WO2022011439A1

WO2022011439A1 - Long-lasting resorbable subcutaneous implant with prolonged release of pre-concentrated pharmacologically active substance in polymer for the treatment of obesity, and method

Info

Publication number: WO2022011439A1
Application number: PCT/BR2020/050348
Authority: WO
Inventors: Edson LUIZ PERACCHI
Original assignee: Luiz Peracchi Edson
Priority date: 2020-07-16
Filing date: 2020-08-31
Publication date: 2022-01-20
Also published as: BR102020014545A2

Abstract

The present invention patent application pertains to the healthcare sector and comprises a long-lasting resorbable subcutaneous implant with prolonged release of a pre-concentrated pharmacologically active substance in a polymer for the treatment of obesity. The implant is inserted subcutaneously and provides continuous release of the active substance for a prolonged period of time, guaranteeing a drug serum level that is effective and constant in the treatment of obesity. The composition of the implant may include particles of the appetite depressant uniformly dispersed in a bioerodible and bioabsorbable polymer matrix. The implant may have a polymer coating membrane and the polymer used for the coating may be bioabsorbable and enable passage of the active substance.

Description

LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRECONCENTRATED POLYMER PRECONCENTRATE PHARMACOLOGICALLY ACTIVE SUBSTANCE FOR TREATMENT OF

OBESITY AND PROCESS

field of invention

[001] The present application for the privilege of invention is aimed at the health sector and comprises a long-lasting resorbable subcutaneous implant with prolonged release of pre-concentrated pharmacologically active substance in polymer for the treatment of obesity.

Fundamentals of the invention

[002] Obesity is a chronic disease associated with several medical conditions and a high mortality rate. It is considered a multifactorial disease, since many factors influence weight control and eating habits, such as genetics, culture, behavioral and situational factors.

[003] Obesity is characterized by an imbalance between caloric intake and expenditure, with a positive energy balance. This can be due to intake greater than expenditure, reduction in total caloric expenditure, or a combination of these two factors. It is possible that obesity is caused by other factors such as endocrine disorders, drugs or neurological disorders, but they constitute a very small fraction of cases. It is also characterized by an excessive accumulation of adipose tissue in the body, reflecting on the obese phenotype and compromising the individual's health.

[004] Some metrics are used to quantify obesity, the most common being the body mass index (BMI). The BMI is an index calculated from the weight divided by the square of the person's height (kg/m ² ), the result obtained indicates in which category the individual fits in terms of body composition. The existing categories are: underweight (BMI<18 kg/m ² ); normal (BMI between 18-25 kg/m ² ), overweight (BMI between 25-30 kg/m ² ) and obesity (BMI> 30 kg/m ² ). Obesity can be subdivided into degrees: I (BMI between 30 and 34.9 kg/m ² ); II (BMI between 35 and 39.9 kg/m ² ); III (BMI>40 kg/m ² ). [005] In addition to BMI, there are other techniques to quantify obesity, such as measuring waist circumference, measuring skinfolds, magnetic resonance imaging of the total amount of adipose tissue, among others.

[006] Obesity is associated with the emergence of several comorbidities, such as diabetes mellitus, arterial hypertension, cardiovascular diseases, dyslipidemia, osteoporosis, gallbladder diseases and some types of cancer. A third of hypertension cases in the West are associated with obesity, whereas type 2 diabetes mellitus is five times more prevalent in moderately obese people and ten times more prevalent in severely obese people.

[007] Furthermore, for an increase of 5 kg/m ² in people with a BMI above 25 kg/m ² there is a 30% increase in the mortality rate. Furthermore, for every 5 cm increase in waist circumference above normal, there is a 17% increase in mortality for men and 13% for women. Individuals with a BMI>40 kg/m ² have a 52 to 62% higher risk of dying from cancer compared to patients with a normal BMI.

[008] The increased susceptibility to health problems associated with obesity is not the only problem faced by sufferers of this disease. There is also a whole compromise of the quality of life in the social and professional scope. Obese people are victims of prejudice and discrimination and, in practice, are less likely to get jobs and promotions.

[009] A study entitled “Health and Economic Burden of Obesity in

Brazif' was carried out to project data on obesity, related diseases and costs associated with obesity in the health system in Brazil for the year 2050. For the collection and analysis of data, thirteen obesity-related diseases were considered: coronary artery disease, stroke, hypertension, type 2 diabetes, knee osteoarthritis, and eight types of cancer (breast; kidney; colorectal; esophageal; endometrial; pancreatic; liver; gallbladder). In addition, three scenarios were proposed. hypothetical, without intervention in the progression of obesity; 1% reduction in the BMI of the obese population; 5% reduction in the BMI of the obese population.

