WO2009125432A2 - Systèmes d'administration de médicament expansible alimentés par gaz - Google Patents

Systèmes d'administration de médicament expansible alimentés par gaz Download PDF

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Publication number
WO2009125432A2
WO2009125432A2 PCT/IN2009/000222 IN2009000222W WO2009125432A2 WO 2009125432 A2 WO2009125432 A2 WO 2009125432A2 IN 2009000222 W IN2009000222 W IN 2009000222W WO 2009125432 A2 WO2009125432 A2 WO 2009125432A2
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Prior art keywords
delivery system
drug delivery
expandable
drug
polymers
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PCT/IN2009/000222
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WO2009125432A3 (fr
Inventor
Hans E. Junginger
Assal M. M. Sadeghi
Farid Dorkoosh
Mohammad Reza Avadi
Morteza Rafiee-Tehrani
Pandharinath Jadhav
Rajesh Kulkarni
Shirishkumar Kulkarni
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Lupin Ltd
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Lupin Ltd
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Publication of WO2009125432A3 publication Critical patent/WO2009125432A3/fr
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    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus

Definitions

  • the invention relates to a single unit expandable drug delivery system of hydrophilic macromolecular or low molecular active ingredients, one or more force generating components, preferentially achieved by the formation of carbon dioxide bubbles, absorption modifiers and a nano/microsized matrix of mucoadhesive components for oral application.
  • the active ingredient is entrapped into the nano/microsized particles of a mucoadhesive polymer matrix.
  • the single unit dosage form is optionally coated with a degradable separating and/or enteric coating layer.
  • the invention is primarily intended for the delivery of hydrophilic drugs in the intestinal tract and colon.
  • site specific delivery is required to deploy the peptides and proteins intactly to specifically targeted parts of the body through a platform that can control their release by means of physiological or chemical triggers.
  • Therapeutics like protein, peptide and nucleotide are unstable against acidic, alkaline and/or enzymatic degradation upon systemic uptake and additionally they show poor intestinal absorption due to their high hydrophilicity. Therefore, these compounds are administered by parenteral injection, which has the disadvantages of painful application, risk of infections, low patient compliance and the need of trained personnel.
  • oral route is the easiest and most preferred way of drug administration for most high molecular weight drugs or active ingredients.
  • oral absorption of peptide drugs like insulin is hampered by the properties of the drug since the peptide molecule is unable to cross the lipophilic enterocyte membrane and also due to the hostile environment of the gastro-intestinal tract (high acid concentration in the stomach and high amount of enzymes (peptidases)) in the lumen of the gut).
  • micro- or nanosized systems based on mucoadhesive and multifunctional polymers which are able to adhere to the enteral mucosa for a certain period of time, interact with the tight junctions protein to reversibly open the tight-junctions, locally de-activate the gut enzymes and finally release the peptide drug at the preferred site in the Gl tract.
  • these micro- or nanosized delivery systems are only capable of inducing substantial blood peptide drug levels in small animals like mice and rats, but unable to be effective in bigger animals like pigs of 25 - 30 kg or humans.
  • EP-A-O 873 750 discloses tablets for localized drug delivery of actives. These tablets adhere to biological material by means of a bioadhesive layer that becomes adhesive after impregnation with water or biological fluids. After adhesion, an active ingredient is released.
  • the matrix system consists of polymers such as cellulose derivatives. The drug delivery system in presence of food will not have a desired release pattern.
  • US 5292518 discloses a prolonged release composition consisting of active, gel forming dietary fiber and mineral salts which release gas upon ingestion.
  • the delivery system described above is not feasible for site-specific drug delivery (small intestine).
  • EP0542364 discloses a device, which essentially contains an aperture through which the drug is released.
  • the release rate is independent of the environmental pH and can release the drug even in stomach.
  • This sort of a delivery system is a disadvantage for the acid sensitive active agents like peptides and proteins.
  • WO01/30322 has disclosed the use of superporous hydrogels (SPHs) or SPHs Composites (SPHCs) the latter system also containing a super disintegrant like Ac-Di Sol. These polymers swell up on contact with aqueous fluid up to 200-fold of their dry volume and contain voids filled with drug composition which are sealed and coated.
  • SPHs superporous hydrogels
  • SPHCs SPHs Composites
  • the polymers Upon removal of the enteric coating, the polymers swell to mechanically attach to the intestinal wall for a certain period of time at a desired position of the intestine to bring the peptide delivery subunit system in direct contact with the mucosal membrane and further release the drug.
  • the SPHs or SPHC carrier systems shuttle system
  • the peristaltic forces of the gut to be excreted as fine polymer powder.
