MXPA00003413A - Parenteral formulations comprising carbamazepine or its derivatives - Google Patents

Abstract

The invention is concerned with a parenteral formulation comprising a 5H-dibenz(b,f)azepine-5-carboxamide and an aqueous-based solvent. The parenteral formulation is useful in the treatment of seizures resulting from, e.g. epileptic attack.

Description

t ^ t3Mrtt.Ar: tr > ? JF.fi PftPi; wt? R? T, y.fi QTTF: rOM Rpympw CARB? MAZEPINE OR ITS DERIVATIVES This invention relates to parenteral formulations of 5H-dibenz (b, f) azepine-5-carboxamides. 5 H-dibenz (b, f) azepine-5-carboxamides are known anticonvulsants useful in the treatment of attacks resulting from, for example, an epileptic seizure. The oral forms of 5H-dibenz (b, f) azepine-5-carboxyamides are known and are suitable for repeated administration over a prolonged treatment period, in order to ensure a uniform concentration of the active agent in the blood. However, in emergency situations, oral administration to an epileptic patient may not be possible, and in any case, may not provide the immediate response needed. Accordingly, there is a need to develop parenteral formulations, in particular that are suitable for intravenous use, of an anticonvulsant, based on 5H-dibenz (b, f) azepine-5-carboxamides. It has now been discovered that 5H-dibenz (b, f) azepine-5-carboxamides can be formulated as a parenteral formulation in water, optionally with an organic co-solvent. The invention provides, in one of its aspects, a parenteral formulation comprising, as an active agent, a 5H-dibenz (b, f) azepine-5-carboxamide, and a solvent consisting of water, and optionally an organic co-solvent , and no other solubilization aid. Solubilization aids are understood as any compounds that help to solubilize the drug molecules, by accommodating a drug molecule in a cavity formed in the solubilization aid, to form inclusion complexes. These solubilization aids are in particular cyclodextrins, and more particularly beta-cyclodextrin. The parenteral formulation may be suitable for intravenous administration. The immediate response of this form of administration is highly desirable in emergency situations. In addition, since an absorption process is not involved, the dose or blood concentration of the active agent can be obtained with greater precision and speed. The active agents and the synthesis for the preparation thereof are known in the art. The active agents can be substituted or unsubstituted in the 10 or 11 position. The 10 or 11 position can be substituted with mono- or divalent substituents selected from oxa, halogen, or hydroxyl groups, preferably oxa or hydroxyl groups. When there is an oxa or hydroxy group in the 10-position, the 11-position is preferably unsubstituted, and vice versa.

