WO1988005661A1 - Compositions pharmaceutiques a base de vasopressine - Google Patents

Compositions pharmaceutiques a base de vasopressine Download PDF

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Publication number
WO1988005661A1
WO1988005661A1 PCT/US1988/000349 US8800349W WO8805661A1 WO 1988005661 A1 WO1988005661 A1 WO 1988005661A1 US 8800349 W US8800349 W US 8800349W WO 8805661 A1 WO8805661 A1 WO 8805661A1
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WO
WIPO (PCT)
Prior art keywords
administration
polypeptide
vasopressin
composition according
composition
Prior art date
Application number
PCT/US1988/000349
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English (en)
Inventor
Uwe Schrell
Original Assignee
Biomed Research Consultants, Limited
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 Biomed Research Consultants, Limited filed Critical Biomed Research Consultants, Limited
Publication of WO1988005661A1 publication Critical patent/WO1988005661A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to novel pharmaceutical compositions containing biologically-active vasopressin-based. polypeptides in combination with carboxymethylcellulose.
  • the invention is concerned with vasopressin-based polypeptides which have been mixed with carboxymethylcellulose to produce non-orally administered pharmaceutical compositions, and which exhibit prolonged activity and increased bioavailability of the polypeptide.
  • vasopressin has biological effects, such as antidiuretic activity and vasoconstriction of visceral blood flow. Its utility, however, is limited by its relatively short half-life in the blood stream, as well as its well known general circulatory systemic pressor effect, and cardiac toxicity.
  • vasopressin A variety of analogs of vasopressin have been synthesized in an effort to modify the properties of vasopressin and provide products having increased pharmaceutical utility.
  • vasopressin has been modified by deamination of cysteine at the 1 position and replacement of arginine by its D-isomer at the 8 position to yield desmopressin ("dDAVP").
  • dDAVP desmopressin
  • Desmopressin which is immune to enzymatic cleavage of the 1-2 and 8-9 carbon-nitrogen bonds, exhibits prolonged antidiuretic activity with low pressor activity. See U.S. Patent No. 3,497,491.
  • the disulfide bridge has been replaced with a "monocarba” linkage (-CH-S- or -SCH 2 ⁇ ) or a dicarba (-CH 2 -CH_-) linkage.
  • vasopressin analogs having a chain of cleavable peptide residues attached to the active molecule.
  • a short peptide chain is attached to the N-terminal amino group.
  • N(glycyl-glycyl-glycyl)-8-lysine-vasopressin, or tGLVP also referred to as terlipressin or glypressin
  • tGLVP also referred to as terlipressin or glypressin
  • a short peptide side chain may be attached to the N position of 8-lysine. In any event, the additional amino acids of the side chain are slowly cleaved enzymatically so that prolonged release of active nonapeptide 8-lysine-vasopressin is achieved.
  • vasopressin-based polypeptides have been administered by a variety of routes and in combination with a variety of pharmaceutical carriers and additives.
  • terlipressin has been administered by i.v. injection in the form of a physiological saline solution at pH 4
  • desmopressin has been administered intranasally, subcutaneously, intravenously, and intramuscularly in physiological saline at pH 4.
  • vasopressin-based polypeptides such as desmopressin. It has traditionally been accepted that such peptides are decomposed in the gastrointestinal tract with little nonapeptide absorption taking place. Nonetheless, desmopressin has been incorporated in gelatin-based sub-lingual lozenges. (A. Grossman et al. "Two new modes of desmopressin (dDAVP) administration", British Medical Journal, May 17, 1980, 1215.) Additionally, desmopressin has been formulated into an orally administered composition in the form of a tablet with various fillers and inert constituents, including crosslinked carboxymethylcellulose. (International Patent Application No. PCT/US84/01860, H. Hagsta et al. ) , but the effective unit dosage appears to be ten times the effective intranasal dosage conventionally required, and no difference in duration of antidiuretic action was reported or claimed.
  • U.S. Patent No. 3,454,549 discloses still another vasopressin analog, l-desamino-[8-L-Arg]-vasopressin, and states that it can be used in the form of its free base, or as a salt of an organic or inorganic acid, on an acid-radical containing polymer, with carboxymethylcellulose being mentioned as an illustrative acid polymer. There is no recognition, however, that any acid salt, much less the CMC salt, has any effect on the activity of the vasopressin analog.
  • Still another object of this invention is the provision of a method for administering a vasopressin-based polypeptide to a patient in which the activity of the polypeptide is prolonged.
  • the present invention provides a pharmaceutical composition which comprises a vasopressin-based polypeptide combined with carboxymethylcellulose in an amount sufficient to provide improved activity of the polypeptide.
