WO2000032218A1 - Controlled release formulation comprising gnrh-ii - Google Patents

Controlled release formulation comprising gnrh-ii Download PDF

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Publication number
WO2000032218A1
WO2000032218A1 PCT/GB1999/004045 GB9904045W WO0032218A1 WO 2000032218 A1 WO2000032218 A1 WO 2000032218A1 GB 9904045 W GB9904045 W GB 9904045W WO 0032218 A1 WO0032218 A1 WO 0032218A1
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WO
WIPO (PCT)
Prior art keywords
xaa
peptide
polymer
gnrh
gly
Prior art date
Application number
PCT/GB1999/004045
Other languages
English (en)
French (fr)
Inventor
Steve Qi
Karen Akinsanya
Amanda Hayward
Original Assignee
Ferring Bv
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
Priority to MXPA01005543A priority Critical patent/MXPA01005543A/es
Priority to NZ511984A priority patent/NZ511984A/xx
Priority to PL99348575A priority patent/PL348575A1/xx
Priority to KR1020017006883A priority patent/KR20010089538A/ko
Application filed by Ferring Bv filed Critical Ferring Bv
Priority to IL14349699A priority patent/IL143496A0/xx
Priority to EEP200100293A priority patent/EE200100293A/xx
Priority to SK755-2001A priority patent/SK7552001A3/sk
Priority to BR9915943-0A priority patent/BR9915943A/pt
Priority to CA002353798A priority patent/CA2353798A1/en
Priority to JP2000584909A priority patent/JP2002531411A/ja
Priority to AU15732/00A priority patent/AU770676B2/en
Priority to EP99958357A priority patent/EP1140133A1/en
Publication of WO2000032218A1 publication Critical patent/WO2000032218A1/en
Priority to NO20012636A priority patent/NO20012636L/no
Priority to HR20010421A priority patent/HRP20010421A2/hr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
    • 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
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical preparatior that releases a therapeutic agent over an extended period
  • GnRH gonadotropin releasing hormone
  • LHRH gonadotropin releasing hormone
  • FSH follicle-stimulating hormone
  • GnRH pyroGlu-H ⁇ s-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 (SEQ I D No 5)
  • GnRH-II pyroGlu-H ⁇ s-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH 2 (SEQ I D No 6)
  • GnRH-II is, to some extent, misleading The new peptide is a separate gene product, and is clearly distinguishable from GnRH in its tissue distribution It seems unlikely that GnRH-II acts as an endogenous releaser of LH and FSH Since no clear evidence for a physiological role for GnRH-II has been presented, no attentio ⁇ has been paid to the practical aspects of using this peptide as a therapeutic agent
  • GnRH-II has an important role in the function of a number of organs For example, it influences osteogenesis and it modulates the proliferation of prostatic epithelial cells Accordingly, we have considered the means by which this agent and its analogues might usefully be delivered in a clinical situation and it is an object of the present invention to provide suitable formulations for acnieving this purpose
  • the formulations according to the present invention rely on the use of a biodegradable polymer to hold the peptide in a depot from which it is released into the systemic circulation at a controlled rate
  • These formulations comprise two key elements the biologically active peptide and the biodegradable polymer
  • the biologically active peptide is a decapeptide according to the sequence
  • Xaa 1 is His or Tyr
  • Xaa 3 is Tyr or Arg
  • the polymer is any pharmaceutically acceptable biodegradable polymer, and preferably a co- polymer of glycolic and lactic acids
  • the invention further comprises the use of the formulations for the treament of human pathologies
  • Figure 1 shows the effect of increasing doses of GnRH-II on serum calcium concentrations in ova ⁇ ectomised rats.
  • ammo acids have their conventional meanings and indicate the natural L-isomer (except for the achiral ammo acid glycine)
  • the invention as disclosed herein comprises a pharmaceutical formulation that releases a therapeutic peptide at a controlled rate and for an extended period of time (i e for a period of at least one day, preferably several days, and more preferably at least one week), particularly for the treatment of diseases of the bone and prostate
  • the therapeutic peptide is a decapeptide according to the sequence
  • Xaa 1 is either His or Tyr Xaa 2 is either Trp or Leu and Xaa 3 is either Tyr or Arg, provided that when Xaa 1 is Tyr and Xaa 2 is Leu then Xaa 3 is not Arg
  • Xaa 1 is His Xaa 2 is Trp and Xaa 3 is Tyr
  • acids for example, acetic acid t ⁇ fluoroacetic acid benzoic acid, hydrochloric acid, phosDho ⁇ c acid and the like
  • a second essential component of the formulation is a biodegradable, pharmaeutically acceptable polymer
  • polymers are known in the art They can either be homopolymers (i e polymers of a single monomer) or copolymers (i e formed from two or more different monomers) Suitable monomers include ammo and hydroxy dervatives of carboxylic acids
  • the polymer is composed of hydroxyacyl monome ⁇ c units, and more preferably of ⁇ - hydroxyacyl units
  • the polymer is a poly(glycol ⁇ c acid), a poly(lact ⁇ c acid) or a copolymer of glycolic and lactic acids
  • Such a polymer has the following chemical structure
  • R is hydrogen in poly(glycol ⁇ c acid), methyl in poly(lact ⁇ c acid), and randomly hydrogen or methyl in the copolymer
  • the peptide can either be incorporated into a matrix of the polymer, or, more preferably, it can be encapsulated by the polymer
  • the peptide that is encapsulated may be either a solid or in solution It is preferred for the peptide to be a solid
  • This formulation is useful in the treatment of human pathologies, including disorders of bone growth (including age-related osteoporosis and osteoporosis associated with post-menopausal hormone status primary and secondary hyperparathyroidism disuse osteoporosis diabetes-related osteoporosis, and glucocorticoid-related osteoporosis) and prostate growth (including benign prostatic hyperplasia and prostate cancer)
  • disorders of bone growth including age-related osteoporosis and osteoporosis associated with post-menopausal hormone status primary and secondary hyperparathyroidism disuse osteoporosis diabetes-related osteoporosis, and glucocorticoid-related osteoporosis
  • prostate growth including benign prostatic hyperplasia and prostate cancer
  • co er ses a method for the treatment of an individual suffering from a disorder of bone or prostate growth or considered to be at risk of so suffering
  • This method of t r eatment comprises the administration to said individual of a therapeutically effective amount of a formulation containing as an active principal, a peptide according to the sequence
  • the method of treatment may comprise a single administration of the formulation, but is more likely to comprise a course of repeated administrations
  • the frequency of the administrations may be from once per day to once per month
  • the amount of active peptide in each dose will depend on the dosing schedule and the route of administration Generally, it will be between one milligram (1mg) and one gram (1g)
  • the supervising physician will determine the precise dose depending on the parameters generally considered in the art to be relevant
  • the formulation is administered by intramuscular or subcutaneous injection
  • the peptides that comprise the active agents of the compositions of the present invention can be prepared by the methods generally known in the art
  • the peptides may be prepared by solid-phase synthesis This involves the sequential addition of ammo acid residues to a resin-bound intermediate according to the following strategy
