WO2008150269A1 - Nanocapsules polymères destinées à être utilisées dans l'administration de médicament - Google Patents

Nanocapsules polymères destinées à être utilisées dans l'administration de médicament Download PDF

Info

Publication number
WO2008150269A1
WO2008150269A1 PCT/US2007/013647 US2007013647W WO2008150269A1 WO 2008150269 A1 WO2008150269 A1 WO 2008150269A1 US 2007013647 W US2007013647 W US 2007013647W WO 2008150269 A1 WO2008150269 A1 WO 2008150269A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
block
drug
insulin
composition
Prior art date
Application number
PCT/US2007/013647
Other languages
English (en)
Inventor
Robert J. Gyurik
Zhengmao Li
Original Assignee
Cpex Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cpex Pharmaceuticals, Inc. filed Critical Cpex Pharmaceuticals, Inc.
Priority to PCT/US2007/013647 priority Critical patent/WO2008150269A1/fr
Publication of WO2008150269A1 publication Critical patent/WO2008150269A1/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the pertinent field of the present invention relates to drug delivery formulations that form nanoparticles which absorb drugs and deliver them to the body.
  • drugs include, for example, peptides and proteins, which are delivered by nanoparticles to the gastrointestinal tract and other portions of the body.
  • the technology relating to the general aspect of the invention employs copolymers that form nanocapsules in aqueous solution.
  • These formulations enable the oral and mucosal delivery of polypeptides and macromolecules, e.g., insulin and other polypeptides, that heretofore have not been successfully formulated for oral and mucosal drug delivery.
  • patent publication 2003194438 Al (10/16/2003) to Prescott et al. which is said to disclose an extended-release analgesic for controlling pain comprised of an opioid or non- opioid analgesic drug ionically bound to hyaluronic acid, polyglutamic acid or other ionic polymers;
  • WO 2003079972 A2 (10/02/2003) to Piccariello et al. which is said to relate to active agent delivery systems, specifically to compounds that comprise amino acids, as single amino acids or peptides, covalently attached to active agents;
  • WO 2003055935 Al (07/10/2003) to Li et al.
  • patent publication 2002099013 Al (07/25/2002) to Piccariello et al., which is said to claim compounds comprising a polypeptide and an active agent covalently attached to the polypeptide and a method for delivery of an active agent to a patient by administering the compound to a patient;
  • WO 2002026241 Al (04/04/2002) to Kataoka et al., which is said to disclose a complex comprising cisplatin and a poly(ethylene glycol)/poly(glutamic acid) block copolymer, wherein the cisplatin is enclosed in the copolymer through ligand displacement in which a carboxyl anion of the copolymer is replaced with a chlorine ion of the cisplatin;
  • WO 2001089477 A2 (11/29/2001) to Mcginniss et al., which is said to disclose compounds and methods for controllably releasing a material or active ingredient from a polymer matrix;
  • Controlled Release 110 (2006) 587-594 also states that polymeric carriers, lipid-based carriers such as liposomes and solid lipid nanoparticles show low bioavailability as insulin delivery agents.
  • lipid-based carriers such as liposomes and solid lipid nanoparticles show low bioavailability as insulin delivery agents.
  • BioSante Pharmaceuticals, Inc. announced what it said were positive results of a preclinical study of a calcium phosphate nanoparticle (CAP) delivery system or oral delivery of insulin.
  • CAP calcium phosphate nanoparticle
  • nanocapsules refers to a number of nanoparticles, including, but not limited to, nanovesicles, micelles, lamellae shaped particles, polymersom.es, dendrimers, and nano-size particles of various other small fabrications that are known to those in the art.
  • the nanocapsules falling within the general scope of the present invention are drug delivery vehicles that deliver drugs, particularly, peptides and proteins such as insulin, to the gastrointestinal portions of the body where they are absorbed without appreciable degradation by resident enzymes. More particularly, in one aspect of the invention, the nanocapsules are comprised of amphiphilic diblock amino acid or amino acid derivative polymers.
