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WO2002051432A1 - Nouveau compose pharmaceutique, ses procedes de preparation, et son utilisation - Google Patents

Nouveau compose pharmaceutique, ses procedes de preparation, et son utilisation Download PDF

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Publication number
WO2002051432A1
WO2002051432A1 PCT/US2001/043115 US0143115W WO02051432A1 WO 2002051432 A1 WO2002051432 A1 WO 2002051432A1 US 0143115 W US0143115 W US 0143115W WO 02051432 A1 WO02051432 A1 WO 02051432A1
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WIPO (PCT)
Prior art keywords
active agent
polypeptide
release
amino acid
composition
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2001/043115
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English (en)
Inventor
Thomas Piccariello
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
New River Pharmaceuticals Inc
Original Assignee
New River Pharmaceuticals Inc
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Filing date
Publication date
Application filed by New River Pharmaceuticals Inc filed Critical New River Pharmaceuticals Inc
Priority to PCT/US2001/043115 priority Critical patent/WO2002051432A1/fr
Publication of WO2002051432A1 publication Critical patent/WO2002051432A1/fr
Anticipated expiration legal-status Critical
Priority to US10/923,088 priority patent/US7427600B2/en
Ceased legal-status Critical Current

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    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to diacetylmorphine, as well as methods for protecting and administering diacetylmorphine.
  • This novel compound referred to as a CARRIERWANETM Molecular Analogue (CMA)
  • CMA CARRIERWANETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to oxymorphone, as well as methods for protecting and administering oxymorphone.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to dihydrocodeine, as well as methods for protecting and administering dihydrocodeine.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to codeine, guaifenesin and pseudoephidrine, as well as methods for protecting and administering codeine, guaifenesin and pseudoephidrine.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to aspirin, carisoprodol, and codeine, as well as methods for protecting and administering aspirin, carisoprodol, and codeine.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to acetaminophen and hydrocodone, as well as methods for protecting and administering acetaminophen and hydrocodone.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to guaifenesin and hydrocodone, as well as methods for protecting and administering guaifenesin and hydrocodone.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists.
  • the novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
  • Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid . are used to provide timed release of human O 02/051432
  • Diacetylmorphine is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
  • the novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists.
  • the novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers.
  • Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.
  • This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines.
  • the released dexamethasone active agent was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream.
  • Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker.
  • HARs highly ordered lipid films
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers.
  • Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • Active agent delivery systems also provide the ability to control the release of the active agent.
  • formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent.
  • copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone.
  • a wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids.
  • Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
  • Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.
  • This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines.
  • the released dexamethasone active agent was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream.
  • Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker.
  • HARs highly ordered lipid films
  • the novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists.
  • the novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers.
  • Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • Active agent delivery systems also provide the ability to control the release of the active agent.
  • formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent.
  • copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone.
  • a wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids.
  • Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
  • Variable molecular weights have unpredictable diffusion rates and pharmacokinetics.
  • High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes.
  • High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.
  • Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.
  • This prodrug formulation was designed as a colon-specific drag delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines.
  • the released dexamethasone active agent was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream.
  • Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker.
  • HARs highly ordered lipid films
  • Dihydromorphine is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Methyldihydromorphinone is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
  • the novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists.
  • the novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration.
  • Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • Codeine, phenylephrine and promethazine is a known pharmaceutical agent that is used in the treatment of coughs and colds.
  • the structure of codeine is shown in Figure 1.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Abso ⁇ tion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers.
  • Inco ⁇ orating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent.
  • copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone.
  • a wide range of pharmaceuticals pu ⁇ ortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids.
  • Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
  • peptide-drag conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration.
  • timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine.
  • Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Abso ⁇ tion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers.
  • Inco ⁇ orating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of: (a) attaching diacetylmorphine to a side chain of an amino acid to form an active agent/amino acid complex;
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, diacetylmo ⁇ hine and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the invention also provides a method for protecting hydromo ⁇ hone from degradation comprising covalently attaching it to a polypeptide.
  • the present invention provides covalent attachment of the active agent (hydrocodone) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • the invention also provides a method for delivering hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • hydrocodone is released from the composition by an enzyme-catalyzed release.