  • a protected am o acid is reacted with a functionalised resin.
  • the protecting group (PG) is most commonly terf-butyloxycarbonyl (Boc) or 9- fluorenylmethyloxycarbonyl (Fmoc).
  • the functional group on the resin (FG) is commonly a chloroalkyl group, a hydroxyl group or an amine group.
  • the linker group (L) is an oxygen atom ( -O- ).
  • L is -NH-.
  • step two the protecting group (PG) is removed from the ⁇ -amino group.
  • PG is Boc
  • this can be accomplished by treating the resin with acids such as trifluoroacetic acid or hydrogen chloride in dichloromethane.
  • PG is Fmoc
  • the deprotection can be accomplished by treating the resin with bases such as piperidine.
  • step three the peptide chain is extended by one ammo acid residue.
  • a protected ammo acid is coupled to the amine group liberated in step two.
  • Many reagents are known in the art for achieving this conversion.
  • One combination is dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBt).
  • DCC dicyclohexylcarbodiimide
  • HOBt hydroxybenzotriazole
  • a base will also be necessary Suitable bases include t ⁇ ethylamine and N.N- diisopropylethylamine.
  • the solvent will generally be dichloromethane, dimethylformamide, or a mixture of these If the side chains of the ammo acids (Aaa - Nnn) contain reactive groups (for example ammo groups, carboxylic acid groups, hydroxyl groups) then these will need protecting
  • the protecting groups chosen for the side chains are generally those that are stable un ⁇ er the conditions required to remove the protecting group (PG) from the ⁇ -amino group If PG is Fmoc, then the side chain protecting groups can conveniently be based on tert-butyl chemistry. On the other hand, if PG is Boc, then the side chain protecting groups can be based on fluorenylmethyl chemistry Other protecting groups known in the art can also be used.
  • step four the deprotection/chain extension cycle is repeated until the desired peptide sequence has been constructed.
  • step five the completed peptide is liberated from the resin.
  • Protecting groups are removed from the side chains either before or after the cleavage.
  • L is -NH-
  • the peptide liberated is in the form of the C-terminal amide.
  • L is -0-
  • the peptide liberated is often the C-terminal free acid and a second step is required to form the C-terminal amide.
  • the peptides may also be prepared by solution-phase synthesis, and this may be more convenient when large quantities of material are needed.
  • the formulation may take the form of a simple dispersion of the peptide in a matrix of the polymer, or the peptide may be microencapsulated with the polymer.
  • Dispersions can be prepared by mixing the peptide (as a solid) and the polymer to homogeneity, then compressing the mixture to form a solid mass. It may be necessary to add a binding agent to the mixture in order to achieve a suitably cohesive composition. The mass can then be ground up to give particles suitable for suspension in a biologically compatible liquid (such as water or isotonic saline) and injection.
  • a biologically compatible liquid such as water or isotonic saline
  • Microencapsulated formulations can be prepared either from the solid peptide (as a powder) or from a solution and particularly an aqueous solution, of the peptide
  • the polymer is first dissolved in a suitable organic solvent
  • the peptide is then added to this solution and the mixture is vigorously stirred to disperse the peptide in the organic phase
  • a second organic solvent is then added This second solvent is chosen to reduce the solubility of the polymer in the organic phase
  • the polymer comes out of solution to form a coating around the particles of solid peptide (or around the droplets of dispersed aqueous solution)
  • the resultant microcapsules are then hardened by washing to remove traces of the organic solvents They are then ready to be suspended in an appropriate liquid for a ⁇ ministration
  • This peptide was prepared using standard solid-phase methods starting from Boc-
  • Benzot ⁇ azolyl esters were used as the activated esters throughout the synthesis These were prepared from the corresponding protected ammo acids by reaction with 1 -hydroxy benzotriazole (1 eq ) and dicyclohexylcarbodiimide (1 eq ) The quantities used (in relation to the resin substitution capacity) are listed in Table 2
  • Example 1A The peptidoresm prepared in Example 1A was placed in a linen bag in a pressure vessel The vessel was then charged with gaseous ammonia to a final pressure of 4 atm After 72h the excess ammonia was vented and the resin was extracted with acetic acid (3* 10OmL) and ethanol (3 ⁇ 1 OOmL) The combined extracts were degassed with nitrogen, 10% palladium-on-carbon was added, and the mixture was stirred under an atmosphere of hydrogen When the reaction was complete (as judged by HPLC), the mixture was filtered and the filtrate was evaporated The residue was purified by reverse-phase HPLC to give the title compound
  • Copoly(D,L-lact ⁇ c acid, glycolic acid) with a lactic acid/glycolic acid ratio of 50/50 is used to a solution of this polymer (3 7g) in dichloromethane (100mL) in a reaction vessel equipped with a stirrer is added GnRH-II acetate (0 15g, prepared by dissolving the peptide of example 1 in acetic acid and lyophilismg the resultant solution) The mixture is stirred at 500revolut ⁇ ons/m ⁇ nute, then silico ⁇ e oil (Dow Corning 360 Medical Fluid®, 45g) is added over 0 minutes The mixture is then introduced as a thin jet into caprylic-cap ⁇ c acid-trigiyce ⁇ de (Miglyol® 812, 3 3L) with continuous stirring at lOOOrevolutions/minute When addition is complete, stirring is continued for 1 hour, then the microcapsules are collected by filtration, washed twice with isopropanol, and
  • the peptides of the invention caused significant effects at concentrations below 10O ⁇ M
  • Bone marrow cells removed from human bone fragments were cultured in the presence of 10nM 1 ,25-(OH) 2 vitamin D 3 for seven days to generate multinucleated osteoclasts using standard techniques known in the art (Takahashi et al , Endocnnol 122 1473-1482, 1988)
  • the culture medium ( ⁇ -MEM) was removed and replaced by a fresh phenol red free medium supplemented with antibiotics and 10% charcoal-stripped heat-inactivated FCS containing GnRH-l, GnRH-II or analogues and the cultures were maintained for a further 24 hours
  • Floating cells were harvested and osteoclasts stained for tartrate-resistant aci ⁇ phosphatase (TRAP) expression a marker of osteoclast differentiation ( Hughes et al Nat Med 2 1 132-1 1 35 1996)
  • the peptides of the invention caused significant effects at concentrations below 100 ⁇ M
  • Bone mineral density was assessed by dual energy x-ray absorptometry-DEXA) On day 28 serum calcium levels were determined by colo ⁇ met ⁇ c assay using a commercial kit
  • Example 1 demonstrates the preparation of the peptides of the invention, which can then be formulated as illustrated in Example 2
  • Examples 3 to 7 demonstrate the biological activity of the peptides of interest
  • the scope of the invention is not intended to be limited in any way by these Examples
  • variety of controlled release formulations of these peptides can be prepared by varying the polymer and/or the physical nature of the combination of the peptide and polymer
  • these variations give formulations with equivalent biological properties and are intended to be within the scope of the invention as defined in the following Claims
  • SEQ I D Nos 1 to 4 referred to in Example 5 are as follows

