MXPA01007576A - Lyophilisates with improved reconstitutibility - Google Patents

Abstract

The present invention relates to lyophilisates with an improved dissolution rate and particle-free reconstitution. This is achieved by additionally heating the filled solutions to temperatures between 30°and 95°C and directly at the freezer dryer.

Description

LYOPHILISATED WITH IMPROVED RECONSTITUTION CAPACITY CAHPO OF THE INVENTION The present invention relates to lyophilizates having an improved rate of dissolution and an improved capacity for reconstitution, and to a process for their preparation. Freeze drying, also known as freeze drying, is a long-known and widely used method for the preservation of certain substances under mild conditions, such as, for example, heat-sensitive foods, or in particular, medicines. In this method, the substances are dried in the frozen state and can be restored to their original state in a particularly easy manner by the addition of water or another solvent. In this method, the first step is, in general, the freezing of the starting materials at temperatures below -70 ° C. The water is subsequently removed from them by sublimation during the drying process, which is carried out in pressure-tight containers (lyophilizers) under a high vacuum, giving the lyophilized substance. Lyophilization is used in particular for the preservation of sensitive medicines, since it is very important in the case of medicinal products, in particular, that REF: 131581 do not change during storage, that is, that its structure does not change, is not re-arranged or even decomposes, which would mean a considerable deterioration with respect to its effectiveness. Efforts have always been made during lyophilization, to incorporate the largest possible amount of the active ingredient in the smallest volume possible. This results in concentrations being used in the vicinity of the saturation concentration of the active ingredient. This is necessary for the economic efficiency of the processes. However, in these cases, the lyophilizate frequently can not be reconstituted in a particulate-free manner after the iodization has been carried out, meaning that parenteral administration is no longer possible. This is attributed to crystals that have formed due to cooling after the saturation solubility has been exceeded. The speed of distribution of the crystals is significantly slower than that of the molecules in the amorphous form. Therefore, the object of the present invention was to provide a process for the preparation of lyophilizates having an improved rate of dissolution and can be reconstructed in a particle-free manner, even if they are dosed close to the saturation concentration. Surprisingly, it has been found that heating the already prepared solution for the lyophilization process, directly in the lyophilizer and the rapid cooling from this elevated temperature to the freezing temperature gives lyophilisates that achieve the desired, advantageous properties. Therefore, the invention relates to a process for the preparation of lyophilisates having an improved rate of dissolution, characterized in that the corresponding solutions already removed for lyophilization, which have been previously heated, if necessary, in order to accelerate the solution of the substance, have been filtered, optionally filtered sterile, and have been removed, re-heated from 30 ° to 95 ° C, directly in the bottles in the lyophilizer, and the freezing phase is then carried out rapidly from this elevated temperature at the low lyophilization temperature, desired. The characteristic "quickly" in this respect means a period of 10 minutes to 4 hours, preferably from 30 minutes to 2 hours, very particularly preferably from 30 minutes to 1 hour. The desired lyophilization temperature can be lowered to less than -70 ° C, with a temperature of about -50 ° C being preferred. In the conventional lyophilization process, the substance or active ingredient is heated in order to accelerate the dissolution. The dissolution is followed, in the case of sterile preparation, which is unusual in the case of medications, by the steps of sterile filtration and withdrawal. These two steps, depending on the size of the lot, can take a few hours. In the process, the solutions are automatically cooled to room temperature. The lyophilizer is then charged at room temperature, and the freezing phase is then carried out as rapidly as possible from room temperature to about -50 ° C. The drying phase in the lyophilizer then begins. In the process according to the invention, the dissolution, filtration or sterile filtration and removal are carried out analogously to the known process. Then, however, the lyophilizer is loaded with the prepared bottles, corresponding to room temperature, and these bottles are re-heated to 30 ° C - 95 ° C in the apparatus. The freezing phase starts from this elevated temperature and is set at the desired freezing temperature as quickly as possible. The drying phase is then carried out in a usual manner.

