LONG-LASTING RESORBABLE SUBCUTANEOUS IMPLANT WITH SUSTAINED RELEASE OF PRE-CONCENTRATED PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR THE TREATMENT OF PARKINSONS DISEASE

Abstract

Long-lasting, resorbable subcutaneous implant with extended release of pre-concentrated pharmacologically active substance in polymer for treatment of Parkinson's disease. The implant is inserted subcutaneously and has continuous release of the active ingredient for an extended period. The implant may have only nicotinamide adenine dinucleotide (NADH), but is preferably formed of NADH particles homogeneously dispersed in a bioerodible and bioabsorbable polymer matrix. 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 ingredient, it is necessary to use geometric shapes that maintain their surface area over time. The implant may have a polymeric coating membrane and the polymer used for the coating must be bioabsorbable and allow the passage of the active substance.

Claims

1. A long-acting resorbable subcutaneous implant with extended release of pharmacologically active substance for the treatment of Parkinson's disease comprising: a polymer matrix that is bioerodible and bioabsorbable; a biodegradable implant containing 50 mg to 250 mg of nicotinamide adenine dinucleotide in particles, wherein said particles are dispersed homogeneously in said polymer matrix, wherein said polymer matrix has a weight that is between 1% and 20% of of said nicotinamide adenine dinucleotide.

2. The long-acting resorbable subcutaneous implant according to claim 1, wherein said polymer matrix is made from a polymer selected from a group comprising poly(D-lactic acid), poly(L-lactic acid), poly(racemic lactic acid), poly(glycolic acid), poly(caprolactone), methylcellulose, ethyl cellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, polyvinylpyrrolidone, poly(vinyl alcohol), poly(ethylene oxide), polyethylene glycol, starch, natural and synthetic gum and wax.

3. The long-acting resorbable subcutaneous implant according to claim 1, wherein said subcutaneous implant is rod-shaped with straight or rounded tips and has a length between 2 mm and 25 mm and a diameter from 1 mm to 6 mm.

4. The long-acting resorbable subcutaneous implant according to claim 2, wherein said nicotinamide adenine dinucleotide is mixed with said polymer in dry form and is set in a mold to carry out a molding for said subcutaneous implant under mechanical force.

5. The long-acting resorbable subcutaneous implant according to claim 1, further including a polymeric coating membrane covering at least part of said subcutaneous implant with a thickness between 0.1 mm and 0.7 mm, wherein said polymeric coating membrane is made from material selected from a group comprising polylactic-glycolic acid and copolymers of D,L-lactic acid.

6. A long-acting resorbable subcutaneous implant with extended release of pharmacologically active substance for the treatment of Parkinson's disease comprising: nicotinamide adenine dinucleotide having a weight between 50 mg and 250 mg; a central core formed by a polymer matrix wherein said polymer matrix is between 1% and 20% of said weight of said nicotinamide adenine dinucleotide, wherein said central core is surrounded by a non-degradable polymeric membrane.

7. The long-acting resorbable subcutaneous implant according to claim 6, wherein said non-degradable polymeric membrane is selected from a group consisting of silicone, urethane, acrylates and their copolymers, polyvinylidene fluoride copolymers, ethylene polyethylene vinyl acetate-vinyl and dimethylpolysiloxane, said non-degradable polymeric membrane having a thickness of 0.2 mm to 1 mm.

Description

DESCRIPTION OF THE DRAWINGS

[0039] For a better understanding of the present invention, the following drawings are presented:

[0040] FIG. 1—shows a representation of the chemical structure of the substance nicotinamide adenine dinucleotide (NADH).

[0041] FIG. 2—shows a dimensional design of the bioabsorbable nicotinamide adenine dinucleotide (NADH) implant.

[0042] FIG. 3—shows a dimensional design of the non-bioabsorbable nicotinamide adenine dinucleotide (NADH) implant.

