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WO2007033427A1 - Stabilisation de peptides comprenant des acides aminés basiques - Google Patents

Stabilisation de peptides comprenant des acides aminés basiques Download PDF

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Publication number
WO2007033427A1
WO2007033427A1 PCT/AU2006/001391 AU2006001391W WO2007033427A1 WO 2007033427 A1 WO2007033427 A1 WO 2007033427A1 AU 2006001391 W AU2006001391 W AU 2006001391W WO 2007033427 A1 WO2007033427 A1 WO 2007033427A1
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WO
WIPO (PCT)
Prior art keywords
peptide
amino acid
basic amino
formulation according
formulation
Prior art date
Application number
PCT/AU2006/001391
Other languages
English (en)
Inventor
Frieder K. Hofmann
Original Assignee
Metabolic Pharmaceuticals 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
Priority claimed from AU2005905247A external-priority patent/AU2005905247A0/en
Application filed by Metabolic Pharmaceuticals Limited filed Critical Metabolic Pharmaceuticals Limited
Publication of WO2007033427A1 publication Critical patent/WO2007033427A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats

Definitions

  • This invention relates to pharmaceutical or veterinary formulations comprising a peptide as an active ingredient and methods for improving the stability of peptides in formulations, particularly where said peptides are orally available .
  • Peptides are susceptible to aggregation and/or chemical degradation when stored in an aqueous solution for extended periods of time. This tendency of peptides to aggregate or degrade is generally characterized as "instability" . To extend the long term storage of peptides are often dried (for example by spray-drying or freeze-drying) for long-term storage.
  • the present invention in a first aspect provides a pharmaceutical or veterinary formulation comprising as an active ingredient a peptide susceptible to degradation by acid hydrolysis and amount of free base basic amino acid sufficient to reduce the acid hydrolysis of the peptide.
  • the invention provides a method of increasing the shelf-life of a pharmaceutical or veterinary formulation comprising as an active ingredient a peptide susceptible to degradation by acid hydrolysis comprising the step of adding a free base basic amino acid to the formulation.
  • the peptide and the amino acid are present in a dry form and particularly as a dry powder.
  • AOD9604 The applicant has studied the storage stability of their orally available peptide, AOD9604, described in International Patent application PCT/AU98/00724 and published as WO99/12969 (herein incorporated by reference) .
  • Lyophilised pharmaceutical formulations of AOD9604, Tyr-hGH 177-191, amino acid sequence NH 2 -Tyr-Leu- Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Gln-Gly-Ser-Cys-Gly-Phe- COOH (SEQ ID NO: 1) are unstable at room temperature in dry form after three months .
  • AOD9604 is manufactured using conventional solid phase chemical synthesis and its final form is as a lyophilized hydrochloride salt.
  • HCl is present in the peptide formulation and that this HCl causes the AOD9604 to degrade, via acid hydrolysis.
  • Such peptides include the applicant's orally available conotoxin peptide ACV-3 as described in their PCT application PCT/AU2006/001098 and having the amino acid sequence provided as SEQ ID NO: 2.
  • ACV-3 Ac-Tyr-Leu-Arg-Ile-Val-Gly-Cys-Cys-Ser-Asp-Pro-Arg- Cys-Asn-Tyr-Asp-His-Pro-Glu-Ile-Cys-NH 2 (SEQ ID NO: 2)
  • the formulation is a solid dosage form, in particular for oral use, such as a tablet or a capsule and the peptide is AOD9604 or ACV-3.
  • the solid dosage form may also be for administration to the respiratory tract .
  • the present invention provides a tablet comprising AOD9604 or ACV-3 as active ingredient and a free base basic amino acid.
  • the present invention provides a capsule comprising AOD9604 or ACV-3 as active ingredient and a free base basic amino acid.
  • the present invention provides a method of making a pharmaceutical or veterinary formulation comprising the step of adding to a peptide susceptible to degradation by acid hydrolysis a suitable amount of a free base basic amino acid to reduce the acid hydrolysis of the peptide .
  • the peptide and amino acid are provided in dry form.
  • the peptide and amino acid are dry blended to homogeneity to form the formulation.
  • Figure 1 shows the four formulations used to assess the effect of arginine on stability in capsule formulations.
  • Figure 2 shows a graph plotting the 6 month stability of various formulations containing Arginine, stored at 25 degrees Celsius and 60% relative humidity.
  • Figure 3 shows a graph plotting the 6 month stability of various formulations containing Arginine, stored at 40 degrees Celsius and 75% relative humidity.
  • Figure 4 shows a graph plotting the 6 month stability of various formulations containing Arginine, stored at 60 degrees Celsius.
  • Figure 5 shows the percentage of total related substances present in each formulation initially, and at 1, 3, and 6 month time points.
  • Figure 6 shows a graph plotting the 12 month stability of various capsule formulations containing Arginine, stored at 25 degrees Celsius and 60% relative humidity.
