US20040127397A1 - Active agent delivery systems and methods for protecting and administering active agents - Google Patents

Active agent delivery systems and methods for protecting and administering active agents Download PDF

Info

Publication number
US20040127397A1
US20040127397A1 US10/727,565 US72756503A US2004127397A1 US 20040127397 A1 US20040127397 A1 US 20040127397A1 US 72756503 A US72756503 A US 72756503A US 2004127397 A1 US2004127397 A1 US 2004127397A1
Authority
US
United States
Prior art keywords
active agent
amino acid
polypeptide
acid
complex
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.)
Abandoned
Application number
US10/727,565
Inventor
Thomas Piccariello
Lawrence Olon
Randall Kirk
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by New River Pharmaceuticals Inc filed Critical New River Pharmaceuticals Inc
Priority to US10/727,565 priority Critical patent/US20040127397A1/en
Publication of US20040127397A1 publication Critical patent/US20040127397A1/en
Priority to US10/923,088 priority patent/US7427600B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K47/54—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 an organic compound
    • A61K47/55—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 an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Detergent Compositions (AREA)

Abstract

A composition comprising a polypeptide and an active agent covalently attached to the polypeptide. Also provided is a method for delivery of an active agent to a patient comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. Also provided is a method for protecting an active agent from degradation comprising covalently attaching the active agent to a polypeptide. Also provided is a method for controlling release of an active agent from a composition comprising covalently attaching the active agent to the polypeptide.

