MXPA03008839A - Formulation of lamotrigine tablets with sustained-release. - Google Patents

Abstract

The present invention refers to sustained-release tablets of lamotrigine in a concentration of from about 5mg to about 500mg useful for obtaining the same therapeutic effect but with a reduced dose and in single daily doses. The invention is useful for treating bipolar depression and reducing the secondary effects thereof.

Description

FORMULATION OF LAMOTRIGINE TABLETS OF SUSTAINED RELEASE FIELD OF THE INVENTION Pharmaceutical Technology OBJECT OF THE INVENTION The purpose of making a lamotrigine sustained-release tablet formulation is that the formulation can continuously and consistently release lamotrigine and not release it in its entirety, as occurs with normal tablets, when released continuously the drug is bound to plasma proteins and the rest is free to carry out its pharmacological action, in addition to decreasing its stay in large quantities in the liver, in this way it leads to making spaced shots of a single shot per day and that the drug is less toxic than if it were the immediate-release tablet.

BACKGROUND Background of lamotrigine and Chemical Formula.

Lamotrigine is a derivative of phenyltriazine approved by the FDA to treat partial seizures in adults when used with other drugs.

Its chemical name in 3,5-diamino-6- (2-3-dichlorophenol) -1, 2,4-triazine with a molecular weight of DE 256.0 g, its molecular formula is C9H7N5CI2. fifteen twenty Pharmacological effects and mechanisms of action.

Lamotrigine inhibits the tonic extension of the hindquarters in the model of maximum electric shock seizures. Lamotrigine blocks sustained repetitive activation induced by the depolarization of spinal cord neurons "in vitro", action compatible with blocking voltage-dependent (Na +) Sodium channels.

Together, these results are similar to those observed with phenylhydantoin and carbamazepine.

Therefore, lamotrigine selectively increases the threshold of activity of localized epileptics, which suggests that this is the mechanism that blocks the onset of depressive or manic phases.

Xie Xiemin and Hagan have suggested a possible mechanism of therapeutic efficacy in bipolar disorders indirectly it is proposed that lamotrigine decreases the excessive release of neurotransmitters in the brain, it would be expected that this activity gives away the transmission of aberrant signals of intracellular origin and intercellular in critical regions of the frontal region of the limbic system, so we can infer that lamotrigine is a mood stabilizer.

Excessive release of glutamate and depolarization of neurons, play an important role in the generation of seizures as well as in mania and depression disorders this mechanism is the vital point of action of lamotrigine that blocks pathophysiological events, respecting the neurophysiology of neurotransmitters evidencing their clinical - therapeutic efficacy.

Pharmacokinetics Lamotrigine is completely absorbed from the digestive tract, and is metabolized primarily by glucuromidation, the plasma half-life of a single dose is up to 24 hours. The simultaneous use of Phenylhydantoin, Carbamazepine, Phenobarbital or Prednisone reduces the half-life of lamotrigine by up to 37.5%, which is up to approximately 15 hours.

Adverse effects.

In the combined data from the monotherapy studies, lamotrigine was better tolerated than the comparative agents, with respect to its effects on the central nervous system (CNS). For example, reports of sedation, asthenia, and ataxia were significantly less frequent than in patients on lamotrigine treatment compared to those treated with carbamazepine, and dizziness occurred significantly more than in patients treated with carbamazepine Table 1. The overall frequency of rash was similar in all treatment groups, despite the relatively high doses of lamotrigine used during the first month of double-blind studies.

Table 1.

Lamotrigine (n = 433)% Carbamazepine (N = 246)% Adverse Effect Of the patients who from reported patients reported (95% CI).

Headache 20 17 (-3.9) Asthenia 16 24 (-15, -2) Skin rash 12 14 (-8,3) Nausea 10 10 (-5,5) Dizziness 8 14 (-11, -1) Sedation 8 20 (-18, -6) Insomnia 6 2 (1, 7) Tremor 2 < 1 Ataxia < 1 6 (-8, -2) The adverse events reported most frequently in the placebo-controlled studies of lamotrigine as additional treatment are rash, diplopia, blurred vision, dizziness, drowsiness, headache, ataxia, fatigue, tremor, gastrointestinal disorders, irritability / aggression, agitation and confusion.

Although these events were reported more frequently in patients treated with lamotrigine than in those treated with placebo, the differences rarely reached statistical significance, either in the individual studies or in a meta-analysis of four controlled studies.

The adverse events reported in the open studies of additional treatment for adults and those reported spontaneously, are qualitatively similar to those reported in the controlled studies.

In a study by Calabrese et al., Lamotrigine was well tolerated and the incidence of gastrointestinal effects (nausea, diarrhea) and neurological adverse effects (headache, drowsiness, insomnia) occurred more frequently in the lithium group compared to lamotrigine and placebo. The adverse events that led to the discontinuation of lithium included: nausea (8%) and tremor (5%), both of which were significantly higher than with lamotrigine. No rash was reported.