  • the inventive composition has enhanced- physiological activity and a long effective lifetime as compared with the polypeptide alone.
  • vasopressin-based polypeptides employed in the invention may be represented by the following formula: B-Tyr-X 1 -Gln-Asn-CH-CO-X 2 -D-X 3 -NH. t I ⁇
  • A is disulfide or a monocarba (-CH-S- or -SCH--) linkage;
  • B is -C IH Z_, -CIHNH Z, or -CjHENH Z_;
  • E is a peptide chain of from 1 to 3 amino acid residues;
  • D is a basic amino acid residue, e.g. D-Arg or Lys, or a lysine peptide residue which is substituted at the W ⁇ position with a peptide chain of from 1 to 3 peptide residues; and each of X 1, X2 and X3 is an amino acid residue.
  • an "amino acid residue” is the divalent moiety obtained by removing a hydrogen from the alpha amino group and the hydroxyl group from the carboxyl group of an alpha-amino acid.
  • Especially preferred polypeptides which can be used according to the invention, and which are encompassed by the above formula, are desmopressin ("dDAVP") and terlipressin ("tGLVP").
  • dDAVP desmopressin
  • tGLVP terlipressin
  • X is phenylalanine (Phe)
  • X 2 is prolm. e (Pro)
  • X3 is glycine (Gly).
  • the invention is also directed to a method for treating a patient with a vasopressin-based polypeptide, especially a patient suffering from diabetes insipidus, incontinence, enuresis, or sickle cell anemia. Additionally, the invention pertains to a method for minimizing or preventing gastrointestinal or uterine bleeding in a patient suffering such distress, and for controlling the blood pressure changes associated with hemorrage and the management of burns. According to the inventive method, a pharmaceutical composition which comprises a vasopressin-based polypeptide having the above formula and carboxymethylcellulose is administered to a patient in an amount effective to produce and prolong the intended physiological response.
  • vasopressin-based pharmaceutical composition which has enhanced pharmacological activity and increased duration of action by combining a vasopressin-based polypeptide with carboxmethylcellulose.
  • vasopressin-based polypeptide includes vasopressin itself, as well as its homologs, analogs, hormonogens and other variants possessing similar activity.
  • polypeptides of the invention may be represented by the following formula:
  • A is a disulfide (-S-S-) or monocarba (-CH-S- or -SCH--) linkage?
  • B is a divalent moeity selected from the group consisting of -CHNH 2 , _ CH 2 , and -CHENH 2 ;
  • E is a peptide chain of from 1 to 3 amino acid residues;
  • D is a basic amino acid residue, such as arginine (Arg), lysine (Lys), or ornithine (Orn) , or a lysine peptide residue substituted at the N position with a chain of 1 to 3 amino acid residues; and each of X 1, X2 and X3 is an amino acid residue.
  • the polypeptide may be vasopressin. If so, B is -CHNH 2 ; A is disulfide; D is Arg; and the 1 and 6 positions are cysteine (Cys).
  • the peptide preferably is an analog or hormonogen which exhibits increased resistance to enzymatic cleavage so that the biovailability of the peptide is enhanced.
  • the peptide is desmopressin or terlipressin.
  • desmopressin A is disulfide
  • B is -CH (the 1 position is mercaptopropionic acid)
  • D is -[-D-Arg]-.
  • terlipressin A is disulfide
  • B is -CH-Gly-Gly-Gly-NH 2
  • E is a tripeptide chain of three Gly residues
  • D is Lys.
  • CMC carboxymethylcellulose
  • CMC has been used as an inert and safe "filler" in tablet formulations, while the sodium salt of CMC has been given orally as a weak antacid. CMC has also been safely used in injectable formulations in connection with other molecules than the peptides encompassed by the formula given.
  • the present invention is premised on the previously unrecognized fact that CMC can be noncovalently complexed or otherwise combined with a vasopressin-based polypeptide to provide a pharmaceutical composition showing increased bioavailability and prolonged effect of the polypeptide.
  • CMC is not critical, provided it is water soluble.
  • the amount of CMC should be sufficient to impart improved polypeptide activity, as reflected by increased activity and/or increased half-life.
  • the weight ratio of CMC to polypeptide should be at least 100:1. Ratios of from about 100:1 to 200:1 are preferred, with a ratio of about 100:1 being especially preferred.
  • higher amounts of CMC should be avoided. Otherwise/ the viscosity of the resulting solution will be too high.
  • a minimum amount of CMC must be complexed with the peptide in order to achieve the advantages of the invention.
  • the degree to which the peptide is complexed at any pH will depend to some extent on the isoelectric point of the peptide selected, and the amount and type of other ionic and polar molecules which are present to compete with the peptide and CMC.