Description

    CROSS-REFERENCED AND RELATED APPLICATIONS
  • This application is a divisional of U.S. application Ser. No. 09/642,820 filed Aug. 22, 2000 which is hereby incorporated by reference in its entirety.[0001]
    • FIELD OF THE INVENTION
  • The present invention relates to active agent delivery systems and, more specifically, to compositions that comprise polypeptides covalently attached to active agents and methods for protecting and administering active agents. [0002]
    • BACKGROUND OF THE INVENTION
  • 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. 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. [0003]
  • 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. [0004]
  • 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 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. [0005]
  • Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release. [0006]
  • In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of 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. 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, in turn, 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. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration. [0007]
  • It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. 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 drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns. [0008]
    • SUMMARY OF THE INVENTION
  • The present invention provides covalent attachment of active agents to a polymer of peptides or amino acids. The invention is distinguished from the above mentioned technologies by virtue of covalently attaching the active agent, which includes, for example, pharmaceutical drugs and nutrients, 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. In certain applications, 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. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absorption by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism. [0009]
  • The invention provides a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. Preferably, 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. [0010]
  • The active agent preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide. [0011]
  • 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. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter. [0012]
  • Preferably, 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. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner. [0013]
  • The invention also provides a method for protecting an active agent from degradation comprising covalently attaching the active agent to a polypeptide. [0014]
  • The invention also provides a method for controlling release of an active agent from a composition wherein the composition comprises a polypeptide, the method comprising covalently attaching the active agent to the polypeptide. [0015]
  • The invention also provides a method for delivering an active agent 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. In a preferred embodiment, the active agent is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, the active agent is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and the active agent is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, the active agent is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, the active agent 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. [0016]
  • 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: [0017]
  • (a) attaching the active agent to a side chain of an amino acid to form an active agent/amino acid complex; [0018]
  • (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and [0019]
  • (c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA). [0020]
  • In a preferred embodiment, the active agent is a pharmaceutical agent or an adjuvant. In another preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, the active agent and second active agent can be copolymerized in step (c). In another preferred embodiment, 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. In another preferred embodiment, 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. In yet another preferred embodiment, 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. [0021]
  • It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.[0022]
    • BRIEF DESCRIPTION OF THE DRAWING
  • The invention is best understood from the following detailed description when read in connection with the accompanying drawing. Included in the drawing are the following figures. [0023]
  • FIG. 1 illustrates an acid active agent/N-terminus scheme of the invention. [0024]
  • FIG. 2 illustrates an amine active agent/C-terminus scheme of the invention. [0025]
  • FIG. 3 illustrates an alcohol active agent/N-terminus scheme of the invention. [0026]
  • FIG. 4 illustrates an alcohol active agent/glutamic acid dimer preparation and conjugation scheme of the invention. [0027]
  • FIG. 5 illustrates a mechanism of alcohol active agent from glutamic acid dimer scheme.[0028]
    • DETAILED DESCRIPTION OF INVENTION
  • The present invention provides several benefits for active agent delivery. First, the invention can stabilize the active agent and prevent digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of the active agent. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption 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. [0029]
  • The composition of the invention comprises a polypeptide and an active agent covalently attached to the polypeptide. Preferably, 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. [0030]
  • Proteins, oligopeptides and polypeptides are polymers of amino acids that have primary, secondary and tertiary structures. The secondary structure of the protein is the local conformation of the polypeptide chain and consists of helices, pleated sheets and turns. The protein's amino acid sequence and the structural constraints on the conformations of the chain determine the spatial arrangement of the molecule. The folding of the secondary structure and the spatial arrangement of the side chains constitute the tertiary structure. [0031]
  • Proteins fold because of the dynamics associated between neighboring atoms on the protein and solvent molecules. 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. [0032]
  • The major forces contributing to the thermodynamics of protein folding are Van der Waals interactions, hydrogen bonds, electrostatic interactions, configurational entropy and the hydrophobic effect. Considering protein stability, the hydrophobic effect refers to the energetic consequences of removing apolar groups from the protein interior and exposing them to water. Comparing the energy of amino acid hydrolysis with protein unfolding in the solid reference state, the hydrophobic effect is the dominant force. Hydrogen bonds are established during the protein fold process and intramolecular bonds are formed at the expense of hydrogen bonds with water. Water molecules are “pushed out” of the packed, hydrophobic protein core. All of these forces combine and contribute to the overall stability of the folded protein where the degree to which ideal packing occurs determines the degree of relative stability of the protein. The result of maximum packing is to produce a center of residues or hydrophobic core that has maximum shielding from solvent. [0033]
  • Since it is likely that lipophilic drugs would reside in the hydrophobic core of a peptide, it would require energy to unfold the peptide before the drug can be released. The unfolding process requires overcoming the hydrophobic effect by hydrating the amino acids or achieving the melting temperature of the protein. The heat of hydration is a destabilization of a protein. Typically, the folded state of a protein is favored by only 5-15 kcal/mole over the unfolded state. Nonetheless, protein unfolding at neutral pH and at room temperature requires chemical reagents. In fact, partial unfolding of a protein is often observed prior to the onset of irreversible chemical or conformation processes. Moreover, protein conformation generally controls the rate and extent of deleterious chemical reactions. [0034]
  • Conformational protection of active agents by proteins depends on the stability of the protein's folded state and the thermodynamics associated with the agent's decomposition. Conditions necessary for the agent's decomposition should be different than for protein unfolding. [0035]
  • Selection of the amino acids will depend on the physical properties desired. For instance, if increase in bulk or lipophilicity is desired, then the carrier polypeptide will be enriched in the amino acids in the table provided below. Polar amino acids, on the other hand, can be selected to increase the hydrophilicity of the polypeptide. [0036]
  • Ionizing amino acids can be selected for pH controlled peptide unfolding. Aspartic acid, glutamic acid and tyrosine carry a neutral charge in the stomach, but will ionize upon entry into the intestine. Conversely, basic amino acids, such as histidine, lysine and arginine, ionize in the stomach and are neutral in an alkaline environment. [0037]
  • Other factors such as π-π interactions between aromatic residues, kinking of the peptide chain by addition of proline, disulfide crosslinking and hydrogen bonding can all be used to select the optimum amino acid sequence for a given application. Ordering of the linear sequence can influence how these interactions can be maximized and is important in directing the secondary and tertiary structures of the polypeptide. [0038]
  • Furthermore, amino acids with reactive side chains (e.g., glutamic acid, lysine, aspartic acid, serine, threonine and cysteine) can be incorporated for attaching multiple active agents or adjuvants to the same carrier peptide. This is particularly useful if a synergistic effect between two or more active agents is desired. [0039]
  • As stated above, variable molecular weights of the carrier compound can have profound effects on the active agent release kinetics. As a result, low molecular weight active agent delivery systems are preferred. An advantage of this invention is that chain length and molecular weight of the polypeptide can be optimized depending on the level of conformational protection desired. This property can be optimized in concert with the kinetics of the first order release mechanism. Thus, another advantage of this invention is that prolonged release time can be imparted by increasing the molecular weight of the carrier polypeptide. Another, significant advantage of the invention is that the kinetics of active agent release is primarily controlled by the enzymatic hydrolysis of the key bond between the carrier peptide and the active agent. [0040]
  • Dextran is the only polysaccharide known that has been explored as a macromolecular carrier for the covalent binding of drug for colon specific drug delivery. Generally, it was only possible to load up to {fraction (1/10)} of the total drug-dextran conjugate weight with drug. As stated earlier, polysaccharides are digested mainly in the colon and drug absorption is mainly limited to the colon. As compared to dextran, this invention has two major advantages. First, peptides are hydrolyzed by any one of several aminopeptidases found in the intestinal lumen or associated with the brush-border membrane and so active agent release and subsequent absorption can occur in the jejunum or the ileum. Second, the molecular weight of the carrier molecule can be controlled and, thus, active agent loading can also be controlled. [0041]
  • As a practical example, the following table lists the molecular weights of lipophilic amino acids (less one water molecule) and selected analgesics and vitamins. [0042]
    TABLE
    Amino acid MW Active agent MW
    Glycine 57 Acetaminophen 151
    Alanine 71 Vitamin B6 (Pyroxidine) 169
    Valine 99 Vitamin C (Ascorbic acid) 176
    Leucine 113 Aspirin 180
    Isoleucine 113 Ibuprofen 206
    Phenylalanine 147 Retinoic acid 300
    Tyrosine 163 Vitamin B2 (Riboflavin) 376
    Vitamin D2 397
    Vitamin E (Tocopherol) 431
  • Lipophilic amino acids are preferred because conformational protection through the stomach is important for the selected active agents, which were selected based on ease of covalent attachment to an oligopeptide. Eighteen was subtracted from the amino acid's molecular weight so that their condensation into a polypeptide is considered. For example, a decamer of glycine (MW=588) linked to aspirin would have a total molecular weight of 750 and aspirin would represent 24% of the total weight of the active agent delivery composition or over two times the maximum drug loading for dextran. This is only for an N- or C-terminus application, for those active agents attached to pendant groups of decaglutamic acid, for instance, a drug with a molecular weight of 180 could conceivably have a loading of 58%, although this may not be entirely practical. [0043]
  • The alcohol, amine or carboxylic acid group of the active agent is covalently attached to the N-terminus, the C-terminus or the side chain of the oligopeptide or polypeptide. The location of attachment depends somewhat on the functional group selection. For instance, if the active drug is a carboxylic acid (e.g., aspirin) then the N-terminus of the oligopeptide is the preferred point of attachment as shown in FIG. 1. If the active agent is an amine (e.g., ampicillin), then the C-terminus is the preferred point of attachment in order to achieve a stable peptide linked active agent as shown in FIG. 2. In both, the C- and N-terminus examples, the peptide is, in essence, extended by one monomeric unit forming a new peptide bond. If the active agent is an alcohol, then either the C-terminus or the N-terminus is the preferred point of attachment in order to achieve a stable composition. As in the example above where the alcohol, norethindrone, was covalently attached to poly(hydroxypropylglutamine), an alcohol can be converted into an alkylchloroformate with phosgene. This invention, then, pertains to the reaction of this key intermediate with the N-terminus of the peptide carrier as shown in FIG. 3. FIGS. 1 through 3 also depict the release of the active ingredient from the peptide carrier by intestinal peptidases. [0044]
  • The alcohol can be selectively bound to the gamma carboxylate of glutamic acid and then this conjugate covalently attached to the C-terminus of the peptide carrier. Because the glutamic acid-drug conjugate can be considered a dimer, this product adds two monomeric units to the C-terminus of the peptide carrier where the glutamic acid moiety serves as a spacer between the peptide and the drug as shown in FIG. 4. Intestinal enzymatic hydrolysis of the key peptide bond releases the glutamic acid-drug moiety from the peptide carrier. The newly formed free amine of the glutamic acid residue will then undergo an intramolecular transamination reaction, thereby, releasing the active agent with coincident formation of pyroglutamic acid as shown in FIG. 5. Alternatively, the glutamic acid-drug dimer can be converted into the gamma ester of glutamic acid N-carboxyanhydride. This intermediate can then be polymerized, as described above, using any suitable initiator as shown in FIG. 4. The product of this polymerization is polyglutamic acid with active ingredients attached to multiple pendant groups. Hence, maximum drug loading of the carrier peptide can be achieved. In addition, other amino acid-NCA's can be copolymerized with the gamma ester glutamic acid NCA to impart specific properties to the drug delivery system. [0045]
  • The invention also provides a method of imparting the same mechanism of action for other polypeptides containing functional side chains. Examples include, but are not limited to, polylysine, polyasparagine, polyarginine, polyserine, polycysteine, polytyrosine, polythreonine and polyglutamine. The mechanism can translate to these polypeptides through a spacer or linker on the pendant group, which is terminated, preferably, by the glutamic acid-drug dimer. This carrier peptide-drug conjugate is distinguished from the prior art by virtue of the fact that the primary release of the drug moiety relies on peptidases and not on esterases. Alternatively, the active agent can be attached directly to the pendant group where some other indigenous enzymes in the alimentary tract can affect release. [0046]
  • The active agent can be covalently attached to the N-terminus, the C-terminus or the side chain of the polypeptide using known techniques. Examples of linking organic compounds to the N-terminus type of a peptide include, but are not limited to, the attachment of naphthylacetic acid to LH-RH, coumarinic acid to opioid peptides and 1,3-dialkyl-3-acyltriazenes to tetragastrin and pentagastrin. As another example, there are known techniques for forming peptide linked biotin and peptide linked acridine. [0047]
  • The polypeptide carrier can be prepared using conventional techniques. A preferred technique is copolymerization of mixtures of amino acid N-carboxyanhydrides. Alternatively, if a specific sequence is desired, a solid state automated peptide synthesizer can be used. [0048]
  • The addition of stabilizers to the composition has the potential of stabilizing the polypeptide further. Stabilizers such as sugar, amino acids, polyethylene glycol (PEG) and salts have been shown to prevent protein unfolding. In another embodiment of the invention, a pre-first order release of the active agent is imparted by microencapsulating the carrier polypeptide-active agent conjugate in a polysaccharide, amino acid complex, PEG or salts. [0049]
  • There is evidence that hydrophilic compounds are absorbed through the intestinal epithelia efficiently via specialized transporters. The entire membrane transport system is intrinsically asymmetric and responds asymmetrically to cofactors. Thus, one can expect that excitation of the membrane transport system will involve some sort of specialized adjuvant resulting in localized delivery of active agents. There are seven known intestinal transport systems classified according to the physical properties of the transported substrate. They include the amino acid, oligopeptide, glucose, monocarboxic acid, phosphate, bile acid and the P-glycoprotein transport systems and each has its own associated mechanism of transport. The mechanisms can depend on hydrogen ions, sodium ions, binding sites or other cofactors. The invention also allows targeting the mechanisms for intestinal epithelial transport systems to facilitate absorption of active agents. [0050]
  • In another embodiment of the invention, the composition includes one or more adjuvants to enhance the bioavailability of the active agent. Addition of an adjuvant is particularly preferred when using an otherwise poorly absorbed active agent. Suitable adjuvants, for example, include: papain, which is a potent enzyme for releasing the catalytic domain of aminopeptidase-N into the lumen; glycorecognizers, which activate enzymes in the BBM; and bile acids, which have been attached to peptides to enhance absorption of the peptides. [0051]
  • Preferably, the resultant peptide-active agent conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed. [0052]
  • Compositions of the invention are, in essence, the formation of amides from acids and amines and can be prepared by the following examples. [0053]
  • Acid/N-Terminus Conjugation (FIG. 1) [0054]
  • An acid bioactive agent can be dissolved in DMF under nitrogen and cooled to 0° C. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the amine peptide carrier. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, the product precipitated out in ether and purified using gel permeation chromatography (GPC) or dialysis. [0055]
  • Amine/C-Terminus Conjugation (FIG. 2) [0056]
  • The peptide carrier can be dissolved in DMF under nitrogen and cooled to 0° C. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the amine bioactive agent. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, the product precipitated out in ether and purified using GPC or dialysis. [0057]
  • Alcohol/N-Terminus Conjugation (FIG. 3) [0058]
  • In the following example the combination of the alcohol with triphosgene produces a chloroformate, which when reacted with the N-terminus of the peptide produces a carbamate. Pursuant to this, an alcohol bioactive agent can be treated with triphosgene in dry DMF under nitrogen. The suitably protected peptide carrier is then added slowly and the solution stirred at room temperature for several hours. The product is then precipitated out in ether The crude product is suitably deprotected and purified using GPC. [0059]
  • Other solvents, activating agents, cocatalysts and bases can be used. Examples of other solvents include dimethylsulfoxide, ethers such as tetrahydrofuran or chlorinated solvents such as chloroform. Examples of other activating agents include dicyclohexylcarbodiimide or thionyl chloride. An example of another cocatalyst is N-hydroxysuccinimide. Examples of bases include pyrrolidinopyridine, dimethylaminopyridine, triethylamine or tributylamine. [0060]
  • Preparation of γ-Alkyl Glutamate (FIG. 4) [0061]
  • There have been over 30 different γ-alkyl glutamates prepared any one of which may be suitable for the drug alcohol of choice. For example, a suspension of glutamic acid, the alcohol and concentrated hydrochloric acid can be prepared and heated for several hours. The γ-alkyl glutamate product can be precipitated out in acetone, filtered, dried and recrystallized from hot water. [0062]
  • γ-Alkyl Glutamate/C-Terminus Conjugation (FIG. 4) [0063]
  • The peptide carrier can be dissolved in DMF under nitrogen and cooled to 0° C. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the γ-alkyl glutamate bioactive agent. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, the product precipitated out in ether and purified using GPC or dialysis. [0064]
  • Preparation of γ-Alkyl Glutamate-NCA [0065]
  • y-Alkyl glutamate can be suspended in dry THF where triphosgene is added and the mixture refluxed under a nitrogen atmosphere until the mixture becomes homogenous. The solution can be poured into heptane to precipitate the NCA product, which is filtered, dried and recrystallized from a suitable solvent. [0066]
  • Preparation of Poly[γ-Alkyl Glutamate][0067]
  • γ-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. [0068]
  • Although illustrated and described above with reference to specific embodiments, the invention is nevertheless not intended to be limited to the details shown. Rather, various modifications may be made in the details within the scope and range of equivalents of the claims and without departing from the spirit of the invention. [0069]

