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WO1999004824A1 - Compositions pharmaceutiques a base de polymeres destinees a une administration ciblee d'agents biologiquement actifs - Google Patents

Compositions pharmaceutiques a base de polymeres destinees a une administration ciblee d'agents biologiquement actifs Download PDF

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Publication number
WO1999004824A1
WO1999004824A1 PCT/US1998/015457 US9815457W WO9904824A1 WO 1999004824 A1 WO1999004824 A1 WO 1999004824A1 US 9815457 W US9815457 W US 9815457W WO 9904824 A1 WO9904824 A1 WO 9904824A1
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WO
WIPO (PCT)
Prior art keywords
acid
polymeric
serotonin
construct
poly
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Application number
PCT/US1998/015457
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English (en)
Inventor
John R. Lau
W. Blair Geho
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Sdg, Inc.
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Filing date
Publication date
Application filed by Sdg, Inc. filed Critical Sdg, Inc.
Priority to AU85912/98A priority Critical patent/AU8591298A/en
Priority to EP98937127A priority patent/EP0999855A1/fr
Priority to CA002297025A priority patent/CA2297025A1/fr
Priority to JP2000503875A priority patent/JP2001510811A/ja
Publication of WO1999004824A1 publication Critical patent/WO1999004824A1/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • This invention relates generally to polymeric constructs useful for the delivery of biologically active agents.
  • it relates to polymeric constructs useful for delivery of biogenic amines, pharmaceutical compositions thereof, and methods for treating disease states therewith.
  • 4,131,648, 4,138,344, 4,293,539 and 4,675,189 disclose the preparation and use of biocompatible, biodegradable polymers, such as poly (lactic acid), poly(glycolic acid), copolymers of glycolic and lactic acids, poly (o-hydroxycarboxy lie acid), polylactones, polyacetals, polyorthoesters and polyorthocarbonates, for the encapsulation of drugs and medicaments.
  • biocompatible, biodegradable polymers such as poly (lactic acid), poly(glycolic acid), copolymers of glycolic and lactic acids, poly (o-hydroxycarboxy lie acid), polylactones, polyacetals, polyorthoesters and polyorthocarbonates, for the encapsulation of drugs and medicaments.
  • These polymers mechanically entrap the active constituents and later provide controlled release of the active ingredient via polymer dissolution or degradation.
  • Certain condensation polymers formed from divinyl ethers and polyols are described in Polymer Letters, 18,
  • This invention thus provides a polymeric construct for delivering a biologically active agent to a host comprising a first and primary polymeric matrix, a biologically active agent entrapped within the first polymeric matrix, and a second polymeric component chemically bound to the biologically active agent, which second polymer is present in an amount effective to minimize leakage of the active agent from the polymeric carrier.
  • the polymeric construct further comprises targeting moieties associated with its surface for directing the construct to the desired situs.
  • the second polymeric component may optionally be copolymerized or otherwise bound to the first polymeric matrix.
  • compositions of the polymeric constructs with pharmaceutically acceptable excipients are also provided.
  • Treatment of conditions responsive to biogenic amines, particularly the treatment of Type II diabetes with serotonin or a serotonergic agonist is particularly preferred.
  • this invention provides a polymeric construct for delivering a biologically active agent to a host comprising a first and primary polymeric matrix, a biologically active agent entrapped within the first polymeric matrix, and a second polymeric component chemically bound to the biologically active agent, which second polymer is present in an amount effective to minimize leakage of the active agent from the first polymeric matrix.
  • the polymeric construct further comprises targeting moieties associated with its surface for directing the construct to the desired situs.
  • the second polymeric component may optionally be copolymerized or otherwise bound to the first polymeric matrix.
  • the first polymeric matrix may be, but is not limited to, poly(lactide/glycolide) copolymers (PLGA), poly (lactic acid), poly (glycolic acid), poly (o-hydroxycarboxy lie acids), poly(lactones), poly(acetals), poly(orthoesters), poly(orthocarbonates), poly(amino acids), chitosan glutamate, poly(acrylic acid), poly (divinyl glycol), albumin, polycarbonates, poly amines, poly (hydroxy butyric acid), scleroglucans, polyoxypropylene- polyoxyethylenes, polygalacturonic acid (partially esterified) and xanthan gum.
  • combinations of these primary polymers may be used together.
  • the second polymeric component comprises a polymer that carries negatively charged functional groups.
  • the second polymeric component comprises a poly(amino acid) carrying a net negative charge.
  • the second polymeric component comprises a copolymer of polylysine with other amino acids or compounds.
  • more than one anchoring secondary polymeric component may be used in the polymeric construct of the present invention.
  • this invention comprises a method of making a polymeric construct comprising mixing a first biocompatible polymer, a second copolymer of polylysine-poly(glutamic acid/aspartic acid), a biogenic amine, and a targeting moiety, whereby said first and second polymers form a composite polymeric carrier containing the biogenic amine and the targeting moiety.
