A method of preparing a freeze-dried formulation containing a drug

Abstract: In a freeze-drying method for producing a dried pharmaceutical compound or preparation, a first liquid is frozen, a second liquid is added to the frozen first liquid and is frozen thereon, and the frozen first and second liquids are freeze-dried together, in which at least one of said first and second liquids contains said pharmaceutical compound or preparation dissolved or suspended therein. The other liquid or liquids may be pure solvent (generally water) or may contain one or more other substances.

Description: The present invention relates to a method of preparing a freeze-dried (or "lyophilized") formulation containing a drug or a mixture of drugs, which enables the freeze-drying technique to be used even in many cases where freeze-drying has hitherto not been practical. Preparation of dried formulations by freeze-drying has been widely used for a variety of pharmaceutical compositions, and much research has been carried out in an attempt to determine how various problems associated with the technique may be overcome. A general review of the freeze-drying techniques used for pharmaceuticals may be found in "The Lyophilization of Pharmaceuticals: A Literature Review" by N. A. Williams and G. P. Polli, J. Parenteral Science and Technology, 38 , 48 - 55 (1976). Other specific techniques or processes for freeze-drying specific drugs are disclosed in Japanese Patent Application Kokai No. 68412/1986, J. Parenteral Science and Technology, 42 , 47 - 52 (1988) and European Patent Application No. 211 257. In essence, freeze-drying consists of at least two steps: 1. Freezing a solution or suspension (almost invariably aqueous) of the material to be freeze-dried; and 2. Raising the temperature of the frozen material so that the frozen solvent (almost invariably ice) sublimes without melting. Freeze-dried formulations are often mixtures of two or more active ingredients, and various other components (such as vehicles, stabilizers, isotonic agents, etc.) other than the active ingredients may be added in many cases. However, the eutectic temperature of the system during freezing changes with the nature of the additives, and, in particular, the addition of an inorganic substance will often markedly lower the eutectic point [Arimoto et al , "Journal of The Research Society of Freezing and Drying", 22 , 48 - 55 (1976)]. Also, if the aqueous solution of a principal drug has a low eutectic point, further lowering of the eutectic point may sometimes occur as a result of the inclusion of additives [Arimoto et al , "Journal of The Research Society of Freezing and Drying", 22 , 48 - 55 (1976)]. In general, a freeze-dried composition can be prepared by freeze-drying the frozen composition at a product temperature not higher than the eutectic point, and this will give a freeze-dried product having a good appearance (N. A. Williams et al , op. cit. ), but the appearance of the freeze-dried product becomes less desirable, and it may even appear syrupy, if the freeze-drying is carried out at a temperature higher than the eutectic point [Koji Ito et al , Farumashia, 5 , 99 (1969)], which can markedly impair its commercial value, and may, in practice, render it useless. In practice, however, in order to increase the freeze-drying speed, it is desirable that the drying shelf temperature (and hence the product temperature) should be set at as high a temperature as possible. However, when the solution to be dried contains several different kinds of solute components, because this lowers the eutectic point, it is not easy to increase the drying temperature by very much. Accordingly, freeze-drying of a drug having a low eutectic point has to be carried out at a low temperature, but this means that the primary drying process must be effected for a long time, which adversely affects the economics of the freeze-drying process. Various contrivances have been proposed in order to increase the speed of freeze-drying in cases of this sort. For example, the drying speed may be considerably increased by increasing the size of the frozen ice crystals by performing certain specific types of thermal treatment during freezing [see, for example, Japanese Patent Application Kokai No. 68412/1986, and J. Parenteral Science and Technology, 42 , 47 - 52 (1988)]. Another way of increasing the speed of freeze-drying is to increase the surface area available for evaporation of moisture. In the case of a drug, where the freeze-drying normally takes place in the vial in which the drug is to be sold (for improved sterility), this may be achieved by freezing over the