MX2013014166A - Active enantiomers and the salts thereof for treating obesity. - Google Patents

Abstract

The purpose of the invention is to develop three novel drugs S (+)-fenproporex, S (+)-diethylpropion and S (+)-bupropion and the salts thereof presenting important advantages for treating obesity unlike the corresponding racemic drugs. One of the advantages is that only the half of the developed drug of the present invention is used for reaching the same dopaminergic capacity of the racemic active principle. Reducing the drug dosage promotes the reduction of the side effects, amongst which are severe cardiovascular disorders. In addition, the fact of removing the enantiomers with different activities, and in some cases side effects, provides an obesity treatment with a higher quality unlike the drugs applied with racemic active principles.

Description

ACTIVE ENANTIOMERS AND THEIR SALTS FOR THE TREATMENT OF OBESITY I FIELD OF THE INVENTION The purpose of the present invention is the development of three drugs, whose metabolites manifest specific dopaminergic activity and therefore their capacity on the central nervous system is superior to that of their corresponding racemic mixtures, so its application in the treatment of Obesity, as well as the pharmaceutical compositions developed, have advantages over that of the products currently available.

BACKGROUND In racemic amphetamine, both the enantiomer dextro-amphetamine and levo-amphetamine exert their effects by binding to monoamine transporters and increasing the extracellular levels of dopamine, norepinephrine and a smaller serotonin. That is, when amphetamines are used mainly the neurotransmitters dopamine and norepinephrine are released from the nerve endpoint, at the synapse, and their recapture is inhibited. : Dextro-amphetamine acts mainly on the dopaminergic systems, while levo-amphetamine acts mainly on the norépinergic systems. Thus, the effects of primary reinforcement and behavioral stimulant amphetamine are linked to a high dopaminergic activity, mainly in the dopaminemesolimbic system. ? Dextro-amphetamine and levo-amphetamine present different types of physiological activity. Dextro-amphetamine is several times more important in the central nervous system than levo-amphetamine, but the two enantiomers have comparable activity in the sympathetic part of the peripheral nervous system. The greater power of dextro-amphetamine to the central actions suggests that this form has greater potential for assiduity.

I In the specific case of dextro-amphetamine this enantiomer increases the release of acetylcholine. Studies have shown that at high doses, acetylcholine can increase between 110% and 210% in the hippocampus and up to 35% % and 54% in the Caudato core. This release of acetylcholine is through the activation of the Di receptor of dopamine. The high cholinergic activity is likely to contribute to the nootropic effects that amphetamine has on memory and learning (E. Braunwald, et al., Harrison's Principles of Internal Medicine, 15th Edition, Me Graw Hill, 2001).

In an important investigation published in TheLancet (BrainDopamine and Obesity, Volume 357, February 3, 2001), it was reported that obese people have fewer receptors for dopamine, "the transmitter that helps produce feelings of satisfaction and pleasure." . According to the authors this implies that obese people can eat more, trying to stimulate the dopamine circuits that cause pleasure. Since eating is a behavior of reinforcing the feelings of gratification and pleasure, the authors assume that obese people may have abnormalities in the activity of dopamine in the brain. To test this hypothesis, scientists measured the number of dopamine receptors in the brain of 10 severely obese individuals and 10 normal controls. His method was to give each volunteer an injection containing a radiotracer11C-Raclopride, which is a compound that binds to dopamine receptors in the brain. Once the radiotracer was delivered, the researchers scanned the brains of the volunteers using a positron emission tomography (PET) scan. The PET tomography camera captures the radioactive signal from the tracer and shows whether it is bound to the dopamine receptors in the brain. The intensity of the signal indicates the number of receivers; The researchers found that obelos had relatively fewer dopamine receptors than subjects of normal weight, and within the obese group, the number of dopamine receptors decreased as the body mass index increased. That is, the more obese the individuals, the fewer the number of recipients. It is possible that obese people have lower numbers of dopamine receptors because their brains are trying to compensate for this lack of dopamine to reach better levels of pleasure, which they achieve with an addictive behavior eating compulsively. i Another subsequent study, conducted by the same Gene-Jack research group! Wang (PeripheralInsulinResistenceEffectsBrainDopaminergicSignalingAfterGuycoselngest ion, SNMMIs 60th Annual Meeting, ScientificPaper 29, June 8 to 12, 2013, Vancouver, British Columbia), consisted in comparing the effect of a sugary drink on 11 normal individuals versus 8 individuals with insulin resistance. Insulin controls the penetration of glucose into cells, which is the source of energy. Insulin-resistant individuals produced lower amounts of dopamine when drinking the sweetened beverage than normal individuals. The brain tomography performed with the PET camera showed that both groups had similar numbers of dopamine receptors in their reward (satisfaction) centers in the brain. The reward centers help motivate people to look for food high in sugar and fat. Insulin resistance in association with less dopamine in the reward centers can cause people to overeat to compensate for having a lower sense of satisfaction with the I eat regular amounts.

