WO2013056326A1

WO2013056326A1 - Controlled release pharmaceutical composition containing naltrexone and topiramate

Info

Publication number: WO2013056326A1
Application number: PCT/BR2012/000392
Authority: WO
Inventors: Marcelo Reis PERILLO
Original assignee: Fbm Indústria Farmacêutica Ltda.
Priority date: 2011-10-17
Filing date: 2012-10-17
Publication date: 2013-04-25
Also published as: BRPI1106938A2

Abstract

The present invention relates to a pharmaceutical composition for the treatment of diseases related to a drug addiction containing from 250 to 500 mg of naltrexone, preferably 300 to 400 mg of naltrexone, and most preferably 380 mg of naltrexone, and 700 to 3500mg, preferably 1000 to 2000mg, more preferably 1540mg of topiramate where the active pharmaceutical ingredients (API's) are formulated as depot on PLGA polymer base (polylactic glycolic acid), whose ratio should be 75:25 (75% lactic acid and 25% glycolic acid).

Description

CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION CONTAINING

NALTREXONE AND TOPIRAMATE

FIELD OF APPLICATION

The present invention relates to a pharmaceutical composition for the treatment of illnesses related to chemical dependency.

STATE OF THE ART

The document US3332950 describes molecules morphine derivatives and compositions containing these with narcotic properties and antagonists with analgesic activity without the same side effects of morphine and also describes the methods of production of these molecules, however, this document only claims the compounds.

Documents US5916598, US6194006, US6264987, US6379704, US6403114, US6495166, US6534092 describes a method for the preparation of microparticles involving the use of a polymer, solvent and an active ingredient. In the document US6264987 is claimed the use of the active principles naltrexone and oxybutynin.

Documents US6331317, US6395304, US6537586,

US6713090, US6939033 describe a method of preparing micro- particles and the equipment used in this process.

US6379703, US6596316 documents describe a method for the preparation of microparticles with controlled release feature involving the use of a polymer, solvent and an active ingredient.

Documents US6495164, US6667061, US7799345 describe an injectable composition containing microparticles and method of preparation of this composition.

The document US7919499 describes and claims a method of treatment by administering a composition containing long- acting naltrexone. SUMMARY OF THE INVENTION

The present invention describes a new composition for the treatment of chemical dependency, this composition containing 250 to 500 mg of Naltrexone, preferably 300 to 400 mg of Naltrexone, and even more preferably 380 mg of Naltrexone, and containing dosage equivalent to oral daily dose of 100 mg of topiramate, preferably 25 to 125 mg of oral daily dose of topiramate, and even more preferably the equivalent of 100 mg of oral daily dose of topiramate, or otherwise the 700 to 3500mg, preferably from 1000 to 2000mg, more preferably with 1540mg of topiramate where active pharmaceutical ingredients (API 's) are formulated as DEPOT in a polymer base of PLGA (Poly-glycolic lactic acid) , whose proportion should be 75: 25 (75% lactic acid and 25% glycolic acid) .

GOALS OF THIS INVENTION

Proposes to obtain an injectable DEPOT formulation of two closely related active ingredients, naltrexone and topiramate, which will release simultaneously without interfering with each other as their pharmacological action.

The release will last 28 days and will be used in the treatment of chemical dependency.

ADVANTAGES OF THE PRESENT INVENTION IN RELATION TO THE STATE OF THE ART The advantages to highlight are:

Do not exists a unic application injectable medication that last 28 days and permits to administer the both active ingredients mentioned above and without interferences .

- Ensures the beginning and the end of medical treatment since only requires the initial injection that releases sustainably the active ingredients in the required quantities. In other words, it is possible to better control the patient and obtain greater adherence to the treatment.

Each active ingredient has not changed his pharmacokinetics or pharmacodynamics action individually by the presence of the other.

The present invention generates a unique alternative to measure out the active ingredients above and replace the oral daily dose treatments, with a sustainable life of 28 days time.

