RU2822514C1 - Long-acting controlled-release subcutaneous polymer implant of pharmacological pre-concentrated substance for treatment of erectile dysfunction and benign prostatic hyperplasia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to long-acting subcutaneous polymer implants with controlled release of pharmacological pre-concentrated substance for treatment of erectile dysfunction and benign prostatic hyperplasia. Disclosed is a long-acting controlled-release subcutaneous polymer implant of a pharmacological pre-concentrated substance for the treatment of erectile dysfunction and benign prostatic hyperplasia, which is characterized by the fact that the biodegradable implant contains from 25 to 250 mg of tadalafil in the form of particles homogeneously dispersed in the biodegradable and bioabsorbable polymer matrix, wherein the polymer matrix contains from 1 to 20% of a biodegradable polymer with respect to the weight of tadalafil. Disclosed is a long-acting controlled-release subcutaneous polymer implant of a pharmacological pre-concentrated substance for the treatment of erectile dysfunction and benign prostatic hyperplasia, which is characterized by that the implant is presented in a non-biodegradable form, has a central core formed by a polymer matrix in percentage ratio of 1 to 20% with respect to the weight of drug - 25 to 250 mg of tadalafil, and the core itself is surrounded by a non-degradable polymer membrane.

EFFECT: said group of inventions provides prolonged release of the drug into the bloodstream in low doses, allows minimizing side effects and improving quality of life in patients with erectile dysfunction and benign prostatic hyperplasia.

7 cl, 3 dwg

Description

[001] The present invention application is directed to the medical sector and is a long-acting absorbable subcutaneous polymer implant with controlled release of a pharmacologically active substance for the treatment of erectile dysfunction (ED) and benign prostatic hyperplasia (BPH).

STATE OF TECHNOLOGY

[002] One treatment for ED and BPH is the use of tadalafil, a reversible and selective phosphodiesterase type 5 (PDE5) inhibitor.

[003] Erectile dysfunction is defined as the inability to achieve and maintain a penile erection that allows for a satisfactory sex life, and is more common in men over 40 years of age. This is not exactly a disease, but a manifestation of symptoms of one or more pathologies. Normal erection depends on the relaxation of the smooth muscles of the cavernous bodies, increasing the flow of arterial blood and limiting the outflow of venous blood. Changes in this system ultimately negatively affect the erection mechanism and lead to erectile dysfunction. Examples of pathologies that can impair erection are: systemic arterial hypertension, diabetes mellitus, metabolic syndrome, smoking, dyslipidemia, neurological diseases, hormonal disorders and chronic use of certain medications. Additionally, other causes may include depression, mental disorders, relationship conflicts, and anxiety during sexual intercourse.

[004] As for BPH, its pathological signs usually appear in men aged 40 to 50 years and tend to progress from the first and second stages to the third as age increases. Benign prostatic hyperplasia is an increase in the number of cells in the bladder/urethra area. There is an imbalance between the number of cells that are born and the number of cells that die, resulting in increased volume in the area that can put pressure on the bladder and urethra. Benign growth of the prostate gland is not directly related to cancer, and the diagnosis is made on the basis of clinical and laboratory studies of histology and pathology. Patients suffering from BPH complain of lower urinary tract symptoms (LUTS - Lower Urinary Tract Symptoms), which include difficulties such as: holding in urine, the need to force urination, a weak or loose stream urine and a feeling of incomplete urination.

[005] For the exclusive treatment of erectile dysfunction, there is a powdered dosage form of alprostadil injection (prostaglandin E1 analogue) 10 mcg or 20 mcg with a 1 ml ampoule of water for injection for injection directly into the penis before sexual intercourse. The effect usually occurs 20 minutes after administration and lasts a maximum of 2 hours, depending on the patient. This is an inconvenient and difficult route of administration for the patient, leading to fibrosis, bleeding and hematoma at the injection site or maintaining an erection for an undesirably long time. Another point to consider is that this medicine must be stored in the refrigerator, which requires extra vigilance on the part of the patient.

[006] However, intracavernosal injection does not have the advantage of requiring the physician and patient to be willing to spend a period of time (days or weeks) adjusting the dosage of application, including the need to educate the patient about the procedure.