I This being so, it would be the dextro isomer of amphetamine which; more affects in controlling the appetite, being its main activity acting on; dopaminergic receptors, releasing this transmitter and preventing its recapture. Therefore, this isomer will be the one that generates the greatest reward to the brain, preventing the individual from replacing the lack of dopamine through ingesting food. He The purpose of the present invention is the development of three drugs: S (+) - fenproporex, S (+) - diethylpropion and S (+) - bupropion, which act mainly on dopamine receptors and inhibit dopamine recapture; With these drugs or active principles, pharmaceutical compositions were developed to be used as anorexic medicines for the treatment and control of obesity, offering better alternatives in terms of efficacy and 4 safety by having fewer side effects than drugs currently available in the market. i i BRIEF DESCRIPTION OF THE FIGURES j The preceding aspects and many of the advantages related to this and invention will be more easily appreciated if they come to; be better understood by reference to the following descriptions when taken in I conjunction with the accompanying figures. í Figure 1. Main Metabolites of the Racemic Fenproporex. The double arrow indicates that the metabolites are majority with respect to those of simple arrow. j Figure 2. Main Metabolites of the Racemic Diethylpropion. The double arrow indicates that the metabolites are majority with respect to those of simple arrow.

Figure 3. Main Metabolites of RacemicBupropion. The double arrow indicates that the metabolites are majority with respect to those of simple arrow.

Figure 4. 1H Nuclear Magnetic Resonance Spectrum of the S (+) - Fenproporex Enantiomer Hydrochloride Salt I Figure 5. 13C Nuclear Magnetic Resonance Spectrum of the S (+) enantiomer hydrochloride salt - Fenproporex Figure 6. Spectrum of TF-Infrared salt Chloride of the enantiomer S (+) - Fenproporex Figure 7. Mass Spectrum by the method of Chemical Ionization of the salt Chlorohydrate of the enantiomer S (+) - Fenproporexobtenndose the molecule ion (M - 1) = 187 Figure 8. Thermogram determined by Differential Banimetry Calorimetry of the salt Chloride of the enantiomer S (+) - Fenproporex, showing an endotherm with the initiation of defusion at 148.41 ° C.

Figure 9. Nuclear Magnetic Resonance Spectrum of 1H of the salt Hydrochloride of the enantiomer S (+) - Diethylpropion | Figure 10. 13C Nuclear Magnetic Resonance Spectrum of the Enantiomer S (+) - Diethylpropion Hydrochloride Salt Figure 11. Infrared TF-spectrum of the salt Hydrochloride of the enantiomer S (+) - Diethylpropion i Figure 12. Mass Spectrum by the Electronic Impact method of the salt Chlorohydrate of the enantiomer S (+) - Diethylpropion, obtaining the molecular ion (M + 1) = 206 ' I Figure 13. Thermogram determined by Differential Scanning Calorimetry, of the salt Chloride of the enantiomer S (+) - Diethylpropion, showing an endotherm with the initiation of fusion at 176.53 ° C. j i Figure 14. 1FI Nuclear Magnetic Resonance Spectrum of the S (+) - Bupropion enantiomer salt Chlorohydrate ^ Figure 15. Nuclear Magnetic Resonance Spectrum of 13C of saul Hydrochloride of enantiomer S (+) - Bupropion j Figure 16. Spectrum of TF-Infrared salt Hydrochloride of the enantiomer S (+) - Bupropion j Figure 17. Mass Spectrum by Electronic Impact, of the salt Chlorohydrate of the enantiomer S (+) - Bupropion, obtaining the molecular ion (M + 1) = 240 6 Figure 18. Thermogram determined by Differential Scanning Calorimetry, of the enantio chloride salt Sro (+) - Bupropion, showing an endotherm with the initiation of fusion at 243.06 ° C.

DESCRIPTION OF THE INVENTION I There are several medications used to decrease appetite and hence obesity. Among the most popular is fenproporex, which was launched on the market in 1960 and is perhaps the oldest in the family, after amphetamine, which has been known since 1887. Other drugs for the control of hunger are diethylpropion, also called amphepramone and the drug bupropion.