  • the nanocapsules when these diblocks are in solution, such as the environment of the stomach and intestines, the nanocapsules form and adhere to, or partially adhere to, absorb or encapsulate, the drug molecules of interest, including those that heretofore have not been successfully formulated for oral drug delivery, such as polypeptides and macromolecules, e.g., insulin.
  • the drug molecules of interest including those that heretofore have not been successfully formulated for oral drug delivery, such as polypeptides and macromolecules, e.g., insulin.
  • Nanocapsule full or partial absorption or encapsulation of such drug molecules enables their delivery via oral or mucosal means including by the inclusion of the diblock formulation in tablet, capsule, caplet, powder, liquid, suspension and other pharmaceutical forms known to those of skill in the art of the drug and pharmaceutical industries.
  • one general aspect of the present application is directed to diblock copolymers, and certain single polymers.
  • conventional thinking is that a triblock polymer is important to form a proper wall for a nanoparticulate drug carrier.
  • a diblock polymer form is a particularly effective nanoparticulate drug carrier.
  • the present invention pertains to molecules with a particular mechanism of action.
  • the linear amphiphilic molecules herein described comprise a diblock polymer ("A-B Polymer") with the A chain being at least partially hydrophobic and the B chain being at least partially hydrophilic.
  • the A and B copolymer units comprise amino acids or derivatized amino acids.
  • diblock polymers comprising one aspect of the present invention.
  • a diblock polymer comprising polymer blocks A and B, wherein A is at least a partially hydrophobic block and B is at least a partially hydrophilic block, and wherein A and B further comprise amino acids or derivatized amino acids.
  • nanocapsules e.g., micelles and/or lamellae shaped particles
  • the nanocapsule assembly can resemble a particle, since the individual lipophilic ends are attracted with a force called Van der Waals attraction.
  • the process of nanocapsule (e.g., micelle) formation is sometimes called hydrophobic bonding.
  • one object of the present invention is to provide molecules that are designed to deliver drugs by routes difficult to pursue by other means, such as oral delivery of sensitive drug molecules such as insulin and other peptides or polypeptides.
  • Another object of the invention is to provide nanocapsules that at least partially adhere to, absorb and/or encapsulate drug molecules in the body.
  • Another object of the invention is to provide a delivery vehicle for drugs to be absorbed into the stomach, intestines and/or gastrointestinal tract without degradation of such drugs, e.g., insulin, by enzymes resident in those areas of the body.
  • Another object of the invention is to provide a new oral or mucosal delivery means for drug molecules in general.
  • Another object of the invention of the present invention is to provide a delivery system, such as a tablet, capsule, liquid, suspension, intravenous, intraperitoneal, subcutaneous, intrathecal, and opththalmic means for the delivery or administration to a patient of insulin and other polypeptides and proteins.
  • a delivery system such as a tablet, capsule, liquid, suspension, intravenous, intraperitoneal, subcutaneous, intrathecal, and opththalmic means for the delivery or administration to a patient of insulin and other polypeptides and proteins.
  • Another object of the invention is to provide a diblock polymer that forms nanocapsules when the polymer is introduced into aqueous media.
  • Another object of the invention is to provide nanocapsules that are capable of at least partially absorbing, encapsulating or adhering to drug molecules and serving as drug carriers.
  • Figure 1 is a graphical representation of the results of a study measuring inter alia the concentration over time of glucose and insulin in an insulin formulation of the present invention wherein said insulin formulation was administered orally to an animal.
  • Figure 2 is a graphical representation of the results of a study measuring inter alia concentration over time of insulin and glucose levels wherein insulin was not formulated in accordance with the present invention and wherein the insulin was administered orally to an animal.
  • nanoparticle is a term that relates to a number of entities, many of which are known to one of skill in the art and which are incorporated herein by reference.
