscopio ottico del campione liquido che ha previsto l’osservazione al microscopio ottico OM, mod BX 50 Olympus. An optical microscope analysis of the liquid sample was also performed which included observation under the OM optical microscope, mod BX 50 Olympus.
In conclusione, i risultati ottenuti da tutti i test sperimentali eseguiti hanno rivelato che il complesso ferro liposomiale presenta in generale caratteristiche di stabilità nel tempo. I dati sono stati come suddetto ottenuti da analisi di microscopia ottica ed elettronica supportate da analisi granulometriche. In conclusion, the results obtained from all the experimental tests carried out revealed that the liposomal iron complex generally exhibits characteristics of stability over time. The data were obtained as above from optical and electron microscopy analyzes supported by particle size analyzes.
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Citations (5)
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US5534268A (en) * | 1993-11-09 | 1996-07-09 | Juan Carlos Ferroni | Liposomes containing bioavailable iron (II) and process for obtaining them |
WO2008080369A1 (en) * | 2006-12-30 | 2008-07-10 | Shanghai Allist Pharmaceuticals, Inc. | Steady liposomal composition |
CN101336931A (en) * | 2008-02-29 | 2009-01-07 | 河北师范大学 | Iron liposomes used as iron supplementary and preparation method thereof |
US20130101651A1 (en) * | 2005-06-07 | 2013-04-25 | University Of South Australia | Dried formulations of nanoparticle-coated capsules |
CN105496992A (en) * | 2015-12-08 | 2016-04-20 | 青岛正大海尔制药有限公司 | Ambroxol salbutamol lipid solid dispersion |
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US5534268A (en) * | 1993-11-09 | 1996-07-09 | Juan Carlos Ferroni | Liposomes containing bioavailable iron (II) and process for obtaining them |
US20130101651A1 (en) * | 2005-06-07 | 2013-04-25 | University Of South Australia | Dried formulations of nanoparticle-coated capsules |
WO2008080369A1 (en) * | 2006-12-30 | 2008-07-10 | Shanghai Allist Pharmaceuticals, Inc. | Steady liposomal composition |
CN101336931A (en) * | 2008-02-29 | 2009-01-07 | 河北师范大学 | Iron liposomes used as iron supplementary and preparation method thereof |
CN101336931B (en) * | 2008-02-29 | 2011-09-14 | 河北师范大学 | Iron liposomes used as iron supplementary |
CN105496992A (en) * | 2015-12-08 | 2016-04-20 | 青岛正大海尔制药有限公司 | Ambroxol salbutamol lipid solid dispersion |
Non-Patent Citations (4)
Title |
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DATABASE GNPD [online] MINTEL; 17 December 2012 (2012-12-17), ANONYMOUS: "Iron Dietary Supplement Capsules", XP055714060, retrieved from www.gnpd.com Database accession no. 1954968 * |
DATABASE GNPD [online] MINTEL; 26 July 2017 (2017-07-26), ANONYMOUS: "Liposomal Iron and Vitamin D Dietary Supplement Solution", XP055714065, retrieved from www.gnpd.com Database accession no. 4981971 * |
DATABASE WPI Week 200909, Derwent World Patents Index; AN 2009-E28595 * |
DATABASE WPI Week 201656, Derwent World Patents Index; AN 2016-27262X * |
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