I I When acute and chronic doses of fenproporex are administered it has been shown that brain energy metabolism increases in young rats, increasing the activity of the enzymes: citrate synthetase, malate dehydrogenase, succinate dehydrogenase, cretin kinase and complexes I, II, III and IV (GT Gislaincy et al, BrainEnergyMetabolismisActivatedAfterAcute and ChronicaAdministration of Fenproporex in Young Rats, International Journal of DevelopmentalNeuroscience, 29, 937-942 (2011)). Drugs whose metabolism causes amphetamine are adjectives due to their ability to increase the release of dopamine. The main metabolite of fenproporex (60% to 80%) is rapidly metabolized to produce amphetamine (T. Kraemer et al. (Collaborators).) Fenproporex N-dealkylation to Amphetamine-enantioselective in Vitro Studies in Human Liver Microsomes as well as Enantioselective in Vivo Studies in Wistar and Dark Agouti rats, Biochemistry and Pharmacology, 68, 947-957 (2004), RT Coutss et al. Metabolism and disposition of N- (2-cyanoethylamphetamine): Fenproporex and Amphetamine: Study in the Rat Brain, Canadian Journal of Physiology and Pharmacology, 64, 724-728 (1986); G. Tognoni, et al., amphetamine concentrations in rat brain and human urine after Fenproporex administration, European Journal of Pharmacology.20, 125-126 (1972); JT Cody, Metabolic Precursors to Amphetamine and Methamphetamine, Forensic Science Reviews, 5, 109-112 (1993)) 'In addition to i amphetamine and fenproporex without being metabolized, other 14 metabolites have been identified in urine samples in smaller amounts. Two roads i I 7 Metabolic interacting agents have been proposed. The predominant pathway involves degradation of the ring by aromatic hydroxylation to give 4-hydroxyamphetamine or methylation or degradation of the side chain by N-dealkylation to form amphetamine. The minor pathway involves beta-hydroxylation of amphetamine to I to form norephedrine (Tomás Kraemer et al., Studies on the metabolism and toxicological detection of the amphetamine-like anorectic phenproporex in human urine by gas chromatography-mass spectrometry and fluorescence polarization immune assay Journal of Chromatography B: Biomedical Sciences and Applications 738, 107-118 (2000)). The description of the main metabolites of fenproporex is shown in Figure 1. i I Based on the foregoing, and given the background of the studies conducted with obese individuals, the fact that fenproporex is metabolized mainly to racemic latamtamine implies that its action to reduce appetite will be due to i enantiomer having dopaminergic action, which as described above corresponds to the dextro-amphetamine enantiomer. This implies that if only the dextro-fenproporex enantiomer was supplied, its main metabolite would be dextro-amphetamine, which will therefore be the active enantiomer in the inhibition of dopamine reuptake in the synaptic space (GM Miller, TheEmerging Role of Trace Amine Associatedto Receptor 1 in the FunctionalRegulation of Monoamine Transporters and DopaminergicActivity, J. Neurochemistry, 116, 164-176 (2011) and R. Kuczenski, DS Segal, Effects of Methylphenidateon Extracellular Dopamine, Serotonin, and Norepinephrine: ComparisonwithAmphetamine, J. Neurochemistry., 68, 2032 -2037 (1997)), and therefore it will also be the active enantiomer to diminish the appetite according to the PET study published in the journal TheLancet, previously cited: That is, the levo-fenproporex enantiomer is omitted, which its important activity is to act primarily on the norepinephrotic system. i I On the other hand, it is generalized that a good number of inactive enantiomers are responsible for some of the side effects shown by racemic drugs. In particular, fenproporex has been banned in the United States and other countries in Europe and Latin America for its side effects severe, mainly of the cardiovascular type. The supply of only the dopaminergic enantiomer, in addition to its specific effect on the dopamine receptors that are our target (target), will be that half the dose will achieve the same effect or potency in the decrease of hunger and its effect on the recipients of reward (satisfaction), than those achieved with him double of i amount using racemic fenproporex. Using half the concentration to achieve the same dopaminergic effect will favor the reduction of the side effects observed with the consumption of racemic fenproporex. 1 I Another drug used for its anorectic activity is diethylpropion. This drug stimulates the neurons to release or maintain high levels of norepinephrine and dopamine, acting in a manner similar to that of amphetamine. The metabolism of the drug occurs rapidly and extensively, with only 3% or 4% of the drug remaining unmetabolized within a few hours j after oral administration (AH, Beckett and M. Stanojcic, Pharmaceutical and i Pharmacology, 39, 409-415 (1987)). Diethylpropion and its metabolites are excreted mainly by the kidney. Between 75% and 106% of the dose is recovered in the urine, within 48 hours after ingestion. Mono-N-detylation is the main metabolic pathway and is equivalent to 35% of the ingested dose. The second route of metabolization consists of the reduction of the ketone to hydroxyl, without any other change in the drug, reaching up to 20% of the dose taken. Another 30% of the metabolism of the drug occurs by deamination, followed by oxidation and conjugation to give hippuric acid (AH, Beckett and M. Stanojcic, Re-evaluation of the Metabolism and Excretion of Diethylpropion in Non-Sustained and Sustained Relase Formulations.Pharmaceutical and Pharmacology , 39, 409-415 (1987)). Then, among the most important metabolites is (+/-) - 2-ethylamino-1-phenyl-propan-1-one, to which all the in vivo activity attributed to diethylpropion (H. Yu, and Col. Uptake and Release Effects of Diethylpropion and its Metaboliteswith Biogenic Amine Transporters, Biorganic Medicinal Chemistry, 8, 2689-2692 (2000)), Consequently, given the structural analogy of this metabolite with amphetamine it is possible to understand the dopaminergic and norepinephrinergic activity of diethylpropion. Also, extrapolating the known about the I amphetamine, the enantiomer (+) - 2-ethylamino-1-phenyl-propan-1-one should be the causing the inhibition of dopamine recapture and therefore being the main drug causing appetite suppression. Other important metabolites are (1R, 2S) - (-) - N, N-diethylnorephedrine and (1 S, 2R) - (-) - N, N-diethylnorephrine, although these metabolites show little or no related effect with the activity of diethylpropion. Figure 2 shows the main metabolites of di-ethyl propion. i Consequently, the use of only the S (+) - diethylpropion enantiomer whose metabolites will correspond to dextrous forms will be sufficient to achieve the desired objectives of satisfying the receptors of recompjensa and satisfaction through facilitating the release of dopamine and inhibiting its recapture, to avoid deprivation of the satisfaction that restriction produces! of food.