Due to the re-heating of the solutions, the saturation solubility is significantly increased, which is attributable to the reduction in the size of the water groupings. The increased solubility thus results in improved hydration. In the case of rapid cooling, water molecules first lack the time to form relatively large clusters, and second the active ingredient molecules lack time to rearrange themselves into crystalline cores. The resulting product is therefore amorphous and can be reconstituted in a particle-free manner. The heating of the solutions takes place at temperatures from 30 ° to 95 ° C, the temperatures in the range of 30 ° to 70 ° C being selected preferentially. The process according to the invention thus allows for significantly higher concentrations to be introduced into a volume. The drying time is reduced in this way and the economic efficiency of the process is increased. Lyophilizates prepared in this manner exhibit an improved rate of dissolution and can be reconstituted in a particle-free manner although they can be dosed close to the saturation concentration.

The invention also relates to the preparation of lyophilizates of the methanesulfonate substance of 2-methyl-5-methylsulfonyl-4- (1-pyrrolyl) benzoylguanidine by the process described herein (see Example 1). This substance (EMD 96785), which is known, for example, from DE 4430861, is an NHE inhibitor that blocks the Na + / H + ion pump in myocardial cells. This prevents the over-acidification of the cells in the case of an infarction, which results in the death of the myocardial tissue. The invention also relates to the preparation of lyophilizates of the hydrochloride substance of N- [2-methyl-4,5-bis (methylsulfonyl) benzoylguanidine by the process described herein (see Example 2). This substance (EMD 87580), which is known, for example from EO 0 758 644 Al, is probably an inhibitor of NHE that blocks the Na + / H + ion pump in the myocardial cells. This prevents over-acidification of the cells during a heart attack, which results in the death of the myocardial tissue. The invention also relates to the preparation of lyophilizates of the methanesulfonate substance of 4-isopropyl-3-methylsulfonyl-benzoylguanidine by the process described herein. This substance (cariporide) which is known, for example, from EP 589 336, is probably an inhibitor of NHE. Additionally, the invention relates to pharmaceutical preparations comprising at least one lyophilizate according to the invention. The pharmaceutical preparations can be used as drugs in humans in human and veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example, oral), parenteral or topical administration and do not react with lyophilizates, for example, water, vegetable oils, benzylic alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc or petrolatum. Suitable for oral administration are in particular tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, are suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, preferably solutions based in oil or aqueous, additionally, suspensions, emulsions or implants and suitable for topical application are ointments, creams or powders. The stated preparations may have been sterilized and / or comprise auxiliaries, such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, colorants, flavors and / or a plurality of additional active ingredients. , for example, one or more vitamins. The preparations preferably comprise lyophilizates, for example, for the preparation of injection preparations. Even without additional details, it is assumed that a person skilled in the art can use the above description in the broadest scope. The preferred modalities, therefore, will only be considered as a descriptive description, but in no way as a description that is limiting in some way. The complete content of the description of all the applications and publications mentioned above and subsequently incorporated in this application by way of reference.

Example 1 100 mg of methanesulfonate of 2-methyl-5-methylsulfonyl-4- (1-pyrrolyl) benzoylguanidine (an inhibitor of NHE) were dissolved in 20 ml of water upon heating to 40 ° C in order to accelerate the dissolution. The solution was subsequently sterile filtered and withdrawn in bottles suitable for lyophilization. In the process, the solution was cooled to room temperature. The lyophilizer was charged with the bottles at room temperature and these bottles were subsequently re-heated to about 50 ° C. The freezing was then carried out from + 50 ° C to -50 ° C in the space of 1 hour. The drying phase then proceeds in a conventional manner. The resulting lyophilizates are amorphous and can be reconstituted in a particle-free manner. b) Comparative Example 100 mg of methanesulfonate of 2-methyl-5-methylsulfonyl-4- (1-pyrrolyl) benzoylguanidine in 20 ml of water are again dissolved with stirring at 40 ° C. The solution is sterile filtered and removed, during which the solution is cooled to room temperature. The bottles are then cooled from room temperature to -50 ° C during the course of 1 hour in the lyophilizer and frozen. In this conventional process, crystal formation occurs even during lyophilization, which results in lyophilisates not dissolving completely during reconstitution. In order to obtain a lyophilizate comparable to a), the concentration here has to be reduced to 50 mg / 20 ml. However, this means that a higher concentration of the active ingredient can be selected in the process according to the invention and yet lyophilizates having an improved rate of dissolution are obtained.