Claims (15)

1. A method for controlling release of an active agent other than an amino acid in a patient comprising orally administering to said patient an amino acid/active agent complex comprising a polypeptide covalently attached to the active agent through an alcohol, an amine or a carboxylic acid functionality wherein said active agent enzymatically releases into the bloodstream following oral administration.
2. The method of claim 1, wherein the polypeptide includes of one or more of the twenty naturally occurring amino acids.
3. The method of claim 1, wherein said amino acid is glutamic acid, aspartic acid, arginine, asparagine, cysteine, lysine, threonine or serine.
4. The method of claim 1, wherein said amino acid is glutamic acid.
5. The method of claim 1, wherein said complex is in the form of an ingestible tablet, a capsule, or an oral suspension.
6. The method of claim 1, wherein said complex further comprises a microencapsulating agent.
7. The method of claim 1, wherein said complex further comprises an adjuvant covalently attached to said polypeptide.
8. A method for preparing a composition comprising a polypeptide and an active agent covalently attached to said polypeptide comprising the steps of:
(a) attaching the active agent to an amino acid to form an active agent/amino acid complex;
(b) forming an N-carboxyanhydride (NCA) from said active agent/amino acid complex; and
(c) polymerizing said N-carboxyanhydride (NCA).
9. The method of claim 8, wherein the active agent is attached to the side chain of said amino acid.
10. The method of claim 8, wherein the active agent is attached to the N-terminus of said amino acid.
11. The method of claim 8, wherein the active agent is attached to the C-terminus of said amino acid
12. The method of claim 8, further comprising the step of (d) granulating said complex.
13. The method of claim 8, wherein said amino acid is glutamic acid, aspartic acid, arginine, asparagine, cysteine, lysine, threonine or serine.
14. The method of claim 8, wherein said amino acid is glutamic acid.
15. The method of claim 8, wherein said amino acid is a synthetic amino acid with a pendant amine, alcohol, sulfhydryl, amide, urea, or acid functionality.
US10/727,565 2000-08-22 2003-12-05 Active agent delivery systems and methods for protecting and administering active agents Abandoned US20040127397A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/727,565 US20040127397A1 (en) 2000-08-22 2003-12-05 Active agent delivery systems and methods for protecting and administering active agents
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 (2)

Application Number Priority Date Filing Date Title
US09/642,820 US6716452B1 (en) 2000-08-22 2000-08-22 Active agent delivery systems and methods for protecting and administering active agents
US10/727,565 US20040127397A1 (en) 2000-08-22 2003-12-05 Active agent delivery systems and methods for protecting and administering active agents

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US09/642,820 Division US6716452B1 (en) 1999-03-10 2000-08-22 Active agent delivery systems and methods for protecting and administering active agents
PCT/US2003/005524 Continuation-In-Part WO2003079972A2 (en) 2000-08-22 2003-02-24 Active agent delivery systems and methods for protecting and administering active agents

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US09/933,708 Continuation-In-Part US20020099013A1 (en) 2000-08-22 2001-08-22 Active agent delivery systems and methods for protecting and administering active agents
US10/923,088 Division US7427600B2 (en) 2000-08-22 2004-08-23 Active agent delivery systems and methods for protecting and administering active agents
US10/923,088 Continuation-In-Part US7427600B2 (en) 2000-08-22 2004-08-23 Active agent delivery systems and methods for protecting and administering active agents

Publications (1)

Publication Number Publication Date
US20040127397A1 true US20040127397A1 (en) 2004-07-01

Family

ID=24578160

Family Applications (3)

Application Number Title Priority Date Filing Date
US09/642,820 Expired - Lifetime US6716452B1 (en) 1999-03-10 2000-08-22 Active agent delivery systems and methods for protecting and administering active agents
US10/727,565 Abandoned US20040127397A1 (en) 2000-08-22 2003-12-05 Active agent delivery systems and methods for protecting and administering active agents
US10/923,088 Expired - Lifetime US7427600B2 (en) 2000-08-22 2004-08-23 Active agent delivery systems and methods for protecting and administering active agents

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US09/642,820 Expired - Lifetime US6716452B1 (en) 1999-03-10 2000-08-22 Active agent delivery systems and methods for protecting and administering active agents

Family Applications After (1)

Application Number Title Priority Date Filing Date
US10/923,088 Expired - Lifetime US7427600B2 (en) 2000-08-22 2004-08-23 Active agent delivery systems and methods for protecting and administering active agents

Country Status (6)

Country Link
US (3) US6716452B1 (en)
EP (1) EP1311242B1 (en)
AU (2) AU8659901A (en)
CA (1) CA2420590A1 (en)
IL (1) IL154583A0 (en)
WO (1) WO2002034237A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2292577A1 (en) 2007-05-09 2011-03-09 Pharmacofore, Inc. (+)-stereoisomer of 2,6-di-sec-butylphenol and analogs thereof
EP2392559A1 (en) 2007-05-09 2011-12-07 Pharmacofore, Inc. Therapeutic compounds
US8106016B2 (en) 2003-09-30 2012-01-31 Shire Llc Compounds and compositions for prevention of overdose of oxycodone
US8133881B2 (en) 2003-01-13 2012-03-13 Shire Llc Carbohydrate conjugates to prevent abuse of controlled substances
US8394813B2 (en) 2000-11-14 2013-03-12 Shire Llc Active agent delivery systems and methods for protecting and administering active agents
US11931419B2 (en) * 2017-11-16 2024-03-19 Sony Group Corporation Programmable polymeric drugs