  • compositions of the invention dosage and route of administration will ultimately depend upon the'patient's unique conditions, and the judgment of his attending physician, they can generally be administered to the patient being treated at dosages and by routes calculated to deliver effective amounts of polypeptide to the site of action.
  • they may be administered by intravenous, subcutaneous, or intramuscular injection, or they may be administered intranasally in the form of nose drops or spray.
  • the composition of this invention can be administered as a dispersion or in solution in a suitable liquid medium, such as water, saline, isotonic aqueous solution and alcohol.
  • a suitable liquid medium such as water, saline, isotonic aqueous solution and alcohol.
  • the medium may contain various pharmaceutically acceptable fillers and additives, such as anticlotting agents, dispersing agents, acidifying agents and the like.
  • a preferred medium is physiological saline solution.
  • concentration of the polypeptide in the solution is not narrowly critical and and will depend upon the polypeptide, the presence or absence of a disulfide linkage, the pH, the intended mode of administration, and dosage.
  • solutions intended for intranasal applications may contain higher concentrations than solutions intended to be administered by injection, but dimerisation and peptide stability are usually the decisive factors here.
  • the dosage of the composition which is administered will depend greatly upon the specific action(s) of the polypeptide, the level(s) of such action(s), the effect intended, and the mode of administration. For example, when administered in the form of nose drops, the applied dosage will be about 10 times the applied dose administered by intravenous routes.
  • the effective dosage may be significantly decreased for all modes of administration pursuant to the invention.
  • Aii acid physiological saline solution (pH 4) containing 10 ug/ml of Desmopressin (dDAVP) (manufactured by Ferring AB) and chlorobutanol was prepared and divided into two aliquots. One of the aliquots was set aside, while the other aliquot was mixed with sufficient Na-CMC (Tylopur C30, manufactured by Kalle) to obtain a CMC concentration of 2 mg/ml.
  • the CMC:dDAVP weight ratio of the CMC-containing aliquot was 200:1, at a pH of 4.
  • mice having a body weight of 180-200 g Male rats having a body weight of 180-200 g were anesthetised with Methohexital-Na (Brevimytal, manufactured by Lilly), and then surgically prepared by inserting a tracheal cannula into a carotid artery in order to draw blood samples (0.5 ml/sample) into heparinised tuberculin syringes, and a polyethylene cannula into a jugular vein to rehydrate and replace blood volumes lost during sampling, by injecting equal volumes of iso-oncotic dextran in saline. Both cannulas were inserted in a central direction. Zero-time samples were withdrawn to serve as a baseline.
  • Methohexital-Na (Brevimytal, manufactured by Lilly)
  • dDAVP and dDAVP-CMC solutions were then subcutaneously injected into the rats in a volume dose of 0.1 ml/lOOg body weight. Blood samples were withdrawn at 5, 10, 20, and 40 minutes after injection. These times were chosen because the half-life ( ⁇ -,/ 2 ) °f dDVAP in man after i.v. injection has already been determined to be 17-18 min. (K.E. Andersson et al., Acta Endocrinol, 69:640, 1972), as opposed to about 3 min. for the natural vasopressins and tGLVP. (V. Pliska et al., Exoerientia, 29:767, 1973).
  • the heparinised samples were stirred and centrifuged. Then, the supernatant plasma was pipetted off and stored in separate plastic tubes at -70°C until analyzed.
  • RIA radio-immune assay
  • a commercial goat-anti-rabbit plasma was used to precipitate An-Ab complexes, while 125I was used to label the 2-Tyr of the dDAVP. Even though the Ab used was Arg-vasopressin specific, it showed sufficient cross-reactivity with other vasopressins, including dDAVP, to allow detection of plasma levels of dDAVP down to 7 pg/ml.
  • Terlipressin (manufactured by the Chemical Works of Gedeon Richter, Ltd., Budapest) was prepared in two aliquots of tGLVP and tGLVP-CMC at the same concentrations and under the same conditions as was dDAVP in Example 1 above.
  • mice having weights of 180-200 g, were anaesthetised with urethane i.p. and s.c, but otherwise were surgically prepared exactly as in Example 1 above. This time, however, after the withdrawal of the 0-time blood samples, tGLVP and tGLVP-CMC were given i.v. into the jugular vein cannula. Because tGLVP is a long-acting polypeptide, the times of sampling were longer than in Example 1: 10, 20, 40, 60 and 180 min. sampling times were used.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Compositions pharmaceutiques contenant des polypeptides biologiquement actifs à base de vasopressine en combinaison avec de la cellulose de carboxyméthyle. Ces compositions présentent une activité prolongée et une plus grande biodisponibilité du polypeptide.
PCT/US1988/000349 1987-01-30 1988-01-27 Compositions pharmaceutiques a base de vasopressine WO1988005661A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US884187A 1987-01-30 1987-01-30
US008,841 1987-01-30