In addition, because using only the dopaminergic active enantiomer will be used i only half of the dose used with the racemic diethylpropion, the reduced dose will allow the side effects shown by the drug to be substantially reduced. j A third anorectic drug is bupropion. The primary activity of the drug is to act as a mild inhibitor of dopamine reuptake and a very weak inhibitor of norepinephrine reuptake. The bupropion anoréxigénicadel activity was estimated from a meta-analysis of anti-obesity drugs, allowing to conclude that the weight loss was similar to that achieved by other anorectic as diethylpropion (Z.Li, et al "Meta-analysis. Pharmacologic Treatment of Obesity. "Annales of Internal Medicine, 142, 532-46 (2005)). i Three active metabolites of racemic bupropion are hydroxybupropion, which is generated by hydroxylation of the tertbutyl group and the isomers amino-alcoholstreohydrobupropion and erythrohydrobupropion; which are formed by reduction of the ketone group. The activities of metabolites have been i found that hydroxibupropión is as potent as the racemic bupropion in inhibiting norepinephrine and dopamine, while the increased activity in the diastereomer (2S, 3S) -hidroxibupropión being more than 20 times more potent than the diastereomer (2S, 3R ) -hydroxybupropion, (Ml Darriaj et al., EnantioselectiveEffects of Hydroxymetabolites of BupropiononBehavior and 5 onFunction of Monoamine Transporters and Nicotinic Receptors, 'Molecular Pharmacology, 66, 675-682 (2004)) while threohydrobupropion and erythrohydrobupropion are 5 times less potent than bupropion. In particular the diastereoisomer (2S, 3S) -hidroxibupropión is more potent than the diastereomer (2S, 3R) -hidroxibupropión and even more potent than bupropion itself, its activities io dopamine receptors, the enantiomer! (2R, 3R) - I hydroxybupropion is less active compared to the other diastereoisomers (M.L. Damaj et al., Enantioselectiveeffects of hydroxymetabolites of bupropiononbehavior and onfunction of monoaminetranspdrters and nicotinicreceptors, Molecular Pharmacology, 66, 675-682 (2004)). fifteen In the case of supplying only the enantiomer S (+) - bupropion, the predominant diastereomer will then be (2S, 3S) -hydroxybupropion, which is the most active, without any presence of diastereomers! (2S, 3R) - hydroxybupropion and (2R, 3R) -hidroxibupropión and little presence of less active diastereoisomer 0 (2R, 3S) -hidroxibupropión.La possible presence of threohydrobupropion isomers and erythrohydrobupropion is very relevant as their activity as already noted is low. Figure 3 shows the main metabolites of bupropion. 5 then will be a great advantage to supply only the enantiomer S (+) - bupropion, ensuring the predominance of diastereomer, (2S, 3S) - hydroxybupropion, that act on dopamine receptors and inhibiting reuptake of dopamine, preventing the individual from ingesting i food in excess, so that the recipients of reward or satisfaction can count on enough dopamine to feel the comfort they require.

The great advantage, as noted above, is that with only half of the enantiomer of the drug S (+) - bupropion the same amount of the diastereoisomer dopaminergic (2S, 3S) -hydroxybupropion will be produced as that achieved with the i 5 racemic bupropion, so that the recipients of reward or satisfaction will be stimulated in the same magnitude of dopamine and will avoid the consumption of excess food by the individual to compensate their system.