Families Citing this family (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7060708B2 (en) * 1999-03-10 2006-06-13 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
US6716452B1 (en) * 2000-08-22 2004-04-06 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
US7164034B2 (en) 1999-06-10 2007-01-16 Pfizer Inc. Alpha2delta ligands for fibromyalgia and other disorders
US20070060500A1 (en) * 2000-08-22 2007-03-15 New River Pharmaceuticals Inc. Pharmaceutical compositions for prevention of overdose or abuse
CA2428971A1 (en) * 2000-11-14 2003-05-01 New River Pharmaceuticals Inc. Conjugates of a therapeutic agent and a peptide carrier
US20090306228A1 (en) * 2000-11-14 2009-12-10 Shire Llc Active agent delivery systems and methods for protecting and administering active agents
EP1357928B1 (en) * 2000-11-16 2011-11-16 Shire LLC A novel pharmaceutical compound and methods of making and using same
US20030055026A1 (en) 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
US20030199587A1 (en) * 2001-08-14 2003-10-23 Franz G. Andrew Levothyroxine compositions having unique Cmax properties
US7338939B2 (en) * 2003-09-30 2008-03-04 New River Pharmaceuticals Inc. Abuse-resistant hydrocodone compounds
US20070066537A1 (en) * 2002-02-22 2007-03-22 New River Pharmaceuticals Inc. Compounds and compositions for prevention of overdose of oxycodone
US7375082B2 (en) * 2002-02-22 2008-05-20 Shire Llc Abuse-resistant hydrocodone compounds
US20060014697A1 (en) * 2001-08-22 2006-01-19 Travis Mickle Pharmaceutical compositions for prevention of overdose or abuse
US7659253B2 (en) 2002-02-22 2010-02-09 Shire Llc Abuse-resistant amphetamine prodrugs
US7700561B2 (en) * 2002-02-22 2010-04-20 Shire Llc Abuse-resistant amphetamine prodrugs
US7105486B2 (en) * 2002-02-22 2006-09-12 New River Pharmaceuticals Inc. Abuse-resistant amphetamine compounds
IL163666A0 (en) * 2002-02-22 2005-12-18 New River Pharmaceuticals Inc Active agent delivery systems and methods for protecting and administering active agents
KR20050010756A (en) * 2002-02-22 2005-01-28 뉴 리버 파마슈티칼스, 인크. Use of peptide-drug conjugation to reduce inter-subject variability of drug serum levels
ES2500117T3 (en) * 2002-02-22 2014-09-30 Shire Llc Novel sustained release pharmaceutical compounds to prevent the abuse of controlled substances
US20040156844A1 (en) * 2002-05-22 2004-08-12 Curtis Wright Tamper resistant oral dosage form
MXPA04012518A (en) * 2002-06-11 2005-02-17 Lilly Co Eli Prodrugs of excitatory amino acids.
WO2004041208A2 (en) * 2002-11-05 2004-05-21 New River Pharmaceuticals Inc. Controlled absorption of mixed thyroyd hormone formulations
WO2004052841A1 (en) 2002-12-06 2004-06-24 Xenoport, Inc. Carbidopa prodrugs and uses thereof
KR20070108953A (en) 2003-04-22 2007-11-13 소시에떼 더 콘세이유 더 레세르세 에 다플리까띠옹 시엔띠피끄, 에스.아.에스. Peptide vectores
DK1644019T4 (en) * 2003-05-29 2018-04-23 Shire Llc AMPHETAMINE COMPOUNDS RESISTANT TO ABUSE
TWI359675B (en) 2003-07-10 2012-03-11 Dey L P Bronchodilating β-agonist compositions
SG147485A1 (en) * 2003-09-30 2008-11-28 Shire Llc Pharmaceutical compositions for prevention of overdose or abuse
US7176185B2 (en) * 2003-11-25 2007-02-13 Tsrl, Inc. Short peptide carrier system for cellular delivery of agent
MXPA06012220A (en) * 2004-04-21 2007-07-18 Teva Pharma Processes for preparing montelukast sodium.
JP2008519055A (en) * 2004-11-08 2008-06-05 シャイア エルエルシー Synergistic effect of combined administration of mirtazapine and stimulant complex
US8318756B2 (en) * 2004-12-03 2012-11-27 Adherex Technologies, Inc. Methods for administering DPD inhibitors in combination with 5-FU and 5-FU prodrugs
US20070122843A1 (en) * 2005-09-23 2007-05-31 Fazlul Sarkar Isoflavonoid analogs and their metal complexes as anti-cancer agents
EP2206736B1 (en) 2005-12-05 2012-02-08 Nitto Denko Corporation Polyglutamate-amino acid conjugates and methods
US20110136742A1 (en) 2006-02-24 2011-06-09 Travis Mickle Antidepressant prodrugs
US8524663B2 (en) * 2006-03-03 2013-09-03 New York University Method for site-specific polyvalent display on polymers
WO2007120648A2 (en) * 2006-04-10 2007-10-25 Shire Llc Mono and di-substituted oxycodone compounds and compositions
EP2007389A2 (en) * 2006-04-14 2008-12-31 Shire LLC Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse
JP5200011B2 (en) * 2006-06-15 2013-05-15 セル セラピューティクス インコーポレーテッド セーデ セコンダリア Process for producing poly-α-glutamic acid and derivatives thereof
EP1867657A1 (en) * 2006-06-15 2007-12-19 Cell Therapeutics Europe S.R.L. Process for the preparation of poly-a-glutamic acid and derivatives thereof
US20080161400A1 (en) * 2006-10-26 2008-07-03 Xenoport, Inc. Use of forms of propofol for treating diseases associated with oxidative stress
US20080181852A1 (en) * 2007-01-29 2008-07-31 Nitto Denko Corporation Multi-functional Drug Carriers
CN104800856A (en) * 2007-04-10 2015-07-29 日东电工株式会社 Multi-functional polyglutamate drug carriers
JP2010526917A (en) * 2007-05-09 2010-08-05 日東電工株式会社 Polyglutamate complex and polyglutamate-amino acid complex having plural kinds of drugs
EP2155255B1 (en) 2007-05-09 2013-08-14 Nitto Denko Corporation Compositions that include a hydrophobic compound and a polyamino acid conjugate
CN101730549B (en) * 2007-05-09 2015-12-09 日东电工株式会社 The polymer be combined with platinum medicine
JP2010539245A (en) * 2007-09-14 2010-12-16 日東電工株式会社 Drug carrier
WO2009097508A2 (en) 2008-01-30 2009-08-06 Mcanulty, Jonathan Methods and compositions for wound healing
WO2009100441A2 (en) * 2008-02-08 2009-08-13 Impax Laboratories, Inc. Depot formulations
AU2009222230A1 (en) * 2008-03-06 2009-09-11 Nitto Denko Corporation Polymer paclitaxel conjugates and methods for treating cancer
RU2010146489A (en) 2008-04-16 2012-05-27 Момента Фармасьютикалз, Инк. (Us) ANALYSIS OF THE AMINO ACIDS POLYMER COMPOSITIONS
JP2010043063A (en) * 2008-05-09 2010-02-25 Agency For Science Technology & Research Diagnosis and treatment of kawasaki disease
KR101123292B1 (en) * 2008-09-26 2012-03-19 주식회사 엘지생명과학 Process for Preparation of Montelukast Sodium Salt
WO2010065362A1 (en) * 2008-11-25 2010-06-10 Innovative Technologies, L.L.C. Improvements in polypeptide synthesis for drug delivery
JP2012512914A (en) 2008-12-19 2012-06-07 ピナクル ファーマシューティカルズ インコーポレイテッド Phenazopyridine compound
CA2761624C (en) 2009-05-19 2016-10-18 Neuroderm Ltd. Compositions for continuous administration of dopa decarboxylase inhibitors
JP2013527124A (en) 2009-07-17 2013-06-27 シャイア エルエルシー Novel carbamate amino acid and peptide prodrugs of opioids and uses thereof
EP2488182B1 (en) * 2009-10-14 2017-07-19 Elion Oncology LLC Treating neurotoxicity associated with combinations of 5-FU or its prodrugs and DPD inhibitors
SG181899A1 (en) * 2009-12-23 2012-07-30 Sanford Burnham Med Res Inst Methods and compositions related to annexin 1-binding compounds
EP2533772B1 (en) * 2010-02-10 2021-09-08 Imbed Biosciences, Inc. Methods and compositions for wound healing
PL2580210T3 (en) 2010-06-10 2017-09-29 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
HUE037005T2 (en) 2010-11-15 2018-08-28 Neuroderm Ltd Continuous administration of l-dopa, dopa decarboxylase inhibitors, catechol-o-methyl transferase inhibitors and compositions for same
WO2012114342A1 (en) 2011-02-23 2012-08-30 Coeruleus Ltd. Flumazenil complexes, compositions comprising same and uses thereof
TWI432204B (en) * 2011-06-03 2014-04-01 Taiwan Hopax Chems Mfg Co Ltd Pharmaceutical compositions against free radicals
EP3848055A1 (en) 2011-06-03 2021-07-14 Ophidion Inc. Compositions and methods for transport across the blood brain barrier
KR101598679B1 (en) 2011-06-17 2016-02-29 일라이 릴리 앤드 캄파니 Bicyclo(3.1.0)hexane-2,6-dicarboxylic acid derivatives as mglu2 receptor agonist
WO2013009885A2 (en) 2011-07-11 2013-01-17 Momenta Pharmaceuticals, Inc. Evaluation of copolymer diethylamide
US8575198B1 (en) 2011-09-07 2013-11-05 Momenta Pharmaceuticals, Inc. In-process control for the manufacture of glatiramer acetate
WO2013090829A1 (en) 2011-12-14 2013-06-20 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US9526701B2 (en) 2011-12-20 2016-12-27 Keith R. Latham Sustained drug release and improved product stability using non-covalent particle coating methods
CN104349768B (en) 2012-06-05 2017-11-07 纽罗德姆有限公司 Composition comprising apomorphine and organic acid and application thereof
WO2014026329A1 (en) * 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. N-alkylated indole and indazole compounds as rorgammat inhibitors and uses thereof
WO2014026328A1 (en) * 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. 3-cyclohexenyl substituted indole and indazole compounds as rorgammat inhibitors and uses thereof
AU2014306759B2 (en) 2013-08-12 2018-04-26 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
EP3019559A4 (en) 2013-08-22 2017-04-05 Sony Corporation Water soluble fluorescent or colored dyes and methods for their use
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
WO2015095391A1 (en) 2013-12-17 2015-06-25 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10258585B2 (en) 2014-03-13 2019-04-16 Neuroderm, Ltd. DOPA decarboxylase inhibitor compositions
EP3116475B1 (en) 2014-03-13 2020-11-04 Neuroderm Ltd Dopa decarboxylase inhibitor compositions
US10653709B2 (en) * 2014-05-19 2020-05-19 North Carolina State University Methods of folding a graft copolymer with dual anticancer drugs and related applications
WO2016010771A1 (en) 2014-07-17 2016-01-21 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
EP3209282A4 (en) 2014-10-20 2018-05-23 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US11084932B2 (en) 2015-02-26 2021-08-10 Sony Group Corporation Phenylethynylnaphthalene dyes and methods for their use
CN107454903B (en) 2015-02-26 2021-01-01 索尼公司 Water-soluble fluorescent or colored dyes containing conjugated groups
CN107847608A (en) * 2015-06-09 2018-03-27 联邦科学和工业研究组织 The antiviral conjugate of polyanionic polymer and antiviral drugs
KR102525252B1 (en) 2016-04-01 2023-04-26 소니그룹주식회사 Very bright dimeric or polymeric dyes with rigid space groups
RU2762328C2 (en) 2016-04-01 2021-12-17 Сони Корпорейшн Ultra-bright dimer or polymer dyes
JP7069033B2 (en) 2016-04-06 2022-05-17 ソニーグループ株式会社 Super bright dimer or polymer dye with a spacing linker group
JP7068192B2 (en) 2016-05-10 2022-05-16 ソニーグループ株式会社 Compositions containing polymer dyes and cyclodextrins, and their use
EP3455238A1 (en) 2016-05-10 2019-03-20 Sony Corporation Ultra bright polymeric dyes with peptide backbones
EP3455300A1 (en) 2016-05-11 2019-03-20 Sony Corporation Ultra bright dimeric or polymeric dyes
EP3464477A1 (en) 2016-06-06 2019-04-10 Sony Corporation Ionic polymers comprising fluorescent or colored reporter groups
CN109843343A (en) 2016-07-29 2019-06-04 因贝德生物科学公司 Method and composition for wound healing
US9695138B1 (en) 2016-10-17 2017-07-04 Acenda Pharma, Inc. Phenothiazine derivatives and methods of use thereof
JP2020536847A (en) 2017-10-05 2020-12-17 ソニー株式会社 Programmable polymer drug
US11874280B2 (en) 2018-03-19 2024-01-16 Sony Group Corporation Use of divalent metals for enhancement of fluorescent signals
EP3768689A1 (en) 2018-03-21 2021-01-27 Sony Corporation Polymeric tandem dyes with linker groups
US10799496B2 (en) 2018-07-13 2020-10-13 Alkermes Pharma Ireland Limited Naphthylenyl compounds for long-acting injectable compositions and related methods
WO2020012245A1 (en) 2018-07-13 2020-01-16 Alkermes Pharma Ireland Limited Thienothiophene-naltrexone prodrugs for long-acting injectable compositions
RS64436B1 (en) 2018-09-14 2023-09-29 Enlitisa Shanghai Pharmaceutical Co Ltd Conjugates of montelukast and peptides
US10975099B2 (en) 2018-11-05 2021-04-13 Alkermes Pharma Ireland Limited Thiophene compounds for long-acting injectable compositions and related methods
EP3861074A2 (en) 2019-09-26 2021-08-11 Sony Group Corporation Polymeric tandem dyes with linker groups
US11213502B1 (en) 2020-11-17 2022-01-04 Neuroderm, Ltd. Method for treatment of parkinson's disease
US11331293B1 (en) 2020-11-17 2022-05-17 Neuroderm, Ltd. Method for treatment of Parkinson's disease
US11844754B2 (en) 2020-11-17 2023-12-19 Neuroderm, Ltd. Methods for treatment of Parkinson's disease
FR3122571B1 (en) * 2021-05-10 2023-05-12 Hydro Fill Tech Compositions and their use for restoring intestinal permeability and/or preventing or combating multifactorial diseases
WO2023215279A1 (en) * 2022-05-03 2023-11-09 Nocion Therapeutics, Inc. Compositions and methods for treatment of inflammatory bowel disease
WO2024042226A2 (en) * 2022-08-25 2024-02-29 Biosynth Gmbh Procedure for production of opioid-antagonist-releasing compounds and their use as a medicine