Preferred compounds are selected from α-carbamazepine (Tegretol), 10-oxacarbazepine (Trileptal), and 10-hydroxy-10,11-tetrahydrocarbamazepine (hereinafter referred to as COMPOUND A). COMPOUND A has a chiral center, and can be used as its racemic mixture. We have now discovered that COMPOUND A, which previously has not been available in a commercial manner, can be formed into a well tolerated and stable, commercially acceptable formulation, for example, from 3 months to 2 or even 3 years, for intravenous administration. Preferred active agents, for example, COMPOUND A, can have a solubility in water of up to 4.5 milligrams / milliliter, preferably 3.2 to 4.2 milligrams / -mililiter, more preferably 2.5 milligrams / milliliter at 25 ° C, and preference at a pH of 4.0 to 7.0. Within these ranges of solubility, the active agents are conveniently formulated without the need for an organic co-solvent or any other solubilization aid. In parenteral formulations suitable for intravenous administration, the solvent for the active agent is water, or is based on water. "Water-based" means a solution consisting of water and a solvent or organic solvents miscible in water. When an organic co-solvent is used, it is preferred that it be used in amounts of up to 10 weight percent, for example 0.5 to 10, and more particularly 1 to 10 weight percent. Suitable solvents are those miscible solvents in water commonly used in the art, for example, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, and ethanol. Preferably, the organic co-solvents are only used in cases where the active agent is not sufficiently soluble in water so that a therapeutically effective amount is provided in a single dosage form. Preferably, the solvent consists exclusively of water. As an alternative, or in addition to the use of an organic co-solvent, it may be useful to employ a solubilization aid, for example, cyclodextrins. Cyclodextrins can be useful solubilization aids when the active agent ® is selected from 10-oxacarbazepine (Trileptal) and the COMPOSITE A. The invention provides, in another of its aspects, a parenteral formulation, for example, a formulation, intravenous, comprising a 5H-dibenz (b, f) azepine-5-carboxamide, for example, COMPOUND A, and a solvent consisting of water. Preferably, parenteral formulations suitable for intravenous administration are formulated to have the same osmotic pressure as the body fluid. Accordingly, a parenteral formulation according to the invention comprises an isotonic agent having the effect of making the osmotic pressure of the formulation equal to that of the body fluid. Accordingly, in another aspect of the invention, a parenteral formulation comprising, as an active agent, a 5H-dibenz (b, f) azepine-5-carboxamide, for example, COMPOUND A, and a solvent is provided. which consists entirely of water, or water and an organic co-solvent, and an isotonic agent. The isotonic agent can be selected from any of those commonly used in the art, for example, mannitol, sodium chloride, dextran, and glucose. As the isotonic agents, sodium chloride and glucose can be mentioned in particular. The isotonic agents can be used in amounts that impart to the parenteral formulation the same osmotic pressure as that of the body fluid. The precise amount necessary to achieve the desired effect may depend on factors such as the concentration of the active agent in the parenteral formulation, and is a matter of routine experimentation that the skilled person can determine without exercising inventive thinking, and using only the common general knowledge. The selection of the isotonic agent is preferably made considering the properties, for example, the stability of the active agent. It has been found that certain isotonic agents, for example, sodium chloride, can promote the formation of degradation products by oxidation of the active agents. This can be particularly problematic when the parenteral formulation is entirely water based, and the degradation product or products of the active agent, for example, of COMPOUND A, are insoluble in water. In order to reduce the possibility of forming degradation products by oxidation, it is preferred that, particularly in the case of wholly water-based solutions, the parenteral formulation be carefully purged of air when packed. However, even when care is taken to purge a filled container of air, high volume parenteral formulations, for example, greater than 100 milliliters, more particularly about 250 milliliters, of an active agent, for example, COMPOSITE A, which comprise sodium chloride as the isotonic agent, can be detected degradation products by oxidation after only relatively short storage periods. Surprisingly, we have found that, in the case of low volume parenteral formulations, for example, of about 100 milliliters or less of active agent, for example, of COMPOUND A, when carefully purging a container filled with nitrogen or other Inert gas, the formation of degradation products by oxidation can be eliminated. When the formulations are carefully purged of oxygen, the content of dissolved oxygen may be less than 2 milligrams / milliliter, for example 1 milligram / milliliter or lower. We have surprisingly found that, even for high volume parenteral formulations of an active agent, for example, of COMPOUND A, by judicious selection of the type and amount of isotonic agent, the formation of degradation products by oxidation can be eliminated. . This may be the case, regardless of whether precaution is taken or not to purge the air system. Preferably, the isotonic agent is glucose. The use of glucose