ITMI991317A1 - THERAPEUTIC SYSTEMS WITH MODIFIED RELEASE FOR ORAL PHARMACEUTICAL FORM - Google Patents
THERAPEUTIC SYSTEMS WITH MODIFIED RELEASE FOR ORAL PHARMACEUTICAL FORM Download PDFInfo
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- ITMI991317A1 ITMI991317A1 IT1999MI001317A ITMI991317A ITMI991317A1 IT MI991317 A1 ITMI991317 A1 IT MI991317A1 IT 1999MI001317 A IT1999MI001317 A IT 1999MI001317A IT MI991317 A ITMI991317 A IT MI991317A IT MI991317 A1 ITMI991317 A1 IT MI991317A1
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Description
Descrizione dell'invenzione industriale avente per titolo: Description of the industrial invention entitled:
"SISTEMI TERAPEUTICI A RILASCIO MODIFICATO PER FORME FARMACEUTICHE ORALI" "MODIFIED RELEASE THERAPEUTIC SYSTEMS FOR ORAL PHARMACEUTICAL FORMS"
La presente invenzione ha per oggetto composizioni per formulati a rilascio modificato contenenti uno o più principi attivi inglobati in una struttura a matrice a tre componenti, formata cioè da matrici successive di natura anfifila, lipofila o inerte e infine incorporate o disperse in matrici idrofile. L'accoppiamento di più sistemi di controllo della dissoluzione del principio attivo permette di modulare la velocità con cui il principio attivo passa allo stato disciolto nei fluidi acquosi e/o biologici e, pertanto di controllarne la cinetica di rilascio nel tratto gastroenterico. The present invention relates to compositions for modified release formulations containing one or more active principles incorporated in a three-component matrix structure, i.e. formed by successive matrices of an amphiphilic, lipophilic or inert nature and finally incorporated or dispersed in hydrophilic matrices. The coupling of several control systems of the dissolution of the active principle allows to modulate the speed with which the active principle passes to the dissolved state in the aqueous and / or biological fluids and, therefore, to control its release kinetics in the gastrointestinal tract.
Le composizioni a rilascio modificato dell'invenzione possono contenere principi attivi appartenenti alle classi terapeutiche degli analgesici, antiinfiammatori, cardioattivi, tranquillanti, antiipertensivi, disinfettanti e antibatterici, antiparkinson, antistaminici e sono adatte alla somministrazione orale o ad agire topicamente su alcuni settori dell’ apparato gastroenterico. SFONDO DELL’INVENZIONE The modified release compositions of the invention can contain active ingredients belonging to the therapeutic classes of analgesics, anti-inflammatory, cardioactive, tranquilizers, antihypertensives, disinfectants and antibacterials, antiparkinson's, antihistamines and are suitable for oral administration or to act topically on some sectors of the apparatus. gastrointestinal. BACKGROUND OF THE INVENTION
L'ottenimento di un preparato a cessione protratta, controllata, ritardata, comunque modificata, può essere perseguito con diverse tecniche note: The obtainment of a preparation with prolonged, controlled, delayed release, however modified, can be pursued with various known techniques:
1. Utilizzo di matrici inerti, in cui il componente principale della struttura matriciale oppone una certa resistenza alla penetrazione del solvente per scarsa affinità con i fluidi acquosi; proprietà, questa, nota come lipofilia. 1. Use of inert matrices, in which the main component of the matrix structure opposes a certain resistance to the penetration of the solvent due to poor affinity with aqueous fluids; this property is known as lipophilicity.
2. Utilizzo di matrici idrofile, in cui il componente principale della struttura matriciale oppone una resistenza elevata all'avanzamento del fronte del solvente, in quanto la presenza di gruppi fortemente idrofili nelle sue catene, per lo più ramificate ed intrecciate, provoca un notevole aumento di viscosità localizzato aH'intemo dello strato idratato. 2. Use of hydrophilic matrices, in which the main component of the matrix structure opposes a high resistance to the advancement of the solvent front, as the presence of strongly hydrophilic groups in its chains, mostly branched and intertwined, causes a considerable increase of viscosity localized inside the hydrated layer.
3. Utilizzo di matrici bioerodibili, in grado cioè di poter essere demolite metabolicamente dagli enzimi di qualche comparto biologico. 3. Use of bioerodible matrices, that is capable of being metabolically demolished by the enzymes of some biological compartment.
Tutte le metodiche sopra elencate, tuttavia, non sono esenti da difetti ed imperfezioni. All the methods listed above, however, are not free from defects and imperfections.
Le matrici inerti, ad esempio, danno generalmente luogo ad una caratteristica di rilascio del principio attivo, che non è lineare ma esponenziale. Inert matrices, for example, generally give rise to a release characteristic of the active principle, which is not linear but exponential.
Le matrici idrofile hanno un comportamento lineare alla dissoluzione fino ad una certa frazione di principio attivo ceduto e poi deviano significativamente dalla linearità di cessione. The hydrophilic matrices have a linear dissolution behavior up to a certain fraction of released active ingredient and then significantly deviate from the linearity of release.
Le matrici bioerodibili. ideali per realizzare il cosiddetto "site-release", pongono comunque il problema di trovare l'enzima o il reattivo idoneo alla demolizione. Inoltre, rilasciano frequentemente in situ metaboliti non propriamente inerti dal punto di vista tossicologico. The bioerodible matrices. ideal for carrying out the so-called "site-release", however, they pose the problem of finding the enzyme or reagent suitable for demolition. Furthermore, they frequently release metabolites in situ which are not strictly inert from a toxicological point of view.
Sono state descritte diverse formulazioni che utilizzano matrici ìipofile inerti: in Drug Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) viene descritto un processo che utilizza quantità variabili di silice colloidale come elemento di porizzazione di una matrice lipofila inerte in cui viene incorporato il principio attivo. Several formulations using inert hypophilic matrices have been described: in Drug Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) a process is described which uses variable quantities of colloidal silica as a porization element of an inert lipophilic matrix in which the active principle is incorporated.
