MX2013010045A - Pharmaceutical compositions of 1-phenyl-2-aminopropane salts. - Google Patents

Abstract

Four pharmaceutical compositions have been developed using a mixture of enantiomers of 1-fenyl-2-amonopropane salts as an active principle. The salts do not contain the racemic shapes that have been usually incorporated in these type of formulations. According to the composition of the active and the development of the compositions, suitable profiles of dissolution have been achieved for an adequate treatment which is advantageous over current formulations. An oral formulation in the form of caplets of immediate release have been particularly developed as well as three formulations of long-lasting release, two in the form of caplets and the other in the form of hard gelatin capsules.

Description

PHARMACEUTICAL COMPOSITIONS OF 1-PHENYL-2-AMINOPROPAN SALTS FIELD OF THE INVENTION The purpose of the present invention is the development of new pharmaceutical compositions employing as active principle a mixture of 1-phenyl-2-aminopropane salts, used for the treatment of attention deficit hyperactivity disorder. The new pharmaceutical compositions offer a more effective and safe formulation than those commercially available today.

BACKGROUND In racemic 1-phenyl-2-aminopropane, both the enantiomer d-1-phenyl-2-aminopropane and l-1-phenyl-2-aminopropane exert their effects by binding to monoamine transporters and increasing extracellular levels of dopamine, norepinephrine and a smaller scale of serotonin. The d-1-phenyl-2-aminopropane acts mainly on the dopaminergic systems, while the l-1-phenyl-2-aminopropane acts mainly on the norepinergic systems. However, the effects of primary reinforcement and behavioral stimulation of 1-Phenyl-2-aminopropane are linked to a high dopaminergic activity, mainly in the dopaminemesolimbic system. In the specific case of d-1-Phenyl-2-aminopropane, this 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 caudate nucleus. This release of acetylcholine is through the activation of the dopamine Di receptor. The high cholinergic activity is likely to contribute to the nootropic effects that 1-Phenyl-2-aminopropane has on memory and learning (E. Braunwald, et al., Harrison's Principles of Internal Medicine, 5th Edition, Me Graw Hill, 2001 ).

The d-1-phenyl-2-aminopropane and the l-1-phenyl-2-aminopropane present different types of physiological action. D-1-Phenyl-2-aminopropane is several times more potent in the central nervous system than l-1-Phenyl-2-aminopropane, but the two enantiomers have comparable activity in the peripheral nervous system. The greater potency of d-1-Phenyl-2-aminopropane to the central actions suggests that this form has greater potential for assiduity.

A first-line medication in attention deficit hyperactivity disorder (ADHD) and narcolepsy is the mixture of 1-Phenyl-2-aminopropane salts, although it has also been prescribed for cognitive improvement, memory, depression, obesity, etc. Combined salts as active ingredients in pharmaceutical compositions have been shown to reduce the symptoms associated with ADHD and have minimal side effects. Compared with the alternative medication methylphenidate, the mixture of 1-Phenyl-2-aminopropane salts is slightly more potent and has a longer period of efficacy, especially at low doses. For patients with experience of adverse effects who do not find effective methylphenidate, the mixture of 1-Phenyl-2-aminopropane salts is often recommended as a substitute.

In the United States of America, the FDA approved in 1960 a drug called Obetrol, consisting of a mixture of 1-Phenyl-2-aminopropane salts. This formulation was used between 1965 and 1973 with the indication of exogenous obesity. The formulation consisted of equal amounts of two salts of methamphetamine, racemic 1-phenyl-2-aminopropane sulfate and d-1-phenyl-2-aminopropane sulfate. This formulation in 1973 was not considered effective and safe, according to the evaluation made by the FDA, so it was required to provide more clinical tests or withdraw the product from the market. However, there are data in the literature indicating that without providing the clinical tests requested by the FDA, Laboratorios Rexar Pharmacal, the owner of the drug at that time, continued to market it until 1993, when it became the property of Richwood Parmaceuticals. In June 1994 the drug was reformulated, prescribed for attention deficit hyperactivity disorder (ADHD), the name was changed to Adderall and it was launched on the market. Faced with these actions FDA ies called attention to prevent them from removing the product from the market, for having marketed the drug without authorization from the health authority. In response, Richwood Pharmaceuticals submitted its formulation before the FDA with the application "NDA 11 -522" for approval, which was obtained in March 1996. This same formulation is still being marketed to date, by Shire Laboratories, Inc., which in 1995 was merged with Richwood Pharmaceuticals.

The immediate release formulation authorized in 1994 for the first time by the FDA contained the excipients, colloidal silicon dioxide, compressible sugar, corn starch, magnesium stearate, microcrystalline cellulose and sodium saccharin. The active ingredient consisted of a mixture of four salts: d-1-phenyl-2-aminopropane sulfate, racemic 1-phenyl-2-aminopropane sulfate, racemic 1-phenyl-2-aminopropane aspartate and saccharate of d-1. -1-Phenyl-2-aminopropane. Later, dated July 1999 Shire Laboratories, Inc. submitted the PCT application number WO 01/05407, claiming a new immediate release formulation in which only some of the inactive excipients are changed.