THE MAIN PHYSICAL-CHEMICAL CHARACTERISTICS OF THE COMPOSITION

It is freeze dried microspheres of PLGA containing inside each mentioned active ingredient in corresponding proportion and have a defined size.

This preparation will be suspended again in a water- based medium determined immediately before their application in the patient.

The erosion by biodegradation of the constituent polymer of the microspheres allows to reach a dose in the blood equivalent to the obtained at daily oral doses of 50 mg of naltrexone and 100 mg of topiramate.

COMPOSITION PREPARATION METHOD

The composition is obtained by means of a double emulsion /O/ (water/oil/water) . First is obtained an emulsion /O (water/oil) , where it dissolves the API (Active ingredient) in aqueous base and the PLGA in volatile organic base (such as methylene chloride, chloroform, ethyl acetate, or another) .

This initial emulsion is formed by a ratio of 250 to

500 mg, preferably from 300 to 400 mg, more preferably from 3500mg, preferably from 1000 to 2000mg, more preferably from 1540mg of topiramato and , 5g of PLGA.

Prepare this first emulsion with vigorous mechanical agitation .

This emulsion is formed with intense agitation of an aqueous solution containing PVA (phosphoric acid buffer) , dissolved salts and additives to obtain the final emulsion W/O/W.

This emulsion comprised of microdrops is subjected to evaporation of organic solvents yielding a dispersion of microspheres in aqueous medium.

These microspheres are rinsed with water for injectable and loaded in vials to your lyophilization .

In other words, one should follow the following steps:

a. In an aqueous solution of phosphate buffer pH 7.4 mechanically shake vigorously, 250 to 500 mg, preferably from 300 to 400 mg, more preferably from 380mg naltrexone (its equivalent as hydrochloride) ; and 700 to 3500mg, preferably from 1000 to 2000mg, more preferably from 1540mg of topiramate suspending until it reaches a rate of 2% and 10% respectively;

b. Add to this suspension a 4 , 5g solution of PLGA (75:25) dissolved in organic solvent, such as methylene chloride, chloroform, ethyl acetate, or another, in a proportion of 10%, and emulsifies mechanically with vigorous shaking ;

c. Shake the emulsion during 30 minutes to 2 hours under laminar flow, coming up to an emulsion containing 250 to 500 mg, preferably from 300 to 400 mg, more preferably from 380mg of naltrexone (its equivalent as hydrochloride) ; 700 to 3500mg, preferably from 1000 to 2000mg, more preferably from 1540mg of topiramate and 4 , 5g of PLGA; d. Add the aqueous-organic emulsion obtained above under mechanical agitation on an aqueous solution, in a proportion of 1 to 3, containing PVA at 5% (85% hydrolyzed) , phosphate buffer (pH 7.4), mannitol and emulsifying additives to obtain the final water/oil/water emulsion;

e. Submit the emulsion consisting of microdrops to evaporation of the organic solvent under laminar flow, mechanical depression and forced ventilation, obtaining a dispersion of solid microspheres of PLGA microparticles in an aqueous medium;

f. Filter and wash the microspheres with WFI water quality (water for injectable compositions) containing mannitol in the ratio of 1% to 5%.

g. Resuspend in WFI quality water in the ratio of 1% to 5%;

h. Sift the suspension up gently by a mesh size of 100 to 200 microns;

i. Collecting the microspheres passing through the mesh, filter them and finally washing them with WFI quality water containing mannitol 1% to 5%.

j . Filling the microspheres in vials ampoules or vials type flasks; e

k. Freezing and lyophilizing the microspheres to obtain sticks or billets arriving at a dose of 250 to 500mg, preferably 300 to 400mg, more preferably 380mg of naltrexone (equivalent thereof as hydrochloride) , and 700 to 3500mg, preferably 1000 to 2000mg, most preferably 1540mg of topiramate in each vial .