  • the invivo study in pigs resulted in reproducible absolute octreotide bioavailabilities of 16 ⁇ 3.3%. (F.A. Dorkoosh et.al; J. Control. Release. 2004, 99:199-206)
  • SPHs and SPHCs formulations fulfill the requirements bringing the peptide drugs in direct contact with the absorption membrane.
  • the synthesis and fabrication of the delivery systems is based on SPHs or SPHCs technology, which is difficult and not commercially feasible on production scale.
  • Another disadvantage is their big size (i.e. capsule size 000), which is not easily swallowed.
  • the present invention aims at developing a modified formulation, which overcomes the demerits associated with the exiting technologies disclosed in the prior art.
  • the primary objective of the invention is to deliver primarily hydrophilic actives to the intestinal tract and to make their absorption across the intestinal wall possible by fixing multiparticles containing active compounds by direct contact with the absorbing membrane of the gut tissue using mucoadhesive polymer.
  • Another objective of the invention is to use a delivery platform for the drug carrier nanosized particles or capsules, microsized particles or capsules including liposomes or other similar systems, micro tablets or microcapsules, quantum dots or similar systems.
  • Another objective of the invention is to prepare an expandable drug delivery system by generating gas bubbles using a simple chemical reaction without involving complex procedures.
  • Another objective of the invention is the forced transport of the micro/nanosized drug carriers by the gas bubbles to the absorbing membrane simultaneously protecting their mucoadhesive properties through the gas bubbles
  • Another objective of the invention is to prepare an expandable drug delivery system comprising absorption modifiers to facilitate opening of the tight junctions of the intestinal epithelium.
  • Another objective of the invention is to deliver the peptide drugs (which are sensitive to the pH and the digestive enzymes of GIT) without exposing the drug to the GIT contents.
  • Yet another objective of the invention is to release the drug at the specific site after a lag time, which is achieved by enteric coating.
  • the present invention relates to the preparation of an Expandable drug delivery system or gas empowered drug delivery system comprising of actives, force generating component, absorption modifiers, optionally coated with enteric coating polymers.
  • the preparation may further include pharmaceutical excipients or carriers.
  • the present invention also relates to preparation of an expandable drug delivery system, which delivers the drug at a specific site of the intestinal tract by adhering to the mucous membrane using bioadhesive polymers.
  • the present invention also aims at the preparation of an expandable delivery system whereby the dosage form reaches the desired site of action after administration for imbibes the intestinal fluids into the core. Consequently, it dissolves the absorption modifiers in the core which generates a force to expand the dosage form and adheres firmly to the lumen.
  • the drug present in micro/nano particles diffuses through the polymer matrix and is absorbed across the intestinal wall primarily by the paracellular pathway.
  • the micro/nano particles which is adhered to the intestinal wall, slides down as the mucous membrane is shed off and reaches the large intestine where the micro/nano particles is degraded or expelled as such.
  • the dosage form of the present invention may contain carbon dioxide releasing agent (force generating component) that pushes the nano/microsized multiparticles to the absorbing membrane and forms a bubble layer around the nano/microsized multiparticles acting as a protective layer against enzymatic degradation of the drug.
  • the carbon dioxide bubbles formed by the gas generating components may additionally act as penetration enhancers when reaching the mucosal surface.
  • the enteric coating dissolves and the carbon dioxide bubbles are formed due to the gas releasing agent.
  • the bubbles also prevent the hydration of the mucoadhesive polymer off the nano/microsized delivery systems until it reaches the mucosal surface preventing the mucoadhesive polymers in the delivery systems from being de-activated by soluble mucins present in the gut lumen
  • FIG.1 depicts the schematic description of the behaviour of gas empowered expandable drug delivery system (GEDDS) after oral administration
  • GEDDS gas empowered expandable drug delivery system
  • FIG.2 The effect of the GEDD system on the transport of the insulin across the sheep's intestine.
  • An expandable drug delivery system/ gas empowered expandable drug delivery system is a system, which consists of more than one microparticles . Each microparticles acts as separate delivery system in which the active agent(s) is entrapped.
  • the expandable drug delivery system may be a multiparticulate or single unit system. Multiparticulate is manufactured with any of the techniques known in the prior art or known to the person skilled in the art.
  • multiparticulate drug delivery system examples include nanoparticles or nanocapsules, micro particles or microcapsules, liposomes or niosomes in unilamellar or multilamellar structure, micro tablets or quantum dots, pellets or all other delivery systems which are filled in the capsules or punched in to mini tablets and filled in to capsule or compressed in to tablets.
  • the single unit drug delivery system is prepared by conventional granulation technique or by hot melt technique where in the non-multiparticulate is a monolithic tablet prepared by hot melt technique.