Subsequently, Shire Laboratories, Inc., proposes the patent US 6,322,819 of November 27, 2001 (submitted on October 21, 1998), consisting of microgranules of sugars, coated with an enteric layer of delayed release, containing 50% of the active, which in turn is covered by an inert layer that acts as a separation of another layer of active immediate release, containing the remaining 50% of the active. The composition of the asset is similar to that used in the case of the immediate release tablet and corresponds to the traditional proportion of the four salts of 1-Phenyl-2-aminopropane that has been used since it was released in its new formulation of 1994. In patent US 6,605, August 300, 2003, Shire Laboratories, Inc. claims a new formulation consisting of three types of sugar microgranules, some are immediate release microgranules, others are delayed-release microgranules called "pulse" "or type 1 and others are delayed release or" sustained "or type 2 microgranules.

Various other proposals for sustained release formulations have been presented by Shire Laboratories, Inc., as it is in the patent US 6,913,768 of March 25, 2004, in which they use two types of microgranules coated with active, a type of immediate release and another type of sustained release. Likewise, other authors using the traditional mixture of 1-Phenyl-2-aminopropane salts as an active ingredient have developed new delayed-release compositions, as in the patent US 2004/0220277 of February 10, 2004 and in the patent application US 2006 / 0204575 of September 14, 2006.

The purpose of the present invention is the development of a new pharmaceutical composition of immediate release in the form of a tablet, which offers advantages over the traditional formulation used in the mixture of commercially available 1-Phenyl-2-aminopropane salts. Also, three new pharmaceutical compositions have been developed in the present invention, two in the form of controlled release tablets and one in the presentation of controlled release capsules, which allow a more effective release for the treatment of the ADHD condition.

BRIEF DESCRIPTION OF THE FIGURES The foregoing aspects and many of the advantages related to this invention will be more readily appreciated if they become better understood by reference to the following descriptions when taken in conjunction with the accompanying figures.

FIGURE 1. Shows the dissolution profile of immediate release tablets (Ll) compared to the dissolution profile of microgranules containing the immediate release drug described in US Pat. No. 6,322,819, Example 1, Figure 3 and compared with the profile of dissolving microgranules containing the immediate-release drug described in patent application US2006 / 0204575, Example 1, Figure 2. The formulation and the manufacturing process of this invention are described in Example 1.

FIGURE 2. Shows the dissolution profile of tablets with immediate release drug coating, which is released in a two-hour interval (pH 1.1) and a matrix with extended release drug (pH 6.8). The formulation and the manufacturing process of this invention are described in Example 2.

FIGURE 3. Shows the dissolution profile of immediate release drug coated tablets and extended modified release drug coating system. The profile has been achieved to be similar to that shown in example 2. The formulation and the manufacturing process of this invention are described in Example 3.

FIGURE 4. Shows the dissolution profile of capsules with microgranules coated with immediate release drug and extended drug release coating system. The profile has been achieved to be similar to that shown in Example 2. The formulation and the manufacturing process of this invention are described in Example 4.

FIGURE 5. Delayed or extended release profile according to the procedure described in example 2, compared to the dissolution profile of delayed release microgranules described in US Pat. No. 6,913,768, Example 10, and compared with the dissolution profile of microgranules of release delayed described in the application US2006 / 0204575, Figure 1.

FIGURE 6. Delayed or extended release profile according to the one described in example 3, compared with the microgranules dissolution profile described in the patent US 6,913,768, Example 10 and compared with the dissolution profile of delayed release microgranules according to the application US 2006/0204575, Figure 1.

FIGURE 7. Delayed or extended release profile according to that described in example 4 compared to the delayed release microgranule dissolution profile described in US Pat. No. 6,913,768 Example 10 and compared with the dissolution profile of delayed release microgranules according to US application 2006/0204575, Figure 1.

DESCRIPTION OF THE INVENTION The purpose of the present invention is the development of pharmaceutical compositions that have greater efficacy or advantages in the supply of the active principles, consisting of a mixture of 1-phenyl-2-aminopropane salts. The innovative product formulation that is currently marketed consists of a combination of racemic 1-phenyl-2-aminopropane salts with d-1-phenyl-2-aminopropane salts, in such proportion that the ratio of salts of d-1- Phenyl-2-aminopropane and l-1-Phenyl-2-Aminopropane is 3 to 1. The ratio of the mixture of salts is adequate for the pharmacodynamic and pharmacokinetic properties of each enantiomer to favor the treatment of ADHD. Thus, l-1-Phenyl-2-aminopropane will act mainly on the norepinephrine systems while d-1-Phenyl-2-aminopropane will act mainly on the dopaminergic systems. However, the effects of primary reinforcement and behavioral stimulation of 1-Phenyl-2-aminopropane are linked to a high dopaminergic activity. Dextro-1-Phenyl-2-aminopropane is several times more potent in the central nervous system than levo-1-Phenyl-2-aminopropane, but the two enantiomers have comparable activity in the peripheral nervous system. The half-life of the two enantiomeric forms of 1-Phenyl-2-Aminopropane varies with the age of the patients and the stereochemistry of the salts. D-1-Phenyl-2-aminopropane is metabolized more rapidly than l-1-Phenyl-2-aminopropane. In adults, the half-life of d-1-Phenyl-2-aminopropane is 10 hours and the levo form is 13 hours. For ages between 13 and 17 the average life of the dextro form is 1 1 hours, while the average life is 13 to 14 hrs. For children aged 9 to 12 years, the average life of the dextro form is 9 hours while the average life is 11 hours. It is this complementarity of pharmacological activities, half-lives and the adequate proportion of each enantiomer and each salt, which allows obtaining favorable results in the treatment of ADHD. That is, the pharmacokinetic and pharmacodynamic effects are influenced by the type of salt, its assimilation, its solubility, its half-life and also by the formulation and excipients that are used in the pharmaceutical composition. So, with the proportion The use of 1-Phenyl-2-aminopropane salts in the formulation has found that the l-1-Phenyl-2-aminopropane form favors faster assimilation and a longer lasting effect than the mixture of salts with d-1- Phenyl-2-aminopropane alone. Inclusively, it has been found that certain children have a better clinical response to l-1-Phenyl-2-aminopropane in the treatment of ADHD.

