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WO1994020136A1 - Cyclodextrin-peptide compositions - Google Patents

Cyclodextrin-peptide compositions Download PDF

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Publication number
WO1994020136A1
WO1994020136A1 PCT/US1994/001847 US9401847W WO9420136A1 WO 1994020136 A1 WO1994020136 A1 WO 1994020136A1 US 9401847 W US9401847 W US 9401847W WO 9420136 A1 WO9420136 A1 WO 9420136A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
peptide
peptides
cyclodextrin
administered
Prior art date
Application number
PCT/US1994/001847
Other languages
French (fr)
Inventor
Peter K. Chiang
Dennis L. Butler
Nesbit D. Brown
Original Assignee
Department Of The Army, United States Government
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 Department Of The Army, United States Government filed Critical Department Of The Army, United States Government
Publication of WO1994020136A1 publication Critical patent/WO1994020136A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin

Definitions

  • This invention relates to a method of presenting pharma ⁇ ceutically active peptides, particularly receptor bloc ers and i munogenic peptides, in cyclodextrin compositions.
  • Cyclodextrins are cyclic molecules containing six or more ⁇ -D-glucopyranose units linked together at the 1,4 positions.
  • the 2-hydoxypropyl- ⁇ -cyclodextrin (HPCD) has been used for stabilization and solubilization of various compounds,
  • 35 does not disclose the solubilization of peptides in cyclodex ⁇ trin.
  • TP-5 is effective in blocking the stimulation of smooth muscle contraction caused by the neurotoxin (+)-anatoxin-a (ANTX) .
  • ANTX is a bicyclic a ine exotoxin produced by the blue-green algae, Anabaena flos-a ⁇ uae, and has been found to cause death to livestock and waterfowl.
  • the toxin acts by depolarizing blockade of neuromuscular transmission. Such depolarization results in respiratory paralysis.
  • the action of ANTX has been ascribed to its potent nicotinic cholinergic agonist activities in skeletal muscle and mammalian skeletal muscle and the central nervous system.
  • ANTX can also cause cardiovascular aberrations by activation of nicotinic receptors in the adrenal medulla and sympathetic ganglia.
  • the antagonist effect of TP-5 has been attributed to its ability to block nicotinic receptors in a noncompetitive manner.
  • compositions containing cyclodextrin complexes of peptides particularly synthetic peptides and peptides of £ 40 amino acids.
  • Such peptides are particularly useful for administration as receptor agonists, receptor antagonists, and as vaccines.
  • the compositions of the invention provide improved means for delivery of such peptides.
  • peptides especially peptides of about three to 20 amino acids, are unstable in low concentrations and tend to loose biological activity. While Brewster describes the value of preparing formulations of cyclodextrin and regulatory proteins to avoid conformational changes, there is no sugges ⁇ tion therein that cyclodextrin would be useful for increasing stability of small peptides such as thymopentin.
  • the instant invention improves methods of administration of peptides to the ucosa of mammals in need of treatment with effective peptides.
  • the invention provides a means of formulating peptides to avoid loss of efficacy and to facilitate delivery of the active peptides to the reactive site.
  • the method has been exemplified using the synthetic peptides corresponding position 32-36 of thymopoietin and known as TP-5 (Arg-Lys-Asp-Val-Tyr) . While the hydroxypropyl cyclodextrin has been exemplified, other cyclodextrins, including mixed cyclodextrins, may be used in the method of the invention.
