BR102020025389A2 - Long-term resorbable subcutaneous implant with sustained release of pre-concentrated, polymer-concentrated pharmacologically active substance for the treatment of nicotine addiction and process - Google Patents

Abstract

The present application for the privilege of invention is aimed at the health sector and comprises a long-term resorbable subcutaneous implant with prolonged release of a pre-concentrated polymer pharmacologically active substance for the treatment of nicotine dependence. The present application is a biodegradable implant with an agent for treating nicotine addiction 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 nicotine addiction. The implant may have in its constitution only the agent for the treatment of nicotine dependence, but it is preferably formed by particles of the active dispersed homogeneously in a bioerodible and bioabsorbable polymeric matrix. Implants can have any size, shape or structure that facilitates their fabrication and subcutaneous insertion, however, in order 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.

Description

LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRECONCENTRATED POLYMER PRECONCENTRATE PHARMACOLOGICALLY ACTIVE SUBSTANCE FOR THE TREATMENT OF NICOTINE ADDICTION 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 a pre-concentrated pharmacologically active substance in polymer for the treatment of nicotine dependence.

Fundamentals of the invention

[002] Nicotine is an alkaloid found in abundance in tobacco plants. Tobacco is the main access route to nicotine found commercially, since nicotine is its main active ingredient.

[003] Tobacco is marketed in several ways, such as manufactured cigarettes, hand-rolled cigarettes, cigars, pipes, hookahs, chewing tobacco, among others. All these forms of presentation of tobacco, and consequently of nicotine, have the potential for addiction, but among them the most harmful is the cigarette, for quickly making nicotine available to the brain and in high doses.

[004] Nicotine is a drug classified as a stimulant, but it acts as both a stimulant and a depressant. Among its stimulating effects are increases in concentration, memory, information processing and learning. As a depressive it can relieve anxiety, depression and pain.

[005] Nicotine acts on the central nervous system by binding to nicotinic receptors and its use produces acute and chronic tolerance. Among its actions, it releases dopamine and other neurotransmitters, resulting in a variety of physiological effects, including behavioral arousal and neural activation. The release of dopamine, noradrenaline and serotonin are associated with feelings of pleasure and also with appetite suppression. The release of acetylcholine is related to increased attention, increased concentration on repetitive tasks and improved memory.

[006] According to the World Health Organization (WHO) nicotine meets the criteria of a drug that can cause addiction. Dependence can be characterized by neurochemical and psychological processes that cause a person to continuously use a substance and lose control over its use. In addition, dependence on a substance is also characterized by the difficulty in discontinuing its use, even with many reasons for this and even presenting imminent damage to the user's health.

[007] The 1988 "Surgeon" report on nicotine dependence adds some criteria to those established by the WHO. The report states that for a substance to be characterized as addictive it must produce psychoactive effects and there must be evidence that the behavior that drives users to use this substance is reinforced by its effect. Nicotine, as stated in the publication, meets this criterion, as it has psychoactive effects desired by the user, such as relaxation and mood improvement, and it also serves as a positive reinforcement for smoking, since that regular tobacco smokers modify their tobacco use patterns to maintain nicotine levels in the body.

[008] In addition to addiction, nicotine can cause withdrawal. Dependence is characterized by the repetitive and compulsive use of a drug, while withdrawal is a syndrome characterized by a set of symptoms resulting from a sudden cessation of consumption of a substance.

[009] Nicotine dependence is potentiated by the way it is ingested. Cigarettes, for example, deliver nicotine repetitively, as the addict smokes several cigarettes throughout the day, making its addictive potential even greater. Nicotine dependence is also characterized by difficulty in giving up smoking and an increase in the body's tolerance to the substance.

[010] Nicotine withdrawal generates many adverse symptoms in the first 24 hours after abrupt withdrawal of the substance, such as depressive and dysphoric mood, insomnia, irritability, frustration, anger, anxiety, difficulty concentrating, restlessness, decreased heart rate, appetite increase. These symptoms are more intense 24 to 48 hours after substance withdrawal and gradually decrease, lasting up to a few weeks.