Lo stesso concetto di canalizzazione di una matrice inerte viene descritto in US 4,608,248 in cui una piccola quantità di polimero idrofilo è miscelata con le sostanze che formano una matrice inerte, in una compenetrazione non sequenziale di materiali matriciali diversi. The same concept of channeling an inert matrix is described in US 4,608,248 in which a small amount of hydrophilic polymer is mixed with the substances forming an inert matrix, in a non-sequential interpenetration of different matrix materials.
in EP 375,063 viene descritta una tecnica di preparazione di granuli multiparticolati a rilascio controllato di principio attivo che prevede una codissoluzione di polimeri o sostanze idonee a formare una matrice inerte con il principio attivo e la successiva deposizione di tale soluzione su un supporto inerte che funge da core dei device. In alternativa, il supporto inerte viene impastato con la soluzione contenente il polimero inerte ed il principio attivo e quindi il solvente organico, utilizzato per la loro dissoluzione, viene evaporato fino ad ottenere un residuo solido. La struttura realizzata è di tipo "reservoir", cioè non macroscopicamente omogenea lungo tutti gli assi di simmetria della forma finale. EP 375,063 describes a technique for the preparation of multiparticulate granules with controlled release of the active principle which involves a codissolution of polymers or substances suitable for forming an inert matrix with the active principle and the subsequent deposition of this solution on an inert support which acts as a core of the devices. Alternatively, the inert support is mixed with the solution containing the inert polymer and the active principle and then the organic solvent, used for their dissolution, is evaporated until a solid residue is obtained. The structure created is of the "reservoir" type, that is, it is not macroscopically homogeneous along all the symmetry axes of the final shape.
La stessa struttura "reservoir" viene descritta anche in Chem. Pharm. Bull. 46 (3), 531-533,, (1998) che perfeziona l’applicazione attraverso una tecnica di annealing (tempera) dello strato polimerico inerte che viene deposto sulla superficie dei pellets. The same "reservoir" structure is also described in Chem. Pharm. Bull. 46 (3), 531-533 ,, (1998) which perfects the application through an annealing technique (tempering) of the inert polymeric layer that is deposited on the surface of the pellets.
Sempre di struttura "reservoir" sono i prodotti ottenuti secondo la tecnica descritta in WO 93/00889 in cui viene descritto un processo di ottenimento di pellets in matrice idrofila che prevede: The products obtained according to the technique described in WO 93/00889 in which a process of obtaining pellets in a hydrophilic matrix is described which includes:
la dissoluzione del principio attivo con polimeri idrofili gastroresistenti in solventi organici; the dissolution of the active principle with gastro-resistant hydrophilic polymers in organic solvents;
l’essiccamento di tale sospensione; the drying of this suspension;
il successivo impasto e formulazione dei pellets in una matrice o idrofila o lipofila senza distinzione di efficacia tra le due tipologie di applicazione. the subsequent mixing and formulation of the pellets in a hydrophilic or lipophilic matrix without distinction of effectiveness between the two types of application.
EP 0 453 001 descrive un multiparticolato con struttura "reservoir" inserito in una matrice idrofila. Il multiparticolato di base utilizza due membrane di rivestimento per ottenere una riduzione della velocità di cessione del principio attivo, una membrana pH-dipendente con finalità di gastroprotezione ed una membrana pH-indipendente a base metacrilica con finalità di rallentare la penetrazione del fluido acquoso. EP 0 453 001 describes a multiparticulate with a "reservoir" structure inserted in a hydrophilic matrix. The basic multiparticulate uses two coating membranes to obtain a reduction in the rate of release of the active ingredient, a pH-dependent membrane with the purpose of gastroprotection and a pH-independent membrane based on methacrylate with the aim of slowing the penetration of the aqueous fluid.
In WO 95/16451 viene descritta una composizione formata solo da una matrice idrofila rivestita da un film gastroresistente per l’ottenimento del controllo della velocità di dissoluzione della mesalazina. WO 95/16451 describes a composition consisting only of a hydrophilic matrix coated with a gastro-resistant film for obtaining control of the mesalazine dissolution rate.
Dovendo realizzare dei preparati a cessione protratta e modificata per un farmaco che abbia un'attività locale nel tratto gastroenterico o che abbia un'attività sistemica, diventa importante garantire una liberazione controllata fin dalle prime fasi successive alla somministrazione, cioè quando le matrici inerti presentano la massima velocità di cessione all'interno della fase logaritmica, ossia la maggior deviazione dalla linearità di cessione. Having to make preparations with prolonged and modified release for a drug that has a local activity in the gastrointestinal tract or that has a systemic activity, it becomes important to guarantee a controlled release from the first phases following administration, that is when the inert matrices show the maximum speed of release within the logarithmic phase, i.e. the greatest deviation from linearity of release.
Tale obiettivo è stato raggiunto in accordo con la presente invenzione, attraverso la combinazione di una matrice anfifila all’interno di una matrice inerte, quest’ultima formulata con un polimero di natura lipofila in una matrice di contenimento superficialmente idrofila. Le composizioni dell'invenzione sono caratterizzate dall'assenza di una fase iniziale di spunto veloce della quota di farmaco superficialmente presente sulla matrice, che sarebbe passata immediatamente in soluzione, e della compensazione con lo strato anfifilo della non affinità del solvente acquoso con le sostanze lipofile formanti la matrice inerte interna. This objective was achieved in accordance with the present invention, through the combination of an amphiphilic matrix within an inert matrix, the latter formulated with a lipophilic polymer in a superficially hydrophilic containment matrix. The compositions of the invention are characterized by the absence of an initial phase of rapid start-up of the amount of drug superficially present on the matrix, which would have immediately passed into solution, and by the compensation with the amphiphilic layer of the non-affinity of the aqueous solvent with the lipophilic substances. forming the internal inert matrix.