[010] The model estimated for 2050 a growth of 57% to 95% of the overweight and obese male population compared to 2010 numbers. In numbers, 49% of the population by 2050 will be overweight and 46% obese. The growth among the female population was from 43% to 52%, with 32% being overweight and 20% obese by 2050.

[011] The projection for 2050 is that type 2 diabetes, knee osteoarthritis and eight types of cancer will double compared to 2010. Coronary artery disease and stroke will almost double from 2010 to 2050. Also in this same period the projection for the increase in cases of hypertension is 62%.

[012] If it were possible to reduce the BMI of the obese population by 1% by 2050, the cases of obesity-related diseases would also reduce. There would be a reduction, in relation to the total Brazilian population, of: 10,000 cases of the eight types of cancer; 222,000 cases of coronary artery disease and stroke; 700,000 cases of knee osteoarthritis; 800,000 cases of type 2 diabetes; 1,600,000 cases of hypertension.

[013] A 5% reduction in the BMI of the obese population by 2050 would reduce the cases of obesity-related diseases, in relation to the total Brazilian population, by: 21,000 cases of the eight types of cancer; 600,000 cases of coronary artery disease and stroke; 2,500,000 cases of knee osteoarthritis; 2,100,000 cases of type 2 diabetes; 5,400,000 cases of hypertension.

[014] Another study titled “Obesity and Severe Obesity Forecasts

Through 2030' 2010 analyzed data from 1990 to 2008 for 18-year-old American adults and extrapolated that data to predict the incidence of obesity and severe obesity in adults in the year 2030. The study found a 33% increase in cases projected of obesity in these two decades.

[015] The significant increase in obesity-related numbers is alarming and there must be an effort so that patients affected by this disease are treated with all available resources, thus reducing the burden on the health system and improving the quality of life of this huge portion of the population.

[016] There are several approaches to the treatment of obesity, but to obtain effective and lasting results it is necessary to use a dynamic approach, which treats the patient as a whole. The existing treatments for obesity consist of: diet and food reeducation, physical exercises, behavioral changes, use of medication and surgical intervention. It should be noted that it is not only necessary to lose weight, but also to be able to maintain the weight loss. Weight loss strategies that do not address weight loss maintenance are counterproductive and have no value in a chronic disease such as obesity. [017] The Latin American Obesity Consensus states that obese patients undergoing treatment often fail to comply with diet and physical activity prescriptions, making it necessary to use medications to assist in weight loss and maintenance. Patients who should be evaluated regarding the use of medication in their treatment are those with a BMI equal to or greater than 30 kg/m ² , categorized as obese, those with a BMI equal to or greater than 25 kg/m ² and who have other factors risk factors such as hypertension, type 2 diabetes mellitus, hyperlipidemia, among others, and patients in whom conventional treatment with diet and exercise alone was not effective.

[018] Drug therapy for the treatment and control of obesity has three mechanisms of action: acting on the central nervous system, altering appetite and eating habits, called appetite suppressants; increasing thermogenesis, called thermogenic agents; acting on the gastrointestinal system by inhibiting the absorption of fat, called digestion inhibitors.

[019] Appetite suppressants, also known as anorectics, are divided into two classes, noradrenergic and serotonergic, which act on the appetite center and satiety center, respectively.

[020] Some examples of noradrenergic anorectics are diethylpropion, phenproporex, phentermine, mazindol and phenylpropalamine. Diethylpropion, fenproporex and phentermine are derivatives of amphetamine, originally used for weight loss. Due to the addictive potential of amphetamine its chemical structure was changed, through the manipulation of its side chains and rings, to the alternatives found on the market today. The drugs used today maintain the anorectic properties of amphetamine, but have a significant reduction in the stimulant effect and its additive potential. Diethylpropion, dosage of 40-120 mg/day, fenproporex, dosage of 20-50 mg/day and phentermine, dosage of 30-60 mg/day, act on the central nervous system by increasing the neurotransmission of catecholamine and stimulating its receptors, increasing the sympathetic activity, thereby reducing appetite and, consequently, food intake.

[021] Mazindol, dosage of 1-3 mg/day, acts by decreasing food intake by a noradrenergic and dopaminergic mechanism, blocking the reuptake of noradrenaline in presynaptic neurons and suppressing neurons in the lateral region of the hypothalamus.

[022] Phenylpropanolamine, dosage of 50-75 mg/day, is a non-catecholamine sympathomimetic agent, which mimics the action of adrenaline and noradrenaline and acts as an appetite suppressant.

[023] Serotonergic anorectics, such as fenfluramine, dexfenfluramine, fluoxetine and sertraline, affect the satiety center. Fenfluramine, dosage of 60-120 mg/day and dexfenfluramine, dosage of 30 mg/day, act on the hypothalamus causing decreased food intake through partial inhibition of serotonin reuptake and serotonin release in the synaptic cleft.