[011] The combination of tobacco dependence with the symptoms of the withdrawal crisis when trying to stop its consumption makes nicotine addiction extremely difficult to overcome, especially without associated treatment. Tobacco dependence, sustained by nicotine addiction, can be considered a chronic disease, as most smokers need several interventions during their lifetime before achieving total abstinence from these substances.

[012] Also according to the WHO, about 70% of smokers around the world would like to stop smoking, but it is estimated that only 1% of those who decide to stop without professional and/or medication help succeed in one year. Another research points out that only 33% of those nicotine users who quit tobacco on their own manage to remain abstinent for 2 days. Still, approximately 80% of smokers who try to quit on their own relapse within the first month, and only 3% of them manage to remain abstinent for 6 months.

[013] In addition to the high mental burden that smokers are subjected to due to the difficulty in giving up nicotine dependence, there are also several health problems associated with tobacco consumption. Tobacco burning produces many toxic substances that are associated with various chronic diseases such as cancer, heart and lung disease, diabetes and cardiovascular disease. Smoking also causes other types of problems in the body, such as inflammation and reduced immunity. Passive tobacco smoker may also be at increased risk of respiratory, cardiovascular and cancer diseases.

[014] According to the World Health Organization (WHO), tobacco dependence prematurely kills one person every six seconds. One in two long-term smokers, particularly in low- and middle-income countries, will die prematurely as a result of nicotine addiction.

[015] The fatality rate associated with tobacco consumption is alarming around the world. 2014 WHO data estimate that more than 6 million people die each year from tobacco use and more than 600,000 people die from passive cigarette exposure alone, with 28% of these deaths in children. Globally, tobacco is responsible for 7% and 12% of deaths in women and men, respectively. Projections for deaths from tobacco use are 8 million deaths annually in 2030, accounting for 10% of all deaths worldwide.

[016] The high mortality rate associated with smoking results in a high economic burden for countries, either by the costs associated with the medical treatment of the disease, by the loss of productivity of affected individuals and also by the premature deaths of individuals who constitute the force of work in these countries. A 2015 study points out that the costs associated with smoking in Brazil in 2011 represent approximately 23 billion reais for the health system, with 31% attributable to heart disease, 27% to chronic obstructive pulmonary disease, 7% to lung cancer. and 7% to stroke. Passive smoking and perinatal causes accounted for 12% of these costs. The costs to the healthcare system were four times higher than the taxes levied on cigarettes for the same period of time.

[017] Due to the high mortality rates associated with the disease, the health problems that smoking causes and the overload of the health system, it is essential that people with nicotine and tobacco addiction receive adequate and effective treatment, as it is possible to avoid deaths. associated with this addiction.

[018] The most effective treatment for smoking consists of a drug approach associated with psychological help, encouraging behaviors that support the smoker in his decision to follow treatment and quit.

[019] Among the behavioral techniques indicated are increasing water intake, using dietary candies or gums, practicing physical activities, practicing relaxation exercises, abstaining from coffee and/or alcohol, brushing teeth more frequently, managing situations better and/or stress factors, start physical-recreational activities and modify previous life habits.

[020] The main drug approach is known as nicotine replacement therapy (NRT) and consists of replacing the nicotine present in tobacco with pure nicotine, which is the cause of dependence, but which does not have the adverse side effects resulting from tobacco burning. Nicotine is administered to the tobacco user in the form of a spray, chewing gum, mouthwash, or patch over a period of time, with a gradual reduction in dosage until complete withdrawal of the substance.

[021] In addition to nicotine replacement therapy (NRT) there are other treatment options available with different approaches. One class of drugs used are antihypertensives such as clonidine and mecamylamine. These drugs have a central action on brain receptors and act by minimizing the effects of the nicotine withdrawal crisis.