  • the biologically active agent comprises a biogenic amine, which includes the sympathomimetic amines, i.e. naturally occurring catecholamines and drugs that mimic their action, and autacoids that act at serotonin receptors to elicit an hepatic glucose storage response.
  • a biogenic amine which includes the sympathomimetic amines, i.e. naturally occurring catecholamines and drugs that mimic their action, and autacoids that act at serotonin receptors to elicit an hepatic glucose storage response.
  • biogenic amines include, but are not limited to, L- ⁇ -3,4-dihydroxyphenylalanine (L-DOPA), 3-(2- aminoethyl)-5-hydroxyindole (5 -hydroxy tryptamine or serotonin), 2-(4-imidazolyl)ethyl amine (histamine), 4-[l-hydroxy-2-(methylamino)ethyl]-l,2-benzenediol (epinephrine), 1- [3 , 4-dihydroxyphenyl] -2-aminoethanol (nor epinephrine) , ⁇ -amino-n-butyric acid , acetylcholine and amino acids.
  • L-DOPA L- ⁇ -3,4-dihydroxyphenylalanine
  • the biogenic amine is serotonin, a serotonin analog, or a serotonergic agonist.
  • serotonin analog and “serotonergic agonist” refer to compounds which mimic the activity of serotonin, in particular compounds which act at 5-HT 2A/2C receptors of hepatocytes, which interaction is blocked by methysergide.
  • the targeting molecule attached to the surface of the polymeric construct directs the polymeric construct to an appropriate receptor, such as for example, a hepatobiliary receptor.
  • a hepatobiliary receptor such as for example, a hepatobiliary receptor.
  • target molecules for hepatobiliary receptors can be selected from substituted iminodiacetic acids, N' -substituted derivatives of ethylene diamine N,N- diacetic acid (EDDA), hepatobiliary dyes, hepatobiliary contrast agents, bile salts, hepatobiliary thiol complexes, and hepatobiliary amine complexes.
  • the first polymeric matrix is selected from polymers such as poly ly sine, poly(lactide/glycolide), chitosan glutamate, poly (acrylic acid), poly(divinyl glycol), albumin, polycarbonates, polyamines, poly(hydroxybutyric acid), scleroglucans, poly oxypropylene-polyoxy ethylene, polygalacturonic acid (partially esterified) and xanthan gum and the second polymeric component is a copolymer of polylysine and poly(glutamic/aspartic acid).
  • polymers such as poly ly sine, poly(lactide/glycolide), chitosan glutamate, poly (acrylic acid), poly(divinyl glycol), albumin, polycarbonates, polyamines, poly(hydroxybutyric acid), scleroglucans, poly oxypropylene-polyoxy ethylene, polygalacturonic acid (partially esterified) and xanthan gum
  • the second polymeric component
  • the polymeric constructs and pharmaceutical compositions of this invention are useful for the treatment of disease states responsive to biogenic amines, including sympathomimetic amines and autacoids.
  • disease states may include, for example, hypertension, shock, cardiac failure, arrhythmias, asthma, allergy, anaphylaxis and diabetes.
  • the invention comprises a method of treating a disease state in a mammal by administering to the mammal a therapeutically effective amount of a biogenic amine in a pharmaceutical composition comprising a polymeric construct containing the biogenic amine and a second copolymer of polylysine and poly(glutamic/aspartic acid).
  • biogenic amines which as potent neurotransmitters, should be sequestered tightly within a polymeric construct in order to minimize or substantially eliminate interactions with receptors of organs or tissues other than those targeted by the construct.
  • the biogenic amine neurotransmitters are water soluble and have polar chemical functionalities.
  • the quaternary amines such as epinephrine and acetylcholine, manifest a positive charge over a broad pH range, while the other biogenic amine neurotransmitters are primary amines, positively charged at physiological pH and below.
  • biogenic amines evince a pronounced polarity contributed by either a positively charged quaternary amine group or a positively charged primary amine group at physiological pH, they demonstrate unusual water-activity. They are thus difficult to retain within a polymeric construct, resulting in poor storage stability and undesirable, and potentially toxic, leakage after administration.
  • Biogenic amines interact with a wide variety of receptors on different cell types, not necessarily associated with the condition to be treated. These cells include, inter alia, neurons, platelets, mast cells, and enterochromaffin cells.
  • this invention is directed to the retention of biogenic amines, such as serotonin or a serotonergic agonist, within a targeted polymeric construct.
  • biogenic amines such as serotonin or a serotonergic agonist
  • the sequestration of serotonin is required not only due to its hormonal function, but also because serotonin acts in vivo as a neurotransmitter in many different cell types not associated with the liver. Therefore if exogenous serotonin, which has been incorporated in a targeted polymer, is not strongly sequestered or retained by the polymer structure, it may leak from the polymer and elicit undesirable pharmacological responses with other cell types that manifest serotonin receptors.
  • novel polymeric constructs of this invention provide a means to deliver a biologically active agent within a chemically stable carrier, due to strong ionic bonding and dipole-dipole interactions between the various carrier constituents.