[024] Fluoxetine, dosage of 20-60 mg/day and sertraline, dosage of 50-150 mg/day, selectively inhibit serotonin reuptake and despite not being regulated as drugs for obesity they promote weight loss. and can be useful in patients who have a condition of compulsion, bulimia nervosa and/or depression.

[025] There is also sibutramine, which is a combination of noradrenergic and serotonergic anorectic and acts centrally and peripherally, inhibiting the uptake of both serotonin and noradrenaline, decreasing food intake and increasing caloric expenditure. Its dosage is 10-20 mg/day.

[026] Another line of treatment for obesity is using thermogenic drugs. One of them is the combination of ephedrine with caffeine and/or aminophylline, which has both thermogenic and anorexic properties. Ephedrine, dosage of 50-75 mg/day, increases the release of noradrenaline, decreasing food intake. Caffeine and aminophylline, dosage of 100-300 mg/day and 300-450 mg/day, respectively, increase the action of noradrenaline on nerve endings, potentiating and acting in synergy with ephedrine.

[027] Another type of treatment for obesity is through the use of digestion-inhibiting medications. Orlistat, dosage of 120 mg at most three times a day, is a drug that acts by inhibiting the lipase enzyme. This enzyme, present in the stomach and pancreas, breaks down the fat present in food. Orlistat inhibits the action of this enzyme, consequently inhibiting the digestion of triglycerides and decreasing the absorption of cholesterol and fat-soluble vitamins.

[028] Other digestion-inhibiting drugs act by replacing fat in food, aiming to reduce fat intake, but maintain the flavor in the food consumed by patients. These substitutes can be made from carbohydrates and improve the texture, thickness, stability and moisture of the food. They can be substitutes produced from proteins, which give the food the sensation of fat in palatability, but can increase the amount of calories. They can also be substitutes made from fats that are low in calories and add a creamy, fat-like texture to foods. These substitutes can increase patients' adherence to the diet.

[029] A paper entitled “A comparative study of five centrally acting drugs on the pharmacological treatment of obesity performed a 52-week, single-blind, randomized, placebo-controlled study with 174 obese premenopausal female patients to assess the efficacy and safety of five anorectics - diethylpropion, fenproporex, mazindol, fluoxetine and sibutramine - in weight loss. The results found in this study group showed that the drug approach associated with changes in the patients' lifestyle was more effective than with the placebo for the treatment of obesity. The placebo group lost an average of 3.1 kg and only 7.45% of patients lost 10% or more of their initial weight. The drugs with the best results were diethylpropion and sibutramine. Patients treated with diethylpropion lost 6.9 kg more than those on placebo and 64.3% of them lost more than 10% of their initial weight. When comparing these results with other studies carried out with diethylpropion, but in a shorter period of time, it was possible to perceive that the effectiveness of drug treatment for obesity increases with time. Patients treated with sibutramine lost 6.4 kg more than those treated with placebo and 50% of them lost 10% or more of their initial weight. Patients treated with fenproporex and mazindol lost 4.7 and 4.3 kg more than those treated with placebo, respectively. In addition, 34.5% and 37.9% of patients lost at least 10% of their initial weight, treated with fenproporex and mazindol respectively. Patients treated with fluoxetine had very similar results to those treated with placebo. In addition, 60% of patients who discontinued treatment due to therapy failure were taking either placebo or fluoxetine.

[030] The main side effects of the treatment were dry mouth and constipation, but these were well tolerated and controlled with simple interventions. In patients treated with diethylpripione and fenproporex, there was a higher incidence of anxiety and irritability, but these symptoms occurred mainly in the first month of treatment, after the second month, adverse symptoms decreased in intensity and frequency. This behavior is consistent with other published studies that report that adverse symptoms are more common in the first three months of treatment, decreasing over time.

[031] Drug treatment of obesity is used in practice for a short period of time, which can compromise weight loss and maintenance of weight loss in patients. When discontinuing the medication in obese patients, the effect of this medication is lost, which may lead to a recurrence of weight gain. Obesity is a chronic disease, like diabetes and hypertension, and must be treated in the long term. Often, the treatment must last for the entire life of the patient, both for weight loss, but also for the maintenance of that loss.