  • TP-5 (10" 2 M) was synthesized as describe in Chiang, et al, Life Sci 49; (1991) PL13-19 and was made up in various percentages of HPCD dissolved in sterile water. Mixtures were stirred for about one hour. The solutions were then maintained at room tempera- ture. Control solutions of TP-5 dissolved in sterile water without HPCD were also prepared in the same manner. The two sets of solutions were stored at ambient room temperatures (25°C) for 14 months. Aliquots were removed monthly for stability testing.
  • TP-5 The stability study was performed by assaying the ability of the TP-5 solutions to counteract the stimulation of contraction of guinea pig ileum by ANTX. Guinea pig ileum contraction stimulated by ANTX was performed as reported in Chiang, et al. (supra) . The final concentration of TP-5 for use was obtained by diluting with Krebs-Ringer buffer.
  • EXAMPLE I Aqueous solution of 2-hydroxy- ⁇ -cyclodextrin (HPCD) were prepared at concentration of 2.5%, 5.0%, 10%, 15%, 20%, 25% and 30% (w/v) . TP-5 was added in sufficient amounts to provide a final molarity of 10 "2 molar solution of TP-5.
  • IC 50 values of the inhibition by TP-5 of guinea-pig ileum contraction stimulation by ANTX at 3 x 10 "5 N was compared using freshly made 10_ 2 molar solutions of TP-5 and similar concentrations of TP-5 in 5%, 15% and 20% solutions of HPCD which had been stored for 14 months at ambient temperature to determine relative activity. The results are shown as mean + s.e. of four separate experiments as indicated in Table I TABLE I
  • a composition containing 0.5 mg TP-5 is administered intraperitoneally to rabbits to provide protection against ANTX.
  • Formulations may be administered for up to 4 days. Dosage range for thymopentin may vary from 1 ⁇ g/kg/day to 1 g/kg/day. It is, of course, understood that smaller animals will require higher dosage per kilogram than larger mammals.
  • Formulations of active agents in HPCD for administration may be prepared using any pharmaceutically appropriate solvent, including water, isotonic saline, glucose, or saline.
  • the formulations may be administered orally in the form of liquid bolus, or may be administered as lyophilized powders or tablets. When provided as lyophilized powders, many of the compositions may be administered nasally for inhalation.
  • Compositions of the invention may be administered parenterally by, for example intramuscular, subcutaneous or intraperitoneal routes. Solutions of the cyclodextrin inclusion complexes can be administered to the mucosa by any means appropriate such as by nasal spray, buccal tablet or sublingually as drops.
  • the site of administration will be governed, in many instances, by the site of effective response. For example, it is often advantageous to administer immunogenic peptides to the mucosa.
  • peptides could be formulated in a similar manner.
  • Such peptides include splenopentin (SP-5) having the structure Arg-Lys-Glu-Val-Tyr. This peptide is effective for inducing T-cell differentiation and for modulation of neuromus- cular transmission.
  • SP-5 splenopentin
  • DSIP delta sleep inducing peptide
  • vasoactive intestinal peptide VIP
  • biotinyl-VIP from human, porcin, chick, rat or other sources, having the sequence His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu- Arg-Lys-Gln-Met-Ala-Val-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH j for prevention for cell killing by human immunodeficiency virus (Nature 335; 639-642 (1984)) and for pharmacological treatment of tissues involving neuromuscular transmission (Arch, int.
  • the peptide HG165-178 representing the sequence 165.-178 of gpl20 is represented by the sequence Asn-Ile-Ser-Thr-Ser-Ile-Arg-Gly-Lys-Val-Gln-Lys- Gln-Lys-Glu-Tyr, which is analogous to sequences in snake neurotoxins and rabies virus glycoprotein is conjugated to a keyhole limpet hemocyanin (KLH) and can be, thereafter, encapsulated in cyclodextrin to prevent the binding of viruses, toxins, viral coatings and gpl20 to cells. (See FEBS Letters 311; 115-118 (1992)).
  • KLH keyhole limpet hemocyanin
  • the methods of the invention should be particularly considered to stabilize peptides containing asparytyl, asparaginyl and glycine residues.