  • These chemical interactions effectively lower the water activity of the biologically active agent, e.g. the biogenic amine, within the polymeric construct and thus minimize diffusion of the agent from the polymeric carrier.
  • the chemical and physical interactions among the active agents themselves are decreased.
  • This invention provides a secondary polymeric anchor by which biologically active agents, including biogenic amines such as serotonin, can be effectively sequestered within a first polymeric matrix for an extended period of time to minimize their leakage to the external environment.
  • the invention provides for the sequestration of biogenic amines such as serotonin within a hepatobiliary targeted polymeric construct.
  • biogenic amines such as serotonin
  • hepatobiliary targeted polymeric construct are retained within the first polymeric matrix using a secondary copolymeric anchor comprising polylysine-poly(glutamic-aspartic acid).
  • the use of the polymeric constructs of this invention facilitates the sequestering and delivery of biogenic amines by specific functional group interactions described in this disclosure.
  • the carbonyl and amino functional groups of the primary and secondary polymers can react with biogenic amines by engaging in hydrogen bond formation.
  • the negatively charged polymeric carboxyl groups can form ionic linkages with positively charged primary and quaternary biogenic amines.
  • the targeting and cargo molecules may be retained more securely, which effectively prevents drug leakage into the external aqueous phase.
  • PLGA lactic and glycolic acids
  • PLGA microspheres generally range in diameter from about 200 to about 1500 Angstroms depending upon the degree of polymerization.
  • the first is the incorporation of a copolymer of lysine and glutamic and aspartic acids (or glutamate and aspartate) in the first polymeric matrix as an anchoring molecule for biogenic amines.
  • the second aspect is the use of hepatobiliary target molecules bound either to the first polymeric matrix or, optionally, to the anchoring polymer, for delivering the biogenic amine to the hepatocytes of the liver.
  • the secondary copolymer may function both to chemically anchor hepatobiliary target molecules and also to retain the biogenic amine.
  • the third aspect relates to the interaction between the primary and secondary polymers which contributes to construct stability among the primary polymeric matrix, the secondary polymeric anchor, the active agent, and other construct constituents.
  • Representative hepatobiliary targeting molecules include substituted iminodiacetic acids such as N-(2,6-diisopropylphenylcarbamoylmethyl)iminodiacetic acid, N-(2,6- diethylphenyl-carbamoyl methyl)iminodiacetic acid, N-(2,6- dimethylphenylcarbamoylmethyl)iminodiacetic acid, N-(4- isopropy lphenylcarbamoylmethyl) iminodiacetic acid , N-(4-butylphenylcarbamoyl-methyl) iminodiacetic acid, N-(2,3-dimethylphenylcarbamoylmethyl)iminodiacetic acid, N-(3- butylphenyl-carbamoylmethyl)iminodiacetic acid, N-(2-butylphenylcarbamoylmethyl) iminodiacetic acid, N-(4-t-butyl
  • a primary polymeric matrix in conjunction with a secondary polylysine- poly(glutamic/aspartic acid) copolymer provides a polymeric construct which anchors not only biogenic amines, but also hepatobiliary target molecules. This construct manifests a complex synergy of interaction that maintains the structural integrity of the entire targeted polymeric carrier system.
  • Several polymers have been employed to illustrate the concept and benefits of the dual polymer construct and to delineate the specialized interactions that occur when different primary polymeric matrices are mixed with secondary copolymers.
  • One embodiment of a polymeric construct of this invention comprises a polylysine primary polymeric matrix and a secondary anchoring copolymer of polylysine- poly(glutamic-aspartic acids).
  • the ionic interaction between the negatively charged ⁇ - and ⁇ -carboxyl groups of glutamic and aspartic acids, respectively, with the positively charged amine groups of biogenic amines enhances retention of the active agent.
  • ionic bonding between the carboxyl groups of the hepatobiliary targeting molecule and the amino group of polylysine enhances retention of the targeting molecule on the surface of the polymeric carrier.
  • Another embodiment of the invention uses PLGA as the primary polymeric matrix. By varying the molar ratio of glycolide-to-lactide the hydrophilicity of the copolymeric construct may be regulated.
  • the primary polymeric matrix thus provides numerous carbonyl functional groups that can participate in hydrogen bond formation.
  • the polylysine-poly(glutamic/aspartic) acid secondary copolymeric anchor provides multiple binding sites for all constituents of the carrier. Furthermore, ionic interaction between the positively charged nitrogen atoms of the biogenic amines and the ⁇ -carboxyl groups of aspartic acid and the ⁇ -carboxyl groups of glutamic acid enhances stability.
  • a third embodiment of a polymeric construct of this invention employs chitosan glutamate as the primary polymeric matrix.
  • Chitosan glutamate is a deacylated derivative of chitin and may be prepared by mixing chitosan and glutamic acid together.
  • a key distinction between chitosan glutamate and native chitosan is that chitosan glutamate is water soluble, whereas native chitosan is generally only soluble in dilute organic acids.