[022] Another therapeutic approach uses antidepressant drugs such as bupropion, nortiptyline, moclobemide, doxepin and fluoxetine. This class of medication works by minimizing anxiety and depression that are related to the maintenance of tobacco dependence. In addition, mood swings such as anxiety and depression are factors that increase the likelihood of a relapse on the part of smokers undergoing treatment. In population-based studies, it is possible to observe that smokers are more likely to present symptoms of affective disorders than the non-smoking population and are also more likely to start smoking and less likely to be able to quit smoking. These effects may be related to changes in dopaminergic activity in the brain caused by nicotine addiction, so the use of these drugs is presented as a joint therapy for effective and lasting treatment against nicotine addiction.

[023] It is also possible to use opioid antagonist drugs, which act by competitively binding to opioid receptors present mainly in the central nervous system, blocking the effect of the opioid agents themselves, in this case nicotine. A drug used for this purpose is naltrexone, already used for the treatment of alcoholism and which has also shown promising results in the fight against smoking. Naltrexone works by decreasing the pleasure that smokers get from smoking and decreasing the urge to smoke.

[024] Naltrexone in addition to acting on opioid receptors in the central nervous system, can also act on opioid receptors present in the reward system and the melanocortin system in the hypothalamus, helping to regulate the homeostatic energy balance in the body. The effect of this interaction is that there is a decrease in appetite and binge eating in patients, so naltrexone works to minimize the weight gain that often occurs after smoking abstinence. Weight gain is a very common consequence after quitting smoking, there can be a gain of 2-3 kg in 12 weeks of abstinence and a gain of 4-6 kg in up to a year. This weight gain is one of the major barriers to successful treatment of nicotine addiction and is one of the main reasons that lead patients to relapse to cigarettes or even not to start the treatment itself.

[025] Nicotine replacement therapy (NRT) is the most widely used treatment against smoking. Among the available options for nicotine replacement, the one with the best results is in the form of a patch, as it releases nicotine in the body in a slow and passive way. The patches sold have different dosages, and can contain from 5 to 52.5 mg of nicotine in patches that last up to 24 hours. The treatment can last from 2 to 12 months, as the clinical picture improves. According to studies comparing treatment with nicotine replacement therapy and placebo, the success rate with nicotine replacement therapy after 6 months is twice as high as compared to the use of placebo.

[026] Among the treatment options with antidepressants, bupropion is widely used for decreasing the craving for smoking and for reducing withdrawal symptoms. Its mechanism of action is not fully established, but it is believed that bupropion acts by inhibiting the uptake of noradrenaline and/or dopamine, without affecting the reuptake of serotonin. For the treatment of nicotine addiction, the recommended dosage is 150 mg of sustained-release bupropion twice daily. The duration of treatment is recommended for 7 to 12 weeks, which may vary according to clinical follow-up and patient evolution.

[027] A paper entitled “A comparison of sustained-release bupropion and placebo for smoking cessation” reported a randomized, double-blind, placebo-controlled trial of 615 volunteers who smoked 15 cigarettes or more in at least one year prior to the study and who were committed to quitting smoking. Volunteers were divided into four groups receiving 100 mg, 150 mg or 300 mg of bupropion daily or placebo for 6 weeks. At the end of treatment, the success rates of patients who used bupropion were much higher than those who used placebo.

[028] The group that used the highest amount of bupropion, 300 mg per day, achieved better results than those that used only 100 mg of bupropion per day. The rates of participants who stopped smoking after six weeks of treatment were 19% and 44.2% for the placebo and bupropion group, respectively. After one year of treatment, the rates were 12% with placebo versus 23.1% with bupropion.

[029] Another alternative to the use of bupropion is to make its use associated with nicotine replacement therapy (NRT). The treatment combines oral bupropion and nicotine by means of patches and lasts for at least 2 months. The article “A controlled trial of sustained-release bupropion, a nicotine patch or both for smoking cessation” followed the treatment of 893 patients who underwent a 9-week smoking cessation treatment. They were divided into four groups that received either placebo, nicotine patch, bupropion, or a combination of bupropion and nicotine patch. Patients in the bupropion groups took 150 mg of sustained-release bupropion twice daily. The groups that used the nicotine patch received a dosage of 7, 14 or 21 mg of nicotine, depending on the week of treatment. Of the patients who completed the treatment, it was possible to observe that the long-term abstinence rates were higher for the groups that used both bupropion alone and in combination with the nicotine patch compared to the placebo.