COMPOSITION PREPARATION EXAMPLE Suspend 0.380 g of naltrexone (equivalent thereof as hydrochloride) and 1.540 g of topiramate in aqueous phosphate buffer solution with pH 7.4 until a ratio of 2% and 10% respectively. Adds to - the previous 4.5g aqueous solution of PLGA (75:25) dissolved in an organic solvent in a proportion of 10% and emulsifies it mechanically with vigorous shaking.

The previously obtained emulsion becomes, with mechanical agitation, an 5% aqueous solution of PVA in the ratio of 1 to 3.

Stir the double emulsion mechanically while the organic solvent is evaporated gently.

Obtained PLGA microspheres containing the active ingredients in the required proportions.

Are filtered and washed with water. The suspension of PLGA microspheres is frozen and lyophilized to give the product as a taco (dowel) .

MECHANISM OF ACTION AND TARGETS OF THE PRESENT INVENTION

1. Topiramate

Topiramate is a replaced sulphamate derivative of D- fructose natural monosaccharide with known antiepileptic activity.

Its mechanism of action involves three main processes: blockade of sodium channels with consequent reduction of epileptiforms discharges and the number of potential generated; increased of the γ-aminobutyric acid (GABA) activity, interacting directly with the GABA receptor and increasing the chlorine flow; antagonism of the glutamate receptor type cainato reducing the neuronal excitability.

The latter mechanism is unique to topiramate. The blockade of sodium channels have also been observed with phenytoin and carbamazepine .

But the effect on the flow of chlorine is not blocked by antagonists of benzodiazepines. It also exerts inhibitory properties of carbonic anhydrase, but that has no relevance on anticonvulsant activity (Korolkovas, A., & Carneiro de Franga, F. F. (2004). Dicionario Terapeutico Guanabara. Rio de Janeiro: Guanabara Koogan) .

Studies have shown the efficacy of topiramate in alcohol -dependent patients. This effectiveness is related to the glutamate AMPA receptor antagonist activity, that reduces the trait positive reinforcement related to alcohol consumption. Double-blind and placebo-controlled clinical study directed by Johnson et al . (2003) demonstrated the effectiveness of topiramate in alcohol -dependent patients, with respect to rates of abstinence, reduction of the fissure and decreased plasma levels of gamma-glutamyl transpeptidase (GGT) (Castro, L . A., & Baltieri, D. A. (2004). Tratamento farmacologico da dependencia do alcdol . Revista Brasileira de Psiquiatria, 26, 43-46) .

2. Naltrexone

Naltrexone is a synthetic congener of oximorfona, whose structure differs by replacing the methyl group on the nitrogen atom by a group ciclopropilmetila . (Bula Revia . (s.d.). Accessed on August 30, 2011, available at http : //www.2cristalia. com. br/ler_bula . php?id_medicamento=94B ) .

Naltrexone is an opioid-receptor blocker, which reduces or stops completely, reversibly, the subjective effects of opioids administered intravenously. This blockage occurs due to competitive binding of naltrexone with the opioid receptors.

It is indicated as part of the treatment of alcoholism and as antagonist in opioid addiction treatment administered exogenously. The neurobiological mechanisms responsible for reducing alcohol consumption observed in alcohol -dependent patients treated with naltrexone are not fully known.

However, preclinical data suggest the involvement of endogenous opioid system.

The mechanism of action of naltrexone in the alcoholism is not known, however, preclinical studies suggest the involvement of endogenous opioid system.

Opioid antagonists have been shown to reduce alcohol consumption by animals and naltrexone has been shown to reduce the alcohol consumption in clinical studies. {Bula Revia. (s.d.) . Accessed on August 30, 2011, available at http : //www.2cristalia . com. br/ler_bula . php?id_medicamento=94B )

TESTS AND RESULTS FROM THE USE OF THE PRESENT INVENTION

For the product some tests are made in the laboratory before the clinical trials in order to predict their behavior "in vivo".

This invention was checked in in-vitro studies to analyze and adjust your design until it reaches the pharmacokinetic profile sought for 28 days of sustained release, for this we used a type IV apparatus dissolutor equipment of the American Pharmacopoeia (USP) .