  • Absorption modifiers is defined as the substances that influence absorption of a drug in the gastrointestinal tract by an increase in the rate and/or the extent of absorption of the drugs that are known or suspected of having poor bioavailability. It is believed that such increase can rise from one or all of the following mechanisms:
  • Bioadhesion is defined as the ability of a material to adhere to a biological tissue for an extended period of time. Bioadhesion is one solution to the problem of inadequate residence time resulting from stomach emptying and intestinal peristalsis, and from displacement by ciliary movement. For sufficient bioadhesion to occur, an intimate contact must exist between the bioadhesive and the mucosal tissue, the bioadhesive must penetrate into the crevice of the tissue surface and/or mucus, to form mechanical, electrostatic, or chemical bonds. Bioadhesive properties of polymers are affected by both the nature of the polymer as well as the surrounding media. The terms bioadhesive and mucoadhesive can be used interchangeably.
  • multilayered dosage form is a dosage form which is made up of one or more layers. If it is more than on layer the layers can be laminated horizontally, vertically or by concentric layered (where in the core has a coated layer).
  • Carrier or excipients comprises of a material that is not biologically or otherwise undesirable.
  • the carriers or excipients may include any biologically inactive substance known in prior art used for the preparation of any pharmaceutical dosage form.
  • the formulation will, in general comprise of one or more excipients.
  • excipients include, but are not limited to, diluents, disintegrants, lubricant, glident, binders, fillers, surfactant, solubilizers, and wetting agents.
  • excipients will include diluents such as mannitol, dextrose, xylitol, sorbitol, gelatin, acacia, sucrose, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, lactose, starches, vinyl polymers and the likes.
  • Disintegrants referred to in the present invention include one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, sodium starch glycolate and the likes.
  • Binders referred to in the present invention include one or more celluloses such as hydroxypropyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose or mixtures thereof, acrylates, methacrylates, povidone, sucrose, corn or maize starch, pregelatinized starch and the like, coloring agents such as ferric oxide, FD&C dyes, lakes and the likes and flavoring agent.
  • glidents include but are not limited to silica, sodium benzoate, magnesium trisilicate, powdered cellulose, talc, and starch.
  • force-generating component is defined as the component that is responsible for generating force for expanding the drug delivery system and give sufficient strength or pushing power to transport the drug to the absorbing membrane for the time period sufficient to release the drug.
  • the force generating component comprises of gas generating components like carbon dioxide releasing agents e.g. acid base mixtures, carbonates and bicarbonate, swelling polymers, osmogens and the like the force generating component can be a swellable or a non swellable substance.
  • expandable drug delivery system is a delivery system which can expand or swell, which is fabricated in combination of gas forming compounds, swellable polymers and/or mucoadhesive polymers and the latter two components are able to adhere to the mucous membrane and expand at the site of the lumen after being pushed there by the force generating components.
  • the delivery system can release sub unit delivery (multi particles) platforms, which are driven either by the swellable polymers and/or by the gas to the absorbing membrane.
  • These sub-units delivery system can consist of nanoparticles or nanocapsules, micro particles or microcapsules, liposomes or niosomes in unilamellar or multilamellar structure, micro tablets or quantum dots or all other delivery systems sized from 4 mm down to nanometer size, with or without mucoadhesive properties using mucoadhesive polymers as described below with or without substances which allow endocytosis or transcytosis of the particles across the enterocyctes of the intestine (like invasins and other similar particles across or along the enterocytes of the intestine (like invasins and other similar substances), with or with out enzyme inhibitors.
  • Active agents suitable for use in the present invention include biologically active agents (actives) and chemically active agents (high and low molecular weight), including, but not limited to, pharmacological agents, and therapeutic agents.
  • Suitable active agents include those that are rendered less effective, ineffective or are destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes and the like.
  • macromolecular agents that their physiochemical characteristics such as: size, structure or charge, prohibit or impede absorption when dosed orally.
  • biologically or chemically active agents suitable for use in the present invention include, but are not limited to, proteins, polypeptides, peptides, hormones, polysaccharides, mixtures of muco-polysaccharides; carbohydrates, lipids, organic compounds and finally compounds which do not pass or only a fraction of their administered dose can pass through the intestinal mucosa and/or are susceptible to chemical cleavage by acids and enzymes in the gastro-intestinal tract; or any combination thereof.
  • growth hormones including human growth hormones (hGH), recombinant human growth hormones (rhGH), bovine growth hormones, and porcine growth hormones
  • growth hormone releasing hormones growth hormone releasing factor, interferons, including [alpha] (e.g., interferon alfacon-1), [beta] and [gamma]
  • interferons including [alpha] (e.g., interferon alfacon-1), [beta] and [gamma]
  • interleukin-1 e.g., interleukin-2; glucagon
  • insulin including porcine, bovine, human, and human recombinant, optionally having counter ions including zinc, sodium, calcium and ammonium
  • insulin-like growth factor including IGF-I
  • heparin including un-fractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin and ultra low molecular
  • swellable polymer can encompass other polymers like mucoadhesive polymers and the like.