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WO1988005661A1 true WO1988005661A1 (fr) 1988-08-11

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WO (1) WO1988005661A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0381345A1 (fr) * 1989-01-30 1990-08-08 Corint, Ltd. Composition aqueuse à base de desmopressine-CMC
DE4229880A1 (de) * 1992-09-04 1994-03-31 Knauf Siegfried Medikament bzw. Medikamentenzusammensetzung
WO1995001183A1 (fr) * 1993-06-29 1995-01-12 Ferring B.V. Compositions permettant l'administration par voie nasale de desmopressine
WO1998043661A1 (fr) * 1997-03-27 1998-10-08 Thomas Lundeberg Utilisation de substances ayant une activite d'oxytocine dans la preparation de medicaments pour la suberification d'une blessure
US5968895A (en) * 1996-12-11 1999-10-19 Praecis Pharmaceuticals, Inc. Pharmaceutical formulations for sustained drug delivery

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB155919A (en) * 1919-09-29 1920-12-29 Eugene Bregeon Temple An improved hydraulic variable speed transmitter
US3502545A (en) * 1968-09-27 1970-03-24 Monsanto Co Process for the separation of water-soluble polymeric materials from unbound protein or peptide using semiporous gel
US3679653A (en) * 1968-09-27 1972-07-25 Monsanto Co Hormonally-active reaction product of a polymer with a hormone
US3980631A (en) * 1973-11-09 1976-09-14 Ceskoslovenska Akademie Ved Novel analogs of deamino-vasopressin with a modified disulfide bridge and manufacturing process thereof
US4093610A (en) * 1977-01-31 1978-06-06 American Home Products Corporation Process for producing triglycyl-lysine vasopressin and intermediates therefor
US4261980A (en) * 1980-05-16 1981-04-14 Vega Laboratories, Inc. Method for prophylaxis and/or treatment of sickle cell disease
US4263283A (en) * 1980-05-16 1981-04-21 Ferring Pharmaceuticals, Inc. Method for prophylaxis and/or treatment of sickle cell disease
US4399125A (en) * 1981-03-24 1983-08-16 Maurice Manning Novel antagonists of the antidiuretic action of arginine vasopressin
US4613500A (en) * 1983-03-09 1986-09-23 Teijin Limited Powdery pharmaceutical composition for nasal administration
US4649130A (en) * 1984-01-26 1987-03-10 Medical College Of Ohio Novel derivatives of arginine vasopressin antagonists

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8306367L (sv) * 1983-11-18 1985-05-19 Ferring Ab Antidiuretiskt verkande farmaceutiskt preparat
SE457055B (sv) * 1986-08-18 1988-11-28 Ferring Ab Topisk straalskyddsgel foer mukosa innehaallande kaerlsammandragande substanser

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB155919A (en) * 1919-09-29 1920-12-29 Eugene Bregeon Temple An improved hydraulic variable speed transmitter
US3502545A (en) * 1968-09-27 1970-03-24 Monsanto Co Process for the separation of water-soluble polymeric materials from unbound protein or peptide using semiporous gel
US3679653A (en) * 1968-09-27 1972-07-25 Monsanto Co Hormonally-active reaction product of a polymer with a hormone
US3980631A (en) * 1973-11-09 1976-09-14 Ceskoslovenska Akademie Ved Novel analogs of deamino-vasopressin with a modified disulfide bridge and manufacturing process thereof
US4093610A (en) * 1977-01-31 1978-06-06 American Home Products Corporation Process for producing triglycyl-lysine vasopressin and intermediates therefor
US4261980A (en) * 1980-05-16 1981-04-14 Vega Laboratories, Inc. Method for prophylaxis and/or treatment of sickle cell disease
US4263283A (en) * 1980-05-16 1981-04-21 Ferring Pharmaceuticals, Inc. Method for prophylaxis and/or treatment of sickle cell disease
US4399125A (en) * 1981-03-24 1983-08-16 Maurice Manning Novel antagonists of the antidiuretic action of arginine vasopressin
US4613500A (en) * 1983-03-09 1986-09-23 Teijin Limited Powdery pharmaceutical composition for nasal administration
US4649130A (en) * 1984-01-26 1987-03-10 Medical College Of Ohio Novel derivatives of arginine vasopressin antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0300036A4 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0381345A1 (fr) * 1989-01-30 1990-08-08 Corint, Ltd. Composition aqueuse à base de desmopressine-CMC
DE4229880A1 (de) * 1992-09-04 1994-03-31 Knauf Siegfried Medikament bzw. Medikamentenzusammensetzung
WO1995001183A1 (fr) * 1993-06-29 1995-01-12 Ferring B.V. Compositions permettant l'administration par voie nasale de desmopressine
US5498598A (en) * 1993-06-29 1996-03-12 Ferring Ab Composition for nasal administration of desmopressin
CN1101701C (zh) * 1993-06-29 2003-02-19 凡林有限公司 由鼻给药的去氨加压素组合物及其制备方法和用途
US5968895A (en) * 1996-12-11 1999-10-19 Praecis Pharmaceuticals, Inc. Pharmaceutical formulations for sustained drug delivery
US6180608B1 (en) 1996-12-11 2001-01-30 Praecis Pharmaceuticals, Inc. Pharmaceutical formulations for sustained drug delivery
US6699833B1 (en) 1996-12-11 2004-03-02 Praecis Pharmaceuticals, Inc. Pharmaceutical formulations for sustained drug delivery
WO1998043661A1 (fr) * 1997-03-27 1998-10-08 Thomas Lundeberg Utilisation de substances ayant une activite d'oxytocine dans la preparation de medicaments pour la suberification d'une blessure
US6262021B1 (en) 1997-03-27 2001-07-17 Entretech Medical Ab Use of substances having oxytocin activity for preparation of medicaments for wound healing
AU749479B2 (en) * 1997-03-27 2002-06-27 Entretech Medical Ab Use of substances having oxytocin activity for preparation of medicaments for wound healing

Also Published As

Publication number Publication date
EP0300036A1 (fr) 1989-01-25
EP0300036A4 (fr) 1989-06-14

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