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
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PCT/GB1999/004045 1998-12-03 1999-12-02 Controlled release formulation comprising gnrh-ii WO2000032218A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
EEP200100293A EE200100293A (et) 1998-12-03 1999-12-02 Kontrollitud vabanemisega ravivorm, mis sisaldab GnRH-II
PL99348575A PL348575A1 (en) 1998-12-03 1999-12-02 Controlled release formulation comprising gnrh-ii
KR1020017006883A KR20010089538A (ko) 1998-12-03 1999-12-02 Ｇｎｒｈ-ｉｉ를 포함하는 조절 방출형 제형
BR9915943-0A BR9915943A (pt) 1998-12-03 1999-12-02 Formulação de liberação controlada compreendendo gnrh-ii
IL14349699A IL143496A0 (en) 1998-12-03 1999-12-02 Controlled release formulation comprising gnrh-ii
NZ511984A NZ511984A (en) 1998-12-03 1999-12-02 Controlled release formulation comprising GnRH-II
SK755-2001A SK7552001A3 (en) 1998-12-03 1999-12-02 Controlled release formulation comprising gnrh-ii
MXPA01005543A MXPA01005543A (es) 1998-12-03 1999-12-02 Formulacion de liberacion controlada que consta de gnrh-ii.
CA002353798A CA2353798A1 (en) 1998-12-03 1999-12-02 Controlled release formulation comprising gnrh-ii
JP2000584909A JP2002531411A (ja) 1998-12-03 1999-12-02 Ｇｎｒｈ−ｉｉを含んで成る制御放出製剤
AU15732/00A AU770676B2 (en) 1998-12-03 1999-12-02 Controlled release formulation comprising GnRH-II
EP99958357A EP1140133A1 (en) 1998-12-03 1999-12-02 Controlled release formulation comprising gnrh-ii
NO20012636A NO20012636L (no) 1998-12-03 2001-05-29 Kontrollert frigivelsesformulering som omfatter GNRH-II
HR20010421A HRP20010421A2 (en) 1998-12-03 2001-06-01 Controlled release formulation comprising gnrh-ii