  • a swellable polymer/mucoadhesive is a polymer that expands upon ingestion such that the pharmaceutical composition is retained in the stomach for 30 minutes, 90 minutes, 4 hours, 6 hours, 12 hours, 24 hours or more post administration.
  • the swellable polymer may cause the pharmaceutical composition to increase in size 10%, 15%, 50%, 100% or 200% or more as compared to its pre-ingested volume.
  • the swellable polymers have a molecular weight in excess of 50,000 Daltons. In another embodiment, the swellable polymer has a molecular weight in excess of 200,000 Daltons. In another embodiment, the swellable polymer has a molecular weight in excess of 7,000,000 Daltons.
  • Swellable polymers include, but are not limited to, cross linked poly(acrylic acid), poly (alkylene oxide), polyvinyl alcohol, polyvinyl pyrrolidone); polyurethane hydrogel, maleic anhydride polymer, such as a maleic anhydride copolymer, a cellulose polymer, polysaccharide, starch, and starch based polymers.
  • poly (alkylene oxides) include, but are not limited to, polymers, which contain as a unit, ethylene oxide, propylene oxide, ethylene oxide, or propylene oxide. These polymers may consist entirely of any of the above units (as a monomer), combinations of any of the above units, such as a copolymer.
  • the swellable polymer is a block copolymer in which one of the repeating units consists of ethylene oxide, propylene oxide, ethylene oxide, or propylene oxide or combination thereof.
  • cellulose polymers include, but are not limited to, cellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy propyl methylcellulose (also known as hypromellose), and carboxymethyl cellulose or combination thereof.
  • polysaccharides include, but are not limited to, dextran, xanthan gum, gellan gum, welan gum, rhamsan gum, sodium alginate, calcium alginate, chitosan, gelatin, and maltodextrin.
  • starch-based polymers include, but are not limited to, hydrolyzed starch polyacrylonitrile graft copolymers, starch-acrylate-acrylamide copolymers or combination thereof.
  • Polyox 303(TM) Polyethylene oxide, molecular weight 7,000,000
  • Polyox WSR N-12K Polyethylene oxide, molecular weight 1 ,000,000
  • Polyox WSR N-60K Polyethylene oxide, molecular weight 2,000,000
  • Polyox WSR 301 Polyethylene oxide, molecular weight 4,000,000
  • Polyox WSR Coagulant PolyoxWSR 303
  • Polyox WSR 308, NFgrade(TM) Poly(ethylene oxide molecular weight 1 ,000,000) or combination thereof.
  • Swellable polymers can also be used as rate controlling polymers.
  • Release controlling polymers are often selected from the same class as swellable polymers.
  • release controlling polymers include, for example, poly(ethylene oxide), poly(acrylic acid), polyvinyl alcohol, alginate, chitosan and chitosan derivatives like trimethyl chitosan (TMC), polyvinylpyrrolidone, cellulose polymers and polysaccharides and the like. Addition of hydro-attractants can improve the swelling properties of a dosage form significantly, and hence can constitute a swellable polymer.
  • hydro-attractants which can be incorporated into pharmaceutical compositions of the present invention include crosslinked poly(acrylic acid), crosslinked polyvinyl pyrrolidone), microcrystalline cellulose, crosslinked carboxymethyl cellulose, starch granules, sodium carboxymethyl starch, alginates, low substituted hydroxypropyl cellulose (L-HPC, 10-13% substitution by weight, Shin-Etsu Chemical Company, Ltd, distributed by Biddle Sawyer), Croscarmellose Sodium (Primellose) (Avebe, distributed by Generichem), Sodium Starch Glycolate (Avebe, distributed by Generichem) sodium phosphates, such as disodium phosphate, sodium chloride, sodium citrate, sodium acetate, succinic acid, fumaric acid, tartaric acid, tannic acid, sugars (e.g. mannitol, sucrose, lactose, fructose, sorbitol) and natural amino acids. Amino acids can also be used as
  • An orally ingested product swells and adheres to either the epithelial surface or the mucus lining of the gastrointestinal tract.
  • a polymeric drug delivery device adhering to the epithelium or to the mucous layer.
  • Bioadhesion in the gastrointestinal tract proceeds in two stages: (1) viscoelastic deformation at the point of contact of the synthetic material into the mucus substrate, and (2) formation of bonds between the adhesive synthetic material and the mucus or the epithelial cells.
  • adhesion of polymers to tissues may be achieved by (i) physical or mechanical bonds, (ii) primary or covalent chemical bonds, and/or (iii) secondary chemical bonds (i.e., ionic).
