Pharmaceutical formulation

Details Pharmaceutical formulation Pharmaceutical formulation

1995-05-30

1997-06-03

Rose, Shep K.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

514534, 514535, 514561, 514565, 514567, 514649, A61K 914, A61K 3124, A61K 31135, A61K 31195

Patent

active

056352131

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a pharmaceutical formulation for intraduodenal administration. More specifically, the invention relates to such a formulation comprising at least one pharmacologically active agent having a limited solubility in water. Still more specifically, the invention relates to such a formulation for the treatment of Parkinson's disease and comprising L-DOPA or an agent having similar properties. The term "limited solubility" is used in this patent application to refer to substances with low solubility in water and pharmacologically active substances for which the therapeutically active unit dose exceeds the solubility in water. The solubility of L-DOPA in water is about 5 mg/ml, and this patent covers drugs with both lower and higher solubility compared to L-DOPA.
L-DOPA (L-3,4-dihydroxyphenyalanine) has found a wide use for the treatment of patients suffering from Parkinson's disease, and good results are usually achieved by such a treatment. However, it is important in such a treatment that a stable level of the active agent is maintained in the patient's blood, and this has often been difficult to achieve in more conventional ways of administration, such as orally by tablets or capsules.
It has also been difficult to prepare liquid dosage forms of administration, as the compound L-DOPA has a very low solubility in water, so that large volumes of liquid have to be administered in order to give the patient an adequate dose. In several reports, the use of intraduodenal administration of aqueous solutions of drugs have shown several advantageous features as compared to oral administration of both tablets, suspensions and solutions (e.g. Watari et al., J. Pharmacokinet. Biopharm, Oct. 1983 11 (5), p. 529-545). Especially, the variation of drug plasma concentration was substantially reduced by using the intraduodenal route, mainly due to avoidance of the effect of variations in gastric emptying times. However, for drugs with limited solubility in water, the drug in suspended form is also an interesting possibility for intraduodenal administration. Furthermore, the compound L-DOPA is quite sensitive to oxidation and will decompose in solutions which are in contact with atmospheric air. These problems have practically ruled out the use of aqueous solutions of L-DOPA in therapy.
To eliminate the disadvantages mentioned, L-DOPA has been administered intraduodenally by an intraduodenal catheter through the abdominal wall of the patient, or by a naso-duodenal catheter. The formulation administered has then consisted of a suspension of L-DOPA in an aqueous carrier, thereby avoiding the problem of the low drug solubility. This method has given very good results as regards the maintaining of a stable level of L-DOPA in the patient's blood. But, to obtain a useful preparation still two further problems have to be considered. First, the risk of sedimentation of drug particles during storage and administration (referred to in this patent as the physical stability). Secondly, the chemical instability of L-DOPA due to oxidation.
Through the present invention, the drawbacks mentioned above are eliminated to a large extent. According to the invention a pharmaceutical formulation for intraduodenal administration is provided, comprising at least one pharmacologically active agent with a limited solubility in an aqueous carrier. What characterizes the invention is that the pharmacologically active agent has a particle size not exceeding 20 .mu.m, and that the aqeuous carrier has a viscosity of at least 300 mPas, measured at a moderate shear rate. These two characteristics have to be carefully controlled to produce an suspension with acceptable physical stability.
Preferably, the active agent has a particle size within the range 0.1 to 20 .mu.m, and especially then between 0.1 and 5 .mu.m.
The active agent is preferably L-DOPA and at least one of the agents, carbidopa or benserazide. It is preferably present in the formulation in an amount from 0.01 up to 20 weight percent, and especially then from 1 to 5

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