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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
  • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
  • A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
  • A23L29/37—Sugar alcohols
• • 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
  • A61K47/02—Inorganic 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
  • A61K9/0012—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

• a common reactivity of sugar glasses is the reducing action of the carbonyl group and the degradation products formed are often the familiar carbonyl-amine compounds of the Maillard reaction (Ellis G.P. The Maillard reaction. Adv. Carbohyd. Chem. 14 63-134 (1959)). Because the Maillard reaction is temperature dependent, it is only slowly progressive at low temperatures. Many glass-forming materials give excellent preservation of activity during the drying process itself but the product subsequently undergoes progressive deterioration unless stored under refrigeration.
• trehalose Because it is subsequently degraded in the body by the specific enzyme, trehalase, to two molecules of glucose, trehalose possesses many of the properties of the ideal industrial stabiliser for foods and medical products.
• a large scientific and patent literature has now developed on trehalose stabilisation of foods, vaccines, diagnostics and drugs.
• the disadvantages of trehalose are that it is as yet not approved by the regulatory authorities, it is expensive and it contains contaminating reducing sugars, especially glucose, in all but the most rigorously purified material.
• the effect of these substances is dose dependent and below a threshold concentration they do not work.
• the substances useful in accordance with this invention promote the drying of mannitol solutions as glasses rather than crystals.
• One of the most potent materials is the borate ion either as boric acid, or tetraborate salts of sodium or potassium. This probably forms a network complex with mannitol or even a covalent compound, sodium mannitoborate.
• the quality of the glasses made by this process is high.
• the glass transition temperature (Tg) of 1 :1 w/w mannitol/calcium lactate glass is around 68°C ( Figure 1). This compares with a Tg of around 90°C for a trehalose/sodium sulphate glass dried under the same conditions ( Figure 2). Both types of glass have Tg's well above any possible ambient storage temperature and, because the glasses are chemically inert and non-reactive, the entrapped products are stable at room temperatures and require no refrigeration of any kind.
• Figure 1 shows differential scanning calorimetry of a 50 / 50 w/w mannitol / calcium lactate glass showing a clear glass transition at a temperature of 68 °C;
• Figure 2 shows differential scanning calorimetry of a 50 / 50 w/w trehalose / calcium lactate glass showing a clear glass transition at a temperature of 90 °C;
• Figure 3 shows the percentage recovery of alkaline phosphatase activity after vacuum- drying in either trehalose or formula 7 containing mannitol, inositol, galactitol and degraded gelatin (Byco C) followed by storage at 37°C or 50°C for up to 6 weeks. There is no loss with formula 7 but serious losses with trehalose;
• Figure 4 shows the percentage recovery of alkaline phosphatase activity after freeze-drying in either trehalose or formula 7 containing mannitol, inositol, galactitol and degraded gelatin (Byco C) followed by storage at 37°C or 50°C for up to 7 weeks. There is little loss with either stabiliser;
• Figure 5 shows the percentage recovery of Erythropoietin (EPO) after vacuum-drying in either trehalose or formula 8 containing mannitol, inositol, galactitol and calcium lactate followed by storage at 37°C or 50°C for up to 6 weeks. While there is serious losses with trehalose, no loss occurs with formula 8; and
• Figure 6 shows the percentage recovery of EPO after freeze-drying in either trehalose or formula 7 containing mannitol, Inositol, galactitol and degraded gelatin (Byco C) or formula 8 in which calcium lactate was substituted for the gelatin. After storage at 37°C or 50°C for 7 weeks, there is no loss with any of the stabilising formulations.
• Figure 7 shows the percentage recovery of alkaline phosphatase activity after spray drying formula 9 to which had been added insoluble calcium phosphate powder to increase the density of the glass microspheres. After storage at either 37°C or 55°C for up to 90 days there was no significant loss of activity.
• Figure 8 shows the percentage recovery alkaline phosphatase activity after spray drying formula 1 1 to which had been added insoluble barium sulphate powder to increase the density of the glass microspheres. After storage at either 37"C or 55°C for up to 90 days there was again no significant loss of activity.
• a network forming additive such as sodium or potassium tetraborate
• a network forming additive such as sodium or potassium tetraborate
• Affinity purified alkaline phosphatase from bovme intestinal mucosa (Sigma Chemical Co cat No p-8647) was vacuum-d ⁇ ed or freeze-d ⁇ ed m 200 ⁇ l volumes in formulation Number 7 above or in trehalose.
• Vacuum drying was done at a shelf temperature of 40°C and a vacuum of 30- 100 milhtorr for 4 hr The temperature was then ramped gradually to 60°C over 1 hr and the vials were stoppered and removed from the vacuum chamber for high temperature storage trials Freeze-drying was done in a Labconco dryer at an initial shelf temperature of-40°C for 3 hr at a vacuum of 30-100 milhtorr The shelf temperature was then ramped to 0°C at 5°C / mm and held for 1 hr The shelf temperature was then raised to 40°C at 5°C / min and secondary drying was continued for a further 3 hr when the vials were stoppered under vacuum and removed for storage trials
• EPO was vacuum dried or freeze-d ⁇ ed as above in the same solutions and also in a va ⁇ ant of formulation 7 in which calcium lactate was substituted for Byco C (Formula 8), and then subjected to the same stability tests before being assayed by a standard 2-s ⁇ te sandwich Enzyme Immunoassay
• the fluorescent protein R-Phycoeryth ⁇ n was air-dried in trehalose, formula 3 or formula 4 on a hotplate as described in Example 1
• the intensity of fluorescence was gauged visually when illuminated with a UV lamp.
• the material dried in formula 3 was masked by an intense silver autofluorescence from the Byco C while the material dried in formula 4 fluoresced with the characteristic orange colour with apparently undimmished intensity

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• 1999
  • 1999-03-17 EP EP99910516A patent/EP1071465A1/de not_active Withdrawn
  • 1999-03-17 WO PCT/GB1999/000820 patent/WO1999047174A1/en not_active Application Discontinuation
  • 1999-03-17 AU AU29451/99A patent/AU2945199A/en not_active Abandoned

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