[007] Several years ago, alpha-blockers such as tamsulosin and terazosin were used to treat BPH. These medications have some side effects such as nausea, drop in blood pressure and sexual dysfunction. It is known that about 70% of patients with BPH also have ED. For this reason, in addition to sexual dysfunction, alpha blockers have been replaced by phosphodiesterase type 5 (PDE5) inhibitors for the treatment of BPH and ED, which has significantly improved the quality of life of patients.

[008] Tadalafil, sildenafil and vardenafil belong to the class of phosphodiesterase type 5 inhibitors (PDE5). These drugs inhibit the action of the enzyme phosphodiesterase type 5, which allows increasing the intracellular concentration of cyclic guanosine monophosphate (cGMP), and this, in turn, helps to relax the smooth muscles of the cavernous body (erectile structure of the penis) and dilate the arteries responsible for transporting blood to the penis. organ. Thus, blood flow in this area improves, an erection occurs and the symptoms of BPH are reduced.

[009] Sildenafil is commercially available in pharmaceutical form as film-coated tablets of 25 mg, 50 mg and 100 mg, and vardenafil in the same dosage form, but only in a dosage of 20 mg. Tadalafin is available in film-coated tablets of 5 mg and 20 mg.

[010] Tadalafil is the only phosphodiesterase type 5 (PDE5) inhibitor available in a low dose of 5 mg and is a daily oral formulation capable of treating ED and BPH simultaneously. Tadalafil is effective both for patients with ED or BPH, and for two concomitant pathologies. The improvement in quality of life with tadalafil is a consequence of the small number of observed side effects, since there are no complaints of hypotension or the occurrence of sexual dysfunction during its use.

[011] In addition, daily oral administration of tadalafil allows the patient to approach natural sexual activity, as the half-life of this drug is 17.5 hours (4.38 times longer than the half-life of sildenafil, which is 4 hours). Thus, daily intake of tadalafil at a dose of 5 mg is enough for the patient to enjoy its effect at any time throughout the day.

[012] Another advantage of tadalafil is that it is highly effective and safe, even at higher doses and in difficult-to-treat patients such as diabetics. The recommended dose is 5 mg daily or a single dose of 20 mg orally before sexual intercourse. Daily use of tadalafil is preferred by 72% of patients, in addition to being the most indicated form of treatment for those who want to have an active and natural sex life. Also, daily treatment with tadalafil for 12 weeks resulted in a clinically significant reduction in BPH symptoms.

[013] Disadvantages of the oral form of treatment for any disease are associated with patient adherence to therapy, first-pass metabolism in the liver and partial loss of the drug during absorption. The success or failure of drug therapy in this case depends entirely on the patient himself.

[014] Adherence to therapy depends on the frequency of administration. Single-dose medications provide greater adherence compared to multi-dose medications. Oral treatment is most often unsuccessful, as it depends on the active participation (or compliance) of the patient. In addition, it includes socioeconomic factors, as well as factors related to medical personnel and the disease itself. Compliance is understood as “participation, active compliance by the patient with the medical prescription.” This refers to the prescription of not only medications, but also all other types of care or measures recommended by a doctor or other health care professional.

[015] Treatment adherence rates tend to be higher among patients with acute conditions compared to patients with chronic conditions, and they decline sharply after the first six months of therapy for chronic conditions. Patients typically improve their medication-taking behavior five days before and after consultation with a physician compared to the previous thirty days. This phenomenon is known as “white coat adherence.”

[016] When patients are asked reasons why they do not take their medications as scheduled, typical reasons given include forgetfulness, other priorities, deciding to skip a dose, lack of information, and emotional factors. Other factors influencing non-adherence include complex prescriptions, lack of knowledge about the benefits and side effects of the drug, incompatibility of the dosage form with the patient's lifestyle, or the cost of the drug.

[017] Overall, patients are non-compliant with treatment in 50% of cases, and in the case of tadalafil, where patients are men, this percentage increases even more. This group is the least adherent to medical recommendations. There is a clinical problem because young men have the lowest rates of treatment adherence.

[018] The oral route contributes to drug misuse, increasing the risk of low dosage or supraphysiological doses. In these two situations, the patient is at risk of a recurrence of symptoms, which may worsen his overall condition. It should be noted that patients suffering from chronic conditions often discontinue treatment when they notice a reversal of symptoms or experience some discomfort due to side effects or adverse reactions, becoming more susceptible to worsening of their clinical condition.