On this basis, the purpose of the present invention is to provide the patient with deobesity of enantiomers precursors of the isomers that specifically act on the dopaminergic receptors, S (+) - fenproporex, S (+) - diethylpropion and S (+) - bupropion. In each case it has been described which are the active metabolites, which being only specific for dopaminergic activity reach their activity with half the drug that achieved with the racemic mixture of the active principle. The use of half of the drug, as discussed in each case, decreases the severe side effects that these anorectics present in their current presentation, so that the drugs generated with our enantiomers will be extremely advantageous compared to those commercially available. ! It has also recently been reported that treatment with drugs that act on dopamine and norepinephrine receptors for the treatment of various conditions, such as attention deficit, alter the density of dopamine transporters. Specifically, an investigation recently conducted by the Gene-Jack Wang Group using the drug methylphenidate (Long TermStimulantTreatmentAffectsBrainDopamineTransporterLevel! in PatientswithAttentionDeficitHyperactiveDisorder, May15, 2013, Open Access Journal PLOS ONE) showed that by continuous use during 12 months of the drug an increase in the density of the dopamine transporters was observed in some regions of the brain and that after treatment this density was significantly higher than in individuals without attention deficit than They had not been treated with the drug. Before the start of treatment there had been no significant differences in the two groups in the levels of the dopamine transpórtadores. According to these results, the use of this type of drugs and particularly specific drugs for dopamine transporters such as those proposed in the present invention would produce a physiological modification in the individuals suffering from obesity, which would remedy their situation in the long term, after a treatment for a certain time, depending on the response to each of the proposed drugs. 5 To obtain the desired enantiomers, from the corresponding racemic mixture, they were separated on a prparative scale by crystallization. The resolvers employed were (-) - di-p-tolui-d-tartaric acid and (+) - di-p-toluyltartaric acid, L-di- (O-benzoyl) tartaric acid. The solvents Suitable io include methanol, isopropyl alcohol, acetonitrile, dichloromethane and acetone. Two diastereoisomeric salts are formed in solution, one salt being I less soluble than the other. The less soluble one precipitates and is separated by filtration of the other enantiomer, which remains in solution. By repeated recrystallization of the isolated crystalline salt, it can be purified to the extent desired. Once The enantiomer is recovered by acidification of the salt with mineral acid, filtration and recrystallization. The precipitate was dried and analyzed obtaining a purity of 97% to 99%., This same procedure was used for the cases of S (+) - fenproporex, S (+) - diethylpropion and S (+) - bupropion, having been achieved similar returns in all three cases. 0 The enantiomers obtained were analyzed in each case by nuclear magnetic resonance (NMR), by infrared TF-spectroscopy (TF-IR), by mass spectrometry, by differential scanning calorimetry. The results obtained are shown in Figures 4 to 16. j 5 i The following describes the procedure for the enantiomeric separation, using as an example the obtaining of one of the three new j active ingredients S (+) - fenproporex, as well as some of the pharmaceutical compositions that were formulated; however, the purposes of the invention extend further, considering that with this idea the connoisseur of the state of the art can make modifications that are not original and that only imply ! variations on this proposal, so the patent is not limited to these examples. i 35 EXAMPLES Example 1. Resolution of Fenproporex racemate by the use of L-di- (O-benzoyl) tartaric acid as a chiral resolution agent.

I A 0.01 mole sample of racemic mixture of (+/-) - fenproporex hydrochloride was dissolved in 50 ml of water and this solution was basified to pH 11 with a Normal sodium hydroxide solution and extracted with 50 ml of dichloromethane. . This extract was dried over sodium sulfate and filtered. To this filtrate was added a solution of 0.10 moles of L-di- (O-benzoyl) tartaric acid in 35 ml of methanol and boiled until it began to crystallize. This solution was allowed to cool to room temperature and was allowed to stand for two hours. The obtained crystals were weighed giving 3.2 grams of colorless crystals, I which were boiled in 100 ml of methanol and this mixture was cooled obtaining colorless crystals, which were separated from the solution by filtration, obtaining 2.04 grams of colorless crystals with a melting point of 188 ° C-190 ° C, corresponding to the salt of the enantiomer (+) - fenproporexmonosal with the L-di- (O-benzoyl) tartaric acid. This salt was stirred with 4 sodium hydroxide normal and the liberated compound was extracted with ethyl acetate. The organic layer was washed with a diluted sodium hydroxide solution, then with water and then dried with sodium sulfate. This was filtered and the filtrate was treated with hydrochloric acid (HCL) in ether, until the precipitation stopped. The crystals were isolated by filtration and dried on a rotary evaporator to yield 0.80 grams of S (+) - fenproporex hydrochloride as colorless crystals, with a melting point of 151 ° C and [a] = + 64.5 °, C = 1 MeOH, which is obtained to obtain substantially free of the corresponding (-) - enantiomer with an enantiomeric excess of between 98.5% and 99.5%. The crystals obtained were analyzed by nuclear magnetic resonance, by TH-Infrared spectroscopy, by mass spectrometry and by differential scanning calorimetry. The results obtained are shown in Figures 4 through 7.

Example 2. Immediate Release Tablets of S (+) - Bupropion Hydrochloride 37.5 mg (milligrams) and S (+) - Bupropion Hydrochloride 50 mg.

FORMULA cbp. How much is enough for.