is particularly convenient when the injectable solution is entirely based on water, and the active agent employed, for example, COMPOUND A, can be degraded oxidatively to form a compound highly insoluble in water, which can even be colored. The amount of glucose used will depend on the concentration of the active agent used. In preferred formulations, glucose may be used in amounts up to 5 weight percent, for example, 0.5 to 5 weight percent, based on the weight of the parenteral formulation, more preferably 4.75 weight percent. In a preferred embodiment of the invention, a parenteral formulation comprising an entirely water-based solution of COMPOUND A, and glucose is provided. In the preferred parenteral formulation, COMPOUND A is present in a concentration of 2 to 4.5, more preferably 2 to 3.5, per example of 2.5 milligrams / milliliter. The glucose is preferably present in an amount of up to 5 weight percent, for example, 0.5 to 5 weight percent, based on the weight of the parenteral formulation, and more preferably 4.75 weight percent. The parenteral formulations according to the invention may contain other excipients commonly employed in parenteral formulations for intravenous administration, in order to provide the required stability and therapeutic efficacy. The excipients may include antioxidants and acidifying agents, and any other excipients commonly used in the preparation of parenteral formulations for intravenous administration. Antioxidants can be employed to protect the active agent from oxidative degradation, particularly under accelerated thermal sterilization conditions. The antioxidants can be selected from any of the compounds known in the art. In a similar manner, the amount of antioxidant employed can be determined using only routine experimentation. As an alternative to the use of antioxidant compounds, the antioxidant effect can be achieved by displacing oxygen (air) from contact with the solution of the active agent. This is commonly done by purging, for example, with nitrogen, a container containing the solution. In another aspect of the invention, there is provided a process for the preparation of a parenteral formulation as defined hereinbefore. The process can be performed in a conventional manner employed in the art of making parenteral formulations, for example, intravenous formulations. The process for the preparation of a parenteral formulation can be carried out in an inert container, for example, a stainless steel reactor, optionally under an inert atmosphere, for example nitrogen. The process comprises the step of adding an isotonic agent, for example glucose, optionally in its on-hydrate form, to a water or water-based solution of the active agent, for example of COMPOUND A, and optionally other excipients. Preferably, the reaction vessel is charged with water, or with water and an organic solvent miscible with water, and heated to a temperature of about 80 ° C. The active agent, for example, COMPOUND A, can be added to the solvent at a high temperature with stirring. The isotonic agent can then be added to the solution of the active agent. If glucose is used as the isotonic agent, it is conveniently used in the form of its monohydrate, to aid in solubility. When glucose is used, it can be added to a cooled solution of the active agent, for example, COMPOUND A, in order to avoid any degradation of glucose. Then the resulting formulation can be diluted with water or with the water-based solvent, to bring it to the final volume for injection. The resulting parenteral formulation is preferably kept under an inert atmosphere, and transferred to containers, for example, through a cannular system, also under the inert atmosphere. The process for filling the containers is discussed later in this. Solvents other than water, when required, and other reagents can be selected from the medical grade reagents and solvents well known in the art. The parenteral formulations according to the invention are packaged in containers. It is possible to select containers that are made of material that is not reactive or that is substantially not reactive with the parenteral formulation. Glass containers can be used, although it is preferred to use plastic containers, for example, plastic infusion bags. Glass containers can be made, for example, of lime soda and borosilicate. The lime glass of soda ers referred to as USP (United States Pharmacopeia) Type II, while the borosilicate glass is referred to as USP Type I. The preferred glass containers are those manufactured by Pharma Hameln FRG. - - Plastic containers, and in particular plastic infusion bags, are preferred over glass containers, since they are relatively lightweight and unbreakable, and therefore, are more easily stored. This is particularly the case for high volume parenterals. The plastic containers can be composed mainly of thermoplastic polymers. The plastic materials may additionally comprise additives, for example plasticizers, fillers, antioxidants, antistatic agents, and other ingredients known in the art for specific purposes. Plastics suitable for use in the present invention are preferably resistant to the high temperatures required for thermal sterilization. The preferred plastic containers are plastic infusion bags made of non-PVC plastic materials, and are known in the art. A primary concern of container systems is the protection they provide to a solution against ultraviolet degradation. If desired, amber glass employing iron oxide or an opaque cover adapted over the container, may provide adequate protection against ultraviolet light.