  • Physical or mechanical bonds can result from deposition and inclusion of the adhesive material in the crevices of the mucus or the folds of the mucosa. Secondary chemical bonds, contributing to bioadhesive properties, consist of depressive interactions (i.e., Van der Waals interactions) and stronger specific interactions, which include hydrogen bonds.
  • the hydrophilic functional groups primarily responsible for forming hydrogen bonds are the hydroxyl and the carboxylic acid groups.
  • the present invention is a tablet for oral delivery of a drug, comprising a core containing the drug to be delivered intestinally, and optionally a polymeric coating, which is not bioadhesive.
  • the present invention is not limited to tablets, it may contain capsules, pellets, mini-tablets, granules, monolithic tablets, spherules and the like, known to a person skilled in the art at the time of invention. Also these dosage forms can be prepared by any I method known in the prior art. Another embodiment of the present invention wherein the expandable drug delivery system is in the form of mini-tables filled into the capsules. '
  • the dosage form of the present invention may contain and release carbon dioxide releasing agent that forms a bubble layer around the micro/nanoparticles which acts as a protective layer against enzymatic degradation.
  • the bubble layer formed by gas generating component will remain intact around the nano/microsized particles until it reaches the intestinal wall and adheres to the intestinal mucosa.
  • the gas generating component is the transport medium bringing the drug compartment to the absorbing mucosal surface.
  • the present invention provides methods for improving the bioadhesive properties of drug delivery systems such as tablets, capsules and drug-eluting devices.
  • the invention also provides methods for improving the adhesion of drug delivery systems to mucosal membranes including membranes of the gastrointestinal tract.
  • the polymeric drug delivery systems of the invention have an improved ability to bind to mucosal membranes, and thus can be used to deliver a wide range of drugs or diagnostic agents in a wide variety of therapeutic applications, and/or improve uptake of the active agent across the intestinal mucosa.
  • the pharmaceutical composition includes a mucoadhesives/ bioadhesives.
  • the mucoadhesive facilitates retention in the GIT by binding to the mucosal surface of the GIT, or by association with the mucus layer.
  • mucoadhesives include, but are not limited to, a polyacrylic acid or polyacrylate optionally cross-linked with allyl sucrose, allyl ethers of sucrose, allylpentaerythritol, pentaerythritol or divinyl glycol; carboxylvinyl polymer; polyvinyl pyrrolidone (PVP); polyvinyl alcohol; chitosan and its quaternary derivatives sodium carboxymethylcellulose (CMC); dextran polymer; copolymer of polymethyl vinyl ether and maleic anhydride; hydroxymethylcellulose; methylcellulose; tragacanth; alginic acid; gelatin; gum arabic; and polysaccharide optionally interrupted with a [beta]-(l-4)-linked D-glucosamine unit and/or a N-acetyl-D-glucosamine unit, and mixtures thereof.
  • a polyacrylic acid or polyacrylate optionally cross-linked with ally
  • the preferred embodiment of the present invention involves the preparation of an expandable delivery system in which the dosage form reaches the desired site of action and will adhere to the mucous surface followed by imbibing the fluids of the intestinal environment in to the core, where it activates the force generating material in the core which creates a force to expand the dosage form and carries it for adhesion to the luminal surface without losing its mucoadhesive properties.
  • the drug present in the polymer matrix diffuses across the intestinal wall by the paracellular route. Once the delivery system is adherered to the intestinal wall, it slides down as the mucous membrane is shed off due to the mucus turnover and reaches the large intestine and colon to be excreted.
  • the preferred embodiment of the present invention may include other excipients such as absorption enhancers and enzyme inhibitors. Also and intestinal motility modifiers can be integrated in the polymer matrix.
  • Examples of such compounds are EDTA, polyacrylates (Carbomer), chitosans and their derivatives such as TMC, anionic surfactants such as sodium lauryl sulfate, nonionic surfactants such as polyoxyethylene ethers and esters, fatty acids such as sodium caprate, trihydroxy bile salts such as taurocholate, dihydroxy bile salts such as taurodeoxycholate, acyl carnitines such as palmitoyl carnitine and salicylates such as sodium salicylate, carbon dioxide and the like.
  • anionic surfactants such as sodium lauryl sulfate
  • nonionic surfactants such as polyoxyethylene ethers and esters
  • fatty acids such as sodium caprate
  • trihydroxy bile salts such as taurocholate
  • dihydroxy bile salts such as taurodeoxycholate
  • acyl carnitines such as palmitoyl carnitine
  • salicylates such as sodium salicylate,
  • Enzyme inhibitors increase the absorption of macromolecular drugs.
  • Compounds, which increase epithelial permeability and reduce enzymatic activity simultaneously, can also be added.
