MXPA06011895A - Liquids containing suspended glass particles. - Google Patents

Abstract

Present proposals to use perfluorocarbons as a medium to suspend glass particles presents the problem of aggregation of the particles within the suspending medium. Overcoming this problem requires careful particle sizing and density matching techniques. An additional disadvantage of the large scale use of perfluorocarbons is their contribution to global warming. The inventor has realised that by replacing perfluorocarbons with the more environmentally friendly fluorinated ethers such as hydrofluoroethers or hydrofluoropolyethers a long lasting suspension of glass particles can be achieved without the need for such rigorous particle sizing or density matching processes.

Description

LIQUIDS CONTAINING SUSPENDED GLASS PARTICLES Field of the Invention This invention relates to a formulation comprising an active ingredient preserved in particles of a glassy or amorphous substance suspended in a liquid. BACKGROUND OF THE INVENTION It is known that sugar crystals have the ability to conserve certain organic, biological, botanical and protein materials and there is a considerable amount of literature devoted to theoretical purposes for the use of this property of sugar crystals to preserve products pharmaceuticals, particularly vaccines. It has been shown that other glassy substances have a similar conservative effect. Because the most commonly accepted method of administering vaccines is by means of injections it has been proposed, e.g. in patent specification WO 02/32402 (Roser) suspend particles of water soluble crystals, containing the vaccine, in a liquid (a perfluorocarbon such as perfluorodecalin) as well as the creation of an injectable formulation. Perfluorocarbons were proposed because they are very stable and are known to be safe for pharmaceutical and medical uses. It was also proposed in the specification of the - PCT patent WO 02/32402 increase the density of the crystals by the addition of calcium phosphate (density approximately 2.7 to 2.8) to the sugar crystals (density 1.5) in order to produce particles equivalent to the density value of 1.97 of the liquid in which they were suspended; keeping them by this in suspension. The techniques cited above show great promise, but the complete stability of perfluorocarbons means that they are persistent in the troposphere and, if used in large quantities, could actually contribute to global warming. In addition, the hydrophilic glass microsphere particles show a slight tendency to agglomerate in perfluorocarbons, which are intensely hydrophobic. SUMMARY OF THE INVENTION According to this invention there is provided a formulation comprising an active ingredient preserved in crystalline or amorphous particles, the particles being suspended in a liquid in which at least one component comprises a hydrofluoroether, perfluoroether, hydrofluoroamine, perfluoroamine, hydrofluorothioether , perfluorothioether, hydrofluoropolyether, perfluoropolyether or a general formula R1-X-R2 or RI-X- (CF2Y) n (CF2CF2Z) m-R2 O - - R1 - [(X-CF-R2) N- (X-CF2) m] 0R3 where x, y, and z are defined as 0 (oxygen), an ether, NR3 (N = nitrogen), an amine or S ( sulfur); and each of R1, R2 and R3 are defined as a non-fluorinated, partially fluorinated or fully fluorinated alkyl, cycloalkyl, aryl or arylalkyl group or an organic functional group, a halogen group or a cyano group. Preferably the hydrofluoroethers or hydrofluoropolyethers are considered ideal and accordingly a formulation comprising an active ingredient preserved in crystalline or amorphous particles is provided, the particles being suspended in a liquid comprising a hydrofluoroether or a hydrofluoropolyether. The inventors discovered that when the mixed glass particles were added to a hydrofluoroether or hydrofluoropolyether they dispersed surprisingly easily to form a milky suspension with little or no signal of aggregation of crystalline particles even after the suspension was left for a while. The inventors have now developed the theory that glass particles have a hydrophilic surface, whereas previously used perfluorocarbons are intensely hydrophobic. For this reason, it is now believed that in the first experiments with - - perfluorocarbons, the glass particles had the tendency to aggregate with each other, because they are repelled by the hydrophobic nature of the perfluorocarbon. The fluorinated ethers, they behave a little more similar to a detergent, facilitating the dispersion of the particles. A variety of fluorinated ethers are currently being administered -co or anesthetic agents through inhalation during surgical procedures. The relatively large amounts (up to 200 gms.) That are used during surgical procedures indicate the low toxicity of the group. In addition their densities are ideally matched to the densities of the crystals used in the formulations described above. For example, with reference to the designations of 3M Limited: HFE 7500 has a density of 1.61 HFE 7200 has a density of 1.43 HFE 7100 has a density of 1.52 These values are coincidentally similar to the density of the sugar crystals, which is approximately 1.5. An additional benefit of the use of the invention is that fluorinated ethers, although highly stable under normal conditions, are unstable when They expose to strong ultraviolet radiation as it occurs in the stratosphere. This avoids the problem associated with perfluorocarbons which are known to contribute to the damaging "greenhouse" effect that is released into the atmosphere after being used. Still another advantage of the invention is that the fluorinated ethers are relatively inexpensive and are readily available in a high degree of purity, greater than 98%. This is compared to PFCS for which a typical example may have a purity of only about 55%. Because the fluorinated ethers also match the crystals, it has been possible to adopt a new procedure to equalize the density. Previously, the crystal was formulated, through the use of additives, to equalize its density to that of the liquid PFC. However, it now becomes unnecessary to constrain the selection of the crystal accordingly to the need to achieve the correct density. The invention makes it possible to select the ideal composition of the crystal / active ingredient; and then mixing a fluorinated ether possibly with the addition of small amounts of PFCs or other liquids in order to equalize the density of the liquid to the density of the particles. It has even become possible to easily take compositions made of active ingredients preserved in a crystalline substance; to grind it into particles and then suspend it - in a liquid equal to the density of the particles. The densities of the particles and the liquid do not have to be identical. However, they should be close enough to the Brownian movement or other thermodynamic influences to keep the particles in suspension. Because the particles have been found to effectively disperse effectively in fluorinated ethers and other liquids cited above, the need to make the particles as small as possible, in order to maintain the suspension, is not as important as it is now. It was previously. The specialists modified the spray drying techniques, which previously the inventors thought were necessary to achieve small particle sizes, are now unnecessary although the standard commercial spray drying process is still a possible technique for making the particles. However, alternative methods such as freeze or ground drying would now also be practicable. It is only necessary that the particles are small enough to allow passage through a hypodermic syringe. It is envisioned that the invention will normally be employed for the formulation of vaccines, therapeutic proteins or other medications for injection through the skin of the patient. - patient However, other uses of the invention may be possible, e.g. for medicinal fluids that are administered orally or inhaled after being sprayed. It is also possible that there may be non-medicinal uses for the invention, which is generally applicable to any situation where it is desired to preserve a biologically active material in a crystalline solid and where there is a need for the composition to be present in liquid form. DETAILED DESCRIPTION OF THE INVENTION One way of carrying out the invention will be described below. A sterile, liquid Hepatitis B vaccine in volume with aluminum hydroxide adjuvant was obtained from Panacea Biotech de Deli. This was mixed with a suspension of sterile colloidal calcium phosphate and a raffinose solution in the correct proportions to give a single adult dose of 10 ug vaccine in 50 mg of total solids. The ratio of calcium phosphate to raffinose was calculated to give solid crystalline particles with a density equal to that of hydrofluoroether HFE 7,500 of 1.61 Kg / L. While being constantly stirred by a magnetic stirrer, this suspension was pumped through a two fluid nozzle in the proportion of 2 ml. per minute with a gas flow nozzle of 2.5 Kg / hr. The resulting droplets were dried in the chamber of a GEA Niro SD Micro sprinkler with a Hot air flow of 30 Kg per hour. The outlet temperature was maintained at 90 ° C when regulating the inlet temperature, keeping the feed flow rate constant. The product was collected in a sterile bottle and transferred to a laminar flow hood with class 100 air fluid. The sterile HFE of 7,500 was added at the rate of 1 ml. per 100 mg. of powder and stirred in an ultrasonic sweep bath of 10 minutes frequency to completely disperse the microspheres. In the flow hood, the liquid was distributed in 0.6 ml volumes into sterile 2 ml serum vials. , covered with neoprene caps and sealed with aluminum caps. The vaccine vials were used to establish a study of the in vitro stability of the vaccine at various storage temperatures.