DESCRIZIONE DELL’INVENZIONE DESCRIPTION OF THE INVENTION
L’invenzione fornisce composizioni farmaceutiche orali a rilascio modificato contenenti uno o più ingredienti attivi comprendenti: The invention provides modified release oral pharmaceutical compositions containing one or more active ingredients including:
a) una matrice costituita da sostanze anfifiliche e da sostanze lipofile con punto di fusione inferiore a 90 °C in cui è almeno parzialmente inglobato l’ingrediente attivo; a) a matrix consisting of amphiphilic substances and lipophilic substances with a melting point below 90 ° C in which the active ingredient is at least partially incorporated;
b) una matrice idrofila esterna in cui viene dispersa la matrice lipofila/anfifilica; b) an external hydrophilic matrix in which the lipophilic / amphiphilic matrix is dispersed;
c) eventuali altri eccipienti. c) any other excipients.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Le composizioni dell'invenzione possono essere ottenute con un metodo costituito dai seguenti stadi: The compositions of the invention can be obtained with a method consisting of the following steps:
a) Dapprima si ingloba il principio attivo per semplice impasto o miscelazione in una matrice o rivestimento di sostanze dotate di proprietà anfifile, più sotto specificate. L’impasto del o dei principi attivi con le sostanze anfifile può avvenire senza l’ausilio di solventi o con piccole quantità di solventi idroalcolici. a) First of all, the active principle is incorporated by simple mixing or mixing in a matrix or coating of substances with amphiphilic properties, specified below. The mixture of the active ingredient (s) with the amphiphilic substances can take place without the aid of solvents or with small amounts of hydroalcoholic solvents.
b) La matrice ottenuta in a) viene incorporata in un eccipiente lipofilo o miscela di eccipienti a basso punto di fusione, provvedendo a somministrare calore, in modo da provocare il rammollimento e/o la fusione dell'eccipiente stesso che incorpora il principio attivo per semplice dispersione. Dopo raffreddamento a temperatura ambiente si forma una matrice inerte, che può essere ridotta di dimensione fino ad ottenere dei granuli matriciali di natura inerte contenenti le particelle di principio attivo. b) The matrix obtained in a) is incorporated into a lipophilic excipient or mixture of excipients with a low melting point, providing heat, so as to cause the softening and / or melting of the excipient itself which incorporates the active ingredient for simple dispersion. After cooling at room temperature, an inert matrix is formed, which can be reduced in size to obtain matrix granules of inert nature containing the particles of the active principle.
c) Successivamente i granuli di matrice inerte sono miscelati ad uno o più eccipienti idrofili che, in presenza di acqua, hanno la capacità di rigonfiarsi. La miscela viene, quindi, sottoposta a compressione o a compattazione. In tal modo, quando la compressa entra in contatto con i fluidi biologici, si viene a formare uno strato rigonfiato dotato di elevata viscosità, che coordina le molecole di solvente e funge da barriera alla penetrazione del fluido acquoso stesso all'intemo della nuova struttura. Tale barriera antagonizza l'iniziale "burst effect” prodotto dalla dissoluzione del farmaco inglobato all'intemo della matrice inerte, a sua volta posta aH’intemo di una matrice idrofila. c) Subsequently, the granules of inert matrix are mixed with one or more hydrophilic excipients which, in the presence of water, have the ability to swell. The mixture is then subjected to compression or compaction. In this way, when the tablet comes into contact with biological fluids, a swollen layer with high viscosity is formed, which coordinates the solvent molecules and acts as a barrier to the penetration of the aqueous fluid itself into the new structure. This barrier antagonizes the initial "burst effect" produced by the dissolution of the drug incorporated within the inert matrix, in turn placed inside a hydrophilic matrix.
Le sostanze anfifiliche impiegabili secondo l'invenzione comprendono lipidi polari di tipo I o II (lecitina, fosfatidilcolina, fosfatidiletanolammina), ceramidi, glicolialchileteri quali dietilenglicolmonoetiletere (Transcutol®). The amphiphilic substances which can be used according to the invention include type I or II polar lipids (lecithin, phosphatidylcholine, phosphatidylethanolamine), ceramides, glycolyalkyl ethers such as diethylene glycol monoethyl ether (Transcutol®).
La matrice lipofila è costituita da sostanze scelte fra acidi grassi insaturi e/o idrogenati, loro sali, esteri o ammidi, mono-, di- o trigliceridi di acidi grassi o loro derivati poliossietilenati, cere, derivati colesterici o loro miscele tali che il punto di fusione si mantenga nell’intervallo da 40 a 90°C. The lipophilic matrix consists of substances selected from unsaturated and / or hydrogenated fatty acids, their salts, esters or amides, mono-, di- or triglycerides of fatty acids or their polyoxyethylene derivatives, waxes, cholesteric derivatives or their mixtures such that the point of melting is maintained in the range from 40 to 90 ° C.
Se desiderato si può inglobare nella matrice lipofila un sale di calcio di acido grasso da disperdere in una matrice idrofila realizzata con l'acido alginico, così da provocare un aumento di viscosità molto pronunciato della matrice idrofila in seguito alla penetrazione del fronte del solvente fino a contatto con i granuli di matrice lipofila dispersi aH'intemo. If desired, a calcium salt of fatty acid can be incorporated in the lipophilic matrix to be dispersed in a hydrophilic matrix made with alginic acid, so as to cause a very pronounced increase in viscosity of the hydrophilic matrix following the penetration of the solvent front up to contact with the granules of the lipophilic matrix dispersed inside.
Secondo una forma di attuazione dell'invenzione, si prepara dapprima una matrice anfifila ad alto contenuto di principio attivo, tipicamente compreso tra il 5 e il 95% p/p, disperdendo il principio attivo o la miscela di principi attivi in una miscela di sostanze anfifile, quale ad es. lecitina, altri lipidi polari di tipo II, tensioattivi oppure in dietilenglicole-monoetilene; la matrice anfifìla così ottenuta viene quindi miscelata o impastata generalmente a caldo con sostanze lipofile idonee a formare una matrice inerte, quali ad esempio acidi grassi saturi o insaturi, quali acido paimitico, stearico, miristico od oleico o miscele degli stessi con altri acidi grassi a catena più corta, oppure sali o derivati degli acidi grassi citati, da soli o in combinazione con cere, ceramidi, o derivati colesterici o altri lipidi apolari in vari rapporti selezionati in modo che il punto di fusione o di rammollimento della miscele di sostanze lipofile si mantenga nell'intervallo tra 40° e 90 °C. According to an embodiment of the invention, an amphiphilic matrix with a high content of active ingredient, typically between 5 and 95% w / w, is first prepared by dispersing the active ingredient or the mixture of active ingredients in a mixture of substances amphiphile, such as eg. lecithin, other type II polar lipids, surfactants or diethylene glycol-monoethylene; the amphiphilic matrix thus obtained is then mixed or mixed generally hot with lipophilic substances suitable for forming an inert matrix, such as for example saturated or unsaturated fatty acids, such as paimitic, stearic, myristic or oleic acid or mixtures thereof with other fatty acids to shorter chain, or salts or derivatives of the fatty acids mentioned, alone or in combination with waxes, ceramides, or cholesteric derivatives or other apolar lipids in various ratios selected so that the melting or softening point of the mixtures of lipophilic substances is keep in the range between 40 ° and 90 ° C.