[019] Regarding the technical condition associated with the use of tadalafil, one can cite patent records BR 10 2017 025256-6, BR 10 2017 021360-9, BR 10 2015 015988-9, BR 11 2016 010411-0, BR 11 2015 032728- 1, PI 1006266-1, PI 0618385-9, PI 0621852-0, PI 0606122-2 and PI 0313484-9. All accounts mention the use of tadalafil, however the substance is released by oral, programmed release injection, transdermal, topical, cream, ovum, spray, aerosol, liquid, solution, gel and ointment. However, there are no records of the use of a long-term, resorbable, sustained-release subcutaneous implant.

[020] The most effective way to increase patient adherence to therapy is to simplify the use of the drug as much as possible, from reducing the number of visits to the pharmacy to purchase the drug, to the dosage form, dose, route of administration, taste of the drug, reducing the number of administrations, the occurrence of side effects and avoiding polypharmacy.

[021] Considering this scenario and aiming to overcome the low therapeutic adherence of patients and self-medication, a pharmaceutical form known as implants or bioabsorbable pellets has been created with doses very close to physiological ones. The implants have a prolonged release of the pharmaceutical active substance to treat pathologies in the most physiological manner and, therefore, avoid the occurrence of side effects. This dosage form is effective in ensuring patient adherence to treatment and, as a result, its success, since the period between the introduction of new implants is quite long and does not require patient participation. There is also no need to remove the pellets after the active release period, since resorbable subcutaneous implants, when implanted in the patient's body, release drugs over an extended period, providing ease of travel and reducing the frequency of administration. These devices provide personalized medicine and treatment with release over a period of weeks, months or years and can be removed if side effects require discontinuation of treatment.

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

[023] Biodegradable implants can be considered as implants that have some mechanism for gradually reducing their mass over a long period of release time. In addition, erosion and gradual dissolution of its components are possible. The term also refers to the complete degradation and absorption by the body that occurs at the implant site, eliminating the need to remove the implants at the end of treatment. This mechanism of release of the active ingredient through the implant is due to the composition of this dosage form, polymers.

[024] The terms "continuous release", "controlled release" or "sustained release" refer to a form of drug release through an implant that occurs continuously and gradually over a long period of time and does not result in immediate and concentrated release of the drug in the body.

[025] Biodegradable polymers or biodegradable polymers refer to a polymer that degrades in vivo and its erosion over time occurs simultaneously with and/or after the release of the therapeutic agent. The biodegradable polymer can be a homopolymer, a copolymer, or a polymer that compresses more than two polymer units. In some cases, the biodegradable polymer may include a mixture of two or more homopolymers or copolymers.

[026] Taking into account the shortcomings and pre-existing problems of standard forms of treatment for ED and BPH, the present invention is directed to the use of the above-described polymeric subcutaneous implant promoting the sustained release of tadalafil directly into the bloodstream in low doses to avoid hepatic metabolism, thereby minimizing unwanted side effects and improving the quality of life of patients. Another advantage of the present invention is the elimination of its residues in the tissues after the end of treatment, which eliminates the need for surgery to remove the implant. A third advantage of the invention is the release of the drug in very low doses close to the normal physiological state. Thus, a patient with ED can have a normal sex life without the discomfort observed with the use of a single dose of tablet or intracavernosal injection.

DESCRIPTION OF DRAWINGS

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

[028] Fig. 1 - Presentation of the chemical structure of the tadalafil composition;

[029] Fig. 2 and 3 - Overall dimensions of tadalafil implants;

DETAILED DESCRIPTION OF THE INVENTION

[030] The present invention is a biodegradable polymer matrix implant containing tadalafil. The implant is inserted subcutaneously and provides continuous active release of the active substance over a long period of time. This release aims to provide effective, consistent and long-lasting serum levels of the drug for the treatment of ED and BPH. The drug belongs to tadalafil, that is, an active molecule that inhibits phosphodiesterase type 5. Its chemical structure is shown in Figure 1.

[031] According to the present invention, the implant may contain only tadalafil, but preferably it is formed by tadalafil particles homogeneously dispersed in a biodegradable and bioabsorbable polymer matrix. This polymer matrix may be formed from a polymer or a mixture of polymers. The amount of tadalafil present in the implant can vary from 25 to 250 mg per implant, and its composition contains from 1 to 20% biodegradable polymer relative to the weight of tadalafil. Preferably it should have from 20 to 110 mg and from 2 to 10% biodegradable polymer by weight, forming a homogeneous mixture.

