Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-12-09
1999-08-24
Rose, Shep K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 3153
Patent
active
059425105
DESCRIPTION:
BRIEF SUMMARY
This application is filed pursuant to 35 U.S.C..sctn. 371 as a United States National Phase Application of International Application No. PCT/US96/02759 filed Jun. 20, 1996 which claims priority from GB9512854.2 filed Jun. 23, 1995.
The present invention relates to a novel pharmaceutical formulation of lamotrigine, a process for its preparation, and its use in medical therapy.
Status Epilepticus (SE) is a life-threatening condition in which the high morbidity and mortality rates are directly related to the duration of seizure activity. There exists a clinical need for an antiepileptic drug (AED) that may be administered rapidly and safely via the intravenous route to achieve therapeutic plasma concentrations for the treatment of SE. The only AED currently available in an intravenous formulation is phenytoin. However, recommended doses must be administered over a period of at least 20 minutes to avoid cardiovascular side-effects (including tachycardia, bradycardia, hypotension and cardiac arrythmias) produced by the drug and its solvent, propylene glycol. Furthermore, intravenous phenytoin administration is commonly associated with injection site reactions including pain, inflammation and sclerosis.
A clinical need for an intravenous AED additionally exists for patients who are unable to swallow an oral formulation for a variety of reasons including unconsciousness (post-ictal or secondary to acute trauma), anesthesia during surgery and post-operative recovery and the presence of an intra-tracheal tube for the facilitation of mechanical ventilation.
Lamotrigine may be chemically named 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine and is disclosed in European patent 21121 and U.S. Pat. No. 4,602,017. It is useful in the treatment of SE and is commercially available under the trade name "Lamictal" as an oral tablet formulation. Typically, a therapeutic dose of lamotrigine for an adult human being comprises a loading dose of, say, 1000-1500 mg followed by a maintenance dose of, say, 500-700 mg/day. Plasma concentrations of lamotrigine of about 24 .mu.g/mL are generally effective in controlling SE for add-on therapy, i.e. when taken concomitantly with other AEDs. Plasma concentrations of about 8-10 .mu.g/ml are generally effective for monotherapy.
The clinical management of SE with lamotrigine would be assisted by the availability of formulations in addition to tablet formulations. In particular, as indicated above, an injectable formulation of lamotrigine would be of advantage in initiating treatment intravenously so as to obtain the required plasma concentrations and bioavailability as rapidly as possible. It would also find utility in an emergency room situation in which patients are already experiencing convulsions and are not able to take the tablet form.
The need for an injectable formulation of lamotrigine has already been recognised. Initially, its development was hampered by the poor solubility of the base form of the drug. The aqueous solubility of lamotrigine is only 0.17 mg/mL at about room temperature and does not significantly vary with pH (Table I).
TABLE 1 ______________________________________
Solubility of Lamotrigine
Aqueous Medium Amount Dissolved (mg/mL)
______________________________________
Water at 25.degree. C.
0.17
Water at 37.degree. C.
0.57
HCl (pH 1.2) at 37.degree. C.
0.46
Phosphate buffer (pH 6.0) at 37.degree. C.
0.68
Phosphate buffer (pH 7.5) at 37.degree. C.
0.56
0.01N Sodium hydroxide at 25.degree. C.
0.30
______________________________________
Consequently, the sparingly soluble nature of lamotrigine base in water would necessitate the administration of an undesirably large volume of solution to provide a therapeutic dose. European patent 247892 and U.S. Pat. No. 4,847,249 disclose the isethionate (2-hydroxyethanesulphonate) salt of lamotrigine and its use in the provision of an injectable formulation. The isethionate salt has an aqueous solubility of 404 mg/mL at about room temperature which is substantially higher than that of the free
REFERENCES:
patent: 4406888 (1983-09-01), Aguiar et al.
patent: 4486354 (1984-12-01), Baxter et al.
patent: 4602017 (1986-07-01), Sawyer et al.
patent: 4847249 (1989-07-01), Sawyer et al.
patent: 5059619 (1991-10-01), Haeger et al.
patent: 5283067 (1994-02-01), Geller et al.
patent: 5545637 (1996-08-01), Fu et al.
patent: 5629312 (1997-05-01), Bousseau et al.
Schmitt et al J. Pharm. Sci. 85(11):1215-1219 "Moisture-Dependent Crystallization of Amorphous Lamotrigine Mesylate", 1996.
Floyd Alison Green
Jain Sunil
Glaxo Wellcome Inc.
Makujina Shah R.
Rose Shep K.
LandOfFree
Pharmaceutical composition containing lamotrigine does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical composition containing lamotrigine, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical composition containing lamotrigine will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-467173