wall surface of the vial, with the vial containing the liquid to be freeze-dried being kept horizontal to increase the surface area and by using any of several techniques, for example: by using an Automatic shell-freezer model (Virtis); by freezing to the wall surface of the vial whilst subjecting it to high speed rotation, e.g. using a Centrifugal freeze dryer model EF6 (Edwards); or by freezing and drying to form granules by adding the aqueous solution to be freeze-dried dropwise to a very cold refrigerant fluid (e.g. a fluorocarbon) or to liquid nitrogen, e.g. as described in Japanese Patent Application Kokai No. 29513/1987. However, although low temperature drying may be achieved by the methods described above, the appearance of the dried product is frequently less than desirable or a partially syrupy dried product may be obtained. The product referred to herein as "syrupy" is a product in which a small amount of water remains, so that some part of it may resemble a syrup or a gum. GB-A-0797774 discloses a method for producing layered pharmaceutical compositions which comprises freezing a first liquid, freezing a second liquid on the first liquid and then freeze-drying the resulting product. FR-A-2109201 discloses a process of lyophilisation of fine-flake frozen liquid products by sublimation of said flakes in a stirred bed in a chamber. It can be seen from the above discussion that it is desirable to shorten the drying time of freeze-dried preparations, in order to reduce the production cost, in order to give a high quality preparation, and in order to improve the appearance of the freeze-dried product. In particular in the case of the mass production of pharmaceuticals, for which sterile operation is required, these problems must be overcome. We have now discovered a new and improved freeze-drying process, which, when carried out in accordance with the preferred embodiments described herein, enables the above disadvantages of the prior art processes to be overcome. In accordance with the present invention, there is provided a method of preparing a freeze-dried formulation comprising the following steps in the following order: (i) freezing an aqueous solution of N -benzoyl-β-alanine at -40°C for 60 minutes to form a frozen first layer; (ii) cooling a second aqueous solution of (5R,6S,8R)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid to 5°C, then adding it onto the frozen first layer and refreezing at -40°C for 60 minutes to form a frozen second layer; (iii) raising the temperature of the two-layer frozen product to 10°C, over a period of time of 3 hours, and then conducting primary drying at 10°C for 24 hours; and (iv) raising the temperature to 50°C over a period of time of 3 hours, and then conducting secondary drying at 50°C for 10 hours. The freeze-drying process of the present invention is normally carried out in a container, which, for convenience is normally and preferably the same container as the material is to be supplied in, normally a vial or similar medical container. However, the nature of the container is of no relevance to the present invention and the container may be chosen having due regard to the usual considerations employed in conventional freeze-drying processes. Freezing may be carried out by charging an appropriate amount of the first aqueous solution into the container to be used for freeze-drying, such as vial or the like, and freezing it, which may be by any known method, for example in a freezer or a freeze-drier or by dipping it in a refrigerant such as acetone/dry ice or liquid nitrogen. After adding the second layer, this is then frozen, which may be achieved by any known method, for example by any of the methods suggested above for freezing the first layer or simply by conventional means used in ordinary freeze-drying processes. There is no need to use any particular freezing technique or temperature for the second layer, and it is possible to use merely those techniques and temperatures which are conventional for freeze-drying. There is no particular restriction on the amount of liquid added and frozen for each layer, and this will clearly depend on the amount of the drug or other material which it is desired to include, as well as upon its concentration in the respective solution. In practice, because of the required time for drying (which will depend also on the bottom area of the container, such as the vial, to be used), the total thickness of the frozen layers is preferably 40 mm or less. Hence, the maximum thickness of each layer should preferably be so chosen that the total thickness does not exceed 40 mm. The minimum thickness, on