  • nanoparticles or “nanostructures” are usually sufficiently small to be measured in nanometers.
  • nanocapsule refers to a number of nanoparticles, including, but not limited to, nanovesicles, micelles, lamellae shaped particles, polymersomes, dendrimers, and other nano-size particles of various other small fabrications that are known to those in the art.
  • nanocapsule refers to a number of nanoparticles, including, but not limited to, nanovesicles, micelles, lamellae shaped particles, polymersomes, dendrimers, and other nano-size particles of various other small fabrications that are known to those in the art.
  • the definitions and understandings of the entities falling within the scope of nanocapsule are known to those of skill in the art, and such definitions are incorporated herein by reference and for the purposes of understanding the general nature of the subject matter of the present application. However, the following discussion is useful as a further understanding of some of these terms.
  • a "micelle”, a useful article in the employment of a general aspect of the present invention, can generally be thought of as a small — on the order of usually nanometers in diameter — aggregate of amphiphilic linear molecules having a polar, or hydrophilic end and an opposite non-polar, or hydrophobic end. These linear molecules can be comprised of simple molecules, or polymeric chains.
  • a micelle can also be referred to as an aggregate of surfactant molecules dispersed in a liquid colloid.
  • a typical micelle in aqueous solution can form an aggregate with the hydrophilic "head” regions in contact with surrounding solvent, and the sequestering of the hydrophobic tail regions in the micelle center.
  • Other and similar definitions, descriptions and understandings of micelles are also known to those of skill in the art and are incorporated herein by reference.
  • Polymersomes can, in general, be thought of as bilayered membranes of amphiphilic synthetic polymers, which are similar in some respects to liposomes, which use naturally occurring lipids. While having some of the properties of natural liposomes, polymersomes exhibit increased stability and reduced permeability. Other and similar definitions, descriptions and understandings and of polymersomes are also known to those of skill in the art and are incorporated herein by reference.
  • Dendrimers have descriptions, definitions and understandings in the literature.
  • dendrimer from the Greek word, "dendron”, for tree can refer to a synthetic, three-dimensional molecule with branching parts. Descriptions and understandings of dendrimers can be gleaned from Holister et ah, DENDRIMERS, Technology White Papers nr. 6, pub. October 2003 by cienti ⁇ ca, as well as the other literature published by those skilled in the art on dendrimers, all of which are incorporated herein by reference.
  • lamella is a term whose definitions, descriptions and understandings are also known to those of skill in the art and which are incorporated herein by reference. In a very general sense, lamella or lamellae refers to plate-like, gill-shaped or other layered structures.
  • nano-vesicle can refer to a variety of small sac, sac-like or globular structures capable of containing fluid or other material therein.
  • the present invention relates to drug delivery formulations that utilize nanocapsules to deliver drugs, particularly, peptides and proteins such as insulin, to the gastrointestinal portions of the body where they are absorbed without appreciable degradation by resident enzymes.
  • the nanocapsules are generally comprised of block and diblock polymers and are formed in solution or suspension where they can be combined with the drug molecule of interest.
  • the diblock polymers are comprised of amphiphilic amino acid, or amino acid derivative, copolymers.
  • nanocapsules form and can adhere to, or partially adhere to, and can at least partially absorb or encapsulate, drug molecules, including, but not limited to, those that heretofore have not been successfully formulated for oral drug delivery, such as polypeptides and macromolecules, e.g., insulin, insulin derivatives and analogues, growth hormones and analogues thereof, eyrthropoeitins, anti-inflammatory peptides, anti-aging peptides, atrial natriuretic peptides, brain injury derived peptides, Calcitonin, defensins, deltorphins, dermorphins and analogues thereof, BAM peptides, ⁇ -casein exorphins, dynorphins, endomorphins, endorphins, enkephalins, gluten exorphins, kyotorphins, methorphamide, neoendorphins