I DESCRIPTION OF THE MANUFACTURING PROCESS. i i A) Mixing process for direct compression of S (+) - Bupropion 37.50 mg Hydrochloride and S (+) - Bupropion Hydrochloride 50 mg, tablets.

S (+) - bupropion hydrochloride is added to a "V" blender with tartaric acid and mixed for 5 minutes, then added to the blender I crospovidone XL, hydroxypropylcellulose EXF and colloidal silicon dioxide, a mixing time of 5 minutes is given and at the end the mixture is sieved by mesh number (No.) 30. Again the sieved mixture is placed in the mixer in "V" together with the PH-112 microcrystalline cellulose to be mixed for 20 minutes, on the other hand, USP talc and stearic acid are screened separately through No. 30 mesh, then added to the mixer in the talc and mixed for 2 minutes. Finally, the stearic acid is added, and a mixing time of 5 minutes is given.

I B) Compression process of the granulate for the formation of the tablet.

The compression process was carried out using a variable speed rotary tablet press with biconcave punches. The feeding speed and the compression speed were adjusted to control the weight of the tablet.

I I I fifteen Example 3. Prolonged Release Tablets of S (+) - Bupropion Hydrochloride 75 mg and S (+) - Bupropion Hydrochloride 150 mg.

FORMULA * It evaporates during the process. cbp: how much is enough for. is: sufficient quantity.

DESCRIPTION OF THE MANUFACTURING PROCESS.

A) Granulation process for S (+) - Bupropion Hydrochloride 75 mg and S (+) - Bupropion Hydrochloride 150 mg. Prolonged Release Tablets.

The components of the formulation are sieved by No. 30 mesh, to favor obtaining a homogeneous mixture. In a high-cut granulation equipment, add bupropion hydrochloride, hydroxypropylcellulose EXF, microcrystalline cellulose PH-101, colloidal silicon dioxide, mix for 10 minutes a I 300 revolutions per minute (rpm) of the main mixer and 1000 rpm of the arm of | cut. The binder solution is prepared separately in a container of Adequate capacity is added to purified water and with stirring, the tartaric acid is added continuously and the agitation is maintained until a homogeneous solution is formed. The granulation process is then carried out by sprinkling the binder solution in the granulation equipment at a flow rate of 24 grams / minute (gr / min), at the end of the addition of the solution adding hypromellose (Methocel) and mixing for 8 minutes, at the end of the granulation remove the wet granulate i of the high cut granulator and place it in the fluid bed dryer, carry out the drying process with the inlet air temperature between 45 ° C and 55 ° C, until the loss test by drying is less than 2%. The dry granulate is passed through No. 20 mesh in QuadroComil equipment. Talc USP and stearic acid are sieved through No. 30 mesh. The dry granulate is added to a "V" mixer together with the talc and mixed for 2 minutes, finally the stearic acid is added and the a final mixing time of 5 minutes.

I B) Compression process of the granulate for the formation of the tablet or i core formation. ' The compression process was carried out using a variable speed rotary tablet press with biconcave punches. The feeding speed and the compression speed were adjusted to control the weight of the tablet.

! D) Coating.

An aesthetic coating is applied to the tablets. The coating to be used for this purpose is Opadry® (hydroxypropylmethylcellulose) and it is prepared, adding in a container of adequate capacity purified water at room temperature (between 20 ° C and 35 ° C) and with continuous stirring, the Opadry coating polymer is added. ®, stirring is maintained for 30 minutes or until the dispersion is homogeneous. The coating dispersion is sprinkled on the tablets in an Ohara LCM coating drum under the following conditions, inlet air temperature between 58 ° C and 65 ° C, product temperature between 38 ° and 42 ° C, air temperature of output between 35 ° C and 40 ° C, spray pressure between 1.5bars and 3.0 bars, spray speed between 12 gr / min and 20 gr / min.

I Example 4. Immediate Release Tablets of S (+) - Amfepramone Hydrochloride 12.5 mg and S (+) - Amphepramone Hydrochloride 25 mg. > FORMULA cbp. How much is enough for.

DESCRIPTION OF THE MANUFACTURING PROCESS.

I A) Mixing process for direct compression of Hydrochloride Amphepramone12.5 mg and Amphepramone Hydrochloride 50 mg.

. S (+) - amphepramone hydrochloride is added to a "V" mixer with tartaric acid and mixed for 5 minutes, then crospovidone XL, hydroxypropylcellulose EXF, colloidal silicon dioxide, is added to give a mixing time of 5 minutes, then the mixture is sieved by No. 30 mesh and placed in the "V" mixer together with the dye ([mixture of aluminum lacquers) previously sieved by No. 40 mesh, to be mixed for 5 minutes, then microcrystalline cellulose PH-112 previously sieved by No. 20 mesh is added, a mixing time of 20 minutes is given. On the other hand, USP talc is screened separately through No. 30 mesh and stearic acid, then the talc is added to the mixer and mixed for 2 minutes, finally the stearic acid is added and a mixing time of 5 minutes is given.