  • hydrocodone is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release.
  • the composition further comprises a microencapsulating agent and hydrocodone is released from the composition by dissolution of the microencapsulating agent.
  • the invention provides a composition comprising a polypeptide and oxymo ⁇ hone covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Oxymo ⁇ hone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting oxymo ⁇ hone from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering oxymo ⁇ hone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • oxymo ⁇ hone is released from the composition by an enzyme-catalyzed release.
  • oxymo ⁇ hone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and oxymo ⁇ hone is released from the composition by dissolution of the microencapsulating agent.
  • oxymo ⁇ hone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, oxymo ⁇ hone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • NCA N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, oxymo ⁇ hone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • Dihydrocodeine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • NCA N-carboxyanhydride
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the invention also provides a method for protecting dihydromo ⁇ hine from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering dihydromo ⁇ hine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • dihydromo ⁇ hine is released from the composition by an enzyme-catalyzed release.
  • dihydromo ⁇ hine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • the adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for delivering methyldihydromo ⁇ hinone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • methyldihydromo ⁇ hinone is released from the composition by an enzyme-catalyzed release.
  • methyldihydromo ⁇ hinone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • N-carboxyanhydride N-carboxyanhydride
  • the present invention provides covalent attachment of the active agent (codeine and promethazine) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching codeine and promethazine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the present invention provides a pharmaceutical composition comprising codeine and promethazine microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and codeine and promethazine covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Codeine and promethazine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the composition further comprises a microencapsulating agent and codeine and promethazine is released from the composition by dissolution of the microencapsulating agent.
  • codeine and promethazine is released from the composition by a pH-dependent unfolding of the polypeptide.
  • codeine and promethazine is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the present invention provides a pharmaceutical composition comprising codeine, phenylephrine and promethazine microencapsulated by a polypeptide.
  • the invention also provides a method for protecting codeine, phenylephrine and promethazine from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering codeine, phenylephrine and promethazine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • codeine, phenylephrine and promethazine is released from the composition by an enzyme- catalyzed release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention provides a composition comprising a polypeptide and codeine and guaifenesin covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Codeine and guaifenesin preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the invention also provides a method for protecting codeine and guaifenesin from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering codeine and guaifenesin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • codeine and guaifenesin is released from the composition by an enzyme-catalyzed release.
  • codeine and guaifenesin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and codeine and guaifenesin is released from the composition by dissolution of the microencapsulating agent.
  • codeine and guaifenesin is released from the composition by a pH-dependent unfolding of the polypeptide.
  • codeine and guaifenesin is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • NCA active agent/amino acid complex N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, codeine and guaifenesin and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the invention provides a composition comprising a polypeptide and codeine, guaifenesin and pseudoephidrine covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting codeine, guaifenesin and pseudoephidrine from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering codeine, guaifenesin and pseudoephidrine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • codeine, guaifenesin and pseudoephidrine is released from the composition by an enzyme- catalyzed release.
  • codeine, guaifenesin and pseudoephidrine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and codeine, guaifenesin and pseudoephidrine is released from the composition by dissolution of the microencapsulating agent.
  • codeine, guaifenesin and pseudoephidrine is released from the composition by a pH-dependent unfolding of the polypeptide.
  • codeine, guaifenesin and pseudoephidrine is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
  • N-carboxyanhydride N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, codeine, guaifenesin and pseudoephidrine and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the present invention provides covalent attachment of the active agent (aspirin, carisoprodol, and codeine) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching aspirin, carisoprodol, and codeine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • the present invention provides a pharmaceutical composition comprising aspirin, carisoprodol, and codeine microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and aspirin, carisoprodol, and codeine covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the • microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • the adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting aspirin, carisoprodol, and codeine from degradation comprising covalently attaching it to a polypeptide.
  • the composition further comprises a microencapsulating agent and aspirin, carisoprodol, and codeine is released from the composition by dissolution of the microencapsulating agent.
  • aspirin, carisoprodol, and codeine is released from the composition by a pH-dependent unfolding of the polypeptide.