La matrice lipofila inerte così realizzata viene quindi ridotta in granuli mediante un processo di estrusione e/o granulazione, o altro processo noto che preservi la struttura di dispersione omogenea e matriciale della mescola iniziale. The inert lipophilic matrix thus obtained is then reduced to granules by means of an extrusion and / or granulation process, or other known process which preserves the homogeneous and matrix dispersion structure of the initial mix.
La matrice idrofila è costituita da eccipienti noti come idrogeli, cioè sostanze che passando dallo stato anidro allo stato idratato, mostrano il fenomeno noto come "rilassamento molecolare" caratterizzato da un notevole aumento di ingombro e di peso a seguito della coordinazione di un grande numero di molecole di acqua da parte dei gruppi polari presenti nelle catene degli eccipienti. The hydrophilic matrix is made up of excipients known as hydrogels, ie substances which, passing from the anhydrous to the hydrated state, show the phenomenon known as "molecular relaxation" characterized by a considerable increase in size and weight following the coordination of a large number of water molecules by the polar groups present in the chains of excipients.
Esempi di idrogeli impiegabili secondo l’invenzione sono sostanze scelte fra polimeri o copolimeri dell’acido acrilico o metacrilico, polimeri alchilvinilici, idrossialchilcellulose, carbossialchilcellulose, polisaccaridi, destrine, pectine, amidi e derivati, acido alginico, gomme naturali o sintetiche. Examples of hydrogels that can be used according to the invention are substances selected from polymers or copolymers of acrylic or methacrylic acid, alkylvinyl polymers, hydroxyalkylcellulose, carboxyalkylcellulose, polysaccharides, dextrins, pectins, starches and derivatives, alginic acid, natural or synthetic gums.
I granuli di matrice lipofila contenenti il principio attivo sono miscelati alle sostanze idrofile sopra citate in rapporto ponderale tipicamente compreso tra 100:0,5 e 100:50 (matrice lipofila: matrice idrofila). Una parte del principio attivo può essere eventualmente miscelato alle sostanze idrofile così da ottenere composizioni in cui regrediente attivo è disperso sia nella matrice lipofila sia nella matrice idrofila, e tali composizioni sono preferibilmente in forma di compresse, capsule o minimatrici. The lipophilic matrix granules containing the active principle are mixed with the hydrophilic substances mentioned above in a weight ratio typically between 100: 0.5 and 100: 50 (lipophilic matrix: hydrophilic matrix). A part of the active principle can optionally be mixed with the hydrophilic substances so as to obtain compositions in which the active regredient is dispersed both in the lipophilic matrix and in the hydrophilic matrix, and these compositions are preferably in the form of tablets, capsules or minimizers.
La compressione della miscela di matrice lipofila, sostanza capace di formare 15 idrogel ed eventualmente ingrediente attivo non inglobato nella matrice lipofila, produce una struttura macroscopicamente omogenea in tutto il suo volume, ossia una matrice contenente una dispersione dei granuli lipofili in una matrice idrofila. Un risultato analogo può essere ottenuto anche rivestendo i granuli di matrice lipofila con uno strato di polimero idrofilo. The compression of the lipophilic matrix mixture, a substance capable of forming 15 hydrogels and possibly an active ingredient not incorporated in the lipophilic matrix, produces a macroscopically homogeneous structure throughout its volume, i.e. a matrix containing a dispersion of the lipophilic granules in a hydrophilic matrix. A similar result can also be obtained by coating the lipophilic matrix granules with a layer of hydrophilic polymer.
Le compresse ottenibili secondo l’invenzione possono essere eventualmente sottoposte a noti processi di rivestimento con un film gastroresistente, costituito ad esempio da polimeri di acidi metacrilici (Eudragit R) o da derivati della cellulosa, quale l’aceto ftalato di cellulosa. The tablets obtainable according to the invention may possibly be subjected to known coating processes with a gastro-resistant film, consisting for example of polymers of methacrylic acids (Eudragit R) or cellulose derivatives, such as cellulose phthalate vinegar.
Ingredienti attivi che possono essere convenientemente formulati secondo l'invenzione comprendono: Active ingredients which can be conveniently formulated according to the invention include:
analgesici, come acetominofene, fenacetina, sodiosalicilato; antitussivi. come destrometorfano, codeina fosfato; broncodilatatori, come albuterolo, procaterolo; analgesics, such as acetominophen, phenacetin, sodium salicylate; antitussives. such as dextromethorphan, codeine phosphate; bronchodilators, such as albuterol, procaterol;
antipsicotici, come aloperidolo, clorpromazina; antipsychotics, such as haloperidol, chlorpromazine;
antiipertensivi e coronarodilatori. come isosorbide mono- e dinitrato, captopril; antihypertensive and coronary heart dilators. as isosorbide mono- and dinitrate, captopril;
beta 2 antagonisti selettivi come salbutamolo, terbutalina, efedrina, orciprenalina sulfato; selective beta 2 antagonists such as salbutamol, terbutaline, ephedrine, orciprenaline sulfate;
calcio antagonisti, come nifedipina, nicardipihàj diltiazem, verapamil; antiparkinson. come pergolide, carpidopa, levodopa; calcium channel blockers, such as nifedipine, nicardipihaj diltiazem, verapamil; antiparkinson. such as pergolide, carpidopa, levodopa;
farmaci antiinfiammatori non steroidei, come ketoprofene, ibuprofene, diclofenac, diflunisal, piroxicam, naprossene. ketorolac, nimesulide; antistaminici, come terfenedina, loratadina; non-steroidal anti-inflammatory drugs, such as ketoprofen, ibuprofen, diclofenac, diflunisal, piroxicam, naproxen. ketorolac, nimesulide; antihistamines, such as terfenedine, loratadine;
antidiarroici e antiinfiammatori intestinali, come loperamide, 5-aminosalicilico, olsalazina, sulfasalazina, budenoside; antispasmolitici come ottiionio bromuro; intestinal antidiarrheal and anti-inflammatory drugs, such as loperamide, 5-aminosalicylic, olsalazine, sulfasalazine, budenoside; antispasmolytics such as octyion bromide;
ansiolitici, come clordiazepossido, oxazepam, medazepam, alprazolam, donazepam, lorazepan; antidiabetici orali, come glipizide, metformina, fenformina, gilclazide, glibenclamide; lassativi, come bisacodil, sodio picosulfato; anxiolytics, such as chlordiazepoxide, oxazepam, medazepam, alprazolam, donazepam, lorazepan; oral antidiabetics, such as glipizide, metformin, phenformin, gilclazide, glibenclamide; laxatives, such as bisacodyl, sodium picosulfate;
antiepilettici, valproato, carbamazepina, fenitoina, gabapentina; antitumorali, come flutammide, etoposide. antiepileptics, valproate, carbamazepine, phenytoin, gabapentine; anticancer drugs, such as flutamide, etoposide.