  • drug molecules including, but not limited to
  • a nanocapsule falling within the scope of the present invention effects full or partial adherence, absorption or encapsulation of such drug molecules and thereby enables their delivery via oral or mucosal means.
  • One aspect of the present invention also employs a single polymer such as is exemplified in some of the alternative embodiments described below.
  • block copolymer a term whose definitions and understandings are well known in the art and which are incorporated by reference herein.
  • block copolymers are comprised of two or more polymer subunits linked by covalent bonds. Block copolymers with two or three distinct blocks are called diblock copolymers and triblock copolymers, respectively. Copolymers may also be described in terms of the existence of or arrangement of branches in the polymer structure. Linear copolymers consist of a single main chain whereas branched copolymers consist of a single main chain with one or more polymeric side chains.
  • Block copolymers are made up of blocks of different polymerized monomers. Triblocks, tetrablocks, multiblocks can be made. Block copolymers are of interest because they can "microphase separate" to form periodic nanostructures.
  • one aspect of the present application is directed to diblock copolymers, although single chain and other polymers may be used.
  • diblock polymers are important to form a proper wall for a nanoparticulate drug carrier.
  • the applicants herein have found that the diblock polymer form, and in some cases the single polymer form, is a particularly advantageous and effective nanoparticulate drug carrier.
  • the evidence strongly suggests that the diblock polymers of the present invention form nanocapsules such as those with a lamella-like configuration, alone or together with nanocapsules of micelle configuration.
  • the lipid block of the nanocapsule (e.g., n-butyl-poly-1-lactide) intercalates or interweaves in aqueous solution and the polar group of the nanocapsule (e.g., polyglutamic acid with associated drug, e.g., insulin) faces the aqueous solution both inside and out when the nanocapsules are formed.
  • the nanocapsule assembly resembles a particle, since the individual lipophilic ends are attracted with a force called Van der Waals attraction.
  • the process of nanocapsule formation is sometimes called hydrophobic bonding.
  • the nanocapsule/drug when the nanocapsule/drug is in the physiological media of the gastrointestinal tract, the drug that has been formulated with it is protected by the nanocapsule so it may be absorbed intact by the tissues of the body and introduced into the blood stream before it can be degraded by gastrointestinal enzymes.
  • Experimental support for this mechanism is set forth in the example below wherein effective oral delivery of insulin utilizing this aspect of the invention is demonstrated.
  • PEG-PLA diblock polymers are diblock polymers, they differ from the poly(lactic acid)- poly(glutamic acid) diblock aspect of the present invention which uses poly(glutamic acid) as the hydrophilic block, instead of polyethylene glycol, PEG.
  • PEG-PLA diblock polymers can only deliver hydrophobic drugs, if at all.
  • One aspect of the present invention is that it can deliver hydrophilic polypeptides and proteins, e.g. insulin.
  • PEG has no charges on the polymer backbone, while poly(glutamic acid), as used within the scope of the present invention, has negative charges at neutral and basic pH, and thus can absorb or encapsulate hydrophilic proteins for drug delivery.
  • both blocks of the diblock polymers included within the present invention are biodegradable.
  • the diblock polymer nanocapsule structures encapsulate aqueous solutions with hydrophilic proteins inside the nanocapsule.
  • the poly(glutamic acid) on the outer surface of the nanocapsule adsorbs hydrophilic proteins.
  • the PEG-PLA block polymers of the prior art are not known to form nanocapsules. Rather they form a hydrophobic PLA hard core with PEG sticking out into the aqueous phase of a solution. Further, PEG does not absorb proteins, and thus a PEG-PLA drug delivery agent mainly depends on the encapsulation of hydrophobic drugs in the PLA core, not the PEG.
