WO2002015882A1 - Composition a liberation retardee et combinaisons - Google Patents

Composition a liberation retardee et combinaisons Download PDF

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Publication number
WO2002015882A1
WO2002015882A1 PCT/US2000/020799 US0020799W WO0215882A1 WO 2002015882 A1 WO2002015882 A1 WO 2002015882A1 US 0020799 W US0020799 W US 0020799W WO 0215882 A1 WO0215882 A1 WO 0215882A1
Authority
WO
WIPO (PCT)
Prior art keywords
physiologically active
active protein
fibrinogen
combination according
effective
Prior art date
Application number
PCT/US2000/020799
Other languages
English (en)
Other versions
WO2002015882A8 (fr
Inventor
William T. H. Chang
Original Assignee
Lytone Enterprise, 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 Lytone Enterprise, Inc. filed Critical Lytone Enterprise, Inc.
Priority to MXPA03001653A priority Critical patent/MXPA03001653A/es
Priority to PCT/US2000/020799 priority patent/WO2002015882A1/fr
Priority to AU2000270527A priority patent/AU2000270527A1/en
Priority to CN00819010.0A priority patent/CN1434703A/zh
Priority to BR0017324-0A priority patent/BR0017324A/pt
Publication of WO2002015882A1 publication Critical patent/WO2002015882A1/fr
Publication of WO2002015882A8 publication Critical patent/WO2002015882A8/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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing 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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Definitions