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biotechnology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

This invention provides improved compositions containing cyclodextrin complexes of peptides, particularly synthetic peptides and peptides of ≤ 40 amino acids. Such peptides are particularly useful for administration as receptor agonists, receptor antagonists, and as vaccines. The compositions of the invention provide improved means for delivery of such peptides.

Description

CYCL0DE5CTRIN-PEPTIDE CC OSITIONS
Field of the Invention:
/ This invention relates to a method of presenting pharma¬ ceutically active peptides, particularly receptor bloc ers and i munogenic peptides, in cyclodextrin compositions.
10 Background of the Invention;
Cyclodextrins are cyclic molecules containing six or more α-D-glucopyranose units linked together at the 1,4 positions. The 2-hydoxypropyl-β-cyclodextrin (HPCD) has been used for stabilization and solubilization of various compounds,
15 including proteins and steroids. Brewster, et al. described use of cyclodextrins in solubilizing proteins to prevent aggregation , precipitation, and loss of biopotency. ("Appli¬ cation of 2-hydroxypropyl beta cyclodextrin to Proteins", Minutes Int. Symp. Cyclodextrins. 5th. 1990. pp 440-444) The
20 proteins studied therein were interleukin-3, and insulin, two large regulatory proteins. There is no suggestion that the 2- hydroxypropyl beta cyclodextrin would be useful in formulating peptides for use as receptor blockers or immunogens. The Brewster article suggests that the improved potency of the
25 proteins is due to the avoidance of hydrolysis, deamidation, racemization, oxidation and disulfide bond exchange, and changes in dimensional protein structure related to folding of the protein. There is no suggestion that the cyclodextrins can be useful for formulations containing synthetic peptides, nor
30 is there any suggestion that the preparations disclosed therein can be administered by application to the mucosa.
Josef Pitha, in U.S. patent 4,727,064, which is incorpo¬ rated herein by reference, suggests the use of cyclodextrin in solubilizing medicinals including steroids and vitamins, but
35 does not disclose the solubilization of peptides in cyclodex¬ trin.
Szejtli, et al., in U.S. patent 4,380,626, teach the use of cyclodextrins in preparations of plant growth regulators including 2-chloroethylphosphonic acid. No use of cyclodex¬ trins for preparation of peptides is taught or suggested therein. Gideon Goldstein, in U.S. Patent 5,140,010, which is incorporated herein by reference, teaches the stabilization of aqueous formulations of synthetic peptides corresponding to position 32-36 of thymopoietin and known as thymopentin or TP-5 (Arg-Lys-Asp-Val-Tyr) in glycine. Goldstein does not disclose or suggest use of cyclodextrin for stabilization of peptides. TP-5 is effective in blocking the stimulation of smooth muscle contraction caused by the neurotoxin (+)-anatoxin-a (ANTX) . ANTX is a bicyclic a ine exotoxin produced by the blue-green algae, Anabaena flos-aσuae, and has been found to cause death to livestock and waterfowl. The toxin acts by depolarizing blockade of neuromuscular transmission. Such depolarization results in respiratory paralysis. The action of ANTX has been ascribed to its potent nicotinic cholinergic agonist activities in skeletal muscle and mammalian skeletal muscle and the central nervous system. ANTX can also cause cardiovascular aberrations by activation of nicotinic receptors in the adrenal medulla and sympathetic ganglia. The antagonist effect of TP-5 has been attributed to its ability to block nicotinic receptors in a noncompetitive manner. summary of the Invention;
This invention provides improved compositions containing cyclodextrin complexes of peptides, particularly synthetic peptides and peptides of £ 40 amino acids. Such peptides are particularly useful for administration as receptor agonists, receptor antagonists, and as vaccines. The compositions of the invention provide improved means for delivery of such peptides.
Many peptides, especially peptides of about three to 20 amino acids, are unstable in low concentrations and tend to loose biological activity. While Brewster describes the value of preparing formulations of cyclodextrin and regulatory proteins to avoid conformational changes, there is no sugges¬ tion therein that cyclodextrin would be useful for increasing stability of small peptides such as thymopentin.
The instant invention improves methods of administration of peptides to the ucosa of mammals in need of treatment with effective peptides. Detailed Description of the Invention;
The invention provides a means of formulating peptides to avoid loss of efficacy and to facilitate delivery of the active peptides to the reactive site. The method has been exemplified using the synthetic peptides corresponding position 32-36 of thymopoietin and known as TP-5 (Arg-Lys-Asp-Val-Tyr) . While the hydroxypropyl cyclodextrin has been exemplified, other cyclodextrins, including mixed cyclodextrins, may be used in the method of the invention.
One problem in use of peptides is their instability in aqueous solution, especially very dilute compositions. Furthermore, many of the solvents used to provide stable, soluble compositions for treatment of other mammals can not be used in man. At present, there is no known compatible solvent for TP-5 in which the peptide is stable and easily adminis- tered. This is a significant problem because the instability will hinder acceptance for prophylactic and/or therapeutic applications. Materials and Methods;