  • Chitosan glutamate is a polymeric amino sugar with a free amino functional group on carbon #2 of every glucosamine residue which is glycosidically linked ⁇ -(l -» 4) in linear sequence to every other glucosamine residue in the polymer.
  • Chitosan glutamate has strong hydrogen bonding functional groups such as hydroxyl and amino groups.
  • the molecule manifests an array of positive charges at physiological pH and below, a high molecular weight, good polymer chain flexibility and surface energy properties which favor molecular interaction with other kinds of polymers, including the secondary copolymer of polylysine-poly(glutamic/aspartic acid).
  • This construct has a polysaccharide primary polymer backbone.
  • the three aforementioned polymer constructs are representative members of distinct polymer classes and illustrate the diversity of polymer carriers.
  • Other representative first and primary polymers include, but are not limited to, polycarbophil, a high molecular weight copolymer of acrylic acid cross-linked with divinyl glycol, albumin, polycarbonates, poly amines and poly hydroxy butyric acid.
  • Nonionic polymers include polysaccharides such as scleroglucans, homopolysaccharides having glucose subunits, e.g. dextran, starch and hydroxy ethyl starch.
  • poly oxy ethylene polymers and copolymers may be used as the primary polymers in this invention.
  • Anionic polymers suitable as primary polymers include some polymeric sugars and are represented by pectin and xanthan gum.
  • the polymeric constructs of this invention are useful for administering an active agent to a host. Accordingly, the constructs of this invention are useful as pharmaceutical compositions in combination with pharmaceutically acceptable carriers. Administration of the constructs described herein can be via any of the accepted modes of administration for the biologically active substances that are desired to be administered. These methods include oral, topical, parenteral, ocular, transdermal, nasal and other systemic or aerosol forms.
  • compositions used may be in the form of solid, semi-solid or liquid dosage forms, such, as for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical compositions will include the polymeric construct as described and a pharmaceutically acceptable excipient, and, optionally, may include other active agents, carriers, adjuvants, etc.
  • Topical formulations composed of the polymeric constructs hereof, penetration enhancers, and other ingredients may be applied in various ways. The solution can be applied dropwise, from a suitable delivery device, to the appropriate area of skin or mucous membranes and rubbed in by hand or simply allowed to air dry.
  • a suitable gelling agent can be added to the solution and the preparation can be applied to the appropriate area and rubbed in.
  • the solution formulation can be placed into a spray device and be delivered as a spray. This type of drug delivery device is particularly well suited for application to large areas of skin, to highly sensitive skin, or to the nasal or oral cavities.
  • Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like.
  • the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolaine oleate, etc.
  • the amount of active compound administered will of course, be dependent on the subject being treated, the type and severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the dosage form is intended for sustained release, the total dose will be integrated over the total time period of the sustained release device in order to compute the appropriate dose required.
  • effective dosage ranges for specific biologically active substances of interest are dependent upon a variety of factors, and are generally known to one of ordinary skill in the art, some dosage guidelines can be generally defined.
  • the polymeric component will be suspended in an aqueous solution and generally not exceed 30% (w/v) of the total formulation.
  • the drug component of the formulation will most likely be less than 20% (w/v) of the formulation and generally greater than 0.01 % (w/v)
  • topical formulations are prepared in gels, creams or solutions having an active ingredient in the range of from 0.001 % to 10% (w/v), preferably 0.01 to 5%, and most preferably about 1 % to about 5 % .
  • these ranges are subject to variation depending upon the potency of the biogenic amine, and could in appropriate circumstances fall within a range as broad as from 0.001 % to 20% .
  • the total dose given will depend upon the size of the affected area of the skin and the number of doses per day.
  • a pharmaceutically acceptable, non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • excipients such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • Such compositions include solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations and the like.
  • the compositions will take the form of a pill or tablet.
  • compositions will contain along with the active ingredient: a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, gelatin, polyvinylpyrolidine, cellulose and derivatives thereof, and the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like
  • a lubricant such as magnesium stearate or the like
  • binder such as starch, gum acacia, gelatin, polyvinylpyrolidine, cellulose and derivatives thereof, and the like.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dispersing or suspending the polymeric construct as described above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycol
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • Dosage forms or compositions containing active ingredient in the range of 0.005% to 95% with the balance made up from non-toxic carrier may be prepared.
  • the exact composition of these formulations may vary widely depending on the particular properties of the biogenic amine in question. However, they will generally comprise from 0.01 % to 95%, and preferably from 0.05% to 10% active ingredient for highly potent agents, and from 40-85% for moderately active agents.
  • the suspension in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
  • a gelatin capsule Such suspensions and the preparation and encapsulation thereof, can be prepared by methods that are disclosed in U.S. Patents Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the suspension may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration.
  • liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the polymeric construct in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and the like, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like.
  • the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, solubility enhancers, and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc.
  • a more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g. , U.S. Patent No. 3,710,795.
  • the percentage of active agent contained in parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01 % to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages.
