LONG-LASTING REABSORBABLE SUBCUTANEOUS IMPLANT WITH SUSTAINED RELEASE OF PRE-CONCENTRATED PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF ERECTILE DYSFUNCTION AND BENIGN PROSTATIC HYPERPLASIA

Abstract

Biodegradable implant containing tadalafil in a polymer matrix. This implant is inserted into the subcutaneous layer of the patient and has continuous release of the pharmaceutical active over an extended period of time. The implant may have in its constitution only tadalafil but is preferably formed by tadalafil particles dispersed homogeneously in a biocompatible and biodegradable polymer matrix. The polymer matrix may be formed by only one polymer or by a mixture of polymers. The implants have a shape and size that facilitates their insertion into the patient and provides a prolonged and uniform release of the active ingredient contained. The implant can contain a polymer coating wall and, as such, the duration of the treatment can vary between 3 and 6 months, thereby configuring the proposed period of time between the insertions of new implants.

Claims

1. A long-lasting reabsorbable subcutaneous implant with prolonged release of a pharmacologically active substance preconcentrated for the treatment of erectile dysfunction and benign prostatic hyperplasia comprising: a bioabsorbable polymer matrix in particle form; between 25 mg and 250 mg of tadalafil, wherein said bioabsorbable polymer matrix has a weight that is between 1 percent and 20 percent that of said tadalafil.

2. The long-lasting reabsorbable subcutaneous implant according to claim 1, said bioabsorbable polymer matrix is formed from a material selected from a group consisting of poly(D-lactic acid), poly(L-lactic acid), poly(racemic lactic acid), poly(glycolic acid), poly(caprolactone), methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, poly(vinyl alcohol, poly(ethylene 6-oxide), polyethylene glycol, starch, wax, natural and synthetic gum.

3. The long-lasting reabsorbable subcutaneous implant according to claim 1, having a cylindrical shape of a rod with straight or rounded tips and a length between 2 mm and 25 mm and a diameter of 1 mm to 6 mm.

4. A long-lasting reabsorbable subcutaneous implant according to claims 1, wherein said bioabsorbable polymer matrix and said tadalafil are mixed dry, compress molded and heat sterilized.

5. The long-lasting reabsorbable subcutaneous implant according to claim 1, further including a polymer membrane coating with a thickness between 0.1 mm and 0.7 mm, wherein said polymer membrane coating contains co-glycolic polylactic acid and copolymers of acid D,L-lactic.

6. A long-lasting reabsorbable subcutaneous implant with prolonged release of a pharmacologically active substance preconcentrated for the treatment of erectile dysfunction and benign prostatic hyperplasia, comprising: 25 mg to 250 mg of tadalafil; a non bioerodible central core formed by a polymer matrix, wherein said polymer matrix has a weight that is between 1 percent and 20 percent that of said tadalafil, a non-degradable polymer membrane coating at least part of said central core.

7. The long-lasting reabsorbable subcutaneous implant according to claim 6, wherein said non-degradable polymer membrane is formed from a material selected from a group containing silicone, urethane, acrylates and their copolymers, copolymers of polyvinylidene fluoride, polyethylene vinyl acetate-vinyl ethylene and dimethylpolysiloxane, wherein said non-degradable polymer membrane has a thickness of 0.2 mm to 1 mm.

Description

DESCRIPTION OF THE DRAWINGS

[0027] For a better understanding of the present invention, the following drawings are attached:

[0028] FIG. 1—shows a representation of the chemical structure of the tadalafil compound;

[0029] FIG. 2—shows a dimensional design of tadalafil implant;

DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention is summarized in a biodegradable implant containing tadalafil in a polymer matrix. The implant is inserted subcutaneously and has a continuous release of the active substance for a prolonged period of time. This release aims to ensure an efficient serum level of the drug for a long time for the treatment of ED and BPH. The drug refers to tadalafil, i.e., an active molecule that inhibits the enzyme 5-phosphodiesterase. Its chemical structure is shown in FIG. 1.

[0031] The proposed bioabsorbable implant may have in its constitution only tadalafil but is preferably formed by tadalafil particles dispersed homogeneously in a bio erodible and bioabsorbable polymer matrix. Such a polymer matrix may be formed of a polymer or a mixture of polymers. The amount of tadalafil in the implant can range from 25 to 250 mg per implant and its composition can have from 1 to 20% biodegradable polymer in relation to its weight of tadalafil. Preferably it should have from 20 to 110 mg and from 2 to 10% of biodegradable polymer in proportion to weight, forming a homogeneous mixture.

[0032] The biodegradable polymer used may be: Poly(D-lactic acid), Poly(L-lactic acid), Poly(racemic lactic acid), Poly(glycolic acid), Poly(caprolactone), methylcellulose, ethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyvinyl alcohol) (PVA), poly(ethylene 6-oxide) (PEO), polyethylene glycol, starch, wax, natural gum and synthetic gum.

[0033] Implants can have any size, shape or structure that facilitates their manufacture and subcutaneous insertion in order to obtain a more constant and uniform release of the active ingredient and to obtain geometric shapes that remain over time.