DETAILED DESCRIPTION OF THE INVENTION

[0043] The present application for privilege of invention is a biodegradable nicotinamide adenine dinucleotide (NADH) implant in polymer matrix. The implant is inserted subcutaneously and has continuous release of the active ingredient for an extended period. This release aims to ensure an efficient, constant and prolonged serum level of the drug for the adjuvant treatment of Parkinson's disease.

[0044] The “active substance”, “active ingredient” or “drug” refers to the substance nicotinamide adenine dinucleotide, which has the chemical structure shown in FIG. 1.

[0045] The implant of the present invention may have in its constitution only nicotinamide adenine dinucleotide (NADH) but is preferably formed of NADH particles homogeneously dispersed in a bioerodible and bioabsorbable polymer matrix. Such a polymer matrix may be formed of a polymer or a polymer blend. The amount of nicotinamide adenine dinucleotide (NADH) present in the implant may range from 50 to 250 mg per implant and its composition has from 1 to 20% biodegradable polymer in proportion to its weight. Preferably it should have from 80 to 200 mg and from 2 to 10% biodegradable polymer in proportion to weight.

[0046] The biodegradable polymer used may be: Poly (D-lactic acid), Poly(L-lactic acid), Poly(racemic lactic acid), Poly(glycolic acid), Poly(caprolactone), methylcellulose, ethyl cellulose, hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), poly(vinyl alcohol) (PVA), poly(ethylene oxide) (PEO), polyethylene glycol, starch, natural and synthetic gum, and wax.

[0047] 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 ingredient, it is necessary to use geometric shapes that maintain their surface area over time.

[0048] Thus, the implant (1) developed and demonstrated in the present application adopts the cylindrical, rod-shaped pattern, provided with straight or rounded tips, with a length between 2 to 25 mm and a diameter of 1 to 6 mm. The schematic drawing of an example implant size (1) is shown in FIG. 2.

[0049] The manufacture of the nicotinamide adenine dinucleotide (NADH) implant can be made from the addition of 50 to 250 mg of the drug in the solution of the biodegradable polymer matrix chosen in a proportion of 1 to 20% in relation to the weight of the drug, with the formation of a homogeneous mixture. If the polymer solvent is not also a nicotinamide adenine dinucleotide (NADH) 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 subsequently shaped to the shape of the implant (1) or other desired shape.

[0050] Another possible form of making the nicotinamide adenine dinucleotide (NADH) implant is from mixing 50 to 250 mg of the drug and 1 to 20% of the chosen biodegradable polymer matrix with respect to the weight of the drug, in its dry, powdered forms. The drug and the polymer matrix are added in a suitable container and the mixture is homogenized.

[0051] The mixture of active ingredients for manufacturing the implant may be shaped from pressure or heat so as not to compromise the efficacy of the drug or degrade the polymeric material. Technique options for implant molding can be: injection molding, hot molding, compression molding, or extrusion molding.

[0052] For the present invention, the technique chosen was compression molding. In this technique, the mixture of the active ingredients, in powder form, is added to a mold and there is the application of mechanical force under the mixture, generating the compression of the particles and consequently the molding of the implant in the shape (1). Then there is the filling and sterilization of the nicotinamide adenine dinucleotide (NADH) implant. Its sterilization can be done by heat or gamma rays.

[0053] The implant may have a polymeric coating membrane, 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 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 poly (lactic-co-glycolic acid) (PLGA) and copolymers of D, L-lactic acid.

[0054] Yet another implant option for treating Parkinson's disease is non-biodegradable implants. Non-biodegradable or non-bioerodible implants (2) (FIG. 3) have a central core (2.1) formed by a polymeric matrix in the percentage of 1 to 20% in relation to the weight of the drug, in this case 50 to 250 mg of nicotinamide adenine dinucleotide (NADH), the core being surrounded by a non-degradable polymeric membrane (2.2) that controls the release rate of the drug.

[0055] The material of manufacture of the polymeric membrane 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 in specific equipment. After molding the membrane from the polymeric material there is the insertion of the mixture of nicotinamide adenine dinucleotide (NADH), forming the central core (2.1) of the implant (2). The polymers used in the polymer matrix and the blend adopt the same compounds and process as the bioabsorbable implant.