Example 2: 100 mg of N- [2-methyl-4,5-bis (methylsulfonyl)] benzoylguanidine hydrochloride is dissolved in 10 ml of water upon heating to 40 ° C. The solution is subsequently sterile filtered and removed in vials or ampoules suitable for lyophilization. The solution is cooled to room temperature of the process. The lyophilizer is cooled to -59 ° C. The bottles filled with the solution are heated to + 40 ° C in a drying cabinet and subsequently introduced as a lyophilizer, which has already cooled down to -50 ° C. The solution freezes as quickly as possible. The drying phase is then carried out in a conventional manner. It is also possible to heat the bottles in the lyophilizer followed by cooling (as described in Example 1). It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Claims (9)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A process for the preparation of lyophilisates having an improved rate of dissolution, characterized in that the corresponding solutions already removed for lyophilization have been heated , previously, if necessary, in order to accelerate the dissolution of the substance, it has been filtered, optionally filtered in a sterile manner and has been removed, re-heated from 30 ° to 90 ° C directly in the bottles in the lyophilizer, the freezing phase is then carried out rapidly from this elevated temperature at the low lyophilization temperature, desired.
2. 2. The process according to claim 1, characterized in that the bottles containing the solutions are heated from 30 ° to 60 ° C in the lyophilizer.
3. 3. The process according to claim 1 or 2, characterized in that the lyophilizates are obtained which can be reconstituted in a particle-free manner.
4. The process according to one of claims 1 or 3, characterized in that the lyophilizates of the methanesulfonate substance of 2-methyl-5-methylsulfonyl-4- (1-pyrrolyl) benzoylguanidine, N- [2] hydrochloride are prepared. -methyl-4, 5-bis- (methylsulfonyl) benzoyl] guanidine or 4-isopropyl-3-methylsulfonyl-benzoylguanidine methanesulfonate.
5. 5. Lyophilisates having an improved rate of dissolution, characterized in that, in the preparation of the lyophilisates, the corresponding solutions already removed for lyophilization, which, if necessary, have been previously heated in order to accelerate the dissolution of the substance, have been filtered or filtered sterile and have been removed, re-heated from 30 ° to 95 ° C directly in the bottles in the lyophilizer, and the freezing phase is then carried out rapidly from this temperature elevated at the low lyophilization temperature, desired.
6. 6. The lyophilizates of the methanesulfonate substance of 2-methyl-5-methylsulfonyl-4- (1-pyrrolyl) benzoylguanidine having an improved reconstitution capacity, characterized in that, in the preparation of the lyophilisates, the corresponding solutions already removed for lyophilization, which have been heated, if necessary, previously, in order to accelerate the dissolution of the substance, have been filtered, or have been filtered in a sterile manner and have been removed, re-heated from 30 ° to 95 ° C, directly in the lyophilizer bottles, and the freezing phase is then carried out rapidly from this elevated temperature at the low lyophilization temperature, desired.
7. 7. The lyophilizates of the substance N- [2-methyl-4,5-bis (methylsulfonyl) benzoyl] guanidine hydrochloride which have an improved reconstitution capacity, characterized in that, in the preparation of the lyophilisates, the corresponding solutions already withdrawals for lyophilization, which have been heated, if necessary, in advance to accelerate the dissolution of the substance, have been filtered, or have been filtered sterile and have been removed, re-heated from 30 ° to 95 ° C, directly in the lyophilizer bottles, and the freezing phase is then carried out rapidly from this elevated temperature at the low lyophilization temperature, desired.
8. 8. The lyophilisates of the substance methanesulfonate of 4-isopropyl-3-methylsulfonyl-benzoylguanidine having an improved reconstitution capacity, characterized in that, in the preparation of the lyophilisates, the corresponding solutions already removed for lyophilization, which have been heated , if necessary, previously, in order to accelerate the dissolution of the substance, have been filtered, or have been filtered in a sterile manner and have been removed, re-heated from 30 ° to 95 ° C, directly in the bottles of lyophilizer, and the freezing phase is then carried out rapidly from this elevated temperature at the low lyophilization temperature, desired.
9. 9. The pharmaceutical preparation characterized in that it comprises at least one lyophilizate according to claims 5-8. LYOPHILISATED WITH IMPROVED RECONSTITUTION CAPACITY SUMMARY OF THE INVENTION The present invention relates to lyophilizates having an improved dissolution rate that can be reconstituted in a particle-free manner, which is achieved by re-heating solutions already removed from 30 ° to 95 ° C directly in the lyophilizer