[032] The following can be used as a biodegradable polymer: poly(D-lactic acid), poly(L-lactic acid), poly(racemic lactic acid), poly(glycolic acid), poly(caprolactone), methylcellulose, ethylcellulose, hydroxypropylcellulose ( HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), poly(vinyl alcohol) (PVA), polyethylene oxide (PEO), polyethylene glycol, starch, natural and synthetic gums and waxes.

[033] Implants can be of any size, shape and structure to facilitate their manufacture and insertion, however, to obtain a more consistent and uniform release of the active substance, it is necessary to use geometric shapes that maintain the surface area of the implants over time.

[034] Therefore, the implant developed and demonstrated in this request takes a cylindrical rod shape with straight or rounded ends, ranging in length from 2 to 25 mm and a diameter from 1 to 6 mm. Schematic drawings of some example implant sizes (1) and (1') can be found in Fig. 2.

[035] The implant manufacturing process begins with the addition of 25 to 250 mg of tadalafil to the selected polymer matrix in a proportion of 1 to 20% relative to the weight of the drug in the form of a dry powder. The mixture is then added to the container for homogenization. If the polymer solvent is not also a tadalafil solvent, it will be dispersed as particulates or a solution, and a mixer can be used to ensure the solution is homogeneous. This solution is then dried and placed into the implant mold or any other desired shape.

[036] The mixture of active substances for the manufacture of an implant can be molded under pressure or heat in such a way as not to reduce the effectiveness of the drug or destroy the polymeric material. Options for implant molding methods include injection molding, thermoforming, compression molding, or extrusion molding.

[037] Compression molding technology was chosen for the present invention. In this method, a mixture of active substances in powder form is added to a mold and a mechanical force is applied to the mixture, causing the particles to compress and thus mold the implant. The implant containing tadalafil is then filled and sterilized. Sterilization is preferably carried out by heating in an oven at 90°C for 1 hour.

[038] The implant may have a polymer membrane coated with a thickness of 0.1 to 0.7 mm. The polymer used for the coating must be bioabsorbable and allow the passage of the active substance. Coating of the implant is preferably accomplished by immersing the implant in a polymer solution. The coating may cover the entire surface of the implant, including the edges, only the longitudinal surface of the implant without covering the edges, or cover only the edges of the implant without covering its length. Polymers that can be used for coating are polylactic-glycolic acids (PLGA) and D,L-lactic acid copolymers.

[039] Another implant option for treating ED and BPH are non-biodegradable implants. Non-biodegradable implants (2) (Fig. 3) have a central core (2.1) formed by a polymer matrix in a percentage of 1 to 20% relative to the weight of the drug, in this case from 25 to 250 mg of tadalafil with the core surrounded by a non-degradable polymer membrane (2.2), which controls the rate of drug release.

[040] The material for the manufacture of the polymer membrane of 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 in-house. After molding the membrane from the polymer material, the active mixture is introduced, forming the central rod (2.1) of the implant (2). The polymers used in the polymer matrix and the mixture use the same compounds and process as the bioabsorbable implant.

[041] Drug release in this system occurs through diffusion at a relatively constant rate, and the rate of drug release can be varied by the thickness or material of this membrane. With this system, it is necessary to remove the implant at the end of treatment.

[042] The shelf life of the implant is approximately 3 to 6 months, and this period is the recommended period for changing implants. Full treatment is continued according to remission of ED markers and/or lower urinary tract symptoms of BPH. The therapeutic window for oral tadalafil in the scientific literature to achieve clinical results in the treatment of ED is 2.5 mg or 5 mg once daily, depending on drug tolerability. When taken orally, there is a loss of the active substance due to first-pass metabolism, as well as a loss of part of the active substance due to the absorption process. Collectively, these losses can reach 50% of the drug taken orally. The implant, in turn, has a release of 0.6 to 2.0 mg of tadalafil per day, depending on the amount of the drug present in it. In practice, when using 2-4 implants with a concentration of 25 to 250 mg, the expected results are consolidated.