[0056] The release of the drug in this system occurs through diffusion, at a relatively constant rate, and it is possible to change the rate of release of the drug through the thickness or material of that membrane. In this system, it is necessary to remove the implant at the end of the treatment.

[0057] The treatment for Parkinson's disease using NADH implants should be defined according to the severity of the symptoms and clinical picture of the patient. The proposed implant lasts approximately 3 to 6 months, and this time is the proposed period between implant insertions. The therapeutic window of NADH in the intramuscular scientific literature is 25 mg twice a week. In total, the amount of active ingredient that can be administered to the patient is 200 mg monthly. Since the treatment with the proposed implant lasts approximately 3 months, the dose used, drawing a parallel with the dose used intramuscularly, is about 600 mg. This dose is equivalent, for example, to 3 implants of 200 mg NADH.

[0058] However, to define an individualized treatment for each patient, it is necessary for the physician to evaluate the clinical condition of this patient, use his laboratory tests and clinical analysis of motor signs as support for dosage decision making and start supplementation with partial doses to monitor the remission of symptoms and evolution of the patient's clinical condition. After this first evaluation, the dose can be adjusted by inserting additional implants, if necessary. Furthermore, if rejection or any adverse reaction occurs after insertion of the implant, it may be removed within the first days of treatment.

[0059] The use of the implant proposed herein is safe and effective in the treatment of Parkinson's disease, considering that the therapy is independent of the patient's will or discipline for the action of the drug, thus ensuring the maintenance of the dosage and regularity of the treatment. It is noteworthy that patients affected by chronic diseases often discontinue treatment when they notice the reversal of symptoms or when they feel some discomfort due to side effects or adverse reactions, becoming more susceptible to a worsening of their clinical condition.

[0060] Thus, the use of these implants in the therapeutic approach prevents discontinuation and guarantees the appropriate treatment, as well as its efficacy. Furthermore, the invention provides patients with Parkinson's disease with a therapy with constant and stable doses of continuous release of the active ingredient, improving their quality of life by improving the adverse clinical symptoms of PD.

[0061] Another benefit of this invention is that the release of the drug through the implants occurs directly into the bloodstream, which makes its action much more efficient and avoids a hepatic metabolism of the drug.

[0062] Another advantage of the invention is the type and form in which the implant is presented, biodegradable and resorbable, and it is not necessary to remove it after the treatment period, since it leaves no residue in the tissues.

[0063] A case study was conducted with a 57-year-old patient with Parkinson's disease, with the onset of the clinical symptoms at 45 years of age, with a history of the disease in the family (brother, paternal uncle and three paternal cousins). The disease history consisted of: unilateral right-sided tremor, bradykinesia, postural instability and muscle stiffness. The patient was medicated with the following medications: Selegiline 5 mg; Pramipexole Dihydrochloride 0.25 mg; Imipramine Hydrochloride 25 mg; Levodopa+Benserazide 100/25 mg; Levothyroxine Sodium 50 mcg; Nortriptyline Hydrochloride 50 mg and Omeprazole 20 mg.

[0064] The physical examination indicated cardiac analysis RCR 2T BNF; blood pressure 137×86; tremor of the lower and upper limbs, being more accentuated on the right side; slowness of movements to drink a glass of water more accentuated on the right side; slow and dragged gait with anterior inclination, with decreased movements of the arms asymmetrically; movement of the forearms alternately with difficulty in execution and muscle fatigue; irregular writing, with spontaneous movements such as “counting money with your fingers”; muscle stiffness in the forearms and hips; and lack of facial expression.

[0065] The patient was treated with 10 resorbable NADH hormone implants (200 mg each). The treatment lasted three months, a period in which it was necessary to reinsert the implants and obtained satisfactory results. The patient evolved with improvement of posture, ambulation and tremors a few hours after the insertion of the implants.

[0066] Progressively, with the insertion of the implants, the patient showed improvement in sleep and depression, reporting better conditions to perform domestic tasks and, after a week of insertion of the implants, she no longer saw the need to use antidepressant drugs.