[032] The article entitled “Effect of sibutramine on weight maintenance after weight loss: a randomized triaf' reports a two-year study with 605 obese patients who underwent an initial 6-month treatment for weight loss, combining diet and use of sibutramine (10 mg/day). After 6 months, 77% of patients who lost more than 5% of their initial weight were randomly divided into two control groups: 2/3 of them received 10 mg/day of sibutramine and 1/3 received placebo for an additional 18 months. If there was weight gain in patients using sibutramine, their dosage was increased to 20 mg/day. Of the 204 sibutramine-treated patients who completed treatment, 43% were able to maintain 80% or more of their weight loss compared with 16% of the placebo patients. In addition to weight loss, patients who were treated with sibutramine had a considerable decrease in triglyceride levels, VLDL cholesterol, insulin, C-peptide and uric acid in the first six months of treatment. This improvement in numbers was maintained in the group that continued treatment with sibutramine, but not in the group that used placebo. HDL cholesterol increased by 20.7% in the sibutramine group versus an 11.7% increase in the placebo group.

[033] Another article entitled “Comparison of continuous and intermittent anorectic therapy in obesity” analyzed the results of a 36-week double-blind study that evaluated the efficacy of continuous and intermittent treatment of the anorectic phentermine. At the beginning of treatment, 108 women were selected who were overweight or obese at least 20% above the standard, aged between 21 and 60 years and without a history of cardiovascular and endocrine diseases. They were divided into three groups: one received a placebo; another received 30 mg/day of phentermine and the third received alternating doses of placebo or phentermine every four weeks. At the end of 36 weeks, 64 patients completed the study. 25 of them were treated with placebo and lost an average of 4.8 kg. Another 17 patients treated with phentermine and 22 treated alternately with phentermine and placebo lost an average of 12.2 kg and 13.0 kg respectively. In addition to weight loss, appetite suppression in patients was monitored; 20% of placebo-treated patients reported felt less hungry compared to 71% of those treated with phentermine. Already 82% of those treated alternately with phentermine and placebo reported reduced appetite. Of these patients, 56% noticed a difference only in the period when they were taking phentermine and not placebo and 39% noticed that in the period when they were taking phentermine the reduction in appetite was more pronounced. [034] The double-blind study “Long-term efficacy of fenfluramine in treatment of obesitf” followed 42 obese women on a 1-year treatment, 21 of them received placebo and 21 received sustained-release fenfluramine. Fenfluramine dosages were individualized and defined based on data collected in a previous 26-week pre-study, in which only patients with a loss greater than or equal to 6 kg were accepted in the study. Of the patients treated with placebo, 19 (90%) gained weight within one year, 8 (38%) of those treated with fenfluramine maintained their weight, 7 (33%) gained weight, and 6 (29%) were withdrawn from the study for any reason. The study concluded that a drug treatment for weight maintenance should be long-term, as it presents better results. Regarding the patients who used fenfluramine and gained weight, the study raised the hypothesis that this weight gain may have occurred due to a treatment failure to keep the plasma levels of the drug in the blood constant. This may be due to the pharmacokinetics of the drug or a failure to adhere to treatment. Be that as it may, the anorectic implant proposed in this patent may come to overcome these flaws in conventional treatment, promoting better results in the treatment of obesity.

[035] The article “Phenylpropanolamine OROS (Acutrim) vs. placebo in combination with caloric restriction and physician-managed behavior modification reports the follow-up of 106 overweight women with normal blood pressure and who did not use medication for chronic diseases, in a 14-week double-blind study. In that study 53 women received placebo and 53 received 75 mg of extended-release phenylpropalamine. All participants began dieting and exercising and implementing some behavioral changes. At the end of treatment, patients who used phenylpropalamine lost 5.1 ±0.6 kg compared to 3.3±0.5 kg. kg with placebo. Weight loss was much more significant in women who used phenylpropalamine, but in both groups they did not notice an effect on hunger. However, women who were treated with phenylpropalamine noted much better appetite control and greater adherence to the prescribed diet. In addition, there was less weight loss in patients who reported less adherence to treatment, both using phenylpropalamine and placebo. In this example, it is also possible to observe a flaw in the traditional treatment that the anorectic implant aims to address, to improve treatment adherence and thus weight loss results.

[036] The study "Sertraline enhances the effects of cognitive-behavioral treatment on weight reduction of obese patients" followed two groups, a control and another treated with 150 mg/day of sertraline for six months. Both groups underwent a treatment cognitive-behavioral to aid in weight loss. All study participants were obese and had no history of diabetes, endocrine, gastrointestinal, kidney or liver diseases. At the end of the study, 59 patients in the sertraline-treated group had a decrease of 6.5± 5.4% of their initial BMI and patients in the control group had a decrease of 3.0±6.3% in their BMI. This result indicates that sertraline associated with a cognitive-behavioral treatment generates much greater weight loss than only psychological and non-drug treatment. In fact, many patients who were not treated with sertraline did not obtain satisfactory results and a portion of them still gained weight during treatment. that there was weight loss in sertraline-treated patients regardless of their mental state, in terms of mood and anxiety. The study concluded that this may be associated with the drug increasing satiety and or suppressing appetite, which corroborates similar results found in animal models.