  • Suitable enzyme inhibitors are aprotinin, cystatin, amino acid and its derivates, soybean trypsin inhibitor, leupeptin, bestatin and small inhibitors based on boron compounds, such ASA- aminoboronic acid derivatives.
  • ketoconazole and levamisol as enzyme inhibitors for cytochromes such as cytochrome P450 and especially for cytochrome P3A4 and for other drug transporters such as P-glycoproteins within the gut wall to overcome multidrug resistance of drugs especially anti-cancer drugs.
  • optional ingredients are compounds that can control the intestinal motility; either decreases the motility for prolonged retention time of the dosage form at the site of action or increase the motility for easier excretion of the dosage form.
  • These compounds can influence the transition of the system through specific parts of the intestine. Examples of such compounds are loperamide. HCI, papaverine. HCI, opiate receptor stimulators and acetylcholine antagonists.
  • the pharmaceutical composition may also contain other conventional pharmaceutical excipients, for example, water soluble diluents such as lactose, dextrose, mannitol, sorbitol, and the like; water insoluble diluents such as starch, microcrystalline cellulose, powdered cellulose, and the like; or lubricants such as talc, stearic acid or its salt, magnesium stearate, sodium benzoate and the like.
  • water soluble diluents such as lactose, dextrose, mannitol, sorbitol, and the like
  • water insoluble diluents such as starch, microcrystalline cellulose, powdered cellulose, and the like
  • lubricants such as talc, stearic acid or its salt, magnesium stearate, sodium benzoate and the like.
  • the invention is not limited to the examples given in the specification it may include other excipients, which are known in the field of invention.
  • the delivery system was prepared by granulation technique with the citric acid, Na- bicarbonate and lactose.
  • TMC Trimethyl chitosan
  • PEO Polyethylene oxide
  • Avicel Avicel
  • drug drug and the Na-benzoate were then added step-wise to the obtained granules and mixed.
  • the granules were then pressed to tablets.
  • the variables were: the percent of polyethylene oxide (PEO) as mucoadhesive polymer, percent of citric acid and Na-bicarbonate (CO gas production), and
  • the enteric coating of the present invention is obtained by coating of the delivery system with one or more polymer which protect the delivery from the acids of the stomach.
  • the entric polymer coat may contain a water insoluble polymer alone or in combination with water soluble substance with may be a polymer Suitable water-soluble polymers include, but are not limited to, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose.hydroxypropylcellulose.hdroxypropylmethylcellulose or polyethylene glycol, and/or mixtures thereof.
  • Suitable water-insoluble polymers also include, but are not limited to, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), poly (ethylene), poly (ethylene) low density, poly (ethylene) high density, poly (ethylene oxide), poly (ethylene terephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly (
  • Matrix-based dosage form can comprise the drug or pro-drug, a filler, such as starch, lactose, or microcrystalline cellulose ; a binder, /controlled-release polymer, such as hydroxypropyl methylcellulose; a disintegrant,; a lubricant,; a surfactant, such as sodium lauryl sulfate or polysorbates; and a glidant, such as colloidal silicon dioxide or talc.
  • a filler such as starch, lactose, or microcrystalline cellulose
  • a binder, /controlled-release polymer such as hydroxypropyl methylcellulose
  • a disintegrant such as hydroxypropyl methylcellulose
  • a lubricant such as sodium lauryl sulfate or polysorbates
  • a glidant such as colloidal silicon dioxide or talc.
  • the amounts and types of polymers, and the ratio of water-soluble polymers to water- insoluble polymers in the inventive formulations are generally selected to achieve a desired release profile of the drug or pro-drug, as described below.
  • Amino methacrylate co-polymers such as Eudragit RS and Eudragit RL (Rohm Pharma) are suitable for use in the modified-release formulations of the present invention. These polymers are insoluble in pure water, dilute acids, buffer solutions, or digestive fluids over the entire physiological pH range. The polymers swell in water and digestive fluids independently of pH. In the swollen state they are then permeable to water and dissolved actives. The permeability of the polymers depends on the ratio of ethylacrylate (EA), methyl methacrylate (MMA), and trimethylammonioethyl methacrylate chloride (TAMCI) groups in the polymer.
  • EA ethylacrylate
  • MMA methyl methacrylate
  • TAMCI trimethylammonioethyl methacrylate chloride
  • Eudragit RL Those polymers having EA:MMA:TAMCI ratios of 1 :2:0.2 (Eudragit RL) are more permeable than those with ratios of 1 :2:0.1 (Eudragit RS).
  • Polymers of Eudragit RL are insoluble polymers of high permeability.
  • Polymers of Eudragit RS are insoluble films of low permeability.
  • the amino methacrylate co-polymers can be combined in any desired ratio.
  • a ratio of Eudragit RS:Eudragit RL (90:10) can be used.
