Improved sterile injectable formulations and a method for their prpeartion

Abstract

A method of preparing parenterally administered formulations including a reduced amount of the added preservative chlorocresol is disclosed. In an embodiment a method of preparing a formulation of trace elements supplemented with Vitamin B12 is disclosed. 7 20 25 20 00 67 06 J an 2 02 5 A B S T R A C T 2 0 2 5 2 0 0 0 6 7 0 6 J a n 2 0 2 5 w i t h V i t a m i n B 1 2 i s d i s c l o s e d . 7

Description

The injectable formulation is prepared according to the manufacturing flowchart provided as Figure 1. According to the manufacturing specification a 100L batch of injectable formulation consisting of the following quantities of ingredients is prepared: Ingredient               Quantity (Kg) Disodium zinc EDTA                   26.144* Disodium manganese EDTA              7.576* Disodium copper EDTA                 9.934* Sodium selenite                       1.101* Cyanocobalamin (Vitamin B12)          1.51** Chlorocresol                          0.100 Hydrochloric acid              Quantum satis to pH Sodium Hydroxide               Quantum satis to pH Water for Injection          Quantum satis to volume Quantities marked with a single asterisk are adjusted according to the supplier's specification for the ingredient. The quantity marked with a double asterisk is a 7.5% (w / v) overage of cyanocobalamin with the quantity adjusted according to the supplier's specification. A volume of water for injection corresponding to 60% (v / v) of the total batch volume, i.e., 60 L for a batch volume of 100 L, is loaded into a first vessel. The batch quantity of chlorocresol is weighed and added to the volume loaded into the first vessel and mixed until completely dissolved. The batch quantity of disodium zinc EDTA is weighed and added to the volume loaded into the first vessel and mixed until completely dissolved. The batch quantity of sodium selenide is weighed and added to the volume loaded into the first vessel and mixed until completely dissolved. The batch quantity of disodium manganese EDTA is weighed and added to the volume loaded into the first vessel and mixed until completely dissolved. The batch quantity of disodium copper EDTA is weighed and added to the volume loaded into the first vessel and mixed until completely dissolved. The volume is maintained at near ambient temperature (without heating to aid dissolution) throughout each of the foregoing addition steps. A volume of water for injection equating to 7.5% (v / v) of the total batch volume is loaded into a second vessel and heated to a temperature of approximately 55 °C. The batch quantity of cyanocobalamin (Vitamin B12) is weighed and added to the heated volume in the second vessel and mixed until completely dissolved. Without cooling, the volumes in the first and second vessels are combined. The ratio of the volumes has been selected to ensure the temperature of the combined volume does not exceed 35°C thereby minimising the potential loss of chlorocresol by volatilization and minimising the required overage. The combined volume is mixed and made up to 97% of the total batch volume by the addition of a further volume of water for injection. The pH of the resulting volume is checked and adjusted to a pH in the range 5.1 to 5.6 using concentrated hydrochloric acid or sodium hydroxide solution. The pH adjusted volume is then made up to the final batch volume with water for injection, mixed well, and the pH of the solution reconfirmed to be in the required range of 5.1 to 5.6. This final batch volume is then filter sterilised (0.2 pm sterilisation grade filter), aliquots dispensed into sterile flexi-packs, closed with sterile rubber stoppers, and sealed by crimping with sterile aluminium seals. The filled and sealed sterile flexi-packs are then packaged with directions for the subcutaneous administration to cattle. Although the invention has been described with reference to embodiments or examples it should be appreciated that variations and modifications may be made to these embodiments or examples without departing from the scope of the invention. Where known equivalents exist to specified elements, features, integers, or other limitations, of the matter described in the Summary of Invention, such equivalents are incorporated as if specifically referred to in this specification. Variations and modifications to the embodiments or examples that include elements, features, integers, or other limitations, disclosed in and selected from the referenced publications are within the scope of the invention unless specifically disclaimed. The advantages provided by the invention and discussed in the description included in this specification may be provided in the alternative or in combination in these different embodiments of the invention. INDUSTRIAL APPLICABILITY A method for the preparation of injectable formulations is described. REFERENCED PUBLICATIONS Ainley et al (1977) Adverse reaction to chlorocresol-preserved heparin [letter] Lancet i: 705. Hancock and Naysmith (1975) Hypersensitivity to chlorocresol-preserved heparin Br Med J. 3: 746-747. Smolinske (1992) Handbook of food, drug and cosmetic excipients Boca Raton, FL: CRC Press, 87-90.

Claims

2025200067   06 Jan 20251) A method of preparing an injectable formulation requiring the addition of no more than 0.10% (w / v) of chlorocresol comprising the combining of a first volume of chlorocresol in solution in water with a second volume of vitamin B12 in solution in water, where the temperature of the first volume is in the range 18 to 25°C, the temperature of the second volume is in the range 50 to 60°C, and the ratio of the first volume to the second volume is in the range 7 to 9.2) The method of claim 1 where the first volume additionally comprises trace elements in solution.3)   The method of claim 2 where the trace elements are a combination of twoor more trace elements selected from the group consisting of copper,manganese, zinc and selenium.4)   The method of claim 3 where the formulation comprises 15 g / L copper, 10g / L manganese, 40 g / L zinc, 1.4 g / L vitamin B12 and 5 g / L selenium.5) A product comprising an injectable formulation prepared according to the method of any one of claims 1 to 4 packaged with directions for the subcutaneous administration to cattle.

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