  • the present invention relates to a delayed release composition or combination of a physiologically active protein, which comprises an effective amount of the physiologically active protein, and fibrin glue or fibrinogen and thrombin in an amount effective to delay the release of the physiologically active protein.
  • porcine growth hormone has been reported to be able to stimulate the rate of pig growth for some time.
  • recombinant porcine somatotropin has been shown to be able to reduce the time needed for a pig to reach a market size of approximately 100 kg body weight by more than 10 days. The economic benefit is significant.
  • rPST should be injected to pigs once a day, from the period when the pigs are at 25 kg body weight, until they reach 70 kg body weight.
  • the labor cost involved and the risk of causing stress in pigs are prohibitive for the above commercial practice of rPST.
  • Fibrin glue also known as fibrin sealant, has been utilized in surgery to facilitate coagulation and wound healing for many years.
  • the mechanism of action of fibrin glue is to rnimic the final step of the coagulation cascade wherein fibrinogen is converted to fibrin by the catalization of thrombin. See for example The Journal of Laryngology and Otology November 1987 " , Vol. 101. pp. 1182-1186; Bx. J. Surg. 1991, Vol. 78, July, 841-843; and Ann. Thorac Surg 1993, 56:387-9.
  • fibrin glue may prolong the delivery of glial cell line-derived neurotrophic factor (GDNF) to CNS tissues.
  • GDNF glial cell line-derived neurotrophic factor
  • Biol. Pharm. Bull. 20(3) 278-281 (1997) describes the site-specific delivery of doxorubicin using a composition of fibrin glue and sodium alginate, which advantageously extends the duration of the drug retained in the tumor extracellular fluid.
  • Cell Transplant 1998 Jan-Feb; 7(1):53-61 teaches a fibrin glue-GDNF slow- release preparation said to be effective for keeping GDNF localized in situ, and protected from circulation and surrounding aqueous humor or CSF.
  • the object of the invention is to provide a method to prolong the effective blood concentration of a physiologically active protein.
  • the invention provides a delayed release composition and combination of a physiologically active protein. After administration, the physiologically active protein can maintain an effective blood concentration in animals for a prolonged period.
  • fibrin glue can result in a sustained yet orderly release of physiologically active proteins, and therefore achieve a systemic effect in prolonging the duration of the physiologically active proteins remaining above an effective blood concentration.
  • the first aspect of the invention provides a delayed release composition of a physiologically active protein, which comprises an effective amount of the physiologically active protein, and fibrin glue in an amount effective to delay the release of the physiologically active protein.
  • the physiologically active protein can be prepared by any method, mcluding genetic engineering recombinant technology.
  • the physiologically active protein can be recombinant porcine somatotropin (rPST).
  • the effective amount of the physiologically active protein in the composition of the invention varies along with the species of the physiologically active protein and the effect to be achieved, and can be determined by persons skilled in the art on the basis of ordinary skills in the art.
  • the composition of the invention may comprise about 20-50 mg/ml of rPST, preferably about 25 mg/ml of rPST.
  • the amount of fibrin glue effective to delay the release of the physiologically active protein also varies along with the species of the protein and the effect to be achieved, and can be determined by persons skilled in the art on the basis of ordinary skills in the art.
  • the composition of the invention comprises fibrin glue in the amount equivalent to about 30-60 mg/ml of fibrinogen and about 10-100 lU/ml of thrombin.
  • the composition of the invention comprises fibrin glue in the amount equivalent to about 50 mg/ml of fibrinogen and about 60 IU/ml of thrombin.
  • Thie fibrin glue of the composition according to the invention can be formed in situ at the time of use and achieve the effect of delaying the release of the physiologically active protein. Therefore, the invention in a further aspect provides a delayed release combination of a physiologically active protein which comprises an effective amount of the physiologically active protein, and fibrinogen and thrombin in an amount effective to delay the release of the physiologically active protein.
  • the individual components of the delayed release combination of a physiologically active protein according to the invention are contained in separate containers, and are mixed at the injection site at the time of administration to form in situ fibrin glue to delay the release of the physiologically active protein.
  • the physiologically active protein and fibrinogen can be premixed and contained in the same container, and thrombin is contained in a separate container. In this case, the mixture of the physiologically active protein and fibrinogen is mixed with thrombin
  • the combination of the invention preferably comprises about 30-60 mg/ml of fibrinogen, and about 10-100
  • the combination of the invention comprises about 50 mg/ml of fibrinogen and about 60 IU/ml of thrombin.
  • the delayed release combination of the invention may also comprise a component in group Ila alkaline earth metals, such as an ionized calcium component, e.g. calcium chloride.
  • the delayed release composition or combination of the invention can delay the release of the physiologically active protein contained therein so as to maintain a longer duration of effective blood concentration for the physiologically active protein.
  • the delayed release composition or combination of the invention can delay the release of the physiologically active protein so that the protein can maintain an effective blood concentration for at least about 21 days. Most preferably, the effective blood concentration can be maintained for about 30 days.
  • the delayed release composition or combination of the invention can achieve various effects.
  • the physiologically active protein is a growth hormone
  • the delayed release composition or combination of the invention can be used to promote the growth of economic ariimals, such as pigs, cattle, horses, camels, poultry, aquaculture fish, shrimp, etc., to reduce feed cost and to improve meat quality.
  • test group FG+pST
  • fibrin glue control group FG
  • DI daily injection group
  • test group rats were injected with lOO ⁇ l Solution A containing 10 mg fibrinogen and 1 lO ⁇ g pST in 80 ⁇ l Hanks buffer plus 20 ⁇ l (100 KIU) bovine lung aprotinin, immediately followed by an injection of lOO ⁇ l Solution B containing 40 mM CaCl 2 and 4.9-11.1 mg/ml thrombin at the same injection site.
  • the rats were raised for 21 days, and weighed on day 14 and day 21.
  • the fibrin glue control group rats were injected with lOO ⁇ l Solution A containing 10 mg fibrinogen in 80 ⁇ l Hanks buffer plus 20 ⁇ l (100 KIU) bovine lung aprotinin, immediately followed by injection of lOO ⁇ l Solution B containing 40 mM CaCl 2 and 4.9-11.1 mg/ml thrombin at the same injection site.
  • the rats were raised for 21 days, and weighed on day 14 and day 21..
  • the daily injection group rats were injected with 12.5 ⁇ l Hanks buffer solution containing 5 ⁇ g pST for 21 days. The rats were raised for 21 days, and weighed on day 14 and day 21.
  • the Hanks buffer solution contains: 5.4 mM KC1, 0.3 mM Na 2 HP0 4 ,
  • test group Sixteen pigs with an average body weight of 50 kg were selected at random, and separated into 2 groups: a test group and a control group.
  • no pST and fibrin glue were used.
  • the pigs were fed for a normal commercial diet suitable for pigs at this age.
  • the body weight of each pig was measured every other week for a total period of 7 weeks, and blood samples were taken at the time when the body weight was measured.
  • the blood samples were analyzed for pH values, urea nitrogen, glucose, and pST concentration.
  • the pigs' loin-eye regions as well as back fat was taken when one half of the control and test pigs were slaughtered at week 3 and the remaining half of the pigs at the conclusion of the trial (week 7).
  • the carcass was also analyzed organoleptically for the meat color, fat tissue, and other meat quality index.
  • the feed efficiency, lean gain, average feed intake, and total body weight were also recorded. Results were statistically analyzed for degree of significance.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
  • Detergent Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition à libération retardée d'une protéine physiologiquement active qui comprend une quantité efficace d'une protéine physiologiquement active, et une colle à base de fibrine dans des quantités efficace pour retarder la libération de la protéine physiologiquement active. L'invention concerne aussi une combinaison à libération retardée d'une protéine physiologiquement active, qui comprend une quantité efficace de la protéine physiologiquement active ainsi que le fibrinogène et la thrombine dans des quantités efficaces pour retarder la libération de la protéine physiologiquement active.
PCT/US2000/020799 2000-08-24 2000-08-24 Composition a liberation retardee et combinaisons WO2002015882A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
MXPA03001653A MXPA03001653A (es) 2000-08-24 2000-08-24 Composiciones y combinaciones de liberacion retardada.
PCT/US2000/020799 WO2002015882A1 (fr) 2000-08-24 2000-08-24 Composition a liberation retardee et combinaisons
AU2000270527A AU2000270527A1 (en) 2000-08-24 2000-08-24 Delayed release compositions and combinations
CN00819010.0A CN1434703A (zh) 2000-08-24 2000-08-24 延迟释放组合物及组合
BR0017324-0A BR0017324A (pt) 2000-08-24 2000-08-24 Aperfeiçoamento introduzido em combinações e composições de liberação prolongada