Le composizioni dell'invenzione possono inoltre contenere eccipienti convenzionali, ad esempio eccipienti bioadesivi quali chitosani, poliacrilammidi, gomme naturali o sintetiche, polimeri dell'acido acrilico. The compositions of the invention can also contain conventional excipients, for example bioadhesive excipients such as chitosans, polyacrylamides, natural or synthetic rubbers, polymers of acrylic acid.
Le composizioni dell'invenzione possono contenere più di un ingrediente attivo, ognuno dei quali può essere eventualmente confinato nella matrice idrofila o nella matrice anfifila inerte, e sono preferibilmente in forma di compresse, capsule o minimatrici. The compositions of the invention can contain more than one active ingredient, each of which can optionally be confined in the hydrophilic matrix or in the inert amphiphilic matrix, and are preferably in the form of tablets, capsules or minimizers.
In termini di caratteristica di dissoluzione, il contatto di tali matrici con acqua o fluidi acquosi provoca l'immediata penetrazione dell’acqua all'interno dello strato più superficiale della matrice che, grazie alla presenza di solvente acquoso, inizia a rigonfiare per distensione delle proprie catene polimeriche di idrogeli. In terms of dissolution characteristics, the contact of these matrices with water or aqueous fluids causes the immediate penetration of water into the most superficial layer of the matrix which, thanks to the presence of aqueous solvent, begins to swell by distension of its own polymer chains of hydrogels.
In tal modo, si forma un fronte idratato ad elevata viscosità che si oppone all'ulteriore penetrazione del solvente stesso rallentando il processo di dissoluzione in modo lineare fino ad un certo punto, mediamente posizionabile a metà dello spessore, fino a quando l'ulteriore penetrazione di solvente provocherebbe lo sfaldamento dello strato idrofilo con conseguente liberazione del contenuto che, essendo costituito da granuli di matrice inerte, mette in azione il meccanismo diffusionale tipico di queste strutture e, pertanto, continua a rallentare la caratteristica di dissoluzione del principio attivo. In this way, a high viscosity hydrated front is formed which opposes the further penetration of the solvent itself, slowing down the dissolution process in a linear way up to a certain point, on average positioned at half the thickness, until the further penetration of solvent would cause flaking of the hydrophilic layer with consequent release of the content which, being made up of granules of inert matrix, activates the diffusion mechanism typical of these structures and, therefore, continues to slow down the dissolution characteristic of the active ingredient.
La presenza della matrice anfifila all’interno della matrice lipofila inerte, tuttavia consente di non avere discontinuità del profilo di liberazione del principio attivo. I tensioattivi presenti nella parte anfifila favoriscono la bagnabilità dei canalicoli porosi che attraversano la matrice inerte evitando o solamente moderando l’instaurarsi di fenomeni di resistenza alla penetrazione del solvente all’interno della matrice inerte. The presence of the amphiphilic matrix within the inert lipophilic matrix, however, allows for no discontinuity in the release profile of the active ingredient. The surfactants present in the amphiphilic part favor the wettability of the porous channels that cross the inert matrix, avoiding or only moderating the onset of phenomena of resistance to the penetration of the solvent inside the inert matrix.
I seguenti Esempi illustrano l'invenzione in maggior dettaglio. The following Examples illustrate the invention in greater detail.
ESEMPIO 1 EXAMPLE 1
500 g di acido 5-Aminosalicilico e 20 g di ottiionio bromuro vengono impastati con 10 g di lecitina di soia disciolta in 50 g di una miscela acqua alcool etilico 1 :3 e mantenuta a 50°C circa. Dopo omogeneizzazione ed essiccamento dell’impasto, i granuli della matrice così ottenuta vengono trattati in impastatore con 20 g di cera carnauba e 50 g di acido stearico a caldo fino a dispersione omogenea e, quindi, estrusi in piccoli granuli a freddo, i granuli di matrice inerte vengono caricati in un miscelatore in cui si aggiungono sequenzialmente 30 g di carbopol 971 P e 65 g di idrossipropilmetilcellulosa. Dopo un primo step di miscelazione per disperdere omogeneamente polveri, vengono aggiunti 60 g di cellulosa microcristallina e 5 g di magnesio stearato. Dopo aver mescolato, si comprime a miscela finale al peso unitario di 760 mg/cpr. Le compresse ottenute vengono sottoposte a filmatura con acetoftalato di cellulosa o polimetacrilati e plasticizzanti per garantire la gastroresistenza alle compresse stesse ed impedire il rilascio precoce di prodotto nello stomaco. 500 g of 5-Aminosalicylic acid and 20 g of octyion bromide are mixed with 10 g of soy lecithin dissolved in 50 g of a 1: 3 ethyl alcohol water mixture and maintained at about 50 ° C. After homogenization and drying of the mixture, the granules of the matrix thus obtained are treated in a kneader with 20 g of carnauba wax and 50 g of hot stearic acid until homogeneous dispersion and, then, extruded into small cold granules, the granules of inert matrix are loaded into a mixer in which 30 g of carbopol 971 P and 65 g of hydroxypropylmethylcellulose are sequentially added. After a first mixing step to homogeneously disperse powders, 60 g of microcrystalline cellulose and 5 g of magnesium stearate are added. After mixing, the final mixture is compressed to the unit weight of 760 mg / tablet. The tablets obtained are filmed with cellulose acetophthalate or polymethacrylates and plasticizers to guarantee the gastro-resistance to the tablets themselves and prevent the premature release of the product in the stomach.