[030] Naltrexone also presents itself as a very viable alternative that is already well established in the treatment of alcohol addiction. Its dosage is 50 mg per day and the treatment lasts an average of 8 to 12 weeks.

[031] The randomized, double-blind, placebo-controlled study entitled “Naltrexone Effects on Short-Term and Long-Term Smoking Cessation” followed 68 smoking patients over a 4-week study. Patients were divided into two groups, one receiving naltrexone at an initial dosage of 25 mg, which could be increased to 50 or 75 mg depending on the patient's tolerance of the drug, and the other receiving placebo. At the end of treatment, the naltrexone group had a 46.7% abstinence rate versus 26.3% with placebo. Six months after the start of treatment, the abstinence rate of patients using naltrexone compared to those using placebo was 26.7% versus 15.2%.

[032] Another alternative to the use of naltrexone is to make its use associated with bupropion. The association of these drugs makes the treatment for nicotine addiction more effective, by improving withdrawal symptoms, reducing the craving for smoking and preventing weight gain often associated with cigarette withdrawal. The study “An open-label study of naltrexone and bupropion combination therapy for smoking cessation in overweight and obese subjects” followed 30 overweight or obese patients for 24 weeks. Patients began treatment using 8 mg naltrexone and 90 mg bupropion daily, with dosages being increased at the end of treatment to 32 mg naltrexone and 360 mg bupropion daily. The abstinence rate during week 4 to 12 was 40.1% of patients, while abstinence from week 4 to 24, at the end of the study, was 40.7%. The weight of patients who managed to stay abstinent through the 24 weeks of the study increased very little, on average 1.3 kg, about half the weight gain seen for other types of nicotine addiction treatment. In addition, there was a significant reduction in smoking cravings and no increase in withdrawal symptoms.

[033] Although drug treatment plays a key role in the successful treatment of nicotine addiction, traditional routes of administration, both oral for the drugs bupropion and naltrexone, and the nicotine patch, have the disadvantage of having low adherence. therapy.

[034] According to the World Health Organization (WHO), therapeutic adherence is determined by the interaction between the health system and 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.

[035] Among the available options for nicotine replacement therapy (NRT) the one with the highest adherence rate and best results is the nicotine patch. One study indicated that in the first week of using nicotine replacement therapy, the adhesion rate to the patch was 82%, compared to 38%, 15%, and 11% for chewing gum, nasal spray, and inhaler, respectively. The main reason for patients to reduce adherence to treatment is forgetting, in the case of the adhesive, and because they believe that they no longer need the treatment, for the other forms of presentation. Through these values, it is possible to affirm that the nicotine patch has better patient adherence compared to other forms of presentation, however, these values refer only to the first week of treatment, these rates tend to decrease significantly over time. Studies show that there is a drop of about 30% in the use of patches in a period of 12 weeks. In addition, in the long term, it is possible to find in the scientific literature rates of, on average, 50% of patients who make adequate use of the patch, with adequate use in only 90% of the days of the study. In addition to the inadequate use of the patch, patients often discontinue its use before the time indicated for treatment, compromising all its effectiveness.

[036] The innovation proposed in this document manages to overcome all the reasons cited for the failure in the conventional treatment of nicotine replacement therapy (NRT), as it does not depend on the active participation of the patient when changing the patches or using the medications at intervals. adequate, making the treatment continuous and effective, since nicotine dependence is a chronic disease that requires long-term treatment, often neglected by patients.

[037] In addition to nicotine replacement therapy (NRT), there is oral treatment with antidepressants or opioid agonists, and the oral route is the most likely to fail, as it is always dependent on the active participation (or compliance) of the patient. . This failure resulting from the patient's faulty participation does not occur with the implants proposed in this document.

[038] Chronic diseases, such as nicotine dependence, make the patient have to take at least one medication, often more than once a day, for an extended period of time to be able to quit smoking. 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.