  • Figure 7 shows a graph plotting the 12 month stability of various capsule formulations containing Arginine, stored at 40 degrees Celsius and 75% relative humidity.
  • Figure 8 shows a graph plotting the 12 month stability of various capsule formulations containing Arginine, stored at 60 degrees Celsius.
  • Figure 9 shows the formulations used to assess the effect of Arginine on stability in tablet formulations.
  • Figure 10 shows a graph plotting the 9 month stability of various tablet formulations containing Arginine, stored at 4, 25 and 40 degrees Celsius (TEAP method) .
  • Figure 11 shows a graph plotting the 9 month stability of various tablet formulations containing Arginine, stored at 4, 25 and 40 degrees Celsius (TFA method) .
  • the free base basic amino acid may be Arginine, Lysine or Histidine or corresponding non-conventional amino acids, for example 5-Hydroxylysine, Homoarginine, Ornithine or Citrulline.
  • a D-amino acid may be used instead of the corresponding L-amino acid, any amino acid may be N- methylated, or the N-terminus may be acetylated.
  • Free-base Arginine is the preferred basic amino acid as it has the highest pKa and accordingly is proposed to be the most effective at reducing the acid hydrolysis of the peptide. Additionally L-Arginine is readily available, has no adverse biological activity and is non-toxic.
  • the basic amino acid is in the L-form.
  • the basic amino acid is L-Arginine in free base form.
  • the formulation is formulated for oral administration.
  • Administration to the respiratory tract is also contemplated.
  • the formulation is in a capsule or formed into a tablet or is provided as a dry powder for use in a dry powder inhaler.
  • the peptide and the amino acid are preferably in dry form.
  • the formulation may also further comprise one or more dry excipients .
  • Dry form as used herein means ingredients that are in solid form, including flowable solids which have some liquid-like properties. These generally contain less than 6% moisture. Dry form peptide formulations include freeze dried, lyophilised or desiccated peptide formulations.
  • the active peptide may be any peptide which is susceptible to acid hydrolysis.
  • the present invention is particularly suited to peptides provided in acid salt form. It is more particularly suited to peptides that are for oral administration, particularly those peptides that are orally bioavailable, such as AOD9604, ACV-3 and certain cyclosporins .
  • the invention may be particularly applicable to peptides that are less than 50 amino acids long, and more particularly applicable to peptides that are less than 25 amino acids long.
  • the peptide is an analogue of the C terminus of human growth hormone of between 8 and 30 amino acids in length.
  • the peptide is active to increase lipolysis and/or decrease lipogenesis in adipocytes.
  • the active peptide is AOD9604 or a lipid metabolising subfragment or analogue thereof.
  • the active peptide is ACV-3 or an active subfragment or analogue thereof.
  • the active peptide may be in the form of a pharmaceutically acceptable derivative, preferably a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic , toluenesulphonic , benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic,
  • the ratio of basic amino acid to peptide in the formulation is more than 2:1 by weight.
  • the ratio of basic amino acid to peptide in the formulation is more than 4:1 by weight.
  • the ratio of basic amino acid to peptide in the formulation is more than 8:1 by weight.
  • Excess basic amino acid may be used in the formulation (as high as a ratio of 20:1 or more by weight) provided the basic amino acid is well tolerated.
  • the pharmaceutical composition described in this invention could be used to treat any mammal .
  • the animal may be a human, or may be a domestic or companion animal. While it is particularly contemplated that the present invention is used in medical treatment of humans, it is also applicable to veterinary treatment, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, cattle and sheep, or zoo animals such as non- human primates, felids, canids, bovids, and ungulates.
  • the mammal is a human.
  • the human may be a child or an adult.
  • peptide in this specification includes polypeptides of any amino acid length, including proteins, unless specifically restricted.
  • oral delivery or “oral administration” are intended to encompass any administration or delivery to the GI tract and includes administration directly to the oropharyngeal cavity, and administration via the mouth in which the actual absorption of the peptide or polypeptide takes place in the gastrointestinal tract, including the stomach, small intestine, or large intestine.
  • Oral administration as used herein encompasses sublingual administration
  • An orally available peptide as defined herein is a peptide that is suitable for oral administration.
  • Oral delivery and oral administration may be used interchangeably herein.
  • Formulations for oral use include tablets containing the active compound in a mixture with non-toxic pharmaceutically acceptable excipients.