  • aspirin, carisoprodol, and codeine is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
  • N-carboxyanhydride N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, aspirin, carisoprodol, and codeine and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • the adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the composition further comprises a microencapsulating agent and himatropine and hydrocodone is released from the composition by dissolution of the microencapsulating agent.
  • himatropine and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide.
  • himatropine and hydrocodone is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, himatropine and hydrocodone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • hydrocodone and phenylpropanolamine to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching hydrocodone and phenylpropanolamine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Hydrocodone and phenylpropanolamine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting hydrocodone and phenylpropanolamine from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering hydrocodone and phenylpropanolamine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • hydrocodone and phenylpropanolamine is released from the composition by an enzyme- catalyzed release.
  • hydrocodone and phenylpropanolamine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and hydrocodone and phenylpropanolamine is released from the composition by dissolution of the microencapsulating agent.
  • hydrocodone and phenylpropanolamine is released from the composition by a pH-dependent unfolding of the polypeptide.
  • hydrocodone and phenylpropanolamine is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drag conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent
  • hydrocodone and phenylpropanolamine and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • acetaminophen and hydrocodone to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching acetaminophen and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the present invention provides a pharmaceutical composition comprising acetaminophen and hydrocodone microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and acetaminophen and hydrocodone covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Acetaminophen and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting acetaminophen and hydrocodone from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering acetaminophen and hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • acetaminophen and hydrocodone is released from the composition by an enzyme-catalyzed release.
  • acetaminophen and hydrocodone is released in a time- dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and acetaminophen and hydrocodone is released from the composition by dissolution of the microencapsulating agent.
  • acetaminophen and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide.
  • acetaminophen and hydrocodone is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of: (a) attaching acetaminophen and hydrocodone to a side chain of an amino acid to form an active agent/amino acid complex;
  • NCA N-carboxyanhydride
  • NCA N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, acetaminophen and hydrocodone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the present invention provides covalent attachment of the active agent (chlo ⁇ heniramine, hydrocodone and pseudoephedrine) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching chlo ⁇ heniramine, hydrocodone and pseudoephedrine to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • Chlo ⁇ heniramine, hydrocodone and pseudoephedrine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C- terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for delivering chlo ⁇ heniramine, hydrocodone and pseudoephedrine to a patient, the patient being a human or a non- human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • chlo ⁇ heniramine, hydrocodone and pseudoephedrine is released from the composition by an enzyme-catalyzed release.
  • chlo ⁇ heniramine, hydrocodone and pseudoephedrine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and chlo ⁇ heniramine, hydrocodone and pseudoephedrine is released from the composition by dissolution of the microencapsulating agent.
  • chlo ⁇ heniramine, hydrocodone and pseudoephedrine is released from the composition by a pH-dependent unfolding of the polypeptide.
  • chlo ⁇ heniramine, hydrocodone and pseudoephedrine is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • N-carboxyanhydride N-carboxyanhydride
  • NCA N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent
  • chlo ⁇ heniramine, hydrocodone and pseudoephedrine and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching guaifenesin and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for delivering guaifenesin and hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • guaifenesin and hydrocodone is released from the composition by an enzyme-catalyzed release.
  • guaifenesin and hydrocodone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and guaifenesin and hydrocodone is released from the composition by dissolution of the microencapsulating agent.
  • guaifenesin and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide.
  • guaifenesin and hydrocodone is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the present invention provides covalent attachment of the active agent (ibuprofen and hydrocodone) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ibuprofen and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the present invention provides a pharmaceutical composition comprising ibuprofen and hydrocodone microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and ibuprofen and hydrocodone covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Ibuprofen and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-deperident manner.
  • the composition further comprises a microencapsulating agent and ibuprofen and hydrocodone is released from the composition by dissolution of the microencapsulating agent.
  • ibuprofen and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide.
  • ibuprofen and hydrocodone is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drag conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of: (a) attaching ibuprofen and hydrocodone to a side chain of an amino acid to form an active agent/amino acid complex;
  • N-carboxyanhydride N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, ibuprofen and hydrocodone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • chlo ⁇ heniramine and hydrocodone to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching chlo ⁇ heniramine and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • the present invention provides a pharmaceutical composition comprising chlo ⁇ heniramine and hydrocodone microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and chlo ⁇ heniramine and hydrocodone covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Chlo ⁇ heniramine and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting chlo ⁇ heniramine and hydrocodone from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering chlo ⁇ heniramine and hydrocodone to a patient, the patient being a human or a non-human animal, comprising
  • chlo ⁇ heniramine and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, chlo ⁇ heniramine and hydrocodone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients .
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • N-carboxyanhydride N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, chlo ⁇ heniramine and hydrocodone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the present invention provides covalent attachment of the active agent (naltrexone) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching naltrexone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the present invention provides a pharmaceutical composition comprising naltrexone microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and naltrexone covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Naltrexone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting naltrexone from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering naltrexone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • naltrexone is released from the composition by an enzyme-catalyzed release.
  • naltrexone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and naltrexone is released from the composition by dissolution of the microencapsulating agent.
  • naltrexone is released from the composition by a pH-dependent unfolding of the polypeptide.
  • naltrexone is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of: (a) attaching naltrexone to a side chain of an amino acid to form an active agent/amino acid complex;
  • N-carboxyanhydride N-carboxyanhydride
  • NCA N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, naltrexone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the thermodynamics of protein folding and unfolding are defined by the free energy of a particular condition of the protein that relies on a particular model.
  • the process of protein folding involves, amongst other things, amino acid residues packing into a hydrophobic core.
  • the amino acid side chains inside the protein core occupy the same volume as they do in amino acid crystals.
  • the folded protein interior is therefore more like a crystalline solid than an oil drop and so the best model for determining forces contributing to protein stability is the solid reference state.
  • Detailed 501 Page 7 be poured into heptane to precipitate the NCA product, which is filtered, dried and recrystallized from a suitable solvent.
  • Preparation of Poly[ ⁇ -Alkyl Glutamate] ⁇ - Alkyl glutamate-NCA can be dissolved in dry DMF where a catalytic amount of a primary amine can be added to the solution until it becomes viscous (typically overnight).
  • the product can be isolated from the solution by pouring it into water and filtering.
  • the product can be purified using GPC or dialysis.
  • the resultant peptide-ethylmo ⁇ hine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and ethylmo ⁇ hine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 1 wherein said polypeptide is capable of releasing ethylmo ⁇ hine from said composition in a pH-dependent manner.
  • a method for controlling release of ethylmo ⁇ hine from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching ethylmo ⁇ hine to said polypeptide.
  • a method for delivering ethylmo ⁇ hine to a patient comprising administering to said patient a composition comprising: a polypeptide; and ethylmo ⁇ hine covalently attached to said polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize diacetylmo ⁇ hine and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of diacetylmo ⁇ hine.
  • active agents can be combined to produce synergistic effects.
  • abso ⁇ tion of the active agent in the intestinal tract can be enhanced.
  • the invention also allows targeted delivery of active agents to specifics sites of action.
  • composition of the invention comprises diacetylmo ⁇ hine covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • diacetylmo ⁇ hine is covalently attached to the polypeptide via a ketal bond.
  • the resultant peptide-diacetylmo ⁇ hine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and diacetylmo ⁇ hine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • a method for protecting diacetylmo ⁇ hine from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for delivering diacetylmo ⁇ hine to a patient comprising administering to said patient a composition comprising: a polypeptide; and diacetylmo ⁇ hine covalently attached to said polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize hydromo ⁇ hone and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of hydromo ⁇ hone.
  • active agents can be combined to produce synergistic effects.
  • abso ⁇ tion of the active agent in the intestinal tract can be enhanced.
  • the invention also allows targeted delivery of active agents to specifics sites of action.
  • the composition of the invention comprises hydromo ⁇ hone covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • hydromo ⁇ hone is covalently attached to the polypeptide via the hydroxyl group.
  • the resultant peptide-hydromo ⁇ hone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and hydromo ⁇ hone covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein hydromo ⁇ hone is conformationally protected by folding of said polypeptide about said active agent.
  • composition of claim 1 wherein said polypeptide is capable of releasing hydromo ⁇ hone from said composition in a pH-dependent manner.
  • a method for protecting hydromo ⁇ hone from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for controlling release of hydromo ⁇ hone from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching hydromo ⁇ hone to said polypeptide.