the other hand, depends on the amount of material to be used, its concentration in the solution and the practical difficulty of adding accurately small amounts of liquid. In general, we prefer that the minimum thickness of each layer should be 1 mm, and it is preferably not less than 2 mm. The freeze-dried preparation after the primary drying and secondary drying steps clearly shows the appearance of two or more fractionated layers. Generally speaking, the appearance of the freezedried products obtained in accordance with the present invention was found to be good. The invention is further illustrated by the following Example. EXAMPLE 1 Preparation of a freeze-dried drug which can usually be dried only with difficulty 5 ml of a 10% w/v aqueous solution of N -benzoylöalanine (an adjuvant) (exhibiting a eutectic point of -36° C) was charged into a 20 ml vial, and frozen in a freezing chamber at -40°C for 60 minutes to form a lower layer. Separately, 5 ml of a 10% w/v aqueous solution of (5 R , 6 S , 8 R )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid (the main drug, an antibiotic) was cooled to 5°C, and this cooled solution was then added onto the frozen layer of N -benzoyl-ö-alanine, prepared as above. Immediately, the vial was transferred into a freezedryer and was refrozen sufficiently at -40°C for 60 minutes to obtain a two layer frozen product. The temperature was then raised to 10°C over a period of 3 hours, and primary drying was conducted at 10°C for 24 hours. Subsequently, the temperature was raised to 50°C over 3 hours, and secondary drying was conducted at 50°C for 10 hours. The resulting freeze-dried preparation had a good appearance. On the other hand, as a Control, separately 5 ml of a 10% w/v aqueous solution of N -benzoyl-ö-alanine and 5 ml of a 10% w/v aqueous solution of (5 R , 6 S , 8 R )-2- [(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid were combined, and the total of 10 ml was charged into a 20 ml vial. After freezing the mixture in a freeze-dryer at -40°C for 60 minutes, the temperature was raised to 10°C over a period of 3 hours and primary drying was conducted at 10°C. However, it took 64 hours before the drying was complete. Subsequently, after the temperature had been raised to 50°C over a period of 3 hours, secondary drying was conducted at 50°C for 10 hours, but it was not possible to obtain a freeze-dried preparation having a good appearance. These preparations and a powdery divided product (prepared by simple mixing of the two components) were subjected to comparative evaluations. The results are shown in Table 1. As is apparent from Table 1, the time required for freeze-drying, the appearance of the dried product and the stability over time (residual percentage of main drug) for the product produced in accordance with the double layer freezing process of the present invention were found to be much better than the values for those produced by the mixing method (Control). Also, the stability over time (main drug residual percentage) of the dried product produced in accordance with the process of the present invention was found to be much better than those of the powdery divided product (Control). Freeze-drying Stability Required time Appearance of dried product (main drug residual percentage at 40°C for 6 months) Double layer freeze-dried product 40 Hr Good 97% Mixing freeze-dried product (Control) 80 Hr Syrupy at bottom 93% Powdery divided product (Control) - - 88%

Claims: A method of preparing a freeze-dried formulation containing a drug comprising the following steps in the following order: (i) freezing an aqueous solution of N -benzoyl-β-alanine at -40°C for 60 minutes to form a frozen first layer; (ii) cooling a second aqueous solution of (5R,6S,8R)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid to 5°C, then adding it onto the frozen first layer and refreezing at -40°C for 60 minutes to form a frozen second layer; (iii) raising the temperature of the two-layer frozen product to 10°C, over a period of time of 3 hours, and then conducting primary drying at 10°C for 24 hours; and (iv) raising the temperature to 50°C over a period of time of 3 hours, and then conducting secondary drying at 50°C for 10 hours.

Inventors: HASHI KUNIO, KUSAI AKIRA, SHIOKARI TAKASHI, UEDA SEIGO, HASHI, KUNIO, KUSAI, AKIRA, SHIOKARI, TAKASHI, UEDA, SEIGO, HASHI, KUNIO, C/O SANKYO COMPANY LIMITED, KUSAI, AKIRA, C/O SANKYO COMPANY LIMITED, SHIOKARI, TAKASHI, C/O SANKYO COMPANY LIMITED, UEDA, SEIGO, C/O SANKYO COMPANY LIMITED
Applicants: SANKYO CO, SANKYO COMPANY LIMITED
Application year: 1990
Main classification: A61K9
IPC codes: A23L3, F26B5, A61K45, A61K9