  • the present invention pertains to amphiphilic molecules comprising a diblock ("A-B Polymer") with the A chain being at least partially hydrophobic and the B chain being at least partially hydrophilic.
  • a and B copolymers comprise amino acids or derivatized amino acids.
  • the B polymer alone is sufficient to provide the nanocapsule drug delivery agent.
  • the diblock polymers comprising one aspect of the present invention can be summarized as follows:
  • a diblock polymer comprising polymer blocks A and B, wherein A is at least a partially hydrophobic block and B is at least a partially hydrophilic block, and wherein A and B further comprise amino acids or derivatized amino acids.
  • amphiphilic diblock amino acid (or derivatized amino acid) polymer of the present invention is such that when it is in suspension or solution it will spontaneously form nanocapsules, with a lipophilic end facing inward to 'hide' from water, which at least partially, encapsulate, absorb, partially or fully, or adhere to, the drug molecule of interest added to the nanocapsules.
  • the nanocapsules when the nanocapsules are in the aqueous media of the stomach, intestines and gastrointestinal tract, they are absorbed by the tissues and the drug, e.g., a polypeptide or protein, is delivered safely and without appreciable degradation by the body's enzymes.
  • the type of molecules of the present invention are generally designed and are useful to deliver drugs by routes difficult to pursue by other means, such as oral delivery of sensitive drug molecules such as insulin and other peptides or polypeptides.
  • other small conventional drug molecules are included within the present invention, and the success depends upon the ionic nature of the compounds, and whether they will form complexes with the diblocks.
  • the nanocapsules formed by the copolymers of this invention adhere to, absorb and/or encapsulate the drug molecule, the drug may be delivered orally or through mucosal membranes. Further, since the nanocapsules formed as described herein are capable of absorbing, encapsulating or adhering to a drug, they are highly useful as drug carriers.
  • the nanocapsules of the present invention provide unique and precise drug carrier capabilities.
  • polypeptide and protein drugs e.g., insulin, and other macromolecules may be delivered orally, or through other mucosal membranes, whereas other technologies have failed or had severe shortcomings.
  • other delivery routes falling within the scope of the present invention include intravenous, intraperitoneal, subcutaneous, intrathecal, opththalmic, intranasal, liquid, inhaler and other delivery routes known in the art.
  • A-B polymer compositions are easily made using standard wet chemical methods.
  • the major step, the coupling of A and B, is usually accomplished under anhydrous conditions using standard peptide dehydrative coupling reactions, such as is achieved with dicyclohexylcarbodiimide.
  • Other coupling reagents are known to practitioners skilled in the art as being useful for coupling, and include polymer fusion reagents and peptide coupling reagents that can carry out the joining of the two polymeric blocks.
  • Diblock copolymers can also be made using living polymerization techniques, such as atom transfer free radical polymerization (ATRP), reversible addition fragmentation chain transfer (RAFT), ring- opening metathesis polymerization (ROMP), and living cationic or living anionic polymerizations.
  • ATRP atom transfer free radical polymerization
  • RAFT reversible addition fragmentation chain transfer
  • RMP ring- opening metathesis polymerization
  • living cationic or living anionic polymerizations such as atom transfer free radical polymerization (ATRP), reversible addition fragmentation chain transfer (RAFT), ring- opening metathesis polymerization (ROMP), and living cationic or living anionic polymerizations.
  • amphiphilic diblock copolymer poly (lactic acid)-poly (glutamic acid) was made by living polymerization of individual poly (lactic acid) and poly (glutamic acid) blocks, then coupling the two blocks together.
  • each poly (lactic acid) block has approximately 150 lactic acid repeating units