The immediate release formulation currently marketed by Shire Laboratories, Inc. contains the following inactive excipients: colloidal silicon dioxide, compressible sugar, corn starch, magnesium stearate, microcrystalline cellulose and sodium saccharin. The active substance being the mixture of the following salts: d-1-phenyl-2-aminopropane sulfate, racemic 1-phenyl-2-aminopropane sulfate, racemic 1-phenyl-2-aminopropane aspartate and d-1 saccharate. -Fenyl-2-aminopropane.

The presentation of 5 mg does not contain dyes, but from the presentation of 7.5 mg they contain aluminum lacquer FD &C blue # 1, or aluminum lacquer FD &C yellow # 6.

Subsequently, Shire Laboratories, Inc. proposed a new formulation of immediate release, using as active ingredient the same traditional mixture of salts but changing some of the inactive excipients (patent application MX PA02000290 or patent US 6,384, 020). The novelty of the new patent is based on the use of a vehicle, the polyol called lactitol. This formulation arises as a solution to the problem generated by the presence of compressible sugar, inactive ingredient that in contact with the amines of the active principle propitiate the Maillard reaction, which results in the formation of brown pigments. This leads to the degradation of the active ingredients, which is why the established stability requirements are not met. This phenomenon is more intense in the case of tablets so that in this presentation even the properties of compressibility and rapid release are altered. With this basis it has been proposed that in general it is desirable to avoid the occurrence of the Maillard reaction, if it is desired to maintain the fast release properties in a formulation of tablets or another in which there is an intimate contact between the components of the formulation. With this base, Shire Laboratories, Inc. in its new patent application (MX PA02000290) justifies the replacement of the compressible sugar by lactitol, which maintains the physical and chemical properties of the composition during the necessary time of stability, also favors the compressibility and the characteristics of an immediate-release tablet. Also, in this patent it is claimed that the composition includes microcrystalline cellulose, wherein the ratio between lactitol and microcrystalline cellulose is from 2 to 5: 0 lactitol per 25 to 1.75 microcrystalline cellulose.

In the cited patent application MX PA02000290 it is disclosed that other polyols, such as mannitol and sorbitol, "do not provide the required characteristics of formulation processing for 1-Phenyl-2-aminopropane tablets". Testing with 1500 starch and 2080LF mannitol, the authors find, when compressing, "unsatisfactory flow properties and stickiness problems, which prevents the compression process even with high compression forces". They mention that, when repeating the test with 1,500 starch and lactitol, there were also irregular flow properties, but adding avicel PH 302 achieved a successful result. However, they do not describe that they have carried out this same test with mannitol, starch 1500 and avicel PH 302, which could have changed their results, maintaining mannitol as a viable excipient.

On the other hand, it should be mentioned that lactitol in medicine is used for the treatment of hepatic encephalopathy in children, and it has been recommended that prolonged use should be avoided. It is also noted as a contraindication in hypersensitivity to lactitol, and in cases of autosomal recessive hereditary intolerance to lactitol. Because, in a good number of cases during the treatment of ADHD, patients are infants, between 5 years and 15 years, the frequent use of a medication with such contraindications is not desirable (Pediamécum, Committee of Medicines of the Spanish Association of Pediatrics, 2012. Edition available at http://www.pediamecum.es.).

In the present invention, for the immediate release formulation, the use of mannitol brand Parteck 200 is proposed, which unlike the mannitol 2080LF used in the aforementioned patent application, has the characteristic of having a humidity less than or equal to 0.50% and with a particle size distribution such that 15% of the particles are less than 53 microns and less than 15% of the particles are greater than 500 microns. These features of the Parteck M 200 mannitol give an excellent flow to the granulate. Thus, when mixing mannitol with microcrystalline cellulose (avicel PH 112 or vivapur 112 or emeocel XLM 90, all with moisture values lower than 1.5%, a mixture with excellent compressibility properties is obtained.) To avoid any problem of adhesion of the granulate to the surface of the punches was used as a vegetable magnesium stearate lubricant of the Parteck LUB MST brand, where 10% of its particles are less than 1 miera, 50% of its particles are 5 microns and 90% of its particles are particles are less than 20 microns.The final pharmaceutical composition allowed us to perform a good compression process obtaining tablets with hardness between 6 and 10 kilopounds.This favorable result is attributed to the low humidity achieved when using low humidity microcrystalline celluloses (less than 1.5 %) and anhydrous mannitol (0.1% moisture) In the examples section the formulation and description of the manufacturing process of the farm composition is shown immediate release in the form of tablets.