With this equipment it is possible to follow the release of the drug for 28 days and confirm the concentration released every 24 hours, in other words, confirmed the daily dose of medicine.

For this test we used as dissolution medium phosphate buffer with pH 7.4.

The microspheres of a dose of naltrexone + topiramate underwent degradation in vitro simulating the conditions of application in patients. Stir the suspension of microspheres mechanically smoothly while kept it immersed in supernatant pH adjusted.

The samples of supernatant, free of microspheres, was analyzed by HPLC in defined time intervals for quantifying the content of each active in the supernatant.

The data were computed on a graph in order to obtain the active ingredient release curve during the 28 days.

The formulation with the most appropriate profile of sustained release during the 28 days that took the test was determined as the formulation of Naltrexone + topiramate.

TREATMENT METHOD OF THE PRESENT INVENTION

The preparation of lyophilized microspheres is accompanied by an ampoule with injectable solution. The product is administered as intramuscularly injectable in one dose, each 28 days. In other words, the present invention is available in a kit for chemical dependency treatment containing an ampoule with lyophilized composition based on naltrexone and topiramate, an ampoule with injectable solution, and an intramuscular application syringe.

At the time of application should proceed with the resuspension of PLGA microspheres containing both active natrexona + topiramate, for this we use the solution that accompanies the product .

On the day "one" of the treatment, the deposit of both active PLGA microspheres (Depot formulation) will biodegrade in the patient's body constantly and continuously (sustained release) for 28 days.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a new association of two pharmaceutical active naltrexone and topiramate in the form of PLGA microspheres, termed DEPOT, drug controlled and differentiated release lasting 28 days in the body of the patient .

The intramuscular injectable pharmaceutical composition of a single application of controlled release of the present invention contains naltrexone and topiramate.

The amount of naltrexone in the composition is 250 to 500 mg, preferably from 300 to 400 mg, more preferably from 380mg.

The amount of topiramate in the composition is 700 to 3500mg, preferably 1000 to 2000mg, more preferably from 1540mg.

The PLGA polymer base of the microspheres has its constitution at a rate of 75% of lactic acid and 25% of glycolic acid.

The microspheres of the composition of naltrexone and topiramate have size between 100 to 200 microns.

The medicine aims to treat drug addicts.

The composition is obtained through a double emulsion water / oil / water being first obtaining a water / oil emulsion where each active ingredient is dissolved in aqueous base under pH control and PLGA in volatile organic base (such as methylene chloride, chloroform, ethyl acetate or other solvent) .

This first emulsion is constituted by a proportion of 0.380 g of naltrexone (the equivalent in the form of the hydrochloride salt), 1.540 g of topiramate and 4.5 g of PLGA.

This first emulsion is prepared using vigorous mechanical stirring, suspending 0.380 g of naltrexone (equivalent as hydrochloride) and 1.540 g of topiramate in phosphate buffer aqueous solution with pH 7.4 until reaching a ratio of 2% and 10% respectively, by adding this suspension to a solution of 4.5 g PLGA (75:25), dissolved in an organic solvent in a proportion of 10%, and mechanically- emulsified with vigorous agitation.

This emulsion is stirred for 30 minutes to 2 hours under laminar flow.

The aqueous-organic emulsion obtained above is added under mechanical stirring on an aqueous solution in a proportion of 1 to 3, containing 5% PVA (85% hydrolyzed) , phosphate buffer (pH 7.4), mannitol and additives emulsifiers for the final emulsion water / oil / water.

This emulsion comprised of droplets is subjected to evaporation of organic solvents under laminar flow and by mechanical depression and forced ventilation, to obtain a dispersion of solid microspheres of PLGA in aqueous medium.

These microspheres are filtered and rinsed with WFI quality water containing mannitol in a proportion of 1% to 5%. Be resuspended in WFI quality water in a proportion of 1% to 5% and be softly sieve by a mesh of 100 to 200 microns size .

The microspheres that cross the mesh are collected, filtered and finally rinsed with WFI quality water containing mannitol in a proportion of 1% to 5%.