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2000/020799 WO2002015882A1 (fr) 2000-08-24 2000-08-24 Composition a liberation retardee et combinaisons

Publications (2)

Publication Number Publication Date
WO2002015882A1 true WO2002015882A1 (fr) 2002-02-28
WO2002015882A8 WO2002015882A8 (fr) 2002-03-28

Family

ID=21741635

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/020799 WO2002015882A1 (fr) 2000-08-24 2000-08-24 Composition a liberation retardee et combinaisons

Country Status (5)

Country Link
CN (1) CN1434703A (fr)
AU (1) AU2000270527A1 (fr)
BR (1) BR0017324A (fr)
MX (1) MXPA03001653A (fr)
WO (1) WO2002015882A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102872450B (zh) * 2012-10-17 2014-09-03 中国人民解放军总医院 一种用于复合给药的组合物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06206899A (ja) * 1992-07-29 1994-07-26 American Cyanamid Co 生物学的活性ブタソマトトロピンポリペプチド及びその使用法
US5795592A (en) * 1993-10-04 1998-08-18 Tonetti; Maurizio Pharmaceutical composition to enhance tissue healing and regeneration and application kit comprising it
US5925344A (en) * 1992-07-08 1999-07-20 Applied Research Systems Ars Holdings Nv Pharmaceutical composition and uses therefor
US6117911A (en) * 1997-04-11 2000-09-12 Neorx Corporation Compounds and therapies for the prevention of vascular and non-vascular pathologies

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925344A (en) * 1992-07-08 1999-07-20 Applied Research Systems Ars Holdings Nv Pharmaceutical composition and uses therefor
JPH06206899A (ja) * 1992-07-29 1994-07-26 American Cyanamid Co 生物学的活性ブタソマトトロピンポリペプチド及びその使用法
US5795592A (en) * 1993-10-04 1998-08-18 Tonetti; Maurizio Pharmaceutical composition to enhance tissue healing and regeneration and application kit comprising it
US6117911A (en) * 1997-04-11 2000-09-12 Neorx Corporation Compounds and therapies for the prevention of vascular and non-vascular pathologies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE JPAB [online] WANG ET AL.: "Biologically active porcine somatotropine polypeptide and use thereof", XP002934868, accession no. WEST *

Also Published As

Publication number Publication date
AU2000270527A1 (en) 2002-03-04
CN1434703A (zh) 2003-08-06
WO2002015882A8 (fr) 2002-03-28
BR0017324A (pt) 2003-07-29
MXPA03001653A (es) 2004-09-10

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