In the case of the present invention, the ratio of salts of d-1-phenyl-2-aminopropane to 1-1-phenyl-2-aminopropane of 3 to 1, as used, is maintained for the immediate release formulation. in the traditional formulation. But, the mixture of salts is constituted only by the enantiomeros dextro and levo, without recourse to any racemic form. Then, the proportion of each salt for the dose of 5 milligrams (mg) is as follows: FORMS I - 0.625 mg of l-1-phenyl-2-aminopropane aspartate monohydrate (MW = 286), corresponding to 0.295 mg of l-1-phenyl-2-aminopropane. - 0.625 mg of l-1-phenyl-2-aminopropane sulfate (MW = 368.49) corresponding to 0.458 mg of l-1-phenyl-2-aminopropane FORMS d - 1,875 mg of d-1-phenyl-2-aminopropane sulfate (MW = 368.49) corresponding to 1,374 mg of d-1-phenyl-2-aminopropane - 1.25 mg of d-1-phenyl-2-aminopropane saccharate (MW = 480.56) corresponding to 0.7114 mg of d-1-phenyl-2-aminopropane - 0.625 mg of d-1-phenyl-2-aminopropane aspartate (MW = 286) corresponding to 0.295 mg of d-1-phenyl-2-aminopropane.

TOTAL 1-PHENYL-2-AMINOPROPAN BASE EQUIVALENCE = 3.13 MG FORMS RELATIONSHIP d / l = 3.1 The relationships for the rest of the presentations with the greatest amount of active ingredients: 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 30 mg being linear, the proportions are calculated directly.

The rationale for using only dextro and levo forms, avoiding the use of racemic forms, is based on the criteria used to establish the bioequivalence of delayed-release formulations in the innovative Adderall XR. The criterion consists in quantifying in plasma during the pharmacokinetics only the two analytes d-1-Phenyl-2-aminopropane and l-1-Phenyl-2-aminopropane (Draft Guidance, CFR 320.24 (b) (6) of September 2012). This indicates that the use of racemic forms combined with the dextrorotatory forms does not influence in any way the bioavailability of the active forms. It can also be taken into account that in the new controlled release formulation of Shire (patent US 6,913, 768), constituted by two types of microgranules both coated with the same traditional mixture of salts, some of immediate release and others of sustained release, for evaluate the bioavailability is used only the pharmacokinetics of the levo and dextro forms, regardless of the participation of racemic forms or the use of different salts. In the patent it is indicated that the pharmacokinetics for each of the forms show to be continuous (Medication Guide Rev. 01/2013, Shire Laboratories, Inc.), which shows that the existence of 5 different types of salts in the mixture of 1-Phenyl-2-aminopropane used does not modify the absorption of any of the enantiomeric forms, being the type of enantiomer dextro or levo what influences predominantly in the absorption, without the possible difference of solubilities of the 5 salts that are used (3 salts in the form of the enantiomer dextro and 2 in the form of the enantiomer levo) impact the pharmacokinetic curve of each of the enantiomers.

Also, in the PCT application with WO 2004/071501 Shire laboratories, Inc, has simplified its formulation to only two active, the enantiomers dextro and levo, but from the same salt, using each enantiomer in different proportions (depending on the time of the day different dosage is released, taking as reference the 13 hours). This allows to conclude that regardless of the use of 5 different salts what is relevant is the proportion of levo and dextro enantiomers and not the presence of racemic forms (WO 2004/071501).

Based on the above, in the present invention only the dextro and levo active forms are used, without introducing racemic forms, which facilitates the pharmacokinetic monitoring and gives greater cleanliness to the components of the asset. This represents a great advantage of the formulation compared to other compositions existing in the market In addition to the immediate release composition, three controlled release pharmaceutical compositions have been developed as part of the present invention. The characteristics of the three controlled release compositions developed in the present invention are described below. 1. Controlled release composition, described in Example 2. The present invention consists of an oral dosage form, wherein the dosage form is a tablet that will be considered as a core and contains one or more salts of 1-Phenyl-2-aminopropane. However, the release form of the drug corresponds to a so-called pulsatile release that makes it possible to achieve a more uniform level of drug in the blood compared to administration than in divided doses.

The use of two layers that allows the combination of an immediate release layer and a modified release layer is considered relevant in this invention. The immediate release layer reduces the time to reach the minimum therapeutic dose for the patient, while the modified release layer provides a maintenance dose, considering that the nucleus does not form a conventional release matrix, this formula uses a polymer that gives origin to a hydrophilic matrix to control the diffusion mechanism of the drug for its release. Once the tablet is formed and exposed in an aqueous medium, the surface drug is rapidly released and a gel layer is formed around the tablet, which is responsible for regulating drug release by diffusion; the components soluble in the formulation form canaliculi, which favor the release of the drug.

The tablets are coated with a suitable pH-dependent coating, said coating is sprinkled on the surface of the tablet in a rotating coating pan. To have a suitable coating the addition between 4 mg / cm2 to 8 mg / cm2 of the dry polymer around the surface of the tablet is considered, this results in an increase in relative weight to the tablet of 2 to 10%, the coating presents a thickness between 0.05 mm to 0.5 mm.

The materials and their mixtures that can be used in this invention to form the enteric coating layer in the tablet include various polymethacrylate polymers, co-processed polyvinyl acetate phthalate, cellulose acetate phthalate, Shellac, hydroxypropylmethylcellulose phthalate polymer and their copolymers.

The coating material is selected in such a way that it is insoluble in the stomach, ie at an acid pH between 1.5 and 2 and soluble in the small intestine, (duodenum pH 6.5-7.6, jejunum pH 6.3-7.3, ileum pH 6.9- 7.9), frequently the coating polymer is soluble at a pH of 4.5 or greater.