  • the ratios can furthermore be adjusted to provide a delay in release of the drug or pro-drug.
  • the ratio of Eudragit RS ⁇ udragit RL can be about 100:0 to about 80:20, about 100:0 to about 90:10, or any ratio in between.
  • the less permeable polymer Eudragit RS would generally comprise the majority of the polymeric material.
  • the amino methacrylate co-polymers can be combined with the methacrylic acid copolymers within the polymeric material in order to achieve the desired delay in release of the drug or pro-drug. Ratios of ammonio methacrylate co-polymer (e.g., Eudragit RS) to methacrylic acid co-polymer in the range of about 99:1 to about 20:80 can be used.
  • the two types of polymers can also be combined into the same polymeric material, or provided as separate coats that are applied to the core.
  • Eudragit polymers In addition to the Eudragit polymers described above, a number of other such copolymers can be used to control drug release. These include methacrylate ester co-polymers (e.g., Eudragit NE 30D). Further information on the Eudragit polymers can be found in "Chemistry and Application Properties of Polymethacrylate Coating Systems," in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (ed. James McGinity, Marcel Dekker Inc., New York. pg 109-114).
  • methacrylate ester co-polymers e.g., Eudragit NE 30D
  • Further information on the Eudragit polymers can be found in "Chemistry and Application Properties of Polymethacrylate Coating Systems," in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (ed. James McGinity, Marcel Dekker Inc., New York. pg 109-114).
  • Methyl acrylate copolymers and amino methacrylate copolymers of the type such as can be obtained under the tradename Eudragit.RTM. RS/RL/NE are particularly preferred.
  • these polymers have ester groups (Eudragit.RTM. NE) or ammonium groups (Eudragit.RTM. RL/RS).
  • Poly(ethyl acrylate, methyl methacrylate) and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) are preferred.
  • polymers are obtainable, for example, as poly(ethyl acrylate, methyl methacrylate) 2:1 in 40% strength aqueous dispersion as Eudragit.RTM.
  • NE 40 D and as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 in 12.5% strength isopropanolic solution as Eudragit.RTM. RS 12.5 and in the composition 1 :2:0.2 as Eudragit.RTM. RL 12.5.
  • the most preferred is Eudragit.RTM.
  • the use of the Co 2 and the TMC had shown a synergist effect on the permeability of the insulin across ex-vivo isolated sheep's intestine.
  • the apparent permeability for insulin using the expandable drug delivery system in the presence of TMC has shown a highest value of 27 x10 "7 (cm/sec) as shown in figure 1.
  • Peptide drug is an example of a drug, which is absorbed, only from the upper part of the intestine.
  • the pharmaceutical composition is given in Table 1.
  • the mucoadhesive properties of the system were evaluated in a piece of sheep's intestine (Jejunum). The experiment was performed according to the method described by Smart et al (Int. J. Pharm. 1 16 (1995) 223-230). with some modifications. Briefly, a small section of fresh sheep's intestine was removed, quickly frozen and was cut into pieces of 3 cm lengths, opened longitudinally to expose the mucous surface and gently washed with PBS buffer pH 6.0. A preliminary histological study indicated the absence of any major damage to the tissue caused by the freeze-thawing process. A layer of mucus was shown to be present on the inner surface of the intestine. The sections of intestine were mounted on a platform and secured using a plastic cap, exposing an 11mm diameter of the test surface. The exposed

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Abstract

L'invention porte sur un système d'administration de médicament expansible comprenant un ou plusieurs actifs, composants générant une force, contenant facultativement un ou plusieurs modificateurs d'absorption et contenant facultativement un ou plusieurs polymères bioadhésifs. L'ingrédient actif est piégé dans les nano/microparticules d'une matrice polymère mucoadhésive. La forme posologique à usage unique est facultativement enrobée d'une couche d'enrobage de séparation et/ou entérique dégradable. Un système d'administration de médicament expansible pour une administration orale consiste en un ou des médicaments à base de protéine ou de peptide, des composants générant une force, avec/sans modificateur d'absorption, la composition étant formulée pour augmenter le temps de séjour de sous-unités contenant le médicament du système d'administration dans le tractus gastro-intestinal (GIT), facultativement enrobées de polymères entériques. L'invention porte également sur un système d'administration de médicament expansible consistant en un médicament à base de peptide, une matrice polymère expansible, des composants de génération de force expansible, qui administre un médicament à la membrane absorbante après un temps mort suivi par une libération en salve ou une libération entretenue.