[043] However, in order to determine individualized treatment for each patient, the physician must evaluate that patient's clinical condition, use the patient's laboratory tests as the basis for dosage decisions, and, based on the daily release of tadalafil by the implants, begin partial dosing. After this first assessment, the dose can be adjusted by placing additional implants if necessary. Additionally, if rejection or any adverse reaction occurs after the implant is placed, it can be removed within the first few days of treatment. In the absence of rejection, removal of the implant after the treatment period is not required, since it does not leave residues in the tissues as they are completely absorbed by the body.

[044] The use of the implant provided herein is safe and effective in the treatment of ED and BPH with lower urinary tract symptoms. This is due to the fact that the therapy does not depend on the patient's discipline in maintaining the dosage, since there is a regularity of treatment due to the low release of the active substance through slow but stable doses, thus improving the quality of the patient's sexual life and providing an interval in the frequency of use new implants.

[045] It should be noted that patients suffering from chronic conditions often discontinue treatment when they notice a decrease in symptoms or experience some discomfort due to side effects or adverse reactions, becoming more susceptible to worsening of their clinical condition.

[046] Therefore, the use of these implants in a therapeutic approach prevents sudden cessation of medication and ensures adequate and effective treatment. In the case of tadalafil, a patient using a biodegradable pellet will be more comfortable performing any daily activity without having to worry about taking the pill, storing the drug in the refrigerator, or having supplies for intracavernosal administration of the drug. The benefits of using a bioabsorbable implant guarantee the patient an almost normal lifestyle.

[047] Another advantage of this invention is that the release of the drug through the implants occurs directly into the bloodstream, which makes its action much more effective and prevents hepatic metabolism of the drug as it is released directly into the systemic circulation, improving the bioavailability of the drug. In this way, the dose required for treatment can be reduced, minimizing unwanted side effects and ensuring patient adherence to therapy.

Claims (7)

1. A long-acting subcutaneous polymer implant with controlled release of a pharmacological preconcentrated substance for the treatment of erectile dysfunction and benign prostatic hyperplasia, which is characterized by the fact that the biodegradable implant contains from 25 to 250 mg of tadalafil in the form of particles homogeneously dispersed in a biodegradable and bioabsorbable polymer matrix, while the polymer matrix contains from 1 to 20% of biodegradable polymer relative to the weight of tadalafil. 2. The implant according to claim 1, which is characterized in that the biodegradable polymer used is the following materials: 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), polyethylene oxide (PEO), polyethylene glycol, starch, natural and synthetic gums and waxes. 3. Implant according to paragraphs. 1 and 2, which is characterized by taking a cylindrical shape in the form of a rod with straight or rounded ends, with a length of 2 to 25 mm and a diameter of 1 to 6 mm. 4. Implant according to the requirements of paragraphs. 1-3, which is characterized by the fact that the implant manufacturing process begins with the addition of 25 to 250 mg of tadalafil to the selected polymer matrix in a proportion of 1 to 20% relative to the weight of the drug in dry powder form, after which the mixture is added to the container for homogenization and easily homogenized powdered active substances are loaded into a mold for molding the implant under the action of mechanical force, compressing the particles and molding the implant, then the implant is filled and sterilized at 90°C in an oven for 1 hour. 5. Implant according to paragraphs. 1-3, which is characterized in that it has a coating formed by a bioabsorbable polymer membrane with a thickness of 0.1 to 0.7 mm, wherein said membrane consists of copolymers of methylvinylsiloxane, dimethylpolysiloxane, polylactic-coglycolic acid (PLGA) and copolymers of D,L- lactic acid. 6. A long-acting subcutaneous polymer implant with controlled release of a pharmacological preconcentrated substance for the treatment of erectile dysfunction and benign prostatic hyperplasia, which is characterized by the fact that the implant is presented in a non-biodegradable form, has a central core formed by a polymer matrix in a percentage of 1 to 20% by weight in relation to the mass of the drug - from 25 to 250 mg of tadalafil, and the core itself is surrounded by a non-degradable polymer membrane. 7. The implant according to clause 6, which is characterized by the fact that the material for the manufacture of the polymer membrane surrounding the non-biodegradable implant is silicone, urethane, acrylates and their copolymers, polyvinylidene fluoride copolymers, polyethylene vinyl acetate-ethylene vinyl acetate and dimethylpolysiloxane, said membrane has a thickness of 0. 2 to 1 mm and the introduction of tadalafil occurs after molding, forming the central core of the implant (2).