Claims (1)

1. CLAIMS 1. A formulation comprising an active ingredient preserved in crystalline or amorphous particles, the particles being suspended in a liquid in which at least one component comprises a hydrofluoroether, perfluoroether, hydrofluoroamine, perfluoroamine, hydrofluorothioether, perfluorothioether, hydrofluoropolyether, perfluoropolyether or a formula general R1-X-R2 or R1-X- (CF2Y) n (CF2CF2Z) m-R2 or R1- [(X-CF-R2) n- (X-CF2) m] 0R3 wherein x, y, yz is define as O (oxygen), an ether, NR3 (N = nitrogen), an amine or S (sulfur); and each of R1, R2 and R3 are defined as a non-fluorinated, partially fluorinated or fully fluorinated alkyl, cycloalkyl, aryl or arylalkyl group or an organic functional group, a halogen group or a cyano group. 2. A formulation according to claim 1, wherein the particles contain a crystal of sugar or a crystal which is a mixture of sugar, metal carboxylate, amino acid and calcium phosphate or any combination thereof. 3. A formulation according to claim 1 or 2 wherein the particles have a density that is equal to the density of the liquid - sufficiently close to the particles that will remain in suspension under normal conditions. . A formulation according to any of the preceding claims in which the liquid contains different components specified in claim 1 mixed in proportions to give the required density. A formulation according to any of the preceding claims wherein the liquid contains a perfluorocarbon mixed with one or more components specified in claim 1. 6. A formulation according to any preceding claim wherein the active ingredient is a vaccine. 7. A formulation according to any of the preceding claim wherein the particles are made by spray drying. 8. A formulation according to any of claims 1 to 6 wherein the particles are made by freeze drying. 9. A formulation according to any of claims 1 to 6 in which the particles are processed by grinding. 10. A method for making a formulation according to claim 4 which includes the step of select the liquids to give the required density equalization properties and mix them with the particles. 11. A formulation comprising an active ingredient preserved in crystalline or amorphous particles, the particles being suspended in a liquid comprising a hydrofluoroether.