The microspheres are filled into ampoules for lyophilization , each ampoule containing the dose of 250 to 500mg, preferably 300 to 400mg, more preferably 380mg of naltrexone (equivalent thereof as hydrochloride) ; 700 to 3500mg, preferably from 1000 to 2000mg, more preferably 1540mg of topiramate.

Claims

1. Intramuscular injectable pharmaceutical composition of single application of controlled release characterized by containing naltrexone and topiramate.

2. Composition according to claim 1 characterized by the amount of naltrexone be from 250 to 500mg.

3. Composition according to claim 1 characterized by the amount of naltrexone be from 300 to 400mg.

4. Composition according to claim 1 characterized by the amount of naltrexone be 380mg.

5. Composition according to claim 1 characterized by the amount of topiramate is from 700 to 3500mg.

6. Composition according to claim 1 characterized by the amount of topiramate is from 1000 to 2000mg.

7. Composition according to claim 1 characterized by the amount of topiramate to be 1540mg.

8. Composition according to claim 1 characterized by the active ingredients naltrexone and topiramate being associated in the form of PLGA microspheres.

9. Composition according to claims 1 to 8 characterized by the PLGA polymer base is in the ratio of 75% lactic acid and 25% glycolic acid.

10. Composition according to claim 3 characterized by the microspheres having size from 100 to 200 microns.

11. Composition according to claim 1 characterized by being released in a controlled manner for 28 days.

12. Process of preparing the composition of claim 1 characterized by following these steps:

a. In a phosphate buffer aqueous solution pH 7.4 mechanically stirred vigorously, 250 to 500 mg, preferably 300 to 400mg, more preferably 380mg of naltrexone (equivalent thereof as hydrochloride) ; and 700 to 3500mg, preferably 1000 to 2000mg, more preferably 1540mg of topiramate suspending until reaching a proportion of 2% and 10% respectively; b. Add to this suspension a solution of 4.5 g PLGA (75:25) dissolved in an organic solvent, such as methylene chloride, chloroform, ethyl acetate, or another, in a proportion of 10%, and mechanically emulsified with vigorous stirring;

c. Stir the emulsion for 30 minutes to 2 hours under laminar flow coming to an emulsion containing 250 to 500 mg, preferably 300 to 400mg, more preferably 380mg of naltrexone (equivalent thereof as hydrochloride) ; 700 to 3500mg, preferably from 1000 to 2000mg, more preferably 1540mg of topiramate and 4.5 g of PLGA;

d. Add the aqueous -organic emulsion obtained above under mechanical stirring on an aqueous solution, in a proportion of 1 to 3, containing 5% PVA (85% hydrolyzed) , phosphate buffer (pH 7.4), mannitol and emulsifying additives for the final emulsion water / oil / water;

e. Subjecting the emulsion comprising droplets to evaporation of organic solvents under laminar flow, mechanical depression and forced ventilation, achieving a dispersion of PLGA solid microspheres in aqueous medium;

f. Filter and wash the microspheres with WFI quality water containing mannitol 1% to 5%.

g. Resuspend in WFI quality water in a proportion of 1% to 5%;

h. Sift the above suspension gently by a mesh size of 100 to 200 microns; i. Collect the microspheres that crossed the mesh, finally filter and wash them with WFI water quality containing mannitol 1% to 5%.

j. Packing the microspheres in ampules; e

k. Freezing and lyophilizing the microspheres until obtain tacos or billets arriving at a dose of 250 to 500mg, preferably 300 to 400mg, more preferably 380mg of naltrexone (equivalent thereof as hydrochloride) ; and 700 to 3500mg, preferably 1000 to 2000mg, most preferably 1540mg of topiramate in each ampoule.

13. Kit for the treatment of drug addiction characterized by containing an ampoule containing the composition of claims 1 to 11, an ampule with a solution for injection and a syringe for infra-muscular application.

14. A drug addiction method of treating characterized by administering the kit of claim 13 to the patient each 28 days .