In the study by Bowden et al., Lamotrigine was well tolerated, in contrast to the high incidence of adverse events observed in patients treated with lithium. Also in this study there were no reports of severe rash.

Previously, the high initial plasmatic concentrations of lamotrigine had been identified as a factor influencing the appearance of cutaneous reactions associated with carbamazepine. Therefore, the frequency of rash in clinical studies of lamotrigine was examined with respect to the initial dosage regimen of lamotrigine and a similar relationship was found. In monotherapy studies, the frequency of skin rash that required discontinuation was 11.6% in patients who received an initial dose of 100 mg and 9.2% in those who received an initial dose of 50 mg, and 2.2% in those who received an initial dose of 50 mg. received an initial dose of 25 mg. The posology recommendations for lamotrigine were reviewed to include a low initial dose and to continue with a slow escalation of the dose.

Subsequent experience with lamotrigine indicates that the rash occurs less frequently with the revised dosage regimen. Therefore, the recommended initial dose should not be exceeded. This is especially important in patients receiving comedication with sodium valproate, as the enzymatic inhibitory effect of this drug results in higher plasma concentrations of lamotrigine.

When they occur, almost all eruptions appear maculopapular and appear within four weeks after starting treatment with lamotrigine, spontaneously remitting to; discontinue the drug. As there have been reports of serious dermatological reactions, all patients who present a rash should be assessed immediately and lamotrigine discontinuation should be considered.

In conjunction with the skin rash, several reactions have been reported, such as fever, malaise, flu-like symptoms, drowsiness, and in rare cases, liver dysfunction, lymphadenopathy, leukopenia, and thrombocytopenia. It is recommended to monitor closely the hepatic, renal and coagulation parameters in patients who present these reactions in acute form, especially in the first month of treatment with lamotrigine.

Discontinuations In clinical studies, discontinuations of lamotrigine treatment due to adverse events occurred with low frequency. In the comparative studies of monotherapy. there were significantly fewer discontinuations in the lamotrigine groups (9.5%) compared to the carbamazepine groups (19.1%).

The most common adverse event that caused the discontinuation of lamotrigine treatment was skin rash, with a maximum dropout rate of 6.0% within all monotherapy studies (compared with 8.9% of those treated with carbamazepine). However, the discontinuation rate dropped to around 2% with the lowest dosage regimen currently used.

The most frequent reasons for the discontinuation of lamotrigine treatment were: asthenia (1%) and headache (1%), while the adverse events responsible for almost all other discontinuations in the studies were nausea, ataxia and diplopia.

In controlled studies, there was no increase in the incidence and severity of adverse events, after the abrupt interruption of lamotrigine. Therefore, patients can finish their treatment without reduction in dose.

Lamotrigine indicates that it is used alone or in combination with other drugs such as antiepileptic drugs, which indicates the deficiency that causes folic acid in people and as a result an anemia is provoked, it does not indicate a how they approach this problem, it also indicates that the initial treatment begins with doses of 25 mg daily and increases to 200 mg and if required have reached the administration of 300 to 500 mg daily, but with consequences of rahs in people, as well as the same drug that does not bind to plasma proteins and is not carrying out its pharmacological action, is stored in the liver, causing as a consequence a progressive chronic nephrosis if it is used for prolonged periods at high doses In summary, this medication is reported to have much more secondary reactions, and many of them have not yet been established, since the information from the laboratory that registers it indicates that it has established all the secondary reactions it causes.

DESCRIPTION OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION Management of the medication.

The medicine that contains lamotrigine that is on the market, it is used in the treatment of epileptic seizures, both in children and adults, which is found as dispersible tablets.

Management of the medication to be protected. The medicine also contains the active ingredient of lamotrigine and can optionally be combined with active ingredients, which helps us to contribute to its therapeutic effect (sodium valproate) or helps us to reduce its side effects (folic acid), lamotrigine which is used for the treatment of epilepsy, we propose its use for bipolar depression and stabilizing your mood.

Amounts Used In the presentations of tablets that are available, which are of 5, 25, 50 and 100 mg, the doses that are administered are the following: the first 2 weeks 25 mg / day, later 2 weeks with 50 mg / day and 100- 400 mg / day in the following weeks, which has even required the administration of doses of 700 mg / day, here it is indicated that the doses may be unique, in the case of concentrations greater than 100 mg are divided.

In the proposed treatment should use doses 5, 50 and 500 mg, at the beginning of treatment with an average of 5 mg / day for the first 2 weeks, then the dose is increased to 50 mg / day for two weeks and continue with a dose of maintenance of 100 to 500 mg / day, the intakes proposed by the present invention are unique per day.