[039] In addition to low adherence to treatment, another disadvantage in the oral use of drugs to combat nicotine dependence is the ease of misuse of the prescribed medication, increasing the risks of supra-physiological doses, making patients more susceptible to adverse effects of the medication, compromising their general condition in the treatment.

[040] 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 this way, it is possible to find an option known as implants or bioabsorbable pellets of agents for the treatment of nicotine addiction and the set of associated symptoms. 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 nicotine dependence and make the treatment independent of the use of medication by the patient.

[041] 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.

[042] 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 release immediate and concentrated drug in the body.

[043] Biodegradable polymers or bioerodible polymers refer to a polymer that degrades in vivo and that its erosion over time occurs concomitantly with and/or subsequent to 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.

[044] Biodegradable implants or bioerodible implants can be understood as implants that have some mechanism that makes the gradual reduction of its mass for a prolonged period of time of release. 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)

[045] 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.

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

[047] Second registration number US9980850 (Bioerodible contraceptive implant and methods of use thereof) describes a bioerodible contraceptive implant and methods of use in the form of a controlled release bioerodible 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.

[048] As in the first above mentioned record, in this US9980850 record 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.

[049] Observing the deficiencies and pre-existing problems in the conventional treatment of nicotine dependence, the present invention aims to be a tool that, combined with changes in the patients' lifestyle, helps these patients to stop smoking and maintain abstinence, avoiding weight gain, anxiety and compulsion associated with cigarette abstinence. The proposed treatment does not depend on the patient's memory and commitment to make correct use of the medication and through the prolonged release of the active substance it is possible to reduce the adverse symptoms that can be observed in the drugs bupropion and naltrexone ingested orally and to avoid the hepatic metabolism of these drugs. , since through the implants they are released directly into the bloodstream. 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

[050] For a better understanding of the present invention, the following drawings are attached:
Figure 1 - Dimensional design of the bioabsorbable implant with active;
Figure 2 - Dimensional design of the non-bioabsorbable implant with active.

Detailed description of the invention

[051] The present application for the privilege of invention is a biodegradable implant with agent for treating nicotine addiction in 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 nicotine addiction.

[052] The "active substance", "active" or "drug" refers to a drug for the treatment of nicotine dependence, which can be: nicotine, bupropion or naltrexone.

[053] The implant of the present invention may have in its constitution only the agent for the treatment of nicotine dependence, but it is preferably formed by particles of the active dispersed homogeneously in a bioerodible and bioabsorbable polymeric matrix. This polymer matrix can be formed by a polymer or a mixture of polymers. The amount of the active nicotine, bupropion or naltrexone 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 of the active nicotine, bupropion or naltrexone.

[054] The biodegradable polymer used can be: Poly(D-lactic acid), Poly(L-lactic acid), Poly(racemic lactic acid), Poly(glycolic acid), Poly(caprolactone), methylcellulose, ethylcellulose, hydroxypropylcellulose ( HPC) hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), poly(vinyl alcohol) (PVA), poly(ethylene oxide) (PEO), polyethylene glycol, starch, natural and synthetic gum and wax.

[055] Implants can have any size, shape or structure that facilitates their fabrication and subcutaneous insertion, however, in order 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.

[056] Therefore, the implant developed and demonstrated in the present application adopts the cylindrical pattern (1), in the shape of a rod, provided with straight or rounded tips, with a length between 2 to 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.

[057] The manufacture of the implant with an agent for the treatment of nicotine dependence can be made from the addition of 25 to 250 mg of the active nicotine, bupropion or naltrexone in the solution of the chosen biodegradable polymer matrix in a proportion of 1 to 20% in relation to to the weight of the drug, with the formation of a homogeneous mixture. If the polymer solvent is not also the drug 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.

[058] Another possible way of manufacturing the implant with an agent for the treatment of nicotine dependence is from the mixture of 25 to 250 mg of the active nicotine, bupropion or naltrexone and 1 to 20% of the biodegradable polymer matrix chosen in relation to weight of the active, in its dry forms, in powder. The drug and polymer matrix are added to a suitable container and the mixture is homogenized.