  • These- excipients may be, for example, inert diluents or fillers ⁇ e.g., sucrose, sorbitol, sugar, mannitol, mirocrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate) ; granulating and disintegrating agents ⁇ e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates or alginic acid); binding agents [e.g.
  • Other pharmaceutically acceptable excipients can be colourants, flavouring agents, plasticisers, humectants, buffering agents and the like.
  • the tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period.
  • the coating may be adapted to release the active compound in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active compound until after passage of the stomach (enteric coating) .
  • the coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone) , or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac and/or ethylcellulose) .
  • a time delay material such as, glyceryl monostearate or glyceryl distearate may be employed.
  • the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, (e.g., chemical degradation prior to the release of the active compound) .
  • Formulations for oral use may also be presented as chewing tablets or as hard gelatin capsules wherein the active compound is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin) .
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g, a mixer, a fluid bed apparatus or a spray drying equipment .
  • the peptide may also be administered to the respiratory tract, for example by intranasal administration, by methods and formulations employed in the art for administration to the respiratory tract.
  • the peptide may be administered to the respiratory tract in the form of a dry powder .
  • Administration to the respiratory tract may be achieved by means of a dry powder inhaler (DPI) .
  • DPI dry powder inhaler
  • the powder composition may be presented in unit dose form, for example in capsules or cartridges of eg. gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the active compound will generally have a small particle size, for example of the order of 5 microns or less .
  • a particle size may be obtained by means known in the art, for example by micronisation.
  • formulations adapted to give sustained release of the active compound may be employed.
  • the active compound may be administered by oral inhalation as a free-flow powder via a "Diskhaler” (trade mark of Glaxo Wellcome pic or a meter dose aerosol inhaler.
  • a "Diskhaler” trade mark of Glaxo Wellcome pic or a meter dose aerosol inhaler.
  • free base is intended to mean the free amino acid, not in the form of a salt.
  • the formulation may comprise pharmaceutically acceptable carrier and, or excipients.
  • Methods and pharmaceutical carriers for preparation of pharmaceutical compositions are well known in the art, as set out in textbooks such as Remington's Pharmaceutical Sciences, 20th Edition, Williams and Williams, Pennsylvania, USA (2000) .
  • the formulation may further contain or be used in conjunction with other pharmaceutical preparations.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, a diluent, a suspending agent, excipient or vehicle for delivering the peptide to the subject.
  • the formulation preferably comprises a bulking agent (which acts as a diluent and disintegrant , for example ProSolv HD90TM) , if necessary a flow enhancer, such as fumed silica (for example Cab-O-silTM) , and if necessary a lubricant, for example magnesium sterate, in addition to the peptide and free base amino acid.
  • a bulking agent which acts as a diluent and disintegrant , for example ProSolv HD90TM
  • a flow enhancer such as fumed silica (for example Cab-O-silTM)
  • a lubricant for example magnesium sterate
  • Preferred AOD tablet formulations are provided in Figure 9.
  • the lubricant need not be present.
  • the components of the formulations will depend upon which peptide is included. However it is envisaged that the presence of free base amino acid in a ratio of 2:1 to 10:1 and possibly up to 20:1 or more will reduce acid hydrolysis of the peptide.
  • the formulations are preferably prepared and administered in dosage units.
  • Solid dosage units include tablets, capsules and suppositories.
  • different daily doses can be used depending on activity of the compound, manner of administration, nature and severity of the disorder, age and body weight of the subject. Under certain circumstances, however, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administration of subdivided doses at specific intervals.
  • the formulations according to the invention may be administered in a therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease and the weight and general state of the subject. Typically, dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of the cytotoxic side effects. Various considerations are described, e.g. in Langer, Science, 249: 1527, (1990) .
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • a peptide includes a plurality of such peptides
  • a reference to “an amino acid” is a reference to one or more amino acids.
  • the present invention employs conventional chemistry and protein chemistry within the capacity of those skilled in the art. Such techniques are well known to the skilled worker, and are explained fully in the literature. See, for example, Coligan, Dunn, Ploegh, Speicher and Wingfield: "Current protocols in Protein Science” (1999) Volumes I and II (John Wiley & Sons Inc . ) .