The differences of the doses previously disclosed as shown can reach concentrations higher than 300 mg / day in order to reach the therapeutic effect, thus favoring the increase of side effects, therefore the present invention proposes administrations of less than 300 mg / day, maintaining the therapeutic effect, but decreasing side effects.

It is preferred to protect the following invention which has 5, 50, 100 and 500 mg are sustained release lamotrigine tablets, at the start the treatment also starts with 5 mg, the maintenance doses are 100 to 500 mg, the difference is that they are intakes only per day, and administrations less than 500 mg.

How it has been used This medicine has been used in the treatment of epilepsy. The present invention proposes its use in the treatment of bipolar depression, as proposed by the part of Xie Ximia background and Hagan on the possible mechanism of its efficiency in bipolar disorder.

Procedure for the formulation.

The purpose of wanting to obtain sustained release tablets, is that the drug itself was found to have a high toxicity as it causes rahs to patients in the long term, it can also cause anemia among other side effects, for this purpose it is intended to release the product continuously without the need to vary doses, which are advised to be unique shots a day, in addition to the patient does not consume or be given greater amounts of lamotrigine to 300 mg / day, thereby reducing the side effects that Lamotrigine The sustained release formulation is for the product to be taken as a support treatment.

Differences The difference with the existing medication in the market. The pharmaceutical form is of sustained release, which gives us longer time of release of active principle, but keeping the therapeutic levels of the drug constant in blood, while the tablets of the innovator are dispersible and is dissolved in a lapse of approximately 1 hour , by the effect of pH.

Another difference is the repeated takings with the innovator. Sometimes 2 or more doses are required according to the prescription by the doctor to cover the amount of the drug in the day, amounts that are even 400 mg -700 mg, in order to reach the therapeutic effect.

Benefits.

The benefits of the medication is that, as it is found in sustained-release tablets, the doses are unique per day, the benefit of treatments for patients with epilepsy, bipolar depression, and that another benefit is that it reduces the side effects and toxicities that are caused by the active ingredient to maintain therapeutic levels, but does not increase concentration to cause side effects.

Bioavailability In the case of tablets, it can not be indicated that it is more bioavailable due to the fact that the comparison study has not been carried out.

TABLETS Lamotrigine 5mg 50mg 100mg 500mg Excipient c.b.p 1 tablet 1 tablet 1 tablet 1 tablet QUANTITATIVE FORMULA: ACTIVE PRINCIPLE: LAMOTRIGINE 5.00 mg 50.00 mg 100.00 mg 500.00 mg EXCIPIENTS: POLYVINYL ACETATE 15-35% 15-35% 15-35% 15-35% Polyvinylpyrrolidone 3-10% 3-10% 3-10% 3-10% LAURIL SODIUM SULFATE 0.01-0.2% 0.01-0.2% 0.01-0.2% 0.01-0.2% CELLULOSE 10-65% 10-65% 10-65% 10-65% MICROCRYSTALLINE SILICON DIOXIDE 0.5-1.5% 0.5-1.5% 0.5-1.5% 0.5-1.5% MAGNESIUM STEARATE 0.5-1.5% 0.5-1.5% 0.5-1.5% 0.5-1.5% COVERING HIDROXIPROPILMETILCE 1.0-3.0% 1.0-3.0% 1.0-3.0% .0 - 3.0% LULOSA HIDROXIPROPILCELULO- 1.0-3.0% 1.0-3.0% 1.0 - 3.0% 1.0-3.0% SA TRIACETIN 0.5 - 2.0% 0.5 - 2.0% 0.5 - 2.0% 0.5 - 2.0% POLYETHYLENE GLYCOL 0.5 - 2.0% 0.5 -2.0% 0.5 - 2.0% 0.5 - 2.0% TITANIUM DIOXIDE 0.1-1.0% 0.1-1.0% 0.1-1.0% 1.0-2.0% PURIFIED WATER 0.01-1.0% 0.01-1.0% 0.01 -1.0% 0.01 -1.0% TOTAL 225.0 mg 225.0 mg 225.0 mg 425.0 mg In this formula lamotrigine is the active principle that will perform the pharmacological effect and side reactions.

Polyvinyl acetate and polyvinylpyrrolidone are the excipients that will make the matrix, due to their characteristics of both excipients in which one is soluble in aqueous solutions in which this absorbs the active principle and the polyvinyl acetate is insoluble in aqueous solutions, the which helps us slow down the release of the drug, this matrix in particular gives sustained release to lamotrigine, because although the formulation was tested with other excipients that give us sustained release, these did not meet the quality parameters required, because they released the active ingredient in a short time, or delayed it more than expected, by which when tested this matrix of polyvinyl acetate and polyvinylpyrrolidone released according to the expected requirements.The tablet to have volume and flow properties, in addition to compaction was placed the microcrystalline cellulose as the diluent of the tablet.