  • each poly (glutamic acid) block has approximately 100 glutamic acid repeating units, which were confirmed by Gel Permeation Chromatography ("GPC") and Multi- Angle Laser Light Scattering ("MALLS").
  • the diblock polymer was precipitated and washed in water. 30 mL of aqueous polymer suspension with about 3% polymer content was sonicated for 15 minutes, then 10 mL of 1% insulin solution was added. The final pH was 7.4. In the final formulation, there were 2.2% d ⁇ block nanocapsule and 0.25% insulin at pH 7.4 ("Formulation A"). The insulin was added after the diblock nanocapsules were formed, so insulin was adsorbed on the outside of the nanocapsules, or freely floating in the aqueous phase.
  • Yucatan pigs were prepared for the study with the surgical implantation of a jugular catheter for easy blood collection.
  • Baseline venous blood specimens were collected just prior to the dosing treatment and blood was thereafter sampled at 0 (just before treatment), 30, 60, 90, 120, 150 and 240 minutes after treatment.
  • Each pig was monitored with a hand-held commercial glucometer (Lifescan, J&J; One Touch Fast TakeTM) at each blood collection time to ensure animal wellness, and to give an immediate indication of any biological activity as is verified by glucose reduction compared to the baseline levels.
  • the blood was collected into sodium heparinized plastic tubes.
  • the plasma was retrieved and stored at -20 0 C until analyzed for insulin and glucose.
  • Heparinized plasma was analyzed for insulin concentration using a commercial ELISA assay for insulin (Linco Research, Inc.; Human Insulin Specific ELISA Kit, Cat# EZHI-14K). Insulin was reported in micro International Units/milliliter of plasma ( ⁇ U/mL).
  • the pigs were dosed with either insulin solution at 0.25% (Control) or nanocapsule associated insulin at 0.25% (Formulation A). Each formulation was dosed by oral gavage, 4 mL of formulation, followed by 4 ml of saline wash to rinse the tubing.
  • Table 2 shows the experimental results of oral 4 mL 0.25% insulin solution at pH 7.4. Glucose levels were also measured and obtained. A graphical representation of these data are shown in Figure 2.
  • the inventors have deduced that in the acidic environment in the stomach, poly (glutamic acid) is protonated, becomes hydrophobic and protects the adsorbed insulin inside.
  • poly (lactic acid) lost protons due to the higher pH and stretched out due to charge repulsion, then released the insulin.
  • the poly (lactic acid) block functioned to aggregate the molecules into nanocapsules of uniformly small particle size that enabled them to be uptaken by an as yet unknown mechanism through the intestinal mucosal cells.
  • the present invention is a breakthrough discovery in the field of oral insulin delivery and is a new way of delivering insulin orally.
  • the polymeric nanocapsule formulations of the present invention show superior results in the drug delivery of insulin.
  • a second embodiment of the invention comprises a composition comprising a diblock polymer having components A and B, wherein A can be at least a partially hydrophobic block, B can be at least a partially hydrophilic block, and wherein said composition may form one or more of the following entities, for example, in solution or suspension: nanovesicles, micelles, lamellae particles, polymersomes, dendrimers, and other nano-size particles of various fabrications, including, but not limited to, those that are known to those of skill in the art.
  • a third embodiment of the invention comprises the composition of the second embodiment wherein a drug may be at least partially absorbed or encapsulated by, or adhered to, one or more of the following entities: nanovesicles, micelles, lamellae particles, polymersomes, dendrimers, and other nano-size particles of various fabrications, including, but not limited to, those that are known to those of skill in the art.
  • a fourth embodiment of the invention comprises the composition of the second embodiment wherein a drug may be at least partially absorbed or encapsulated by, or adhered to, nanocapsules.
  • a fifth embodiment of the invention comprises the composition of the second embodiment wherein the A block may be, for example, a polylactide, polycaprolactide, or polyglycolide composition, of either enantiomeric, racemic, or other isomeric forms such as meso.
  • the A block may be, for example, a polylactide, polycaprolactide, or polyglycolide composition, of either enantiomeric, racemic, or other isomeric forms such as meso.