[059] 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.

[060] 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 implant with an agent for the treatment of nicotine dependence. Its sterilization can be done by heat or gamma rays.

[061] 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 uncoated edges, or coated only 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.

[062] Yet another implant option for treating nicotine addiction 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 nicotine, bupropion or naltrexone, the core being surrounded by a non-degradable polymeric membrane (2.2) that controls the rate of drug release.

[063] 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 or 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 mixture of the active nicotine, bupropion or naltrexone 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.

[064] 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.

[065] Treatment with these implants has the advantage of requiring 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 necessary to maintain the bioavailability of the active. The prolonged release of the active through the implant avoids sub- or supra-physiological plasma concentrations, the "peaks and valleys" that occur with oral administration. In addition, the duration of the implant is approximately 3 to 6 months, this time being the proposed period between implant insertions.

[066] For nicotine treatment the maximum suggested dosage is 52 mg/day. In a three month treatment (90 days) with this dosage the patient would use 4.7 g. With the nicotine implant, the dosage could drop to about 0.4 g (8%) to 0.9 g (20%) in the same time interval, achieving a similar therapeutic effect in addition to all the aforementioned benefits.

[067] For treatment with bupropion the maximum suggested dosage is 300 mg/day. In a three-month (90-day) treatment at this dosage the patient would use 27 g. With the bupropion implant, the dosage could drop to around 2.2 g (8%) to 5.4 g (20%) in the same time interval, achieving a similar therapeutic effect in addition to all the benefits mentioned.

[068] For treatment with naltrexone, the maximum suggested dosage is 50 mg/day. In a three-month (90-day) treatment at this dosage the patient would use 4.5 g. With the naltrexone implant, the dosage could drop to about 0.4 g (8%) to 0.9 g (20%) in the same time interval, achieving a similar therapeutic effect in addition to all the aforementioned benefits.

[069] 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 follow-up his symptoms and his evolution in abstaining from smoking. 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.

[070] Treatment using implants with an agent for the treatment of nicotine dependence should be defined according to the patient's clinical condition and considering that nicotine, bupropion and naltrexone implants can be used together or separately, according to medical evaluation. The nicotine implant aims to maintain nicotine levels in the patient's body to reduce withdrawal symptoms resulting from the abrupt cessation of cigarette use. Bupropion, on the other hand, helps to treat symptoms of anxiety and depression associated with cigarette withdrawal, thus improving the patient's general well-being. Naltrexone acts by competitively binding to receptors in the central nervous system that would be occupied by endogenous opioids that reinforce cigarette use, thus reducing the craving for smoking and the pleasure related to smoking. occurs in most patients who decide to quit smoking. The synergy of these three implants when used together allows a complete treatment for the patient who decides to stop smoking.

[071] The use of the implant proposed here is safe and effective in the treatment of nicotine dependence, given that the therapy does not depend on the patient's will or discipline for the action of the drug, ensuring, therefore, 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, making use of amounts greater than those recommended by the doctor and becoming more susceptible to unwanted side effects and worsening of their clinical condition.

[072] The implant with an agent for the treatment of nicotine dependence avoids the "peaks and valleys" of oral administration and other forms of administration of nicotine replacement therapy (NRT). The mechanism of action of the implant in the body allows a more continuous release of the active for an extended period of time. Daily release of sufficient amounts of the drug maintains efficient serum drug levels, thereby minimizing adverse withdrawal symptoms, decreasing cravings for smoking and adverse physiological effects, preventing relapses, and improving treatment retention rates.

[073] When using nicotine implants there is the daily release of an efficient amount of this asset that makes the patient reduce his craving for smoking. In addition, the mechanism of action of nicotine, even in small doses as is the case with implants, releases noradrenaline, which acts by improving the mood, anxiety, sleep of patients, factors that directly influence their well-being and commitment. with the treatment.