Citations (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US516993A (en) * 1894-03-20 Car-truck
US3331814A (en) * 1962-08-24 1967-07-18 Courtaulds Ltd Synthetic polypeptides of an l-imino acid and an l-amino acid
US3846399A (en) * 1969-04-10 1974-11-05 Merck & Co Inc Process for controlled stepwise synthesis of polypeptides
US3975342A (en) * 1972-05-15 1976-08-17 Biological Developments, Inc. Tyrosyl-class antigenic conjugates, their preparation and antibodies raised thereto
US3998799A (en) * 1973-11-02 1976-12-21 Interx Research Corporation Novel, transient pro-drug forms of l-dopa
US4040907A (en) * 1974-06-20 1977-08-09 Syva Company Iodothyronine enzyme conjugates
US4224316A (en) * 1979-03-30 1980-09-23 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US4297346A (en) * 1976-12-10 1981-10-27 Institut National De La Sante Et De La Recherche Medicale Pseudopeptides used as medicaments
US4358604A (en) * 1981-11-04 1982-11-09 Miles Laboratories, Inc. N-Aminoalkyl iodothyronine derivatives
US4399121A (en) * 1981-11-04 1983-08-16 Miles Laboratories, Inc. Iodothyronine immunogens and antibodies
US4426453A (en) * 1980-09-18 1984-01-17 Amersham International Limited Derivatives of iodothyronine compounds and their use in an assay for the free iodothyronine compounds
US4427660A (en) * 1982-03-03 1984-01-24 Research Corporation Formyl-methionyl chemotatic peptide antibiotic conjugates useful in treating infections
US4457907A (en) * 1982-08-05 1984-07-03 Clear Lake Development Group Composition and method for protecting a therapeutic drug
US4483807A (en) * 1981-01-27 1984-11-20 Japan Atomic Energy Research Institute Process for producing a slow release composite
US4490221A (en) * 1982-04-30 1984-12-25 Spiral Societe A Responsabilite Limitee Dite Process for preparing iodothyronines and iodothyroacetic acids by electrochemical reduction at controlled potential
US4552864A (en) * 1982-05-25 1985-11-12 Reanal Finomvegyszergyar Gonadoliberin derivatives process for the preparation and pharmaceutical compositions thereof
US4650675A (en) * 1983-08-18 1987-03-17 The Children's Medical Center Corporation Oligonucleotide conjugates
US4657873A (en) * 1983-07-29 1987-04-14 Henning Berlin Gmbh Preactivated plastics surfaces for immobilizing organo-chemical and biologic materials
US4766121A (en) * 1985-01-18 1988-08-23 Smith Kline & French Laboratories Ltd. Pyridyl and pyridazinyl substituted thyronine compounds having selective thyromimetic activity
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
US4902505A (en) * 1986-07-30 1990-02-20 Alkermes Chimeric peptides for neuropeptide delivery through the blood-brain barrier
US4960790A (en) * 1989-03-09 1990-10-02 University Of Kansas Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof
US4976962A (en) * 1984-10-19 1990-12-11 Daniel Bichon Biodegradable polypeptide and the use thereof for the gradual release of drugs
US5073641A (en) * 1986-08-26 1991-12-17 Hans Bundgaard Prodrug derivatives of carboxylic acid drugs
US5219564A (en) * 1990-07-06 1993-06-15 Enzon, Inc. Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon
US5225204A (en) * 1991-11-05 1993-07-06 Chen Jivn Ren Stable dosage of levothyroxine sodium and process of production
US5238714A (en) * 1990-10-02 1993-08-24 Board Of Regents, The University Of Texas System Efficient microcapsule preparation and method of use
US5324522A (en) * 1991-12-30 1994-06-28 Akzo N.V. Sustained release thyroactive composition
US5362831A (en) * 1992-06-19 1994-11-08 Farmitalia Carlo Erba S.R.L. Polymer-bound paclitaxel derivatives
US5534496A (en) * 1992-07-07 1996-07-09 University Of Southern California Methods and compositions to enhance epithelial drug transport
US5670477A (en) * 1995-04-20 1997-09-23 Joseph F. Poduslo Method to enhance permeability of the blood/brain blood/nerve bariers to therapeutic agents
US5707979A (en) * 1994-06-30 1998-01-13 Hoechst Aktiengesellschaft Phosphinic acid derivatives, their preparation and their use
US5756291A (en) * 1992-08-21 1998-05-26 Gilead Sciences, Inc. Aptamers specific for biomolecules and methods of making
US5762909A (en) * 1995-08-31 1998-06-09 General Electric Company Tumor targeting with polymeric molecules having extended conformation
US5767227A (en) * 1989-11-03 1998-06-16 Lotus Biochemical Corp. Iodothyronine polymers
US5846743A (en) * 1995-02-22 1998-12-08 Brigham And Women's Hospital, Inc. Polyphoshoinositide binding peptides for intracellular drug delivery
US5882645A (en) * 1992-07-24 1999-03-16 The School Of Pharmacy, University Of London Peptide compounds
US5891459A (en) * 1993-06-11 1999-04-06 The Board Of Trustees Of The Leland Stanford Junior University Enhancement of vascular function by modulation of endogenous nitric oxide production or activity
US5898033A (en) * 1995-06-07 1999-04-27 Swadesh; Joel K. Antigen-processing cell-targeted conjugates
US5910569A (en) * 1994-11-22 1999-06-08 Lotus Biochemical Corporation Iodothyronine polymers
US5935995A (en) * 1996-03-12 1999-08-10 Heochst Aktiengesellschaft Prodrugs for the therapy of tumors and inflammatory disorders
US5952294A (en) * 1996-07-31 1999-09-14 University Of Pittsburgh Of The Commonwealth System Of Higher Education Peptidyl prodrugs and methods of making and using the same
US5955105A (en) * 1995-11-14 1999-09-21 Knoll Pharmaceutical Company Stabilized thyroid hormone preparations and methods of making same
US5977163A (en) * 1996-03-12 1999-11-02 Pg-Txl Company, L. P. Water soluble paclitaxel prodrugs
US6005004A (en) * 1994-08-05 1999-12-21 Molecular / Structural Biotechnologies, Inc. Lipophilic-polycationic delivery systems
US6043230A (en) * 1996-07-26 2000-03-28 Gilead Sciences, Inc. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability
US6048736A (en) * 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6074659A (en) * 1991-09-27 2000-06-13 Noerx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US6093391A (en) * 1992-10-08 2000-07-25 Supratek Pharma, Inc. Peptide copolymer compositions
US6146658A (en) * 1992-10-27 2000-11-14 Hoechst Aktiengesellschaft Prodrugs, their preparation and use as pharmaceuticals
US6306993B1 (en) * 1997-05-21 2001-10-23 The Board Of Trustees Of The Leland Stanford, Jr. University Method and composition for enhancing transport across biological membranes
US6355666B1 (en) * 2000-06-23 2002-03-12 Medinox, Inc. Protected forms of pharmacologically active agents and uses therefor
US20020098999A1 (en) * 2000-10-06 2002-07-25 Gallop Mark A. Compounds for sustained release of orally delivered drugs
US6429223B1 (en) * 2000-06-23 2002-08-06 Medinox, Inc. Modified forms of pharmacologically active agents and uses therefor
US6458842B1 (en) * 1994-02-01 2002-10-01 Knoll Aktiengesellschaft Liquid pharmaceutical compositions comprising thyroid hormones
US20020151526A1 (en) * 2000-10-06 2002-10-17 Gallop Mark A. Bile-acid prodrugs of L-dopa and their use in the sustained treatment of parkinsonism
US20020151529A1 (en) * 2000-10-06 2002-10-17 Cundy Kenneth C. Bile-acid derived compounds for providing sustained systemic concentrations of drugs after oral administration
US6716452B1 (en) * 2000-08-22 2004-04-06 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents

Family Cites Families (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1493824A1 (en) 1964-01-27 1969-05-22 Hoffmann La Roche Process for the preparation of aminocarboxylic acid amides
CH406567A (en) 1964-02-10 1966-01-31 Inventio Ag Device for controlling the setpoint value during the deceleration process in elevators with speed-controlled drives
GB1112347A (en) 1965-08-20 1968-05-01 Pierre Wirth Salts of organic bases with n-carbamyl-l-glutamic acid
US3643696A (en) * 1970-09-02 1972-02-22 Rex Chainbelt Inc Hydraulic control circuit
US3884898A (en) * 1972-08-18 1975-05-20 Syva Co Normorphine derivatives bonded to proteins
US3843696A (en) 1972-09-05 1974-10-22 Syva Co Methadone analog compounds
US3878187A (en) * 1972-09-11 1975-04-15 Syva Co Polypeptide derivatives of amphetamine and analogs for immunoassays
US4025501A (en) * 1975-03-20 1977-05-24 Syva Company Polypeptide propoxyphene derivatives for immunoassay reagents
US4356166A (en) 1978-12-08 1982-10-26 University Of Utah Time-release chemical delivery system
IL58965A (en) 1978-12-19 1982-08-31 Mars Inc Production of microcapsules
DE3008265A1 (en) 1980-03-04 1981-09-17 Siemens AG, 1000 Berlin und 8000 München METHOD FOR MAKING VISIBLE STATIONARY HEAT TRANSFER COEFFICIENT FIELDS ON A PHOTOCHEMICAL WAY
JPS60166657A (en) * 1984-02-10 1985-08-29 Nitto Boseki Co Ltd Arginyl-3-carboxy-4-hydroxyanilide
IT1177384B (en) 1984-12-12 1987-08-26 Boeehringer Biochemia Robin Sp DIETARY GRANULAR PRODUCTS BASED ON AMINO ACIDS AND PROCEDURE FOR THEIR PREPARATION
GB8500209D0 (en) 1985-01-04 1985-02-13 Ceskoslovenska Akademie Ved Synthetic polymeric drugs
US4863735A (en) 1985-02-19 1989-09-05 Massachusetts Institute Of Technology Biodegradable polymeric drug delivery system with adjuvant activity
IN165717B (en) * 1986-08-07 1989-12-23 Battelle Memorial Institute
EP0318512B1 (en) 1986-08-18 1998-06-17 Emisphere Technologies, Inc. Delivery systems for pharmacological agents
US5057317A (en) 1987-03-24 1991-10-15 Chugai Seiyaku Kabushiki Kaisha Slow-release pharmaceutical agent
GB2209937B (en) 1987-09-21 1991-07-03 Depiopharm S A Water insoluble polypeptides
US5169933A (en) 1988-08-15 1992-12-08 Neorx Corporation Covalently-linked complexes and methods for enhanced cytotoxicity and imaging
US5026827A (en) * 1988-09-02 1991-06-25 Matsushita Electric Industrial Co., Ltd. Amphetamine-protein complex as immunogen for obtaining antibodies specific to methamphetamine
US5451410A (en) 1993-04-22 1995-09-19 Emisphere Technologies, Inc. Modified amino acids for encapsulating active agents
IT1244873B (en) * 1990-09-12 1994-09-12 Depha Team Srl DERIVATIVES OF 5-AMINOSALICYLIC ACID (5-ASA) FOR THE THERAPY OF CHRONIC INTESTINAL INFLAMMATIONS
DE69103503T2 (en) * 1990-09-28 1995-01-05 Mercian Corp Adriamycin derivatives.
US5863899A (en) 1991-04-01 1999-01-26 Cortech, Inc. Bradykinin antagonists
HU222501B1 (en) 1991-06-28 2003-07-28 Endorecherche Inc. Controlled release pharmaceutical composition containing mpa or mga and process for its preparation
US5811127A (en) * 1992-06-15 1998-09-22 Emisphere Technologies, Inc. Desferrioxamine oral delivery system
US5792451A (en) 1994-03-02 1998-08-11 Emisphere Technologies, Inc. Oral drug delivery compositions and methods
CA2096495C (en) 1992-06-16 2002-07-09 Kathy Palmer Ordonez Dual analyte immunoassay
IL107400A0 (en) 1992-11-10 1994-01-25 Cortech Inc Bradykinin antagonists
WO1994012158A1 (en) 1992-12-02 1994-06-09 Alkermes Controlled Therapeutics, Inc. Controlled release growth hormone containing microspheres
US5298410A (en) 1993-02-25 1994-03-29 Sterling Winthrop Inc. Lyophilized formulation of polyethylene oxide modified proteins with increased shelf-life
US5643957A (en) 1993-04-22 1997-07-01 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
ES2156156T3 (en) * 1993-08-02 2001-06-16 Commw Scient Ind Res Org THERAPEUTIC COMPOUND - FATTY ACID CONJUGATES.
WO1995012604A1 (en) 1993-11-05 1995-05-11 Aktiebolaget Astra Novel amino acid derivatives
AU5825094A (en) 1993-11-19 1995-06-06 Astra Aktiebolag Novel dipeptide derivatives
US5741705A (en) 1995-02-23 1998-04-21 Quest International Flavors & Food Ingredients Company, Division Of Indopco, Inc. Method for in vitro cell growth of eucaryotic cells using low molecular weight peptides
US5820881A (en) 1995-04-28 1998-10-13 Emisphere Technologies, Inc. Microspheres of diamide-dicarboxylic acids
US5851536A (en) 1995-11-22 1998-12-22 University Of Washington Therapeutic delivery using compounds self-assembled into high axial ratio microstructures
ATE344279T1 (en) 1995-12-13 2006-11-15 Univ California CRYSTALS OF THE LIGAND-BINDING DOMAIN OF THE THYROID HORMONE RECEPTOR COMPLEXED WITH A LIGAND
US6441025B2 (en) * 1996-03-12 2002-08-27 Pg-Txl Company, L.P. Water soluble paclitaxel derivatives
GB9606975D0 (en) 1996-04-02 1996-06-05 Univ Birmingham Anti-tumor agent
US6030941A (en) * 1996-05-01 2000-02-29 Avi Biopharma, Inc. Polymer composition for delivering substances in living organisms
US6013633A (en) * 1997-08-07 2000-01-11 University Of Cincinnati Compounds for control of appetite, blood pressure, cardiovascular response, libido, and circadian rhythm
US5948750A (en) * 1996-10-30 1999-09-07 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
TW460478B (en) 1997-08-15 2001-10-21 Chugai Pharmaceutical Co Ltd Phenethylamine derivatives
CA2312975C (en) * 1997-12-17 2012-08-21 Enzon, Inc. Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents
EP1053238B1 (en) * 1998-01-29 2005-12-28 Monash University Therapeutic compounds
US6225285B1 (en) * 1998-03-11 2001-05-01 Exelixis Pharmaceuticals, Inc. Semaphorin K1
US6473669B2 (en) 1998-07-03 2002-10-29 Kimberly-Clark Worldwide, Inc. Controlling web tension, and accumulating lengths of web, by actively controlling velocity and acceleration of a festoon
US6652864B1 (en) 1998-12-21 2003-11-25 Asilomar Pharmaceuticals, Inc. Compounds for intracellular delivery of therapeutic moieties to nerve cells
US7374779B2 (en) 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
AU771188B2 (en) 1999-03-05 2004-03-18 Shire Llc Use of protein conformation for the protection and release of chemical compounds
WO2000053233A1 (en) 1999-03-10 2000-09-14 Lotus Biochemical Corporation Use of protein conformation for the protection and release of chemical compounds
US7060708B2 (en) * 1999-03-10 2006-06-13 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
US6309633B1 (en) * 1999-06-19 2001-10-30 Nobex Corporation Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same
WO2003034980A2 (en) 2000-11-14 2003-05-01 New River Pharmaceuticals Inc. A novel pharmaceutical compound containing abacavir sulfate and methods of making and using same
US20020099013A1 (en) 2000-11-14 2002-07-25 Thomas Piccariello Active agent delivery systems and methods for protecting and administering active agents
US6740641B2 (en) * 2001-07-27 2004-05-25 Euro-Celtique, S.A. Sugar derivatives of hydromorphone, dihydromorphine and dihydromorphine, compositions thereof and uses for treating or preventing pain
US7375082B2 (en) * 2002-02-22 2008-05-20 Shire Llc Abuse-resistant hydrocodone compounds
US7169752B2 (en) * 2003-09-30 2007-01-30 New River Pharmaceuticals Inc. Compounds and compositions for prevention of overdose of oxycodone
US20060014697A1 (en) * 2001-08-22 2006-01-19 Travis Mickle Pharmaceutical compositions for prevention of overdose or abuse
US7338939B2 (en) * 2003-09-30 2008-03-04 New River Pharmaceuticals Inc. Abuse-resistant hydrocodone compounds
AU2002347404A1 (en) 2001-09-14 2003-04-01 Cytos Biotechnology Ag In vivo activation of antigen presenting cells for enhancement of immune responses induced by virus like particles
CA2472917A1 (en) * 2002-01-08 2003-07-17 New River Pharmaceuticals Inc. Dendritic encapsulation of active agents
KR20050010756A (en) * 2002-02-22 2005-01-28 뉴 리버 파마슈티칼스, 인크. Use of peptide-drug conjugation to reduce inter-subject variability of drug serum levels
US7105486B2 (en) * 2002-02-22 2006-09-12 New River Pharmaceuticals Inc. Abuse-resistant amphetamine compounds
ES2500117T3 (en) * 2002-02-22 2014-09-30 Shire Llc Novel sustained release pharmaceutical compounds to prevent the abuse of controlled substances
EP1603597B1 (en) * 2003-03-13 2010-01-06 Controlled Chemicals, Inc. Oxycodone conjugates with lower abuse potential and extended duration of action
DK1644019T4 (en) * 2003-05-29 2018-04-23 Shire Llc AMPHETAMINE COMPOUNDS RESISTANT TO ABUSE
SG147485A1 (en) * 2003-09-30 2008-11-28 Shire Llc Pharmaceutical compositions for prevention of overdose or abuse