Le compresse cosi ottenute, sottoposte a test di dissoluzione, in ambiente intestinale simulato, hanno evidenziato un rilascio dei principi attivi con il seguente andamento: dopo 60 minuti non più del 30%, dopo 180 minuti non più del 60%, dopo 5 ore non più dell’ 80%. The tablets thus obtained, subjected to dissolution tests, in a simulated intestinal environment, showed a release of the active ingredients with the following trend: after 60 minutes no more than 30%, after 180 minutes no more than 60%, after 5 hours no more than 80%.
ESEMPIO 2 EXAMPLE 2
50 g di dietilenglicole monetil etere vengono distribuiti omogeneamente su 500 g di cellulosa microcristallina; quindi si aggiungono 100 g di Budesonide e si mescola fino a completa omogeneizzazione. A questo impasto si aggiungono ulteriori 400 g di Budesonide che vengono dispersi in un impastatore contenente 100 g di cera carnauba e 100 g di acido stearico preriscaldati alla temperatura di 60°C. Dopo 5 minuti di impasto la miscela viene raffreddata a temperatura ambiente ed estrusa in granuli di dimensioni inferiori al mm. 50 g of diethylene glycol and monetyl ether are homogeneously distributed on 500 g of microcrystalline cellulose; then add 100 g of Budesonide and mix until completely homogenized. To this mixture are added a further 400 g of Budesonide which are dispersed in a mixer containing 100 g of carnauba wax and 100 g of stearic acid preheated to a temperature of 60 ° C. After 5 minutes of mixing, the mixture is cooled to room temperature and extruded into granules smaller than 1 mm.
In un miscelatore di idonea capacità vengono posti i granuli di matrice preparati come sopra e le seguenti quantità di eccipienti idrofili: idrossipropilmetilcellulosa g 1500 e policarbophil g 500. The matrix granules prepared as above and the following quantities of hydrophilic excipients are placed in a mixer of suitable capacity: 1500 g hydroxypropylmethylcellulose and 500 g polycarbophil.
51 miscelano i componenti sino a dispersione omogenea delle matrici e, quindi, si aggiungono: 51 mix the components until homogeneous dispersion of the matrices and, therefore, add:
2450 g di cellulosa microcristallina; 400 g di lattosio; 100 g di silice colloidale e 50 g di magnesio stearato. Dopo ulteriori 5 minuti di miscelazione, la mescola viene sottoposta a compressione al peso unitario di 250 mg/cpr. 2450 g of microcrystalline cellulose; 400 g of lactose; 100 g of colloidal silica and 50 g of magnesium stearate. After a further 5 minutes of mixing, the mixture is subjected to compression at the unit weight of 250 mg / tablet.
ESEMPIO 3 EXAMPLE 3
850 g di metformina vengono dispersi in un granulatore/impastatore con 35 g di dietilenglicole monoetilene previamente fusi con 100 g di acido stearico e 55 g di cera carnauba. 850 g of metformin are dispersed in a granulator / mixer with 35 g of diethylene glycol monoethylene previously fused with 100 g of stearic acid and 55 g of carnauba wax.
Si riscalda il sistema per permettere il caricamento e la granulazione del principio attivo nel sistema a matrice inerte. Quindi, ai 1040 g del formulato così ottenuto vengono addizionati 110 g di idrossipropil metilcellulosa e 20 g di magnesio stearato. The system is heated to allow loading and granulation of the active ingredient in the inert matrix system. Then, 110 g of hydroxypropyl methylcellulose and 20 g of magnesium stearate are added to the 1040 g of the formulation thus obtained.
Si comprime la miscela finale fino a peso unitario di 1170 mg/cpr per somministrare 850 mg di principio attivo. The final mixture is compressed to a unit weight of 1170 mg / tablet to administer 850 mg of active principle.
Le compresse così ottenute, sottoposte al test di dissoluzione, in ambiente intestinale simulato , hanno evidenziato un rilascio del principio attivo con il seguente andamento: dopo 60 minuti non più del 35%, dopo 180 minuti non più del 60%, dopo 5 ore non più dell’80%. The tablets thus obtained, subjected to the dissolution test, in a simulated intestinal environment, showed a release of the active ingredient with the following trend: after 60 minutes no more than 35%, after 180 minutes no more than 60%, after 5 hours no more than 80%.
ESEMPIO 4 EXAMPLE 4
120 g di ottiionio bromuro vengono dispersi in un granulatore/impastatore con 30 g di acido stearico e 15 g di cera d’api ove sono stati previamente fusi 10 g di dietilen glicole monoetilene. 120 g of octyion bromide are dispersed in a granulator / mixer with 30 g of stearic acid and 15 g of beeswax where 10 g of diethylene glycol monoethylene have been previously melted.
Si riscalda il sistema per permettere il caricamento e la granulazione del principio attivo nel sistema a matrice inerte. Quindi, ai 10 g del formulato ottenuto, vengono addizionati 5 g di idrossipropil metilcellulosa e 5 g di policarbophyl; 2 g di magnesio stearato e 3 g di cellulosa microcristallina. Si comprime la miscela finale fino al peso unitario di 200 mg/cpr per somministrare 120 mg di principio attivo. The system is heated to allow loading and granulation of the active ingredient in the inert matrix system. Then, to the 10 g of the obtained formulation, 5 g of hydroxypropyl methylcellulose and 5 g of polycarbophyl are added; 2 g of magnesium stearate and 3 g of microcrystalline cellulose. The final mixture is compressed to a unit weight of 200 mg / tablet to administer 120 mg of active principle.
Le compresse così ottenute, sottoposte a test di dissoluzione, in ambiente intestinale simulato, hanno messo in evidenza un rilascio del principio secondo il seguente andamento: dopo 60 minuti non più del 25%; dopo 180 minuti non più del 50%; dopo 5 ore non più del 70%. The tablets thus obtained, subjected to dissolution tests, in a simulated intestinal environment, showed a release of the principle according to the following trend: after 60 minutes no more than 25%; after 180 minutes not more than 50%; after 5 hours not more than 70%.