  • the composition will comprise 0.2 - 2% of the active agent in solution.
  • Nasal suspensions of the polymeric construct alone or in combination with pharmaceutically acceptable excipients can also be administered.
  • Formulations of the polymeric construct may also be administered to the respiratory tract as an aerosol for a nebulizer.
  • the particles of the formulation have diameters of less than 50 microns, preferably less than 10 microns.
  • Example 1 Association of serotonin HCl with bovine serum albumin.
  • a bovine serum albumin solution was prepared by dissolving 40 mg of albumin in 10 ml of 10 mM HEPES buffer, pH 7.0.
  • a serotonin solution was prepared by adding 10 mg of serotonin HCl (5 -hydroxy tryptamine HCl) to 10 ml of 10 mM HEPES buffer, pH 7.0, and then adding a minute quantity (50 ⁇ l) of radiolabeled 5- hydroxytryptamine creatinine sulfate to the solution.
  • 1.0 ml of the albumin solution was mixed with 1.0 ml of the serotonin solution and vortexed for 20 seconds.
  • a 25 ⁇ l aliquot and a 50 ⁇ l aliquot were taken of this mixture for use as standards.
  • the final concentration of albumin in the mixed solution was 2 mg/ml (0.03 mM).
  • the final concentration of serotonin in the mixed solution was 0.5 mg/ml (2.4 mM).
  • the remaining 1.925 ml solution was placed in a clear Centricon tube having a filter with a molecular weight cut-off of 30,000. The tube was spun for 30 minutes at 6500 rpm. Three 192.5 ⁇ l aliquots of the filtrate were counted on a scintillation counter. The scintillation counter results indicated that 924 ⁇ g serotonin HCl was in the filtrate (95.9% of 963 ⁇ g/ 1.925 ml). Therefore, 4.1 % of the serotonin appeared to have been retained on the filter, presumably due to binding with the albumin.
  • Experiment B One ml of the albumin solution (4 mg/ml) from Experiment A was mixed with 20 ⁇ l of the serotonin solution (1 mg/ml) from Experiment A and vortexed for 20 seconds. A 20 ⁇ l aliquot was taken of this mixture for use as standards. The final concentration of albumin in the mixed solution was 4 mg/ml (0.06 mM). The final concentration of serotonin HCl in the mixed solution was 0.020 mg/ml (0.094 mM).
  • the 1.0 ml of the solution was placed in a green Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was then spun for 30 minutes at 6500 rpm. Two 100 ⁇ l aliquots of the filtrate were counted on the scintillation counter.
  • an albumin solution (40 mg/ml) was prepared by dissolving 120 mg of albumin in 3.0 ml of 10 mM HEPES buffer, pH 7.0.
  • the serotonin solution (1 mg/ml) from Experiment A was used.
  • 1.0 ml of this albumin solution was mixed with 20 ⁇ l of the serotonin solution and vortexed for 20 seconds.
  • a 20 ⁇ l aliquot was taken of this mixture for use as a standard. This mixture was allowed to stand for 20 minutes.
  • the final concentrations of albumin and serotonin HCl in the mixture were 40 mg/ml (0.61 mM) and 0.02 mg/ml (0.094 mM), respectively.
  • Example 2 Association of serotonin with phytic acid, poly-lysine, poly-lysine-succinyl, and N-2,6-(diisopropylphenylcarbamoylmethyl)iminodiacetic acid (DID A).
  • a solution of phytic acid was prepared by mixing 5.6 mg with 10 ml of 10 mM HEPES buffer, pH 7.0.
  • the poly-lysine solution contained 5.6 mg in 10 ml of HEPES buffer, pH 7.0.
  • a poly-lysine-succinyl solution also was prepared with 5.6 mg in 10 ml of HEPES buffer, pH 7.0.
  • the DIDA solution contained 8.4 mg in 10 ml HEPES buffer, pH 7.0.
  • the amount of serotonin HCl in the filtrate was 5.0 ⁇ g (75.8 % of 20 ⁇ g/3.040 ml). This indicates that 24.2 % of the serotonin was retained by the Centricon filter in this experiment, presumably due to ionic and/or hydrogen bonding interactions between the serotonin and the polymeric components of the solution mixture.
  • DIDA N- (2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid
  • chitosan 0.31 mg/ml (1.9 mM)
  • poly-Glu-Lys 0.65 mg/ml (2,7 mM)
  • a 1.0 ml aliquot was placed in a Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was then centrifuged for 30 minutes. 100 ⁇ l aliquots were taken from the original sample and from the filtrate to be counted on the scintillation counter.
  • Example 4 Association of serotonin with poly(L-lactide acid-co-glycolide), poly-Glu- Lys, and N-(2,6-diisopropylphenylcarbamoylmethyl)iminodiacetic acid (DIDA).
  • the poly(L-lactide acid-co-glycolide) polymer (PLGA) does not dissolve with acetic acid, ethanol or NaOH, but does dissolve in dimethyl sulfoxide (DMSO). 10 mg of PLGA was dissolved in 0.5 ml of DMSO at 60°C for 30 seconds. Then 9.5 ml of 10 mM HEPES, pH 7.0 was added to the polymer/DMSO and the mixture vortexed.