B) Compression process of the granulate for the formation of the tablet.

The compression process was carried out using a variable speed rotary tablet press with biconcave punches. The feeding speed and the i compression speed were adjusted to control the weight of the tablet.

Example 5. Prolonged Release Tablets of S (+) - Anfepramone Hydrochloride 37.5mg .. ' FORMULA * It evaporates during the process. cbp: how much is enough to is: sufficient quantity. i i DESCRIPTION OF THE MANUFACTURING PROCESS.

I A) Granulation process for S (+) - Anfepramone hydrochloride ^ 37.5 mg Prolonged Release Tablets.

I I 19 i In a high-cut granulation equipment, sieves are added beforehand by No. 30 mesh, S (+) - amphepramone hydrochloride, hydroxypropylcellulose EXF, microcrystalline cellulose PH-101, colloidal silicon dioxide, mixed for 10 minutes at 300 rpm. Main mixer and 1000 rpm of the cutting arm. Separately, the binder solution is prepared, purified water is added to a container of suitable capacity and, with continuous stirring, the tartaric acid is added and stirred until a homogeneous solution is formed. The granulation process is started by sprinkling the tartaric acid solution in the granulation equipment at a flow rate of 24 g / min, upon the addition of the solution add hypromellose (Methocel K15M) and give a mixing time of 8 minutes, At the end of the granulation, remove the wet granulate from the high cut granulator, place it in the fluid bed dryer and carry out the drying process under the following I conditions, entry air temperature between 45 C and 55 ° C, dry until the test of loss by drying is between 1 and 2%, the dry granulate is passed through No. 20 mesh in QuadroComil equipment. USP talc and stearic acid are sieved through No. 30 mesh. The dry granulate sb is added to a "V" mixer together with the talc and mixed for 2 minutes, finally the stearic acid is added and the a final mixing time of 5 minutes.

! B) Compression process of the granulate for the formation of the tablet.

The compression process was carried out using a rotary tablet press I variable speed with biconcave punches. The feeding speed and the compression speed were adjusted to control the weight of the tablet.

Example 6. Immediate Release Tablets of S (+) - Fenproporex Hydrochloride 5 mg.

FORMULA I twenty cbp: how much is enough for.

I DESCRIPTION OF THE MANUFACTURING PROCESS. 1 i A) Mixing process for direct compression of fenproporex hydrochloride 5 mg. Tablets Add to the mixer "S" (S) - Fenproporex hydrochloride, mannitol (Parteck M 200), colloidal silicon dioxide and mix for 5 minutes, then add crospovidone XL, hydroxypropylcellulose EXF and, give a mixing time After 5 minutes and at the end the mixture is sieved by No. 30 mesh, then the powder mixture is introduced into the "V" mixer and PH-102 microcrystalline cellulose pre-screened by No. 20 mesh is added. mixing time of 20 minutes, finally the magnesium stearate previously sieved by No. 30 mesh to be mixed for 5 minutes. I i B) Compression process of the granulate for the formation of the tablet.

The compression process was carried out using a variable speed rotary tablet press with biconcave punches. The feeding speed and the compression speed were adjusted to control the weight of the tablet.

I Example 7. Prolonged Release Labels of S (+) - Fenproporex Hydrochloride 10 mg. , FORMULA i I I I twenty-one 'It evaporates during the cbp process: How much is enough to is: Enough quantity.

DESCRIPTION OF THE MANUFACTURING PROCESS. i A) Granulation process for S (+) - Fenproporex Hydrochloride 10 mg. Prolonged Release Tablets.

Sift by No.30 mesh the S (+) - Fenproporex Hydrochloride, 50% of hydroxypropylcellulose EXF, mannitol (part M 200), microcrystalline cellulose PH-101, colloidal silicon dioxide, the sifted materials are added to a ! High cut granulator and mix for 10 minutes at 300 rpm of the main mixer and 1000 rpm of the cutting arm. Separately the agglutinate solution is prepared, in a container of suitable capacity purified water is added and with continuous stirring 50% of hydroxypropylcellulose EXF is added and the agitation is maintained until a homogeneous solution is formed. The granulation process is then carried out by sprinkling the binder solution in the granulation equipment at a flow rate of 18-24 g / min, upon completion of the addition of the solution add hypromellose (Methocel) and give an 8 minute mixing time , at the end of the granulation, remove the wet granulate from the high-cut granulator and place it in the fluid bed dryer; the drying process is carried out under the following conditions: inlet air temperature between 45 ° C and 5.5 ° C until the loss test by drying is less than 2%, the dry granulate is passed through No. 20 mesh in QuadroComil equipment. The magnesium stearate is sieved by No. 30 mesh. The dried granulate is added to a I mixer in "V" together with the magnesium stearate gives a mixing time of 5 minutes. i I I B) Compression process of the granulate for the formation of the tablet.