The 2-hydroxypropyl-β-cyclodextrin used in the examples was purchased from Pharmatec in Alachua, Florida. TP-5 (10"2 M) was synthesized as describe in Chiang, et al, Life Sci 49; (1991) PL13-19 and was made up in various percentages of HPCD dissolved in sterile water. Mixtures were stirred for about one hour. The solutions were then maintained at room tempera- ture. Control solutions of TP-5 dissolved in sterile water without HPCD were also prepared in the same manner. The two sets of solutions were stored at ambient room temperatures (25°C) for 14 months. Aliquots were removed monthly for stability testing. The stability study was performed by assaying the ability of the TP-5 solutions to counteract the stimulation of contraction of guinea pig ileum by ANTX. Guinea pig ileum contraction stimulated by ANTX was performed as reported in Chiang, et al. (supra) . The final concentration of TP-5 for use was obtained by diluting with Krebs-Ringer buffer. EXAMPLE I Aqueous solution of 2-hydroxy-β-cyclodextrin (HPCD) were prepared at concentration of 2.5%, 5.0%, 10%, 15%, 20%, 25% and 30% (w/v) . TP-5 was added in sufficient amounts to provide a final molarity of 10"2 molar solution of TP-5. Further dilution to provide final dosage was made using Krebs-Ringer buffer. The solutions were then stored at ambient temperature for 14 months, after which activity of the cyclodextrin solutions was compared to freshly made solutions. As a control a 10"2 solution without cyclodextrin was prepared. After storage at ambient temperature (25eC) for four weeks the control solution showed no activity. EXAMPLE II
Evaluation of Anatoxin-A Response alone and in conjunction with TP-5 was carried out in accord with standard procedures as disclosed in U.S. Patent 4,973,734 issued November 27, 1990, which is incorporated herein by reference. Results:
IC50 values of the inhibition by TP-5 of guinea-pig ileum contraction stimulation by ANTX at 3 x 10"5 N was compared using freshly made 10_2 molar solutions of TP-5 and similar concentrations of TP-5 in 5%, 15% and 20% solutions of HPCD which had been stored for 14 months at ambient temperature to determine relative activity. The results are shown as mean + s.e. of four separate experiments as indicated in Table I TABLE I
HPCD (%) IC50 ( X 10"5 M)
0 (freshly made) 3.9 + 1.9
5% 4.1 + 3.1
15% 4.9 + 4.4 20% 3.3 + 3.0 EXAMPLE III
A composition containing 0.5 mg TP-5 is administered intraperitoneally to rabbits to provide protection against ANTX. Formulations may be administered for up to 4 days. Dosage range for thymopentin may vary from 1 μg/kg/day to 1 g/kg/day. It is, of course, understood that smaller animals will require higher dosage per kilogram than larger mammals.
Formulations of active agents in HPCD for administration may be prepared using any pharmaceutically appropriate solvent, including water, isotonic saline, glucose, or saline. The formulations may be administered orally in the form of liquid bolus, or may be administered as lyophilized powders or tablets. When provided as lyophilized powders, many of the compositions may be administered nasally for inhalation. Compositions of the invention may be administered parenterally by, for example intramuscular, subcutaneous or intraperitoneal routes. Solutions of the cyclodextrin inclusion complexes can be administered to the mucosa by any means appropriate such as by nasal spray, buccal tablet or sublingually as drops. The site of administration will be governed, in many instances, by the site of effective response. For example, it is often advantageous to administer immunogenic peptides to the mucosa.
Many other peptides could be formulated in a similar manner. Such peptides include splenopentin (SP-5) having the structure Arg-Lys-Glu-Val-Tyr. This peptide is effective for inducing T-cell differentiation and for modulation of neuromus- cular transmission. (Proc. Natl. Acad. Sci. USA 81; 2847-2847 (1984)) Others include a nine amino acid sequence known as delta sleep inducing peptide (DSIP) of the structure Trp-Ala- Gly-Gly-Asp-Ala-Ser-Gly-Glu (Neurosci. Biobehav. Rev. ; 83-93 (1984)), vasoactive intestinal peptide (VIP) or biotinyl-VIP from human, porcin, chick, rat or other sources, having the sequence His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu- Arg-Lys-Gln-Met-Ala-Val-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NHj for prevention for cell killing by human immunodeficiency virus (Nature 335; 639-642 (1984)) and for pharmacological treatment of tissues involving neuromuscular transmission (Arch, int. Pharmacodvn 305. 14-24 (1990)). The peptide HG165-178 representing the sequence 165.-178 of gpl20 is represented by the sequence Asn-Ile-Ser-Thr-Ser-Ile-Arg-Gly-Lys-Val-Gln-Lys- Gln-Lys-Glu-Tyr, which is analogous to sequences in snake neurotoxins and rabies virus glycoprotein is conjugated to a keyhole limpet hemocyanin (KLH) and can be, thereafter, encapsulated in cyclodextrin to prevent the binding of viruses, toxins, viral coatings and gpl20 to cells. (See FEBS Letters 311; 115-118 (1992)). The methods of the invention should be particularly considered to stabilize peptides containing asparytyl, asparaginyl and glycine residues.

