Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-11-09
2002-10-01
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S217000
Reexamination Certificate
active
06458770
ABSTRACT:
This invention relates to parenteral formulations of 5H-dibenz(b,f)azepine-5-carboxamides.
5H-dibenz(b,f)azepine-5-carboxamides are known anticonvulsants useful in the treatment of seizures resulting from, for example an epileptic attack.
Oral forms of 5H-dibenz(b,f)azepine-5-carboxamides are known and are suitable for repeat administration over a prolonged period of treatment to ensure a uniform concentration of 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 necessary immediate response.
Accordingly, there is a need to develop parenteral formulations, in particular which are suitable for use intravenously, of an anticonvulsant based on 5H-dibenz(b,f)azepine-5-carboxamides.
It has now been found that 5H-dibenz(b,f)azepine-5-carboxamides may 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 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 solubilising aids.
By solubilising aids is meant any compounds that assist in solubilising drug molecules by accommodating a drug molecule in a cavity formed in the solubilising aid to form inclusion complexes. Said solubilising aids are in particular the cyclodextrins, more particularly beta-cyclodextrin.
The parenteral formulation may be suitable for administering intravenously. The immediate response of this form of administration is highly desirable in emergency situations. Furthermore, as no absorption process is involved, the dose or blood concentration of active agent may be obtained with greater accuracy and speed.
The active agents and the syntheses for preparing same are Known in the art. The active agents may be substituted or unsubstituted at the 10- or 11-position. The 10-or 11-position may be substituted with mono- or divalent substituents selected from oxa, halogen or hydroxy groups, preferably oxa- or hydroxy groups.
When there is an oxa-or a hydroxy group at the 10- position, the 11-position is preferably unsubstituted and vice versa.
Preferred compounds are selected from carbamazepine (Tegretol®), 10-oxacarbazepine (Trileptal ®) and 10-hydroxy-10,11-tetrahydrocarbamazepine (hereinafter referred to as COMPOUND A). COMPOUND A has a chiral centre and may be used as its racemic mixture.
We have now found that COMPOUND A, which has not previously been commercially available may be made up to a commercially acceptable, well tolerated and stable formulation, e.g. from 3 months up to 2 or even 3 years, for intravenous administration.
Preferred active agents, e.g. COMPOUND A may have a solubility in water of up to 4.5 mg/ml, preferably 3.2 to 4.2 mg/ml, more preferably 2.5 at 25° C. and preferably at a pH of 4.0 to 7.0. Within these ranges of solubility, the active agents are advantageously formulated without the need for an organic co-solvent or any other solubilisingaid.
In parenteral formulations suitable for adminstration intravenously, the solvent for the active agent is either water or is aqueous-based. By “aqueous based” is meant a solution consisting of water and a water-miscible organic solvent or solvents. When an organic co-solvent is employed it is preferred that the it is used in amounts of up to 10% by weight, e.g. 0.5 to 10, more particularly 1 to 100% by weight. Suitable solvents are those water-miscible solvents commonly used in the art, for example propyleneglycol, polyethyleneglycol 300, polyethyleneglycol 400 and ethanol. Preferably, organic co-solvents are only used in cases where the active agent is not sufficiently soluble in water for a therapeutically effective amount to be provided in a single dosage form. Preferably the solvent consists solely of water.
As an alternative or in addition to the use of an organic co-solvent it may be useful to employ a solubilisingaid, e.g. cyclodextrins. Cyclodextrins may be useful solubilising aids when the active agent is selected from 10-oxacarbazepine (Trileptal®) and COMPOUND A.
The invention provides in another of its aspects a parenteral formulation, e.g. an i.v. formulation comprising a 5H-dibenz(b,f)azepine-5-carboxamide, e.g. COMPOUND A and a solvent consisting of water.
Preferably the parenteral formulations suitable for intravenous administration are formulated to have the same osmotic pressure as body fluid. Accordingly, a parenteral formulation according to the invention comprises an isotonic agent which has the effect of rendering the osmotic pressure of the formulation the same as that of body fluid.
Accordingly, in another aspect of the invention there is provided a parenteral formulation comprising as active agent a 5H-dibenz(b,f)azepine-5-carboxamide, e.g. COMPOUND A and a solvent consisting entirely of water, or water and an organic co-solvent, and an isotonic agent.
The isotonic agent may be selected from any of those commonly used in the art, e.g. mannitol, sodium chloride, dextran and glucose. As isotonic agents there can be mentioned in particular sodium chloride and glucose.
The isotonic agents may be used in quantities which impart to the parenteral formulation the same osmotic pressure as body fluid. The precise amount necessary to achieve the desired effect may depend on factors such as the concentration of active agent in the parenteral formulation, and is a matter of routine experimentation which the skilled person may determine without exercising any inventive thought and using only common general knowledge.
Selection of the isotonic agent is preferably made having regard to the properties, e.g. stability of the active agent. It has been found that certain isotonic agents, for example sodium chloride may promote the formation of oxidative degradation products of the active agents. This may be particularly problematic when the parenteral formulation is entirely water-based and the degradation product or products of the active agent, e.g. COMPOUND A is insoluble in water.
In order to reduce the likelihood of forming oxidative degradation products it is preferred that, particularly in the case of entirely water-based solutions, the parenteral formulation should be scrupulously purged of air when being packaged. Nevertheless, even if care is taken to purge a filled container of air, Harge Volume parenteral formulations, e.g. larger than 100 ml, more particularly about 250 ml, of an active agent, e.g. COMPOUND A comprising sodium chloride as the isotonic agent, oxidative degradation products may be detected after only relatively short storage periods. Surprisingly, we have found that, in the case of Low Volume parenteral formulations, e.g. about 100 ml or less of active agent, e.g. COMPOUND A, by carefully purging a filled container with nitrogen or other inert gas the formation of oxidative degradation products may be avoided. When the formulations are carefully purged of oxygen, the dissolved oxygen content may be less than 2 mg/ml, e.g. 1 mg/ml or lower.
We have also surprisingly found that even for Harge Volume parenteral formulations of an active agent, e.g. COMPOUND A, by judiciously selecting the type and quantity of isotonic agent the formation of oxidative degradation products may be avoided. This may be the case irrespective of whether the precaution is taken of purging the system of air. Preferably, the isotonic agent is glucose. The use of glucose is particularly advantageous when the injectable solution is entirely water-based and the active agent employed, e.g. COMPOUND A may oxidatively degrade to form a highly water insoluble compound which may even be coloured.
The amount of glucose used will depend upon the concentration of the active agent employed. In preferred formulations glucose may be used in amounts up to 5% by weight, e.g., 0.5 to 5% by weight, based on the weight of the parenteral formulation, more preferably 4.75% by weight.
In a preferred embodiment of the invention there is provided a parenteral formulat
Novartis AG
Thallemer John D.
LandOfFree
Parenteral formulations comprising carbamazepine or its... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Parenteral formulations comprising carbamazepine or its..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Parenteral formulations comprising carbamazepine or its... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2928175