The polymer used to enter enteric coating of the tablets is a copolymer of methacrylic acid (acryl-EZE) that is insoluble at acid pH, but it dissolves at a pH of 5.5. This guarantees that upon reaching a higher pH in the intestine, the coating dissolves increasing the exposed surface of the nucleus which increases the availability of the drug contained in the tablet, however it is controlled, since the core is formulated to ensure that the maintain an extended release speed.

The materials that can be used as a base for the immediate-release coating solution or dispersion containing one or more salts of 1-phenyl-2-aminopropane are polyvinyl alcohol and its derivatives, cellulose and its derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, xanthan gum.

Once the enteric coating is applied on the surface of the tablet, the immediate release coating containing one or more salts of 1-phenyl-2-aminopropane is applied, for which a coating system based on polyvinyl alcohol is prepared ( opadry II) containing the salt or salts of 1-Phenyl-2-aminopropane and applied to the surface of the tablet.

The salts contained in the immediate release coating are released in a time of 15 minutes to 30 minutes. The release of the salts contained in the hydrophilic matrix occurs after 2 hours, its release ending between 6 hours and 8 hours, preferably between 6 and 7 hours. Example No. 2 2. Controlled release composition, described in Example 3. Another development achieved in the present invention consists of an ordinary disintegration tablet (disintegration in less than 30 minutes) with an immediate release coating, containing 50% of the dose of the salt or salts of 1-Phenyl-2-aminopropane and the other remaining 50% is contained in the interior of the tablet, which is coated with a thin layer of extended release (ethylcellulose (surelease®), applied until 4.0 is achieved % increase in weight), said polymer is combined with hydroxypropylmethylcellulose (opadry®), which upon dissolving forms pores on the surface of the coating favoring the release of the drug.

Coating layer in conjunction with the enteric coating (pH-dependent) form an extended modified release system. The salts contained in the immediate release coating are released in a time of 15 minutes to 30 minutes. The delayed or extended release coating layer begins its release after 2 hours, its release ending between 6 hours and 8 hours, preferably between 6 and 7 hours. Example 3 3. Controlled Release pharmaceutical composition, described in Example 4. A process for the manufacture of a multiparticulate product is also discussed here, that is, by coating processes of sugar microgranules with 1-phenyl-2-aminopropane salts. US Pat. No. 6,322,819 describes the use of a non-pH-dependent polymer as a gastric resistance coating, which in turn is also responsible for controlling the release of the drug, this type of coating has the drawback of having to apply a cover sufficiently thick (between 8-18% increase in weight) to avoid that the active is not released in the stomach and therefore as soon as the product passes to the intestine there would be no strict control of the drug's release site. On the other hand, if the non-pH-dependent coating polymer is combined with a soluble pore-forming polymer, then the release of the drug would start in the stomach before the time required for the second dosage of the drug.

Based on the foregoing, in this invention a polymer is used for enteric pH dependent coating, that is to say that it does not dissolve at acid pH of the stomach (between 1.5 and 2) and offers an adequate gastric resistance avoiding the release of the drug, but when passing from the stomach to the intestine where the pH of the medium is basic (between 6.5 and 7.9) enteric coating polymer dissolves rapidly exposing the thin layer of extended release coating (ethylcellulose (surelease®), applied until 4.0% increase in weight is achieved), said polymer is combined with hydroxypropylmethylcellulose (opadry®) which upon dissolving forms pores on the surface of the coating favoring drug release, this coating layer in conjunction with the enteric coating (pH-dependent) form a release system modified extended. The coated microgranules are dosed in hard gelatin capsules for administration. The release of the salts coated with the delayed release layer begins after 2 hours of supplying the medicament and terminating its release between 6 hours and 8 hours, preferably between 6 and 7 hours. Example No 4 The Examples that are described below illustrate 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 they imply variations on this proposal, so the patent is not limited to these examples.

EXAMPLES Example 1. Pharmaceutical composition of Immediate Release. Tablets of 5 mg. It contains as active ingredient a mixture of 5 salts: l-1-phenyl-2-aminopropane sulfate, l-1-phenyl-2-aminopropane aspartate monohydrate, d-1-phenyl-2-aminopropane aspartate monohydrate, d-1-Phenyl-2-aminopropane sulfate, d-1-phenyl-2-aminopropane saccharate.

DESCRIPTION OF THE MANUFACTURING PROCESS.

Sift by No. 40 mesh the salts of 1-Phenyl-2-Aminopropane, and the colloidal silicon dioxide and mix them for 2 min, add 10% of pre-screened mannitol by No. 20 mesh and mix for 5 minutes, add the remaining amount of mannitol, hydroxypropylcellulose, crospovidone, microcrystalline cellulose and sucralose previously sieved by No. 20 mesh and mix for 15 minutes, add the vegetable magnesium stearate to the mixture and mix for 5 minutes. The mixture of powders was compressed in a rotary machine obtaining tablets with a hardness of 6 to 10 Kp.

EXAMPLE 2. Prolonged Release Tablets. Tablets 20 mg. Contains as active ingredient a mixture of 5 salts: l-1-phenyl-2-aminopropane sulfate, l-1-phenyl-2-aminopropane aspartate monohydrate, d-1-phenyl-2-aminopropane aspartate monohydrate, d-1-Phenyl-2-aminopropane, d-1-phenyl-2-aminopropane saccharate.

FORMULA Component mg Tablet * It evaporates during the process DESCRIPTION OF THE MANUFACTURING PROCESS.

A) Granulation process for the controlled release of the tablet.

At the beginning all the components of the formulation are screened by No. 40 mesh to favor the obtaining of a homogeneous mixture. 50% of the salts of 1-Phenyl-2-Aminopropane together with the microcrystalline cellulose PH-101 and mannitol are added to the high-cut granulation equipment, mixed for 10 minutes at 300 rpm of the main mixer and 1000 rpm of the arm of cut. Separately, the binder solution is prepared, purified water is added to a container of suitable capacity and, with continuous stirring, the polyvidone K29 / 32 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 24 g / min. At the end of the granulation, the wet granulate is removed from the high cut granulator and placed in the fluid bed dryer. , to perform the drying process under the following conditions, inlet air temperature of 70-85 ° C until the loss test by drying is less than 0.7% to 2.5%, the dry granulate is passed through mesh No 20 on a Quadro Cornil device. The hydroxypropylmethylcellulose and the colloidal silicon dioxide are screened by No. 20 mesh and mixed with the dry granulate of the 1-Phenyl-2-Aminopropane salts for 10 minutes. The magnesium stearate lubricant is sieved through No. 30 mesh and mixed with the granulate of 1-Phenyl-2-Aminopropane salts for 5 minutes.

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

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

C) Modified release coating (enteric coating) on the surface of the controlled release tablet.

The process of coating tablets with the enteric coating polymer is prepared in the following way, adding in a container of adequate capacity purified water at room temperature (between 20 ° C to 35 ° C) and with continuous stirring add the coating polymer enteric acryl-EZE, keep stirring for 20 minutes and then finish sieving the dispersion by No. 60 mesh (250 μ) to remove any aggregate, keep stirring the dispersion throughout the coating process. The coating dispersion is sprinkled on the tablets (cores) using a coating drum under the following conditions, inlet air temperature 40-65 ° C, product temperature 29 to 35 ° C, outlet air temperature 25 at 32 ° C, spray pressure from 1.5 to 2.6 bar, spray speed from 8 to 16 g / min.

D) Final coating of immediate release containing the salts of 1-Phenyl-2-Aminopropanes.

The process of coating tablets with the immediate release coating polymer is prepared in the following way, adding purified water at room temperature (between 20 ° C and 35 ° C) in a container of adequate capacity and adding the polymer with continuous stirring. of coating opadry II, maintain the agitation for 10 minutes and add the remaining 50% of the salts of 1-Phenyl-2-Aminopropane and stir for 15 minutes at 600 rpm or until the dispersion is homogeneous. The coating dispersion considers 5% of excess salt or salts of 1-Phenyl-2-Aminopropane, to compensate for the loss of the active during the coating process it is necessary to maintain the agitation of the dispersion throughout the coating process, to preserve a homogeneous dispersion. The coating dispersion is sprinkled on the tablets (cores) using a coating drum under the following conditions, inlet air temperature of 58 ° C to 65 ° C, product temperature of 42 ° C to 48 ° C, temperature of the product. output air from 37 ° C to 42 ° C, spray pressure from 1.5 to 2.6 bar. Spray speed from 8 to 16 g / min.

EXAMPLE 3. Prolonged Release Tablets. Tablets 20 mg. Contains as active ingredient a mixture of 5 salts: l-1-phenyl-2-aminopropane sulfate, l-1-phenyl-2-aminopropane aspartate monohydrate, d-1-phenyl-2-aminopropane aspartate monohydrate, d-1-Phenyl-2-aminopropane, d-1-phenyl-2-aminopropane saccharate.

FORMULA * Considers 50% of the total amount of 1-Phenyl-2-aminopropane salts.

** It evaporates during the process.

DESCRIPTION OF THE MANUFACTURING PROCESS.

A) Granulation process for the controlled release of the tablet.

At the beginning all the components of the formulation are screened by No. 40 mesh, to favor obtaining a homogeneous mixture. 50% of the salts of 1-Phenyl-2-Aminopropane together with microcrystalline cellulose PH-01 and mannitol are added to the high-cut granulation equipment, mixed for 10 minutes at 300 rpm of the main mixer and 1000 rpm of the cutting arm. The agglutinate solution is prepared separately, purified water is added to a container of suitable capacity and with continuous agitation, the polyvidone K 29/32 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 24 g / min. At the end of the granulation, the wet granulate is removed from the high cut granulator and placed in the fluid bed dryer. , to perform the drying process, under the following conditions, inlet air temperature from 70 ° C to 85 ° C until the loss test by drying is less than 0.7% to 2.5%, the dry granulate is passed through No. 20 mesh on a Quadro Cornil device. The colloidal silicon dioxide is screened by No. 20 mesh and mixed with the dry granulation of the 1-Phenyl-2-Aminopropane salts for 10 minutes. The magnesium stearate lubricant is sieved through No. 30 mesh and mixed with the granulate of 1-Phenyl-2-Aminopropane salts for 5 minutes.

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

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

C) Extended release coating layer.

The tablets are coated with a thin layer of extended release coating, for which the Surelease® coating polymer is prepared in the following manner. Add in a container of adequate capacity purified water at room temperature (between 20 ° C and 35 ° C) and with continuous stirring add the surelease ® coating polymer, maintain the agitation for 10 minutes and add the corresponding part of opadry® ( responsible for forming channels that favor the release of the drug) and maintaining the agitation for 30 minutes, maintain the agitation of the dispersion throughout the coating process. The coating dispersion is sprinkled on the cores using a coating drum under the following conditions, inlet air temperature between 55 ° C and 75 ° C, product temperature between 28 ° C and 48 ° C, spray pressure between 1 and 3 bars, spray speed from 8 to 20 g / min.

D) Modified release coating (enteric coating) on the extended release coating layer.

The process of coating tablets with the enteric coating polymer is prepared in the following way, adding in a container of adequate capacity purified water at room temperature (between 20 ° C and 35 ° C) and with continuous stirring add the coating polymer enteric acryl-EZE, maintain the agitation for 20 minutes and then finish sifting the dispersion by No. 60 mesh (250 μ) to remove any aggregate, maintain the agitation of the dispersion during the entire coating process. The coating dispersion is sprinkled on the tablets (cores) using a coating drum under the following conditions, inlet air temperature 40-65 ° C, product temperature 29-35 ° C, outlet air temperature between 25 ° C C and 32 ° C, spray pressure between 1.5 and 2.6 bar, spray speed from 8 to 16 g / min.

F) Final coating of immediate release containing the salts of 1-Phenyl-2-aminopropane.

The process of coating tablets with the immediate release coating polymer is prepared in the following manner, adding purified water at room temperature (between 20 ° C and 20 ° C) to a container of adequate capacity. 35 ° C) and with continuous stirring add the coating polymer opadry II, keep stirring for 10 minutes and add the remaining 50% of the salts of 1-Phenyl-2-Aminopropane and stir for 15 minutes at 600 rpm or until the dispersion is homogeneous. The coating dispersion considers 5% of excess salt or salts of 1-Phenyl-2-Aminopropane to compensate for the loss of the active during the coating process, it is necessary to maintain the agitation of the dispersion throughout the coating process for keep a homogeneous dispersion. The coating dispersion is sprinkled on the tablets (cores) using a coating drum under the following conditions, inlet air temperature between 58 ° C and 65 ° C, product temperature between 42 ° C and 48 ° C, temperature of the product. output air between 37 ° C and 42 ° C, spray pressure between 1.5 and 2.6 bar, spray speed from 8 to 16 g / min.

EXAMPLE 4. Prolonged Release Capsules. Capsules 20 mg. It contains as active ingredient a mixture of 5 salts: l-1-phenyl-2-aminopropane sulfate, l-1-phenyl-2-aminopropane aspartate monohydrate, d-1-phenyl-2-aminopropane aspartate monohydrate, d-1-Phenyl-2-aminopropane, d-1-phenyl-2-aminopropane saccharate.

FORMULA * It evaporates during the process DESCRIPTION OF THE MANUFACTURING PROCESS.

This formulation follows an advantageous strategy over that used in Adderall XR, by using a prolonged release polymer before the enteric coating, which allows to extend the time of release of the drug in the intestine further. This would modernize the type of release, which has been reported in more recent patents, it is required to extend the release time for better results in the treatment of ADHD (PCT Application number WO 2007/33203).

(The inactive ingredients of the Adderall XR capsules are: hydroxypropylmethylcellulose, methacrylic acid copolymer, beige opadry, sugar spheres, talcum, and triethyl citrate The active ingredients are: dextrus saccharate-phenyl-2-aminopropane, 1-phenyl aspartate -2-Racemic Aminopropane, sulfate dextrol-Phenyl-2-Aminopropane, racemic 1-phenyl-2-aminopropane sulfate. This information is given here, for comparison with the proposal in this invention and highlight its differences and advantages).

A) Coating of the drug. Fraction 1 The process of coating microgranules with the immediate release coating polymer is prepared in the following way, adding in a container of adequate capacity purified water at room temperature (between 20 ° C and 35 ° C) and with continuous stirring add 50%. % hypromellose coating polymer 2910 (methocel E6LV), keep stirring for 30 minutes and add 50% of the 1-Phenyl-2-Aminopropane salts and stir for 15 minutes at 600 rpm or until the dispersion is homogeneous, I finish sifting the dispersion through No. 60 mesh (250 μ) to remove some aggregate. The coating dispersion should consider 5% excess salt or salts of 1-Phenyl-2-aminopropane to compensate for the loss of the active during the coating process, it is necessary to maintain the dispersion agitation throughout the coating process to preserve a homogeneous dispersion. The coating dispersion is sprinkled on the microgranules (cores) using a fluid bed equipment with Wurster column (Glatt GPCG-3 w / Wurster) under the following conditions, inlet air temperature between 58 ° C and 65 ° C, temperature of the product between 38 ° C and 42 ° C, outlet air temperature between 35 ° C and 40 ° C spray pressure between 1.5 bar and 2.6 bar, spray speed from 8 g / min to 21 g / min.

B) Extended release coating layer.

The microgranules coated with the 1-Phenyl-2-aminopropane salts of the exercise (A) of this formula are applied a thin layer of extended release coating, for which the surelease® coating polymer is prepared in the following manner. Add in a container of adequate capacity purified water at room temperature (between 20 ° C and 35 ° C) and with continuous stirring add the surelease® coating polymer, maintain the stirring for 10 minutes and add the corresponding part of opadry® (responsible of forming channels that favor drug release) and agitation is maintained for 30 minutes, keep stirring the dispersion throughout the coating process. The coating dispersion is sprinkled on the cores using a fluid bed equipment with Wurster column (Glatt GPCG-3 wA / Vurster) under the following conditions, inlet air temperature between 55 ° C and 75 ° C, product temperature between 28 ° C and 48 ° C, spray pressure between 1 and 3 bar, spray speed from 8 to 20 g / min.

C) Modified release coating (enteric coating) on the surface of the microgranules of exercise (B) of this formula.

The process of coating the cores with the enteric coating polymer is prepared in the following manner, adding purified water at room temperature (between 20 ° C and 35 ° C) in a container of adequate capacity and adding the polymer of continuous stirring. enteric coating acryl-EZE, maintain the agitation for 20 minutes and at the end sieve the dispersion by No. 60 mesh (250 μ) to remove any aggregate. It is required to maintain the agitation of the dispersion throughout the coating process. The coating dispersion is sprinkled on the cores using a fluid bed equipment with Wurster column (Glatt GPCG-3 w / Wurster) under the following conditions, inlet air temperature between 40 ° C and 70 ° C, product temperature between 29 ° C and 32 ° C, outlet air temperature between 26 ° C and 30 ° C, spray pressure between 1.5 and 2.0 bar, spray speed from 8 to 21 g / min.

D) Protective coating between enteric coating and final coating with 1-Phenyl-2-Aminopropane salts.

A coating is applied to the enteric-coated microgranules as a protective coating that separates the enteric layer from the layer containing the 1-phenyl-2-aminopropane salts. The coating to be used for this purpose is opadry® and it is prepared in the following way, adding purified water at room temperature (between 20 ° C and 35 ° C) in a container of adequate capacity, and with continuous stirring add the coating polymer opadry ®, keep stirring for 30 minutes or until the dispersion is homogeneous. The coating dispersion is sprinkled on the microgranules using a fluid bed equipment with Wurster column (Glatt GPCG-3 w / Wurster) under the following conditions, inlet air temperature between 58 ° C and 65 ° C, product temperature between 38 ° C and 42 ° C, outlet air temperature between 35 ° C and 40 ° C, spray pressure between 1.5 and 2.6 bars, spray speed from 8 to 20 g / min.

E) Final coating of the immediate release drug containing the 1-phenyl-2-aminopropane salts. Fraction 2 The same process described in exercise (A) of this formulation is carried out again. Finally, a final protective coating can be applied or not using opadry® with an increase in weight of 2%.

Claims (3)

1. An immediate release pharmaceutical composition consisting of an active principle formed by the mixture of salts: 1-1-sulfate-2-aminopropane sulfate, l-1-phenyl-2-aminopropane aspartate monohydrate, d-1- aspartate monohydrate Phenyl-2-aminopropane, d-1-phenyl-2-aminopropane sulfate, d-1-phenyl-2-aminopropane saccharate and with the inactive excipients: colloidal silicon dioxide, mannitol (Parteck M 200), hydroxypropylcellulose, crospovidone , microcrystalline cellulose PH-112, sucralose, vegetable magnesium stearate (Parteck LUB MST), in the proportions indicated in example 1 and according to the manufacturing process described in the same example.

2. A prolonged-release pharmaceutical composition consisting of an active ingredient formed by the mixture of salts: 1-1-sulfate-2-aminopropane sulfate, l-1-phenyl-2-aminopropane aspartate monohydrate, d-1- aspartate monohydrate Phenyl-2-aminopropane, d-1-phenyl-2-aminopropane sulfate, d-1-phenyl-2-aminopropane saccharate and with the inactive excipients: colloidal silicon dioxide, mannitol (Parteck M 200), polyvidone K29 / 32, PH 101 microcrystalline cellulose, hydroxypropylmethylcellulose (HPMC), vegetable magnesium stearate (Parteck LUB MST) and with acry-LEZE coating (methacrylic acid copolymer type C) and opadry II (polyvinyl alcohol base), using the proportions indicated in Example 2 and according to the manufacturing process described in the same example.

3. A prolonged-release pharmaceutical composition consisting of an active ingredient formed by the mixture of salts: 1-1-sulfate-2-aminopropane sulfate, l-1-phenyl-2-aminopropane aspartate monohydrate, d-1- aspartate monohydrate Phenyl-2-aminopropane, d-1-phenyl-2-aminopropane sulfate, d-1-phenyl-2-aminopropane saccharate and with the inactive excipients: colloidal silicon dioxide, mannitol (Parteck M 200), polyvidone K29 / 32, PH 101 microcrystalline cellulose, vegetable magnesium stearate (Parteck LUB MST); using for the extended release coating layer the following excipients: surelease® (ethylcellulose dispersion), opadry® (hydroxypropylmethylcellulose); using for the enteric coating layer acry-LEZE (copolymer of methacrylic acid type C) and for the coating of the drug opadry II (base-polyvinyl alcohol), in the proportions indicated in example 3 and according to the manufacturing procedure described in same example. A prolonged-release pharmaceutical composition consisting of an active ingredient formed by the mixture of salts: 1-1-sulfate-2-aminopropane sulfate, l-1-phenyl-2-aminopropane aspartate monohydrate, d-1- aspartate monohydrate Phenyl-2-aminopropane, d-1-phenyl-2-aminopropane sulfate, d-1-phenyl-2-aminopropane saccharate and with the inactive excipients: hypromellose 2910 (Methocel E6LV), using for the release coating layer extended surelease® (dispersion of ethyl-cellulose), opadry® (hydroxypropylmethylcellulose), enteric coating acryl-EZE® and protective coating opadry® (hydroxypropylmethylcellulose), in the proportions indicated in example 4 and according to the manufacturing procedure described in the same example. In accordance with clauses 1, 2, 3 and 4, the use of pharmaceutical compositions for the Treatment of Attention Deficit, Hyperactivity and Narcolepsy.