  • Example 3 In a clean test tube, one ml of the Poly-Glu-Lys solution (1 mg/ml) from Example 3 was mixed with 20 ⁇ l of the serotonin HCl solution (1 mg/ml) from Example 1, Experiment A, and warmed to 60°C and vortexed. A 10 ⁇ l aliquot a DIDA solution (0.84 mg/ml) was added and the mixture again vortexed. Finally, 0.5 ml of a poly(L-lactide acid-co-glycolide) solution (1 mg/ml) was added. The entire mixture was warmed and vortexed.
  • the final concentrations of the mixture were as follows: poly (L-lactide acid-co-glycolide): 0.33 mg/ml (1.0 mM) poly-Glu-Lys : 0.65 mg/ml (2.7 mM) serotonin HCl: 0.013 mg/ml (0.061 mM)
  • DIDA 0.005 mg/ml (0.0014 mM) 1.0 ml of the solution mixture was placed in a green Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was then centrifuged at 6500 rpm for 1 hour. 100 ⁇ l aliquots were taken of the original sample and of the filtrate and counted on the scintillation counter.
  • Example 5 Association of serotonin with poly oxypropylene-polyoxy ethylene (Pluronic ® F-127), poly-Glu-Lys, ⁇ oly(Tyr-Glu)Ala-Lys, and N-(2,6- diisopropylphenylcarbamoylmethyl) iminodiacetic acid (DIDA).
  • Pluronic ® F-127 poly oxypropylene-polyoxy ethylene
  • DIDA N-(2,6- diisopropylphenylcarbamoylmethyl) iminodiacetic acid
  • 1.0 ml of a poly-Glu-Lys solution (1 mg/ml) was heated to 100°C for two minutes, and then 20 ⁇ l of the 1 mg/ml serotonin HCl solution from Example 1, Experiment A, was added.
  • 1.0 ml of a poly(Tyr-Glu)Ala-Lys solution (1 mg/ml) was heated to 100°C and then added to the above-mentioned solution.
  • 10 ⁇ l of a DIDA solution (0.84 mg/ml) was mixed into the solution mixture. The entire mixture was vortexed and allowed to cool to room temperature and then chilled to 4°C.
  • poly-Glu-Lys 0.40 mg/ml (1.7 mM)
  • poly(Tyr-Glu)Ala-Lys 0.40 mg/ml (0.94 mM)
  • serotonin HCl 0.008 mg/ml (0.04 mM)
  • Pluronic ® F- 127 0.20 mg/ml (1.7 mM) 1.0 ml of the solution mixture was placed in a green Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was centrifuged for 1 hour. 100 ⁇ l aliquots were taken from the filtrate for counting in the scintillation counter.
  • the concentration of serotonin HCl in the filtrate was found to be 7.4 ⁇ g/ml (92.5 % of 20 ⁇ g/2.530 ml). This result indicates that approximately 7.5 % of the serotonin HCl in the original solution mixture was retained on the filter, presumably as part of a complex with the polymers of the solution.
  • Example 6 Association of serotonin with ATP, poly-Glu-Lys, poly-lysine, and N-(2,6- diisopropylphenylcarbamoylmethyl) iminodiacetic acid (DIDA).
  • the ATP solution was prepared by weighing 10 mg in 10 ml of 10 mM HEPES buffer, pH 7.0.
  • 20 ⁇ l of the 1 mg/ml serotonin HCl solution from Example 1, Experiment A was added to 1.13 ml of a poly-Glu-Lys solution (1 mg/ml) and vortexed.
  • 26 ⁇ l of a solution of ATP (1 mg/ml) was added and vortexed.
  • 1.07 ml of a poly-Lys solution (0.56 mg/ml) was added next.
  • 10 ⁇ l of a DIDA solution (0.84 mg/ml) was then added to the mixture and vortexed.
  • DIDA 0.0037 mg/ml (0.01 mM) 1.0 ml of the mixed solution was placed into a green Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was centrifuged for 1 hour. 100 ⁇ l aliquots of the filtrate were taken to be counted on the scintillation counter. The results indicated that serotonin HCl was present in the filtrate at a concentration of 7.4 ⁇ g/ml (82% of 0.02 mg/2.256 ml). Therefore, approximately 18% of the serotonin had been retained at the filter, presumably as part of an ionic and/or hydrogen bonding complex with the polymers of the solution mixture.
  • Example 7 Association of serotonin with poly(acrylic acid), poly-Glu-Lys, and N-(2,6- diisopropylphenylcarbamoylmethyl)iminodiacetic acid (DIDA).