Patent Citations (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US516993A (en) * 1894-03-20 Car-truck
US3331814A (en) * 1962-08-24 1967-07-18 Courtaulds Ltd Synthetic polypeptides of an l-imino acid and an l-amino acid
US3846399A (en) * 1969-04-10 1974-11-05 Merck & Co Inc Process for controlled stepwise synthesis of polypeptides
US3975342A (en) * 1972-05-15 1976-08-17 Biological Developments, Inc. Tyrosyl-class antigenic conjugates, their preparation and antibodies raised thereto
US3998799A (en) * 1973-11-02 1976-12-21 Interx Research Corporation Novel, transient pro-drug forms of l-dopa
US4040907A (en) * 1974-06-20 1977-08-09 Syva Company Iodothyronine enzyme conjugates
US4297346A (en) * 1976-12-10 1981-10-27 Institut National De La Sante Et De La Recherche Medicale Pseudopeptides used as medicaments
US4224316A (en) * 1979-03-30 1980-09-23 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US4426453A (en) * 1980-09-18 1984-01-17 Amersham International Limited Derivatives of iodothyronine compounds and their use in an assay for the free iodothyronine compounds
US4483807A (en) * 1981-01-27 1984-11-20 Japan Atomic Energy Research Institute Process for producing a slow release composite
US4358604A (en) * 1981-11-04 1982-11-09 Miles Laboratories, Inc. N-Aminoalkyl iodothyronine derivatives
US4399121A (en) * 1981-11-04 1983-08-16 Miles Laboratories, Inc. Iodothyronine immunogens and antibodies
US4427660A (en) * 1982-03-03 1984-01-24 Research Corporation Formyl-methionyl chemotatic peptide antibiotic conjugates useful in treating infections
US4490221A (en) * 1982-04-30 1984-12-25 Spiral Societe A Responsabilite Limitee Dite Process for preparing iodothyronines and iodothyroacetic acids by electrochemical reduction at controlled potential
US4552864A (en) * 1982-05-25 1985-11-12 Reanal Finomvegyszergyar Gonadoliberin derivatives process for the preparation and pharmaceutical compositions thereof
US4457907A (en) * 1982-08-05 1984-07-03 Clear Lake Development Group Composition and method for protecting a therapeutic drug
US4657873A (en) * 1983-07-29 1987-04-14 Henning Berlin Gmbh Preactivated plastics surfaces for immobilizing organo-chemical and biologic materials
US4650675A (en) * 1983-08-18 1987-03-17 The Children's Medical Center Corporation Oligonucleotide conjugates
US4976962A (en) * 1984-10-19 1990-12-11 Daniel Bichon Biodegradable polypeptide and the use thereof for the gradual release of drugs
US4766121A (en) * 1985-01-18 1988-08-23 Smith Kline & French Laboratories Ltd. Pyridyl and pyridazinyl substituted thyronine compounds having selective thyromimetic activity
US4902505A (en) * 1986-07-30 1990-02-20 Alkermes Chimeric peptides for neuropeptide delivery through the blood-brain barrier
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
US5073641A (en) * 1986-08-26 1991-12-17 Hans Bundgaard Prodrug derivatives of carboxylic acid drugs
US4960790A (en) * 1989-03-09 1990-10-02 University Of Kansas Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof
US5767227A (en) * 1989-11-03 1998-06-16 Lotus Biochemical Corp. Iodothyronine polymers
US5219564A (en) * 1990-07-06 1993-06-15 Enzon, Inc. Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon
US5238714A (en) * 1990-10-02 1993-08-24 Board Of Regents, The University Of Texas System Efficient microcapsule preparation and method of use
US6074659A (en) * 1991-09-27 2000-06-13 Noerx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US5225204A (en) * 1991-11-05 1993-07-06 Chen Jivn Ren Stable dosage of levothyroxine sodium and process of production
US5324522A (en) * 1991-12-30 1994-06-28 Akzo N.V. Sustained release thyroactive composition
US5362831A (en) * 1992-06-19 1994-11-08 Farmitalia Carlo Erba S.R.L. Polymer-bound paclitaxel derivatives
US5534496A (en) * 1992-07-07 1996-07-09 University Of Southern California Methods and compositions to enhance epithelial drug transport
US5882645A (en) * 1992-07-24 1999-03-16 The School Of Pharmacy, University Of London Peptide compounds
US5756291A (en) * 1992-08-21 1998-05-26 Gilead Sciences, Inc. Aptamers specific for biomolecules and methods of making
US6093391A (en) * 1992-10-08 2000-07-25 Supratek Pharma, Inc. Peptide copolymer compositions
US6146658A (en) * 1992-10-27 2000-11-14 Hoechst Aktiengesellschaft Prodrugs, their preparation and use as pharmaceuticals
US5891459A (en) * 1993-06-11 1999-04-06 The Board Of Trustees Of The Leland Stanford Junior University Enhancement of vascular function by modulation of endogenous nitric oxide production or activity
US6458842B1 (en) * 1994-02-01 2002-10-01 Knoll Aktiengesellschaft Liquid pharmaceutical compositions comprising thyroid hormones
US5707979A (en) * 1994-06-30 1998-01-13 Hoechst Aktiengesellschaft Phosphinic acid derivatives, their preparation and their use
US6005004A (en) * 1994-08-05 1999-12-21 Molecular / Structural Biotechnologies, Inc. Lipophilic-polycationic delivery systems
US5910569A (en) * 1994-11-22 1999-06-08 Lotus Biochemical Corporation Iodothyronine polymers
US5846743A (en) * 1995-02-22 1998-12-08 Brigham And Women's Hospital, Inc. Polyphoshoinositide binding peptides for intracellular drug delivery
US5670477A (en) * 1995-04-20 1997-09-23 Joseph F. Poduslo Method to enhance permeability of the blood/brain blood/nerve bariers to therapeutic agents
US5898033A (en) * 1995-06-07 1999-04-27 Swadesh; Joel K. Antigen-processing cell-targeted conjugates
US5762909A (en) * 1995-08-31 1998-06-09 General Electric Company Tumor targeting with polymeric molecules having extended conformation
US5955105A (en) * 1995-11-14 1999-09-21 Knoll Pharmaceutical Company Stabilized thyroid hormone preparations and methods of making same
US5977163A (en) * 1996-03-12 1999-11-02 Pg-Txl Company, L. P. Water soluble paclitaxel prodrugs
US5935995A (en) * 1996-03-12 1999-08-10 Heochst Aktiengesellschaft Prodrugs for the therapy of tumors and inflammatory disorders
US6043230A (en) * 1996-07-26 2000-03-28 Gilead Sciences, Inc. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability
US5952294A (en) * 1996-07-31 1999-09-14 University Of Pittsburgh Of The Commonwealth System Of Higher Education Peptidyl prodrugs and methods of making and using the same
US6306993B1 (en) * 1997-05-21 2001-10-23 The Board Of Trustees Of The Leland Stanford, Jr. University Method and composition for enhancing transport across biological membranes
US6048736A (en) * 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6355666B1 (en) * 2000-06-23 2002-03-12 Medinox, Inc. Protected forms of pharmacologically active agents and uses therefor
US6429223B1 (en) * 2000-06-23 2002-08-06 Medinox, Inc. Modified forms of pharmacologically active agents and uses therefor
US6716452B1 (en) * 2000-08-22 2004-04-06 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
US20020098999A1 (en) * 2000-10-06 2002-07-25 Gallop Mark A. Compounds for sustained release of orally delivered drugs
US20020151526A1 (en) * 2000-10-06 2002-10-17 Gallop Mark A. Bile-acid prodrugs of L-dopa and their use in the sustained treatment of parkinsonism
US20020151529A1 (en) * 2000-10-06 2002-10-17 Cundy Kenneth C. Bile-acid derived compounds for providing sustained systemic concentrations of drugs after oral administration