  • a sixth embodiment of the invention comprises the composition of the second embodiment wherein the B block may be, for example, polyamino acids with ionic nature, of either enantiomeric, racemic, or other isomeric forms such as meso.
  • a seventh embodiment of the invention comprises the composition of the second embodiment wherein the B block may be polyaminoacids with anionic nature, for example, polyglutamic and polyaspartic amino acids, or copolymers of the two.
  • An eighth embodiment of the invention comprises the composition of the second embodiment wherein the B block may be polyaminoacids with cationic nature, for example, polylysine, polyarginine, polyhistidine, or copolymers of the three taken two or three at a time.
  • the B block may be polyaminoacids with cationic nature, for example, polylysine, polyarginine, polyhistidine, or copolymers of the three taken two or three at a time.
  • a ninth embodiment of the invention comprises the composition of the third embodiment of the invention wherein the drug is a polypeptide or macromolecule.
  • a tenth embodiment of the invention comprises the composition of the third embodiment of the invention wherein the drug is a polypeptide or macromolecule.
  • An eleventh embodiment of the invention comprises the composition of the third embodiment of the invention wherein the drug may be insulin or derivative or analog of insulin.
  • a twelfth embodiment of the invention comprises the composition of the third embodiment of the invention which differs, however, in that instead of having A and B block copolymers, the composition may comprise only the B block as a polyamino acid capable of complexing with the drug in such a way as to protect the drug before being uptaken by the intestine after oral delivery.
  • a thirteenth embodiment of the invention comprises the composition of the sixth embodiment of the invention which differs, however, in that instead of having A and B block copolymers, the composition may comprise only the B block as disclosed in embodiments 6 through 8.
  • a fourteenth embodiment of the invention comprises the composition of the seventh embodiment of the invention which differs, however, in that instead of having A and B block copolymers, the composition may comprise only the B block as disclosed in embodiments 6 through 8.
  • a fifteenth embodiment of the invention comprises the composition of the eighth embodiment of the invention which differs, however, in that instead of having A and B block copolymers, the composition may comprise only the B block as disclosed in embodiments 6 through 8.
  • compositions of the second through fifteenth embodiments of the invention comprise the composition of the second through fifteenth embodiments of the invention wherein one or more of the blocks may vary in length between approximately 10 and 500 monomelic units, preferably between approximately 25 and 200 units, and most preferably between approximately 50 and 150 units.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Nanotechnology (AREA)
  • Biomedical Technology (AREA)
  • Physics & Mathematics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des préparations destinées à l'administration de médicament. Lesdites préparations utilisent des nanocapsules, telles que des nanovésicules, des micelles, des particules lamellaires, des polymersomes, des dendrimères et d'autres particules de diverses autres fabrications de taille nano, incluant celles connues dans l'art. La présente invention utilise des copolymères à deux blocs ou des polymères à bloc unique qui maintiennent, adhèrent à, absorbent ou encapsulent les molécules de médicament, y compris, sans s'y limiter, celles qui n'ont pu jusqu'à présent être formulées pour une administration médicamenteuse par voie orale, telles que l'insuline. Le maintien, l'adhérence, l'absorption ou l'encapsulation par les nanocapsules de ces médicaments ou d'autres molécules permettent leur administration par voie orale ou par les muqueuses.
PCT/US2007/013647 2007-06-08 2007-06-08 Nanocapsules polymères destinées à être utilisées dans l'administration de médicament WO2008150269A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2007/013647 WO2008150269A1 (fr) 2007-06-08 2007-06-08 Nanocapsules polymères destinées à être utilisées dans l'administration de médicament