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9826662.0 1998-12-03
GB9826662A GB2344287A (en) 1998-12-03 1998-12-03 Controlled release pharmaceutical formulation

Publications (1)

Publication Number Publication Date
WO2000032218A1 true WO2000032218A1 (en) 2000-06-08

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PCT/GB1999/004045 WO2000032218A1 (en) 1998-12-03 1999-12-02 Controlled release formulation comprising gnrh-ii

Country Status (22)

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EP (1) EP1140133A1 (ja)
JP (1) JP2002531411A (ja)
KR (1) KR20010089538A (ja)
CN (1) CN1332635A (ja)
AU (1) AU770676B2 (ja)
BR (1) BR9915943A (ja)
CA (1) CA2353798A1 (ja)
CZ (1) CZ20011893A3 (ja)
EE (1) EE200100293A (ja)
GB (1) GB2344287A (ja)
HR (1) HRP20010421A2 (ja)
HU (1) HUP0104943A3 (ja)
IL (1) IL143496A0 (ja)
MX (1) MXPA01005543A (ja)
NO (1) NO20012636L (ja)
NZ (1) NZ511984A (ja)
PL (1) PL348575A1 (ja)
RU (1) RU2233170C2 (ja)
SK (1) SK7552001A3 (ja)
TR (1) TR200102273T2 (ja)
WO (1) WO2000032218A1 (ja)
ZA (1) ZA200104530B (ja)

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WO2011032099A1 (en) 2009-09-11 2011-03-17 The Board Of Trustees Of The University Of Illinois Methods of treating diastolic dysfunction and related conditions
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