A wide range of container sizes can be used. The size of the container can be conveniently categorized as Low Volume, that is, 100 milliliters or less, and High Volume, that is, greater than 100 milliliters, and usually 250 milliliters. In view of the relatively low solubility of the active agents in water, for example, of COMPOUND A, which has a solubility of 3.2 to 4.2 milligrams / milliliter at 25 ° C and a pH of 5.8 to 6.0, it is preferable to use a parenteral formulation. High Volume, for example, greater than 100, and more particularly 250 milliliters, in order to have an effective amount of active agent in a single container. Of course, Low Volume parenteral formulations could be employed, but this may require the use of an organic co-solvent or other solubilization aid, which is less desirable than a fully water-based formulation. According to the above, in another embodiment of the invention, a single dosage form of an active agent, for example, of COMPOUND A, is provided in a solution entirely based on water, in a container whose dosage form contains an amount effective of the active agent. In a more preferred embodiment, the single dosage form contains 600 milligrams of COMPOUND A in 240 milliliters of water. Preferably, when the only dosage form contains 600 milligrams of COMPOUND A in 240 milliliters of water, the isotonic agent is glucose, preferably in an amount of 4.75 percent by weight. Regardless of the fact that it may be preferable to employ organic co-solvents in parenteral Low Volume formulations, the Low Volume parenteral formulation offers the advantage of being easier to store and use. In addition, the containers used for parenteral Low Volume formulations have a smaller upper space when filled, which contains less oxygen (air) than the larger containers needed for high volume parenteral formulations. The containers used in the parenteral formulations of Low Volume, therefore, are more easily purged of air, for example, using nitrogen or other inert gases. It is a characteristic of parenteral formulations of Low Volume that, for an intravenous solution sealed in a container and purged of air using nitrogen, the active agent, for example, COMPOUND A, may not be subject to degradation by oxidation during periods of prolonged storage, for example, up to 24 months. This may be the case, regardless of the choice of isotonic agent, for example, NaCl or glucose. While for high volume parenteral formulations, degradation by oxidation of the active agent, for example, of COMPOUND A, even after a nitrogen purge, can be observed if isotonic agents other than glucose are used, for example NaCl. In parenteral formulations of High and Low Volume, which employ glucose as an isotonic agent, the active agent, for example, COMPOUND A, may not be subject to degradation by oxidation during prolonged storage periods, for example, up to 24 months, regardless of whether the filled container is purged or not with nitrogen. The containers for use in the storage of the parenteral formulations according to the invention can be used to administer a single dose of active agent. The device used to transfer the parenteral formulation from the container to the body of a patient can be any of the devices commonly used in the art to apply therapeutic agents such as parenteral formulations from containers, such as the High or Low Volume containers mentioned above. . Although the contact time between the device and the parenteral formulation can usually be shortHowever, it can be intimate, and therefore, compatibility with the injectable formulation must be guaranteed. According to the foregoing, the material of the device may be the same as that of the containers, or may include other materials commonly used in these devices, if short-term contact with them is acceptable. Although, as mentioned above, certain active agents, for example, COMPOUND A, when used in conjunction with glucose as the isotonic agent, may not be susceptible to degradation by oxidation, as a precaution, the process of filling the The containers can be made under an inert atmosphere, for example nitrogen. The process for filling the containers with the parenteral formulation must be carried out under sterile aseptic conditions according to the procedures well known in the art. Preferably, the process is carried out in a clean area Grade C (Class 10,000). The parenteral formulation prepared as described hereinabove can be filtered under a nitrogen pressure through a sterile filter, for example, with a pore size of 0.22 microns, and is collected in the containers. Subsequently, the containers can be capped and sealed, provided with an opaque cover, for example, of aluminum foil, and heated in an autoclave at a temperature greater than about 121 ° C for about 15 minutes. The parenteral formulations according to the invention, and packaged in the containers as described above, are stable both for the high temperature sterilization process in an autoclave, and for the prolonged storage periods. Parenteral formulations containing an active agent, for example, COMPOUND A, and glucose, may be stable during storage at a temperature of 25 ° C, for at least 24 months, with or without nitrogen purge. Parenteral Low Volume formulations containing an active agent, for example, COMPOUND A, and NaCl as the isotonic agent, can be stable during sterilization at elevated temperature, and storage at a temperature of 2 to 8 ° C, during at least 10 months, while injectable Low Volume formulations containing an active agent, for example, COMPOUND A and glucose as the isotonic agent, may be stable during sterilization at elevated temperature and storage at a temperature of 25 ° C for at least 24 months. Parenteral formulations according to the invention exhibit an anticonvulsant action, and are useful for initiating anticonvulsant therapy in patients experiencing attacks, for example, resulting from newly established epilepsy, status epilepticus, cerebrovascular disorders, head injury , and alcohol withdrawal. They are also useful as a replacement therapy when the administration of established courses of oral anticonvulsants is not possible, for example, in the case of patients who can not swallow, who are vomiting, who are unconscious, or who are undergoing surgery. Doses of up to 10 milligrams / ki-dose can be administered intravenously. The exact dosage required, and the duration of administration, will depend on the seriousness of the condition being treated, and the concentration of the administration. The preferred active agent, COMPOUND A, can be administered in a dosage form of 600 milligrams up to 4 times a day. A single preferred dose may be 600 milligrams / 240 milliliters. Preferably, a dose may be delivered at a rate of 240 milliliters for a period of 30 minutes. Because the dose can be administered intravenously, the dose received and the blood concentration can be determined precisely on the basis of known in vitro and in vivo techniques. Now follows a series of examples to illustrate the invention.