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8394813B2 (en) 2000-11-14 2013-03-12 Shire Llc Active agent delivery systems and methods for protecting and administering active agents
US8133881B2 (en) 2003-01-13 2012-03-13 Shire Llc Carbohydrate conjugates to prevent abuse of controlled substances
US8106016B2 (en) 2003-09-30 2012-01-31 Shire Llc Compounds and compositions for prevention of overdose of oxycodone
EP2292577A1 (en) 2007-05-09 2011-03-09 Pharmacofore, Inc. (+)-stereoisomer of 2,6-di-sec-butylphenol and analogs thereof
EP2301908A1 (en) 2007-05-09 2011-03-30 Pharmacofore, Inc. (-)-stereoisomer of 2,6-di-sec-butylphenol and analogs thereof for promoting antiemetic effect and treatment of nausea and vomiting
EP2392559A1 (en) 2007-05-09 2011-12-07 Pharmacofore, Inc. Therapeutic compounds
EP2810927A1 (en) 2007-05-09 2014-12-10 Sowood Healthcare LLC Therapeutic compounds
US11931419B2 (en) * 2017-11-16 2024-03-19 Sony Group Corporation Programmable polymeric drugs

Also Published As

Publication number Publication date
EP1311242B1 (en) 2010-03-31
AU2001286599B2 (en) 2007-06-21
EP1311242A1 (en) 2003-05-21
US6716452B1 (en) 2004-04-06
AU8659901A (en) 2002-05-06
WO2002034237A1 (en) 2002-05-02
US7427600B2 (en) 2008-09-23
CA2420590A1 (en) 2002-05-02
IL154583A0 (en) 2003-09-17
US20070232529A1 (en) 2007-10-04
EP1311242A4 (en) 2005-09-28

Similar Documents

Publication Publication Date Title
US6716452B1 (en) Active agent delivery systems and methods for protecting and administering active agents
AU772074B2 (en) Enzymatically activated polymeric drug conjugates
JP4522852B2 (en) Polyamino acids functionalized with α-tocopherol and uses thereof, particularly therapeutic uses
US20020099013A1 (en) Active agent delivery systems and methods for protecting and administering active agents
Wiwattanapatapee et al. Dendrimers conjugates for colonic delivery of 5-aminosalicylic acid
JP4970731B2 (en) Polyamino acids functionalized by at least one (oligo) amino acid group and their applications, in particular medical applications
WO2003101476A1 (en) Active agent delivery systems and methods for protecting and administering active agents
AU2001286599A1 (en) Active agent delivery systems and methods for protecting and administering active agents
CZ308395A3 (en) Complex for b12 vitamin reception, process of its preparation, compositions containing thereof and its use
CA2302523A1 (en) Cross-linked particles
WO2003074586A1 (en) Compound of hydrophilic polymer-polycarboxyl oligopeptide and medicines, medical composite comprising above compound and use of above compound in medicimes
CN101448875A (en) Polymer conjugate of podophyllotoxin
US7163918B2 (en) Iodothyronine compositions
US7018654B2 (en) Pharmaceutical composition containing an active agent in an amino acid copolymer structure
WO2000053233A1 (en) Use of protein conformation for the protection and release of chemical compounds
WO2002051432A1 (en) A novel pharmaceutical compound and methods of making and using same
EP1357928B1 (en) A novel pharmaceutical compound and methods of making and using same
EP1401374B1 (en) A novel pharmaceutical compound containing atenolol and methods of making and using same
CN100415801C (en) Polyethylene glycol amino acid N-internal ring carbonyl anhydride active derivatives, and medicinal bonding compound and gel thereof
De Marre et al. Synthesis of macromolecular Mitomycin C derivatives
CA2428971A1 (en) Conjugates of a therapeutic agent and a peptide carrier
JPH06256220A (en) Polymer for drug-carrier
KR100905628B1 (en) Active Agent Delivery Systems and Methods for Protecting and Administering Active Agents
WO2003072047A2 (en) Idothyronine compositions
EP2080511A2 (en) Active agent delivery systems and methods for protecting and administering active agents

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION