MX2013002803A - Pharmaceutical composition with floating units of modified release and units of immediate or modified release. - Google Patents

Abstract

The present invention refers to a composition comprising a system of biphasic delivery that includes: a) one or more floating units of modified release containing i) at least a lipase inhibiting agent or the pharmaceutically acceptable salts thereof and/or derivatives and/or prodrugs and/or polymorphes and/or amorphes and/or ii) one or more hydrophilic polymers, and or iii) one or more silicon salts and/or iv) one or more pharmaceutically acceptable excipients; b) one or more units of immediate release containing i) at least a natural quaternary amine selected from Carnitine or L-carnitine and derivatives of acyl-carnitine, the pharmaceutically acceptable salts thereof and/or derivatives and/or prodrugs and/or polymorphes and/or amorphes, and/or ii) one or more pharmaceutically acceptable excipients thereof; and in an optional manner, c) one or more units of immediate and/or modified release containing i)one or more liposoluble vitamins and/or the pharmaceutically acceptable salts the reof and/or derivatives and/or prodrugs and/or polymorphes and/or amorphes; and/or ii) one or more pharmaceutically acceptable excipients.

Description

PHARMACEUTICAL COMPOSITION WITH FLOATING MODIFIED RELEASE UNITS AND IMMEDIATE OR MODIFIED RELEASE UNITS FIELD OF THE INVENTION The present invention relates to a composition consisting of a biphasic delivery system comprising a) one or more modified release controlled flotation units. containing i) at least one lipase inhibitory agent and / or its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous, and / or ii) one or more hydrophilic polymers, and / or iii ) one or more silicon salts and / or iv) one or more pharmaceutically acceptable excipients; b) one c plus immediate release units containing i) reindeer a natural quaternary amine selected from carnitine or LB-hydroxy- and N-trimethyl-aminobutyric acid, L-carnitine or levocarnitine and its acyl-carnitine derivatives, its salts pharmaceutically acceptable and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous, and / or ii) one or more pharmaceutically acceptable excipients; and optionally, c) one or more immediate and / or modified release units containing i) one or more liposolub vitamins! s and / or its pharmaceutically salts acceptable and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous; and / or ii) one or more pharmaceutically acceptable excipients.

BACKGROUND Overweight and obesity are defined as an abnormal or excessive accumulation of fat that can be detrimental to health. The most prevalent risk factors related to overweight and obesity at present are: birth weight, absence of breastfeeding, hours of sleep, fat intake greater than or equal to 38%, high consumption of flours, soft drinks and sausages, numerous hours a day watching television, low consumption of fruits and vegetables, socioeconomic level, low educational level, sedentary activity and absence of sports activity.

A simple indicator to identify overweight and obesity is the body mass index (BMI) which evaluates the relationship between weight and height in adults (regardless of sex) and is calculated by dividing a person's weight in kilos by the square of its size in meters (kg / m2). According to the World Health Organization (WHO), a BMI equal to or greater than 25 is indicative of overweight, while a BMI equal to or greater than 30 is indicative of obesity.

Obesity and overweight are some of the main global health problems reported by the World Health Organization (WHO), which affects children and adults has reached epidemic proportions causing annually, the death of approximately 2.8 million people, that has considered it the fifth leading factor of risk of death in the world. In addition, different chronic diseases such as diabetes, cardiovascular diseases, locomotor disorders and cancer are attributable to overweight and obesity.

In the psychosocial aspect, some of the main problems that overweight and obesity people experience are: discrimination, emotional and behavioral problems, problems with body image, personality disorders, addictive behaviors, lack of social skills, among others.

According to the Official Mexican Standard NOM-008-SSA3-2010, is known as comprehensive treatment of overweight and obesity to the set of actions that are made from the complete and individualized study of the patient with overweight or obesity, includes medical treatment , nutritional, psychological, physical activity regime and exercise; in his case, surgical, aimed at achieving a change in style of life and to diminish or eradicate the risks for the health, to correct the comorbidities and to improve the quality of life of the patient.

The guidelines for the treatment of obesity recommend pharmacological treatment for patients with a body mass index (BMI) greater than 30, or greater than 27 and who have some comorbidity, such as hypertension, diabetes or dyslipidemia, in women with a circumference of waist greater than 88 cm or in men with a circumference greater than 102 cm or 2 or more associated comorbidities.

In pharmacological treatment, different active ingredients are used for the treatment of overweight and obesity, among which are: aloin, amphepramone, atropine, carnitine, clobenzorex, horsetail. { Equisetum arvense), diazepam, diethylpropion, fenproporex, phentermine, Garcinia co bogía, guaraná. { Paullinia cupanal), kelp. { Fucus versiculosus), kola nut, 1-carnitine, soy lecithin, mazindol, cactus (Opuntia ficus indica), norpseudoephedrine, orlistat, konjac powder, wheat bran, calcium sennoside, sibutramine (currently discontinued due to its effects) and triiodothyronine, among others.

Among the adverse effects that occur during the pharmacological treatment of overweight or obesity are find: rectal tenesmus and incontinence, flatulence and steatorrhea, headache, anxiety, fatigue, irregular menstrual cycles, upper and lower respiratory tract infections, influenza and hypersensitivity, pruritus, cutaneous exanthema, urticaria, angioedema, bronchospasm, anaphylaxis, flushing or pallor teguments, palpitations, dysrhythmias, precordial chest pain, gastrointestinal spasm, colicky pain, diarrhea or constipation, drowsiness, ataxia, nausea, vomiting, vertigo, dizziness, mydriasis and visual accommodation disorders, increase or decrease in blood pressure , dry mouth and mucous membranes, thirst and polydipsia sensation, headache, fever, diaphoresis, metallic taste, urinary retention, palpitations, tachycardia, arrhythmia, hypertension, dizziness, nervousness, restlessness, insomnia, weakness or fatigue, agitation, headache , dry mouth, nausea, vomiting, constipation, rash, erythema, eye irritation, mydriasis, dysuria, poly irritation, excitement, dysrhythmias, dry mouth and mucous membranes, fever, mydriasis, photophobia, cyclopegia, urinary retention, restlessness, euphoria, tremor, malaise, anxiety, insomnia, dizziness, depression, drowsiness, mydriasis, headache. Palpitation, tachycardia, changes in the ECG, increase in blood pressure, precordial pain, arrhythmias, spots oily, oily or fatty stools, flatulence with fecal discharge, fecal urgency, oily evacuation, decreased absorption of fat-soluble vitamins among which are vitamins A, D, E, K, B and beta carotene, increased defecation and fecal incontinence. These adverse effects can be reduced with the proper management of medications and the application of a comprehensive treatment that includes diet and exercise.

The deficiency of fat-soluble vitamins in the body can produce: malnutrition, weakness, skin disorders, irritation, nervousness, softening of the bones, alterations in the menstrual cycle, increase in the clotting time, decrease in the resistance of the liver to toxic substances , among other.

Orlistat, also known as 1- (3-hexyl-4-oxo-oxetane-2-yl) -tridecan-2-yl-2-formyiamino-4-methyl-pentanoate, whose molecular structure binds to the active site of lipase gastrointestinal, pancreatic lipase and carboxylester blocking the activity of these enzymes, which is why it is indicated for the treatment of long-term obesity, once that enzyme is inactive, is unable to hydrolyze triglycerides in free fatty acids and absorbable monoglycerides, in this way, the absorption of the fat decreases considerably, approximately 30%, in this way, said fat passes through the gastrointestinal tract without any change.

The therapeutic activity of Orlistat is carried out in the lumen of the stomach and in the small intestine, creating a covalent union with the active site of gastric and pancreatic lipases. Because it inhibits pancreatic lipase, it can prevent the absorption of fat-soluble vitamins, requiring administration of vitamin supplement 2 hours before or after the dose of Orlistat.

Once administered, Orlistat is minimally absorbed, it binds to plasma proteins by more than 99%, mainly in lipoproteins and albumin. Its main metabolites are MI and M3, which are considered pharmacologically inactive, because they have a very weak inhibitory activity of lipase, that is, 1000 and 2500 times lower than orlistat, respectively. 97% of the administered dose is excreted in faeces, reaching complete excretion in approximately 3 to 5 days with approximately 83% unaltered orlistat.

Adverse effects and side effects associated with Orlistat commonly observed are fatty spots, flatulence, secretion, fecal urgency, fatty stools oily evacuation increased defecation, fecal incontinence, abdominal pain / discomfort, rectal pain / discomfort, dental and gingival alterations. In patent US4598089, the synthesis of the l- (3-hexyl-4-oxo-oxetane-2yl) -tridecan-2-yl-2-formylamino-4-methyl-1-pentanoate molecule, that is, Orlistat, is described. .

On the other hand, Carnitine or LB-hydroxy-and N-trimethylaminobutyric acid, L-Carnitine or levocarnitine and its acyl-carnitine derivatives are natural quaternary amines synthesized in the liver, kidneys and brain of mammals, is highly relevant because Its main function is the oxidation of lipids or fatty acids acting as a compulsory cofactor of the ß-oxidation of fatty acids facilitates the aerobic metabolism of carbohydrates, increases the speed of oxidative phosplation, promotes glucose metabolism, energy generation and favors the excretion of some organic acids.

The therapeutic activity of Carnitine, levocarnitine and its acyl-carnitine derivatives for energy metabolism is carried out by facilitating the entry of long-chain fatty acids through the inner mitochondrial membrane as acylcarnitine esters, and in that site releases the substrate for oxidation and subsequent energy production.

In addition, Carnitine stimulates the activity of pyruvate dehydrogenase by reducing the acetyl CoA / CoA ratio by trapping acetyl groups, which generates the activation of the glycolytic pathway.

The Cmax after oral administration of 1980 mg twice a day is 80 nmol / mL with a Tmax of 3.3 hours, a volume of distribution of 29 Liters and a half-life of 17.4 hours, being eliminated in the urine approximately 76% of free L-carnitine. The main metabolites of Carnitine are trimethylamine N-oxide and butyrobetaine.

Adverse effects and side reactions associated with Carnitine are unusual and if present, are nausea, transient vomiting, body odor and gastritis.

In the state of the art, it is described in the patent application WO / 2003/009840, pharmaceutical compositions comprising at least one lipase inhibitor (Orlistat) in combination with Carnitine or acyl-carnitine or a salt thereof. The proportion of the composition is from 10 to 8000 mg of Carnitine per 100 mg of lipase inhibitor (Orlistat) with a content of 10 to 1000 mg of said lipase inhibitor, optionally, indicates the addition of at least one lipophilic vitamin (Vitamin A, Vitamin D or Vitamin E) in a proportion of 8 to 800 mg per dosage unit or per 100 mg of the lipase inhibitor.

Patent application WO / 2011/033356 and its equivalent in Mexico patent application MX / a / 2009/009971, refer to a composition containing Orlistat and L-carnitine tartrate, levocarnitine, L-carnitine fumarate or orotate L-Carnitine in pharmaceutical form of oral solid (tablet, capsule or powder to be reconstituted by adding a liquid), said composition contains Orlistat adsorbed or coated with a water-soluble diluent (maltose, isomalt, lactitol, sugar, mannitol or dextrose) or a diluent not soluble in an alcohol (calcium phosphate). In Mexico, the combination Tartrate of L-carnitine and Orlistat in the form of hard gelatine capsules is commercially available in presentations with 600 mg of L-carnitine Tartrate and 60 mg of Orlistat, and with 600 mg of L-carnitine Tartrate and 120 mg of Orlistat with the trademark Aliduet® for the treatment of overweight or obesity in conjunction with a hypocaloric diet and exercise plan.

The compositions described in the state of the art present, as a drawback, adverse effects and reactions secondary effects of the pharmacological effect of Orlistat, among which are oily spots, oily or fatty stools, flatulence with fecal discharge, fecal urgency, oily evacuation, increased defecation, constipation, loose stools, liquid stools, upset stomach and incontinence Fecal, among others. Said adverse effects and side reactions have been observed in the immediate release compositions of orlistat alone or in combination with other active principles, however, are not described in the state of the art, controlled release compositions that regulate the time of release of orlistat to reduce or eliminate the main adverse effects and / or adverse reactions.

Another problem when combining the active ingredients is the stability of each of the active ingredients in the pharmaceutical form of both drugs, which consequently causes a lower stability of the composition.

OBJECT OF THE INVENTION The object of the present invention is to provide a composition consisting of a biphasic delivery system comprising a) one or more modified release controlled flotation units containing i) at least one lipase inhibiting agent and / or its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous, and / or ii) one or more hydrophilic polymers, and / or iii) one or more silicon salts and / or iv) one or more pharmaceutically acceptable excipients.; b) one or more immediate release units containing i) at least one natural quaternary amine selected from Carnitine or LB-hydroxy- and N-trimethylaminobutyric acid, L-Carnitine or levocarnitine and its acyl-carnitine derivatives, its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous, and / or ii) one or more pharmaceutically acceptable excipients; and optionally, c) one or more immediate and / or modified release units containing i) one or more fat-soluble vitamins and / or their pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous; and / or ii) one or more pharmaceutically acceptable excipients.

The release system makes it possible to reduce the adverse effects of the lipase inhibiting agent due to the modified release of the system itself.

In addition, the method for preparing the composition for the preparation of a medicine useful for the prevention and / or treatment and / or control of overweight and / or obesity is presented.

DETAILED DESCRIPTION OF THE INVENTION The present invention consists of a composition useful for the prevention and / or treatment and / or control of overweight and / or obesity consisting of a biphasic delivery system comprising a) one or more modified release controlled flotation units that contains i) at least one lipase inhibitory agent and / or its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous, and / or ii) one or more hydrophilic polymers, and / or iii) one or more silicon salts and / or iv) one or more pharmaceutically acceptable excipients; b) one or more immediate release units containing i) at least one natural quaternary amine selected from Carnitine or LB-hydroxy-and N-trimethiamincbutyric acid, L-Carnitine or levocarnitine and their acyl-carnitine derivatives, their pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous, and / or ii) one or more pharmaceutically acceptable excipients; and optionally, c) one or more immediate and / or modified release units containing i) one or more liposo-soluble vitamins and / or their pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous; and / or ii) one or more pharmaceutically acceptable excipients.

The biphasic delivery system is comprised of at least two release systems, comprising one or more modified release floating units; and / or one or more immediate release units; and optionally, one or more units of modified release and / or immediate release.

The modified release floating units are characterized in that the release of the lipase inhibiting agent can be carried out in a delayed and / or controlled and / or pulsatile and / or gradual manner, such that the initiation of the release of the lipase inhibiting agent contained in said tablet is carried out in at least 30 minutes, preferably in a time greater than 60 minutes. Subsequently, the release of the lipase inhibiting agent is controlled to maintain a constant concentration for 8 hours, 12 hours and up to 24 hours significantly reducing the variability in bioavailability with respect to the compositions reported in the state of the art.

The lipase inhibiting agent is in the composition in a concentration range of 20 mg to 200 mg, contained in one or more modified release floating units is selected from the following group: orlistat and / or esterastin and / or ebelactone A and / or ebelactone B and / or lipstatin and / or FL-386 and / or WAY-121898 and / or Bay-N-3176 and / or valilactone and / or sterastine and / or RHC 80267 their pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or combinations thereof.

The preferred lipase inhibitory agent for the present composition is Orlistat, its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or combinations thereof, the preference of said agent is due to which has a short half-life (less than 2 hours), which is why, according to the current state of the art, it must be administered three times a day in order to avoid the side effects and adverse reactions that occur at high concentrations . By administration in floating units, modified release, it is achieved to increase the permanence of active ingredient in the stomach and control the release thereof.

The immediate release units are characterized because the release of a natural quaternary amine is carried out immediately, such that the beginning of the Release of said natural quaternary amine is carried out at least 30 minutes before the release of the lipase inhibiting agent contained in the modified release float units.

The natural quaternary amine is in the composition in a concentration range of ICO mg to 3000 mg, contained in one or more immediate release units is selected from the following group: Carnitine or LB-hydroxy-and N-trimethylaminobutyric acid, L-Carnitine or levocarnitine and its acyl-carnitine derivatives, its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or combinations thereof.

Carnitine or LB-hydroxy- and N-trimethylaminobutyric acid, L-Carnitine or levocarnitine and their acyl-carnitine derivatives, their pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or combinations of they are used because the time in which reaches the maximum concentration (Tmax) is about 3.3 hours, so it is important to release quickly in the stomach to begin its dissolution and then be absorbed.

The novel system of liberation developed by means of one or more units of controlled flotation of liberation modified containing at least one lipase inhibitory agent and / or its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous; and one or more immediate release units containing at least one natural quaternary amine its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous allows the synergistic therapeutic effect to be carried out mainly in two steps: first stage consists in the release of the natural quaternary amine in the organism, which acts in the oxidation of lipids or fatty acids, the increase in the oxidative phosphorylation rate, the glucose metabolism impulse, facilitate the entry of fatty acids of long chain through the inner mitochondrial membrane as acylcarnitine esters, with subsequent independent energy production and activation of the glycolytic pathway, allows oxidation and / or utilization of excess fats and lipids in the patient; the second stage consists of the release of the lipase inhibiting agent contained in the modified release floating units, said units have a lower density than the gastric content, that is, lower than 1,004 g / cm3 and therefore, said units will float in the stomach increasing the gastric residence of lipase inhibiting agent controlling the release thereof, starting the release at least 30 minutes after the release of the natural quaternary amine, at this time, the concentration of fats and lipids has decreased considerably, and that is when the natural quaternary amine has decreased or eliminated the excess of fats and lipids present in the organism, allowing that when the inhibition of gastric and / or pancreatic lipases by the lipase inhibitor agent is carried out, the amount of fats and lipids is lower, accelerating the therapeutic effect for weight reduction and minimizing or eliminating the secondary and adverse reactions that occur due to the consumption of lipase inhibitors, such as oily stains, fatty stools, oily stools, flatulence with fecal discharge, oily evacuation, increase in defecation, fecal incontinence, stomach pain, upset stomach, liquid stools, loose stools, constipation among other gastrointestinal side effects.

The hydrophilic polymer useful for the present composition is found in. the composition in a concentration range of 10 mg to 200 mg, is selected from the following group: polymers of hydroxypropylmethylcellulose, alcohol polyvinyl, polyethylene oxide, hydroxypropyl cellulose polymers, guar gum, carboxymethyl cellulose, xanthan gum, hydroxyethyl cellulose, polyvinyl pyrrolidone, methyl cellulose, ethyl cellulose, cellulose esters, polyvinyl acetate, copolymers of acrylic acid, methacrylic acid copolymers, acrylic acid esters, esters of methacrylic acid, polyethylene glycol, carrageenan, alginates, starches, crosslinked homopolymers and acrylic acid copolymers, among others.

The adsorbing agents useful for the present invention in a non-limiting manner are: silicon oxide and / or calcium silicate and / or magnesium aluminum silicate and / or aluminum silicate and / or magnesium silicate and / or colloidal silicon dioxide and / or aluminum magnesium metasilicate and / or dextrins and / or magnesium aluminate and / or silicon microcrystalline cellulose and / or hydroxyapatite and / or magnesium carbonate and / or aluminum hydroxide and / or magnesium oxide and / or magnesium hydroxide and aluminum and / or titanium hydroxide and / or magnesium trisilicate, among others In addition, the present invention may use by way of non-limiting example the use of one or more diluents, humectants, pH regulating agents, one or more disintegrants, one or more binders, one or more lubricants, one or more coating agents, one or more superdisintegrants, one or more glidants, one or more flavorings, one or more colorants, or another excipient existing in the state of the art. Said excipients are selected from alginic acid and / or crospovidone and / or ion exchange resins and / or aluminum silicate and / or magnesium silicate and / or microcrystalline cellulose and / or starch and / or sodium starch glycolate and / or sodium modified cellulose and / or PVP and / or sodium dodecyl sulfate corn starch and / or rice starch and / or the crosslinked N-vinyl-2-pyrrolidone and / or croscarmellose sodium and / or formaldehyde-casein and / or sorbitol and / or starch and / or pregentalized starch and / or corn starch and / or sucrose and / or sugar and / or compressible sugar and / or isomaltose and / or tragacanth and / or talc and / or trehalose and / or xylitol and / or acacia and / or agar and / or alginic acid and / or calcium carbonate and / or calcium lactate and / or carbomer and / or calcium carboxymethylcellulose and / or microcrystalline cellulose and / or cellulose and / or ceratonia and / or chitosan and / or copovidone and / or dextrates and / or dextrin and / or dextrose and / or ethylcellulose and / or gelatin and / or glyceryl behenate and / or guar gum and / or hydroxyethyl cellulose and / or hydroxymethyl cellulose and / or or hydroxypropyl cellulose low-substitution and / or hydroxypropyl starch and / or hypromellose and / or inulin and / or lactose monohydrate and / or aluminum silicate and / or magnesium and / or maltodextrin and / or methylcellulose and / or polycarbophil and / or polydextrose and / or polyethylene oxide and / or polymethacrylates and / or povidone and / or sodium alginate and / or starch and / or pregelatinized starch and / or sucrose and / or polyethylene glycol succinate and / or zein and / or calcium stearate and / or glyceryl behenate and / or glyceryl monostearate and / or glyceryl palmitostearate and / or lauric acid and / or leucine and / or magnesium stearate and / or maltodextrin and / or mineral oil and / or light mineral oil and / or myristic acid and / or palmitic acid and / or polyethylene glycol and / or polyvinyl alcohol and / or potassium benzoate and / or sodium chloride and / or sodium hyaluronate and / or sodium lauryl sulfate and / or sodium stearyl fumarate and / or stearic acid and / or talc and / or oil hydrogenated vegetable and / or zinc stearate and / or adipic acid and / or boric acid and / or calcium carbonate and / or calcium lactate and / or meglumine and / or calcium phosphate and / or cytic acid monohydrate and / or glycine and / or maleic acid and / or methionine and / or monosodium glutamate and / or potassium citrate and / or sodium acetate and / or sodium borate and / or sodium carbonate and / or sodium citrate d ihydrate and / or sodium hydroxide and / or dibasic sodium phosphate and / or monobasic sodium phosphate and / or potassium citrate and / or sodium citrate and / or sodium hydroxide and / or potassium hydroxide and / or sodium bicarbonate sodium and / or carbonate of sodium and / or calcium bicarbonate and / or calcium carbonate and / or potassium bicarbonate and / or disodium hydrogen phosphate and / or trisodium phosphate and / or arginine and / or talc and / or acetyltributyl citrate and / or citrate acetriltrietil and / or calcium carbonate and / or calcium carboxymethylcellulose and / or sodium carboxymethylcellulose and / or cellulose acetate and / or cellulose acetate phthalate and / or ceresin and / or cetyl alcohol and / or chitosan and / or diethyl phthalate and / or dimethyl phthalate and / or ethyl cellulose and / or gelatin and / or liquid glucose and / or glycerin and / or glyceryl behenate and / or glyceryl palmitostearate and / or hydroxyethyl cellulose and / or hydroxymethyl cellulose and / or hydroxypropyl cellulose and / or hypromellose and / or hypromellose acetate succinate and / or hypromellose phthalate and / or isomalt and / or maltitol and / or maltodextrin and / or methylcellulose and / or paraffin and / or poloxamer and / or polydextrose and / or poly LD-lactic acid and / or / or polyethylene oxide and / or polymethacrylates and / or poly (methyl vinyl ether / maleic anhydride) and / or polyvinyl acetate phthalate and / or ropylene glycol and / or shellac and / or sodium chloride and / or stearic acid and / or sucrose and / or talc and / or titanium dioxide and / or triacetin and / or tributyl citrate and / or triethyl citrate and / or triolein and / or carnauba wax and / or microcrystalline wax and / or white wax and / or yellow wax and / or xylitol and / or zein, among others.

The biphasic delivery system consisting of at least two delivery systems is further characterized in that the modified release floating units and / or the immediate release units are prepared in the form of a tablet, pellet, pellet, microsphere, microtablet, liposomes, micropellets, effervescent tablets, among others. The units may or may not be contained for administration within a hard gelatin capsule or in the form of a tablet of two or more layers.

Optionally, the present composition may contain one or more immediate and / or modified release units containing i) one or more fat-soluble vitamins and / or their pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous; and / or ii) one or more pharmaceutically acceptable excipients.

The fat-soluble vitamins contained in one or more immediate and / or modified release units are selected from the following group: vitamin A and / or vitamin D and / or vitamin E and / or vitamin K and / or vitamin Bl and / or vitamin B6 and / or vitamin B12 and / or vitamin B5 and / or vitamin B7 and / or vitamin D3 and / or beta carotene and / or lipoic acid and / or its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous; and / or combinations thereof.

The immediate and / or controlled release units are further characterized in that said vitamins are released at least 30 minutes before and / or 30 minutes after the release of the lipase inhibiting agent, this with the purpose of delivering in a single intake, at less a fat-soluble vitamin, of which there is a decrease in absorption due to the activity of the lipase-inhibiting agent.

The excellent stability of the composition is achieved because each active ingredient is found in independent units of release, ie the lipase inhibiting agent, the natural quaternary amine and the fat-soluble vitamin are each in separate units that do not come into contact during the shelf life of the product, or at the time of administration because the release of each of the ingredients is carried out at different times and in different sites of the gastrointestinal tract.

The present composition is characterized in that it is prepared from the same in the form of a medicament for its use for the control and / or prevention and / or treatment of overweight and obesity for the loss of corporal weight, avoiding the decrease of liposoluble vitamins vital for the organism.

Next, the compositions used during the development of the invention are described, by way of illustrative examples, but not limiting: EXAMPLES Example 1: Pellet containing hard gelatin capsule plus Orlistat extended release controlled flotation units and L-Carnitine immediate release pellets.

Example 2: Hard gelatin capsule containing controlled release prolonged-release pellets containing Orlistat and immediate release pellets of L-Carnitine and controlled release units of vitamin B12.

Example 3: Hard gelatin capsule containing Orlistat extended-release floating pellets, immediate release granules of L-Carnitine and controlled-release granules of thiamine hydrochloride, pyridoxine hydrochloride and cyanocobalamin.

* It evaporates during the process Example 4: Double-layer tablet containing a floating prolonged-release inner tablet of Orlistat and an external tablet of immediate release with L-Carnitine, thiamine hydrochloride, pyridoxine hydrochloride and cyanocobalamin.

In a non-limiting manner, the present invention has the following advantages: - Comprehensive treatment for the control and / or prevention and / or treatment of overweight and obesity.

- Composition that diminishes or eliminates the adverse and adverse reactions by the consumption of a lipase inhibiting agent.

- Composition that prevents the decompensation of liposoluble vitamins proper to the treatment with lipase inhibitors.

- The composition is stable since it contains the active ingredients in independent units, avoiding contact between them.

- The composition increases facilitates the synergistic activity of the active ingredients releasing them at different times in the body.

- The composition allows the lipase inhibiting agent to have a longer gastric residence time, enhancing its effect.

- The composition reduces the variability in bioavailability.

Claims (1)

1. CLAIMS Having described the invention, the content of the following claims is claimed as property: Pharmaceutical compositions characterized in that they consist of a biphasic delivery system comprising a) one or more modified release controlled flotation units containing i) at least one lipase inhibitory agent and / or its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous, and / or ii) one or more hydrophilic polymers, and / or iii) one or more silicon salts and / or iv) one or more pharmaceutically acceptable excipients; b) one or more immediate release units containing i) at least one natural quaternary amine selected from Carnitine or LB-hydroxy- and N-trimethylaminobutyric acid, L-Carnitine or levocarnitine and its acyl-carnitine derivatives and / or its salts pharmaceutically acceptable and / or derivatives. and / or prodrugs and / or polymorphs and / or amorphous, and / or ii) one or more pharmaceutically acceptable excipients. The pharmaceutical composition according to claim 1, characterized in that the lipase inhibiting agent is selected from orlistat and / or sterastin and / or ebelactone A and / or ebelactone B and / or lipstatin and / or FL-386 and / or WAY- 121898 and / or Bay-N-3176 and / or valilactone and / or sterastine and / or RHC 80267 their pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or combinations thereof. same. The pharmaceutical composition according to claim 1, characterized in that the hydrophilic polymer is selected from polymers of hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene oxide, quistosan, agave inulin, hydroxypropylcellulose polymers, guar gum, sodium alginate, carboxymethylcellulose, xanthan gum , hydroxyethylcellulose, polyvinylpyrrolidone, methylcellulose, ethylcellulose, cellulose esters, polyvinyl acetate, copolymers of acrylic acid, copolymers of methacrylic acid, esters of acrylic acid, esters of methacrylic acid, polyethylene glycol, carrageen, alginates, starches, crosslinked homopolymers and copolymers of acrylic acid and / or combinations thereof. The pharmaceutical composition according to claim 1, characterized in that the adsorbent agent is selected from silicon oxide and / or calcium silicate and / or magnesium aluminum silicate and / or aluminum silicate and / or magnesium silicate and / or magnesium dioxide. colloidal silicon and / or aluminum magnesium metasilicate and / or dextrins and / or magnesium aluminate and / or silicon microcrystalline cellulose and / or hydroxyapatite and / or magnesium carbonate and / or aluminum hydroxide and / or magnesium oxide and / or / or magnesium aluminum hydroxide and / or titanium hydroxide and / or magnesium trisilicate and / or combinations thereof. The pharmaceutical composition according to claim 1, characterized in that the natural quaternary amine is selected from Carnitine or LB-hydroxy- and N-trimethylaminobutyric acid, L-Carnitine or levocarnitine and its acyl-carnitine derivatives, its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or combinations thereof. The pharmaceutical composition according to claims 1 and 2, characterized in that the lipase inhibiting agent is Orlistat and / or its salts pharmaceutically acceptable and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or combinations thereof. The pharmaceutical composition according to claims 1 and 5, characterized in that the natural quaternary amine is L-Carnitine and / or its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or hydrates, and / or combinations thereof. The pharmaceutical composition according to claims 1 to 4, characterized in that the modified release controlled flotation units release the lipase inhibitor form delayed, controlled, pulsatile, gradual and / or combinations thereof. A pharmaceutical composition characterized in that it consists of a biphasic delivery system comprising a) one or more modified release floating units containing i) at least one lipase inhibitory agent and / or its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous, and / or ii) one or more hydrophilic polymers, and / or iii) one or more silicon salts and / or iv) one or more excipients pharmaceutically acceptable; b) one or more immediate release units containing i) at least one natural quaternary amine selected from Carnitine or LB-hydroxy- and N-trimethylaminobutyric acid, L-Carnitine or levocarnitine and its acyl-carnitine derivatives and / or its salts pharmaceutically acceptable and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous, and / or ii) one or more pharmaceutically acceptable excipients; and / or c) one or more immediate and / or modified release units containing i) one or more fat-soluble vitamins and / or their pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous; and / or ii) one or more pharmaceutically acceptable excipients. ). The pharmaceutical composition according to claim 9, characterized in that the lipase inhibiting agent is selected from orlistat and / or sterastin and / or ebelactone A and / or ebelactone B and / or lipstatin and / or FL-386 and / or WAY- 121898 and / or Bay-N-3176 and / or valilactone and / or sterastine and / or RHC 80267 their pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or combinations thereof . The pharmaceutical composition according to claim 9, characterized in that the hydrophilic polymer is selected from polymers of hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene oxide, polymers of hydroxypropylcellulose, guar gum, carboxymethylcellulose, xanthan gum, hydroxyethylcellulose, polyvinylpyrrolidone, methylcellulose, ethylcellulose, esters of cellulose, polyvinyl acetate, agave inulin, chitosan, acrylic acid copolymers ,. copolymers of methacrylic acid, esters of acrylic acid, esters of methacrylic acid, polyethylene glycol, carrageen, alginates, starches, crosslinked homopolymers and copolymers of acrylic acid and / or combinations thereof. The pharmaceutical composition according to claim 9, characterized in that the adsorbent agent is selected from silicon oxide and / or calcium silicate and / or magnesium aluminum silicate and / or aluminum silicate and / or magnesium silicate and / or magnesium dioxide. colloidal silicon and / or aluminum magnesium metasilicate and / or dextrins and / or magnesium aluminate and / or silicon microcrystalline cellulose and / or hydroxyapatite and / or magnesium carbonate and / or aluminum hydroxide and / or magnesium oxide and / or magnesium aluminum hydroxide and / or magnesium hydroxide and / or magnesium trisilicate and / or combinations thereof. 13. The pharmaceutical composition according to claim 9, characterized in that the natural quaternary amine is selected from Carnitine or LB-hydroxy- and N-trimethylaminobutyric acid, L-Carnitine or levocarnitine and its acyl-carnitine derivatives, its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or combinations thereof. 14. The pharmaceutical composition according to claims 9 and 10, characterized in that the lipase inhibiting agent is Orlistat and / or its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or combinations thereof. same. 15. The pharmaceutical composition according to claims 9 and 13, characterized in that the natural quaternary amine is L-Carnitine and / or its pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous and / or hydrates, and / or combinations thereof. The pharmaceutical composition according to claims 9 and 12, characterized in that the modified release floating units release the lipase inhibitor agent in delayed, controlled, pulsatile, gradual and / or combinations thereof. The pharmaceutical composition according to claim 9, characterized in that the liposoluble vitamin is selected from vitamin A and / or vitamin D and / or vitamin E and / or vitamin K and / or vitamin Bl and / or vitamin B6 and / or vitamin B12. and / or vitamin B5 and / or vitamin B7 and / or vitamin D3 and / or beta carotene and / or lipoic acid and / or their pharmaceutically acceptable salts and / or derivatives and / or prodrugs and / or polymorphs and / or amorphous; and / or combinations thereof. The composition according to claims 9 to 17, characterized in that at least one quaternary amine and at least one fat-soluble vitamin are in an immediate-release unit. The composition according to claims 1 to 18, characterized in that the modified release floating units and / or the Immediate release units are prepared in the form of a tablet and / or granule and / or powder for encapsulation and / or powder for reconstitution and / or liquid suspension and / or pellet and / or micro-sphere and / or microtablette and / or liposomes and / or or micropellets. 20. The composition according to claims 1 to 19, characterized in that the modified release floating units and / or the immediate release units are prepared for administration in the form of a hard gelatin capsule and / or in the form of a tablet of two or more layers. 21. Use of the composition according to claims 1 to 20 for the prevention and / or control and / or treatment of overweight, obesity and / or related disorders.