Example 1 COMPOUND A is dissolved under a blanket of nitrogen with stirring at 60-80 ° C in water for injection (WFI), at a concentration of 2.5 milligrams / milliliter. After cooling to room temperature, anhydrous glucose is added for injection, and dissolved by stirring under nitrogen purge, to obtain a concentration of 4.75 percent glucose in water. After filtering through a 0.22 micron pore size filter, the solution is purged with nitrogen, filled into glass jars (Class II quality), sealed with a rubber seal and aluminum lid (alu -cap), and sterilized by autoclaving at 121 ° C for 15 minutes. The bottles are stable and transparent colored particles for at least 2 years at 2-8 ° C.

Example 2 COMPOUND A was dissolved with agitation at 60-80 ° C in water for injection, at a concentration of 2.5 milligrams / milliliter. After cooling to room temperature, glucose is added for injection (anhydrous), and dissolved by stirring, to obtain a concentration of 4.75 percent glucose in water. After filtering through a 0.22 micron pore size filter, the solution is filled into glass jars, sealed with a rubber seal and aluminum cap (alu-cap), and sterilized by autoclaving. at 121 ° C for 15 minutes. The bottles are stable and transparent to colored particles for at least three months at 2-8 ° C.

Example 3 COMPOUND A was dissolved under a blanket of nitrogen with stirring at 60-80 ° C in water for injection, at a concentration of 2.5 milligrams / milliliter. After cooling to room temperature, sodium chloride is added, and it is dissolved with agitation under nitrogen purge, to obtain a 0.9 percent concentration of sodium chloride in water.

After filtration through a 0.22 micron pore size filter, the solution is purged with nitrogen, filled into glass jars, sealed with a rubber seal and aluminum cap (alu-cap), and it is sterilized by autoclaving at 121 ° C for 15 minutes. The bottles are inspected after storage for 3 months at 2-8 ° C, and show the presence of red particles.

Example 4 COMPOUND A is dissolved with agitation at 60-80 ° C in water for injection, at a concentration of 2.5 milligrams / milliliter. After cooling to room temperature, sodium chloride is added, and dissolved with stirring to obtain a 0.9 percent concentration of sodium chloride in water. After filtering through a 0.22 micron pore size filter, the solution is filled into glass jars, sealed with a rubber seal and aluminum cap (alu-cap), and sterilized by autoclaving. at 121 ° C for 15 minutes. The solutions of the flasks show, in a storage of six weeks at 2-8 ° C, the presence of red colored particles.

Claims (10)

RF.TVI DIC? CTONES

1. A parenteral formulation comprising a 5H-dibenz (b, f) azepine-5-carboxamide and water or a water-based solvent, wherein the formulation contains no other solubilization aids.

2. A parenteral formulation comprising a 5H-dibenz (b, f) azepine-5-carboxamide, water or a solvent based on water, and glucose.

3. A parenteral formulation comprising 10-hydroxy-10, 11-tetrahydrocarbamazepine and water.

4. A parenteral formulation according to claim 3, which additionally comprises an isotonic agent.

5. A parenteral formulation according to claim 3 or claim 4, wherein the isotonic agent is glucose.

6. A parenteral formulation according to claim 2 and 5, wherein the glucose is present in an amount of 4.75 weight percent, based on the total weight of the parenteral formulation.

7. A unit dosage form comprising an effective amount of a 5H-dibenz (b, f) azepine-5-carboxamide and water, or a water-based solvent, wherein the unit dosage form does not contain other solubilization aids. .

8. A container having a volume filled from about 100 to about 250 milliliters, and containing, in solution, a therapeutically effective amount of a 5H-dibenz (b, f) azepine-5-carboxamide.

9. A method for the treatment of epilepsy in a subject, which comprises administering a parenteral formulation as claimed in any of the preceding claims.

10. The use of a parenteral formulation as defined in any of the preceding claims, in the treatment of epilepsy.