Claims

1. A pharmaceutically effective composition comprising an 5 effective amount of a receptor agonist, antagonist or
\ immunogenic peptide of 3 to 40 amino acids in a cyclo¬ dextrin inclusion complex in a pharmaceutically accept¬ able diluent.
10 2. A composition of claim 1 wherein the immunogenic peptide is TP-5.
3. A composition of claim 1 wherein cyclodextrin is present at a concentration of .5% to 30%. 15
4 A composition of claim 3 wherein a cyclodextrin is 2- hydroxypropyl-β-cyclodextrin.
5. A composition of claim 1 wherein the active peptide is an 20 immunogen.
6. A composition of claim 1 wherein the peptide is spleno- pentin.
25 7. A composition of claim 1 wherein the peptide is delta sleep-inducing peptide.
8. A composition of claim 1 wherein the peptide is vasoac- tive intestinal peptide.
30
9. A composition of claim 1 wherein the peptide is HG 165- 178.
10. A method of administering an immunogen to an animal by 35 administering an immunogenic effective amount of a pharmaceutical composition of claim 5.
11. A method of claim 10 wherein the pharmaceutical composi¬ tion is administered directly to the mucosa.
12. A method of claim 11 wherein the pharmaceutical composi¬ tion is administered sublingually.
13. A method of claim 11 wherein the pharmaceutical composi¬ tion is administered to the nasal mucosa by inhalation.
PCT/US1994/001847 1993-03-08 1994-02-28 Cyclodextrin-peptide compositions WO1994020136A1 (en)

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US2752493A 1993-03-08 1993-03-08
US08/027,524 1993-03-08

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999002177A1 (en) * 1997-07-07 1999-01-21 Peptichemio Ag Pharmaceutical composition containing peptichemio
DE10014007A1 (en) * 2000-03-22 2001-10-11 Strathmann Ag & Co Medicament for pulmonary or intranasal administration, useful for treating withdrawal symptoms, sleeping disorders or stress, comprises delta-sleep inducing peptide
US6767992B1 (en) 1998-11-19 2004-07-27 Ptc Pharma Ag Method for producing L-prolyl-L-M-sarcolysyl-L-p-fluorophenylalanine and derivatives thereof
US6858584B2 (en) 2000-05-02 2005-02-22 Theravance, Inc. Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin
WO2021183863A1 (en) 2020-03-13 2021-09-16 Constant Therapeutics Llc Methods and compositions for treatment of coronavirus infection

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4923964A (en) * 1987-05-22 1990-05-08 Ortho Pharmaceutical Corporation Human splenin
US4956274A (en) * 1987-04-06 1990-09-11 Microgenics Corporation Reagent stabilization in enzyme-donor and acceptor assay
US5024998A (en) * 1987-12-30 1991-06-18 University Of Florida Pharmaceutical formulations for parenteral use
US5140010A (en) * 1989-09-28 1992-08-18 Immunobiology Research Institute Stabilized aqueous formulations of thymopentin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4956274A (en) * 1987-04-06 1990-09-11 Microgenics Corporation Reagent stabilization in enzyme-donor and acceptor assay
US4923964A (en) * 1987-05-22 1990-05-08 Ortho Pharmaceutical Corporation Human splenin
US5024998A (en) * 1987-12-30 1991-06-18 University Of Florida Pharmaceutical formulations for parenteral use
US5140010A (en) * 1989-09-28 1992-08-18 Immunobiology Research Institute Stabilized aqueous formulations of thymopentin

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FEBS LETTERS, Volume 311, No. 2, issued October 1992, L. BRACCI et al., "Binding of HIV-1 gp120 to the Nicotinic Receptor", pages 115-118. *
NATURE, Volume 335, issued 13 October 1988, D.E. BRENNEMAN et al., "Neuronal Cell Killing by the Envelope Protein of HIV and its Prevention by Vasoactive Intestinal Peptide", pages 639-642. *
PROCEEDINGS NATIONAL ACADEMY OF SCIENCES USA, Volume 81, issued May 1984, T. AUDHYA et al., "Contrasting Biological Activities of Thymopentin and Splenin, Two Closely Related Polypeptide Products of Thymus and Speen", pages 2847-2849. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999002177A1 (en) * 1997-07-07 1999-01-21 Peptichemio Ag Pharmaceutical composition containing peptichemio
US6767992B1 (en) 1998-11-19 2004-07-27 Ptc Pharma Ag Method for producing L-prolyl-L-M-sarcolysyl-L-p-fluorophenylalanine and derivatives thereof
DE10014007A1 (en) * 2000-03-22 2001-10-11 Strathmann Ag & Co Medicament for pulmonary or intranasal administration, useful for treating withdrawal symptoms, sleeping disorders or stress, comprises delta-sleep inducing peptide
US6858584B2 (en) 2000-05-02 2005-02-22 Theravance, Inc. Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin
US7026288B2 (en) 2000-05-02 2006-04-11 Theravance, Inc. Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin
US7067483B2 (en) 2000-05-02 2006-06-27 Theravance, Inc. Pharmaceutical compositions containing a gycopeptide antibiotic and a cyclodextrin
US8158580B2 (en) 2000-05-02 2012-04-17 Theravance, Inc. Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin
WO2021183863A1 (en) 2020-03-13 2021-09-16 Constant Therapeutics Llc Methods and compositions for treatment of coronavirus infection

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