The compression process was carried out using a rotary tablet press I variable speed with biconcave punches. The feeding speed and the compression speed were adjusted to control the weight of the tablet.

I

Claims (9)

1. The drug S (+) - N-2-cyanoethylamphetamine with the generic name S (+) - fenproporex and its salts, characterized by the properties of the following hydrochloride salt: | 'a) A 1 H NMR spectrum with localized shifts in: 1.14 ppm (d, 3 H), 2.68 ppm (c, 1 H), 3.13 ppm (t, 2 H), 3.29 - 3.56 ppm (m, 5 H), 7.22 - 7.40 ppm (m, 5H). j b) A 13 C NMR spectrum with localized shifts in: 14. 40 ppm, 14.87 ppm, 38.11 ppm, 54.52 ppm, 117.52 ppm, 126.64 ppm, 128.43 ppm, 129.11 ppm, 136.55 ppm. j c) A spectrum of TF-Infrared with main absorptions located at: 3164 cm 1, 2258 cm 1, 1581 cm 1, d) A mass spectrum determined by the method he has Electron Impact with a molecular ion (M - 1) of187 e) A differential scanning calorimetric analysis with an endotherm located at 148.40 ° C.

2. The drug S (+) - 2-diethylaminopropiophenone with the generic name S (+) - diethylpropion and its salts, characterized by the following properties of the hydrochloride salt: a) A 1 H NMR spectrum with displacements located at: 1.52 ppm (t, 3 H), 1.56 ppm (t, 3 H), 1.83 ppm (d, 2 H), 3.32 - 3. 3 ppm (m, 1 H), 3.47 - 3.64 ppm (m, 3H), 5.44 - 5.52 ppm (m, 1H), 7.55 (t, 2H), 7.69 (t, 1H), 8.05 ppm (dd, 2H).; b) A 13 C NMR spectrum with displacements located in: 10. 12 ppm, 11.36 ppm, 15.46 ppm, 46.15 ppm, 47.03 ppm, 60.65 ppm, 128.70 ppm, 129.36 ppm, 133.53 ppm, 134.94 pfDm, 195.39 ppm. c) A spectrum of TF-Infrared with main absorptions located at: 3353cm1,1688cm1,1100cm1y750cm1 i ! d) A mass spectrum determined by the method of Chemical Ionization with a molecular ion (M + 1) of 206. e) A differential scanning calorimetric analysis with an endotherm located at 176.53 ° C.

3. The drug S (+) - 2-terbutylaminopropiophenone with the generic name S (+) - I bupropion and its salts, characterized by the following properties of the hydrochloride salt: a) A 1 H NMR spectrum with displacements located at: 1.39 ppm (s, 9H), 1.61 ppm (d, 3H), 5.39 ppm (t, 1 H), 7.69 ppm (t, 1H), 7.86 ppm (m, 1H), 8.24 ppm (m, 1H), 8.30 ppm (t, 1H), 8.68 ppm (broadband, 1H), 10.13 ppm (broadband, 1H). ' b) A 13 C NMR spectrum with displacements, located at: 17.96 ppm, 25.98 ppm, 52.95 ppm, 58.12 ppm, 127.74 ppm, 128.51 ppm, 131.20 ppm, 134.15 ppm, 134.24 ppm, 134.54 ppm, 195.40 ppm. i c) A spectrum of TF-Infrared with main absorptions located at: 3358, 1691, 1135, 740 cm 1. d) A mass spectrum determined by the XXX method with a molecular ion (M + 1) of 240 1 e) A differential scanning calorimetric analysis with an endotherm located at 243.06 ° C. i i

4. In accordance with clause 1, pharmaceutical compositions of immediate release and prolonged release employing as an active ingredient the drug S (+) - fenproporex or its pharmaceutically acceptable salts.

5. According to clause 2, pharmaceutical compositions of; immediate release and prolonged release using the drug S (+) - diethylpropion or its pharmaceutically acceptable salts as an active principle. i I

6. According to clause 3, pharmaceutical compositions of immediate release and prolonged release employing as an active ingredient the drug S (+) - bupropion or its pharmaceutically acceptable salts.

7. According to clauses 1 and 4 the use of pharmaceutical compositions for the control of appetite and the treatment of obesity containing as an active ingredient the drug S (+) - fenproporexo their pharmaceutically acceptable salts. !

8. According to clauses 2 and 5 the use of the pharmaceutical compositions developed for the control of appetite and the treatment of obesity containing as an active ingredient the drug S (+) - i diethylpropionate its pharmaceutically acceptable salts. !

9. In accordance with clauses 3 and 6 the use of pharmaceutical compositions developed for the control of appetite and the treatment of obesity containing as an active ingredient the drug S (+) - bupropion or its pharmaceutically acceptable salts i