  • DIDA N-(2,6- diisopropylphenylcarbamoylmethyl)iminodiacetic acid
  • the final concentrations of the reaction mixture components were as follows: poly (acrylic acid) : 0.13 mg/ml (1.9 mM) poly-Glu-Lys: 0.46 mg/ml (1.9 mM) serotonin HCl: 0.01 mg/ml (0.04 mM)
  • N-(2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid DIDA
  • 3.3 ml of a poly (vinyl sulfonic acid) solution (15% aqueous) was added to 20 ⁇ l of the 1.0 mg/ml serotonin HCl solution from Example 1, Experiment A, and vortexed for 20 seconds.
  • 13 ml of a 1.0 mg/ml solution of poly-Glu-Lys was added to 10 ⁇ l of 0.84 mg/ml solution of DIDA and vortexed for 20 seconds. The two vials were then vortexed together and three 200 ⁇ l aliquots were taken for use as standards in the scintillation counter.
  • the final concentrations of the components of the solution mixture were as follows: poly(vinyl sulfonic acid): 0.10 mg/ml (1.0 mM) poly-Glu-Lys : 0.25 mg/ml (1.0 mM) serotonin HCl ; 0.0004 mg/ml (0.02 mM)
  • Example 9 Association of serotonin with poly(aspartic acid), poly-Glu-Lys, and N- (2,6-diisopropylphenylcarbamoylmethyl)iminodiacetic acid (DIDA) .
  • 0.62 ml of a poly(aspartic acid) solution (1.0 mg/ml) was added to 20 ⁇ l of 1.0 mg/ml serotonin HCl from Example 1, Experiment A, and vortexed for 20 seconds.
  • 1.13 ml of a 1.0 mg/ml solution of poly-Glu-Lys was added to 10 ⁇ l of a 0.84 mg/ml solution of DIDA and vortexed for 20 seconds. The two vials were vortexed together and two 200 ⁇ l aliquots were taken for use as standards.
  • the final concentrations of the individual components of the vortexed solution mixture were as follows: poly(aspartic acid) 0.35 mg/ml (2.6 mM) poly-Glu-Lys 0.63 mg/ml (2.6 mM) serotonin HCl 0.01 mg/ml (0.05 mM)
  • Example 10 Association of serotonin with poly(lysine), phytic acid, poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethy)iminodiacetic acid (DIDA) .
  • DIDA N-(2,6-diisopropylphenylcarbamoylmethy)iminodiacetic acid
  • Glu-Lys was also added to the second vial.
  • the contents of the second vial were vortexed for 20 seconds.
  • the two vials were then vortexed together and two 200 ⁇ l aliquots were taken for use as standards.
  • the final concentrations of the various components of the mixed solution were as follows: poly(lysine): 0.17 mg/ml (1.3 mM) phytic Acid: 0.21 mg/ml (0.2 mM) poly-Glu-Lys: 0.32 mg/ml (1.3 mM) serotonin HCl: ⁇ 0.01 mg/ml ( ⁇ 0.01 mM) DIDA: ⁇ 0.01 mg/ml ( ⁇ 0.01 mM) 0.5 ml of this mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000. The tube was centrifuged for 30 minutes. Two 200 ⁇ l aliquots were then taken from the filtrate and counted on the scintillation counter.
  • Example 11 Association of serotonin with poly(glutamic acid), chitosan, and N-(2,6- diisopropylphenylcarbamoylmethy)iminodiacetic acid (DIDA).
  • DIDA N-(2,6- diisopropylphenylcarbamoylmethy)iminodiacetic acid
  • 1.06 ml of 0.5 mg/ml poly (glutamic acid) was added to 20 ⁇ l of the 1.0 mg/ml solution of serotonin HCl from Example 1, Experiment A, and vortexed for 20 seconds.
  • 0.76 of a 1.0 mg/ml solution of low molecular weight (MW) chitosan was added to 10 ⁇ l of a 0.84 mg/ml solution of DIDA and vortexed for 20 seconds.
  • the two vials were vortexed together, and two 200 ⁇ l aliquots were taken for use as standards in the scintillation counter.
  • Example 12 Association of serotonin with poly(galacturonic acid), poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethy)iminodiacetic acid (DIDA) .
  • DIDA N-(2,6-diisopropylphenylcarbamoylmethy)iminodiacetic acid
  • DIDA N-(2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid
  • a solution of DIDA was prepared by weighing out 8.4 mg of DIDA and dissolving it in 10 ml of 10 mM HEPES buffer, pH 7.0.
  • 0.85 ml of the low molecular weight chitosan solution (1.0 mg/ml) from Example 3 was added to 10 ⁇ l of the DIDA solution, and the mixture was vortexed for 20 seconds.
  • the two vials were mixed together and two 100 ⁇ l aliquots were taken for use as standards.
  • serotonin may be unable to form a stable association with primary polymeric matrices such as poly(L-lactide acid- co-glycolide) and chitosan.

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Abstract

Cette invention concerne une construction polymère permettant d'administrer un agent biologiquement actif à un mammifère, laquelle construction comprend une première matrice polymère, un agent biologiquement actif contenu dans la matrice polymère et un second polymère chimiquement lié à l'agent biologiquement actif, ledit second polymère comprenant un copolymère d'acides aminés, ledit second polymère étant présent selon une dose efficace, pour réduire la fuite de l'agent actif de la construction polymère avant l'administration à l'emplacement voulu.