Magnesium stearate is used as a lubricant and silicon dioxide as an anti-adherent, whose purpose is to provide the powder with adequate fluidity and lubrication to prevent it from sticking to the punches of the tableting machine, in addition to avoiding problems of variation of Weight during tablet compression.

The rest of the excipients are mixed and dispersed in water, these are used to coat the tablet with a certain thickness limit, which will give the tablet the aesthetic part where it looks smooth, as well as avoiding the taste of the active ingredient in this The only thing that is said or indicated is the formulation of the tablet to be protected.

PROCESS OF MANUFACTURING TABLETS. 1. Sifting raw materials through the established mesh. 2. Place the raw materials in the following order to the ribbon mixer. to. Polyvinyl acetate. b. Polyvinyl pyrrolidone. c. Lamotrigine d. Microcrystalline cellulose. 3. Once the above-mentioned raw materials have been placed, proceed to mix the suitable time. 4. After having made the mixture, without lowering the product place the following raw materials. to. Silicon dioxide b. Magnesium stearate. 5. Proceed to mix the established time, once finished mixing, lower the product, collect it and proceed to tablet according to the specifications given.

Once the product is tabletted, proceed to coat, for this the suspension is prepared with the raw materials described below to. Hydroxypropylmethylcellulose b. Hydroxypropylcellulose c. Triacetin d. Polyethylene glycol and. Titanium dioxide. F. Purified water 7. Once the suspension is done, proceed to coat the tablets according to established specifications. Once the coating is finished, lower the product and proceed to condition.

Claims (1)

- twenty-one - CLAIMS Having described my invention sufficiently and clearly, I consider as a novelty and therefore claim of my exclusive property, what is contained in the following clauses:

1. FORMULATION OF SUSTAINED RELEASE TABLETS OF LAMOTRIGINA CHARACTERIZED BY: Contain the following components. From 5 mg to 500 mg of lamotrigine. From 15.0% to 35% polyvinyl acetate 4.0% to 10.0% polyvinylpyrrolidone 10.0% to 65.0% microcrystalline cellulose. From 0.5% to 1.5% of silicon dioxide. From 0.5% to 1.5% Magnesium Stearate. From 1.0% to 3.0% of Hydroxypropylmethylcellulose. From 1.0% to 3.0% of Hydroxypropylcellulose. From 0.5% up to 2.0% Triacetin. From 0.1% to 1.0% titanium dioxide. From 5.0% to 20% of purified water. The composition according to claim 1 is claimed where the following formulation of sustained release tablets is preferred for the following concentrations. ACTIVE SUBSTANCE: LAMOTRIGINE 5.00 mg 50.00 mg 100.00 mg 500.00 mg EXCIPIENTS: POLYVINYL ACETATE 16.0% 16.0% 16.0% 16.9% Polyvinylpyrrolidone 3.88% 3.88% 3.88% 4.02% LAURIL SODIUM SULFATE 0.16% 0.16% 0.16% 0.17% CELLULOSE 62.0% 50.88% 26.44% 25.41% MICROCRYSTALLINE SILICON DIOXIDE 1.0% 1.0% 1.0% 1.0% MAGNESIUM ESTEARATE 1.0% 1.0% 1.0% 1.0% COVERING HYDROXIPROPILMETILCE 1.33% 1. 33% 1.33% 1.33% LULOSA HIDROXIPROPILCELULO- 1.33% 1.33% 1.33% 1.33% SA TRIACETIN 0.88% 0.88% 0.88% 0.94% POLYETHYLENE GLYCOL 0.88% 0.88% 0.88% 0.94% TITANIUM DIOXIDE 0.44% 0.44% 0.44% 0.47% PURIFIED WATER 0.017% 0.017% 0.017% 0.018% TOTAL 225.0 mg 225.0 mg 225.0 mg 425.0 mg Sustained-release tablets are claimed according to claim 1, as well as the concentrations in which their compositions are specified. They are claimed for sustained release tablets, their use according to the preceding claims for the manufacture of a medicament useful in the treatment of bipolar depression and as a mood stabilizer. The use of the sustained release tablets according to claim 4, the dose administered for a sustained treatment with lamotrigine ranges from 25 mg / day to 200 mg / day. The use according to claim 5 wherein the preferred suspending dose used is 200 mg / day. The use of sustained release tablets of lamotrigine, with an optional combination of folic acid of 5 mg, whose concentration of the latter is constant for all concentrations of sustained release tablets of lamotrigine. F - 24 - RESU IN The formulation to be protected, are sustained-release tablets of lamotrigine with a concentration of 5 mg to 500 mg, which seek to perform at a lower dose and in single doses per day to obtain the same therapeutic effect, which functions as a treatment for bipolar depression, in addition to diminishing its side effects.