ESEMPIO 5 EXAMPLE 5
12 g di dietilenglicole monoetil etere vengono caricati su 6 g di cellulosa microcristallina e 6 grammi di calcio carbonato, e quindi si aggiungono 100 g di Gabapentin e si procede ad omogeneizzare la miscela; a questo punto si aggiungono 800 g di Gabapentin che vengono dispersi in un granulatore/impastatore con 4,5 g di cera bianca e 5 g di acido stearico. Si riscalda il sistema per permettere il caricamento e la granulazione del principio attivo nel sistema a matrice inerte. Quindi, ai 916,5 g del formulato ottenuto vengono addizionati 39,5 g di idrossipropil metiicellulosa, 10 g di acido alginico, 11 g di magnesio stearato e 6 g di syloid. Si comprime la miscela finale fino al peso unitario di 1000 mg/cpr per somministrare 900 mg di principio attivo. 12 g of diethylene glycol monoethyl ether are loaded onto 6 g of microcrystalline cellulose and 6 grams of calcium carbonate, and then 100 g of Gabapentin are added and the mixture is homogenized; at this point 800 g of Gabapentin are added which are dispersed in a granulator / mixer with 4.5 g of white wax and 5 g of stearic acid. The system is heated to allow loading and granulation of the active ingredient in the inert matrix system. Then, 39.5 g of hydroxypropyl methiicellulose, 10 g of alginic acid, 11 g of magnesium stearate and 6 g of syloid are added to the 916.5 g of the obtained formulation. The final mixture is compressed to a unit weight of 1000 mg / tablet to administer 900 mg of active principle.
ESEMPIO 6 EXAMPLE 6
50 g (25 g) di carbidopa e 200 g (100 g) di levodopa vengono dispersi in un granulatore/impastatore con 60 g (30 g) di acido stearico e 30 g (15 g) di cera flava, in cui sono stati previamente fusi 10 (5) g di dietilenglicole monoetil etere. 50 g (25 g) of carbidopa and 200 g (100 g) of levodopa are dispersed in a granulator / mixer with 60 g (30 g) of stearic acid and 30 g (15 g) of cera flava, in which they have been previously melts 10 (5) g diethylene glycol monoethyl ether.
51 riscalda il sistema per permettere il caricamento e la granulazione del principio attivo nel sistema a matrice inerte. Quindi, ai 340 g (170 g) del formulato ottenuto vengono addizionati 20 g (10 g) di idrossipropil metilcellulosa; 10 g (5 g) di xantangum; 16 g (8 g) di cellulosa microcristallina; 4 g (2g) di magnesio stearato. 51 heats the system to allow the loading and granulation of the active ingredient in the inert matrix system. Then, 20 g (10 g) of hydroxypropyl methylcellulose are added to the 340 g (170 g) of the obtained formulation; 10 g (5 g) of xantangum; 16 g (8 g) of microcrystalline cellulose; 4 g (2g) of magnesium stearate.
Si comprime la miscela finale fino al peso unitario di 400 (200) mg/cpr per somministrare 50(25) mg di carbidopa e 200 (100) mg di levodopa. The final mixture is compressed to a unit weight of 400 (200) mg / tablet to administer 50 (25) mg of carbidopa and 200 (100) mg of levodopa.
ESEMPIO 7 EXAMPLE 7
4 g di Nimesulide vengono solubilizzati in 50 g di dietilenglicole monoetil etere. 4 g of Nimesulide are solubilized in 50 g of diethylene glycol monoethyl ether.
Si caricano quindi in 100 g di cellulosa microcristallina fino ad ottenere una miscela omogenea. They are then loaded into 100 g of microcrystalline cellulose until a homogeneous mixture is obtained.
Alla miscela ottenuta, in un granulai ore/imp astato re si aggiungono 196 g di Nimesulide, 50 g di acido stearico e 25 g di cera carnauba. Si riscalda il sistema per permettere il caricamento e la granulazione del principio attivo nel sistema a matrice inerte ed anfifila. To the mixture obtained, 196 g of Nimesulide, 50 g of stearic acid and 25 g of carnauba wax are added in a granule / paste. The system is heated to allow the loading and granulation of the active ingredient in the inert and amphiphilic matrix system.
A 425 g del granulare così ottenuto vengono addizionati 60 g di idrossipropilmetilcellulosa, 5 g di policarbophil e 10 g di magnesio stearato. 60 g of hydroxypropylmethylcellulose, 5 g of polycarbophil and 10 g of magnesium stearate are added to 425 g of the granular so obtained.
Si comprime la miscela finale fino a un peso unitario di 500 mg/cpr per somministrare 200 mg di principio attivo. The final mixture is compressed to a unit weight of 500 mg / tablet to administer 200 mg of active principle.
Le compresse così ottenute, sottoposte al test di dissoluzione hanno evidenziato, in ambiente intestinale simulato, un rilascio con il seguente andamento: dopo 1 ora non più del 25%, dopo 2 ore non più del 40%, dopo 4 ore non più del 60%, dopo 8 ore non più del 90%. The tablets thus obtained, subjected to the dissolution test, showed, in a simulated intestinal environment, a release with the following trend: after 1 hour not more than 25%, after 2 hours not more than 40%, after 4 hours not more than 60 %, after 8 hours not more than 90%.
ESEMPIO 8 EXAMPLE 8
500 g di propionilcamitina vengono dispersi in un granulatore/impastatore con 90 g di acido stearico e 40 g di cera carnauba, in cui sono stati previamente fusi 20 g di dietilenglicole monoetil etere. Si riscalda il sistema per permettere il caricamento e la granulazione del principio attivo nel sistema a matrice inerte/anfifila. 500 g of propionylcamitine are dispersed in a granulator / mixer with 90 g of stearic acid and 40 g of carnauba wax, in which 20 g of diethylene glycol monoethyl ether have been previously melted. The system is heated to allow loading and granulation of the active ingredient in the inert / amphiphilic matrix system.
Quindi, ai 650 g del formulato così ottenuto vengono addizionati 60 g di idrossipropil metilcellulosa e 10 g di magnesio stearato. Then, 60 g of hydroxypropyl methylcellulose and 10 g of magnesium stearate are added to the 650 g of the formulation thus obtained.
Si comprime la miscela finale fino a peso unitario di 720 mg/cpr per somministrare 500 mg di principio attivo. The final mixture is compressed to a unit weight of 720 mg / tablet to administer 500 mg of active principle.