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2007/013647 WO2008150269A1 (fr) 2007-06-08 2007-06-08 Nanocapsules polymères destinées à être utilisées dans l'administration de médicament

Publications (1)

Publication Number Publication Date
WO2008150269A1 true WO2008150269A1 (fr) 2008-12-11

Family

ID=40093949

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/013647 WO2008150269A1 (fr) 2007-06-08 2007-06-08 Nanocapsules polymères destinées à être utilisées dans l'administration de médicament

Country Status (1)

Country Link
WO (1) WO2008150269A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120121670A1 (en) * 2009-04-22 2012-05-17 Lopez Victoria Lozano Polyarginine nanocapsules

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040228794A1 (en) * 1998-04-10 2004-11-18 Battelle Memorial Institute Therapeutic agent carrier compositions
US20060040879A1 (en) * 2004-08-21 2006-02-23 Kosak Kenneth M Chloroquine coupled nucleic acids and methods for their synthesis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040228794A1 (en) * 1998-04-10 2004-11-18 Battelle Memorial Institute Therapeutic agent carrier compositions
US20060040879A1 (en) * 2004-08-21 2006-02-23 Kosak Kenneth M Chloroquine coupled nucleic acids and methods for their synthesis

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
QIU L.Y. ET AL.: "Polymer Architecture and Drug Delivery", PHARMACEUTICAL RESEARCH, vol. 23, no. 1, January 2006 (2006-01-01), pages 1 - 30, XP019370961 *
RIESS G.: "Micellization of block copolymers", PROGRESS IN POLYMER SCIENCE, vol. 28, no. 7, July 2003 (2003-07-01), pages 1107 - 1170, XP002465087 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120121670A1 (en) * 2009-04-22 2012-05-17 Lopez Victoria Lozano Polyarginine nanocapsules

Similar Documents

Publication Publication Date Title
Acar et al. Molecular engineering solutions for therapeutic peptide delivery
Song et al. Synthesis of CSK-DEX-PLGA nanoparticles for the oral delivery of exenatide to improve its mucus penetration and intestinal absorption
Mishra et al. Nanoparticle systems as tools to improve drug delivery and therapeutic efficacy
AU2012251971B2 (en) Polymeric nanoparticles for drug delivery
Bassyouni et al. Advances and new technologies applied in controlled drug delivery system
AU2014218717B2 (en) Targeted buccal delivery comprising cisplatin-loaded chitosan nanoparticles
Bourganis et al. On the synthesis of mucus permeating nanocarriers
Ribeiro et al. Advances in Hybrid Polymer‐Based Materials for Sustained Drug Release
Zhu et al. Highly efficient nanomedicines assembled via polymer–drug multiple interactions: Tissue-selective delivery carriers
Martin-Banderas et al. Nanostructures for drug delivery to the brain
Chinnagounder Periyasamy et al. Nanomaterials for the local and targeted delivery of osteoarthritis drugs
Mogoşanu et al. Natural and synthetic polymers for drug delivery and targeting
CN112274651B (zh) 用于靶向活化cd44分子的聚多巴胺纳米载体递送系统、其制备方法和应用
Bhattacharya et al. A critical review on the dissemination of PH and stimuli-responsive polymeric nanoparticular systems to improve drug delivery in cancer therapy
Maria et al. Synthesis and characterization of pre-activated thiolated chitosan nanoparticles for oral delivery of octreotide
US20100143484A1 (en) Oral submicron particle delivery system for proteins and process for its production
CN112206326B (zh) 用于靶向活化cd44分子的氨基酸自组装纳米载体递送系统、其制备方法和应用
US20080305174A1 (en) Polymeric nanocapsules for use in drug delivery
Ward et al. Halloysite nanoclay for controlled release applications
Parashar et al. Preparation and characterization of ligand anchored polymeric nanoparticles for the treatment of epilepsy
Xu et al. Microparticles based on alginate/chitosan/casein three‐dimensional system for oral insulin delivery
Patil et al. Biodegradable nanoparticles: a recent approach and applications
UA123665C2 (uk) Фармацевтична композиція, її одержання і застосування
B Goudoulas Polymers and biopolymers as drug delivery systems in nanomedicine
Sabu et al. Advanced nanostructures for oral insulin delivery

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07795955

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07795955

Country of ref document: EP

Kind code of ref document: A1