PCT/US1998/015457 1997-07-25 1998-07-24 Compositions pharmaceutiques a base de polymeres destinees a une administration ciblee d'agents biologiquement actifs WO1999004824A1 (fr)

Priority Applications (4)

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AU85912/98A AU8591298A (en) 1997-07-25 1998-07-24 Polymer based pharmaceutical compositions for targeted delivery of biologically active agents
EP98937127A EP0999855A1 (fr) 1997-07-25 1998-07-24 Compositions pharmaceutiques a base de polymeres destinees a une administration ciblee d'agents biologiquement actifs
CA002297025A CA2297025A1 (fr) 1997-07-25 1998-07-24 Compositions pharmaceutiques a base de polymeres destinees a une administration ciblee d'agents biologiquement actifs
JP2000503875A JP2001510811A (ja) 1997-07-25 1998-07-24 生物活性物質を標的に供給するための重合体ベースの薬剤組成物

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7588754B2 (en) 2005-05-10 2009-09-15 Nitto Denko Corporation Biodegradable polyacetals and methods
US7674452B2 (en) 2005-03-16 2010-03-09 Nitto Denko Corporation Polymer coating of cells
US8383091B2 (en) 2003-09-29 2013-02-26 Nitto Denko Corporation Biodegradable polyacetals for in vivo polynucleotide delivery
US10611857B2 (en) 2017-08-02 2020-04-07 Exxonmobil Chemical Patents Inc. Bisphenolate transition metal complexes, production and use thereof
US11634512B2 (en) 2017-01-27 2023-04-25 Cornell University Zwitterionically modified polymers and hydrogels

Citations (6)

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Publication number Priority date Publication date Assignee Title
EP0086627A1 (fr) * 1982-02-12 1983-08-24 Unitika Ltd. Produit anti-cancéreux
WO1990005522A1 (fr) * 1988-11-17 1990-05-31 Per Prisell Preparation pharmaceutique
EP0467389A2 (fr) * 1990-07-19 1992-01-22 University Of Kentucky Research Foundation Système de délivrance de drogue à l'aide de l'interaction entre une protéine ou polypeptide et un polymère biodégradable hydrophobe
WO1994011015A1 (fr) * 1992-11-12 1994-05-26 Molecular Dynamics, Inc. Porteurs lipophiles a base de peptides destines a l'administration ciblee de medicaments selon un concept rationnel de fixation des medicaments
WO1995000547A1 (fr) * 1993-06-22 1995-01-05 E.I. Du Pont De Nemours And Company Composition antimicrobienne comprenant un polymere et un peptide formant des helices amphiphiles du type magainine
WO1996004001A1 (fr) * 1994-08-05 1996-02-15 Molecular/Structural Biotechnologies, Inc. Complexes biomoleculaires diriges

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0086627A1 (fr) * 1982-02-12 1983-08-24 Unitika Ltd. Produit anti-cancéreux
WO1990005522A1 (fr) * 1988-11-17 1990-05-31 Per Prisell Preparation pharmaceutique
EP0467389A2 (fr) * 1990-07-19 1992-01-22 University Of Kentucky Research Foundation Système de délivrance de drogue à l'aide de l'interaction entre une protéine ou polypeptide et un polymère biodégradable hydrophobe
WO1994011015A1 (fr) * 1992-11-12 1994-05-26 Molecular Dynamics, Inc. Porteurs lipophiles a base de peptides destines a l'administration ciblee de medicaments selon un concept rationnel de fixation des medicaments
WO1995000547A1 (fr) * 1993-06-22 1995-01-05 E.I. Du Pont De Nemours And Company Composition antimicrobienne comprenant un polymere et un peptide formant des helices amphiphiles du type magainine
WO1996004001A1 (fr) * 1994-08-05 1996-02-15 Molecular/Structural Biotechnologies, Inc. Complexes biomoleculaires diriges

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8383091B2 (en) 2003-09-29 2013-02-26 Nitto Denko Corporation Biodegradable polyacetals for in vivo polynucleotide delivery
US7674452B2 (en) 2005-03-16 2010-03-09 Nitto Denko Corporation Polymer coating of cells
US8216558B2 (en) 2005-03-16 2012-07-10 Nitto Denko Corporation Polymer coating of cells
US7588754B2 (en) 2005-05-10 2009-09-15 Nitto Denko Corporation Biodegradable polyacetals and methods
US11634512B2 (en) 2017-01-27 2023-04-25 Cornell University Zwitterionically modified polymers and hydrogels
US10611857B2 (en) 2017-08-02 2020-04-07 Exxonmobil Chemical Patents Inc. Bisphenolate transition metal complexes, production and use thereof

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CN1264310A (zh) 2000-08-23
AU8591298A (en) 1999-02-16

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