[0034] Thus, the implant developed and exposed in the present application adopts the cylindrical pattern (1), rod-shaped with straight or rounded tips and length between 2 to 25 mm and diameter of 1 to 6 mm. An approximate illustration of the biodegradable implant can be seen in FIG. 2.

[0035] The implant manufacturing process starts with the addition of 25 to 250 mg of tadalafil in the polymer matrix chosen in the proportion of 1 to 20% in relation to the weight of the drug, in its dry forms, in powder. The mixture is then added into a container to be homogenized. If the polymer solvent is not also tadalafil solvent, it will be dispersed in the form of particles or suspension, and a mixer can be used to make the solution homogeneous. Then, this solution is dried and later molded to the shape of the implant (1) or other desired shape.

[0036] The mixture of actives in the manufacture of the implant can be molded by pressure or heat, so as not to compromise the effectiveness and chemical structure of tadalafil, nor to degrade the polymer. The options of techniques for molding the implant can be: injection molding, hot molding, compression molding or extrusion molding.

[0037] For the present invention, the technique chosen was compression molding. In this technique, the homogenized powder actives are added in a mold and there is the application of mechanical force under the mixture, compressing the particles and molding the implant. Then there is the filling and sterilization of the implant containing tadalafil. Sterilization, in this case, is done by exposing the contents to 90° C. in an oven for 1 hour.

[0038] The implant ay have a coating polymer membrane, with a thickness that may range from 0.1 to 0.7 mm. The polymer used for the coating must be bioabsorbable and allow the passage of the active substance. The coating of the implant is preferably done by dipping the implant in a polymer solution. The coating may 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: co-glycolic polylactic acid (PLGA) and D,L-lactic acid copolymers.

[0039] Another type of implant option for treatment of erectile dysfunction and benign prostatic hyperplasia are non-biodegradable implants. Non-biodegradable or non-bioerodible implants (2) (FIG. 3) have a central core (2.1) formed by a polymer matrix in the percentage of 1 to 20% in relation to the weight of the drug, in this case 25 to 250 mg of tadalafil, with the core being surrounded by a non-degradable polymer membrane (2.2) that controls the release rate of the drug.

[0040] The polymer membrane manufacturing material surrounding the implant may be: silicone, urethane, acrylates and their copolymers, polyvinylidene fluoride copolymers, ethylene polyethylene vinyl acetate-vinyl, dimethylpolysiloxane. This membrane has a thickness of 0.2 to 1 mm and is molded by specific equipment. After molding the membrane from the polymer 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.

[0041] The release of the drug in this system occurs through diffusion, at a relatively constant rate, and it is possible to change the speed of release of the drug 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.

[0042] The proposed implant has a duration of approximately 3 to 6 months, and this is the period proposed between the insertions of the implants. The complete treatment lasts according to remission of symptoms of ED and/or symptoms in the lower urinary tract from BPH. The therapeutic window of tadalafil in the scientific literature, orally and 2.5 mg or 5 mg once a day, depends on drug tolerance in order to achieve clinical results in the treatment of ED. In oral administration there is a loss of active principle due to first-pass metabolism, as well as the loss of part of the active due to the absorptive process, added these losses can reach 50% of the drug ingested. The implant has a release of 0.6 to 2.0 mg of tadalafil per day, depending on the amount of drug present in it. In practice with the use of 2-4 implants, with concentrations between 25 and 250 mg, the expected results are consolidated.

[0043] However, to define an individualized treatment for each patient, the physician must evaluate the clinical condition of this patient, use his laboratory tests as support for the decision making of the dosage and, based on the daily release of tadalafil by the implants, begin supplementation with partial doses. After this first evaluation, the dose can be adjusted by inserting additional implants, if necessary. Furthermore, if there is a rejection or any adverse reaction after insertion of the implant, it can be removed within the first days of treatment. If there is no rejection, removal of the implant is not necessary after the treatment period, since it leaves no residues in the tissues because they are fully absorbed by the body.

[0044] The use of the implant proposed herein is safe and effective in the treatment of ED and BPH with symptoms in the lower urinary tract. This is because the therapy does not depend on patient discipline for maintaining the dosage, and there is regularity of the treatment due to the low release of the active principle through slow but stable doses, promoting the patient quality of life through a close to natural sexual life while at the same time producing an interval in the frequency of application of new implants.

[0045] It should be noted once again that patients affected by chronic diseases often discontinue treatment when they notice the reduction of symptoms or when they feel some discomfort due to adverse reactions, becoming more susceptible to a worsening of their clinical condition.

[0046] Thus, the use of implants in drug therapy avoids discontinuity and ensures proper treatment, as well as the effectiveness of such. In the case of tadalafil, patients who use the biodegradable pellet will have more convenience in performing any daily activity without worrying about the administration of the tablet or if the drug is stored in the refrigerator or if they are carrying accessories for intracavernous application of the drug. The advantages of using the bioabsorbable implant guarantee the patient a practically normal routine in life.

[0047] Another benefit of the invention is the release of the drug directly into the bloodstream, which makes its action much more efficient, avoiding gastrointestinal metabolism and the effect of the first hepatic passage of the drug, as it is released directly into the systemic circulation, improving the bioavailability of the drug. Thus, the dose required for treatment can be reduced, minimizing unwanted side effects and ensuring the therapeutic adherence of the patient.