Le compresse così ottenute, sottoposte al test di dissoluzione, in ambiente intestinale simulato , hanno evidenziato un rilascio del principio attivo con il seguente andamento: dopo 60 minuti non più del 40%, dopo 180 minuti non più del 60%, dopo 4 ore non più dell’ 80%, dopo 8 ore non più del 90%. The tablets thus obtained, subjected to the dissolution test, in a simulated intestinal environment, showed a release of the active ingredient with the following trend: after 60 minutes no more than 40%, after 180 minutes no more than 60%, after 4 hours no more than 80%, after 8 hours not more than 90%.
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DE60005819T DE60005819T2 (en) | 1999-06-14 | 2000-06-09 | TASTE-MASKED ORAL PHARMACEUTICAL COMPOSITIONS WITH CONTROLLED DELIVERY |
AT00942044T ATE251449T1 (en) | 1999-06-14 | 2000-06-09 | FLAVOR-MASKED ORAL PHARMACEUTICAL COMPOSITIONS WITH CONTROLLED DELIVERY |
JP2001502812A JP4790950B2 (en) | 1999-06-14 | 2000-06-09 | Controlled release and taste-masked oral pharmaceutical composition |
DK00942044T DK1183014T3 (en) | 1999-06-14 | 2000-06-09 | Flavored controlled release oral pharmaceutical compositions |
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CA002377301A CA2377301C (en) | 1999-06-14 | 2000-06-09 | Controlled release and taste masking oral pharmaceutical compositions |
PT00942044T PT1183014E (en) | 1999-06-14 | 2000-06-09 | ORAL PHARMACEUTICAL COMPOSITIONS FOR CONTROLLED LIBERATION AND TISSUE DISSIMULATION |
MXPA01012889A MXPA01012889A (en) | 1999-06-14 | 2000-06-09 | Controlled release and taste masking oral pharmaceutical compositions. |
TR2002/00562T TR200200562T2 (en) | 1999-06-14 | 2000-06-09 | Pharmaceutical compositions for oral release that can be secreted in the body in a controlled manner and prevent unpleasant taste |
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AU56801/00A AU5680100A (en) | 1999-06-14 | 2000-06-09 | Controlled release and taste masking oral pharmaceutical compositions |
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RU2002100367/15A RU2246293C2 (en) | 1999-06-14 | 2000-06-09 | Pharmaceutical compositions for oral administration with sustained-releasing active component and masking taste |
NO20016108A NO331642B1 (en) | 1999-06-14 | 2001-12-14 | Controlled release and taste masking oral pharmaceutical compositions |
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US11/268,500 US7410651B2 (en) | 1999-06-14 | 2005-11-08 | Controlled release and taste masking oral pharmaceutical composition |
US11/378,378 US7410652B2 (en) | 1999-06-14 | 2006-03-20 | Controlled release and taste masking oral pharmaceutical composition |
US12/210,969 US8029823B2 (en) | 1999-06-14 | 2008-09-15 | Controlled release and taste masking oral pharmaceutical composition |
JP2011000092A JP5279851B2 (en) | 1999-06-14 | 2011-01-04 | Controlled release and taste-masked oral pharmaceutical composition |
JP2011000091A JP5279850B2 (en) | 1999-06-14 | 2011-01-04 | Controlled release and taste-masked oral pharmaceutical composition |
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US13/249,839 US20120021053A1 (en) | 1999-06-14 | 2011-09-30 | Controlled release and taste-masking oral pharmaceutical composition |
US13/462,430 US20120220559A1 (en) | 1999-06-14 | 2012-05-02 | Controlled Release and Taste Masking Oral Pharmaceutical Composition |
US13/462,409 US8293273B2 (en) | 1999-06-14 | 2012-05-02 | Controlled release and taste masking oral pharmaceutical composition |
US13/477,592 USRE43799E1 (en) | 1999-06-14 | 2012-05-22 | Controlled release and taste masking oral pharmaceutical composition |
US13/585,190 US9132093B2 (en) | 1999-06-14 | 2012-08-14 | Controlled release and taste making oral pharmaceutical composition |
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US13/617,138 US8784888B2 (en) | 1999-06-14 | 2012-09-14 | Controlled release and taste masking oral pharmaceutical composition |
US13/660,308 US20130053360A1 (en) | 1999-06-14 | 2012-10-25 | Controlled release and taste masking oral pharmaceutical composition |
US14/308,279 US9320716B2 (en) | 1999-06-14 | 2014-06-18 | Controlled release and taste masking oral pharmaceutical compositions |
US14/308,305 US9532954B2 (en) | 1999-06-14 | 2014-06-18 | Controlled release and taste masking oral pharmaceutical compositions |
US14/491,363 US9192581B2 (en) | 1999-06-14 | 2014-09-19 | Controlled release and taste masking oral pharmaceutical composition |
US14/514,967 US20150056279A1 (en) | 1999-06-14 | 2014-10-15 | Controlled Release and Taste Masking Oral Pharmaceutical Compositions |
US14/832,845 US20150352128A1 (en) | 1999-06-14 | 2015-08-21 | Controlled release and taste masking oral pharmaceutical composition |
US15/202,962 US9592203B2 (en) | 1999-06-14 | 2016-07-06 | Controlled release and taste masking oral pharmaceutical composition |
US15/368,911 US9737489B2 (en) | 1999-06-14 | 2016-12-05 | Controlled release and taste masking oral pharmaceutical composition |
US15/369,296 US10064878B2 (en) | 1999-06-14 | 2016-12-05 | Controlled release and taste masking oral pharmaceutical compositions |
US15/646,585 US10052286B2 (en) | 1999-06-14 | 2017-07-11 | Controlled release and taste masking oral pharmaceutical composition |
US15/646,538 US10105374B2 (en) | 1999-06-14 | 2017-07-11 | Controlled release and taste masking oral pharmaceutical compositions |
US15/646,330 US10143698B2 (en) | 1999-06-14 | 2017-07-11 | Controlled release and taste masking oral pharmaceutical compositions |
US16/132,718 US20190015428A1 (en) | 1999-06-14 | 2018-09-17 | Controlled release and taste masking oral pharmaceutical compositions |
US16/139,672 US20190022112A1 (en) | 1999-06-14 | 2018-09-24 | Controlled release and taste masking oral pharmaceutical compositions |
US16/234,951 US20190134061A1 (en) | 1999-06-14 | 2018-12-28 | Controlled release and taste masking oral pharmaceutical compositions |
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