[074] The bupropion implant works synergistically with the nicotine implant, minimizing depression and anxiety in patients who experience cigarette withdrawal, improving their well-being and decreasing their adverse symptoms. The bupropion implant does not cause the "peaks and valleys" of active concentration in the body compared to the oral route of administration. The lower, more continuous and extended release achieved through the implant means that the patient does not deal with the adverse symptoms encountered with the administration of bupropion orally.

[075] The naltrexone implant, in addition to helping with the urge to smoke, also prevents weight gain associated with cigarette withdrawal. In the treatment of cigarette addiction, it is counterproductive for the patient to have to do an associated treatment to control food intake to avoid weight gain, the combination of these two treatments often results in lower rates of abstinence, due to the high mental burden to be had. that patients are exposed to. Thus, it is imperative that treatment for nicotine addiction helps patients maintain their weight without having to change their eating habits.

[076] Yet another advantage of the implants of this invention is the decrease in the amount of drug needed for the therapeutic effect, thus limiting side effects. The simplification of dosage and decrease in the frequency of administration promotes greater adherence to treatment.

[077] Another advantage is in the form of presentation of the implant, which makes the gradual reduction of its concentration through an extended time release of the active in the patient's body. This gradual reduction in concentration causes a natural weaning of the drug in the last month of treatment, so at the end of treatment the patient is already accustomed to the lowest concentration of the drug in the body, until its total withdrawal. This avoids sharp differences in concentration often found in traditional routes of administration, which cause unfavorable physiological symptoms.

[078] 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.

Claims (7)

LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRECONCENTRATED PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF NICOTINE DEPENDENCE, CHARACTERIZED by having 25 to 250 mg of nicotine, bupropion or naltrexone in particles homogeneously dispersed in a matrix in the constitution of the biodegradable implant bioerodible and bioabsorbable polymer, the composition of the polymeric matrix being from 1 to 20% of biodegradable polymer in proportion to the weight of the active nicotine, bupropion or naltrexone; SUBCUTANEOUS IMPLANT REABSORBABBLE WITH PROLONGED RELEASE OF PRECONCENTRATED PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR TREATMENT OF NICOTINE ADDICTION, 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, starch, natural and synthetic gum and wax; LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRECONCENTRATED PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF NICOTINE DEPENDENCE, 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; SUBCUTANEOUS IMPLANT REABSORBABBLE OF LONG TERM WITH PROLONGED RELEASE OF PRECONCENTRATELY PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR TREATMENT OF NICOTINE ADDICTION, according to claims 1, 2 and 3, CHARACTERIZED in that the implant has a polymeric membrane coating, with a thickness between 0.1 and 0.7 mm, with the implant being fully coated including the edges, only its longitudinal surface with the uncoated edges or coated only on the edges of the implant without coating its length, using poly(lactic acid) as a polymeric membrane -co-glycolic acid) (PLGA) and copolymers of D,L-lactic acid; LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRECONCENTRATED PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF NICOTINE DEPENDENCE, 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 nicotine, bupropion or naltrexone, the core being surrounded by a non-degradable polymeric membrane (2.2); LONG-TERM REABSORBABBLE SUBCUTANEOUS IMPLANT WITH PROLONGED RELEASE OF PRECONCENTRATED PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF NICOTINE DEPENDENCE, according to claim 6, CHARACTERIZED in that the fabrication material of the polymeric membrane surrounding the non-biodegradable implant is urethane , acrylates and their copolymers, polyvinylidene fluoride copolymers, polyethylene vinyl acetate-ethylene vinyl acetate, or dimethylpolysiloxane, said membrane having a thickness of 0.2 to 1 mm and the insertion of nicotine, bupropion or naltrexone occurring after its molding, forming the central core (2.1) of the implant (2); 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 active nicotine, bupropion or naltrexone in the solution of the biodegradable polymer matrix chosen in the proportion of 1 to 20 % in relation to the weight of the active, with the formation of a homogeneous mixture, followed by the drying of the solution and subsequent compression molding using a mold and application of mechanical force under the mixture to form the implant (1), ending the process with the filling and sterilization of the implant done by heat or by gamma rays.

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