  • AOD9604 has the sequence provided as SEQ ID NO" 1.
  • Wang resin (0.625 g, 0.5 mmol) was placed in a 10 ml reaction vessel .
  • Fmoc-L-phenylalanine Fmoc-Phe, 0.388 g, 1.0 mmol
  • NMP-DCM 1:5, v/v
  • DIC 0.135 g, 1.0 mmol
  • 1.0 ml NMP 4-dimethylaminopyridine (DMAP, 0.074g, 0.06 mmol) in 0.6 ml DMF was added.
  • DMAP 4-dimethylaminopyridine
  • the reaction in the solution was allowed to continue for 68 minutes at room temperature. The solution was then drained, the resin was washed thoroughly with NMP (4 ml x 3) and OCM (4 ml x 3) .
  • the Fmoc-Phe-Wang Resin complex was dried in vacuo overnight to yield 0.781 g of material.
  • the coupling level of amino acid to resin was determined to be 0.80 mmol/g resin by using spectrophotometry measurement of the Fmoc- piperidine adduct . Step 3.
  • Fmoc-Phe-Wang Resin (0.263 g, 0.20 tnmol) was placed in the 10 ml reaction vessel. DMF (8 ml) was added to wash and swell the resin by stirring for 2 minutes. The solution was then drained from the reaction vessel.
  • Fmoc-glycine (Fmoc-Gly, 0.238 g, 0.8 mmol) , HOBt (108 mg; 0.8 mmol) and DIC (128 ⁇ l ; 0.8 mmol) were added to a 10 ml test tube containing 2 ml DMF. The mixture was stirred for 10 minutes to start the activation of amino acid. The solution was then added to the resin which originally was placed in the reaction vessel . The resulting mixture was stirred for 1.5 hours or until a negative ninhydrin test was obtained. The solution was then drained from the reaction vessel . Step 7 .
  • Fmoc-Cys Acm) Fmoc-Ser (t-Bu) Fmoc-Gly Fmoc-Glu (O-tBu) Fmoc-Val Fmoc-Ser (t-Bu) Fmoc-Arg (Pmc) Fmoc-Cys (Acm) Emoc-Gln Fmoc-Val Fmoc-lle Fmoc-Arg (Pmc) Fmoc-Leu Fmoc-Tyr (t-Bu)
  • the reaction vessel containing the peptide-resin was then placed in a desiccator and dried overnight under vacuum.
  • the yield of peptide-resin was 0.635 g.
  • the dried peptide-resin was removed from the reaction vessel and placed in a 50 ml round-bottom flask containing a magnetic stirring bar.
  • the cleavage of the peptide from the resin with TFA was carried out with the following procedure: A scavenger solution, containing 0.75 g phenol, 0.5 ml H20, 0.5 ml thioanisole, and 0.25 ml ethanedithio, was added to the round-bottom flask. The resulting mixture was stirred for 5 minutes. 10 ml TFA was added drop by drop into the flask while kept stirring vigorously. The resulting mixture was stirred for 2.5 hours at room temperature .
  • the mixture was filtered through a medium-porosity filter, fritted glass funnel .
  • the TFA-peptide solution was sucked into another 500 ml round-bottom flask containing 200 ml cold diethyl ether by applying vacuum. Peptide was allowed to be precipitated in the ether solution at 4OC overnight, then collected by filtering the mixture through a fine- porosity, fritted glass funnel.
  • the peptide pellet on the filter was washed with cold ether (10 ml x 3) to remove the scavenger.
  • the peptide pellet was then dissolved with 25% aqueous acetic acid and then lyophilized to yield the crude peptide (about 400 mg dry weight, purity -80%) .
  • the crude peptide was purified by reversed-phase high performance liquid chromatography (RP-HPLC) . Purification was carried out on a preparative 21.2 x 250mm Supelcosil PLC-18 (octadecyl, C18) column (120 Angstrom pore size, 12 ⁇ m particle size, 190 m2/g surface area; Supelco, Beliefonte, PA, U.S.A.) at 5.0 ml/mm flow rate at room temperature. A linear gradient program was utilized , where solvent A was water with 0.1 % TEA, and solvent B was acetonitrile-water (50/50: v/v, containing 0.1% TEA). The gradient was developed from 20 to 100% over 80mm.
  • RP-HPLC reversed-phase high performance liquid chromatography
  • AOD9604 acetate salt was dissolved in 1OmM HCl and relyophilised to yield AOD9604 Hydrochloride salt .
  • the final powder blend was encapsulated using the Dott Bonopace encapsulator fitted with size 0 change parts.
  • Formulation 4 was hazy and did not fully dissolve in solution at initial testing point. Solution remained hazy despite additional sonication/shaking and remained cloudy for up to 5 days after preparation. This probably accounts for the lower levels of AOD9604 detected at the initial timepoint .
  • Tablets comprising ltng, 0.5 mg, 0.25 mg and 0 mg of AOD9604 were formulated with varying amounts of Arginine were made. Stability analysis on the tablet formulations were performed to determine the optimum level of Arginine that improves the stability characteristics of the formulation.
  • Direct Compression Tablets The ProSolv, L-Arginine, Cab- O-sil and AOD9604 were accurately weighed and placed in a V-blender and blended for between 5 and 20 minutes. The Mg Stearate was added to the shell and blended for a further 5 - 20 minutes. The total blend time was 25 minutes . The blend was placed in the tablet press hopper and adjusted for weight and thickness settings to yield 100 mg tablets with thickness of approximately 4.2mm.
  • the graphs show the results of HPLC methods used to determine the purity of AOD . Two methods are required in case an impurity is eluting at the same time as the main peak, this would be less likely to occur under two differenent sets of conditions.
  • TFA refers to Trifluoro acetic acid
  • TEAP refers to Triethylammonium phosphate .