[037] Although drug treatment plays a key role in weight loss and maintenance, adherence to this treatment is low, less than 10% in treatment for one year and 2% in treatment for two years. According to the World Health Organization, therapeutic adherence is determined by the interaction between the health system and the health team, socioeconomic factors, factors related to the patient, treatment and disease. Adherence to treatment is one of the main factors related to the success or failure of a drug therapy approach. Often the therapeutic result is not as positive as expected due to the patient's behavior, for various reasons he does not continue the treatment and, therefore, the drug does not produce the expected effect.

[038] In the treatment of obesity, one of the causes of low adherence to treatment is the lack of recognition, by both the medical staff and the patient, that obesity is a chronic disease and requires long-term treatment and that weight loss it is just the beginning of the treatment of obesity, and it is essential to maintain weight loss. Maintaining weight loss requires not just lifestyle changes, but often medication or surgery to counteract the neurobiological and endocrine changes that aim to gain weight back to the previous state.

[039] Another factor that compromises patients' adherence to treatment for obesity is the traditional route of administration of these drugs. In traditional drug treatment, the oral route is the most used, but it is also the most likely to fail, as it is always dependent on the active participation (or compliance) of the patient.

[040] Chronic diseases, such as obesity, make the patient have to take at least one medication, often more than once a day, indefinitely to keep the disease under control. The increase in the number of drugs ingested by the patient per day decreases adherence to treatment by about 20% and drugs used in multiple doses also decrease adherence compared to a single dose.

[041] In addition, approximately 50% of patients with chronic conditions do not take their medications as prescribed. Consistency in taking medication among these patients is very low and decreases dramatically after the first six months of therapy. Chronic diseases are long-lasting and can significantly impair the quality of life of those who suffer from them due to the potential for a high physical, emotional and/or economic burden. Management of these chronic conditions requires ongoing attention and commitment from patients. [042] In addition to low adherence to treatment, another disadvantage in the oral use of anorectics is the ease of misuse of the prescribed medication, increasing the risks of supraphysiological doses, making patients more susceptible to the adverse effects of medication, compromising their general status on treatment.

[043] The most effective way to increase patient adherence to treatment is to simplify medication dosages. For many chronic diseases, the development of extended-release drugs has made it possible to simplify dosages. In addition to simplifying dosages, extended-release drugs can reduce the adverse side effects of treatment with anorectics, effects that may result from the high serum concentration of these drugs after oral intake.

[044] In this way, it is possible to find an option known as implants or bioabsorbable anorectic pellets for the treatment of obesity. Such implants present sustained drug release for a long period of time, avoiding concentration peaks and rapid decline of the drug in the body, in order to treat and control the disease and make the treatment independent of the patient taking medication, thus improving weight loss and maintenance.

[045] The terms “implant” or “pellet” refer to this pharmaceutical form already consolidated in the official collections of standards for drugs and pharmaceutical substances. They are characterized by being solid, sterile preparations of a suitable size and shape for parenteral implantation and delivery of the active substance(s) over an extended period of time.

[046] The terms “extended release”, “slow release” or “sustained release” refer to the form of drug release through the implant, which occurs in a continuous and gradual manner over an extended period of time and does not result in a immediate and concentrated drug in the body.

[047] Biodegradable polymers or bioerodible polymers refer to a polymer that degrades in vivo and that its erosion over time occurs. concomitantly with and/or subsequently the release of the therapeutic agent. A biodegradable polymer can be a homopolymer, copolymer or a polymer compressing more than two polymer units. In some cases, a biodegradable polymer may include the blending of two or more homopolymers or copolymers.

[048] Biodegradable implants or bioerodible implants can be understood as implants that have some mechanism that gradually reduces their mass over a prolonged period of release time. The forces involved in this mass reduction can be cellular interaction or shear forces on the implant surface. In addition, erosion and gradual dissolution of its components are possible. The terms also refer to the total degradation and absorption by the body that occurs at the place where the implants were applied, excluding the need to remove the implants at the end of the treatment.

State of the art (Background of the invention)

[049] Referring to patent registrations aimed at resorbable implants, document US4957119 ( Contraceptive implant) mentions an implant of polymeric material that can release a contraceptive agent for a relatively long time when adjusted subcutaneously or locally. The implant comprises an ethylene/vinyl acetate copolymer core material that functions as a matrix for a contraceptive substance, an ethylene/vinyl acetate membrane surrounding the core material, and a contact layer at the interface of the core material and membrane that prevents the material from separating from the membrane core.

[050] Although it claims a resorbable implant, the US4957119 registration uses different active substances, its production is carried out through extrusion and the release period of the active substance is very long (at least 1 year), distinguishing it from the resorbable subcutaneous implant. of the present invention.

[051] The second registration number US9980850 (Bioerodible contraceptive implant and methods of use ΐ bGboή describes a bioerodible contraceptive implant and methods of use in the form of a bioerodible controlled-release granule for subdermal implantation. The bioerodible sediment provides the sustained release of a contraceptive agent over an extended period. Bioerosion products are water soluble, bioresorbable or both, avoiding the need for surgical removal of the implant.

[052] As in the first registration of prior art cited, in this registration US9980850 it also uses different active substances, the period of release of the active substance is very long (from 6 months to 4 years) and the preferred method to manufacture the granules is the hot fusion molding process.

[053] Observing the deficiencies and pre-existing problems in the conventional treatment of obesity, the present invention aims to be a tool, which combined with changes in the patients' lifestyle, promotes weight loss and maintenance of this loss through a resorbable implant. with anorectic agent. The proposed treatment does not depend on the patient's memory and commitment to make the correct use of the medication and through the prolonged release of the active substance it is possible to reduce the adverse symptoms observed orally and avoid the hepatic metabolism of the drug, since it is released directly into the body. blood flow. In addition, at the end of the implants' duration, it is not necessary to remove them, only the reinsertion of new ones to maintain the treatment.

Description of figures

[054] For a better understanding of the present invention, the following drawings are attached:

Figure 1 - Dimensional design of the bioabsorbable implant with anorectic agent;

Figure 2 - Dimensional design of the non-bioabsorbable implant with anorectic agent;

Figure 3 - Graph that relates a scale from 0 to 10 of factors monitored by the patient in the case study using implants bioabsorbables of diethylpropion as a function of time, for the first three weeks of treatment, in which 0 is the equivalent of “little” and 10 is the equivalent of “a lot”, whether for hunger, sleep quality, anxiety and disposition.

Detailed description of the invention

[055] The present application for the privilege of invention is a biodegradable implant with an anorectic agent in a polymer matrix. The implant is inserted subcutaneously and has a continuous release of the active for an extended period of time. This release aims to ensure an efficient, constant and prolonged serum level of the drug for the treatment of obesity.

[056] The “active substance”, “active” or “drug” refers to an anorectic, which can be: diethylpropion, fenproporex, phentermine, mazindol, phenylpropalamine, fenfluramine, dexfenfluramine, fluoxetine and sertraline.

[057] The implant of the present invention may have only the anorectic in its constitution, but it is preferably formed by particles of the anorexigen homogeneously dispersed in a bioerodible and bioabsorbable polymeric matrix. This polymer matrix can be formed by a polymer or a mixture of polymers. The amount of anorectic present in the implant can vary from 25 to 250 mg per implant and its composition has from 1 to 20% of biodegradable polymer in proportion to its weight.

[058] The biodegradable polymer used can be: Poly(D-lactic acid),

Poly(L-lactic acid), Poly(racemic lactic acid), Poly(glycolic acid), Poly(caprolactone), methyl cellulose, ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), poly(vinyl alcohol) ( PVA), poly(ethylene oxide) (PEO), polyethylene glycol, starch, natural and synthetic gum and wax.

[059] Implants can have any size, shape or structure that facilitates their manufacture and subcutaneous insertion, however, to obtain a more constant and uniform release of the active, it is necessary to use geometric shapes that maintain their surface area over time.

[060] Therefore, the implant developed and demonstrated in the The present order adopts the cylindrical pattern (1), in the shape of a rod, provided with straight or rounded ends, with a length between 2 and 25 mm and a diameter of 1 to 6 mm. A schematic drawing of an example of implant dimension (1 ) is shown in figure 1.

[061] The manufacture of the anorectic implant can be made from the addition of 25 to 250 mg of the drug in the chosen biodegradable polymer matrix solution in a proportion of 1 to 20% in relation to the weight of the drug, with the formation of a mixture homogeneous. If the polymer solvent is not also the anorectic solvent, it will be dispersed in the form of particles or suspension, and a mixer can be used to make the solution homogeneous. This solution is then dried and then molded to the shape of the implant (1) or other desired shape.

[062] Another possible way of manufacturing the anorectic implant is from the mixture of 25 to 250 mg of the drug and 1 to 20% of the biodegradable polymer matrix chosen in relation to the weight of the drug, in its dry, powdered forms. The drug and polymer matrix are added to a suitable container and the mixture is homogenized.

[063] The mixture of actives for manufacturing the implant can be molded from pressure or heat, so as not to compromise the effectiveness of the drug or degrade the polymeric material. The options for implant molding techniques can be: injection molding, hot molding, compression molding or extrusion molding.

[064] For the present invention, the technique chosen was compression molding. In this technique, the mixture of actives, in powder form, is added to a mold and mechanical force is applied under the mixture, generating the compression of the particles and, consequently, the molding of the implant in the format (1). Then there is the filling and sterilization of the anorectic implant. Its sterilization can be done by heat or gamma rays.

[065] The implant may have a polymeric membrane coating, with a thickness between 0.1 to 0.7 mm. The polymer used for the coating must be bioabsorbable and allow the passage of the active. The implant coating is preferably done by immersing the implant in a polymeric solution. The coating can cover the entire surface of the implant including the edges, only its longitudinal surface with the edges uncoated or coated only on the edges of the implant without coating its length. The polymers that can be used for the coating are: poly(lactic acid-co-glycolic acid) (PLGA) and copolymers of D,L-lactic acid.

[066] Yet another implant option for treating obesity is non-biodegradable implants. Non-biodegradable or non-bioerodible implants (2) (figure 2) have a central core (2.1) formed by polymeric matrix in the percentage of 1 to 20% in relation to the weight of the drug, in this case from 25 to 250 mg of anorectic, with the core surrounded by a non-degradable polymeric membrane (2.2) that controls the rate of drug release.

[067] The material for manufacturing the polymeric membrane that surrounds the implant can be: silicone, urethane, acrylates and their copolymers, polyvinylidene fluoride copolymers, polyethylene vinyl acetate-ethylene vinyl acetate, dimethylpolysiloxane. This membrane has a thickness of 0.2 to 1 mm and is molded using our own equipment. After molding the membrane from the polymeric material, the active mixture is inserted, forming the central core (2.1) of the implant (2). The polymers used in the polymer matrix and the mixture adopt the same compounds and process as the bioabsorbable implant.

[068] Drug release in this system occurs through diffusion at a relatively constant rate, and it is possible to change the rate of drug release through the thickness or material of this membrane. In this system, there is a need to remove the implant at the end of the treatment.

[069] The treatment for obesity using anorectic implants should be defined according to the patient's clinical condition, taking into account that the duration of the implant is approximately 3 to 6 months, this time being the proposed period between implant insertions.

[070] Treatment with anorectic implants has the advantage of needing about 8-20% of the doses used orally. The dose reduction is due to the implantation of the drug in the subcutaneous layer, which prevents its first-pass metabolism, thus reducing the dose required to maintain active bioavailability. The prolonged release of the active through the implant avoids sub- or supraphysiological plasma concentrations, the “peaks and valleys” that occur with oral administration. Thus, it is possible to reduce the unwanted side effects of anorectics, such as dry mouth, nausea, sweating, sleep disturbance, irritability, headache, constipation, keeping the drug concentration within the therapeutic window found in the literature.

[071] For diethylpropion, for example, the maximum suggested dosage is 120 mg/day. In a three-month (90-day) treatment with this dosage the patient would use 10.8 g. With the diethylpropion implant, the dosage could drop to about 0.9 g (8%) to 2.2 g (20%) in the same time interval, achieving a similar therapeutic effect in addition to all the aforementioned benefits.

[072] However, in order to define an individualized treatment for each patient, it is necessary for the physician to evaluate the clinical condition of this patient and to follow the evolution of both the weight and the quality of life reported by the patients. During the course of treatment, the dose can be adjusted by inserting additional implants, if necessary. In addition, if rejection or any adverse reaction occurs after implant insertion, the implant can be removed within the first few days of treatment.

[073] The use of the implant proposed here is safe and effective in the treatment of obesity, given that the therapy does not depend on the patient's will or discipline for the action of the drug, thus ensuring the maintenance of the dosage and regularity of the treatment. . The use of these implants in therapeutic management prevents discontinuation without medical assistance and guarantees adequate treatment, as well as its effectiveness. Furthermore, the invention prevents the patient from misusing the medication, ingesting larger amounts than those recommended by the doctor and becoming more susceptible to unwanted side effects and worsening of their clinical condition.

[074] The anorectic implant avoids the “peaks and valleys” of oral administration and decreases the amount of medication needed for the therapeutic effect, limiting the side effects. The simplification of dosage and decrease in the frequency of administration also adds economic value to the product and promotes greater adherence to treatment.

[075] Another benefit of this invention is the release of the drug, through the implants, directly into the bloodstream, which makes its action much more efficient and avoids the first-pass metabolism of the drug.

[076] A case study was performed with a 36-year-old female patient with grade III obesity - BMI of 44.3 kg/m ² - and a history of thyroid nodules, hypertension and hypovitaminosis B12. The patient was treated with a multifactorial approach for six months, through vitamin replacement, anorectics, diet and physical exercise. During the treatment, 5 resorbable implants of 75 mg of diethylpropion were used in the patient, which lasted approximately three months. Figure 3 contains a graph on a scale from 0 to 10, with 0 being a little and 10 a lot, of some factors monitored by the patient - hunger, sleep quality, anxiety and disposition - during the first three weeks of treatment. The disposition results were added to the general balance only on the third day of treatment, when the patient saw a significant improvement in this aspect and began to take notes of her own volition. On the sixteenth day, the patient reported feeling sick with a food she had consumed, which reduced her hunger and disposition on the day and the following day.

[077] The results found for this patient were very promising, as, at the end of six months of multifactorial treatment, the patient lost 26 kg, BMI dropped to 35.7 kg/m ² , in an expressive decrease of almost 20% in weight. initial. The patient reported feeling generally with excellent mood and sleep, decreased hunger and no symptoms of anxiety, in addition to being more motivated to follow the treatment to continue weight loss.

[078] Another study was carried out with a 49-year-old patient with obesity grade III - BMI of 45.0 kg/m ² - history of hypertension and binge eating, mainly at night and early morning. The patient was treated with a multifactorial approach for three months, with anorectic and diet prescription, without physical exercise. During the treatment, 5 resorbable implants of 75 mg diethylpropion in the patient.

[079] At the end of three months the patient had lost 12.6 kg, her BMI had dropped to 40.4 kg/m ² , a 10.3% reduction from her initial weight. In addition, her hip measurement decreased by 11 cm and waist circumference decreased by 3 cm. In addition to weight loss, the patient reported a significant decrease in binge eating, reflecting a decrease in uncontrolled eating at night and in the early hours of the morning.

Claims

1. LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRECONCENTRATED PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF OBESITY, CHARACTERIZED by the fact that the biodegradable implant contains 25 to 250 mg of the anorectic diethylpropion, phenproporex, phentermine, mazindol, phenylpropalamine, , dexfenfluramine, fluoxetine and sertraline in particles homogeneously dispersed in a bioerodible and bioabsorbable polymeric matrix, the composition of the polymeric matrix being from 1 to 20% of biodegradable polymer in proportion to the weight of anorectic;

2. SUBCUTANEOUS IMPLANT FOR LONG TERM RESORBABBLE WITH PROLONGED RELEASE OF PRECONCENTRATELY PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF OBESITY, according to claim 1, CHARACTERIZED in that the biodegradable polymer used is Poly(D-lactic acid), Poly( L-lactic acid), Poly(racemic lactic acid), Poly(glycolic acid), Poly(caprolactone), methyl cellulose, ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), poly(vinyl alcohol) (PVA) , poly(ethylene oxide) (PEO), polyethylene glycol, natural and synthetic starch and wax;

3. LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRECONCENTRATELY PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF OBESITY, according to claims 1 and 2, CHARACTERIZED in that the implant adopts the cylindrical pattern (1), in the form of a rod with straight or rounded tips and length between 2 to 25 mm and diameter from 1 to 6 mm;

4. LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRE-CONCENTRATELY PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF OBESITY, according to claims 1, 2 and 3, CHARACTERIZED in that the implant has a polymeric coating membrane, with a thickness between 0.1 to 0.7 mm, with the total covering of the implant, including the edges, only its surface longitudinal with the edges uncoated or coated only on the edges of the implant without coating its length, using polylactic-glycolic acid (PLGA) and copolymers of D,L-lactic acid as a polymeric membrane;

5. LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRECONCENTRATELY PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF OBESITY, CHARACTERIZED in that the implant is presented in a non-biodegradable or non-bioerodible form (2), having a central core (2.1) formed by polymeric matrix in the percentage of 1 to 20% in relation to the weight of the drug, in this case from 25 to 250 mg of anorectic, the core being surrounded by a non-degradable polymeric membrane (2.2);

6. LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRECONCENTRATELY PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF OBESITY, according to claim 6, CHARACTERIZED in that the material of manufacture of the polymeric membrane surrounding the non-biodegradable implant is silicone , urethane, acrylates and their copolymers, polyvinylidene fluoride copolymers, polyethylene vinyl acetate-vinyl ethylene and dimethylpolysiloxane, said membrane having a thickness of 0.2 to 1 mm and the insertion of anorectic after its molding, forming the core center (2.1) of the implant (2);

7. PROCESS, according to claims 1, 2 and 3, CHARACTERIZED in that the implant manufacturing process starts with the addition of 25 to 250 mg of the anorectic in the chosen polymer matrix in a proportion of 1 to 20% in relation to the weight of the drug, in its dry forms, in powder, occurring the addition of the mixture in a container to be homogenized, having, in the sequence, the insertion of the readily homogenized powder actives in a mold to carry out the molding of the implant under mechanical force, compressing the particles and molding the implant into the shape (1), finally taking place the filling and sterilization of the anorectic implant by heat or by gamma rays;