  • a method for delivering hydromo ⁇ hone to a patient comprising administering to said patient a composition comprising: a polypeptide; and hydromo ⁇ hone covalently attached to said polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize hydrocodone and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of hydrocodone.
  • active agents can be combined to produce synergistic effects.
  • abso ⁇ tion of the active agent in the intestinal tract can be enhanced.
  • the invention also allows targeted delivery of active agents to specifics sites of action.
  • composition of the invention comprises hydrocodone covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • hydrocodone is covalently attached to the polypeptide via a ketal bond.
  • the resultant peptide-hydrocodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and hydrocodone covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein said polypeptide is capable of releasing hydrocodone from said composition in a pH-dependent manner.
  • a method for protecting hydrocodone from degradation comprising covalently attaching said active agent to a polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • a method for protecting dihydromo ⁇ hine from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for delivering dihydromo ⁇ hine to a patient comprising administering to said patient a composition comprising: a polypeptide; and dihydromo ⁇ hine covalently attached to said . polypeptide.
  • composition of the invention comprises methyldihydromo ⁇ hinone covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-methyldihydromo ⁇ hinone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and methyldihydromo ⁇ hinone covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 1 wherein said polypeptide is capable of releasing methyldihydromo ⁇ hinone from said composition in a pH-dependent manner.
  • a method for delivering methyldihydromo ⁇ hinone to a patient comprising administering to said patient a composition comprising: a polypeptide; and methyldihydromo ⁇ hinone covalently attached to said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize codeine and promethazine and prevent its digestion in the stomach.
  • composition of the invention comprises codeine and promethazine covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-codeine and promethazine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and codeine and promethazine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein said polypeptide is capable of releasing codeine and promethazine from said composition in a pH-dependent manner.
  • a method for protecting codeine and promethazine from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for delivering codeine and promethazine to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine and promethazine covalently attached to said polypeptide.
  • codeine and promethazine is released from said composition by an enzyme-catalyzed release.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize codeine, phenyleplirine and promethazine and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of codeine, phenylephrine and promethazine.
  • active agents can be combined to produce synergistic effects.
  • abso ⁇ tion of the active agent in the intestinal tract can be enhanced.
  • the invention also allows targeted delivery of active agents to specifics sites of action.
  • composition of the invention comprises codeine, phenylephrine and promethazine covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-codeine, phenylephrine and promethazine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and codeine, phenylephrine and promethazine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 wherein codeine, phenylephrine and promethazine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of the invention comprises codeine and guaifenesin covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein said polypeptide is capable of releasing codeine and guaifenesin from said composition in a pH-dependent manner.
  • a method for protecting codeine and guaifenesin from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for controlling release of codeine and guaifenesin from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching codeine and guaifenesin to said polypeptide.
  • a method for delivering codeine and guaifenesin to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine and guaifenesin covalently attached to said polypeptide.
  • codeine and guaifenesin is released from said composition by an enzyme-catalyzed release.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • composition of the invention comprises codeine, guaifenesin and pseudoephidrine covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-codeine, guaifenesin and pseudoephidrine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and codeine, guaifenesin and pseudoephidrine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein codeine, guaifenesin and pseudoephidrine is conformationally protected by folding of said polypeptide about said active agent.
  • a method for delivering codeine, guaifenesin and pseudoephidrine to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine, guaifenesin and pseudoephidrine covalently attached to said polypeptide.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein aspirin, carisoprodol, and codeine is conformationally protected by folding of said polypeptide about said active agent.
  • a method for protecting aspirin, carisoprodol, and codeine from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for controlling release of aspirin, carisoprodol, and codeine from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching aspirin, carisoprodol, and codeine to said polypeptide.
  • a method for delivering aspirin, carisoprodol, and codeine to a patient comprising administering to said patient a composition comprising: a polypeptide; and aspirin, carisoprodol, and codeine, covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • a method for protecting himatropine and hydrocodone from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for controlling release of himatropine and hydrocodone from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching himatropine and hydrocodone to said polypeptide.
  • a method for delivering himatropine and hydrocodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and himatropine and hydrocodone covalently attached to said polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize hydrocodone and phenylpropanolamine and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of hydrocodone and phenylpropanolamine.