PCT/IN2009/000222 2008-04-11 2009-04-01 Systèmes d'administration de médicament expansible alimentés par gaz Ceased WO2009125432A2 (fr)

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Cited By (9)

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CN103705325A (zh) * 2012-10-08 2014-04-09 理大产学研基地(深圳)有限公司 具有多层结构的仿生肠道支架及其制备方法
EP2974721A1 (fr) * 2014-07-18 2016-01-20 Nanomega Medical Corporation Composition pharmaceutique comprenant un agent generateur de gaz
WO2017136745A1 (fr) 2016-02-05 2017-08-10 Entrega Inc. Forme galénique orale comprenant un agent dessiccatif pour l'administration d'un agent actif
EP3363442A4 (fr) * 2015-10-13 2019-03-06 Techno Guard CO. LTD. Composition protectrice de la muqueuse gastro-intestinale
US10744095B2 (en) 2014-12-23 2020-08-18 Universität Greifswald Pharmaceutical dosage form for application to mucous membranes
WO2022195586A1 (fr) 2021-03-15 2022-09-22 Epitomee Medical Ltd. Dispositifs expansibles pour l'administration d'agents actifs à des tissus
WO2024062466A1 (fr) 2022-09-21 2024-03-28 Epitomee Medical Ltd. Dispositifs ingérables auto-expansibles pouvant se désintégrer de manière contrôlable
WO2024243887A1 (fr) * 2023-05-31 2024-12-05 清华大学 Appareil d'administration de médicament à micro-aiguilles et son procédé de préparation
EP4376813A4 (fr) * 2021-07-26 2025-06-04 Ahmed, Suzanne Plateforme d'administration de médicament permettant l'administration d'agents thérapeutiques et procédés d'utilisation et de fabrication de cette dernière

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US5458879A (en) * 1994-03-03 1995-10-17 The Procter & Gamble Company Oral vehicle compositions
DE19756314C2 (de) * 1997-12-12 2000-06-29 Roland Bodmeier Zubereitung mit verlängerter Verweildauer am Applikationsort
US6350470B1 (en) * 1998-04-29 2002-02-26 Cima Labs Inc. Effervescent drug delivery system for oral administration
WO2000035418A2 (fr) * 1998-12-18 2000-06-22 Bayer Corporation Systeme d'administration de medicament a croquer
WO2003086297A2 (fr) * 2002-04-08 2003-10-23 Lavipharm Laboratories, Inc. Dispositif mucoadhesif multicouche d'administration de medicaments presentant une couche de liberation par eclatement
GB0221712D0 (en) * 2002-09-19 2002-10-30 Ardana Bioscience Ltd Methods of treatment
US20060013873A1 (en) * 2004-07-16 2006-01-19 Chih-Chiang Yang Bioadhesive dosage form of steroids
EP1891937A1 (fr) * 2006-08-25 2008-02-27 Novartis AG Formulations galéniques de l'aliskiren
WO2008065144A2 (fr) * 2006-11-29 2008-06-05 Novartis Ag Préparations galéniques de composés organiques

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103705325A (zh) * 2012-10-08 2014-04-09 理大产学研基地(深圳)有限公司 具有多层结构的仿生肠道支架及其制备方法
EP2974721A1 (fr) * 2014-07-18 2016-01-20 Nanomega Medical Corporation Composition pharmaceutique comprenant un agent generateur de gaz
US10744095B2 (en) 2014-12-23 2020-08-18 Universität Greifswald Pharmaceutical dosage form for application to mucous membranes
US12186431B2 (en) 2014-12-23 2025-01-07 Esocap Ag Pharmaceutical dosage form for application to mucous membranes
EP3363442A4 (fr) * 2015-10-13 2019-03-06 Techno Guard CO. LTD. Composition protectrice de la muqueuse gastro-intestinale
WO2017136745A1 (fr) 2016-02-05 2017-08-10 Entrega Inc. Forme galénique orale comprenant un agent dessiccatif pour l'administration d'un agent actif
WO2022195586A1 (fr) 2021-03-15 2022-09-22 Epitomee Medical Ltd. Dispositifs expansibles pour l'administration d'agents actifs à des tissus
JP2024514047A (ja) * 2021-03-15 2024-03-28 エピトミー メディカル リミテッド 組織に活性剤を送達するための拡張可能なデバイス
EP4376813A4 (fr) * 2021-07-26 2025-06-04 Ahmed, Suzanne Plateforme d'administration de médicament permettant l'administration d'agents thérapeutiques et procédés d'utilisation et de fabrication de cette dernière
WO2024062466A1 (fr) 2022-09-21 2024-03-28 Epitomee Medical Ltd. Dispositifs ingérables auto-expansibles pouvant se désintégrer de manière contrôlable
WO2024243887A1 (fr) * 2023-05-31 2024-12-05 清华大学 Appareil d'administration de médicament à micro-aiguilles et son procédé de préparation
CN119768151A (zh) * 2023-05-31 2025-04-04 清华大学 微针给药装置及其制备方法

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