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Abstract

La présente invention concerne une formulation pharmaceutique ou vétérinaire comprenant, en tant que principe actif, un peptide pouvant être dégradé par hydrolyse acide et une quantité d’acide aminé basique sous forme de base libre, suffisante pour réduire l’hydrolyse acide du peptide. La présente invention concerne également un procédé visant à accroître la durée de conservation des formulations peptidiques en ajoutant un acide aminé basique sous forme de base libre.
PCT/AU2006/001391 2005-09-23 2006-09-22 Stabilisation de peptides comprenant des acides aminés basiques WO2007033427A1 (fr)

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AU2005905247A AU2005905247A0 (en) 2005-09-23 Peptide fomulation
AU2005905247 2005-09-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020012243A2 (fr) 2018-07-09 2020-01-16 Abbott Laboratories Gmbh Composition pharmaceutique contenant un peptide

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816568A (en) * 1986-05-16 1989-03-28 International Minerals & Chemical Corp. Stabilization of growth hormones
WO1993012812A1 (fr) * 1991-12-20 1993-07-08 Novo Nordisk A/S Formulation pharmaceutique stabilisee comportant une somatotrophine et de l'histidine
WO1997039768A1 (fr) * 1996-04-24 1997-10-30 Novo Nordisk A/S Formulation pharmaceutique contenant une hormone de croissance, un acide amine et un detergent non ionique
US6013773A (en) * 1996-02-02 2000-01-11 Mitsui Chemicals, Inc. Pharmaceutical preparation containing human growth hormone
US6204036B1 (en) * 1995-03-09 2001-03-20 Aventis Behring Gmbh Stable transglutaminase preparations and processes for their production
WO2001049314A2 (fr) * 1999-12-30 2001-07-12 Nps Allelix Corp. Formulations de glp-2

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816568A (en) * 1986-05-16 1989-03-28 International Minerals & Chemical Corp. Stabilization of growth hormones
WO1993012812A1 (fr) * 1991-12-20 1993-07-08 Novo Nordisk A/S Formulation pharmaceutique stabilisee comportant une somatotrophine et de l'histidine
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