  • active agents can be combined to produce
  • a pharmaceutical composition comprising: a polypeptide; and hydrocodone and phenylpropanolamine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • a method for controlling release of hydrocodone and phenylpropanolamine from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching hydrocodone and phenylpropanolamine to said polypeptide.
  • composition of the invention comprises acetaminophen and hydrocodone covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-acetaminophen and hydrocodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 wherein said polypeptide is capable of releasing acetaminophen and hydrocodone from said composition in a pH-dependent manner.
  • a method for controlling release of acetaminophen and hydrocodone from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching acetaminophen and hydrocodone to said polypeptide.
  • a method for delivering acetaminophen and hydrocodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and acetaminophen and hydrocodone covalently attached to said polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize chlo ⁇ heniramine, hydrocodone and pseudoephedrine and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of chlo ⁇ heniramine, hydrocodone and pseudoephedrine.
  • active agents can be combined to produce synergistic effects. Also, abso ⁇ tion of the active agent in the intestinal tract can be enhanced.
  • the invention also allows targeted delivery of active agents to specifics sites of action.
  • composition of the invention comprises chlo ⁇ heniramine, hydrocodone and pseudoephedrine covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-chlo ⁇ heniramine, hydrocodone and pseudoephedrine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 wherein chlo ⁇ heniramine, hydrocodone and pseudoephedrine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne de nouvelles compositions pharmaceutiques comprenant un polypeptide et un agent actif lié audit polypeptide. L'agent actif est, de préférence, lié de manière covalente à ce polypeptide. Les compositions de l'invention sont utilisées pour améliorer la stabilité chimique du composé original, pour altérer le profil libéré d'un produit administré oralement, pour améliorer la digestion et l'absorption et pour être distribué de manière ciblée à un tissu/type de cellule particulier.
PCT/US2001/043115 2000-08-22 2001-11-16 Nouveau compose pharmaceutique, ses procedes de preparation, et son utilisation Ceased WO2002051432A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US2001/043115 WO2002051432A1 (fr) 2001-11-16 2001-11-16 Nouveau compose pharmaceutique, ses procedes de preparation, et son utilisation
US10/923,088 US7427600B2 (en) 2000-08-22 2004-08-23 Active agent delivery systems and methods for protecting and administering active agents

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2001/043115 WO2002051432A1 (fr) 2001-11-16 2001-11-16 Nouveau compose pharmaceutique, ses procedes de preparation, et son utilisation

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US98803401A Continuation-In-Part 2000-08-22 2001-11-16
PCT/US2001/043117 Continuation-In-Part WO2003020200A2 (fr) 2000-08-22 2001-11-16 Nouveau compose pharmaceutique et procedes de fabrication et d'utilisation de ce compose

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PCT/US2001/043117 Continuation-In-Part WO2003020200A2 (fr) 2000-08-22 2001-11-16 Nouveau compose pharmaceutique et procedes de fabrication et d'utilisation de ce compose
US10/156,527 Continuation-In-Part US7060708B2 (en) 1999-03-10 2002-05-29 Active agent delivery systems and methods for protecting and administering active agents

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EP1490090A4 (fr) * 2002-02-22 2006-09-20 New River Pharmaceuticals Inc Systemes de distribution d'agents actifs et methodes de protection et d'administration d'agents actifs
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

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US4801575A (en) * 1986-07-30 1989-01-31 The Regents Of The University Of California Chimeric peptides for neuropeptide delivery through the blood-brain barrier
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1490090A4 (fr) * 2002-02-22 2006-09-20 New River Pharmaceuticals Inc Systemes de distribution d'agents actifs et methodes de protection et d'administration d'agents actifs
EP2266590A3 (fr) * 2002-02-22 2011-04-20 Shire LLC Système d'administration de substances actives et méthodes de protection et d'administration de substances actives
EP2316468A1 (fr) * 2002-02-22 2011-05-04 Shire LLC Système de distribution et méthodes de protection et d'administration de dextroamphetamine
EP2316469A1 (fr) * 2002-02-22 2011-05-04 Shire LLC Système de distribution et méthodes de protection et d'administration de dextroamphetamine
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

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